Hematopoietic stem cell transplantation (HSCT) is the transplantation of multipotent hematopoietic stem cells, usually derived from bone marrow, peripheral blood, or umbilical cord blood.[1][2] It may be autologous (the patient's own stem cells are used), allogeneic (the stem cells come from a donor) or syngeneic (from an identical twin).[1][2] It is a medical procedure in the field of hematology, most often performed for patients with certain cancers of the blood or bone marrow, such as multiple myeloma or leukemia.[2] In these cases, the recipient's immune system is usually destroyed with radiation or chemotherapy before the transplantation. Infection and graft-versus-host disease are major complications of allogeneic HSCT.[2]

Hematopoietic stem cell transplantation remains a dangerous procedure with many possible complications; it is reserved for patients with life-threatening diseases. As survival following the procedure has increased, its use has expanded beyond cancer, such as autoimmune diseases.[3][4]

Indications for stem cell transplantation are as follows:

Many recipients of HSCTs are multiple myeloma[5] or leukemia patients[6] who would not benefit from prolonged treatment with, or are already resistant to, chemotherapy. Candidates for HSCTs include pediatric cases where the patient has an inborn defect such as severe combined immunodeficiency or congenital neutropenia with defective stem cells, and also children or adults with aplastic anemia[7] who have lost their stem cells after birth. Other conditions[8] treated with stem cell transplants include sickle-cell disease, myelodysplastic syndrome, neuroblastoma, lymphoma, Ewing's sarcoma, desmoplastic small round cell tumor, chronic granulomatous disease and Hodgkin's disease. More recently non-myeloablative, "mini transplant(microtransplantation)," procedures have been developed that require smaller doses of preparative chemo and radiation. This has allowed HSCT to be conducted in the elderly and other patients who would otherwise be considered too weak to withstand a conventional treatment regimen.

In 2006 a total of 50,417 first hematopoietic stem cell transplants were reported as taking place worldwide, according to a global survey of 1327 centers in 71 countries conducted by the Worldwide Network for Blood and Marrow Transplantation. Of these, 28,901 (57 percent) were autologous and 21,516 (43 percent) were allogeneic (11,928 from family donors and 9,588 from unrelated donors). The main indications for transplant were lymphoproliferative disorders (54.5 percent) and leukemias (33.8 percent), and the majority took place in either Europe (48 percent) or the Americas (36 percent).[9]

In 2014, according to the World Marrow Donor Association, stem cell products provided for unrelated transplantation worldwide had increased to 20,604 (4,149 bone marrow donations, 12,506 peripheral blood stem cell donations, and 3,949 cord blood units).[10]

Autologous HSCT requires the extraction (apheresis) of haematopoietic stem cells (HSC) from the patient and storage of the harvested cells in a freezer. The patient is then treated with high-dose chemotherapy with or without radiotherapy with the intention of eradicating the patient's malignant cell population at the cost of partial or complete bone marrow ablation (destruction of patient's bone marrow's ability to grow new blood cells). The patient's own stored stem cells are then transfused into his/her bloodstream, where they replace destroyed tissue and resume the patient's normal blood cell production. Autologous transplants have the advantage of lower risk of infection during the immune-compromised portion of the treatment since the recovery of immune function is rapid. Also, the incidence of patients experiencing rejection (and graft-versus-host disease is impossible) is very rare due to the donor and recipient being the same individual. These advantages have established autologous HSCT as one of the standard second-line treatments for such diseases as lymphoma.[11]

However, for other cancers such as acute myeloid leukemia, the reduced mortality of the autogenous relative to allogeneic HSCT may be outweighed by an increased likelihood of cancer relapse and related mortality, and therefore the allogeneic treatment may be preferred for those conditions.[12] Researchers have conducted small studies using non-myeloablative hematopoietic stem cell transplantation as a possible treatment for type I (insulin dependent) diabetes in children and adults. Results have been promising; however, as of 2009[update] it was premature to speculate whether these experiments will lead to effective treatments for diabetes.[13]

Allogeneics HSCT involves two people: the (healthy) donor and the (patient) recipient. Allogeneic HSC donors must have a tissue (HLA) type that matches the recipient. Matching is performed on the basis of variability at three or more loci of the HLA gene, and a perfect match at these loci is preferred. Even if there is a good match at these critical alleles, the recipient will require immunosuppressive medications to mitigate graft-versus-host disease. Allogeneic transplant donors may be related (usually a closely HLA matched sibling), syngeneic (a monozygotic or 'identical' twin of the patient - necessarily extremely rare since few patients have an identical twin, but offering a source of perfectly HLA matched stem cells) or unrelated (donor who is not related and found to have very close degree of HLA matching). Unrelated donors may be found through a registry of bone marrow donors such as the National Marrow Donor Program. People who would like to be tested for a specific family member or friend without joining any of the bone marrow registry data banks may contact a private HLA testing laboratory and be tested with a mouth swab to see if they are a potential match.[14] A "savior sibling" may be intentionally selected by preimplantation genetic diagnosis in order to match a child both regarding HLA type and being free of any obvious inheritable disorder. Allogeneic transplants are also performed using umbilical cord blood as the source of stem cells. In general, by transfusing healthy stem cells to the recipient's bloodstream to reform a healthy immune system, allogeneic HSCTs appear to improve chances for cure or long-term remission once the immediate transplant-related complications are resolved.[15][16][17]

A compatible donor is found by doing additional HLA-testing from the blood of potential donors. The HLA genes fall in two categories (Type I and Type II). In general, mismatches of the Type-I genes (i.e. HLA-A, HLA-B, or HLA-C) increase the risk of graft rejection. A mismatch of an HLA Type II gene (i.e. HLA-DR, or HLA-DQB1) increases the risk of graft-versus-host disease. In addition a genetic mismatch as small as a single DNA base pair is significant so perfect matches require knowledge of the exact DNA sequence of these genes for both donor and recipient. Leading transplant centers currently perform testing for all five of these HLA genes before declaring that a donor and recipient are HLA-identical.

Race and ethnicity are known to play a major role in donor recruitment drives, as members of the same ethnic group are more likely to have matching genes, including the genes for HLA.[18]

As of 2013[update], there were at least two commercialized allogeneic cell therapies, Prochymal and Cartistem.[19]

To limit the risks of transplanted stem cell rejection or of severe graft-versus-host disease in allogeneic HSCT, the donor should preferably have the same human leukocyte antigens (HLA) as the recipient. About 25 to 30 percent of allogeneic HSCT recipients have an HLA-identical sibling. Even so-called "perfect matches" may have mismatched minor alleles that contribute to graft-versus-host disease.

In the case of a bone marrow transplant, the HSC are removed from a large bone of the donor, typically the pelvis, through a large needle that reaches the center of the bone. The technique is referred to as a bone marrow harvest and is performed under general anesthesia.

Peripheral blood stem cells[20] are now the most common source of stem cells for HSCT. They are collected from the blood through a process known as apheresis. The donor's blood is withdrawn through a sterile needle in one arm and passed through a machine that removes white blood cells. The red blood cells are returned to the donor. The peripheral stem cell yield is boosted with daily subcutaneous injections of Granulocyte-colony stimulating factor, serving to mobilize stem cells from the donor's bone marrow into the peripheral circulation.

It is also possible to extract stem cells from amniotic fluid for both autologous or heterologous use at the time of childbirth.

Umbilical cord blood is obtained when a mother donates her infant's umbilical cord and placenta after birth. Cord blood has a higher concentration of HSC than is normally found in adult blood. However, the small quantity of blood obtained from an Umbilical Cord (typically about 50 mL) makes it more suitable for transplantation into small children than into adults. Newer techniques using ex-vivo expansion of cord blood units or the use of two cord blood units from different donors allow cord blood transplants to be used in adults.

Cord blood can be harvested from the Umbilical Cord of a child being born after preimplantation genetic diagnosis (PGD) for human leucocyte antigen (HLA) matching (see PGD for HLA matching) in order to donate to an ill sibling requiring HSCT.

Unlike other organs, bone marrow cells can be frozen (cryopreserved) for prolonged periods without damaging too many cells. This is a necessity with autologous HSC because the cells must be harvested from the recipient months in advance of the transplant treatment. In the case of allogeneic transplants, fresh HSC are preferred in order to avoid cell loss that might occur during the freezing and thawing process. Allogeneic cord blood is stored frozen at a cord blood bank because it is only obtainable at the time of childbirth. To cryopreserve HSC, a preservative, DMSO, must be added, and the cells must be cooled very slowly in a controlled-rate freezer to prevent osmotic cellular injury during ice crystal formation. HSC may be stored for years in a cryofreezer, which typically uses liquid nitrogen.

The chemotherapy or irradiation given immediately prior to a transplant is called the conditioning regimen, the purpose of which is to help eradicate the patient's disease prior to the infusion of HSC and to suppress immune reactions. The bone marrow can be ablated (destroyed) with dose-levels that cause minimal injury to other tissues. In allogeneic transplants a combination of cyclophosphamide with total body irradiation is conventionally employed. This treatment also has an immunosuppressive effect that prevents rejection of the HSC by the recipient's immune system. The post-transplant prognosis often includes acute and chronic graft-versus-host disease that may be life-threatening. However, in certain leukemias this can coincide with protection against cancer relapse owing to the graft versus tumor effect.[21]Autologous transplants may also use similar conditioning regimens, but many other chemotherapy combinations can be used depending on the type of disease.

A newer treatment approach, non-myeloablative allogeneic transplantation, also termed reduced-intensity conditioning (RIC), uses doses of chemotherapy and radiation too low to eradicate all the bone marrow cells of the recipient.[22]:320321 Instead, non-myeloablative transplants run lower risks of serious infections and transplant-related mortality while relying upon the graft versus tumor effect to resist the inherent increased risk of cancer relapse.[23][24] Also significantly, while requiring high doses of immunosuppressive agents in the early stages of treatment, these doses are less than for conventional transplants.[25] This leads to a state of mixed chimerism early after transplant where both recipient and donor HSC coexist in the bone marrow space.

Decreasing doses of immunosuppressive therapy then allows donor T-cells to eradicate the remaining recipient HSC and to induce the graft versus tumor effect. This effect is often accompanied by mild graft-versus-host disease, the appearance of which is often a surrogate marker for the emergence of the desirable graft versus tumor effect, and also serves as a signal to establish an appropriate dosage level for sustained treatment with low levels of immunosuppressive agents.

Because of their gentler conditioning regimens, these transplants are associated with a lower risk of transplant-related mortality and therefore allow patients who are considered too high-risk for conventional allogeneic HSCT to undergo potentially curative therapy for their disease. The optimal conditioning strategy for each disease and recipient has not been fully established, but RIC can be used in elderly patients unfit for myeloablative regimens, for whom a higher risk of cancer relapse may be acceptable.[22][24]

After several weeks of growth in the bone marrow, expansion of HSC and their progeny is sufficient to normalize the blood cell counts and re-initiate the immune system. The offspring of donor-derived hematopoietic stem cells have been documented to populate many different organs of the recipient, including the heart, liver, and muscle, and these cells had been suggested to have the abilities of regenerating injured tissue in these organs. However, recent research has shown that such lineage infidelity does not occur as a normal phenomenon[citation needed].

HSCT is associated with a high treatment-related mortality in the recipient (1 percent or higher)[citation needed], which limits its use to conditions that are themselves life-threatening. Major complications are veno-occlusive disease, mucositis, infections (sepsis), graft-versus-host disease and the development of new malignancies.

Bone marrow transplantation usually requires that the recipient's own bone marrow be destroyed ("myeloablation"). Prior to "engraftment" patients may go for several weeks without appreciable numbers of white blood cells to help fight infection. This puts a patient at high risk of infections, sepsis and septic shock, despite prophylactic antibiotics. However, antiviral medications, such as acyclovir and valacyclovir, are quite effective in prevention of HSCT-related outbreak of herpetic infection in seropositive patients.[26] The immunosuppressive agents employed in allogeneic transplants for the prevention or treatment of graft-versus-host disease further increase the risk of opportunistic infection. Immunosuppressive drugs are given for a minimum of 6-months after a transplantation, or much longer if required for the treatment of graft-versus-host disease. Transplant patients lose their acquired immunity, for example immunity to childhood diseases such as measles or polio. For this reason transplant patients must be re-vaccinated with childhood vaccines once they are off immunosuppressive medications.

Severe liver injury can result from hepatic veno-occlusive disease (VOD). Elevated levels of bilirubin, hepatomegaly and fluid retention are clinical hallmarks of this condition. There is now a greater appreciation of the generalized cellular injury and obstruction in hepatic vein sinuses, and hepatic VOD has lately been referred to as sinusoidal obstruction syndrome (SOS). Severe cases of SOS are associated with a high mortality rate. Anticoagulants or defibrotide may be effective in reducing the severity of VOD but may also increase bleeding complications. Ursodiol has been shown to help prevent VOD, presumably by facilitating the flow of bile.

The injury of the mucosal lining of the mouth and throat is a common regimen-related toxicity following ablative HSCT regimens. It is usually not life-threatening but is very painful, and prevents eating and drinking. Mucositis is treated with pain medications plus intravenous infusions to prevent dehydration and malnutrition.

Graft-versus-host disease (GVHD) is an inflammatory disease that is unique to allogeneic transplantation. It is an attack of the "new" bone marrow's immune cells against the recipient's tissues. This can occur even if the donor and recipient are HLA-identical because the immune system can still recognize other differences between their tissues. It is aptly named graft-versus-host disease because bone marrow transplantation is the only transplant procedure in which the transplanted cells must accept the body rather than the body accepting the new cells.[27]

Acute graft-versus-host disease typically occurs in the first 3 months after transplantation and may involve the skin, intestine, or the liver. High-dose corticosteroids such as prednisone are a standard treatment; however this immuno-suppressive treatment often leads to deadly infections. Chronic graft-versus-host disease may also develop after allogeneic transplant. It is the major source of late treatment-related complications, although it less often results in death. In addition to inflammation, chronic graft-versus-host disease may lead to the development of fibrosis, or scar tissue, similar to scleroderma; it may cause functional disability and require prolonged immunosuppressive therapy. Graft-versus-host disease is usually mediated by T cells, which react to foreign peptides presented on the MHC of the host.[citation needed]

Graft versus tumor effect (GVT) or "graft versus leukemia" effect is the beneficial aspect of the Graft-versus-Host phenomenon. For example, HSCT patients with either acute, or in particular chronic, graft-versus-host disease after an allogeneic transplant tend to have a lower risk of cancer relapse.[28][29] This is due to a therapeutic immune reaction of the grafted donor T lymphocytes against the diseased bone marrow of the recipient. This lower rate of relapse accounts for the increased success rate of allogeneic transplants, compared to transplants from identical twins, and indicates that allogeneic HSCT is a form of immunotherapy. GVT is the major benefit of transplants that do not employ the highest immuno-suppressive regimens.

Graft versus tumor is mainly beneficial in diseases with slow progress, e.g. chronic leukemia, low-grade lymphoma, and some cases multiple myeloma. However, it is less effective in rapidly growing acute leukemias.[30]

If cancer relapses after HSCT, another transplant can be performed, infusing the patient with a greater quantity of donor white blood cells (Donor lymphocyte infusion).[30]

Patients after HSCT are at a higher risk for oral carcinoma. Post-HSCT oral cancer may have more aggressive behavior with poorer prognosis, when compared to oral cancer in non-HSCT patients.[31]

Prognosis in HSCT varies widely dependent upon disease type, stage, stem cell source, HLA-matched status (for allogeneic HSCT) and conditioning regimen. A transplant offers a chance for cure or long-term remission if the inherent complications of graft versus host disease, immuno-suppressive treatments and the spectrum of opportunistic infections can be survived.[15][16] In recent years, survival rates have been gradually improving across almost all populations and sub-populations receiving transplants.[32]

Mortality for allogeneic stem cell transplantation can be estimated using the prediction model created by Sorror et al.,[33] using the Hematopoietic Cell Transplantation-Specific Comorbidity Index (HCT-CI). The HCT-CI was derived and validated by investigators at the Fred Hutchinson Cancer Research Center (Seattle, WA). The HCT-CI modifies and adds to a well-validated comorbidity index, the Charlson Comorbidity Index (CCI) (Charlson et al.[34]) The CCI was previously applied to patients undergoing allogeneic HCT but appears to provide less survival prediction and discrimination than the HCT-CI scoring system.

The risks of a complication depend on patient characteristics, health care providers and the apheresis procedure, and the colony-stimulating factor used (G-CSF). G-CSF drugs include filgrastim (Neupogen, Neulasta), and lenograstim (Graslopin).

Filgrastim is typically dosed in the 10 microgram/kg level for 45 days during the harvesting of stem cells. The documented adverse effects of filgrastim include splenic rupture (indicated by left upper abdominal or shoulder pain, risk 1 in 40000), Adult respiratory distress syndrome (ARDS), alveolar hemorrage, and allergic reactions (usually expressed in first 30 minutes, risk 1 in 300).[35][36][37] In addition, platelet and hemoglobin levels dip post-procedure, not returning to normal until one month.[37]

The question of whether geriatrics (patients over 65) react the same as patients under 65 has not been sufficiently examined. Coagulation issues and inflammation of atherosclerotic plaques are known to occur as a result of G-CSF injection. G-CSF has also been described to induce genetic changes in mononuclear cells of normal donors.[36] There is evidence that myelodysplasia (MDS) or acute myeloid leukaemia (AML) can be induced by GCSF in susceptible individuals.[38]

Blood was drawn peripherally in a majority of patients, but a central line to jugular/subclavian/femoral veins may be used in 16 percent of women and 4 percent of men. Adverse reactions during apheresis were experienced in 20 percent of women and 8 percent of men, these adverse events primarily consisted of numbness/tingling, multiple line attempts, and nausea.[37]

A study involving 2408 donors (1860 years) indicated that bone pain (primarily back and hips) as a result of filgrastim treatment is observed in 80 percent of donors by day 4 post-injection.[37] This pain responded to acetaminophen or ibuprofen in 65 percent of donors and was characterized as mild to moderate in 80 percent of donors and severe in 10 percent.[37] Bone pain receded post-donation to 26 percent of patients 2 days post-donation, 6 percent of patients one week post-donation, and <2 percent 1 year post-donation. Donation is not recommended for those with a history of back pain.[37] Other symptoms observed in more than 40 percent of donors include myalgia, headache, fatigue, and insomnia.[37] These symptoms all returned to baseline 1 month post-donation, except for some cases of persistent fatigue in 3 percent of donors.[37]

In one metastudy that incorporated data from 377 donors, 44 percent of patients reported having adverse side effects after peripheral blood HSCT.[38] Side effects included pain prior to the collection procedure as a result of GCSF injections, post-procedural generalized skeletal pain, fatigue and reduced energy.[38]

A study that surveyed 2408 donors found that serious adverse events (requiring prolonged hospitalization) occurred in 15 donors (at a rate of 0.6 percent), although none of these events were fatal.[37] Donors were not observed to have higher than normal rates of cancer with up to 48 years of follow up.[37] One study based on a survey of medical teams covered approximately 24,000 peripheral blood HSCT cases between 1993 and 2005, and found a serious cardiovascular adverse reaction rate of about 1 in 1500.[36] This study reported a cardiovascular-related fatality risk within the first 30 days HSCT of about 2 in 10000. For this same group, severe cardiovascular events were observed with a rate of about 1 in 1500. The most common severe adverse reactions were pulmonary edema/deep vein thrombosis, splenic rupture, and myocardial infarction. Haematological malignancy induction was comparable to that observed in the general population, with only 15 reported cases within 4 years.[36]

Georges Math, a French oncologist, performed the first European bone marrow transplant in November 1958 on five Yugoslavian nuclear workers whose own marrow had been damaged by irradiation caused by a criticality accident at the Vina Nuclear Institute, but all of these transplants were rejected.[39][40][41][42][43] Math later pioneered the use of bone marrow transplants in the treatment of leukemia.[43]

Stem cell transplantation was pioneered using bone-marrow-derived stem cells by a team at the Fred Hutchinson Cancer Research Center from the 1950s through the 1970s led by E. Donnall Thomas, whose work was later recognized with a Nobel Prize in Physiology or Medicine. Thomas' work showed that bone marrow cells infused intravenously could repopulate the bone marrow and produce new blood cells. His work also reduced the likelihood of developing a life-threatening complication called graft-versus-host disease.[44]

The first physician to perform a successful human bone marrow transplant on a disease other than cancer was Robert A. Good at the University of Minnesota in 1968.[45] In 1975, John Kersey, M.D., also of the University of Minnesota, performed the first successful bone marrow transplant to cure lymphoma. His patient, a 16-year-old-boy, is today the longest-living lymphoma transplant survivor.[46]

At the end of 2012, 20.2 million people had registered their willingness to be a bone marrow donor with one of the 67 registries from 49 countries participating in Bone Marrow Donors Worldwide. 17.9 million of these registered donors had been ABDR typed, allowing easy matching. A further 561,000 cord blood units had been received by one of 46 cord blood banks from 30 countries participating. The highest total number of bone marrow donors registered were those from the USA (8.0 million), and the highest number per capita were those from Cyprus (15.4 percent of the population).[47]

Within the United States, racial minority groups are the least likely to be registered and therefore the least likely to find a potentially life-saving match. In 1990, only six African-Americans were able to find a bone marrow match, and all six had common European genetic signatures.[48]

Africans are more genetically diverse than people of European descent, which means that more registrations are needed to find a match. Bone marrow and cord blood banks exist in South Africa, and a new program is beginning in Nigeria.[48] Many people belonging to different races are requested to donate as there is a shortage of donors in African, Mixed race, Latino, Aboriginal, and many other communities.

In 2007, a team of doctors in Berlin, Germany, including Gero Htter, performed a stem cell transplant for leukemia patient Timothy Ray Brown, who was also HIV-positive.[49] From 60 matching donors, they selected a [CCR5]-32 homozygous individual with two genetic copies of a rare variant of a cell surface receptor. This genetic trait confers resistance to HIV infection by blocking attachment of HIV to the cell. Roughly one in 1000 people of European ancestry have this inherited mutation, but it is rarer in other populations.[50][51] The transplant was repeated a year later after a leukemia relapse. Over three years after the initial transplant, and despite discontinuing antiretroviral therapy, researchers cannot detect HIV in the transplant recipient's blood or in various biopsies of his tissues.[52] Levels of HIV-specific antibodies have also declined, leading to speculation that the patient may have been functionally cured of HIV. However, scientists emphasise that this is an unusual case.[53] Potentially fatal transplant complications (the "Berlin patient" suffered from graft-versus-host disease and leukoencephalopathy) mean that the procedure could not be performed in others with HIV, even if sufficient numbers of suitable donors were found.[54][55]

In 2012, Daniel Kuritzkes reported results of two stem cell transplants in patients with HIV. They did not, however, use donors with the 32 deletion. After their transplant procedures, both were put on antiretroviral therapies, during which neither showed traces of HIV in their blood plasma and purified CD4 T cells using a sensitive culture method (less than 3 copies/mL). However, the virus was once again detected in both patients some time after the discontinuation of therapy.[56]

Since McAllister's 1997 report on a patient with multiple sclerosis (MS) who received a bone marrow transplant for CML,[57] over 600 reports have been published describing HSCTs performed primarily for MS.[58] These have been shown to "reduce or eliminate ongoing clinical relapses, halt further progression, and reduce the burden of disability in some patients" that have aggressive highly active MS, "in the absence of chronic treatment with disease-modifying agents".[58]

Clincs performing HSCT includes Northwestern University and Karolinska University Hospital.

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Hematopoietic stem cell transplantation - Wikipedia

Recommendation and review posted by sam

Progress in basic research, starting with the work on neural stem cells in the middle 1990's to embryonic stem (ES) cells and induced pluripotent stem (iPS) cells at present, will lead the cell therapy (regenerative medicine) of various organs, including the central nervous system to a big medical field in the future. The author's group transplanted iPS cell-derived retinal pigment epithelial (RPE) cell sheets to the eye of a patient with exudative age-related macular degeneration (AMD) in 2014 as a clinical research. Replacement of the RPE with the patient's own iPS cell-derived young healthy cell sheet will be one new radical treatment of AMD that is caused by cellular senescence of RPE cells. Since it was the first clinical study using iPS cell-derived cells, the primary endpoint was safety judged by the outcome one year after surgery. The safety of the cell sheet has been confirmed by repeated tumorigenisity tests using immunodeficient mice, as well as purity of the cells, karyotype and genetic analysis. It is, however, also necessary to prove the safety by clinical studies. Following this start, a good strategy considering cost and benefit is needed to make regenerative medicine a standard treatment in the future. Scientifically, the best choice is the autologous RPE cell sheet, but autologous cell are expensive and sheet transplantation involves a risky part of surgical procedure. We should consider human leukocyte antigen (HLA) matched allogeneic transplantation using the HLA 6 loci homozyous iPS cell stock that Prof. Yamanaka of Kyoto University is working on. As the required forms of donor cells will be different depending on types and stages of the target diseases, regenerative medicine will be accomplished in a totally different manner from the present small molecule drugs. Proof of concept (POC) of photoreceptor transplantation in mouse is close to being accomplished using iPS cell-derived photoreceptor cells. The shortest possible course for treatment is now being investigated in preclinical research. Among the mixture of rod and cone photoreceptors in the donor cells, the percentage of cone photoreceptors is still low. Donor cells with more. cone photoreceptors will be needed. If that will work well, photoreceptor transplantation will be the first example of neural network reconstruction in the central nervous system. These efforts will reach to variety of retinal cell transplantations in the future.

Read more here:
[Retinal Cell Therapy Using iPS Cells]. - ncbi.nlm.nih.gov

Recommendation and review posted by Bethany Smith

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Mount Sinai Health System - New York City | Mount Sinai ...

Recommendation and review posted by sam

This article is about genetic tests for disease and ancestry or biological relationships. For use in forensics, see DNA profiling.

Genetic testing, also known as DNA testing, allows the the determination of bloodlines and the genetic diagnosis of vulnerabilities to inherited diseases. In agriculture, a form of genetic testing known as progeny testing can be used to evaluate the quality of breeding stock. In population ecology, genetic testing can be used to track genetic strengths and vulnerabilities of species populations.

In humans, genetic testing can be used to determine a child's parentage (genetic mother and father) or in general a person's ancestry or biological relationship between people. In addition to studying chromosomes to the level of individual genes, genetic testing in a broader sense includes biochemical tests for the possible presence of genetic diseases, or mutant forms of genes associated with increased risk of developing genetic disorders.

Genetic testing identifies changes in chromosomes, genes, or proteins.[1] The variety of genetic tests has expanded throughout the years. In the past, the main genetic tests searched for abnormal chromosome numbers and mutations that lead to rare, inherited disorders. Today, tests involve analyzing multiple genes to determine the risk of developing certain more common diseases such as heart disease and cancer.[2] The results of a genetic test can confirm or rule out a suspected genetic condition or help determine a person's chance of developing or passing on a genetic disorder. Several hundred genetic tests are currently in use, and more are being developed.[3][4]

Because genetic mutations can directly affect the structure of the proteins they code for, testing for specific genetic diseases can also be accomplished by looking at those proteins or their metabolites, or looking at stained or fluorescent chromosomes under a microscope.[5]

Genetic testing is "the analysis of chromosomes (DNA), proteins, and certain metabolites in order to detect heritable disease-related genotypes, mutations, phenotypes, or karyotypes for clinical purposes."[6] It can provide information about a person's genes and chromosomes throughout life. Available types of testing include:

Non-diagnostic testing includes:

Many diseases have a genetic component with tests already available.

over-absorption of iron; accumulation of iron in vital organs (heart, liver, pancreas); organ damage; heart disease; cancer; liver disease; arthritis; diabetes; infertility; impotence[15]

Obstructive lung disease in adults; liver cirrhosis during childhood; when a newborn or infant has jaundice that lasts for an extended period of time (more than a week or two), an enlarged spleen, ascites (fluid accumulation in the abdominal cavity), pruritus (itching), and other signs of liver injury; persons under 40 years of age that develops wheezing, a chronic cough or bronchitis, is short of breath after exertion and/or shows other signs of emphysema (especially when the patient is not a smoker, has not been exposed to known lung irritants, and when the lung damage appears to be located low in the lungs); when you have a close relative with alpha-1 antitrypsin deficiency; when a patient has a decreased level of A1AT.

Elevation of both serum cholesterol and triglycerides; accelerated atherosclerosis, coronary heart disease; cutaneous xanthomas; peripheral vascular disease; diabetes mellitus, obesity or hypothyroidism

Muscle weakness (rapidly progressive); frequent falls; difficulty with motor skills (running, hopping, jumping); progressive difficulty walking (ability to walk may be lost by age 12); fatigue; intellectual retardation (possible); skeletal deformities; chest and back (scoliosis); muscle deformities (contractures of heels, legs; pseudohypertrophy of calf muscles)

Reduced synthesis of the hemoglobin-beta chain; microcytic hypochromic anemia

Venous thrombosis; certain arterial thrombotic conditions; patients with deep vein thrombosis, pulmonary embolism, cerebral vein thrombosis, and premature ischemic stroke and also of women with premature myocardial infarction; family history of early onset stroke, deep vein thrombosis, thromboembolism, pregnancy associated with thrombosis/embolism, hyperhomocystinemia, and multiple miscarriage. Individuals with the mutation are at increased risk of thrombosis in the setting of oral contraceptive use, trauma, and surgery.

Venous thrombosis; pulmonary embolism; transient ischemic attack or premature stroke; peripheral vascular disease, particularly lower extremity; occlusive disease; cerebral vein thrombosis; multiple spontaneous abortions; intrauterine fetal demise

Venous thrombosis; increased plasma homocysteine levels

Independent risk factor for coronary artery disease, ischemic stroke, venous thrombosis (including osteonecrosis)

Uncontrolled division of cancer cells

Inflammation confined to the colon; abdominal pain and bloody diarrhea; anal fistulae and peri-rectal abscesses can also occur

Large amount of abnormally thick mucus in the lungs and intestines; leads to congestioni, pneumonia, diarrhea and poor growth

Congenital loss of hearing; -prelingual, non-syndromic deafness

Tendon xanthomas; elevated LDL cholesterol; premature heart disease

Predisposition of acute myeloid leukemia; skeletal abnormalities; radial hypoplasia and vertebral defect and other physical abnormalities, bone marrow failure (pancytopenia), endocrine dysfunction, early onset osteopenia/osteoporosis and lipid abnormalities, spontaneous chromosomal breakage exacerbated by exposure to DNA cross-linking agents.

Mental retardation or learning disabilities of unknown etiology; autism or autistic-like characteristics; women with premature menopause. Subtle dysmorphism, log face with prominent mandible and large ears, macroorchidism in postpubertal males, behavioral abnormalities, due to lack of FMR1 in areas such as the cerebral cortex, amygdala, hippocampus and cerebellum

Characterized by slowly progressive ataxia; typically associated with depressed tendon reflexes, dysarthria, Babinski responses, and loss of position and vibration senses

over-absorption of iron; accumulation of iron in vital organs (heart, liver, pancreas); organ damage; heart disease; cancer; liver disease; arthritis; diabetes; infertility; impotence

Absence of ganglia in the gut

Progressive disorder of motor, cognitive, and psychiatric disturbances.

Hypolactasia; persistent diarrhea; abdominal cramps; bloating; nausea; flatus

MEN2A (which affects 60% to 90% of MEN2 families):Medullary thyroid carcinoma; Pheochromocytoma (tumor of the adrenal glands); Parathyroid adenomas (benign [noncancerous] tumors) or hyperplasia (increased size) of the parathyroid gland; MEN2B (which affects 5% of MEN2 families): Medullary thyroid carcinoma; Pheochromocytoma; Mucosal neuromas (benign tumors of nerve tissue on the tongue and lips); Digestive problems; Muscle, joint, and spinal problems; Typical facial features; Familial medullary thyroid carcinoma (FMTC) (which affects 5% to 35% of MEN2 families):Medullary thyroid carcinoma only

Affects skeletal and smooth muscle as well as the eye, heart, endocrine system, and central nervous system; clinical findings, which span a continuum from mild to severe, have been categorized into three somewhat overlapping phenotypes: mild, classic, and congenital.

Pseudocholinesterase (also called butyrylcholinesterase or "BCHE") hydrolyzes a number of choline-based compounds including cocaine, heroin, procaine, and succinylcholine, mivacurium, and other fast-acting muscle relaxants.[16] Mutations in the BCHE gene lead to deficiency in the amount or function of the protein, which in turn results in a delay in the metabolism of these compounds, which prolongs their effects. Succinylcholine is commonly used as an anaesthetic in surgical procedures, and a person with BCHE mutations may suffer prolonged paraylasis. Between 1 in 3200 and 1 in 5000 people carry BCHE mutations; they are most prevalent in Persian Jews and Alaska Natives.[16][17] As of 2013 there are 9 genetic tests available.[18]

Variable degrees of hemolysis and intermittent episodes of vascular occlusion resulting in tissue ischemia and acute and chronic organ dysfunction; complications include anemia, jaundice, predisposition to aplastic crisis, sepsis, cholelithiasis, and delayed growth. Diagnosis suspected in infants or young children with painful swelling of the hands and feet, pallor, jaundice, pneumococcal sepsis or meningitis, severe anemia with splenic enlargement, or acute chest syndrome.

Lipids accumulate in the brain; neurological dysfunction; progressive weakness and loss of motor skills; decreased social interaction, seizures, blindness, and total debilitation

Cutaneous photosensitivity; acute neurovisceral crises

Genetic testing is often done as part of a genetic consultation and as of mid-2008 there were more than 1,200 clinically applicable genetic tests available.[19] Once a person decides to proceed with genetic testing, a medical geneticist, genetic counselor, primary care doctor, or specialist can order the test after obtaining informed consent.

Genetic tests are performed on a sample of blood, hair, skin, amniotic fluid (the fluid that surrounds a fetus during pregnancy), or other tissue. For example, a medical procedure called a buccal smear uses a small brush or cotton swab to collect a sample of cells from the inside surface of the cheek. Alternatively, a small amount of saline mouthwash may be swished in the mouth to collect the cells. The sample is sent to a laboratory where technicians look for specific changes in chromosomes, DNA, or proteins, depending on the suspected disorders, often using DNA sequencing. The laboratory reports the test results in writing to a person's doctor or genetic counselor.

Routine newborn screening tests are done on a small blood sample obtained by pricking the baby's heel with a lancet.

The physical risks associated with most genetic tests are very small, particularly for those tests that require only a blood sample or buccal smear (a procedure that samples cells from the inside surface of the cheek). The procedures used for prenatal testing carry a small but non-negligible risk of losing the pregnancy (miscarriage) because they require a sample of amniotic fluid or tissue from around the fetus.

Many of the risks associated with genetic testing involve the emotional, social, or financial consequences of the test results. People may feel angry, depressed, anxious, or guilty about their results. The potential negative impact of genetic testing has led to an increasing recognition of a "right not to know".[20] In some cases, genetic testing creates tension within a family because the results can reveal information about other family members in addition to the person who is tested. The possibility of genetic discrimination in employment or insurance is also a concern. Some individuals avoid genetic testing out of fear it will affect their ability to purchase insurance or find a job.[21] Health insurers do not currently require applicants for coverage to undergo genetic testing, and when insurers encounter genetic information, it is subject to the same confidentiality protections as any other sensitive health information.[22] In the United States, the use of genetic information is governed by the Genetic Information Nondiscrimination Act (GINA) (see discussion below in the section on government regulation).

Genetic testing can provide only limited information about an inherited condition. The test often can't determine if a person will show symptoms of a disorder, how severe the symptoms will be, or whether the disorder will progress over time. Another major limitation is the lack of treatment strategies for many genetic disorders once they are diagnosed.

A genetics professional can explain in detail the benefits, risks, and limitations of a particular test. It is important that any person who is considering genetic testing understand and weigh these factors before making a decision.

Direct-to-consumer (DTC) genetic testing is a type of genetic test that is accessible directly to the consumer without having to go through a health care professional. Usually, to obtain a genetic test, health care professionals (such as doctors) acquire their patient's permission and then order the desired test. DTC genetic tests, however, allow consumers to bypass this process and order DNA tests themselves.

There is a variety of DTC tests, ranging from tests for breast cancer alleles to mutations linked to cystic fibrosis. Benefits of DTC testing are the accessibility of tests to consumers, promotion of proactive healthcare, and the privacy of genetic information. Possible additional risks of DTC testing are the lack of governmental regulation, the potential misinterpretation of genetic information, issues related to testing minors, privacy of data, and downstream expenses for the public health care system.[23]

DTC genetic testing has been controversial due to outspoken opposition within the medical community. Critics of DTC testing argue against the risks involved, the unregulated advertising and marketing claims, and the overall lack of governmental oversight.[24]

DTC testing involves many of the same risks associated with any genetic test. One of the more obvious and dangerous of these is the possibility of misreading of test results. Without professional guidance, consumers can potentially misinterpret genetic information, causing them to be deluded about their personal health.

Some advertising for DTC genetic testing has been criticized as conveying an exaggerated and inaccurate message about the connection between genetic information and disease risk, utilizing emotions as a selling factor. An advertisement for a BRCA-predictive genetic test for breast cancer stated: There is no stronger antidote for fear than information.[25]

Ancestry.com, a company providing DTC DNA tests for genealogy purposes, has reportedly allowed the warrantless search of their database by police investigating a murder.[26] The warrantless search led to a search warrant to force the gathering of a DNA sample from a New Orleans filmmaker; however he turned out not to be a match for the suspected killer.[27]

Currently, the U.S. has no strong federal regulation moderating the DTC market. Though there are several hundred tests available, only a handful are approved by the Food and Drug Administration (FDA); these are sold as at-home test kits, and are therefore considered "medical devices" over which the FDA may assert jurisdiction. Other types of DTC tests require customers to mail in DNA samples for testing; it is difficult for the FDA to exercise jurisdiction over these types of tests, because the actual testing is completed in the laboratories of providers. As of 2007, the FDA had not yet officially substantiated with scientific evidence the claimed accuracy of the majority of direct-to-consumer genetic tests.[28]

With regard to genetic testing and information in general, legislation in the United States called the Genetic Information Nondiscrimination Act prohibits group health plans and health insurers from denying coverage to a healthy individual or charging that person higher premiums based solely on a genetic predisposition to developing a disease in the future. The legislation also bars employers from using individuals genetic information when making hiring, firing, job placement, or promotion decisions.[29] The legislation, the first of its kind in the U.S.,[30] was passed by the United States Senate on April 24, 2008, on a vote of 95-0, and was signed into law by President George W. Bush on May 21, 2008.[31][32] It went into effect on November 21, 2009.

In June 2013 the US Supreme Court issued two rulings on human genetics. The Court struck down patents on human genes, opening up competition in the field of genetic testing.[33] The Supreme Court also ruled that police were allowed to collect DNA from people arrested for serious offenses.[34]

The American Academy of Pediatrics (AAP) and the American College of Medical Genetics (ACMG) have provided new guidelines for the ethical issue of pediatrics genetic testing and screening of children in the United States. Their guidelines state that performing pediatric genetic testing should be in the best interest of the child. In hypothetical situations for adults getting genetically tested 84-98% expressing interest in getting genetically tested for cancer predisposition.[35] Though only half who are at risk of would get tested. AAP and ACMG recommend holding off on genetic testing for late-onset conditions until adulthood. Unless diagnosing genetic disorders during childhood and start early intervention can reduce morbidity or mortality. They also state that with parents or guardians permission testing for asymptomatic children who are at risk of childhood onset conditions are ideal reasons for pediatrics genetic testing. Testing for pharmacogenetics and newborn screening is found to be acceptable by AAP and ACMG guidelines. Histocompatibility testing guideline states that its permissible for children of all ages to have tissue compatibility testing for immediate family members but only after the psychosocial, emotional and physical implications has been explored. With a donor advocate or similar mechanism should be in place to protect the minors from coercion and to safeguard the interest of said minor. Both AAP and ACMG discourage the use of direct-to-consumer and home kit genetic because of the accuracy, interpretation and oversight of test content. Guidelines also state that if parents or guardians should be encouraged to inform their child of the results from the genetic test if the minor is of appropriate age. If minor is of mature appropriate age and request results, the request should be honored. Though for ethical and legal reasons health care providers should be cautions in providing minors with predictive genetic testing without the involvement of parents or guardians. Within the guidelines AAP and ACMG state that health care provider have an obligation to inform parents or guardians on the implication of test results. To encourage patients and families to share information and even offer help in explain results to extend family or refer them to genetic counseling. AAP and ACMG state any type of predictive genetic testing for all types is best offer with genetic counseling being offer by Clinical genetics, genetic counselors or health care providers.[35][36][37]

Israel uses DNA testing to determine if people are eligible for legal privileges given to specific ethnic groups. The policy where "many Jews from the Former Soviet Union (FSU) are asked to provide DNA confirmation of their Jewish heritage in order to immigrate as Jews and become citizens under Israel's Law of Return" has generated controversy. [38]

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Recommendation and review posted by simmons

The journal is using Editorial Manager System for quality in review process. Editorial Manager is an online manuscript submission, review and tracking system. Review processing is performed by the editorial board members of Journal of Bone Research or outside experts; at least two independent reviewers approval followed by editor approval is required for acceptance of any citable manuscript. Authors may submit manuscripts and track their progress through the system, hopefully to publication. Reviewers can download manuscripts and submit their opinions to the editor. Editors can manage the whole submission/review/revise/publish process.

Arthritis is an inflammation of the joints. It can affect one joint or multiple joints. There are more than 100 different types of arthritis, with different causes and treatment methods. Two of the most common types are Osteoarthritis (OA) and Rheumatoid Arthritis (RA).Normal wear and tear causes osteoarthritis, one of the most common forms of arthritis. An infection or injury to the joints can exacerbate this natural breakdown of cartilage tissue. Another common form of arthritis. Rheumatoid Arthritis, is an autoimmune disorder. It occurs when your bodys immune system attacks the tissues of the body. These attacks affect the synovium, a soft tissue in your joints that produces a fluid that nourishes the cartilage and lubricates the joints.

Related Journals of Arthritis

Orthopedics Journals, Orthopedic & Muscular System: Current Research, Journal of Osteoarthritis, Journal of Arthritis, Journal of Aging Science

Arthroplasty is a surgical procedure to restore the function of a joint. A joint can be restored by resurfacing the bones. An artificial joint (called a prosthesis) may also be used. Arthroplasty is surgery to relieve pain and restore range of motion by realigning or reconstructing a joint.

Related Journals of Arthroplasty

Orthopedics Journals, Orthopedic & Muscular System: Current Research, Journal of Osteoarthritis, Journal of Arthritis, Journal of Aging Science

Bone cancer can be distinguished into primary bone cancer or secondary bone cancer. Primary bone cancer starts in the bone, where the cancer spreads within the cells of the bone. Secondary cancer, on the other hand, starts elsewhere in the body and spreads to the bones. Examples of primary bone cancer include steosarcoma, Ewing sarcoma, malignant fibrous histiocytoma, and chondrosarcoma.

Related Journals of Arthroplasty

Journal of Bone Research, Orthopedics Journals, Orthopedic & Muscular System: Current Research, Journal of Osteoarthritis, Journal of Arthritis, Journal of Aging Science

A bone graft is a surgical procedure used to fix problems with bones or joints. Bone grafting, or transplanting of bone tissue, is beneficial in fixing bones that are damaged from trauma, or problem joints. Its also useful for growing bone around an implanted device, such as a total knee replacement. A bone graft may fill a void where bone is absent or help provide structural stability. The bone used in a bone graft can come from your body, a donor, or it can be entirely man-made. The bone graft can provide a framework where new, living bone can grow if its accepted by the body.

Related Journals of Bone Oncology

Orthopedics Journals, Orthopedic & Muscular System: Current Research, Journal of Osteoarthritis, Journal of Arthritis, Journal of Aging Science

Bone joint and Muscle Disorders are one that affects the Musculoskeletal system as well as connective tissue such as Osteoporosis, Osteopenia, Osteomalacia, Pagets disease of bone

Related Journals for Bone, Joint, and Muscle Disorders

Orthopedics Journals, Orthopedic & Muscular System: Current Research, Journal of Osteoarthritis, Journal of Arthritis, Journal of Aging Science

Bone Marrow is a flexible, spongy tissue present inside most of the bones in human body. It occupies 4% of body weight in a normal adult human being. It produces red blood cells by a process called Hematopoiesis and also produces lymphocytes and blood platelets. It contains myelopoietic stem cells, erythropoietic stem cells and various other kinds of cells.

Related Journals of Bone Marrow

Journal of Bone Research, Journal of Hematology & Thromboembolic Diseases, Journal of Cardiovascular Diseases & Diagnosis, Journal of Regenerative Medicine, Journal of Blood, Biology of Blood and Marrow Transplantation, Bone Marrow Research, Bone Marrow Transplantation, Journal of Bone Marrow Biology, Open Bone Journal

Bone marrow disease/disorders arise when bone marrow stops producing blood cells or alters production of blood cells. These conditions are potentially life threatening. They include Fanconi anemia, Myelodysplastic syndrome, Aplastic anemia, Hodgkins Lymphoma and Non-Hodgkins Lymphoma, Leukemia, Myeloma etc.

Related Journals of Bone marrow disease/disorders

Journal of Hematology & Thromboembolic Diseases, Journal of Cardiovascular Diseases & Diagnosis, Journal of Regenerative Medicine,Journal of Blood Disorders & Transfusion,Blood Cells, Molecules, and Diseases, Current Hematologic Malignancy Reports, Haemophilia, Journal of Thrombosis and Thrombolysis, Thrombosis and Haemostasis, Clinical Hemorheology and Microcirculation,BMC Blood Disorders

A bone scan is a nuclear imaging test that helps diagnose and track several types of bone disease.A bone scan is also an important tool for detecting cancer that has spread (metastasized) to the bone from the tumor's original location, such as the breast or prostate. The ability to scan the entire skeleton makes a bone scan very helpful in diagnosing a wide range of bone disorders. bone imaging can be done through X-ray, MRI etc.

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Bone Oncology is the study of bone tumors, A malignancy of bone. Primary bone cancer (cancer that begins in bone) is rare, but it is not unusual for cancers to metastasize (spread) to bone from other parts of the body, such as the breast, lung, and prostate. The most common type of primary bone cancer is osteosarcoma, which develops in new tissue in growing bones.

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A child's musculoskeletal problems are different from those of an adult. Because children are still growing, the body's response to injuries, infections, and deformities may be quite different than what would be seen in a full-grown person. Children with complex pediatric problems are best managed by a medical-surgical team approach. Pediatric orthopaedic surgeons diagnose, treat, and manage children's musculoskeletal problems, such as: Limb and spine deformities noted at birth or later in life (clubfoot, scoliosis, limb length differences), Gait abnormalities (limping), Broken bones, Bone or joint infections and tumors

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A fracture is the medical term for a broken boneThey occur when the physical force exerted on the bone is stronger than the bone itself.There are many types of fractures, but the main categories are displaced, non-displaced, open, and closed. Displaced and non-displaced fractures refer to the way the bone breaks.

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Osteoimmunology is a new research field that investigates the interaction of the immune system with the skeleton. Osteoimmunology has contributed significantly to the understanding of joint destruction in rheumatoid arthritis and other forms of arthropathiesOsteoimmunology has also allowed an improvement in our knowledge of the structure-sparing effects of antirheumatic drug therapy.

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Pain is complex, so there are many treatment options -- medications, therapies, and mind-body techniques. Medications, mind-body techniques, and acupuncture can help relieve chronic pain. Learn about your options.A pain clinic is a health care facility that focuses on the diagnosis and management of chronic pain.Research shows that acupuncture and other nonmedical treatments can provide pain relief.

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Radiation therapy uses high-energy rays or particles to kill cancer cells. External beam radiation therapy uses radiation delivered from outside the body that is focused on the cancer. This is the type of radiation therapy that has been tried as a treatment for bone cancer. Often radiation is used to treat bone cancers that are unresectable (they cannot be completely removed by surgery). Radiation may also be used after surgery if cancer cells were present in the edges of the removed tissueIf the cancer comes back after treatment, radiation can help control symptoms like pain and swelling.

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Future prospects for nanotechnology and biomaterials in medical applications appear to be excellent.Bone is a nanocomposite material comprised of hierarchically arranged collagen fibrils, hydroxyapatite and proteoglycans in the nanometer scaleCells are accustomed to interact with nanostructures, thus providing the cells with a natural bone-like environment that potentially enhance bone tissue regeneration/repair.In this direction, nanotechnology provides opportunities to fabricate as well as explore novel properties and phenomena of functional materials, devices, and systems at the nanometer-length scale.

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The musculoskeletal system provides form, support, stability, and movement to the body. It is made up of the bones of the skeleton, muscles, cartilage, tendons, ligaments, joints, and other connective tissue that supports and binds tissues and organs together.

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Recommendation and review posted by sam

Female () is the sex of an organism, or a part of an organism, that produces non-mobile ova (egg cells). Most female mammals, including female humans, have two X chromosomes.

The ova are defined as the larger gametes in a heterogamous reproduction system, while the smaller, usually motile gamete, the spermatozoon, is produced by the male. A female individual cannot reproduce sexually without access to the gametes of a male (an exception is parthenogenesis). Some organisms can reproduce both sexually and asexually.

There is no single genetic mechanism behind sex differences in different species and the existence of two sexes seems to have evolved multiple times independently in different evolutionary lineages.[1] Patterns of sexual reproduction include

Other than the defining difference in the type of gamete produced, differences between males and females in one lineage cannot always be predicted by differences in another. The concept is not limited to animals; egg cells are produced by chytrids, diatoms, water moulds and land plants, among others. In land plants, female and male designate not only the egg- and sperm-producing organisms and structures, but also the structures of the sporophytes that give rise to male and female plants.

The word female comes from the Latin femella, the diminutive form of femina, meaning "woman". It is not etymologically related to the word male, but in the late 14th century the spelling was altered in English to parallel the spelling of male.[3]

A distinguishing characteristic of the class Mammalia is the presence of mammary glands. The mammary glands are modified sweat glands that produce milk, which is used to feed the young for some time after birth. Only mammals produce milk. Mammary glands are most obvious in humans, as the female human body stores large amounts of fatty tissue near the nipples, resulting in prominent breasts. Mammary glands are present in all mammals, although they are vestigial in the male of the species.

Most mammalian females have two copies of the X chromosome as opposed to the male which carries only one X and one smaller Y chromosome (but some mammals, such as the Platypus, have different combinations). To compensate for the difference in size, one of the female's X chromosomes is randomly inactivated in each cell of placental mammals while the paternally derived X is inactived in marsupials. In birds and some reptiles, by contrast, it is the female which is heterozygous and carries a Z and a W chromosome whilst the male carries two Z chromosomes. Intersex conditions can also give rise to other combinations, such as XO or XXX in mammals, which are still considered as female so long as they do not contain a Y-chromosome. However, these conditions frequently result in sterility.

Mammalian females bear live young (with the rare exception of monotremes, which lay eggs). Some non-mammalian species, such as guppies, have analogous reproductive structures; and some other non-mammals, such as sharks, whose eggs hatch inside their bodies, also have the appearance of bearing live young.

A common symbol used to represent the female sex is (Unicode: U+2640 Alt codes: Alt+12), a circle with a small cross underneath. According to Schott,[4] the most established view is that the male and female symbols "are derived from contractions in Greek script of the Greek names of these planets, namely Thouros (Mars) and Phosphoros (Venus). These derivations have been traced by Renkama[5] who illustrated how Greek letters can be transformed into the graphic male and female symbols still recognised today." Thouros was abbreviated by , and Phosphoros by , both in the handwriting of alchemists so somewhat different from the Greek symbols we know. These abbreviations were contracted into the modern symbols.

The sex of a particular organism may be determined by a number of factors. These may be genetic or environmental, or may naturally change during the course of an organism's life. Although most species with male and female sexes have individuals that are either male or female, hermaphroditic animals have both male and female reproductive organs.

The sex of most mammals, including humans, is genetically determined by the XY sex-determination system where males have X and Y (as opposed to X and X) sex chromosomes. During reproduction, the male contributes either an X sperm or a Y sperm, while the female always contributes an X egg. A Y sperm and an X egg produce a male, while an X sperm and an X egg produce a female. The ZW sex-determination system, where males have ZZ (as opposed to ZW) sex chromosomes, is found in birds, reptiles and some insects and other organisms. Members of Hymenoptera, such as ants and bees, are determined by haplodiploidy, where most males are haploid and females and some sterile males are diploid.[citation needed]

The young of some species develop into one sex or the other depending on local environmental conditions, e.g. many crocodilians' sex is influenced by the temperature of their eggs. Other species (such as the goby) can transform, as adults, from one sex to the other in response to local reproductive conditions (such as a shortage of males).

Ayers, Donald M. English Words from Latin and Greek Elements. Second Edition. 1986. University of Arizona Press. United States.

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Recommendation and review posted by Bethany Smith

A male () organism is the physiological sex that produces sperm. Each spermatozoon can fuse with a larger female gamete, or ovum, in the process of fertilization. A male cannot reproduce sexually without access to at least one ovum from a female, but some organisms can reproduce both sexually and asexually. Most male mammals, including male humans, have a Y chromosome, which codes for the production of larger amounts of testosterone to develop male reproductive organs.

Not all species share a common sex-determination system. In most animals, including humans, sex (as opposed to gender) is determined genetically, but in some species it can be determined due to social, environmental or other factors. For example, Cymothoa exigua changes sex depending on the number of females present in the vicinity.[1]

The existence of two sexes seems to have been selected independently across different evolutionary lineages (see convergent evolution). The repeated pattern is sexual reproduction in isogamous species with two or more mating types with gametes of identical form and behavior (but different at the molecular level) to anisogamous species with gametes of male and female types to oogamous species in which the female gamete is very much larger than the male and has no ability to move. There is a good argument that this pattern was driven by the physical constraints on the mechanisms by which two gametes get together as required for sexual reproduction.[2]

Accordingly, sex is defined operationally across species by the type of gametes produced (i.e.: spermatozoa vs. ova) and differences between males and females in one lineage are not always predictive of differences in another.

Male/female dimorphism between organisms or reproductive organs of different sexes is not limited to animals; male gametes are produced by chytrids, diatoms and land plants, among others. In land plants, female and male designate not only the female and male gamete-producing organisms and structures but also the structures of the sporophytes that give rise to male and female plants. As of the year 2012, the United Arab Emirates has the highest ratio of human males in the world, followed by Qatar.[3]

A common symbol used to represent the male sex is the Mars symbol, (Unicode: U+2642 Alt codes: Alt+11)a circle with an arrow pointing northeast. The symbol is identical to the planetary symbol of Mars. It was first used to denote sex by Carl Linnaeus in 1751. The symbol is often called a stylized representation of the Roman god Mars' shield and spear. According to Stearn, however, all the historical evidence favours that it is derived from , the contraction of the Greek name for the planet, Thouros.[4]

The sex of a particular organism may be determined by a number of factors. These may be genetic or environmental, or may naturally change during the course of an organism's life. Although most species with male and female sexes have individuals that are either male or female, hermaphroditic animals, such as worms, have both male and female reproductive organs.

Most mammals, including humans, are genetically determined as such by the XY sex-determination system where males have an XY (as opposed to XX) sex chromosome. It is also possible in a variety of species, including human beings, to be XXY or have other intersex/hermaphroditic qualities, though one would still be considered genotypically (if not necessarily phenotypically) male so long as one has a Y-chromosome. During reproduction, a male can give either an X sperm or a Y sperm, while a female can only give an X egg. A Y sperm and an X egg produce a male, while an X sperm and an X egg produce a female.

The part of the Y-chromosome which is responsible for maleness is the sex-determining region of the Y-chromosome, the SRY. The SRY activates Sox9, which forms feedforward loops with FGF9 and PGD2 in the gonads, allowing the levels of these genes to stay high enough in order to cause male development;[5] for example, Fgf9 is responsible for development of the spermatic cords and the multiplication of Sertoli cells, both of which are crucial to male sexual development.[6]

The ZW sex-determination system, where males have a ZZ (as opposed to ZW) sex chromosome may be found in birds and some insects (mostly butterflies and moths) and other organisms. Members of the insect order Hymenoptera, such as ants and bees, are often determined by haplodiploidy, where most males are haploid and females and some sterile males are diploid.[citation needed]

In some species of reptiles, including alligators, sex is determined by the temperature at which the egg is incubated. Other species, such as some snails, practice sex change: adults start out male, then become female. In tropical clown fish, the dominant individual in a group becomes female while the other ones are male.[citation needed]

In some arthropods, sex is determined by infection. Bacteria of the genus Wolbachia alter their sexuality; some species consist entirely of ZZ individuals, with sex determined by the presence of Wolbachia.[citation needed]

In those species with two sexes, males may differ from females in ways other than production of spermatozoa. In many insects and fish the male is smaller than the female. In seed plants, which exhibit alternation of generations, the female and male parts are both included within the sporophyte sex organ of a single organism. In mammals, including humans, males are typically larger than females. In birds, the male often exhibits a colorful plumage that attracts females.[citation needed]

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Recommendation and review posted by sam

Evolution is change in the heritable characteristics of biological populations over successive generations.[1][2] Evolutionary processes give rise to biodiversity at every level of biological organisation, including the levels of species, individual organisms, and molecules.[3]

All life on Earth shares a common ancestor known as the last universal common ancestor (LUCA),[4][5][6] which lived approximately 3.53.8 billion years ago,[7] although a study in 2015 found "remains of biotic life" from 4.1 billion years ago in ancient rocks in Western Australia.[8][9] In July 2016, scientists reported identifying a set of 355 genes from the LUCA of all organisms living on Earth.[10]

Repeated formation of new species (speciation), change within species (anagenesis), and loss of species (extinction) throughout the evolutionary history of life on Earth are demonstrated by shared sets of morphological and biochemical traits, including shared DNA sequences.[11] These shared traits are more similar among species that share a more recent common ancestor, and can be used to reconstruct a biological "tree of life" based on evolutionary relationships (phylogenetics), using both existing species and fossils. The fossil record includes a progression from early biogenic graphite,[12] to microbial mat fossils,[13][14][15] to fossilized multicellular organisms. Existing patterns of biodiversity have been shaped both by speciation and by extinction.[16] More than 99 percent of all species that ever lived on Earth are estimated to be extinct.[17][18] Estimates of Earth's current species range from 10 to 14 million,[19] of which about 1.2 million have been documented.[20] More recently, in May 2016, scientists reported that 1 trillion species are estimated to be on Earth currently with only one-thousandth of one percent described.[21]

In the mid-19th century, Charles Darwin formulated the scientific theory of evolution by natural selection, published in his book On the Origin of Species (1859). Evolution by natural selection is a process demonstrated by the observation that more offspring are produced than can possibly survive, along with three facts about populations: 1) traits vary among individuals with respect to morphology, physiology, and behaviour (phenotypic variation), 2) different traits confer different rates of survival and reproduction (differential fitness), and 3) traits can be passed from generation to generation (heritability of fitness).[22] Thus, in successive generations members of a population are replaced by progeny of parents better adapted to survive and reproduce in the biophysical environment in which natural selection takes place. This teleonomy is the quality whereby the process of natural selection creates and preserves traits that are seemingly fitted for the functional roles they perform.[23] Natural selection, including sexual selection, is the only known cause of adaptation but not the only known cause of evolution. Other, nonadaptive evolutionary processes include mutation, genetic drift and gene migration.[24]

In the early 20th century the modern evolutionary synthesis integrated classical genetics with Darwin's theory of evolution by natural selection through the discipline of population genetics. The importance of natural selection as a cause of evolution was accepted into other branches of biology. Moreover, previously held notions about evolution, such as orthogenesis, evolutionism, and other beliefs about innate "progress" within the largest-scale trends in evolution, became obsolete scientific theories.[25] Scientists continue to study various aspects of evolutionary biology by forming and testing hypotheses, constructing mathematical models of theoretical biology and biological theories, using observational data, and performing experiments in both the field and the laboratory.

In terms of practical application, an understanding of evolution has been instrumental to developments in numerous scientific and industrial fields, including agriculture, human and veterinary medicine, and the life sciences in general.[26][27][28] Discoveries in evolutionary biology have made a significant impact not just in the traditional branches of biology but also in other academic disciplines, including biological anthropology, and evolutionary psychology.[29][30]Evolutionary computation, a sub-field of artificial intelligence, involves the application of Darwinian principles to problems in computer science.

The proposal that one type of organism could descend from another type goes back to some of the first pre-Socratic Greek philosophers, such as Anaximander and Empedocles.[32] Such proposals survived into Roman times. The poet and philosopher Lucretius followed Empedocles in his masterwork De rerum natura (On the Nature of Things).[33][34] In contrast to these materialistic views, Aristotle considered all natural things, not only living things, as being imperfect actualisations of different fixed natural possibilities, known as "forms," "ideas," or (in Latin translations) "species."[35][36] This was part of his teleological understanding of nature in which all things have an intended role to play in a divine cosmic order. Variations of this idea became the standard understanding of the Middle Ages and were integrated into Christian learning, but Aristotle did not demand that real types of organisms always correspond one-for-one with exact metaphysical forms and specifically gave examples of how new types of living things could come to be.[37]

In the 17th century, the new method of modern science rejected Aristotle's approach. It sought explanations of natural phenomena in terms of physical laws that were the same for all visible things and that did not require the existence of any fixed natural categories or divine cosmic order. However, this new approach was slow to take root in the biological sciences, the last bastion of the concept of fixed natural types. John Ray applied one of the previously more general terms for fixed natural types, "species," to plant and animal types, but he strictly identified each type of living thing as a species and proposed that each species could be defined by the features that perpetuated themselves generation after generation.[38] The biological classification introduced by Carl Linnaeus in 1735 explicitly recognized the hierarchical nature of species relationships, but still viewed species as fixed according to a divine plan.[39]

Other naturalists of this time speculated on the evolutionary change of species over time according to natural laws. In 1751, Pierre Louis Maupertuis wrote of natural modifications occurring during reproduction and accumulating over many generations to produce new species.[40]Georges-Louis Leclerc, Comte de Buffon suggested that species could degenerate into different organisms, and Erasmus Darwin proposed that all warm-blooded animals could have descended from a single microorganism (or "filament").[41] The first full-fledged evolutionary scheme was Jean-Baptiste Lamarck's "transmutation" theory of 1809,[42] which envisaged spontaneous generation continually producing simple forms of life that developed greater complexity in parallel lineages with an inherent progressive tendency, and postulated that on a local level these lineages adapted to the environment by inheriting changes caused by their use or disuse in parents.[43][44] (The latter process was later called Lamarckism.)[43][45][46][47] These ideas were condemned by established naturalists as speculation lacking empirical support. In particular, Georges Cuvier insisted that species were unrelated and fixed, their similarities reflecting divine design for functional needs. In the meantime, Ray's ideas of benevolent design had been developed by William Paley into the Natural Theology or Evidences of the Existence and Attributes of the Deity (1802), which proposed complex adaptations as evidence of divine design and which was admired by Charles Darwin.[48][49][50]

The crucial break from the concept of constant typological classes or types in biology came with the theory of evolution through natural selection, which was formulated by Charles Darwin in terms of variable populations. Partly influenced by An Essay on the Principle of Population (1798) by Thomas Robert Malthus, Darwin noted that population growth would lead to a "struggle for existence" in which favorable variations prevailed as others perished. In each generation, many offspring fail to survive to an age of reproduction because of limited resources. This could explain the diversity of plants and animals from a common ancestry through the working of natural laws in the same way for all types of organism.[51][52][53][54] Darwin developed his theory of "natural selection" from 1838 onwards and was writing up his "big book" on the subject when Alfred Russel Wallace sent him a version of virtually the same theory in 1858. Their separate papers were presented together at a 1858 meeting of the Linnean Society of London.[55] At the end of 1859, Darwin's publication of his "abstract" as On the Origin of Species explained natural selection in detail and in a way that led to an increasingly wide acceptance of concepts of evolution. Thomas Henry Huxley applied Darwin's ideas to humans, using paleontology and comparative anatomy to provide strong evidence that humans and apes shared a common ancestry. Some were disturbed by this since it implied that humans did not have a special place in the universe.[56]

Precise mechanisms of reproductive heritability and the origin of new traits remained a mystery. Towards this end, Darwin developed his provisional theory of pangenesis.[57] In 1865, Gregor Mendel reported that traits were inherited in a predictable manner through the independent assortment and segregation of elements (later known as genes). Mendel's laws of inheritance eventually supplanted most of Darwin's pangenesis theory.[58]August Weismann made the important distinction between germ cells that give rise to gametes (such as sperm and egg cells) and the somatic cells of the body, demonstrating that heredity passes through the germ line only. Hugo de Vries connected Darwin's pangenesis theory to Weismann's germ/soma cell distinction and proposed that Darwin's pangenes were concentrated in the cell nucleus and when expressed they could move into the cytoplasm to change the cells structure. De Vries was also one of the researchers who made Mendel's work well-known, believing that Mendelian traits corresponded to the transfer of heritable variations along the germline.[59] To explain how new variants originate, de Vries developed a mutation theory that led to a temporary rift between those who accepted Darwinian evolution and biometricians who allied with de Vries.[44][60][61] In the 1930s, pioneers in the field of population genetics, such as Ronald Fisher, Sewall Wright and J. B. S. Haldane set the foundations of evolution onto a robust statistical philosophy. The false contradiction between Darwin's theory, genetic mutations, and Mendelian inheritance was thus reconciled.[62]

In the 1920s and 1930s a modern evolutionary synthesis connected natural selection, mutation theory, and Mendelian inheritance into a unified theory that applied generally to any branch of biology. The modern synthesis was able to explain patterns observed across species in populations, through fossil transitions in palaeontology, and even complex cellular mechanisms in developmental biology.[44][63] The publication of the structure of DNA by James Watson and Francis Crick in 1953 demonstrated a physical mechanism for inheritance.[64]Molecular biology improved our understanding of the relationship between genotype and phenotype. Advancements were also made in phylogenetic systematics, mapping the transition of traits into a comparative and testable framework through the publication and use of evolutionary trees.[65][66] In 1973, evolutionary biologist Theodosius Dobzhansky penned that "nothing in biology makes sense except in the light of evolution," because it has brought to light the relations of what first seemed disjointed facts in natural history into a coherent explanatory body of knowledge that describes and predicts many observable facts about life on this planet.[67]

Since then, the modern synthesis has been further extended to explain biological phenomena across the full and integrative scale of the biological hierarchy, from genes to species. This extension, known as evolutionary developmental biology and informally called "evo-devo," emphasises how changes between generations (evolution) acts on patterns of change within individual organisms (development).[68][69][70]

Evolution in organisms occurs through changes in heritable traitsthe inherited characteristics of an organism. In humans, for example, eye colour is an inherited characteristic and an individual might inherit the "brown-eye trait" from one of their parents.[71] Inherited traits are controlled by genes and the complete set of genes within an organism's genome (genetic material) is called its genotype.[72]

The complete set of observable traits that make up the structure and behaviour of an organism is called its phenotype. These traits come from the interaction of its genotype with the environment.[73] As a result, many aspects of an organism's phenotype are not inherited. For example, suntanned skin comes from the interaction between a person's genotype and sunlight; thus, suntans are not passed on to people's children. However, some people tan more easily than others, due to differences in genotypic variation; a striking example are people with the inherited trait of albinism, who do not tan at all and are very sensitive to sunburn.[74]

Heritable traits are passed from one generation to the next via DNA, a molecule that encodes genetic information.[72] DNA is a long biopolymer composed of four types of bases. The sequence of bases along a particular DNA molecule specify the genetic information, in a manner similar to a sequence of letters spelling out a sentence. Before a cell divides, the DNA is copied, so that each of the resulting two cells will inherit the DNA sequence. Portions of a DNA molecule that specify a single functional unit are called genes; different genes have different sequences of bases. Within cells, the long strands of DNA form condensed structures called chromosomes. The specific location of a DNA sequence within a chromosome is known as a locus. If the DNA sequence at a locus varies between individuals, the different forms of this sequence are called alleles. DNA sequences can change through mutations, producing new alleles. If a mutation occurs within a gene, the new allele may affect the trait that the gene controls, altering the phenotype of the organism.[75] However, while this simple correspondence between an allele and a trait works in some cases, most traits are more complex and are controlled by quantitative trait loci (multiple interacting genes).[76][77]

Recent findings have confirmed important examples of heritable changes that cannot be explained by changes to the sequence of nucleotides in the DNA. These phenomena are classed as epigenetic inheritance systems.[78]DNA methylation marking chromatin, self-sustaining metabolic loops, gene silencing by RNA interference and the three-dimensional conformation of proteins (such as prions) are areas where epigenetic inheritance systems have been discovered at the organismic level.[79][80] Developmental biologists suggest that complex interactions in genetic networks and communication among cells can lead to heritable variations that may underlay some of the mechanics in developmental plasticity and canalisation.[81] Heritability may also occur at even larger scales. For example, ecological inheritance through the process of niche construction is defined by the regular and repeated activities of organisms in their environment. This generates a legacy of effects that modify and feed back into the selection regime of subsequent generations. Descendants inherit genes plus environmental characteristics generated by the ecological actions of ancestors.[82] Other examples of heritability in evolution that are not under the direct control of genes include the inheritance of cultural traits and symbiogenesis.[83][84]

An individual organism's phenotype results from both its genotype and the influence from the environment it has lived in. A substantial part of the phenotypic variation in a population is caused by genotypic variation.[77] The modern evolutionary synthesis defines evolution as the change over time in this genetic variation. The frequency of one particular allele will become more or less prevalent relative to other forms of that gene. Variation disappears when a new allele reaches the point of fixationwhen it either disappears from the population or replaces the ancestral allele entirely.[85]

Natural selection will only cause evolution if there is enough genetic variation in a population. Before the discovery of Mendelian genetics, one common hypothesis was blending inheritance. But with blending inheritance, genetic variance would be rapidly lost, making evolution by natural selection implausible. The HardyWeinberg principle provides the solution to how variation is maintained in a population with Mendelian inheritance. The frequencies of alleles (variations in a gene) will remain constant in the absence of selection, mutation, migration and genetic drift.[86]

Variation comes from mutations in the genome, reshuffling of genes through sexual reproduction and migration between populations (gene flow). Despite the constant introduction of new variation through mutation and gene flow, most of the genome of a species is identical in all individuals of that species.[87] However, even relatively small differences in genotype can lead to dramatic differences in phenotype: for example, chimpanzees and humans differ in only about 5% of their genomes.[88]

Mutations are changes in the DNA sequence of a cell's genome. When mutations occur, they may alter the product of a gene, or prevent the gene from functioning, or have no effect. Based on studies in the fly Drosophila melanogaster, it has been suggested that if a mutation changes a protein produced by a gene, this will probably be harmful, with about 70% of these mutations having damaging effects, and the remainder being either neutral or weakly beneficial.[89]

Mutations can involve large sections of a chromosome becoming duplicated (usually by genetic recombination), which can introduce extra copies of a gene into a genome.[90] Extra copies of genes are a major source of the raw material needed for new genes to evolve.[91] This is important because most new genes evolve within gene families from pre-existing genes that share common ancestors.[92] For example, the human eye uses four genes to make structures that sense light: three for colour vision and one for night vision; all four are descended from a single ancestral gene.[93]

New genes can be generated from an ancestral gene when a duplicate copy mutates and acquires a new function. This process is easier once a gene has been duplicated because it increases the redundancy of the system; one gene in the pair can acquire a new function while the other copy continues to perform its original function.[94][95] Other types of mutations can even generate entirely new genes from previously noncoding DNA.[96][97]

The generation of new genes can also involve small parts of several genes being duplicated, with these fragments then recombining to form new combinations with new functions.[98][99] When new genes are assembled from shuffling pre-existing parts, domains act as modules with simple independent functions, which can be mixed together to produce new combinations with new and complex functions.[100] For example, polyketide synthases are large enzymes that make antibiotics; they contain up to one hundred independent domains that each catalyse one step in the overall process, like a step in an assembly line.[101]

In asexual organisms, genes are inherited together, or linked, as they cannot mix with genes of other organisms during reproduction. In contrast, the offspring of sexual organisms contain random mixtures of their parents' chromosomes that are produced through independent assortment. In a related process called homologous recombination, sexual organisms exchange DNA between two matching chromosomes.[102] Recombination and reassortment do not alter allele frequencies, but instead change which alleles are associated with each other, producing offspring with new combinations of alleles.[103] Sex usually increases genetic variation and may increase the rate of evolution.[104][105]

The two-fold cost of sex was first described by John Maynard Smith.[106] The first cost is that in sexually dimorphic species only one of the two sexes can bear young. (This cost does not apply to hermaphroditic species, like most plants and many invertebrates.) The second cost is that any individual who reproduces sexually can only pass on 50% of its genes to any individual offspring, with even less passed on as each new generation passes.[107] Yet sexual reproduction is the more common means of reproduction among eukaryotes and multicellular organisms. The Red Queen hypothesis has been used to explain the significance of sexual reproduction as a means to enable continual evolution and adaptation in response to coevolution with other species in an ever-changing environment.[107][108][109][110]

Gene flow is the exchange of genes between populations and between species.[111] It can therefore be a source of variation that is new to a population or to a species. Gene flow can be caused by the movement of individuals between separate populations of organisms, as might be caused by the movement of mice between inland and coastal populations, or the movement of pollen between heavy metal tolerant and heavy metal sensitive populations of grasses.

Gene transfer between species includes the formation of hybrid organisms and horizontal gene transfer. Horizontal gene transfer is the transfer of genetic material from one organism to another organism that is not its offspring; this is most common among bacteria.[112] In medicine, this contributes to the spread of antibiotic resistance, as when one bacteria acquires resistance genes it can rapidly transfer them to other species.[113] Horizontal transfer of genes from bacteria to eukaryotes such as the yeast Saccharomyces cerevisiae and the adzuki bean weevil Callosobruchus chinensis has occurred.[114][115] An example of larger-scale transfers are the eukaryotic bdelloid rotifers, which have received a range of genes from bacteria, fungi and plants.[116]Viruses can also carry DNA between organisms, allowing transfer of genes even across biological domains.[117]

Large-scale gene transfer has also occurred between the ancestors of eukaryotic cells and bacteria, during the acquisition of chloroplasts and mitochondria. It is possible that eukaryotes themselves originated from horizontal gene transfers between bacteria and archaea.[118]

From a Neo-Darwinian perspective, evolution occurs when there are changes in the frequencies of alleles within a population of interbreeding organisms.[86] For example, the allele for black colour in a population of moths becoming more common. Mechanisms that can lead to changes in allele frequencies include natural selection, genetic drift, genetic hitchhiking, mutation and gene flow.

Evolution by means of natural selection is the process by which traits that enhance survival and reproduction become more common in successive generations of a population. It has often been called a "self-evident" mechanism because it necessarily follows from three simple facts:[22]

More offspring are produced than can possibly survive, and these conditions produce competition between organisms for survival and reproduction. Consequently, organisms with traits that give them an advantage over their competitors are more likely to pass on their traits to the next generation than those with traits that do not confer an advantage.[119]

The central concept of natural selection is the evolutionary fitness of an organism.[120] Fitness is measured by an organism's ability to survive and reproduce, which determines the size of its genetic contribution to the next generation.[120] However, fitness is not the same as the total number of offspring: instead fitness is indicated by the proportion of subsequent generations that carry an organism's genes.[121] For example, if an organism could survive well and reproduce rapidly, but its offspring were all too small and weak to survive, this organism would make little genetic contribution to future generations and would thus have low fitness.[120]

If an allele increases fitness more than the other alleles of that gene, then with each generation this allele will become more common within the population. These traits are said to be "selected for." Examples of traits that can increase fitness are enhanced survival and increased fecundity. Conversely, the lower fitness caused by having a less beneficial or deleterious allele results in this allele becoming rarerthey are "selected against."[122] Importantly, the fitness of an allele is not a fixed characteristic; if the environment changes, previously neutral or harmful traits may become beneficial and previously beneficial traits become harmful.[75] However, even if the direction of selection does reverse in this way, traits that were lost in the past may not re-evolve in an identical form (see Dollo's law).[123][124]

Natural selection within a population for a trait that can vary across a range of values, such as height, can be categorised into three different types. The first is directional selection, which is a shift in the average value of a trait over timefor example, organisms slowly getting taller.[125] Secondly, disruptive selection is selection for extreme trait values and often results in two different values becoming most common, with selection against the average value. This would be when either short or tall organisms had an advantage, but not those of medium height. Finally, in stabilising selection there is selection against extreme trait values on both ends, which causes a decrease in variance around the average value and less diversity.[119][126] This would, for example, cause organisms to slowly become all the same height.

A special case of natural selection is sexual selection, which is selection for any trait that increases mating success by increasing the attractiveness of an organism to potential mates.[127] Traits that evolved through sexual selection are particularly prominent among males of several animal species. Although sexually favoured, traits such as cumbersome antlers, mating calls, large body size and bright colours often attract predation, which compromises the survival of individual males.[128][129] This survival disadvantage is balanced by higher reproductive success in males that show these hard-to-fake, sexually selected traits.[130]

Natural selection most generally makes nature the measure against which individuals and individual traits, are more or less likely to survive. "Nature" in this sense refers to an ecosystem, that is, a system in which organisms interact with every other element, physical as well as biological, in their local environment. Eugene Odum, a founder of ecology, defined an ecosystem as: "Any unit that includes all of the organisms...in a given area interacting with the physical environment so that a flow of energy leads to clearly defined trophic structure, biotic diversity and material cycles (ie: exchange of materials between living and nonliving parts) within the system."[131] Each population within an ecosystem occupies a distinct niche, or position, with distinct relationships to other parts of the system. These relationships involve the life history of the organism, its position in the food chain and its geographic range. This broad understanding of nature enables scientists to delineate specific forces which, together, comprise natural selection.

Natural selection can act at different levels of organisation, such as genes, cells, individual organisms, groups of organisms and species.[132][133][134] Selection can act at multiple levels simultaneously.[135] An example of selection occurring below the level of the individual organism are genes called transposons, which can replicate and spread throughout a genome.[136] Selection at a level above the individual, such as group selection, may allow the evolution of cooperation, as discussed below.[137]

In addition to being a major source of variation, mutation may also function as a mechanism of evolution when there are different probabilities at the molecular level for different mutations to occur, a process known as mutation bias.[138] If two genotypes, for example one with the nucleotide G and another with the nucleotide A in the same position, have the same fitness, but mutation from G to A happens more often than mutation from A to G, then genotypes with A will tend to evolve.[139] Different insertion vs. deletion mutation biases in different taxa can lead to the evolution of different genome sizes.[140][141] Developmental or mutational biases have also been observed in morphological evolution.[142][143] For example, according to the phenotype-first theory of evolution, mutations can eventually cause the genetic assimilation of traits that were previously induced by the environment.[144][145]

Mutation bias effects are superimposed on other processes. If selection would favor either one out of two mutations, but there is no extra advantage to having both, then the mutation that occurs the most frequently is the one that is most likely to become fixed in a population.[146][147] Mutations leading to the loss of function of a gene are much more common than mutations that produce a new, fully functional gene. Most loss of function mutations are selected against. But when selection is weak, mutation bias towards loss of function can affect evolution.[148] For example, pigments are no longer useful when animals live in the darkness of caves, and tend to be lost.[149] This kind of loss of function can occur because of mutation bias, and/or because the function had a cost, and once the benefit of the function disappeared, natural selection leads to the loss. Loss of sporulation ability in Bacillus subtilis during laboratory evolution appears to have been caused by mutation bias, rather than natural selection against the cost of maintaining sporulation ability.[150] When there is no selection for loss of function, the speed at which loss evolves depends more on the mutation rate than it does on the effective population size,[151] indicating that it is driven more by mutation bias than by genetic drift. In parasitic organisms, mutation bias leads to selection pressures as seen in Ehrlichia. Mutations are biased towards antigenic variants in outer-membrane proteins.

Genetic drift is the change in allele frequency from one generation to the next that occurs because alleles are subject to sampling error.[152] As a result, when selective forces are absent or relatively weak, allele frequencies tend to "drift" upward or downward randomly (in a random walk). This drift halts when an allele eventually becomes fixed, either by disappearing from the population, or replacing the other alleles entirely. Genetic drift may therefore eliminate some alleles from a population due to chance alone. Even in the absence of selective forces, genetic drift can cause two separate populations that began with the same genetic structure to drift apart into two divergent populations with different sets of alleles.[153]

It is usually difficult to measure the relative importance of selection and neutral processes, including drift.[154] The comparative importance of adaptive and non-adaptive forces in driving evolutionary change is an area of current research.[155]

The neutral theory of molecular evolution proposed that most evolutionary changes are the result of the fixation of neutral mutations by genetic drift.[156] Hence, in this model, most genetic changes in a population are the result of constant mutation pressure and genetic drift.[157] This form of the neutral theory is now largely abandoned, since it does not seem to fit the genetic variation seen in nature.[158][159] However, a more recent and better-supported version of this model is the nearly neutral theory, where a mutation that would be effectively neutral in a small population is not necessarily neutral in a large population.[119] Other alternative theories propose that genetic drift is dwarfed by other stochastic forces in evolution, such as genetic hitchhiking, also known as genetic draft.[152][160][161]

The time for a neutral allele to become fixed by genetic drift depends on population size, with fixation occurring more rapidly in smaller populations.[162] The number of individuals in a population is not critical, but instead a measure known as the effective population size.[163] The effective population is usually smaller than the total population since it takes into account factors such as the level of inbreeding and the stage of the lifecycle in which the population is the smallest.[163] The effective population size may not be the same for every gene in the same population.[164]

Recombination allows alleles on the same strand of DNA to become separated. However, the rate of recombination is low (approximately two events per chromosome per generation). As a result, genes close together on a chromosome may not always be shuffled away from each other and genes that are close together tend to be inherited together, a phenomenon known as linkage.[165] This tendency is measured by finding how often two alleles occur together on a single chromosome compared to expectations, which is called their linkage disequilibrium. A set of alleles that is usually inherited in a group is called a haplotype. This can be important when one allele in a particular haplotype is strongly beneficial: natural selection can drive a selective sweep that will also cause the other alleles in the haplotype to become more common in the population; this effect is called genetic hitchhiking or genetic draft.[166] Genetic draft caused by the fact that some neutral genes are genetically linked to others that are under selection can be partially captured by an appropriate effective population size.[160]

Gene flow involves the exchange of genes between populations and between species.[111] The presence or absence of gene flow fundamentally changes the course of evolution. Due to the complexity of organisms, any two completely isolated populations will eventually evolve genetic incompatibilities through neutral processes, as in the Bateson-Dobzhansky-Muller model, even if both populations remain essentially identical in terms of their adaptation to the environment.

If genetic differentiation between populations develops, gene flow between populations can introduce traits or alleles which are disadvantageous in the local population and this may lead to organisms within these populations evolving mechanisms that prevent mating with genetically distant populations, eventually resulting in the appearance of new species. Thus, exchange of genetic information between individuals is fundamentally important for the development of the biological species concept.

During the development of the modern synthesis, Sewall Wright developed his shifting balance theory, which regarded gene flow between partially isolated populations as an important aspect of adaptive evolution.[167] However, recently there has been substantial criticism of the importance of the shifting balance theory.[168]

Evolution influences every aspect of the form and behaviour of organisms. Most prominent are the specific behavioural and physical adaptations that are the outcome of natural selection. These adaptations increase fitness by aiding activities such as finding food, avoiding predators or attracting mates. Organisms can also respond to selection by cooperating with each other, usually by aiding their relatives or engaging in mutually beneficial symbiosis. In the longer term, evolution produces new species through splitting ancestral populations of organisms into new groups that cannot or will not interbreed.

These outcomes of evolution are distinguished based on time scale as macroevolution versus microevolution. Macroevolution refers to evolution that occurs at or above the level of species, in particular speciation and extinction; whereas microevolution refers to smaller evolutionary changes within a species or population, in particular shifts in gene frequency and adaptation.[170] In general, macroevolution is regarded as the outcome of long periods of microevolution.[171] Thus, the distinction between micro- and macroevolution is not a fundamental onethe difference is simply the time involved.[172] However, in macroevolution, the traits of the entire species may be important. For instance, a large amount of variation among individuals allows a species to rapidly adapt to new habitats, lessening the chance of it going extinct, while a wide geographic range increases the chance of speciation, by making it more likely that part of the population will become isolated. In this sense, microevolution and macroevolution might involve selection at different levelswith microevolution acting on genes and organisms, versus macroevolutionary processes such as species selection acting on entire species and affecting their rates of speciation and extinction.[174][175]

A common misconception is that evolution has goals, long-term plans, or an innate tendency for "progress," as expressed in beliefs such as orthogenesis and evolutionism; realistically however, evolution has no long-term goal and does not necessarily produce greater complexity.[176][177][178] Although complex species have evolved, they occur as a side effect of the overall number of organisms increasing and simple forms of life still remain more common in the biosphere.[179] For example, the overwhelming majority of species are microscopic prokaryotes, which form about half the world's biomass despite their small size,[180] and constitute the vast majority of Earth's biodiversity.[181] Simple organisms have therefore been the dominant form of life on Earth throughout its history and continue to be the main form of life up to the present day, with complex life only appearing more diverse because it is more noticeable.[182] Indeed, the evolution of microorganisms is particularly important to modern evolutionary research, since their rapid reproduction allows the study of experimental evolution and the observation of evolution and adaptation in real time.[183][184]

Adaptation is the process that makes organisms better suited to their habitat.[185][186] Also, the term adaptation may refer to a trait that is important for an organism's survival. For example, the adaptation of horses' teeth to the grinding of grass. By using the term adaptation for the evolutionary process and adaptive trait for the product (the bodily part or function), the two senses of the word may be distinguished. Adaptations are produced by natural selection.[187] The following definitions are due to Theodosius Dobzhansky:

Adaptation may cause either the gain of a new feature, or the loss of an ancestral feature. An example that shows both types of change is bacterial adaptation to antibiotic selection, with genetic changes causing antibiotic resistance by both modifying the target of the drug, or increasing the activity of transporters that pump the drug out of the cell.[191] Other striking examples are the bacteria Escherichia coli evolving the ability to use citric acid as a nutrient in a long-term laboratory experiment,[192]Flavobacterium evolving a novel enzyme that allows these bacteria to grow on the by-products of nylon manufacturing,[193][194] and the soil bacterium Sphingobium evolving an entirely new metabolic pathway that degrades the synthetic pesticide pentachlorophenol.[195][196] An interesting but still controversial idea is that some adaptations might increase the ability of organisms to generate genetic diversity and adapt by natural selection (increasing organisms' evolvability).[197][198][199][200][201]

Adaptation occurs through the gradual modification of existing structures. Consequently, structures with similar internal organisation may have different functions in related organisms. This is the result of a single ancestral structure being adapted to function in different ways. The bones within bat wings, for example, are very similar to those in mice feet and primate hands, due to the descent of all these structures from a common mammalian ancestor.[203] However, since all living organisms are related to some extent,[204] even organs that appear to have little or no structural similarity, such as arthropod, squid and vertebrate eyes, or the limbs and wings of arthropods and vertebrates, can depend on a common set of homologous genes that control their assembly and function; this is called deep homology.[205][206]

During evolution, some structures may lose their original function and become vestigial structures.[207] Such structures may have little or no function in a current species, yet have a clear function in ancestral species, or other closely related species. Examples include pseudogenes,[208] the non-functional remains of eyes in blind cave-dwelling fish,[209] wings in flightless birds,[210] the presence of hip bones in whales and snakes,[202] and sexual traits in organisms that reproduce via asexual reproduction.[211] Examples of vestigial structures in humans include wisdom teeth,[212] the coccyx,[207] the vermiform appendix,[207] and other behavioural vestiges such as goose bumps[213][214] and primitive reflexes.[215][216][217]

However, many traits that appear to be simple adaptations are in fact exaptations: structures originally adapted for one function, but which coincidentally became somewhat useful for some other function in the process. One example is the African lizard Holaspis guentheri, which developed an extremely flat head for hiding in crevices, as can be seen by looking at its near relatives. However, in this species, the head has become so flattened that it assists in gliding from tree to treean exaptation. Within cells, molecular machines such as the bacterial flagella[219] and protein sorting machinery[220] evolved by the recruitment of several pre-existing proteins that previously had different functions.[170] Another example is the recruitment of enzymes from glycolysis and xenobiotic metabolism to serve as structural proteins called crystallins within the lenses of organisms' eyes.[221][222]

An area of current investigation in evolutionary developmental biology is the developmental basis of adaptations and exaptations.[223] This research addresses the origin and evolution of embryonic development and how modifications of development and developmental processes produce novel features.[224] These studies have shown that evolution can alter development to produce new structures, such as embryonic bone structures that develop into the jaw in other animals instead forming part of the middle ear in mammals.[225] It is also possible for structures that have been lost in evolution to reappear due to changes in developmental genes, such as a mutation in chickens causing embryos to grow teeth similar to those of crocodiles.[226] It is now becoming clear that most alterations in the form of organisms are due to changes in a small set of conserved genes.[227]

Interactions between organisms can produce both conflict and cooperation. When the interaction is between pairs of species, such as a pathogen and a host, or a predator and its prey, these species can develop matched sets of adaptations. Here, the evolution of one species causes adaptations in a second species. These changes in the second species then, in turn, cause new adaptations in the first species. This cycle of selection and response is called coevolution.[228] An example is the production of tetrodotoxin in the rough-skinned newt and the evolution of tetrodotoxin resistance in its predator, the common garter snake. In this predator-prey pair, an evolutionary arms race has produced high levels of toxin in the newt and correspondingly high levels of toxin resistance in the snake.[229]

Not all co-evolved interactions between species involve conflict.[230] Many cases of mutually beneficial interactions have evolved. For instance, an extreme cooperation exists between plants and the mycorrhizal fungi that grow on their roots and aid the plant in absorbing nutrients from the soil.[231] This is a reciprocal relationship as the plants provide the fungi with sugars from photosynthesis. Here, the fungi actually grow inside plant cells, allowing them to exchange nutrients with their hosts, while sending signals that suppress the plant immune system.[232]

Coalitions between organisms of the same species have also evolved. An extreme case is the eusociality found in social insects, such as bees, termites and ants, where sterile insects feed and guard the small number of organisms in a colony that are able to reproduce. On an even smaller scale, the somatic cells that make up the body of an animal limit their reproduction so they can maintain a stable organism, which then supports a small number of the animal's germ cells to produce offspring. Here, somatic cells respond to specific signals that instruct them whether to grow, remain as they are, or die. If cells ignore these signals and multiply inappropriately, their uncontrolled growth causes cancer.[233]

Such cooperation within species may have evolved through the process of kin selection, which is where one organism acts to help raise a relative's offspring.[234] This activity is selected for because if the helping individual contains alleles which promote the helping activity, it is likely that its kin will also contain these alleles and thus those alleles will be passed on.[235] Other processes that may promote cooperation include group selection, where cooperation provides benefits to a group of organisms.[236]

Speciation is the process where a species diverges into two or more descendant species.[237]

There are multiple ways to define the concept of "species." The choice of definition is dependent on the particularities of the species concerned.[238] For example, some species concepts apply more readily toward sexually reproducing organisms while others lend themselves better toward asexual organisms. Despite the diversity of various species concepts, these various concepts can be placed into one of three broad philosophical approaches: interbreeding, ecological and phylogenetic.[239] The Biological Species Concept (BSC) is a classic example of the interbreeding approach. Defined by Ernst Mayr in 1942, the BSC states that "species are groups of actually or potentially interbreeding natural populations, which are reproductively isolated from other such groups."[240] Despite its wide and long-term use, the BSC like others is not without controversy, for example because these concepts cannot be applied to prokaryotes,[241] and this is called the species problem.[238] Some researchers have attempted a unifying monistic definition of species, while others adopt a pluralistic approach and suggest that there may be different ways to logically interpret the definition of a species.[238][239]

Barriers to reproduction between two diverging sexual populations are required for the populations to become new species. Gene flow may slow this process by spreading the new genetic variants also to the other populations. Depending on how far two species have diverged since their most recent common ancestor, it may still be possible for them to produce offspring, as with horses and donkeys mating to produce mules.[242] Such hybrids are generally infertile. In this case, closely related species may regularly interbreed, but hybrids will be selected against and the species will remain distinct. However, viable hybrids are occasionally formed and these new species can either have properties intermediate between their parent species, or possess a totally new phenotype.[243] The importance of hybridisation in producing new species of animals is unclear, although cases have been seen in many types of animals,[244] with the gray tree frog being a particularly well-studied example.[245]

Speciation has been observed multiple times under both controlled laboratory conditions and in nature.[246] In sexually reproducing organisms, speciation results from reproductive isolation followed by genealogical divergence. There are four mechanisms for speciation. The most common in animals is allopatric speciation, which occurs in populations initially isolated geographically, such as by habitat fragmentation or migration. Selection under these conditions can produce very rapid changes in the appearance and behaviour of organisms.[247][248] As selection and drift act independently on populations isolated from the rest of their species, separation may eventually produce organisms that cannot interbreed.[249]

The second mechanism of speciation is peripatric speciation, which occurs when small populations of organisms become isolated in a new environment. This differs from allopatric speciation in that the isolated populations are numerically much smaller than the parental population. Here, the founder effect causes rapid speciation after an increase in inbreeding increases selection on homozygotes, leading to rapid genetic change.[250]

The third mechanism of speciation is parapatric speciation. This is similar to peripatric speciation in that a small population enters a new habitat, but differs in that there is no physical separation between these two populations. Instead, speciation results from the evolution of mechanisms that reduce gene flow between the two populations.[237] Generally this occurs when there has been a drastic change in the environment within the parental species' habitat. One example is the grass Anthoxanthum odoratum, which can undergo parapatric speciation in response to localised metal pollution from mines.[251] Here, plants evolve that have resistance to high levels of metals in the soil. Selection against interbreeding with the metal-sensitive parental population produced a gradual change in the flowering time of the metal-resistant plants, which eventually produced complete reproductive isolation. Selection against hybrids between the two populations may cause reinforcement, which is the evolution of traits that promote mating within a species, as well as character displacement, which is when two species become more distinct in appearance.[252]

Finally, in sympatric speciation species diverge without geographic isolation or changes in habitat. This form is rare since even a small amount of gene flow may remove genetic differences between parts of a population.[253] Generally, sympatric speciation in animals requires the evolution of both genetic differences and non-random mating, to allow reproductive isolation to evolve.[254]

One type of sympatric speciation involves crossbreeding of two related species to produce a new hybrid species. This is not common in animals as animal hybrids are usually sterile. This is because during meiosis the homologous chromosomes from each parent are from different species and cannot successfully pair. However, it is more common in plants because plants often double their number of chromosomes, to form polyploids.[255] This allows the chromosomes from each parental species to form matching pairs during meiosis, since each parent's chromosomes are represented by a pair already.[256] An example of such a speciation event is when the plant species Arabidopsis thaliana and Arabidopsis arenosa crossbred to give the new species Arabidopsis suecica.[257] This happened about 20,000 years ago,[258] and the speciation process has been repeated in the laboratory, which allows the study of the genetic mechanisms involved in this process.[259] Indeed, chromosome doubling within a species may be a common cause of reproductive isolation, as half the doubled chromosomes will be unmatched when breeding with undoubled organisms.[260]

Speciation events are important in the theory of punctuated equilibrium, which accounts for the pattern in the fossil record of short "bursts" of evolution interspersed with relatively long periods of stasis, where species remain relatively unchanged.[261] In this theory, speciation and rapid evolution are linked, with natural selection and genetic drift acting most strongly on organisms undergoing speciation in novel habitats or small populations. As a result, the periods of stasis in the fossil record correspond to the parental population and the organisms undergoing speciation and rapid evolution are found in small populations or geographically restricted habitats and therefore rarely being preserved as fossils.[174]

Extinction is the disappearance of an entire species. Extinction is not an unusual event, as species regularly appear through speciation and disappear through extinction.[262] Nearly all animal and plant species that have lived on Earth are now extinct,[263] and extinction appears to be the ultimate fate of all species.[264] These extinctions have happened continuously throughout the history of life, although the rate of extinction spikes in occasional mass extinction events.[265] The CretaceousPaleogene extinction event, during which the non-avian dinosaurs became extinct, is the most well-known, but the earlier PermianTriassic extinction event was even more severe, with approximately 96% of all marine species driven to extinction.[265] The Holocene extinction event is an ongoing mass extinction associated with humanity's expansion across the globe over the past few thousand years. Present-day extinction rates are 1001000 times greater than the background rate and up to 30% of current species may be extinct by the mid 21st century.[266] Human activities are now the primary cause of the ongoing extinction event;[267]global warming may further accelerate it in the future.[268]

The role of extinction in evolution is not very well understood and may depend on which type of extinction is considered.[265] The causes of the continuous "low-level" extinction events, which form the majority of extinctions, may be the result of competition between species for limited resources (the competitive exclusion principle).[68] If one species can out-compete another, this could produce species selection, with the fitter species surviving and the other species being driven to extinction.[133] The intermittent mass extinctions are also important, but instead of acting as a selective force, they drastically reduce diversity in a nonspecific manner and promote bursts of rapid evolution and speciation in survivors.[269]

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Duchenne muscular dystrophy (DMD) is a devastating muscle disorder caused by mutations in the dystrophin gene. There is currently no effective treatment for DMD. Muscle satellite cells are tissue-specific stem cells found in the skeletal muscle; these cells play a central role in postnatal muscle growth and regeneration, and are, therefore, a potential source for stem cell therapy for DMD. However, transplantation of satellite cell-derived myoblasts has not yet been successful in humans. Patient-specific induced pluripotent stem (iPS) cells are expected to be a source for autologous cell transplantation therapy for DMD, because iPS cells can proliferate vigorously in vitro and can differentiate into multiple cell lineages both in vitro and in vivo. Here, we discuss the strategies to generate muscle stem cells from iPS cells. So far, the most promising method for generating muscle stem cells from iPS cells is the conditional overexpression of Pax3 or Pax7 in the differentiating mouse embryoid bodies. However, induction methods for human iPS cells have not yet been developed. Thus, iPS cells are expected to serve as an in vitro disease model system, which will enable us to determine the pathology of muscle diseases and develop pharmaceutical treatments.

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[Induced Pluripotent Stem (iPS) Cell-based Cell Therapy ...

Recommendation and review posted by simmons

Life extension science, also known as anti-aging medicine, indefinite life extension, experimental gerontology, and biomedical gerontology, is the study of slowing down or reversing the processes of aging to extend both the maximum and average lifespan. Some researchers in this area, and "life extensionists", "immortalists" or "longevists" (those who wish to achieve longer lives themselves), believe that future breakthroughs in tissue rejuvenation, stem cells, regenerative medicine, molecular repair, gene therapy, pharmaceuticals, and organ replacement (such as with artificial organs or xenotransplantations) will eventually enable humans to have indefinite lifespans (agerasia[1]) through complete rejuvenation to a healthy youthful condition.

The sale of purported anti-aging products such as nutrition, physical fitness, skin care, hormone replacements, vitamins, supplements and herbs is a lucrative global industry, with the US market generating about $50billion of revenue each year.[2] Some medical experts state that the use of such products has not been proven to affect the aging process and many claims regarding the efficacy of these marketed products have been roundly criticized by medical experts, including the American Medical Association.[2][3][4][5][6]

The ethical ramifications of life extension are debated by bioethicists.

During the process of aging, an organism accumulates damage to its macromolecules, cells, tissues, and organs. Specifically, aging is characterized as and thought to be caused by "genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication."[7]Oxidation damage to cellular contents caused by free radicals is believed to contribute to aging as well.[8][8][9]

The longest a human has ever been proven to live is 122 years, the case of Jeanne Calment who was born in 1875 and died in 1997, whereas the maximum lifespan of a wildtype mouse, commonly used as a model in research on aging, is about three years.[10] Genetic differences between humans and mice that may account for these different aging rates include differences in efficiency of DNA repair, antioxidant defenses, energy metabolism, proteostasis maintenance, and recycling mechanisms such as autophagy.[11]

Average lifespan in a population is lowered by infant and child mortality, which are frequently linked to infectious diseases or nutrition problems. Later in life, vulnerability to accidents and age-related chronic disease such as cancer or cardiovascular disease play an increasing role in mortality. Extension of expected lifespan can often be achieved by access to improved medical care, vaccinations, good diet, exercise and avoidance of hazards such as smoking.

Maximum lifespan is determined by the rate of aging for a species inherent in its genes and by environmental factors. Widely recognized methods of extending maximum lifespan in model organisms such as nematodes, fruit flies, and mice include caloric restriction, gene manipulation, and administration of pharmaceuticals.[12] Another technique uses evolutionary pressures such as breeding from only older members or altering levels of extrinsic mortality.[13][14] Some animals such as hydra, planarian flatworms, and certain sponges, corals, and jellyfish do not die of old age and exhibit potential immortality.[15][16][17][18]

Theoretically, extension of maximum lifespan in humans could be achieved by reducing the rate of aging damage by periodic replacement of damaged tissues, molecular repair or rejuvenation of deteriorated cells and tissues, reversal of harmful epigenetic changes, or the enhancement of telomerase enzyme activity.[19][20]

Research geared towards life extension strategies in various organisms is currently under way at a number of academic and private institutions. Since 2009, investigators have found ways to increase the lifespan of nematode worms and yeast by 10-fold; the record in nematodes was achieved through genetic engineering and the extension in yeast by a combination of genetic engineering and caloric restriction.[21] A 2009 review of longevity research noted: "Extrapolation from worms to mammals is risky at best, and it cannot be assumed that interventions will result in comparable life extension factors. Longevity gains from dietary restriction, or from mutations studied previously, yield smaller benefits to Drosophila than to nematodes, and smaller still to mammals. This is not unexpected, since mammals have evolved to live many times the worm's lifespan, and humans live nearly twice as long as the next longest-lived primate. From an evolutionary perspective, mammals and their ancestors have already undergone several hundred million years of natural selection favoring traits that could directly or indirectly favor increased longevity, and may thus have already settled on gene sequences that promote lifespan. Moreover, the very notion of a "life-extension factor" that could apply across taxa presumes a linear response rarely seen in biology."[21]

Much life extension research focuses on nutritiondiets or supplementsas a means to extend lifespan, although few of these have been systematically tested for significant longevity effects. The many diets promoted by anti-aging advocates are often contradictory.[original research?] A dietary pattern with some support from scientific research is caloric restriction.[22][23]

Preliminary studies of caloric restriction on humans using surrogate measurements have provided evidence that caloric restriction may have powerful protective effect against secondary aging in humans. Caloric restriction in humans may reduce the risk of developing Type 2 diabetes and atherosclerosis.[24]

The free-radical theory of aging suggests that antioxidant supplements, such as vitaminC, vitaminE, Q10, lipoic acid, carnosine, and N-acetylcysteine, might extend human life. However, combined evidence from several clinical trials suggest that -carotene supplements and high doses of vitaminE increase mortality rates.[25]Resveratrol is a sirtuin stimulant that has been shown to extend life in animal models, but the effect of resveratrol on lifespan in humans is unclear as of 2011.[26]

There are many traditional herbs purportedly used to extend the health-span, including a Chinese tea called Jiaogulan (Gynostemma pentaphyllum), dubbed "China's Immortality Herb."[27]Ayurveda, the traditional Indian system of medicine, describes a class of longevity herbs called rasayanas, including Bacopa monnieri, Ocimum sanctum, Curcuma longa, Centella asiatica, Phyllanthus emblica, Withania somnifera and many others.[27]

The anti-aging industry offers several hormone therapies. Some of these have been criticized for possible dangers to the patient and a lack of proven effect. For example, the American Medical Association has been critical of some anti-aging hormone therapies.[2]

Although some recent clinical studies have shown that low-dose growth hormone (GH) treatment for adults with GH deficiency changes the body composition by increasing muscle mass, decreasing fat mass, increasing bone density and muscle strength, improves cardiovascular parameters (i.e. decrease of LDL cholesterol), and affects the quality of life without significant side effects,[28][29][30] the evidence for use of growth hormone as an anti-aging therapy is mixed and based on animal studies. There are mixed reports that GH or IGF-1 signaling modulates the aging process in humans and about whether the direction of its effect is positive or negative.[31]

Some critics dispute the portrayal of aging as a disease. For example, Leonard Hayflick, who determined that fibroblasts are limited to around 50cell divisions, reasons that aging is an unavoidable consequence of entropy. Hayflick and fellow biogerontologists Jay Olshansky and Bruce Carnes have strongly criticized the anti-aging industry in response to what they see as unscrupulous profiteering from the sale of unproven anti-aging supplements.[4]

Politics relevant to the substances of life extension pertain mostly to communications and availability.[citation needed]

In the United States, product claims on food and drug labels are strictly regulated. The First Amendment (freedom of speech) protects third-party publishers' rights to distribute fact, opinion and speculation on life extension practices. Manufacturers and suppliers also provide informational publications, but because they market the substances, they are subject to monitoring and enforcement by the Federal Trade Commission (FTC), which polices claims by marketers. What constitutes the difference between truthful and false claims is hotly debated and is a central controversy in this arena.[citation needed]

Research by Sobh and Martin (2011) suggests that people buy anti-aging products to obtain a hoped-for self (e.g., keeping a youthful skin) or to avoid a feared-self (e.g., looking old). The research shows that when consumers pursue a hoped-for self, it is expectations of success that most strongly drive their motivation to use the product. The research also shows why doing badly when trying to avoid a feared self is more motivating than doing well. Interestingly, when product use is seen to fail it is more motivating than success when consumers seek to avoid a feared-self.[32]

The best-characterized anti-aging therapy was, and still is, CR. In some studies calorie restriction has been shown to extend the life of mice, yeast, and rhesus monkeys significantly.[33][34] However, a more recent study has shown that in contrast, calorie restriction has not improved the survival rate in rhesus monkeys.[35] Long-term human trials of CR are now being done. It is the hope of the anti-aging researchers that resveratrol, found in grapes, or pterostilbene, a more bio-available substance, found in blueberries, as well as rapamycin, a biotic substance discovered on Easter Island, may act as CR mimetics to increase the life span of humans.[36]

More recent work reveals that the effects long attributed to caloric restriction may be obtained by restriction of protein alone, and specifically of just the sulfur-containing amino acids cysteine and methionine.[37][38] Current research is into the metabolic pathways affected by variation in availability of products of these amino acids.

There are a number of chemicals intended to slow the aging process currently being studied in animal models.[39] One type of research is related to the observed effects a calorie restriction (CR) diet, which has been shown to extend lifespan in some animals[40] Based on that research, there have been attempts to develop drugs that will have the same effect on the aging process as a caloric restriction diet, which are known as Caloric restriction mimetic drugs. Some drugs that are already approved for other uses have been studied for possible longevity effects on laboratory animals because of a possible CR-mimic effect; they include rapamycin,[41]metformin and other geroprotectors.[42]MitoQ, Resveratrol and pterostilbene are dietary supplements that have also been studied in this context.[36][43][44]

Other attempts to create anti-aging drugs have taken different research paths. One notable direction of research has been research into the possibility of using the enzyme telomerase in order to counter the process of telomere shortening.[45] However, there are potential dangers in this, since some research has also linked telomerase to cancer and to tumor growth and formation.[46] In addition, some preparations, called senolytics are designed to effectively deplete senescent cells which poison an organism by their secretions.[47]

Future advances in nanomedicine could give rise to life extension through the repair of many processes thought to be responsible for aging. K. Eric Drexler, one of the founders of nanotechnology, postulated cell repair machines, including ones operating within cells and utilizing as yet hypothetical molecular computers, in his 1986 book Engines of Creation. Raymond Kurzweil, a futurist and transhumanist, stated in his book The Singularity Is Near that he believes that advanced medical nanorobotics could completely remedy the effects of aging by 2030.[48] According to Richard Feynman, it was his former graduate student and collaborator Albert Hibbs who originally suggested to him (circa 1959) the idea of a medical use for Feynman's theoretical micromachines (see nanotechnology). Hibbs suggested that certain repair machines might one day be reduced in size to the point that it would, in theory, be possible to (as Feynman put it) "swallow the doctor". The idea was incorporated into Feynman's 1959 essay There's Plenty of Room at the Bottom.[49]

Some life extensionists suggest that therapeutic cloning and stem cell research could one day provide a way to generate cells, body parts, or even entire bodies (generally referred to as reproductive cloning) that would be genetically identical to a prospective patient. Recently, the US Department of Defense initiated a program to research the possibility of growing human body parts on mice.[50] Complex biological structures, such as mammalian joints and limbs, have not yet been replicated. Dog and primate brain transplantation experiments were conducted in the mid-20th century but failed due to rejection and the inability to restore nerve connections. As of 2006, the implantation of bio-engineered bladders grown from patients' own cells has proven to be a viable treatment for bladder disease.[51] Proponents of body part replacement and cloning contend that the required biotechnologies are likely to appear earlier than other life-extension technologies.

The use of human stem cells, particularly embryonic stem cells, is controversial. Opponents' objections generally are based on interpretations of religious teachings or ethical considerations. Proponents of stem cell research point out that cells are routinely formed and destroyed in a variety of contexts. Use of stem cells taken from the umbilical cord or parts of the adult body may not provoke controversy.[52]

The controversies over cloning are similar, except general public opinion in most countries stands in opposition to reproductive cloning. Some proponents of therapeutic cloning predict the production of whole bodies, lacking consciousness, for eventual brain transplantation.

Replacement of biological (susceptible to diseases) organs with mechanical ones could extend life. This is the goal of 2045 Initiative.[53]

For cryonicists (advocates of cryopreservation), storing the body at low temperatures after death may provide an "ambulance" into a future in which advanced medical technologies may allow resuscitation and repair. They speculate cryogenic temperatures will minimize changes in biological tissue for many years, giving the medical community ample time to cure all disease, rejuvenate the aged and repair any damage that is caused by the cryopreservation process.

Many cryonicists do not believe that legal death is "real death" because stoppage of heartbeat and breathingthe usual medical criteria for legal deathoccur before biological death of cells and tissues of the body. Even at room temperature, cells may take hours to die and days to decompose. Although neurological damage occurs within 46 minutes of cardiac arrest, the irreversible neurodegenerative processes do not manifest for hours.[54] Cryonicists state that rapid cooling and cardio-pulmonary support applied immediately after certification of death can preserve cells and tissues for long-term preservation at cryogenic temperatures. People, particularly children, have survived up to an hour without heartbeat after submersion in ice water. In one case, full recovery was reported after 45 minutes underwater.[55] To facilitate rapid preservation of cells and tissue, cryonics "standby teams" are available to wait by the bedside of patients who are to be cryopreserved to apply cooling and cardio-pulmonary support as soon as possible after declaration of death.[56]

No mammal has been successfully cryopreserved and brought back to life, with the exception of frozen human embryos. Resuscitation of a postembryonic human from cryonics is not possible with current science. Some scientists still support the idea based on their expectations of the capabilities of future science.[57][58]

Another proposed life extension technology would combine existing and predicted future biochemical and genetic techniques. SENS proposes that rejuvenation may be obtained by removing aging damage via the use of stem cells and tissue engineering, telomere-lengthening machinery, allotopic expression of mitochondrial proteins, targeted ablation of cells, immunotherapeutic clearance, and novel lysosomal hydrolases.[59]

While many biogerontologists find these ideas "worthy of discussion"[60][61] and SENS conferences feature important research in the field,[62][63] some contend that the alleged benefits are too speculative given the current state of technology, referring to it as "fantasy rather than science".[3][5]

Gene therapy, in which nucleic acid polymers are delivered as a drug and are either expressed as proteins, interfere with the expression of proteins, or correct genetic mutations, has been proposed as a future strategy to prevent aging.[64][65]

A large array of genetic modifications have been found to increase lifespan in model organisms such as yeast, nematode worms, fruit flies, and mice. As of 2013, the longest extension of life caused by a single gene manipulation was roughly 150% in mice and 10-fold in nematode worms.[66]

In The Selfish Gene, Richard Dawkins describes an approach to life-extension that involves "fooling genes" into thinking the body is young.[67] Dawkins attributes inspiration for this idea to Peter Medawar. The basic idea is that our bodies are composed of genes that activate throughout our lifetimes, some when we are young and others when we are older. Presumably, these genes are activated by environmental factors, and the changes caused by these genes activating can be lethal. It is a statistical certainty that we possess more lethal genes that activate in later life than in early life. Therefore, to extend life, we should be able to prevent these genes from switching on, and we should be able to do so by "identifying changes in the internal chemical environment of a body that take place during aging... and by simulating the superficial chemical properties of a young body".[68]

According to some lines of thinking, the ageing process is routed into a basic reduction of biological complexity,[69] and thus loss of information. In order to reverse this loss, gerontologist Marios Kyriazis suggested that it is necessary to increase input of actionable and meaningful information both individually (into individual brains),[70] and collectively (into societal systems).[71] This technique enhances overall biological function through up-regulation of immune, hormonal, antioxidant and other parameters, resulting in improved age-repair mechanisms. Working in parallel with natural evolutionary mechanisms that can facilitate survival through increased fitness, Kryiazis claims that the technique may lead to a reduction of the rate of death as a function of age, i.e. indefinite lifespan.[72]

One hypothetical future strategy that, as some suggest, "eliminates" the complications related to a physical body, involves the copying or transferring (e.g. by progressively replacing neurons with transistors) of a conscious mind from a biological brain to a non-biological computer system or computational device. The basic idea is to scan the structure of a particular brain in detail, and then construct a software model of it that is so faithful to the original that, when run on appropriate hardware, it will behave in essentially the same way as the original brain.[73] Whether or not an exact copy of one's mind constitutes actual life extension is matter of debate.

The extension of life has been a desire of humanity and a mainstay motif in the history of scientific pursuits and ideas throughout history, from the Sumerian Epic of Gilgamesh and the Egyptian Smith medical papyrus, all the way through the Taoists, Ayurveda practitioners, alchemists, hygienists such as Luigi Cornaro, Johann Cohausen and Christoph Wilhelm Hufeland, and philosophers such as Francis Bacon, Ren Descartes, Benjamin Franklin and Nicolas Condorcet. However, the beginning of the modern period in this endeavor can be traced to the end of the 19th beginning of the 20th century, to the so-called fin-de-sicle (end of the century) period, denoted as an end of an epoch and characterized by the rise of scientific optimism and therapeutic activism, entailing the pursuit of life extension (or life-extensionism). Among the foremost researchers of life extension at this period were the Nobel Prize winning biologist Elie Metchnikoff (1845-1916) -- the author of the cell theory of immunity and vice director of Institut Pasteur in Paris, and Charles-douard Brown-Squard (1817-1894) -- the president of the French Biological Society and one of the founders of modern endocrinology.[74]

Sociologist James Hughes claims that science has been tied to a cultural narrative of conquering death since the Age of Enlightenment. He cites Francis Bacon (15611626) as an advocate of using science and reason to extend human life, noting Bacon's novel New Atlantis, wherein scientists worked toward delaying aging and prolonging life. Robert Boyle (16271691), founding member of the Royal Society, also hoped that science would make substantial progress with life extension, according to Hughes, and proposed such experiments as "to replace the blood of the old with the blood of the young". Biologist Alexis Carrel (18731944) was inspired by a belief in indefinite human lifespan that he developed after experimenting with cells, says Hughes.[75]

In 1970, the American Aging Association was formed under the impetus of Denham Harman, originator of the free radical theory of aging. Harman wanted an organization of biogerontologists that was devoted to research and to the sharing of information among scientists interested in extending human lifespan.

In 1976, futurists Joel Kurtzman and Philip Gordon wrote No More Dying. The Conquest Of Aging And The Extension Of Human Life, (ISBN 0-440-36247-4) the first popular book on research to extend human lifespan. Subsequently, Kurtzman was invited to testify before the House Select Committee on Aging, chaired by Claude Pepper of Florida, to discuss the impact of life extension on the Social Security system.

Saul Kent published The Life Extension Revolution (ISBN 0-688-03580-9) in 1980 and created a nutraceutical firm called the Life Extension Foundation, a non-profit organization that promotes dietary supplements. The Life Extension Foundation publishes a periodical called Life Extension Magazine. The 1982 bestselling book Life Extension: A Practical Scientific Approach (ISBN 0-446-51229-X) by Durk Pearson and Sandy Shaw further popularized the phrase "life extension".

In 1983, Roy Walford, a life-extensionist and gerontologist, published a popular book called Maximum Lifespan. In 1988, Walford and his student Richard Weindruch summarized their research into the ability of calorie restriction to extend the lifespan of rodents in The Retardation of Aging and Disease by Dietary Restriction (ISBN 0-398-05496-7). It had been known since the work of Clive McCay in the 1930s that calorie restriction can extend the maximum lifespan of rodents. But it was the work of Walford and Weindruch that gave detailed scientific grounding to that knowledge.[citation needed] Walford's personal interest in life extension motivated his scientific work and he practiced calorie restriction himself. Walford died at the age of 80 from complications caused by amyotrophic lateral sclerosis.

Money generated by the non-profit Life Extension Foundation allowed Saul Kent to finance the Alcor Life Extension Foundation, the world's largest cryonics organization. The cryonics movement had been launched in 1962 by Robert Ettinger's book, The Prospect of Immortality. In the 1960s, Saul Kent had been a co-founder of the Cryonics Society of New York. Alcor gained national prominence when baseball star Ted Williams was cryonically preserved by Alcor in 2002 and a family dispute arose as to whether Williams had really wanted to be cryopreserved.

Regulatory and legal struggles between the Food and Drug Administration (FDA) and the Life Extension Foundation included seizure of merchandise and court action. In 1991, Saul Kent and Bill Faloon, the principals of the Foundation, were jailed. The LEF accused the FDA of perpetrating a "Holocaust" and "seeking gestapo-like power" through its regulation of drugs and marketing claims.[76]

In 2003, Doubleday published "The Immortal Cell: One Scientist's Quest to Solve the Mystery of Human Aging," by Michael D. West. West emphasised the potential role of embryonic stem cells in life extension.[77]

Other modern life extensionists include writer Gennady Stolyarov, who insists that death is "the enemy of us all, to be fought with medicine, science, and technology";[78]transhumanist philosopher Zoltan Istvan, who proposes that the "transhumanist must safeguard one's own existence above all else";[79] futurist George Dvorsky, who considers aging to be a problem that desperately needs to be solved;[80] and recording artist Steve Aoki, who has been called "one of the most prolific campaigners for life extension".[81]

In 1991, the American Academy of Anti-Aging Medicine (A4M) was formed as a non-profit organization to create what it considered an anti-aging medical specialty distinct from geriatrics, and to hold trade shows for physicians interested in anti-aging medicine. The A4M trains doctors in anti-aging medicine and publicly promotes the field of anti-aging research. It has about 26,000 members, of whom about 97% are doctors and scientists.[82] The American Board of Medical Specialties recognizes neither anti-aging medicine nor the A4M's professional standing.[83]

In 2003, Aubrey de Grey and David Gobel formed the Methuselah Foundation, which gives financial grants to anti-aging research projects. In 2009, de Grey and several others founded the SENS Research Foundation, a California-based scientific research organization which conducts research into aging and funds other anti-aging research projects at various universities.[84] In 2013, Google announced Calico, a new company based in San Francisco that will harness new technologies to increase scientific understanding of the biology of aging.[85] It is led by Arthur D. Levinson,[86] and its research team includes scientists such as Hal V. Barron, David Botstein, and Cynthia Kenyon. In 2014, biologist Craig Venter founded Human Longevity Inc., a company dedicated to scientific research to end aging through genomics and cell therapy. They received funding with the goal of compiling a comprehensive human genotype, microbiome, and phenotype database.[87]

Aside from private initiatives, aging research is being conducted in university laboratories, and includes universities such as Harvard and UCLA. University researchers have made a number of breakthroughs in extending the lives of mice and insects by reversing certain aspects of aging.[88][89][90][91]

Though many scientists state[92] that life extension and radical life extension are possible, there are still no international or national programs focused on radical life extension. There are political forces staying for and against life extension. By 2012, in Russia, the United States, Israel, and the Netherlands, the Longevity political parties started. They aimed to provide political support to radical life extension research and technologies, and ensure the fastest possible and at the same time soft transition of society to the next step life without aging and with radical life extension, and to provide access to such technologies to most currently living people.[93]

Leon Kass (chairman of the US President's Council on Bioethics from 2001 to 2005) has questioned whether potential exacerbation of overpopulation problems would make life extension unethical.[94] He states his opposition to life extension with the words:

"simply to covet a prolonged life span for ourselves is both a sign and a cause of our failure to open ourselves to procreation and to any higher purpose ... [The] desire to prolong youthfulness is not only a childish desire to eat one's life and keep it; it is also an expression of a childish and narcissistic wish incompatible with devotion to posterity."[95]

John Harris, former editor-in-chief of the Journal of Medical Ethics, argues that as long as life is worth living, according to the person himself, we have a powerful moral imperative to save the life and thus to develop and offer life extension therapies to those who want them.[96]

Transhumanist philosopher Nick Bostrom has argued that any technological advances in life extension must be equitably distributed and not restricted to a privileged few.[97] In an extended metaphor entitled "The Fable of the Dragon-Tyrant", Bostrom envisions death as a monstrous dragon who demands human sacrifices. In the fable, after a lengthy debate between those who believe the dragon is a fact of life and those who believe the dragon can and should be destroyed, the dragon is finally killed. Bostrom argues that political inaction allowed many preventable human deaths to occur.[98]

Life extension is a controversial topic due to fear of overpopulation and possible effects on society.[99] Biogerontologist Aubrey De Grey counters the overpopulation critique by pointing out that the therapy could postpone or eliminate menopause, allowing women to space out their pregnancies over more years and thus decreasing the yearly population growth rate.[100] Moreover, the philosopher and futurist Max More argues that, given the fact the worldwide population growth rate is slowing down and is projected to eventually stabilize and begin falling, superlongevity would be unlikely to contribute to overpopulation.[99]

A Spring 2013 Pew Research poll in the United States found that 38% of Americans would want life extension treatments, and 56% would reject it. However, it also found that 68% believed most people would want it and that only 4% consider an "ideal lifespan" to be more than 120 years. The median "ideal lifespan" was 91 years of age and the majority of the public (63%) viewed medical advances aimed at prolonging life as generally good. 41% of Americans believed that radical life extension (RLE) would be good for society, while 51% said they believed it would be bad for society.[101] One possibility for why 56% of Americans claim they would reject life extension treatments may be due to the cultural perception that living longer would result in a longer period of decrepitude, and that the elderly in our current society are unhealthy.[102]

Religious people are no more likely to oppose life extension than the unaffiliated,[101] though some variation exists between religious denominations.

Most mainstream medical organizations and practitioners do not consider aging to be a disease. David Sinclair says: "Idon't see aging as a disease, but as a collection of quite predictable diseases caused by the deterioration of the body".[103] The two main arguments used are that aging is both inevitable and universal while diseases are not.[104] However, not everyone agrees. Harry R. Moody, Director of Academic Affairs for AARP, notes that what is normal and what is disease strongly depends on a historical context.[105] David Gems, Assistant Director of the Institute of Healthy Ageing, strongly argues that aging should be viewed as a disease.[106] In response to the universality of aging, David Gems notes that it is as misleading as arguing that Basenji are not dogs because they do not bark.[107] Because of the universality of aging he calls it a 'special sort of disease'. Robert M. Perlman, coined the terms aging syndrome and disease complex in 1954 to describe aging.[108]

The discussion whether aging should be viewed as a disease or not has important implications. It would stimulate pharmaceutical companies to develop life extension therapies and in the United States of America, it would also increase the regulation of the anti-aging market by the FDA. Anti-aging now falls under the regulations for cosmetic medicine which are less tight than those for drugs.[107][109]

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Endocrinology (from Greek , endon, "within"; , krn, "to separate"; and -, -logia) is a branch of biology and medicine dealing with the endocrine system, its diseases, and its specific secretions known as hormones. It is also concerned with the integration of developmental events proliferation, growth, and differentiation, and the psychological or behavioral activities of metabolism, growth and development, tissue function, sleep, digestion, respiration, excretion, mood, stress, lactation, movement, reproduction, and sensory perception caused by hormones. Specializations include behavioral endocrinology[1][2][3] and comparative endocrinology.

The endocrine system consists of several glands, all in different parts of the body, that secrete hormones directly into the blood rather than into a duct system. Hormones have many different functions and modes of action; one hormone may have several effects on different target organs, and, conversely, one target organ may be affected by more than one hormone.

Examples of amine hormones

Endocrinology is the study of the endocrine system in the human body. This is a system of glands which secrete hormones. Hormones are chemicals which affect the actions of different organ systems in the body. Examples include thyroid hormone, growth hormone, and insulin. The endocrine system involves a number of feedback mechanisms, so that often one hormone (such as thyroid stimulating hormone) will control the action or release of another secondary hormone (such as thyroid hormone). If there is too much of the secondary hormone, it may provide negative feedback to the primary hormone, maintaining homeostasis.

In the original 1902 definition by Bayliss and Starling (see below), they specified that, to be classified as a hormone, a chemical must be produced by an organ, be released (in small amounts) into the blood, and be transported by the blood to a distant organ to exert its specific function. This definition holds for most "classical" hormones, but there are also paracrine mechanisms (chemical communication between cells within a tissue or organ), autocrine signals (a chemical that acts on the same cell), and intracrine signals (a chemical that acts within the same cell).[4] A neuroendocrine signal is a "classical" hormone that is released into the blood by a neurosecretory neuron (see article on neuroendocrinology).

Examples of steroid hormones

Griffin and Ojeda identify three different classes of hormone based on their chemical composition:[5]

Amines, such as norepinephrine, epinephrine, and dopamine (catecholamines), are derived from single amino acids, in this case tyrosine. Thyroid hormones such as 3,5,3-triiodothyronine (T3) and 3,5,3,5-tetraiodothyronine (thyroxine, T4) make up a subset of this class because they derive from the combination of two iodinated tyrosine amino acid residues.

Peptide hormones and protein hormones consist of three (in the case of thyrotropin-releasing hormone) to more than 200 (in the case of follicle-stimulating hormone) amino acid residues and can have a molecular mass as large as 30,000 grams per mole. All hormones secreted by the pituitary gland are peptide hormones, as are leptin from adipocytes, ghrelin from the stomach, and insulin from the pancreas.

Steroid hormones are converted from their parent compound, cholesterol. Mammalian steroid hormones can be grouped into five groups by the receptors to which they bind: glucocorticoids, mineralocorticoids, androgens, estrogens, and progestogens. Some forms of vitamin D, such as calcitriol, are steroid-like and bind to homologous receptors, but lack the characteristic fused ring structure of true steroids.

Although every organ system secretes and responds to hormones (including the brain, lungs, heart, intestine, skin, and the kidney), the clinical specialty of endocrinology focuses primarily on the endocrine organs, meaning the organs whose primary function is hormone secretion. These organs include the pituitary, thyroid, adrenals, ovaries, testes, and pancreas.

An endocrinologist is a physician who specializes in treating disorders of the endocrine system, such as diabetes, hyperthyroidism, and many others (see list of diseases below).

The medical specialty of endocrinology involves the diagnostic evaluation of a wide variety of symptoms and variations and the long-term management of disorders of deficiency or excess of one or more hormones.

The diagnosis and treatment of endocrine diseases are guided by laboratory tests to a greater extent than for most specialties. Many diseases are investigated through excitation/stimulation or inhibition/suppression testing. This might involve injection with a stimulating agent to test the function of an endocrine organ. Blood is then sampled to assess the changes of the relevant hormones or metabolites. An endocrinologist needs extensive knowledge of clinical chemistry and biochemistry to understand the uses and limitations of the investigations.

A second important aspect of the practice of endocrinology is distinguishing human variation from disease. Atypical patterns of physical development and abnormal test results must be assessed as indicative of disease or not. Diagnostic imaging of endocrine organs may reveal incidental findings called incidentalomas, which may or may not represent disease.

Endocrinology involves caring for the person as well as the disease. Most endocrine disorders are chronic diseases that need lifelong care. Some of the most common endocrine diseases include diabetes mellitus, hypothyroidism and the metabolic syndrome. Care of diabetes, obesity and other chronic diseases necessitates understanding the patient at the personal and social level as well as the molecular, and the physicianpatient relationship can be an important therapeutic process.

Apart from treating patients, many endocrinologists are involved in clinical science and medical research, teaching, and hospital management.

Endocrinologists are specialists of internal medicine or pediatrics. Reproductive endocrinologists deal primarily with problems of fertility and menstrual functionoften training first in obstetrics. Most qualify as an internist, pediatrician, or gynecologist for a few years before specializing, depending on the local training system. In the U.S. and Canada, training for board certification in internal medicine, pediatrics, or gynecology after medical school is called residency. Further formal training to subspecialize in adult, pediatric, or reproductive endocrinology is called a fellowship. Typical training for a North American endocrinologist involves 4 years of college, 4 years of medical school, 3 years of residency, and 2 years of fellowship. In the US, adult endocrinologists are board certified by the American Board of Internal Medicine (ABIM) or the American Osteopathic Board of Internal Medicine (AOBIM) in Endocrinology, Diabetes and Metabolism.

Endocrinology also involves study of the diseases of the endocrine system. These diseases may relate to too little or too much secretion of a hormone, too little or too much action of a hormone, or problems with receiving the hormone.

Because endocrinology encompasses so many conditions and diseases, there are many organizations that provide education to patients and the public. The Hormone Foundation is the public education affiliate of The Endocrine Society and provides information on all endocrine-related conditions. Other educational organizations that focus on one or more endocrine-related conditions include the American Diabetes Association, Human Growth Foundation, American Menopause Foundation, Inc., and Thyroid Foundation of America.

In North America the principal professional organizations of endocrinologists include The Endocrine Society,[6] the American Association of Clinical Endocrinologists,[7] the American Diabetes Association,[8] the Lawson Wilkins Pediatric Endocrine Society,[9] and the American Thyroid Association.[10]

In the United Kingdom, the Society for Endocrinology[11] and the British Society for Paediatric Endocrinology and Diabetes[12] are the main professional organisations. The European Society for Paediatric Endocrinology[13] is the largest international professional association dedicated solely to paediatric endocrinology. There are numerous similar associations around the world.

The earliest study of endocrinology began in China.[14] The Chinese were isolating sex and pituitary hormones from human urine and using them for medicinal purposes by 200 BCE.[14] They used many complex methods, such as sublimation of steroid hormones.[14] Another method specified by Chinese textsthe earliest dating to 1110specified the use of saponin (from the beans of Gleditschia sinensis) to extract hormones, but gypsum (containing calcium sulfate) was also known to have been used.[14]

Although most of the relevant tissues and endocrine glands had been identified by early anatomists, a more humoral approach to understanding biological function and disease was favoured by the ancient Greek and Roman thinkers such as Aristotle, Hippocrates, Lucretius, Celsus, and Galen, according to Freeman et al.,[15] and these theories held sway until the advent of germ theory, physiology, and organ basis of pathology in the 19th century.

In 1849, Arnold Berthold noted that castrated cockerels did not develop combs and wattles or exhibit overtly male behaviour.[16] He found that replacement of testes back into the abdominal cavity of the same bird or another castrated bird resulted in normal behavioural and morphological development, and he concluded (erroneously) that the testes secreted a substance that "conditioned" the blood that, in turn, acted on the body of the cockerel. In fact, one of two other things could have been true: that the testes modified or activated a constituent of the blood or that the testes removed an inhibitory factor from the blood. It was not proven that the testes released a substance that engenders male characteristics until it was shown that the extract of testes could replace their function in castrated animals. Pure, crystalline testosterone was isolated in 1935.[17]

The Graves' disease was named after Irish doctor Robert James Graves,[18] who described a case of goiter with exophthalmos in 1835. The German Karl Adolph von Basedow also independently reported the same constellation of symptoms in 1840, while earlier reports of the disease were also published by the Italians Giuseppe Flajani and Antonio Giuseppe Testa, in 1802 and 1810 respectively,[19] and by the English physician Caleb Hillier Parry (a friend of Edward Jenner) in the late 18th century.[20]Thomas Addison was first to describe Addison's disease in 1849.[21]

In 1902 William Bayliss and Ernest Starling performed an experiment in which they observed that acid instilled into the duodenum caused the pancreas to begin secretion, even after they had removed all nervous connections between the two.[22] The same response could be produced by injecting extract of jejunum mucosa into the jugular vein, showing that some factor in the mucosa was responsible. They named this substance "secretin" and coined the term hormone for chemicals that act in this way.

Joseph von Mering and Oskar Minkowski made the observation in 1889 that removing the pancreas surgically led to an increase in blood sugar, followed by a coma and eventual deathsymptoms of diabetes mellitus. In 1922, Banting and Best realized that homogenizing the pancreas and injecting the derived extract reversed this condition.[23] The hormone responsible, insulin, was not discovered until Frederick Sanger sequenced it in 1953.

Neurohormones were first identified by Otto Loewi in 1921.[24] He incubated a frog's heart (innervated with its vagus nerve attached) in a saline bath, and left in the solution for some time. The solution was then used to bathe a non-innervated second heart. If the vagus nerve on the first heart was stimulated, negative inotropic (beat amplitude) and chronotropic (beat rate) activity were seen in both hearts. This did not occur in either heart if the vagus nerve was not stimulated. The vagus nerve was adding something to the saline solution. The effect could be blocked using atropine, a known inhibitor to heart vagal nerve stimulation. Clearly, something was being secreted by the vagus nerve and affecting the heart. The "vagusstuff" (as Loewi called it) causing the myotropic (muscle enhancing) effects was later identified to be acetylcholine and norepinephrine. Loewi won the Nobel Prize for his discovery.

Recent work in endocrinology focuses on the molecular mechanisms responsible for triggering the effects of hormones. The first example of such work being done was in 1962 by Earl Sutherland. Sutherland investigated whether hormones enter cells to evoke action, or stayed outside of cells. He studied norepinephrine, which acts on the liver to convert glycogen into glucose via the activation of the phosphorylase enzyme. He homogenized the liver into a membrane fraction and soluble fraction (phosphorylase is soluble), added norepinephrine to the membrane fraction, extracted its soluble products, and added them to the first soluble fraction. Phosphorylase activated, indicating that norepinephrine's target receptor was on the cell membrane, not located intracellularly. He later identified the compound as cyclic AMP (cAMP) and with his discovery created the concept of second-messenger-mediated pathways. He, like Loewi, won the Nobel Prize for his groundbreaking work in endocrinology.[25]

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Recommendation and review posted by sam

Hypogonadism means diminished functional activity of the gonadsthe testes in males or the ovaries in femalesthat may result in diminished sex hormone biosynthesis. In layman's terms, it is sometimes called interrupted stage 1 puberty. Low androgen (e.g., testosterone) levels are referred to as hypoandrogenism and low estrogen (e.g., estradiol) as hypoestrogenism, and may occur as symptoms of hypogonadism in both sexes, but are generally only diagnosed in males and females respectively. Other hormones produced by the gonads that hypogonadism can decrease include progesterone, DHEA, anti-Mllerian hormone, activin, and inhibin. Spermatogenesis in males, and ovulation in females, may be impaired by hypogonadism, which, depending on the degree of severity, may result in partial or complete infertility.

Deficiency of sex hormones can result in defective primary or secondary sexual development, or withdrawal effects (e.g., premature menopause) in adults. Defective egg or sperm development results in infertility. The term hypogonadism usually means permanent rather than transient or reversible defects, and usually implies deficiency of reproductive hormones, with or without fertility defects. The term is less commonly used for infertility without hormone deficiency. There are many possible types of hypogonadism and several ways to categorize them. Hypogonadism is also categorized by endocrinologists by the level of the reproductive system that is defective. Physicians measure gonadotropins (LH and FSH) to distinguish primary from secondary hypogonadism. In primary hypogonadism the LH and/or FSH are usually elevated, meaning the problem is in the testicles, whereas in secondary hypogonadism, both are normal or low, suggesting the problem is in the brain.

Hypogonadism can involve just hormone production or just fertility, but most commonly involves both.

Women with hypogonadism do not begin menstruating and it may affect their height and breast development. Onset in women after puberty causes cessation of menstruation, lowered libido, loss of body hair and hot flashes. In boys it causes impaired muscle and beard development and reduced height. In men it can cause reduced body hair and beard, enlarged breasts, loss of muscle, and sexual difficulties. A brain tumor (central hypogonadism) may involve headaches, impaired vision, milky discharge from the breast and symptoms caused by other hormone problems.[3]

The symptoms of hypogonadotrophic hypogonadism, a subtype of hypogonadism, include late, incomplete or lack of development at puberty, and sometimes short stature or the inability to smell; in females, a lack of breasts and menstrual periods, and in males a lack of sexual development, e.g., facial hair, penis and testes enlargement, deepening voice.

Low testosterone can be identified through a simple blood test performed by a laboratory, ordered by a physician. This test is typically ordered in the morning hours, when levels are highest, as levels can drop by as much as 13% during the day.[4]

Normal total testosterone levels range from 240950ng/dL (nanograms per decilitre)[5]

Treatment is often prescribed for total testosterone levels below 230ng/dL.[6] If the serum total testosterone level is between 230 and 350ng/dL, repeating the measurement of total testosterone with sex hormone-binding globulin (SHBG) to calculate free testosterone or free testosterone by equilibrium dialysis may be helpful.

The standard range given is based off widely varying ages and, given that testosterone levels naturally decrease as humans age, age-group specific averages should be taken into consideration when discussing treatment between doctor and patient.[7] In men, testosterone falls approximately 1 to 3 percent each year.[8]

A position statement by The Endocrine Society expressed dissatisfaction with most assays for TT (Total Testosterone) and FT (Free Testosterone).[9] In particular, research has questioned the validity of commonly administered assays of FT by RIA.[9] The FAI (Free Androgen Index) has been found to be the worst predictor of Free Testosterone.[10]

Similar to men, the LH and FSH is used, particularly in women who believe they are in menopause. These levels change during a woman's normal menstrual cycle, so the history of having ceased menstruation coupled with high levels aids the diagnosis of being menopausal. Commonly, the post-menopausal woman is not called hypogonadal if she is of typical menopausal age. Contrast with a young woman or teen, who would have hypogonadism rather than menopause. This is because hypogonadism is an abnormality, whereas menopause is a normal change in hormone levels.

Hypogonadism is often discovered during evaluation of delayed puberty, but ordinary delay, which eventually results in normal pubertal development, wherein reproductive function is termed constitutional delay. It may be discovered during an infertility evaluation in either men or women.

Male hypogonadism is most often treated with testosterone replacement therapy (TRT) in patients who are not trying to conceive.[citation needed] Adverse effects of testosterone replacement therapy include increased cardiovascular events (including strokes and heart attacks) and deaths.[11] The Food and Drug Administration (FDA) stated in 2015 that neither the benefits nor the safety of testosterone have been established for low testosterone levels due to aging.[12][13] The FDA has required that testosterone pharmaceutical labels include warning information about the possibility of an increased risk of heart attacks and stroke.[12][13]

Commonly used testosterone replacement therapies include transdermal (through the skin) using a patch or gel, injections, or pellets. Oral testosterone is no longer used in the U.S. because it is broken down in the liver and rendered inactive; it also can cause severe liver damage.[citation needed] Like many hormonal therapies, changes take place over time. It may take as long as 23 months at optimum level to reduce the symptoms, particularly the wordfinding and cognitive dysfunction.[citation needed] Testosterone levels in the blood should be evaluated to ensure the increase is adequate. Levels between 400 and 700ng/dL are considered appropriate mid-dose levels. Treatment usually starts with 200mg intramuscular testosterone, repeated every 14 days.[citation needed]

While historically, men with prostate cancer risk were warned against testosterone therapy, that has shown to be a myth.[14]

Other side effects can include an elevation of the hematocrit to levels that require blood withdrawal (phlebotomy) to prevent complications from "too thick" blood. Another is that a man may have some growth in the size of the breasts (gynecomastia), though this is relatively rare. Finally, some physicians worry that Obstructive Sleep Apnea may worsen with testosterone therapy, and should be monitored.[15]

Another feasible treatment alternative is human chorionic gonadotropin (hCG).[16]

For both men and women, an alternative to testosterone replacement is Clomifene treatment, which can stimulate the body to naturally increase hormone levels while avoiding infertility and other side effects that can result from direct hormone replacement therapy.[17]

For men, Aquaviron injections may be useful.

For women, estradiol and progesterone are replaced. Some types of fertility defects can be treated, others cannot. Some physicians also give testosterone to women, mainly to increase libido.[citation needed]

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Recommendation and review posted by simmons

Bone marrow is the flexible tissue in the interior of bones. In humans, red blood cells are produced by cores of bone marrow in the heads of long bones in a process known as hematopoiesis.[2] On average, bone marrow constitutes 4% of the total body mass of humans; in an adult having 65 kilograms of mass (143 lbs), bone marrow typically accounts for approximately 2.6 kilograms (5.7lb). The hematopoietic component of bone marrow produces approximately 500 billion blood cells per day, which use the bone marrow vasculature as a conduit to the body's systemic circulation.[3] Bone marrow is also a key component of the lymphatic system, producing the lymphocytes that support the body's immune system.[4]

Bone marrow transplants can be conducted to treat severe diseases of the bone marrow, including certain forms of cancer such as leukemia. Additionally, bone marrow stem cells have been successfully transformed into functional neural cells,[5] and can also potentially be used to treat illnesses such as inflammatory bowel disease.[6]

The two types of bone marrow are "red marrow" (Latin: medulla ossium rubra), which consists mainly of hematopoietic tissue, and "yellow marrow" (Latin: medulla ossium flava), which is mainly made up of fat cells. Red blood cells, platelets, and most white blood cells arise in red marrow. Both types of bone marrow contain numerous blood vessels and capillaries. At birth, all bone marrow is red. With age, more and more of it is converted to the yellow type; only around half of adult bone marrow is red. Red marrow is found mainly in the flat bones, such as the pelvis, sternum, cranium, ribs, vertebrae and scapulae, and in the cancellous ("spongy") material at the epiphyseal ends of long bones such as the femur and humerus. Yellow marrow is found in the medullary cavity, the hollow interior of the middle portion of short bones. In cases of severe blood loss, the body can convert yellow marrow back to red marrow to increase blood cell production.

The stroma of the bone marrow is all tissue not directly involved in the marrow's primary function of hematopoiesis.[2] Yellow bone marrow makes up the majority of bone marrow stroma, in addition to smaller concentrations of stromal cells located in the red bone marrow. Though not as active as parenchymal red marrow, stroma is indirectly involved in hematopoiesis, since it provides the hematopoietic microenvironment that facilitates hematopoiesis by the parenchymal cells. For instance, they generate colony stimulating factors, which have a significant effect on hematopoiesis. Cell types that constitute the bone marrow stroma include:

In addition, the bone marrow contains hematopoietic stem cells, which give rise to the three classes of blood cells that are found in the circulation: white blood cells (leukocytes), red blood cells (erythrocytes), and platelets (thrombocytes).[7]

The bone marrow stroma contains mesenchymal stem cells (MSCs),[7] also known as marrow stromal cells. These are multipotent stem cells that can differentiate into a variety of cell types. MSCs have been shown to differentiate, in vitro or in vivo, into osteoblasts, chondrocytes, myocytes, adipocytes and beta-pancreatic islets cells.

The blood vessels of the bone marrow constitute a barrier, inhibiting immature blood cells from leaving the marrow. Only mature blood cells contain the membrane proteins, such as aquaporin and glycophorin, that are required to attach to and pass the blood vessel endothelium.[9]Hematopoietic stem cells may also cross the bone marrow barrier, and may thus be harvested from blood.

The red bone marrow is a key element of the lymphatic system, being one of the primary lymphoid organs that generate lymphocytes from immature hematopoietic progenitor cells.[4] The bone marrow and thymus constitute the primary lymphoid tissues involved in the production and early selection of lymphocytes. Furthermore, bone marrow performs a valve-like function to prevent the backflow of lymphatic fluid in the lymphatic system.

Biological compartmentalization is evident within the bone marrow, in that certain cell types tend to aggregate in specific areas. For instance, erythrocytes, macrophages, and their precursors tend to gather around blood vessels, while granulocytes gather at the borders of the bone marrow.[7]

Animal bone marrow has been used in cuisine worldwide for millennia, such as the famed Milanese Ossobuco.[citation needed]

The normal bone marrow architecture can be damaged or displaced by aplastic anemia, malignancies such as multiple myeloma, or infections such as tuberculosis, leading to a decrease in the production of blood cells and blood platelets. The bone marrow can also be affected by various forms of leukemia, which attacks its hematologic progenitor cells.[10] Furthermore, exposure to radiation or chemotherapy will kill many of the rapidly dividing cells of the bone marrow, and will therefore result in a depressed immune system. Many of the symptoms of radiation poisoning are due to damage sustained by the bone marrow cells.

To diagnose diseases involving the bone marrow, a bone marrow aspiration is sometimes performed. This typically involves using a hollow needle to acquire a sample of red bone marrow from the crest of the ilium under general or local anesthesia.[11]

On CT and plain film, marrow change can be seen indirectly by assessing change to the adjacent ossified bone. Assessment with MRI is usually more sensitive and specific for pathology, particularly for hematologic malignancies like leukemia and lymphoma. These are difficult to distinguish from the red marrow hyperplasia of hematopoiesis, as can occur with tobacco smoking, chronically anemic disease states like sickle cell anemia or beta thalassemia, medications such as granulocyte colony-stimulating factors, or during recovery from chronic nutritional anemias or therapeutic bone marrow suppression.[12] On MRI, the marrow signal is not supposed to be brighter than the adjacent intervertebral disc on T1 weighted images, either in the coronal or sagittal plane, where they can be assessed immediately adjacent to one another.[13] Fatty marrow change, the inverse of red marrow hyperplasia, can occur with normal aging,[14] though it can also be seen with certain treatments such as radiation therapy. Diffuse marrow T1 hypointensity without contrast enhancement or cortical discontinuity suggests red marrow conversion or myelofibrosis. Falsely normal marrow on T1 can be seen with diffuse multiple myeloma or leukemic infiltration when the water to fat ratio is not sufficiently altered, as may be seen with lower grade tumors or earlier in the disease process.[15]

Bone marrow examination is the pathologic analysis of samples of bone marrow obtained via biopsy and bone marrow aspiration. Bone marrow examination is used in the diagnosis of a number of conditions, including leukemia, multiple myeloma, anemia, and pancytopenia. The bone marrow produces the cellular elements of the blood, including platelets, red blood cells and white blood cells. While much information can be gleaned by testing the blood itself (drawn from a vein by phlebotomy), it is sometimes necessary to examine the source of the blood cells in the bone marrow to obtain more information on hematopoiesis; this is the role of bone marrow aspiration and biopsy.

The ratio between myeloid series and erythroid cells is relevant to bone marrow function, and also to diseases of the bone marrow and peripheral blood, such as leukemia and anemia. The normal myeloid-to-erythroid ratio is around 3:1; this ratio may increase in myelogenous leukemias, decrease in polycythemias, and reverse in cases of thalassemia.[16]

In a bone marrow transplant, hematopoietic stem cells are removed from a person and infused into another person (allogenic) or into the same person at a later time (autologous). If the donor and recipient are compatible, these infused cells will then travel to the bone marrow and initiate blood cell production. Transplantation from one person to another is conducted for the treatment of severe bone marrow diseases, such as congenital defects, autoimmune diseases or malignancies. The patient's own marrow is first killed off with drugs or radiation, and then the new stem cells are introduced. Before radiation therapy or chemotherapy in cases of cancer, some of the patient's hematopoietic stem cells are sometimes harvested and later infused back when the therapy is finished to restore the immune system.[17]

Bone marrow stem cells can be induced to become neural cells to treat neurological illnesses,[5] and can also potentially be used for the treatment of other illnesses, such as inflammatory bowel disease.[6] In 2013, following a clinical trial, scientists proposed that bone marrow transplantation could be used to treat HIV in conjunction with antiretroviral drugs;[18][19] however, it was later found that HIV remained in the bodies of the test subjects.[20]

The stem cells are typically harvested directly from the red marrow in the iliac crest, often under general anesthesia. The procedure is minimally invasive and does not require stitches afterwards. Depending on the donor's health and reaction to the procedure, the actual harvesting can be an outpatient procedure, or can require 12 days of recovery in the hospital.[21]

Another option is to administer certain drugs that stimulate the release of stem cells from the bone marrow into circulating blood.[22] An intravenous catheter is inserted into the donor's arm, and the stem cells are then filtered out of the blood. This procedure is similar to that used in blood or platelet donation. In adults, bone marrow may also be taken from the sternum, while the tibia is often used when taking samples from infants.[11] In newborns, stem cells may be retrieved from the umbilical cord.[23]

The earliest fossilised evidence of bone marrow was discovered in 2014 in Eusthenopteron, a lobe-finned fish which lived during the Devonian period approximately 370 million years ago.[24] Scientists from Uppsala University and the European Synchrotron Radiation Facility used X-ray synchrotron microtomography to study the fossilised interior of the skeleton's humerus, finding organised tubular structures akin to modern vertebrate bone marrow.[24]Eusthenopteron is closely related to the early tetrapods, which ultimately evolved into the land-dwelling mammals and lizards of the present day.[24]

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Hypopituitarism is the decreased (hypo) secretion of one or more of the eight hormones normally produced by the pituitary gland at the base of the brain.[1][2] If there is decreased secretion of most pituitary hormones, the term panhypopituitarism (pan meaning "all") is used.[3]

The signs and symptoms of hypopituitarism vary, depending on which hormones are undersecreted and on the underlying cause of the abnormality. The diagnosis of hypopituitarism is made by blood tests, but often specific scans and other investigations are needed to find the underlying cause, such as tumors of the pituitary, and the ideal treatment. Most hormones controlled by the secretions of the pituitary can be replaced by tablets or injections. Hypopituitarism is a rare disease, but may be significantly underdiagnosed in people with previous traumatic brain injury.[1] The first description of the condition was made in 1914 by the German physician Dr Morris Simmonds.[4]

The hormones of the pituitary have different actions in the body, and the symptoms of hypopituitarism therefore depend on which hormone is deficient. The symptoms may be subtle and are often initially attributed to other causes.[1][5] In most of the cases, three or more hormones are deficient.[6] The most common problem is insufficiency of follicle-stimulating hormone (FSH) and/or luteinizing hormone (LH) leading to sex hormone abnormalities. Growth hormone deficiency is more common in people with an underlying tumor than those with other causes.[1][6]

Sometimes, there are additional symptoms that arise from the underlying cause; for instance, if the hypopituitarism is due to a growth hormone-producing tumor, there may be symptoms of acromegaly (enlargement of the hands and feet, coarse facial features), and if the tumor extends to the optic nerve or optic chiasm, there may be visual field defects. Headaches may also accompany pituitary tumors,[1] as well as pituitary apoplexy (infarction or haemorrhage of a pituitary tumor) and lymphocytic hypophysitis (autoimmune inflammation of the pituitary).[7] Apoplexy, in addition to sudden headaches and rapidly worsening visual loss, may also be associated with double vision that results from compression of the nerves in the adjacent cavernous sinus that control the eye muscles.[8]

Pituitary failure results in many changes in the skin, hair and nails as a result of the absence of pituitary hormone action on these sites.[9]

Deficiency of all anterior pituitary hormones is more common than individual hormone deficiency.

Deficiency of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), together referred to as the gonadotropins, leads to different symptoms in men and women. Women experience oligo- or amenorrhea (infrequent/light or absent menstrual periods respectively) and infertility. Men lose facial, scrotal and trunk hair, as well as suffering decreased muscle mass and anemia. Both sexes may experience a decrease in libido and loss of sexual function, and have an increased risk of osteoporosis (bone fragility). Lack of LH/FSH in children is associated with delayed puberty.[1][5]

Growth hormone (GH) deficiency leads to a decrease in muscle mass, central obesity (increase in body fat around the waist) and impaired attention and memory. Children experience growth retardation and short stature.[1][5]

Adrenocorticotropic hormone (ACTH) deficiency leads to adrenal insufficiency, a lack of production of glucocorticoids such as cortisol by the adrenal gland. If the problem is chronic, symptoms consist of fatigue, weight loss, failure to thrive (in children), delayed puberty (in adolescents), hypoglycemia (low blood sugar levels), anemia and hyponatremia (low sodium levels). If the onset is abrupt, collapse, shock and vomiting may occur.[1][5] ACTH deficiency is highly similar to primary Addison's disease, which is cortisol deficiency as the result of direct damage to the adrenal glands; the latter form, however, often leads to hyperpigmentation of the skin, which does not occur in ACTH deficiency.[10]

Thyroid-stimulating hormone (TSH) deficiency leads to hypothyroidism (lack of production of thyroxine (T4) and triiodothyronine (T3) in the thyroid). Typical symptoms are tiredness, intolerance to cold, constipation, weight gain, hair loss and slowed thinking, as well as a slowed heart rate and low blood pressure. In children, hypothyroidism leads to delayed growth and in extreme inborn forms to a syndrome called cretinism.[1][5]

Prolactin (PRL) plays a role in breastfeeding, and inability to breastfeed may point at abnormally low prolactin levels.[7]

Antidiuretic hormone (ADH) deficiency leads to the syndrome of diabetes insipidus (unrelated to diabetes mellitus): inability to concentrate the urine, leading to polyuria (production of large amounts of clear urine) that is low in solutes, dehydration andin compensationextreme thirst and constant need to drink (polydipsia), as well as hypernatremia (high sodium levels in the blood).[11] ADH deficiency may be masked if there is ACTH deficiency, with symptoms only appearing when cortisol has been replaced.[7]

Oxytocin (OXT) deficiency generally causes few symptoms, as it is only required at the time of childbirth and breastfeeding.[1]

Kallmann syndrome causes deficiency of the gonadotropins only. Bardet-Biedl syndrome and Prader-Willi syndrome have been associated with pituitary hormone deficiencies.

The pituitary gland is located at the base of the brain, and intimately connected with the hypothalamus. It consists of two lobes: the posterior pituitary, which consists of nervous tissue branching out of the hypothalamus, and the anterior pituitary, which consists of hormone-producing epithelium. The posterior pituitary secretes antidiuretic hormone, which regulates osmolarity of the blood, and oxytocin, which causes contractions of the uterus in childbirth and participates in breastfeeding.[12]

The pituitary develops in the third week of embryogenesis from interactions between the diencephalon part of the brain and the nasal cavity. The brain cells secrete FGF-8, Wnt5a and BMP-4, and the oral cavity BMP-2. Together, these cellular signals stimulate a group of cells from the oral cavity to form Rathke's pouch, which becomes independent of the nasal cavity and develops into the anterior pituitary; this process includes the suppression of production of a protein called Sonic hedgehog by the cells of Rathke's pouch.[14] The cells then differentiate further into the various hormone-producing cells of the pituitary. This requires particular transcription factors that induce the expression of particular genes. Some of these transcription factors have been found to be deficient in some forms of rare combined pituitary hormone deficiencies (CPHD) in childhood. These are HESX1, PROP1, POU1F1, LHX3, LHX4, TBX19, SOX2 and SOX3. Each transcription factor acts in particular groups of cells. Therefore, various genetic mutations are associated with specific hormone deficiencies.[14][15] For instance, POU1F1 (also known as Pit-1) mutations cause specific deficiencies in growth hormone, prolactin and TSH.[12][14][15] In addition to the pituitary, some of the transcription factors are also required for the development of other organs; some of these mutations are therefore also associated with specific birth defects.[14][15]

Most of the hormones in the anterior pituitary are each part of an axis that is regulated by the hypothalamus. The hypothalamus secretes a number of releasing hormones, often according to a circadian rhythm, into blood vessels that supply the anterior pituitary; most of these are stimulatory (thyrotropin-releasing hormone, corticotropin-releasing hormone, gonadotropin-releasing hormone and growth hormone-releasing hormone), apart from dopamine, which suppresses prolactin production.[16] In response to the releasing hormone rate, the anterior pituitary produces its hormones (TSH, ACTH, LH, FSH, GH) which in turn stimulate effector hormone glands in the body, while prolactin (PRL) acts directly on the breast gland. Once the effector glands produce sufficient hormones (thyroxine, cortisol, estradiol or testosterone and IGF-1), both the hypothalamus and the pituitary cells sense their abundance and reduce their secretion of stimulating hormones. The hormones of the posterior pituitary are produced in the hypothalamus and are carried by nerve endings to the posterior lobe; their feedback system is therefore located in the hypothalamus, but damage to the nerve endings would still lead to a deficiency in hormone release.[1]

Unless the pituitary damage is being caused by a tumor that overproduces a particular hormone, it is the lack of pituitary hormones that leads to the symptoms described above, and an excess of a particular hormone would indicate the presence of a tumor. The exception to this rule is prolactin: if a tumor compresses the pituitary stalk, a decreased blood supply means that the lactotrope cells, which produce prolactin, are not receiving dopamine and therefore produce excess prolactin. Hence, mild elevations in prolactin are attributed to stalk compression. Very high prolactin levels, though, point more strongly towards a prolactinoma (prolactin-secreting tumor).[5][17]

The diagnosis of hypopituitarism is made on blood tests. Two types of blood tests are used to confirm the presence of a hormone deficiency: basal levels, where blood samples are takenusually in the morningwithout any form of stimulation, and dynamic tests, where blood tests are taken after the injection of a stimulating substance. Measurement of ACTH and growth hormone usually requires dynamic testing, whereas the other hormones (LH/FSH, prolactin, TSH) can typically be tested with basal levels. There is no adequate direct test for ADH levels, but ADH deficiency can be confirmed indirectly; oxytocin levels are not routinely measured.[1]

Generally, the finding of a combination of a low pituitary hormone together with a low hormone from the effector gland is indicative of hypopituitarism.[12] Occasionally, the pituitary hormone may be normal but the effector gland hormone decreased; in this case, the pituitary is not responding appropriately to effector hormone changes, and the combination of findings is still suggestive of hypopituitarism.[5]

Levels of LH/FSH may be suppressed by a raised prolactin level, and are therefore not interpretable unless prolactin is low or normal. In men, the combination of low LH and FSH in combination with a low testosterone confirms LH/FSH deficiency; a high testosterone would indicate a source elsewhere in the body (such as a testosterone-secreting tumor). In women, the diagnosis of LH/FSH deficiency depends on whether the woman has been through the menopause. Before the menopause, abnormal menstrual periods together with low estradiol and LH/FSH levels confirm a pituitary problem; after the menopause (when LH/FSH levels are normally elevated and the ovaries produce less estradiol), inappropriately low LH/FSH alone is sufficient.[1] Stimulation tests with GnRH are possible, but their use is not encouraged.[5][7]

For TSH, basal measurements are usually sufficient, as well as measurements of thyroxine to ensure that the pituitary is not simply suppressing TSH production in response to hyperthyroidism (an overactive thyroid gland). A stimulation test with thyrotropin-releasing hormone (TRH) is not regarded as useful.[7] Prolactin can be measured by basal level, and is required for the interpretation of LH and FSH results in addition to the confirmation of hypopituitarism or diagnosis of a prolactin-secreting tumor.[1]

Growth hormone deficiency is almost certain if all other pituitary tests are also abnormal, and insulin-like growth factor 1 (IGF-1) levels are decreased. If this is not the case, IGF-1 levels are poorly predictive of the presence of GH deficiency; stimulation testing with the insulin tolerance test is then required. This is performed by administering insulin to lower the blood sugar to a level below 2.2mmol/l. Once this occurs, growth hormone levels are measured. If they are low despite the stimulatory effect of the low blood sugars, growth hormone deficiency is confirmed. The test is not without risks, especially in those prone to seizures or are known to have heart disease, and causes the unpleasant symptoms of hypoglycemia.[1][5] Alternative tests (such as the growth hormone releasing hormone stimulation test) are less useful, although a stimulation test with arginine may be used for diagnosis, especially in situations where an insulin tolerance test is thought to be too dangerous.[18] If GH deficiency is suspected, and all other pituitary hormones are normal, two different stimulation tests are needed for confirmation.[7]

If morning cortisol levels are over 500nmol/l, ACTH deficiency is unlikely, whereas a level less than 100 is indicative. Levels between 100-500 require a stimulation test.[5] This, too, is done with the insulin tolerance test. A cortisol level above 500 after achieving a low blood sugar rules out ACTH deficiency, while lower levels confirm the diagnosis. A similar stimulation test using corticotropin-releasing hormone (CRH) is not sensitive enough for the purposes of the investigation. If the insulin tolerance test yields an abnormal result, a further test measuring the response of the adrenal glands to synthetic ACTH (the ACTH stimulation test) can be performed to confirm the diagnosis.[19] Stimulation testing with metyrapone is an alternative.[19] Some suggest that an ACTH stimulation test is sufficient as first-line investigation, and that an insulin tolerance test is only needed if the ACTH test is equivocal.[5][7] The insulin tolerance test is discouraged in children.[5] None of the tests for ACTH deficiency are perfect, and further tests after a period of time may be needed if initial results are not conclusive.[1]

Symptoms of diabetes insipidus should prompt a formal fluid deprivation test to assess the body's response to dehydration, which normally causes concentration of the urine and increasing osmolarity of the blood. If these parameters are unchanged, desmopressin (an ADH analogue) is administered. If the urine then becomes concentrated and the blood osmolarity falls, there is a lack of ADH due to lack of pituitary function ("cranial diabetes insipidus"). In contrast, there is no change if the kidneys are unresponsive to ADH due to a different problem ("nephrogenic diabetes insipidus").[1]

If one of these tests shows a deficiency of hormones produced by the pituitary, magnetic resonance imaging (MRI) scan of the pituitary is the first step in identifying an underlying cause. MRI may show various tumors and may assist in delineating other causes. Tumors smaller than 1cm are referred to as microadenomas, and larger lesions are called macroadenomas.[1]Computed tomography with radiocontrast may be used if MRI is not available.[7] Formal visual field testing by perimetry is recommended, as this would show evidence of optic nerve compression by a tumor.[7]

Other tests that may assist in the diagnosis of hypopituitarism, especially if no tumor is found on the MRI scan, are ferritin (elevated in hemochromatosis), angiotensin converting enzyme (ACE) levels (often elevated in sarcoidosis), and human chorionic gonadotropin (often elevated in tumor of germ cell origin). If a genetic cause is suspected, genetic testing may be performed.[7]

Treatment of hypopituitarism is threefold: removing the underlying cause, treating the hormone deficiencies, and addressing any other repercussions that arise from the hormone deficiencies.[1]

Pituitary tumors require treatment when they are causing specific symptoms, such as headaches, visual field defects or excessive hormone secretion. Transsphenoidal surgery (removal of the tumor by an operation through the nose and the sphenoidal sinuses) may, apart from addressing symptoms related to the tumor, also improve pituitary function, although the gland is sometimes damaged further as a result of the surgery. When the tumor is removed by craniotomy (opening the skull), recovery is less likelybut sometimes this is the only suitable way to approach the tumor.[1][17] After surgery, it may take some time for hormone levels to change significantly. Retesting the pituitary hormone levels is therefore performed 2 to 3 months later.[5]

Prolactinomas may respond to dopamine agonist treatmentmedication that mimics the action of dopamine on the lactrotrope cells, usually bromocriptine or cabergoline. This approach may improve pituitary hormone secretion in more than half the cases, and make supplementary treatment unnecessary.[1][5][17][20]

Other specific underlying causes are treated as normally. For example, hemochromatosis is treated by venesection, the regular removal of a fixed amount of blood. Eventually, this decreases the iron levels in the body and improves the function of the organs in which iron has accumulated.[21]

Most pituitary hormones can be replaced indirectly by administering the products of the effector glands: hydrocortisone (cortisol) for adrenal insufficiency, levothyroxine for hypothyroidism, testosterone for male hypogonadism, and estradiol for female hypogonadism (usually with a progestogen to inhibit unwanted effects on the uterus). Growth hormone is available in synthetic form, but needs to be administered parenterally (by injection). Antidiuretic hormone can be replaced by desmopressin (DDAVP) tablets or nose spray. Generally, the lowest dose of the replacement medication is used to restore wellbeing and correct the deranged results, as excessive doses would cause side-effects or complications.[1][5][7] Those requiring hydrocortisone are usually instructed to increase their dose in physically stressful events such as injury, hospitalization and dental work as these are times when the normal supplementary dose may be inadequate, putting the patient at risk of adrenal crisis.[5][12]

Long-term follow up by specialists in endocrinology is generally needed for people with known hypopituitarism. Apart from ensuring the right treatment is being used and at the right doses, this also provides an opportunity to deal with new symptoms and to address complications of treatment.[5][7]

Difficult situations arise in deficiencies of the hypothalamus-pituitary-gonadal axis in people (both men and women) who experience infertility; infertility in hypopituitarism may be treated with subcutaneous infusions of FSH, human chorionic gonadotropinwhich mimics the action of LHand occasionally GnRH.[1][5][7]

Several hormone deficiencies associated with hypopituitarism may lead to secondary diseases. For instance, growth hormone deficiency is associated with obesity, raised cholesterol and the metabolic syndrome, and estradiol deficiency may lead to osteoporosis. While effective treatment of the underlying hormone deficiencies may improve these risks, it is often necessary to treat them directly.[5]

Several studies have shown that hypopituitarism is associated with an increased risk of cardiovascular disease and some also an increased risk of death of about 50% to 150% the normal population.[5][12] It has been difficult to establish which hormone deficiency is responsible for this risk, as almost all patients studied had growth hormone deficiency.[7] The studies also do not answer the question as to whether the hypopituitarism itself causes the increased mortality, or whether some of the risk is to be attributed to the treatments, some of which (such as sex hormone supplementation) have a recognized adverse effect on cardiovascular risk.[7]

The largest study to date followed over a thousand people for eight years; it showed an 87% increased risk of death compared to the normal population. Predictors of higher risk were: female sex, absence of treatment for sex hormone deficiency, younger age at the time of diagnosis, and a diagnosis of craniopharyngioma. Apart from cardiovascular disease, this study also showed an increased risk of death from lung disease.[7][22]

Quality of life may be significantly reduced, even in those people on optimum medical therapy. Many report both physical and psychological problems. It is likely that the commonly used replacement therapies still do not completely mimic the natural hormone levels in the body.[5] Health costs remain about double those of the normal population.[5]

Hypopituitarism is usually permanent. It requires lifelong treatment with one or more medicines.

There is only one study that has measured the prevalence (total number of cases in a population) and incidence (annual number of new cases) of hypopituitarism.[1] This study was conducted in Northern Spain and used hospital records in a well-defined population. The study showed that 45.5 people out of 100,000 had been diagnosed with hypopituitarism, with 4.2 new cases per year.[6] 61% were due to tumors of the pituitary gland, 9% due to other types of lesions, and 19% due to other causes; in 11% no cause could be identified.[1][6]

Recent studies have shown that people with a previous traumatic brain injury, spontaneous subarachnoid hemorrhage (a type of stroke) or radiation therapy involving the head have a higher risk of hypopituitarism.[23] After traumatic brain injury, as much as a quarter have persistent pituitary hormone deficiencies.[24] Many of these people may have subtle or non-specific symptoms that are not linked to pituitary problems but attributed to their previous condition. It is therefore possible that many cases of hypopituitarism remain undiagnosed, and that the annual incidence would rise to 31 per 100,000 annually if people from these risk groups were to be tested.[1]

The pituitary was known to the ancients, such as Galen, and various theories were proposed about its role in the body, but major clues as to the actual function of the gland were not advanced until the late 19th century, when acromegaly due to pituitary tumors was described.[25] The first known report of hypopituitarism was made by the German physician and pathologist Dr Morris Simmonds. He described the condition on autopsy in a 46-year-old woman who had suffered severe puerperal fever eleven years earlier, and subsequently suffered amenorrhea, weakness, signs of rapid aging and anemia. The pituitary gland was very small and there were few remnants of both the anterior and the posterior pituitary.[1][4] The eponym Simmonds' syndrome is used infrequently for acquired hypopituitarism, especially when cachexia (general ill health and malnutrition) predominates.[26][27] Most of the classic causes of hypopituitarism were described in the 20th century; the early 21st century saw the recognition of how common hypopituitarism could be in previous head injury victims.[1]

Until the 1950s, the diagnosis of pituitary disease remained based on clinical features and visual field examination, sometimes aided by pneumoencephalography and X-ray tomography. Nevertheless, the field of pituitary surgery developed during this time. The major breakthrough in diagnosis came with the discovery of the radioimmunoassay by Rosalyn Yalow and Solomon Berson in the late 1950s.[28] This allowed the direct measurement of the hormones of the pituitary, which as a result of their low concentrations in blood had previously been hard to measure.[25] Stimulation tests were developed in the 1960s, and in 1973 the triple bolus test was introduced, a test that combined stimulation testing with insulin, GnRH and TRH.[29] Imaging of the pituitary, and therefore identification of tumors and other structural causes, improved radically with the introduction of computed tomography in the late 1970s and magnetic resonance imaging in the 1980s.[25]

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acquired trait: A phenotypic characteristic, acquired during growth and development, that is not genetically based and therefore cannot be passed on to the next generation (for example, the large muscles of a weightlifter).

adaptation: Any heritable characteristic of an organism that improves its ability to survive and reproduce in its environment. Also used to describe the process of genetic change within a population, as influenced by natural selection.

adaptive landscape: A graph of the average fitness of a population in relation to the frequencies of genotypes in it. Peaks on the landscape correspond to genotypic frequencies at which the average fitness is high, valleys to genotypic frequencies at which the average fitness is low. Also called a fitness surface.

adaptive logic: A behavior has adaptive logic if it tends to increase the number of offspring that an individual contributes to the next and following generations. If such a behavior is even partly genetically determined, it will tend to become widespread in the population. Then, even if circumstances change such that it no longer provides any survival or reproductive advantage, the behavior will still tend to be exhibited -- unless it becomes positively disadvantageous in the new environment.

adaptive radiation: The diversification, over evolutionary time, of a species or group of species into several different species or subspecies that are typically adapted to different ecological niches (for example, Darwin's finches). The term can also be applied to larger groups of organisms, as in "the adaptive radiation of mammals."

adaptive strategies: A mode of coping with competition or environmental conditions on an evolutionary time scale. Species adapt when succeeding generations emphasize beneficial characteristics.

agnostic: A person who believes that the existence of a god or creator and the nature of the universe is unknowable.

algae: An umbrella term for various simple organisms that contain chlorophyll (and can therefore carry out photosynthesis) and live in aquatic habitats and in moist situations on land. The term has no direct taxonomic significance. Algae range from macroscopic seaweeds such as giant kelp, which frequently exceeds 30 m in length, to microscopic filamentous and single-celled forms such as Spirogyra and Chlorella.

allele: One of the alternative forms of a gene. For example, if a gene determines the seed color of peas, one allele of that gene may produce green seeds and another allele produce yellow seeds. In a diploid cell there are usually two alleles of any one gene (one from each parent). Within a population there may be many different alleles of a gene; each has a unique nucleotide sequence.

allometry: The relation between the size of an organism and the size of any of its parts. For example, an allometric relation exists between brain size and body size, such that (in this case) animals with bigger bodies tend to have bigger brains. Allometric relations can be studied during the growth of a single organism, between different organisms within a species, or between organisms in different species.

allopatric speciation: Speciation that occurs when two or more populations of a species are geographically isolated from one another sufficiently that they do not interbreed.

allopatry: Living in separate places. Compare with sympatry.

amino acid: The unit molecular building block of proteins, which are chains of amino acids in a certain sequence. There are 20 main amino acids in the proteins of living things, and the properties of a protein are determined by its particular amino acid sequence.

amino acid sequence: A series of amino acids, the building blocks of proteins, usually coded for by DNA. Exceptions are those coded for by the RNA of certain viruses, such as HIV.

ammonoid: Extinct relatives of cephalopods (squid, octopi, and chambered nautiluses), these mollusks had coiled shells and are found in the fossil record of the Cretaceous period.

amniotes: The group of reptiles, birds, and mammals. These all develop through an embryo that is enclosed within a membrane called an amnion. The amnion surrounds the embryo with a watery substance, and is probably an adaptation for breeding on land.

amphibians: The class of vertebrates that contains the frogs, toads, newts, and salamanders. The amphibians evolved in the Devonian period (about 370 million years ago) as the first vertebrates to occupy the land. They have moist scaleless skin which is used to supplement the lungs in gas exchange. The eggs are soft and vulnerable to drying, therefore reproduction commonly occurs in water. Amphibian larvae are aquatic, and have gills for respiration; they undergo metamorphosis to the adult form. Most amphibians are found in damp environments and they occur on all continents except Antarctica.

analogous structures: Structures in different species that look alike or perform similar functions (e.g., the wings of butterflies and the wings of birds) that have evolved convergently but do not develop from similar groups of embryological tissues, and that have not evolved from similar structures known to be shared by common ancestors. Contrast with homologous structures. Note: The recent discovery of deep genetic homologies has brought new interest, new information, and discussion to the classical concepts of analogous and homologous structures.

anatomy: (1) The structure of an organism or one of its parts. (2) The science that studies those structures.

ancestral homology: Homology that evolved before the common ancestor of a set of species, and which is present in other species outside that set of species. Compare with derived homology.

anthropoid: A member of the group of primates made up of monkeys, apes, and humans.

antibacterial: Having the ability to kill bacteria.

antibiotics: Substances that destroy or inhibit the growth of microorganisms, particularly disease-causing bacteria.

antibiotic resistance: A heritable trait in microorganisms that enables them to survive in the presence of an antibiotic.

aperture: Of a camera, the adjustable opening through which light passes to reach the film. The diameter of the aperture determines the intensity of light admitted. The pupil of a human eye is a self-adjusting aperture.

aquatic: Living underwater.

arboreal: Living in trees.

archeology: The study of human history and prehistory through the excavation of sites and the analysis of physical remains, such as graves, tools, pottery, and other artifacts.

archetype: The original form or body plan from which a group of organisms develops.

artifact: An object made by humans that has been preserved and can be studied to learn about a particular time period.

artificial selection: The process by which humans breed animals and cultivate crops to ensure that future generations have specific desirable characteristics. In artificial selection, breeders select the most desirable variants in a plant or animal population and selectively breed them with other desirable individuals. The forms of most domesticated and agricultural species have been produced by artificial selection; it is also an important experimental technique for studying evolution.

asexual reproduction: A type of reproduction involving only one parent that ususally produces genetically identical offspring. Asexual reproduction occurs without fertilization or genetic recombination, and may occur by budding, by division of a single cell, or by the breakup of a whole organism into two or more new individuals.

assortative mating: The tendency of like to mate with like. Mating can be assortative for a certain genotype (e.g., individuals with genotype AA tend to mate with other individuals of genotype AA) or phenotype (e.g., tall individuals mate with other tall individuals).

asteroid: A small rocky or metallic body orbitting the Sun. About 20,000 have been observed, ranging in size from several hundred kilometers across down to dust particles.

atheism: The doctrine or belief that there is no god.

atomistic: (as applied to theory of inheritance) Inheritance in which the entities controlling heredity are relatively distinct, permanent, and capable of independent action. Mendelian inheritance is an atomistic theory because in it, inheritance is controlled by distinct genes.

australopithecine: A group of bipedal hominid species belonging to the genus Australopithecus that lived between 4.2 and 1.4 mya.

Australopithecus afarensis: An early australopithecine species that was bipedal; known fossils date between 3.6 and 2.9 mya (for example, Lucy).

autosome: Any chromosome other than a sex chromosome.

avian: Of, relating to, or characteristic of birds (members of the class Aves).

bacteria: Tiny, single-celled, prokaryotic organisms that can survive in a wide variety of environments. Some cause serious infectious diseases in humans, other animals, and plants.

base: The DNA molecule is a chain of nucleotide units; each unit consists of a backbone made of a sugar and a phosphate group, with a nitrogenous base attached. The base in a unit is one of adenine (A), guanine (G), cytosine (C), or thymine (T). In RNA, uracil (U) is used instead of thymine. A and G belong to the chemical class called purines; C, T, and U are pyrimidines.

Batesian mimicry: A kind of mimicry in which one non-poisonous species (the Batesian mimic) mimics another poisonous species.

belemnite: An extinct marine invertebrate that was related to squid, octopi, and chambered nautiluses. We know from the fossil record that belemnites were common in the Jurassic period and had bullet-shaped internal skeletons.

big bang theory: The theory that states that the universe began in a state of compression to infinite density, and that in one instant all matter and energy began expanding and have continued expanding ever since.

biodiversity (or biological diversity): A measure of the variety of life, biodiversity is often described on three levels. Ecosystem diversity describes the variety of habitats present; species diversity is a measure of the number of species and the number of individuals of each species present; genetic diversity refers to the total amount of genetic variability present.

bioengineered food: Food that has been produced through genetic modification using techniques of genetic engineering.

biogenetic law: Name given by Haeckel to recapitulation.

biogeography: The study of patterns of geographical distribution of plants and animals across Earth, and the changes in those distributions over time.

biological species concept: The concept of species, according to which a species is a set of organisms that can interbreed among each other. Compare with cladistic species concept, ecological species concept, phenetic species concept, and recognition species concept.

biometrics: The quantitative study of characters of organisms.

biosphere: The part of Earth and its atmosphere capable of sustaining life.

bipedalism: Of hominids, walking upright on two hind legs; more generally, using two legs for locomotion.

bivalve: A mollusk that has a two-part hinged shell. Bivalves include clams, oysters, scallops, mussels, and other shellfish.

Blackmore, Susan: A psychologist interested in memes and the theory of memetics, evolutionary theory, consciousness, the effects of meditation, and why people believe in the paranormal. A recent book, The Meme Machine, offers an introduction to the subject of memes.

blending inheritance: The historically influential but factually erroneous theory that organisms contain a blend of their parents' hereditary factors and pass that blend on to their offspring. Compare with Mendelian inheritance.

botanist: A scientist who studies plants.

brachiopod: Commonly known as "lamp shells," these marine invertebrates resemble bivalve mollusks because of their hinged shells. Brachiopods were at their greatest abundance during the Paleozoic and Mesozoic eras.

Brodie, Edmund D., III: A biologist who studies the causes and evolutionary implications of interactions among traits in predators and their prey. Much of his work concentrates on the coevolutionary arms race between newts that posess tetrodotoxin, one of the most potent known toxins, and the resistant garter snakes who prey on them.

Brodie, Edmund D., Jr.: A biologist recognized internationally for his work on the evolution of mechanisms in amphibians that allow them to avoid predators. These mechanisms include toxins carried in skin secretions, coloration, and behavior.

Bruner, Jerome: A psychologist and professor at Harvard and Oxford Universities, and a prolific author whose book, The Process of Education, encouraged curriculum innovation based on theories of cognitive development.

bryozoan: A tiny marine invertebrate that forms a crust-like colony; colonies of bryozoans may look like scaly sheets on seaweed.

Burney, David: A biologist whose research has focused on endangered species, paleoenvironmental studies, and causes of extinction in North America, Africa, Madagascar, Hawaii, and the West Indies.

carbon isotope ratio: A measure of the proportion of the carbon-14 isotope to the carbon-12 isotope. Living material contains carbon-14 and carbon-12 in the same proportions as exists in the atmosphere. When an organism dies, however, it no longer takes up carbon from the atmosphere, and the carbon-14 it contains decays to nitrogen-14 at a constant rate. By measuring the carbon-14-to-carbon-12 ratio in a fossil or organic artifact, its age can be determined, a method called radiocarbon dating. Because most carbon-14 will have decayed after 50,000 years, the carbon isotope ratio is mainly useful for dating fossils and artifacts younger than this. It cannot be used to determine the age of Earth, for example.

carnivorous: Feeding largely or exclusively on meat or other animal tissue.

Carroll, Sean: Developmental geneticist with the Howard Hughes Medical Institute and professor at the University of Wisconsin-Madison. From the large-scale changes that distinguish major animal groups to the finely detailed color patterns on butterfly wings, Dr. Carroll's research has centered on those genes that create the "molecular blueprint" for body pattern and play major roles in the origin of new features. Coauthor, with Jennifer Grenier and Scott Weatherbee, of From DNA to Diversity: Molecular Genetics and the Evolution of Animal Design.

Carson, Rachel: A scientist and writer fascinated with the workings of nature. Her best-known publication, Silent Spring, was written over the years 1958 to 1962. The book looks at the effects of insecticides and pesticides on songbird populations throughout the United States. The publication helped set off a wave of environmental legislation and galvanized the emerging ecological movement.

Castle, W.E.: An early experimental geneticist, his 1901 paper was the first on Mendelism in America. His Genetics of Domestic Rabbits, published in 1930 by Harvard University Press, covers such topics as the genes involved in determining the coat colors of rabbits and associated mutations.

cell: The basic structural and functional unit of most living organisms. Cell size varies, but most cells are microscopic. Cells may exist as independent units of life, as in bacteria and protozoans, or they may form colonies or tissues, as in all plants and animals. Each cell consists of a mass of protein material that is differentiated into cytoplasm and nucleoplasm, which contains DNA. The cell is enclosed by a cell membrane, which in the cells of plants, fungi, algae, and bacteria is surrounded by a cell wall. There are two main types of cell, prokaryotic and eukaryotic.

Cenozoic: The era of geologic time from 65 mya to the present, a time when the modern continents formed and modern animals and plants evolved.

centromere: A point on a chromosome that is involved in separating the copies of the chromosome produced during cell division. During this division, paired chromosomes look somewhat like an X, and the centromere is the constriction in the center.

cephalopod: Cephalopods include squid, octopi, cuttlefish, and chambered nautiluses. They are mollusks with tentacles and move by forcing water through their bodies like a jet.

character: Any recognizable trait, feature, or property of an organism. In phylogenetic studies, a character is a feature that is thought to vary independantly of other features, and to be derived from a corresponding feature in a common ancestor of the organisms being studied. A "character state" is one of the possible alternative conditions of the character. For example, "present" and "absent" are two states of the character "hair" in mammals. Similarly, a particular position in a DNA sequence is a character, and A, T, C, and G are its possible states (see bases.)

character displacement: The increased difference between two closely related species where they live in the same geographic region (sympatry) as compared with where they live in different geographic regions (allopatry). Explained by the relative influences of intra- and inter-specific competition in sympatry and allopatry.

chloroplast: A structure (or organelle) found in some cells of plants; its function is photosynthesis.

cholera: An acute infectious disease of the small intestine, caused by the bacterium Vibrio cholerae which is transmitted in drinking water contaminated by feces of a patient. After an incubation period of 1-5 days, cholera causes severe vomiting and diarrhea, which, if untreated, leads to dehydration that can be fatal.

chordate: A member of the phylum Chordata, which includes the tunicates, lancelets, and vertebrates. They are animals with a hollow dorsal nerve cord; a rodlike notochord that forms the basis of the internal skeleton; and paired gill slits in the wall of the pharynx behind the head, although in some chordates these are apparent only in early embryonic stages. All vertebrates are chordates, but the phylum also contains simpler types, such as sea-squirts, in which only the free-swimming larva has a notochord.

chromosomal inversion: See inversion.

chromosome: A structure in the cell nucleus that carries DNA. At certain times in the cell cycle, chromosomes are visible as string-like entities. Chromosomes consist of the DNA with various proteins, particularly histones, bound to it.

chronology: The order of events according to time.

Clack, Jenny: A paleontologist at Cambridge University in the U.K., Dr. Clack studies the origin, phylogeny, and radiation of early tetrapods and their relatives among the lobe-finned fish. She is interested in the timing and sequence of skeletal and other changes which occurred during the transition, and the origin and relationships of the diverse tetrapods of the late Paleozoic.

clade: A set of species descended from a common ancestral species. Synonym of monophyletic group.

cladism: Phylogenetic classification. The members of a group in a cladistic classification share a more recent common ancestor with one another than with the members of any other group. A group at any level in the classificatory hierarchy, such as a family, is formed by combining a subgroup at the next lowest level (the genus, in this case) with the subgroup or subgroups with which it shares its most recent common ancestor. Compare with evolutionary classification and phenetic classification.

cladistic species concept: The concept of species, according to which a species is a lineage of populations between two phylogenetic branch points (or speciation events). Compare with biological species concept, ecological species concept, phenetic species concept, and recognition species concept.

cladists: Evolutionary biologists who seek to classify Earth's life forms according to their evolutionary relationships, not just overall similarity.

cladogram: A branching diagram that illustrates hypotheses about the evolutionary relationships among groups of organisms. Cladograms can be considered as a special type of phylogenetic tree that concentrates on the order in which different groups branched off from their common ancestors. A cladogram branches like a family tree, with the most closely related species on adjacent branches.

class: A category of taxonomic classification between order and phylum, a class comprises members of similar orders. See taxon.

classification: The arrangement of organisms into hierarchical groups. Modern biological classifications are Linnaean and classify organisms into species, genus, family, order, class, phylum, kingdom, and certain intermediate categoric levels. Cladism, evolutionary classification, and phenetic classification are three methods of classification.

cline: A geographic gradient in the frequency of a gene, or in the average value of a character.

clock: See molecular clock.

clone: A set of genetically identical organisms asexually reproduced from one ancestral organism.

coadaptation: Beneficial interaction between (1) a number of genes at different loci within an organism, (2) different parts of an organism, or (3) organisms belonging to different species.

codon: A triplet of bases (or nucleotides) in the DNA coding for one amino acid. The relation between codons and amino acids is given by the genetic code. The triplet of bases that is complementary to a condon is called an anticodon; conventionally, the triplet in the mRNA is called the codon and the triplet in the tRNA is called the anticodon.

coelacanth: Although long thought to have gone extinct about 65 million years ago, one of these deep-water, lungless fish was caught in the 1930s. Others have since been caught and filmed in their natural habitat.

coevolution: Evolution in two or more species, such as predator and its prey or a parasite and its host, in which evolutionary changes in one species influence the evolution of the other species.

cognitive: Relating to cognition, the mental processes involved in the gathering, organization, and use of knowledge, including such aspects as awareness, perception, reasoning, and judgement. The term refers to any mental "behaviors" where the underlying characteristics are abstract in nature and involve insight, expectancy, complex rule use, imagery, use of symbols, belief, intentionality, problem-solving, and so forth.

common ancestor: The most recent ancestral form or species from which two different species evolved.

comparative biology: The study of patterns among more than one species.

comparative method: The study of adaptation by comparing many species.

concerted evolution: The tendency of the different genes in a gene family to evolve in concert; that is, each gene locus in the family comes to have the same genetic variant.

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UT Southwestern has achieved Magnet designation, the highest honor bestowed by the American Nurses Credentialing Center (ANCC).

We've brought the leading-edge therapies and world-class care of UT Southwestern to Richardson/Plano, Las Colinas, and the Park Cities.

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Article

The membrane scaffold SLP2 anchors a proteolytic hub in mitochondria containing PARL and the iAAA protease YME1L

These authors contributed equally to this work

The membrane scaffold SLP2 anchors a large protease complex containing the rhomboid protease PARL and the iAAA protease YME1L in the inner membrane of mitochondria, termed the SPY complex. Assembly into the SPY complex modulates PARL activity toward its substrate proteins PINK1 and PGAM5.

The membrane scaffold SLP2 anchors a large protease complex containing the rhomboid protease PARL and the iAAA protease YME1L in the inner membrane of mitochondria, termed the SPY complex. Assembly into the SPY complex modulates PARL activity toward its substrate proteins PINK1 and PGAM5.

SLP2 assembles with PARL and YME1L into the SPY complex in the mitochondrial inner membrane.

Assembly into SPY complexes modulates PARLmediated processing of PINK1 and PGAM5.

SLP2 restricts OMA1mediated processing of the OPA1.

Timothy Wai, Shotaro Saita, Hendrik Nolte, Sebastian Mller, Tim Knig, Ricarda RichterDennerlein, HansGeorg Sprenger, Joaquin Madrenas, Mareike Mhlmeister, Ulrich Brandt, Marcus Krger, Thomas Langer

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Persons using assistive technology might not be able to fully access information in this file. For assistance, please send e-mail to: mmwrq@cdc.gov. Type 508 Accommodation and the title of the report in the subject line of e-mail.

Please note: An erratum has been published for this article. To view the erratum, please click here.

Clare A. Dykewicz, M.D., M.P.H. Harold W. Jaffe, M.D., Director Division of AIDS, STD, and TB Laboratory Research National Center for Infectious Diseases

Jonathan E. Kaplan, M.D. Division of AIDS, STD, and TB Laboratory Research National Center for Infectious Diseases Division of HIV/AIDS Prevention --- Surveillance and Epidemiology National Center for HIV, STD, and TB Prevention

Clare A. Dykewicz, M.D., M.P.H., Chair Harold W. Jaffe, M.D. Thomas J. Spira, M.D. Division of AIDS, STD, and TB Laboratory Research

William R. Jarvis, M.D. Hospital Infections Program National Center for Infectious Diseases, CDC

Jonathan E. Kaplan, M.D. Division of AIDS, STD, and TB Laboratory Research National Center for Infectious Diseases Division of HIV/AIDS Prevention --- Surveillance and Epidemiology National Center for HIV, STD, and TB Prevention, CDC

Brian R. Edlin, M.D. Division of HIV/AIDS Prevention---Surveillance and Epidemiology National Center for HIV, STD, and TB Prevention, CDC

Robert T. Chen, M.D., M.A. Beth Hibbs, R.N., M.P.H. Epidemiology and Surveillance Division National Immunization Program, CDC

Raleigh A. Bowden, M.D. Keith Sullivan, M.D. Fred Hutchinson Cancer Research Center Seattle, Washington

David Emanuel, M.B.Ch.B. Indiana University Indianapolis, Indiana

David L. Longworth, M.D. Cleveland Clinic Foundation Cleveland, Ohio

Philip A. Rowlings, M.B.B.S., M.S. International Bone Marrow Transplant Registry/Autologous Blood and Marrow Transplant Registry Milwaukee, Wisconsin

Robert H. Rubin, M.D. Massachusetts General Hospital Boston, Massachusetts and Massachusetts Institute of Technology Cambridge, Massachusetts

Kent A. Sepkowitz, M.D. Memorial-Sloan Kettering Cancer Center New York, New York

John R. Wingard, M.D. University of Florida Gainesville, Florida

John F. Modlin, M.D. Dartmouth Medical School Hanover, New Hampshire

Donna M. Ambrosino, M.D. Dana-Farber Cancer Institute Boston, Massachusetts

Norman W. Baylor, Ph.D. Food and Drug Administration Rockville, Maryland

Albert D. Donnenberg, Ph.D. University of Pittsburgh Pittsburgh, Pennsylvania

Pierce Gardner, M.D. State University of New York at Stony Brook Stony Brook, New York

Roger H. Giller, M.D. University of Colorado Denver, Colorado

Neal A. Halsey, M.D. Johns Hopkins University Baltimore, Maryland

Chinh T. Le, M.D. Kaiser-Permanente Medical Center Santa Rosa, California

Deborah C. Molrine, M.D. Dana-Farber Cancer Institute Boston, Massachusetts

Keith M. Sullivan, M.D. Fred Hutchinson Cancer Research Center Seattle, Washington

CDC, the Infectious Disease Society of America, and the American Society of Blood and Marrow Transplantation have cosponsored these guidelines for preventing opportunistic infections (OIs) among hematopoietic stem cell transplant (HSCT) recipients. The guidelines were drafted with the assistance of a working group of experts in infectious diseases, transplantation, and public health. For the purposes of this report, HSCT is defined as any transplantation of blood- or marrow-derived hematopoietic stem cells, regardless of transplant type (i.e., allogeneic or autologous) or cell source (i.e., bone marrow, peripheral blood, or placental or umbilical cord blood). Such OIs as bacterial, viral, fungal, protozoal, and helminth infections occur with increased frequency or severity among HSCT recipients. These evidence-based guidelines contain information regarding preventing OIs, hospital infection control, strategies for safe living after transplantation, vaccinations, and hematopoietic stem cell safety. The disease-specific sections address preventing exposure and disease for pediatric and adult and autologous and allogeneic HSCT recipients. The goal of these guidelines is twofold: to summarize current data and provide evidence-based recommendations regarding preventing OIs among HSCT patients. The guidelines were developed for use by HSCT recipients, their household and close contacts, transplant and infectious diseases physicians, HSCT center personnel, and public health professionals. For all recommendations, prevention strategies are rated by the strength of the recommendation and the quality of the evidence supporting the recommendation. Adhering to these guidelines should reduce the number and severity of OIs among HSCT recipients.

In 1992, the Institute of Medicine (1) recommended that CDC lead a global effort to detect and control emerging infectious agents. In response, CDC published a plan (2) that outlined national disease prevention priorities, including the development of guidelines for preventing opportunistic infections (OIs) among immunosuppressed persons. During 1995, CDC published guidelines for preventing OIs among persons infected with human immunodeficiency virus (HIV) and revised those guidelines during 1997 and 1999 (3--5). Because of the success of those guidelines, CDC sought to determine the need for expanding OI prevention activities to other immunosuppressed populations. An informal survey of hematology, oncology, and infectious disease specialists at transplant centers and a working group formed by CDC determined that guidelines were needed to help prevent OIs among hematopoietic stem cell transplant (HSCT)* recipients.

The working group defined OIs as infections that occur with increased frequency or severity among HSCT recipients, and they drafted evidence-based recommendations for preventing exposure to and disease caused by bacterial, fungal, viral, protozoal, or helminthic pathogens. During March 1997, the working group presented the first draft of these guidelines at a meeting of representatives from public and private health organizations. After review by that group and other experts, these guidelines were revised and made available during September 1999 for a 45-day public comment period after notification in the Federal Register. Public comments were added when feasible, and the report was approved by CDC, the Infectious Disease Society of America, and the American Society of Blood and Marrow Transplantation. The pediatric content of these guidelines has been endorsed also by the American Academy of Pediatrics. The hematopoietic stem cell safety section was endorsed by the International Society of Hematotherapy and Graft Engineering.

The first recommendations presented in this report are followed by recommendations for hospital infection control, strategies for safe living, vaccinations, and hematopoietic stem cell safety. Unless otherwise noted, these recommendations address allogeneic and autologous and pediatric and adult HSCT recipients. Additionally, these recommendations are intended for use by the recipients, their household and other close contacts, transplant and infectious diseases specialists, HSCT center personnel, and public health professionals.

For all recommendations, prevention strategies are rated by the strength of the recommendation (Table 1) and the quality of the evidence (Table 2) supporting the recommendation. The principles of this rating system were developed by the Infectious Disease Society of America and the U.S. Public Health Service for use in the guidelines for preventing OIs among HIV-infected persons (3--6). This rating system allows assessments of recommendations to which adherence is critical.

HSCT is the infusion of hematopoietic stem cells from a donor into a patient who has received chemotherapy, which is usually marrow-ablative. Increasingly, HSCT has been used to treat neoplastic diseases, hematologic disorders, immunodeficiency syndromes, congenital enzyme deficiencies, and autoimmune disorders (e.g., systemic lupus erythematosus or multiple sclerosis) (7--10). Moreover, HSCT has become standard treatment for selected conditions (7,11,12). Data from the International Bone Marrow Transplant Registry and the Autologous Blood and Marrow Transplant Registry indicate that approximately 20,000 HSCTs were performed in North America during 1998 (Statistical Center of the International Bone Marrow Transplant Registry and Autologous Blood and Marrow Transplant Registry, unpublished data, 1998).

HSCTs are classified as either allogeneic or autologous on the basis of the source of the transplanted hematopoietic progenitor cells. Cells used in allogeneic HSCTs are harvested from a donor other than the transplant recipient. Such transplants are the most effective treatment for persons with severe aplastic anemia (13) and offer the only curative therapy for persons with chronic myelogenous leukemia (12). Allogeneic donors might be a blood relative or an unrelated donor. Allogeneic transplants are usually most successful when the donor is a human lymphocyte antigen (HLA)-identical twin or matched sibling. However, for allogeneic candidates who lack such a donor, registry organizations (e.g., the National Marrow Donor Program) maintain computerized databases that store information regarding HLA type from millions of volunteer donors (14--16). Another source of stem cells for allogeneic candidates without an HLA-matched sibling is a mismatched family member (17,18). However, persons who receive allogeneic grafts from donors who are not HLA-matched siblings are at a substantially greater risk for graft-versus-host disease (GVHD) (19). These persons are also at increased risk for suboptimal graft function and delayed immune system recovery (19). To reduce GVHD among allogeneic HSCTs, techniques have been developed to remove T-lymphocytes, the principal effectors of GVHD, from the donor graft. Although the recipients of T-lymphocyte--depleted marrow grafts generally have lower rates of GVHD, they also have greater rates of graft rejection, cytomegalovirus (CMV) infection, invasive fungal infection, and Epstein-Barr virus (EBV)-associated posttransplant lymphoproliferative disease (20).

The patient's own cells are used in an autologous HSCT. Similar to autologous transplants are syngeneic transplants, among whom the HLA-identical twin serves as the donor. Autologous HSCTs are preferred for patients who require high-level or marrow-ablative chemotherapy to eradicate an underlying malignancy but have healthy, undiseased bone marrows. Autologous HSCTs are also preferred when the immunologic antitumor effect of an allograft is not beneficial. Autologous HSCTs are used most frequently to treat breast cancer, non-Hodgkin's lymphoma, and Hodgkin's disease (21). Neither autologous nor syngeneic HSCTs confer a risk for chronic GVHD.

Recently, medical centers have begun to harvest hematopoietic stem cells from placental or umbilical cord blood (UCB) immediately after birth. These harvested cells are used primarily for allogeneic transplants among children. Early results demonstrate that greater degrees of histoincompatibility between donor and recipient might be tolerated without graft rejection or GVHD when UCB hematopoietic cells are used (22--24). However, immune system function after UCB transplants has not been well-studied.

HSCT is also evolving rapidly in other areas. For example, hematopoietic stem cells harvested from the patient's peripheral blood after treatment with hematopoietic colony-stimulating factors (e.g., granulocyte colony-stimulating factor [G-CSF or filgastrim] or granulocyte-macrophage colony-stimulating factor [GM-CSF or sargramostim]) are being used increasingly among autologous recipients (25) and are under investigation for use among allogeneic HSCT. Peripheral blood has largely replaced bone marrow as a source of stem cells for autologous recipients. A benefit of harvesting such cells from the donor's peripheral blood instead of bone marrow is that it eliminates the need for general anesthesia associated with bone marrow aspiration.

GVHD is a condition in which the donated cells recognize the recipient's cells as nonself and attack them. Although the use of intravenous immunoglobulin (IVIG) in the routine management of allogeneic patients was common in the past as a means of producing immune modulation among patients with GVHD, this practice has declined because of cost factors (26) and because of the development of other strategies for GVHD prophylaxis (27). For example, use of cyclosporine GVHD prophylaxis has become commonplace since its introduction during the early 1980s. Most frequently, cyclosporine or tacrolimus (FK506) is administered in combination with other immunosuppressive agents (e.g., methotrexate or corticosteroids) (27). Although cyclosporine is effective in preventing GVHD, its use entails greater hazards for infectious complications and relapse of the underlying neoplastic disease for which the transplant was performed.

Although survival rates for certain autologous recipients have improved (28,29), infection remains a leading cause of death among allogeneic transplants and is a major cause of morbidity among autologous HSCTs (29). Researchers from the National Marrow Donor Program reported that, of 462 persons receiving unrelated allogeneic HSCTs during December 1987--November 1990, a total of 66% had died by 1991 (15). Among primary and secondary causes of death, the most common cause was infection, which occurred among 37% of 307 patients (15).**

Despite high morbidity and mortality after HSCT, recipients who survive long-term are likely to enjoy good health. A survey of 798 persons who had received an HSCT before 1985 and who had survived for >5 years after HSCT, determined that 93% were in good health and that 89% had returned to work or school full time (30). In another survey of 125 adults who had survived a mean of 10 years after HSCT, 88% responded that the benefits of transplantation outweighed the side effects (31).

During the first year after an HSCT, recipients typically follow a predictable pattern of immune system deficiency and recovery, which begins with the chemotherapy or radiation therapy (i.e., the conditioning regimen) administered just before the HSCT to treat the underlying disease. Unfortunately, this conditioning regimen also destroys normal hematopoiesis for neutrophils, monocytes, and macrophages and damages mucosal progenitor cells, causing a temporary loss of mucosal barrier integrity. The gastrointestinal tract, which normally contains bacteria, commensal fungi, and other bacteria-carrying sources (e.g., skin or mucosa) becomes a reservoir of potential pathogens. Virtually all HSCT recipients rapidly lose all T- and B-lymphocytes after conditioning, losing immune memory accumulated through a lifetime of exposure to infectious agents, environmental antigens, and vaccines. Because transfer of donor immunity to HSCT recipients is variable and influenced by the timing of antigen exposure among donor and recipient, passively acquired donor immunity cannot be relied upon to provide long-term immunity against infectious diseases among HSCT recipients.

During the first month after HSCT, the major host-defense deficits include impaired phagocytosis and damaged mucocutaneous barriers. Additionally, indwelling intravenous catheters are frequently placed and left in situ for weeks to administer parenteral medications, blood products, and nutritional supplements. These catheters serve as another portal of entry for opportunistic pathogens from organisms colonizing the skin (e.g., . coagulase-negative Staphylococci, Staphylococcus aureus, Candida species, and Enterococci) (32,33).

Engraftment for adults and children is defined as the point at which a patient can maintain a sustained absolute neutrophil count (ANC) of >500/mm3 and sustained platelet count of >20,000, lasting >3 consecutive days without transfusions. Among unrelated allogeneic recipients, engraftment occurs at a median of 22 days after HSCT (range: 6--84 days) (15). In the absence of corticosteroid use, engraftment is associated with the restoration of effective phagocytic function, which results in a decreased risk for bacterial and fungal infections. However, all HSCT recipients and particularly allogeneic recipients, experience an immune system dysfunction for months after engraftment. For example, although allogeneic recipients might have normal total lymphocyte counts within >2 months after HSCT, they have abnormal CD4/CD8 T-cell ratios, reflecting their decreased CD4 and increased CD8 T-cell counts (27). They might also have immunoglobulin G (IgG)2, IgG4, and immunoglobulin A (IgA) deficiencies for months after HSCT and have difficulty switching from immunoglobulin M (IgM) to IgG production after antigen exposure (32). Immune system recovery might be delayed further by CMV infection (34).

During the first >2 months after HSCT, recipients might experience acute GVHD that manifests as skin, gastrointestinal, and liver injury, and is graded on a scale of I--IV (32,35,36). Although autologous or syngeneic recipients might occasionally experience a mild, self-limited illness that is acute GVHD-like (19,37), GVHD occurs primarily among allogeneic recipients, particularly those receiving matched, unrelated donor transplants. GVHD is a substantial risk factor for infection among HSCT recipients because it is associated with a delayed immunologic recovery and prolonged immunodeficiency (19). Additionally, the immunosuppressive agents used for GVHD prophylaxis and treatment might make the HSCT recipient more vulnerable to opportunistic viral and fungal pathogens (38).

Certain patients, particularly adult allogeneic recipients, might also experience chronic GVHD, which is graded as either limited or extensive chronic GVHD (19,39). Chronic GVHD appears similar to autoimmune, connective-tissue disorders (e.g., scleroderma or systemic lupus erythematosus) (40) and is associated with cellular and humoral immunodeficiencies, including macrophage deficiency, impaired neutrophil chemotaxis (41), poor response to vaccination (42--44), and severe mucositis (19). Risk factors for chronic GVHD include increasing age, allogeneic HSCT (particularly those among whom the donor is unrelated or a non-HLA identical family member) (40), and a history of acute GVHD (24,45). Chronic GVHD was first described as occurring >100 days after HSCT but can occur 40 days after HSCT (19). Although allogeneic recipients with chronic GVHD have normal or high total serum immunoglobulin levels (41), they experience long-lasting IgA, IgG, and IgG subclass deficiencies (41,46,47) and poor opsonization and impaired reticuloendothelial function. Consequently, they are at even greater risk for infections (32,39), particularly life-threatening bacterial infections from encapsulated organisms (e.g., Stre. pneumoniae, Ha. influenzae, or Ne. meningitidis). After chronic GVHD resolves, which might take years, cell-mediated and humoral immunity function are gradually restored.

HSCT recipients experience certain infections at different times posttransplant, reflecting the predominant host-defense defect(s) (Figure). Immune system recovery for HSCT recipients takes place in three phases beginning at day 0, the day of transplant. Phase I is the preengraftment phase (<30 days after HSCT); phase II, the postengraftment phase (30--100 days after HSCT); and phase III, the late phase (>100 days after HSCT). Prevention strategies should be based on these three phases and the following information:

Preventing infections among HSCT recipients is preferable to treating infections. How ever, despite recent technologic advances, more research is needed to optimize health outcomes for HSCT recipients. Efforts to improve immune system reconstitution, particularly among allogeneic transplant recipients, and to prevent or resolve the immune dysregulation resulting from donor-recipient histoincompatibility and GVHD remain substantial challenges for preventing recurrent, persistent, or progressive infections among HSCT patients.

Preventing Exposure

Because bacteria are carried on the hands, health-care workers (HCWs) and others in contact with HSCT recipients should routinely follow appropriate hand-washing practices to avoid exposing recipients to bacterial pathogens (AIII).

Preventing Disease

Preventing Early Disease (0--100 Days After HSCT). Routine gut decontamination is not recommended for HSCT candidates (51--53) (DIII). Because of limited data, no recommendations can be made regarding the routine use of antibiotics for bacterial prophylaxis among afebrile, asymptomatic neutropenic recipients. Although studies have reported that using prophylactic antibiotics might reduce bacteremia rates after HSCT (51), infection-related fatality rates are not reduced (52). If physicians choose to use prophylactic antibiotics among asymptomatic, afebrile, neutropenic recipients, they should routinely review hospital and HSCT center antibiotic-susceptibility profiles, particularly when using a single antibiotic for antibacterial prophylaxis (BIII). The emergence of fluoquinolone-resistant coagulase-negative Staphylococci and Es. coli (51,52), vancomycin-intermediate Sta. aureus and vancomycin-resistant Enterococcus (VRE) are increasing concerns (54). Vancomycin should not be used as an agent for routine bacterial prophylaxis (DIII). Growth factors (e.g., GM-CSF and G-CSF) shorten the duration of neutropenia after HSCT (55); however, no data were found that indicate whether growth factors effectively reduce the attack rate of invasive bacterial disease.

Physicians should not routinely administer IVIG products to HSCT recipients for bacterial infection prophylaxis (DII), although IVIG has been recommended for use in producing immune system modulation for GVHD prevention. Researchers have recommended routine IVIG*** use to prevent bacterial infections among the approximately 20%--25% of HSCT recipients with unrelated marrow grafts who experience severe hypogamma-globulinemia (e.g., IgG < 400 mg/dl) within the first 100 days after transplant (CIII). For example, recipients who are hypogammaglobulinemic might receive prophylactic IVIG to prevent bacterial sinopulmonary infections (e.g., from Stre. pneumoniae) (8) (CIII). For hypogammaglobulinemic allogeneic recipients, physicians can use a higher and more frequent dose of IVIG than is standard for non-HSCT recipients because the IVIG half-life among HSCT recipients (generally 1--10 days) is much shorter than the half-life among healthy adults (generally 18--23 days) (56--58). Additionally, infections might accelerate IgG catabolism; therefore, the IVIG dose for a hypogammaglobulinemic recipient should be individualized to maintain trough serum IgG concentrations >400--500 mg/dl (58) (BII). Consequently, physicians should monitor trough serum IgG concentrations among these patients approximately every 2 weeks and adjust IVIG doses as needed (BIII) (Appendix).

Preventing Late Disease (>100 Days After HSCT). Antibiotic prophylaxis is recommended for preventing infection with encapsulated organisms (e.g., Stre. pneumoniae, Ha. influenzae, or Ne. meningitidis) among allogeneic recipients with chronic GVHD for as long as active chronic GVHD treatment is administered (59) (BIII). Antibiotic selection should be guided by local antibiotic resistance patterns. In the absence of severe demonstrable hypogammaglobulinemia (e.g., IgG levels < 400 mg/dl, which might be associated with recurrent sinopulmonary infections), routine monthly IVIG administration to HSCT recipients >90 days after HSCT is not recommended (60) (DI) as a means of preventing bacterial infections.

Other Disease Prevention Recommendations. Routine use of IVIG among autologous recipients is not recommended (61) (DII). Recommendations for preventing bacterial infections are the same among pediatric or adult HSCT recipients.

Preventing Exposure

Appropriate care precautions should be taken with hospitalized patients infected with Stre. pneumoniae (62,63) (BIII) to prevent exposure among HSCT recipients.

Preventing Disease

Information regarding the currently available 23-valent pneumococcal polysaccharide vaccine indicates limited immunogenicity among HSCT recipients. However, because of its potential benefit to certain patients, it should be administered to HSCT recipients at 12 and 24 months after HSCT (64--66) (BIII). No data were found regarding safety and immunogenicity of the 7-valent conjugate pneumococcal vaccine among HSCT recipients; therefore, no recommendation regarding use of this vaccine can be made.

Antibiotic prophylaxis is recommended for preventing infection with encapsulated organisms (e.g., Stre. pneumoniae, Ha. influenzae, and Ne. meningitidis) among allogeneic recipients with chronic GVHD for as long as active chronic GVHD treatment is administered (59) (BIII). Trimethoprim-sulfamethasaxole (TMP-SMZ) administered for Pneumocystis carinii pneumonia (PCP) prophylaxis will also provide protection against pneumococcal infections. However, no data were found to support using TMP-SMZ prophylaxis among HSCT recipients solely for the purpose of preventing Stre. pneumoniae disease. Certain strains of Stre. pneumoniae are resistant to TMP-SMZ and penicillin. Recommendations for preventing pneumococcal infections are the same for allogeneic or autologous recipients.

As with adults, pediatric HSCT recipients aged >2 years should be administered the current 23-valent pneumococcal polysaccharide vaccine because the vaccine can be effective (BIII). However, this vaccine should not be administered to children aged <2 years because it is not effective among that age population (DI). No data were found regarding safety and immunogenicity of the 7-valent conjugate pneumococcal vaccine among pediatric HSCT recipients; therefore, no recommendation regarding use of this vaccine can be made.

Preventing Exposure

Because Streptococci viridans colonize the oropharynx and gut, no effective method of preventing exposure is known.

Preventing Disease

Chemotherapy-induced oral mucositis is a potential source of Streptococci viridans bacteremia. Consequently, before conditioning starts, dental consults should be obtained for all HSCT candidates to assess their state of oral health and to perform any needed dental procedures to decrease the risk for oral infections after transplant (67) (AIII).

Generally, HSCT physicians should not use prophylactic antibiotics to prevent Streptococci viridans infections (DIII). No data were found that demonstrate efficacy of prophylactic antibiotics for this infection. Furthermore, such use might select antibiotic-resistant bacteria, and in fact, penicillin- and vancomycin-resistant strains of Streptococci viridans have been reported (68). However, when Streptococci viridans infections among HSCT recipients are virulent and associated with overwhelming sepsis and shock in an institution, prophylaxis might be evaluated (CIII). Decisions regarding the use of Streptococci viridans prophylaxis should be made only after consultation with the hospital epidemiologists or infection-control practitioners who monitor rates of nosocomial bacteremia and bacterial susceptibility (BIII).

HSCT physicians should be familiar with current antibiotic susceptibilities for patient isolates from their HSCT centers, including Streptococci viridans (BIII). Physicians should maintain a high index of suspicion for this infection among HSCT recipients with symptomatic mucositis because early diagnosis and aggressive therapy are currently the only potential means of preventing shock when severely neutropenic HSCT recipients experience Streptococci viridans bacteremia (69).

Preventing Exposure

Adults with Ha. influenzae type b (Hib) pneumonia require standard precautions (62) to prevent exposing the HSCT recipient to Hib. Adults and children who are in contact with the HSCT recipient and who have known or suspected invasive Hib disease, including meningitis, bacteremia, or epiglottitis, should be placed in droplet precautions until 24 hours after they begin appropriate antibiotic therapy, after which they can be switched to standard precautions. Household contacts exposed to persons with Hib disease and who also have contact with HSCT recipients should be administered rifampin prophylaxis according to published recommendations (70,71); prophylaxis for household contacts of a patient with Hib disease are necessary if all contacts aged <4 years are not fully vaccinated (BIII) (Appendix). This recommendation is critical because the risk for invasive Hib disease among unvaccinated household contacts aged <4 years is increased, and rifampin can be effective in eliminating Hib carriage and preventing invasive Hib disease (72--74). Pediatric household contacts should be up-to-date with Hib vaccinations to prevent possible Hib exposure to the HSCT recipient (AII).

Preventing Disease

Although no data regarding vaccine efficacy among HSCT recipients were found, Hib conjugate vaccine should be administered to HSCT recipients at 12, 14, and 24 months after HSCT (BII). This vaccine is recommended because the majority of HSCT recipients have low levels of Hib capsular polysaccharide antibodies >4 months after HSCT (75), and allogeneic recipients with chronic GVHD are at increased risk for infection from encapsulated organisms (e.g., Hib) (76,77). HSCT recipients who are exposed to persons with Hib disease should be offered rifampin prophylaxis according to published recommendations (70) (BIII) (Appendix).

Antibiotic prophylaxis is recommended for preventing infection with encapsulated organisms (e.g., Stre. pneumoniae, Ha. influenzae, or Ne. meningitidis) among allogeneic recipients with chronic GVHD for as long as active chronic GVHD treatment is administered (59) (BIII). Antibiotic selection should be guided by local antibiotic-resistance patterns. Recommendations for preventing Hib infections are the same for allogeneic or autologous recipients. Recommendations for preventing Hib disease are the same for pediatric or adult HSCT recipients, except that any child infected with Hib pneumonia requires standard precautions with droplet precautions added for the first 24 hours after beginning appropriate antibiotic therapy (62,70) (BIII). Appropriate pediatric doses should be administered for Hib conjugate vaccine and for rifampin prophylaxis (71) (Appendix).

Preventing Exposure

HSCT candidates should be tested for the presence of serum anti-CMV IgG antibodies before transplantation to determine their risk for primary CMV infection and reactivation after HSCT (AIII). Only Food and Drug Administration (FDA) licensed or approved tests should be used. HSCT recipients and candidates should avoid sharing cups, glasses, and eating utensils with others, including family members, to decrease the risk for CMV exposure (BIII).

Sexually active patients who are not in long-term monogamous relationships should always use latex condoms during sexual contact to reduce their risk for exposure to CMV and other sexually transmitted pathogens (AII). However, even long-time monogamous pairs can be discordant for CMV infections. Therefore, during periods of immuno-compromise, sexually active HSCT recipients in monogamous relationships should ask partners to be tested for serum CMV IgG antibody, and discordant couples should use latex condoms during sexual contact to reduce the risk for exposure to this sexually transmitted OI (CIII).

After handling or changing diapers or after wiping oral and nasal secretions, HSCT candidates and recipients should practice regular hand washing to reduce the risk for CMV exposure (AII). CMV-seronegative recipients of allogeneic stem cell transplants from CMV-seronegative donors (i.e., R-negative or D-negative) should receive only leukocyte-reduced or CMV-seronegative red cells or leukocyte-reduced platelets (<1 x 106 leukocytes/unit) to prevent transfusion-associated CMV infection (78) (AI). However, insufficient data were found to recommend use of leukocyte-reduced or CMV-seronega tive red cells and platelets among CMV-seronegative recipients who have CMV-seropositive donors (i.e., R-negative or D-positive).

All HCWs should wear gloves when handling blood products or other potentially contaminated biologic materials (AII) to prevent transmission of CMV to HSCT recipients. HSCT patients who are known to excrete CMV should be placed under standard precautions (62) for the duration of CMV excretion to avoid possible transmission to CMV-seronegative HSCT recipients and candidates (AIII). Physicians are cautioned that CMV excretion can be episodic or prolonged.

Preventing Disease and Disease Recurrence

HSCT recipients at risk for CMV disease after HSCT (i.e., all CMV-seropositive HSCT recipients, and all CMV-seronegative recipients with a CMV-seropositive donor) should be placed on a CMV disease prevention program from the time of engraftment until 100 days after HSCT (i.e., phase II) (AI). Physicians should use either prophylaxis or preemptive treatment with ganciclovir for allogeneic recipients (AI). In selecting a CMV disease prevention strategy, physicians should assess the risks and benefits of each strategy, the needs and condition of the patient, and the hospital's virology laboratory support capability.

Prophylaxis strategy against early CMV (i.e., <100 days after HSCT) for allogeneic recipients involves administering ganciclovir prophylaxis to all allogeneic recipients at risk throughout phase II (i.e., from engraftment to 100 days after HSCT). The induction course is usually started at engraftment (AI), although physicians can add a brief prophylactic course during HSCT preconditioning (CIII) (Appendix).

Preemptive strategy against early CMV (i.e., <100 days after HSCT) for allogeneic recipients is preferred over prophylaxis for CMV-seronegative HSCT recipients of seropositive donor cells (i.e., D-positive or R-negative) because of the low attack rate of active CMV infection if screened or filtered blood product support is used (BII). Preemptive strategy restricts ganciclovir use for those patients who have evidence of CMV infection after HSCT. It requires the use of sensitive and specific laboratory tests to rapidly diagnose CMV infection after HSCT and to enable immediate administration of ganciclovir after CMV infection has been detected. Allogeneic recipients at risk should be screened >1 times/week from 10 days to 100 days after HSCT (i.e., phase II) for the presence of CMV viremia or antigenemia (AIII).

HSCT physicians should select one of two diagnostic tests to determine the need for preemptive treatment. Currently, the detection of CMV pp65 antigen in leukocytes (antigenemia) (79,80) is preferred for screening for preemptive treatment because it is more rapid and sensitive than culture and has good positive predictive value (79--81). Direct detection of CMV-DNA (deoxyribonucleic acid) by polymerase chain reaction (PCR) (82) is very sensitive but has a low positive predictive value (79). Although CMV-DNA PCR is less sensitive than whole blood or leukocyte PCR, plasma CMV-DNA PCR is useful during neutropenia, when the number of leukocytes/slide is too low to allow CMV pp65 antigenemia testing.

Virus culture of urine, saliva, blood, or bronchoalveolar washings by rapid shell-vial culture (83) or routine culture (84,85) can be used; however, viral culture techniques are less sensitive than CMV-DNA PCR or CMV pp65 antigenemia tests. Also, rapid shell-viral cultures require >48 hours and routine viral cultures can require weeks to obtain final results. Thus, viral culture techniques are less satisfactory than PCR or antigenemia tests. HSCT centers without access to PCR or antigenemia tests should use prophylaxis rather than preemptive therapy for CMV disease prevention (86) (BII). Physicians do use other diagnostic tests (e.g., hybrid capture CMV-DNA assay, Version 2.0 [87] or CMV pp67 viral RNA [ribonucleic acid] detection) (88); however, limited data were found regarding use among HSCT recipients, and therefore, no recommendation for use can be made.

Allogeneic recipients <100 days after HSCT (i.e., during phase II) should begin preemptive treatment with ganciclovir if CMV viremia or any antigenemia is detected or if the recipient has >2 consecutively positive CMV-DNA PCR tests (BIII). After preemptive treatment has been started, maintenance ganciclovir is usually continued until 100 days after HSCT or for a minimum of 3 weeks, whichever is longer (AI) (Appendix). Antigen or PCR tests should be negative when ganciclovir is stopped. Studies report that a shorter course of ganciclovir (e.g., for 3 weeks or until negative PCR or antigenemia occurs) (89--91) might provide adequate CMV prevention with less toxicity, but routine weekly screening by pp65 antigen or PCR test is necessary after stopping ganciclovir because CMV reactivation can occur (BIII).

Presently, only the intravenous formulation of ganciclovir has been approved for use in CMV prophylactic or preemptive strategies (BIII). No recommendation for oral ganciclovir use among HSCT recipients can be made because clinical trials evaluating its efficacy are still in progress. One group has used ganciclovir and foscarnet on alternate days for CMV prevention (92), but no recommendation can be made regarding this strategy because of limited data. Patients who are ganciclovir-intolerant should be administered foscarnet instead (93) (BII) (Appendix). HSCT recipients receiving ganciclovir should have ANCs checked >2 times/week (BIII). Researchers report managing ganciclovir-associated neutropenia by adding G-CSF (94) or temporarily stopping ganciclovir for >2 days if the patient's ANC is <1,000 (CIII). Ganciclovir can be restarted when the patient's ANC is >1,000 for 2 consecutive days. Alternatively, researchers report substituting foscarnet for ganciclovir if a) the HSCT recipient is still CMV viremic or antigenemic or b) the ANC remains <1,000 for >5 days after ganciclovir has been stopped (CIII) (Appendix). Because neutropenia accompanying ganciclovir administration is usually brief, such patients do not require antifungal or antibacterial prophylaxis (DIII).

Currently, no benefit has been reported from routinely administering ganciclovir prophylaxis to all HSCT recipients at >100 days after HSCT (i.e., during phase III). However, persons with high risk for late CMV disease should be routinely screened biweekly for evidence of CMV reactivation as long as substantial immunocompromise persists (BIII). Risk factors for late CMV disease include allogeneic HSCT accompanied by chronic GVHD, steroid use, low CD4 counts, delay in high avidity anti-CMV antibody, and recipients of matched unrelated or T-cell--depleted HSCTs who are at high risk (95--99). If CMV is still detectable by routine screening >100 days after HSCT, ganciclovir should be continued until CMV is no longer detectable (AI). If low-grade CMV antigenemia (<5 positive cells/slide) is detected on routine screening, the antigenemia test should be repeated in 3 days (BIII). If CMV antigenemia indicates >5 cells/slide, PCR is positive, or the shell-vial culture detects CMV viremia, a 3-week course of preemptive ganciclovir treatment should be administered (BIII) (Appendix). Ganciclovir should also be started if the patient has had >2 consecutively positive viremia or PCR tests (e.g., in a person receiving steroids for GVHD or who received ganciclovir or foscarnet at <100 days after HSCT). Current investigational strategies for preventing late CMV disease include the use of targeted prophylaxis with antiviral drugs and cellular immunotherapy for those with deficient or absent CMV-specific immune system function.

If viremia persists after 4 weeks of ganciclovir preemptive therapy or if the level of antigenemia continues to rise after 3 weeks of therapy, ganciclovir-resistant CMV should be suspected. If CMV viremia recurs during continuous treatment with ganciclovir, researchers report restarting ganciclovir induction (100) or stopping ganciclovir and starting foscarnet (CIII). Limited data were found regarding the use of foscarnet among HSCT recipients for either CMV prophylaxis or preemptive therapy (92,93).

Infusion of donor-derived CMV-specific clones of CD8+ T-cells into the transplant recipient is being evaluated under FDA Investigational New Drug authorization; therefore, no recommendation can be made. Although, in a substantial cooperative study, high-dose acyclovir has had certain efficacy for preventing CMV disease (101), its utility is limited in a setting where more potent anti-CMV agents (e.g., ganciclovir) are used (102). Acyclovir is not effective in preventing CMV disease after autologous HSCT (103) and is, therefore, not recommended for CMV preemptive therapy (DII). Consequently, valacyclovir, although under study for use among HSCT recipients, is presumed to be less effective than ganciclovir against CMV and is currently not recommended for CMV disease prevention (DII).

Although HSCT physicians continue to use IVIG for immune system modulation, IVIG is not recommended for CMV disease prophylaxis among HSCT recipients (DI). Cidofovir, a nucleoside analog, is approved by FDA for the treatment of AIDS-associated CMV retinitis. The drug's major disadvantage is nephrotoxicity. Cidofovir is currently in FDA phase 1 trial for use among HSCT recipients; therefore, recommendations for its use cannot be made.

Use of CMV-negative or leukocyte-reduced blood products is not routinely required for all autologous recipients because most have a substantially lower risk for CMV disease. However, CMV-negative or leukocyte-reduced blood products can be used for CMV-seronegative autologous recipients (CIII). Researchers report that CMV-seropositive autologous recipients be evaluated for preemptive therapy if they have underlying hematologic malignancies (e.g., lymphoma or leukemia), are receiving intense conditioning regimens or graft manipulation, or have recently received fludarabine or 2-chlorodeoxyadenosine (CDA) (CIII). This subpopulation of autologous recipients should be monitored weekly from time of engraftment until 60 days after HSCT for CMV reactivation, preferably with quantitative CMV pp65 antigen (80) or quantitative PCR (BII).

Autologous recipients at high risk who experience CMV antigenemia (i.e., blood levels of >5 positive cells/slide) should receive 3 weeks of preemptive treatment with ganciclovir or foscarnet (80), but CD34+-selected patients should be treated at any level of antigenemia (BII) (Appendix). Prophylactic approach to CMV disease prevention is not appropriate for CMV-seropositive autologous recipients. Indications for the use of CMV prophylaxis or preemptive treatment are the same for children or adults.

Preventing Exposure

All transplant candidates, particularly those who are EBV-seronegative, should be advised of behaviors that could decrease the likelihood of EBV exposure (AII). For example, HSCT recipients and candidates should follow safe hygiene practices (e.g., frequent hand washing [AIII] and avoiding the sharing of cups, glasses, and eating utensils with others) (104) (BIII), and they should avoid contact with potentially infected respiratory secretions and saliva (104) (AII).

Preventing Disease

Infusion of donor-derived, EBV-specific cytotoxic T-lymphocytes has demonstrated promise in the prophylaxis of EBV-lymphoma among recipients of T-cell--depleted unrelated or mismatched allogeneic recipients (105,106). However, insufficient data were found to recommend its use. Prophylaxis or preemptive therapy with acyclovir is not recommended because of lack of efficacy (107,108) (DII).

Preventing Exposure

HSCT candidates should be tested for serum anti-HSV IgG before transplant (AIII); however, type-specific anti-HSV IgG serology testing is not necessary. Only FDA-licensed or -approved tests should be used. All HSCT candidates, particularly those who are HSV-seronegative, should be informed of the importance of avoiding HSV infection while immunocompromised and should be advised of behaviors that will decrease the likelihood of HSV exposure (AII). HSCT recipients and candidates should avoid sharing cups, glasses, and eating utensils with others (BIII). Sexually active patients who are not in a long-term monogamous relationship should always use latex condoms during sexual contact to reduce the risk for exposure to HSV as well as other sexually transmitted pathogens (AII). However, even long-time monogamous pairs can be discordant for HSV infections. Therefore, during periods of immunocompromise, sexually active HSCT recipients in such relationships should ask partners to be tested for serum HSV IgG antibody. If the partners are discordant, they should consider using latex condoms during sexual contact to reduce the risk for exposure to this sexually transmitted OI (CIII). Any person with disseminated, primary, or severe mucocutaneous HSV disease should be placed under contact precautions for the duration of the illness (62) (AI) to prevent transmission of HSV to HSCT recipients.

Preventing Disease and Disease Recurrence

Acyclovir. Acyclovir prophylaxis should be offered to all HSV-seropositive allogeneic recipients to prevent HSV reactivation during the early posttransplant period (109--113) (AI). Standard approach is to begin acyclovir prophylaxis at the start of the conditioning therapy and continue until engraftment occurs or until mucositis resolves, whichever is longer, or approximately 30 days after HSCT (BIII) (Appendix). Without supportive data from controlled studies, routine use of antiviral prophylaxis for >30 days after HSCT to prevent HSV is not recommended (DIII). Routine acyclovir prophylaxis is not indicated for HSV-seronegative HSCT recipients, even if the donors are HSV-seropositive (DIII). Researchers have proposed administration of ganciclovir prophylaxis alone (86) to HSCT recipients who required simultaneous prophylaxis for CMV and HSV after HSCT (CIII) because ganciclovir has in vitro activity against CMV and HSV 1 and 2 (114), although ganciclovir has not been approved for use against HSV.

Valacyclovir. Researchers have reported valacyclovir use for preventing HSV among HSCT recipients (CIII); however, preliminary data demonstrate that very high doses of valacyclovir (8 g/day) were associated with thrombotic thrombocytopenic purpura/hemolytic uremic syndrome among HSCT recipients (115). Controlled trial data among HSCT recipients are limited (115), and the FDA has not approved valacyclovir for use among recipients. Physicians wishing to use valacyclovir among recipients with renal impairment should exercise caution and decrease doses as needed (BIII) (Appendix).

Foscarnet. Because of its substantial renal and infusion-related toxicity, foscarnet is not recommended for routine HSV prophylaxis among HSCT recipients (DIII).

Famciclovir. Presently, data regarding safety and efficacy of famciclovir among HSCT recipients are limited; therefore, no recommendations for HSV prophylaxis with famciclovir can be made.

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Recommendation and review posted by sam

If you are sick and tired of being sick and tired, feel yourself gaining more weight, confused about supplements and bioidentical hormones, or lost your libido then you may want to contact the top hormone replacement clinic in the area. Many of us suffer from insomnia, weight gain, wrinkling of skin, fatigue, thinning of hair, hot flashes, night sweats, loss of muscle tone and increased body fat, and have risk factors for heart disease. Our experienced bio identical hormone doctors specialize in the field of bioidentical hormones, functional and regenerative medicine with a proven track record of success.

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Recommendation and review posted by Bethany Smith

Open Access

Article

The Arabidopsis CERK1associated kinase PBL27 connects chitin perception to MAPK activation

These authors contributed equally to this work as first authors

These authors contributed equally to this work as third authors

Chitin receptor CERK1 transmits immune signals to the intracellular MAPK cascade in plants. This occurs via phosphorylation of MAPKKK5 by the CERK1associated kinase PBL27, providing a missing link between pathogen perception and signaling output.

Chitin receptor CERK1 transmits immune signals to the intracellular MAPK cascade in plants. This occurs via phosphorylation of MAPKKK5 by the CERK1associated kinase PBL27, providing a missing link between pathogen perception and signaling output.

CERK1associated kinase PBL27 interacts with MAPKKK5 at the plasma membrane.

Chitin perception induces disassociation of PBL27 and MAPKKK5.

PBL27 functions as a MAPKKK kinase.

Phosphorylation of MAPKKK5 by PBL27 is enhanced upon phosphorylation of PBL27 by CERK1.

Phosphorylation of MAPKKK5 by PBL27 is required for chitininduced MAPK activation in planta.

Kenta Yamada, Koji Yamaguchi, Tomomi Shirakawa, Hirofumi Nakagami, Akira Mine, Kazuya Ishikawa, Masayuki Fujiwara, Mari Narusaka, Yoshihiro Narusaka, Kazuya Ichimura, Yuka Kobayashi, Hidenori Matsui, Yuko Nomura, Mika Nomoto, Yasuomi Tada, Yoichiro Fukao, Tamo Fukamizo, Kenichi Tsuda, Ken Shirasu, Naoto Shibuya, Tsutomu Kawasaki

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Recommendation and review posted by simmons

Some cells are visible to the unaided eye

The smallest objects that the unaided human eye can see are about 0.1 mm long. That means that under the right conditions, you might be able to see an ameoba proteus, a human egg, and a paramecium without using magnification. A magnifying glass can help you to see them more clearly, but they will still look tiny.

Smaller cells are easily visible under a light microscope. It's even possible to make out structures within the cell, such as the nucleus, mitochondria and chloroplasts. Light microscopes use a system of lenses to magnify an image. The power of a light microscope is limited by the wavelength of visible light, which is about 500 nm. The most powerful light microscopes can resolve bacteria but not viruses.

To see anything smaller than 500 nm, you will need an electron microscope. Electron microscopes shoot a high-voltage beam of electrons onto or through an object, which deflects and absorbs some of the electrons. Resolution is still limited by the wavelength of the electron beam, but this wavelength is much smaller than that of visible light. The most powerful electron microscopes can resolve molecules and even individual atoms.

The label on the nucleotide is not quite accurate. Adenine refers to a portion of the molecule, the nitrogenous base. It would be more accurate to label the nucleotide deoxyadenosine monophosphate, as it includes the sugar deoxyribose and a phosphate group in addition to the nitrogenous base. However, the more familiar "adenine" label makes it easier for people to recognize it as one of the building blocks of DNA.

No, this isn't a mistake. First, there's less DNA in a sperm cell than there is in a non-reproductive cell such as a skin cell. Second, the DNA in a sperm cell is super-condensed and compacted into a highly dense form. Third, the head of a sperm cell is almost all nucleus. Most of the cytoplasm has been squeezed out in order to make the sperm an efficient torpedo-like swimming machine.

The X chromosome is shown here in a condensed state, as it would appear in a cell that's going through mitosis. It has also been duplicated, so there are actually two identical copies stuck together at their middles. A human sperm cell contains just one copy each of 23 chromosomes.

A chromosome is made up of genetic material (one long piece of DNA) wrapped around structural support proteins (histones). Histones organize the DNA and keep it from getting tangled, much like thread wrapped around a spool. But they also add a lot of bulk. In a sperm cell, a specialized set of tiny support proteins (protamines) pack the DNA down to about one-sixth the volume of a mitotic chromosome.

The size of the carbon atom is based on its van der Waals radius.

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Cell Size and Scale - Learn Genetics

Recommendation and review posted by sam

ABCDEFGHIJKLMNOPQRSTUVWXYZ

Academic research council

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Acute coronary syndromes

Adenoviridae and iridoviridae

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Antiretroviral agents

Assessing disease frequency

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Attack preparedness events

Avian influenza: zoonosis

Bacterial membrane vesicles

Bacterial vaginosis pregnancy

Bases of biostatistics

Behaviour medical sciences

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Cause epidemiological approach

Central nervous system

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China

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Supercourse: Epidemiology, the Internet, and Global Health

Recommendation and review posted by simmons

Use a sprinkle of common sense and a dash of logic.

by John R. Lee, M.D.

The recent Lancet publication of the Million Women Study (MWS) removes any lingering doubt that there's something wrong with conventional HRT (see Million Woman Study in the UK, Published in The Lancet, Gives New Insight into HRT and Breast Cancer for details). Why would supplemental estrogen and a progestin (e.g. not real progesterone) increase a woman's risk of breast cancer by 30 percent or more? Other studies found that these same synthetic HRT hormones increase one's risk of heart disease and blood clots (strokes), and do nothing to prevent Alzheimer's disease. When you pass through puberty and your sex hormones surge, they don't make you sickthey cause your body to mature into adulthood and be healthy. But, the hormones used in conventional HRT are somehow not rightthey are killing women by the tens of thousands.

The question iswhere do we go from here? My answer iswe go back to the basics and find out where our mistake is. I have some ideas on that.

Over the years I have adopted a simple set of three rules covering hormone supplementation. When these rules are followed, women have a decreased risk of breast cancer, heart attacks, or strokes. They are much less likely to get fat, or have poor sleep, or short term memory loss, fibrocystic breasts, mood disorders or libido problems. And the rules are not complicated.

Rule 1. Give hormones only to those who are truly deficient in them.

The first rule is common sense. We don't give insulin to someone unless we have good evidence that they need it. The same is true of thyroid, cortisol and all our hormones. Yet, conventional physicians routinely prescribe estrogen or other sex hormones without ever testing for hormone deficiency. Conventional medicine assumes that women after menopause are estrogen-deficient. This assumption is false. Twenty-five years ago I reviewed the literature on hormone levels before and after menopause, and all authorities agreed that over two-thirds (66 percent) of women up to age 80 continue to make all the estrogen they need. Since then, the evidence has become stronger. Even with ovaries removed, women make estrogen, primarily by an aromatase enzyme in body fat and breasts that converts an adrenal hormone, androstenedione, into estrone. Women with plenty of body fat may make more estrogen after menopause than skinny women make before menopause.

Breast cancer specialists are so concerned about all the estrogen women make after menopause that they now use drugs to block the aromatase enzyme. Consider the irony: some conventional physicians are prescribing estrogens to treat a presumed hormone deficiency in postmenopausal women, while others are prescribing drugs that block estrogen production in postmenopausal women.

How does one determine if estrogen deficiency exists? Any woman still having monthly periods has plenty of estrogen. Vaginal dryness and vaginal mucosal atrophy, on the other hand, are clear signs of estrogen deficiency. Lacking these signs, the best test is the saliva hormone assay. With new and better technology, saliva hormone testing has become accurate and reliable. As might be expected, we have learned that hormone levels differ between individuals; what is normal for one person is not necessarily normal for another. Further, one must be aware that hormones work within a complex network of other hormones and metabolic mediators, something like different musicians in an orchestra. To interpret a hormone s level, one must consider not only its absolute level but also its relative ratios with other hormones that include not only estradiol, progesterone and testosterone, but cortisol and thyroid as well.

For example, in healthy women without breast cancer, we find that the saliva progesterone level routinely is 200 to 300 times greater than the saliva estradiol level. In women with breast cancer, the saliva progesterone/estradiol ratio is considerably less than 200 to 1. As more investigators become more familiar with saliva hormone tests, I believe these various ratios will become more and more useful in monitoring hormone supplements.

Serum or plasma blood tests for steroid hormones should be abandonedthe results so obtained are essentially irrelevant. Steroid hormones are extremely lipophilic (fat-loving) and are not soluble in serum. Steroid hormones carry their message to cells by leaving the blood flow at capillaries to enter cells where they bond with specific hormone receptors in order to convey their message to the cells. These are called free hormones. When eventually they circulate through the liver, they become protein-bound (enveloped by specific globulins or albumin), a process that not only seriously impedes their bioavailability but also makes them water soluble, thus facilitating their excretion in urine. Measuring the concentration of these non-bioavailable forms in urine or serum is irrelevant since it provides no clue as to the concentration of the more clinically significant free (bioavailable) hormone in the blood stream.

When circulating through saliva glands, the free nonprotein-bound steroid hormone diffuses easily from blood capillaries into the saliva gland and then into saliva. Protein-bound, non-bioavailable hormones do not pass into or through the saliva gland. Thus, saliva testing is far superior to serum or urine testing in measuring bioavailable hormone levels.

Serum testing is fine for glucose and proteins but not for measuring free steroid hormones. Fifty years of blood tests have led to the great confusion that now befuddles conventional medicine in regard to steroid hormone supplementation.

Rule 2. Use bioidentical hormones rather than synthetic hormones.

The second rule is also just common sense. The message of steroid hormones to target tissue cells requires bonding of the hormone with specific unique receptors in the cells. The bonding of a hormone to its receptor is determined by its molecular configuration, like a key is for a lock. Synthetic hormone molecules and molecules from different species (e.g. Premarin, which is from horses) differ in molecular configuration from endogenous (made in the body) hormones. From studies of petrochemical xenohormones, we learn that substitute synthetic hormones differ in their activity at the receptor level. In some cases, they will activate the receptor in a manner similar to the natural hormone, but in other cases the synthetic hormone will have no effect or will block the receptor completely. Thus, hormones that are not bioidentical do not provide the same total physiologic activity as the hormones they are intended to replace, and all will provoke undesirable side effects not found with the human hormone. Human insulin, for example, is preferable to pig insulin. Sex hormones identical to human (bioidentical) hormones have been available for over 50 years.

Pharmaceutical companies, however, prefer synthetic hormones. Synthetic hormones (not found in nature) can be patented, whereas real (natural, bioidentical) hormones can not. Patented drugs are more profitable than non-patented drugs. Sex hormone prescription sales have made billions of dollars for pharmaceutical companies Thus is women's health sacrificed for commercial profit.

Rule 3. Use only in dosages that provide normal physiologic tissue levels.

The third rule is a bit more complicated. Everyone would agree, I think, that dosages of hormone supplements should restore normal physiologic levels. The question ishow do you define normal physiologic levels? Hormones do not work by just floating around in circulating blood; they work by slipping out of blood capillaries to enter cells that have the proper receptors in them. As explained above, protein-bound hormones are unable to leave blood vessels and bond with intracellular receptors. They are non-bioavailable. But they are water-soluble, and thus found in serum, whereas the free bioavailable hormone is lipophilic and not water soluble, thus not likely to be found in serum. Serum tests do not help you measure the free, bioavailable form of the hormone. The answer is saliva testing.

It is quite simple to measure the change in saliva hormone levels when hormone supplementation is given. If more physicians did that, they would find that their usual estrogen dosages create estrogen levels 8 to 10 times greater than found in normal healthy people, and that progesterone levels are not raised by giving supplements of synthetic progestin such as medroxyprogesterone acetate (MPA).

Further, saliva levels (and not serum levels) of progesterone will clearly demonstrate excellent absorption of progesterone from transdermal creams. Transdermal progesterone enters the bloodstream fully bioavailable (i.e., without being protein-bound). The progesterone increase is readily apparent in saliva testing, whereas serum will show little or no change. In fact, any rise of serum progesterone after transdermal progesterone dosing is most often a sign of excessive progesterone dosage. Saliva testing helps determine optimal dosages of supplemented steroid hormones, something that serum testing cannot do.

It is important to note that conventional HRT violates all three of these rules for rational use of supplemental steroid hormones.

A 10-year French study of HRT using a low-dose estradiol patch plus oral progesterone shows no increased risk of breast cancer, strokes or heart attacks. Hormone replacement therapy is a laudable goal, but it must be done correctly. HRT based on correcting hormone deficiency and restoring proper physiologic balanced tissue levels, is proposed as a more sane, successful and safe technique.

Other Factors

Hormone imbalance is not the only cause of breast cancer, strokes, and heart attacks. Other risk factors of importance include the following:

Men share these risks equally with women. Hormone imbalance and exposure to these risk factors in men leads to earlier heart attacks, lower sperm counts and higher prostate cancer risk.

Conclusion

Conventional hormone replacement therapy (HRT) composed of either estrone or estradiol, with or without progestins (excluding progesterone) carries an unacceptable risk of breast cancer, heart attacks and strokes. I propose a more rational HRT using bioidentical hormones in dosages based on true needs as determined by saliva testing. In addition to proper hormone balancing, other important risk factors are described, all of which are potentially correctable. Combining hormone balancing with correction of other environmental and lifestyle factors is our best hope for reducing the present risks of breast cancer, strokes and heart attacks.

A much broader discussion of all these factors can be found in the updated and revised edition of What Your Doctor May Not Tell You About Menopause and What Your Doctor May Not Tell You About Breast Cancer.

More here:
Bioidentical Hormones: Dr. John R. Lee's Three Rules for BHRT

Recommendation and review posted by sam