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Small sheets of healthy skin are being grown from scratch at a Stanford University lab, proof that gene therapy can help heal a rare disease that causes great human suffering.

The precious skin represents growing hope for patients who suffer from the incurable blistering disease epidermolysis bullosa and acceleration of the once-beleaguered field of gene therapy, which strives to cure disease by inserting missing genes into sick cells.

It is pink and healthy. Its tougher. It doesnt blister, said patient and research volunteer Monique Roeder, 33, of Cedar City, Utah, who has received grafts of corrected skin cells, each about the size of an iPhone 5, to cover wounds on her arms.

More than 10,000 human diseases are caused by a single gene defect, and epidermolysis bullosa is among the most devastating. Patients lack a critical protein that binds the layers of skin together. Without this protein, the skin tears apart, causing severe pain, infection, disfigurement and in many cases, early death from an aggressive form of skin cancer.

The corrected skin is part of a pipeline of potential gene therapies at Stanfords new Center for Definitive and Curative Medicine, announced last week.

The center, a new joint initiative of Stanford Healthcare, Stanford Childrens Health, and the Stanford School of Medicine, is designed to accelerate cellular therapies at the universitys state-of-the-art manufacturing facility on Palo Altos California Avenue. Simultaneously, itisaiming to bring cures to patients faster than before and boost the financial value of Stanfords discoveries before theyre licensed out to biotech companies.

With trials such as these, we are entering a new era in medicine, said Dr. Lloyd B. Minor, dean of the Stanford University School of Medicine.

Gene therapy was dealt a major setback in 1999 when Jesse Gelsinger, an Arizona teenager with a genetic liver disease, had a fatal reaction to the virus that scientists had used to insert a corrective gene.

But current trials are safer, more precise and build on better basic understanding. Stanford is also using gene therapy to target other diseases, such as sickle cell anemia and beta thalassemia,a blood disorder that reduces the production of hemoglobin.

There are several diseases that are miserable and worthy of gene therapy approaches, said associate professor of dermatology Dr. Jean Tang, who co-led the trial with Dr. Peter Marinkovich. But epidermolysis bullosa, she said, is one of the worst of the worst.

It took nearly 20 years for Stanford researchers to bring this gene therapy to Roeder and her fellow patients.

It is very satisfying to be able to finally give patients something that can help them, said Marinkovich.In some cases, wounds that had not healed for five years were successfully healed with the gene therapy.

Before, he noted, there was only limited amounts of what you can do for them. We can treat their wounds and give them sophisticated Band-Aids. But after you give them all that stuff, you still see the skin falling apart, Marinkovich said. This makes you feel like youre making a difference in the world.

Roeder seemed healthy at birth. But when her family celebrated her arrival by imprinting her tiny feet on a keepsake birth certificate, she blistered. They encouraged her to lead a normal childhood, riding bicycles and gentle horses. Shes happily married. But shes grown cautious, focusing on photography, writing a blog and enjoying her pets.

Scarring has caused her hands and feet digits to become mittened or webbed. Due to pain and risk of injury, she uses a wheelchair rather than walking long distances.

Every movement has to be planned out in my head so I dont upset my skin somehow, she said. Wound care can take three to six hours a day.

She heard about the Stanford research shortly after losing her best friend, who also had epidermolysis bullosa, to skin cancer, a common consequence of the disease. Roeder thought: Why dont you try? She didnt get the chance.

The team of Stanford experts harvested a small sample of skin cells, about the size of a pencil eraser, from her back. They put her cells in warm broth in a petri dish, where they thrived.

To this broth they added a special virus, carrying the missing gene. Once infected, the cells began producing normal collagen.

They coaxed these genetically corrected cells to form sheets of skin. The sheets were then surgically grafted onto a patients chronic or new wounds in six locations. The team reported their initial results in Novembers Journal of the American Medical Association.

Historically, medical treatment has had limited options: excising a sick organ or giving medicine, said Dr. Anthony E. Oro of Stanfords Institute for Stem Cell Biology and Regenerative Medicine. When those two arent possible, theres only symptom relief.

But the deciphering of the human genome, and new tools in gene repair, have changed the therapeutic landscape.

Now that we know the genetic basis of disease, we can use the confluence of stem cell biology, genome editing and tissue engineering to develop therapies, Oro said.

Its not practical to wrap the entire body of a patient with epidermolysis bullosa in vast sheets of new skin, like a mummy, Oro said.

But now that the team has proved that gene therapy works, they can try related approaches, such as using gene-editing tools directly on the patients skin, or applying corrected cells like a spray-on tan.

A cure doesnt take one step, said Tang. It takes many steps towards disease modification, and this is the first big one. Were always looking for something better.

Read the original here:
Stanford team is growing healthy skin for ill patients - The Mercury News

Recommendation and review posted by simmons

Good News at Fred Hutch Fred Hutch News Service A multi-institutional research team in Seattle recently was awarded more than $3.7 million in federal grant funding to develop a novel gene therapy approach for dangerous genetic disorders that affect hemoglobin, the blood's oxygen-carrying molecules.

Link:
Good News at Fred Hutch - Fred Hutch News Service

Recommendation and review posted by sam

By delivering a benign virus to the ear of mice, scientists have enabled deaf lab mice to hear for the first time.

GENE therapy delivered by a benign virus enabled deaf lab mice to hear for the first time, researchers revealed this week, offering hope for people suffering with genetic hearing impairments.

The breakthrough could pave the way for gene-based treatments, they reported in two studies, published in Nature Biotechnology.

With more than 100 genes already known to cause deafness in humans, there are many patients who may eventually benefit from this technology, said Konstantina Stankovic, a professor at Harvard Medical School.

Genetic hearing disorders affect some 125 million people worldwide, according to the World Health Organisation.

An expert not involved in the research welcomed the findings as very encouraging, but cautioned the technique has yet to be proven safe, and that human trials are likely years away.

In the first study, Stankovic and colleagues used a harmless virus to transport deep into the mouse ear a gene that can fix a specific form of hereditary deafness.

Previous attempts had failed, but this time the viral package was delivered to the right address: the so-called outer hair cells that tune the inner ear to sound waves.

Outer hair cells amplify sound, allowing inner hair cells to send a stronger signal to the brain, explained Gwenaelle Geleoc, a researcher at the F.M. Kirby Neurobiology Center at Boston Childrens Hospital.

The technique bestowed hearing and balance to a level thats never been achieved before, she said in a statement.

Now you can whisper, and the mice can hear you. In the second study, a team led by Geleoc used the same viral courier to treat mice with a mutated gene responsible for Usher syndrome, a rare childhood genetic disease that causes deafness, loss of balance, and in some cases blindness.

The virus carried a normal version of the same gene to damaged ear hair cells soon after the mice were born.

NARROW TIME WINDOW

The results far exceeded anything to date: 19 of 25 treated mice heard sounds quieter than 80 decibels. Normal human conversation is about 70 decibels.

A few of the mice could hear sounds as soft as 25 to 30 decibels roughly equivalent to whispering.

According to Margaret Kenna, a specialist in genetic hearing loss at Boston Childrens Hospital not involved in the studies, cochlear implants are great, but your own hearing is better. Electronic implants work by bypassing damaged hair cells in the ear to send sound signals directly to the brain.

Anything that could stabilise or improve native hearing at an early age would give a huge boost to a childs ability to learn and use spoken language, she said.

The need for early intervention, however, could be a problem in itself, other experts pointed out.

In humans, such an intervention would ideally have to happen before a child is born, said Jonathan Ashmore, a professor at University College Londons Ear Institute.

Alan Boyd, president of Britains Faculty of Pharmaceutical Medicine hailed a very encouraging result.

But it is only a mouse model, he cautioned, noting that it is still unknown how the human immune system might react.

Any gene deafness treatment is at least three years away, if not more, Boyd conjectured.

Follow three people who hope the mapping of the human genome will transform their lives. Will the Human Genome Project change our relationship with ourselves forever?

Visit link:
Hearing impairment cure? Gene therapy allows deaf mice to hear - NEWS.com.au

Recommendation and review posted by sam

February 07, 2017 07:45 ET | Source: Abeona Therapeutics Inc

Multiple Oral Platform Presentations and Poster Sessions Highlighting Gene Therapy Programs, Tuesday, February 14th through Thursday, February 16th

NEW YORK and CLEVELAND, Feb. 07, 2017 (GLOBE NEWSWIRE) -- Abeona Therapeutics Inc. (NASDAQ:ABEO), a leading clinical-stage biopharmaceutical company focused on developing therapies for life-threatening rare genetic diseases, today announced that data on gene therapy programs for Sanfilippo syndrome Type A (MPS IIIA), Infantile Batten Disease (CLN1) and Juvenile Batten Disease will be highlighted at the upcoming 13th Annual WORLDSymposium 2017 lysosomal storage disorders conference, February 13-17, San Diego, CA. Details for the two oral presentations and three poster sessions are listed below.

Platform Presentations:

ABO-102 Phase 1/2 Clinical trial update - Sanfilippo syndrome Type A (MPS IIIA):

ABO-202 CLN1, Infantile Batten Disease (INCL):

Poster Sessions:

ABO-102 Phase 1/2 Clinical trial update - Sanfilippo syndrome Type A:

ABO-202 CLN1, Infantile Batten Disease (INCL):

ABO-201 CLN3, Juvenile Batten Disease (JNCL):

Abeona Recent ABO-102 Program Highlights:

About WORLDSymposium: The goal of WORLDSymposium is to provide an interdisciplinary forum to explore and discuss specific areas of interest, research and clinical applicability related to lysosomal diseases. Each year, WORLDSymposiumhosts a scientific meeting presenting the latest information from basic science, translational research, and clinical trials for lysosomal diseases. This symposium is designed to help researchers and clinicians to better manage and understand diagnostic options for patients with lysosomal diseases, identify areas requiring additional basic and clinical research, public policy and regulatory attention, and identify the latest findings in the natural history of lysosomal diseases. For more information, visit http://www.worldsymposia.org/

About Abeona: Abeona Therapeutics Inc. is a clinical-stage biopharmaceutical company developing gene therapies for life-threatening rare genetic diseases. Abeona's lead programs include ABO-102 (AAV-SGSH) and ABO-101 (AAV-NAGLU), adeno-associated virus (AAV) based gene therapies for Sanfilippo syndrome (MPS IIIA and IIIB, respectively). Abeona is also developing EB-101 (gene-corrected skin grafts) for recessive dystrophic epidermolysis bullosa (RDEB), EB-201 for epidermolysis bullosa (EB), ABO-201 (AAV-CLN3) gene therapy for juvenile Batten disease (JNCL), ABO-202 (AAV-CLN1) gene therapy for treatment of infantile Batten disease (INCL), and ABO-301 (AAV-FANCC) for Fanconi anemia (FA) disorder and ABO-302 using a novel CRISPR/Cas9-based gene editing approach to gene therapy for rare blood diseases. In addition, Abeona has a plasma-based protein therapy pipeline, including SDF Alpha (alpha-1 protease inhibitor) for inherited COPD, using its proprietary SDF (Salt Diafiltration) ethanol-free process. For more information, visit http://www.abeonatherapeutics.com.

This press release contains certain statements that are forward-looking within the meaning of Section 27a of the Securities Act of 1933, as amended, and that involve risks and uncertainties. These statements are subject to numerous risks and uncertainties, including but not limited to continued interest in our rare disease portfolio, our ability to enroll patients in clinical trials, the impact of competition; the ability to develop our products and technologies; the ability to achieve or obtain necessary regulatory approvals; the impact of changes in the financial markets and global economic conditions; and other risks as may be detailed from time to time in the Company's Annual Reports on Form 10-K and other reports filed by the Company with the Securities and Exchange Commission. The Company undertakes no obligations to make any revisions to the forward-looking statements contained in this release or to update them to reflect events or circumstances occurring after the date of this release, whether as a result of new information, future developments or otherwise.

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Abeona Therapeutics Announces Presentations and Posters at the 13th Annual WORLDSymposium 2017 - GlobeNewswire (press release)

Recommendation and review posted by simmons

In a recent article, a doctor in China has identified a man who has 44 chromosomes instead of the usual 46. Except for his different number of chromosomes, this man is perfectly normal in every measurable way.

His chromosomes are arranged in a stable way that could be passed on if he met a nice girl who had 44 chromosomes too. And this would certainly be possible in the future given his family history.

But why doesn't he have any problems? A loss of one let alone two chromosomes is almost always fatal because so many essential genes are lost.

In this case, he has fewer chromosomes but is actually missing very few genes. Instead, he has two chromosomes stuck to two other chromosomes. More specifically, both his chromosome 14's are stuck to his chromosome 15's.

So he has almost all the same genes as any other person. He just has them packaged a bit differently.

This is an important finding because it tells us about a key genetic event in human prehistory. All the evidence points to humans, like their relatives the chimpanzees, having 48 chromosomes a million or so years ago. Nowadays most humans have 46.

What happened to this 44 chromosome man shows one way that the first step in this sort of change might have happened in our past. Scientists could certainly predict something like this. But now there is proof that it can actually happen.

Note added in Proof: Here are some older papers that I missed that have very similar findings:

And the current one:

Case Report: Potential Speciation in Humans Involving Robertsonian Translocations.

His Story

So how did this man end up with 44 chromosomes? It is a story of close relatives having children together. And a chromosomal rearrangement called a balanced translocation.

A balanced translocation is when one chromosome sticks to another. Because no genes are lost in this process, it usually doesn't have any effect. Until these folks try to have kids that is.

Usually around 2/3 of pregnancies involving one person with a balanced translocation will end in miscarriage. This has to do with how chromosomes separate when eggs and sperm are made. This process is called meiosis.

Remember, humans (and most other living things) have two copies of each chromosome. So they have two copies of chromosome 1, two copies of chromosome 2, etc. Only one chromosome from each pair gets put into any one sperm or egg. That way, when the sperm fertilizes the egg, the fetus has the right number of chromosomes.

This is where the problem starts for people with a balanced translocation. They have one unpaired chromosome and a pair with an extra chromosome. Here is what can happen in this situation:

The top row represents two potential parents. The parent on the right has a balanced translocation. There are two possible ways for the fused chromosome to line up.

In the figure, only two chromosomes are shown. Numbers 14 and 15 were chosen because these are the two that are fused in the 44 chromosome man.

The parent with the balanced translocation can make 4 different kinds of sperm or egg (the second row). As the figure shows, when the eggs and sperm combine, 1/2 of the time the fetus ends up with an extra or missing chromosome. Unless this chromosome is the X, Y or number 21, the usual result is miscarriage or being born with severe problems.

In this case it would almost certainly result in miscarriage. In fact, the 44 chromosome man's family has a long history of miscarriages and spontaneous abortions.

To get two of the same balanced translocations, both parents need to have the same balanced translocation. This is incredibly rare. Except when the parents are related.

In this case, both parents are first cousins and they share the same translocation. When these parents try to have kids, they run into the same kinds of problems that can happen with one balanced translocation. Except that the problems are doubled. This makes for the many possibilities outlined below:

This very complicated table shows the 36 possible outcomes when two parents with the same balanced translocation attempt to have a child.

In this representation, the father's possible sperm are shown on the top and the mother's eggs on the side. Each pregnancy has only an 8 in 36 chance for success. And 1 out of 36 would have two of the same balanced translocation (the circled possibility).

Theoretically the 44 chromosome man should have fewer problems having children than his parents did. As this figure shows, there are no unpaired chromosomes when he and a woman with 46 chromosomes have children. But all of their kids would have a balanced translocation:

So this is how he came to have 44 chromosomes. This might also be how humans started on the road to 46 chromosomes a million or so years ago.

See the article here:
The 44 Chromosome Man | Understanding Genetics

Recommendation and review posted by simmons

After a long summer break it is time to review recent events and update the portfolio. As far as clinical readouts go, my portfolio had a brutal summer with one complete P3 failure from Array Biopharma (ARRY), a mixed data set from Aurinia (AUPH) and a win from SAGE (SAGE) that resulted in limited share appreciation. This was offset by strong performance from Exelixis (EXEL), my biggest holding which is up 48% quarter to date.

For the remainder of 2016 I plan to gradually increase exposure to gene therapy, which I hope will become one of the industrys primary growth drivers in the coming years. In parallel, as I am still pessimistic about the biotech field in general (R&D productivity, pricing, biosimilars), I intend to keep my short ETFs and a significant cash position.

Data readouts Array and Aurinia disappoint, SAGE delivers

Array Biopharma Astrazenecas (AZN) selumetinib, originally developed by Array, failed to improve PFS or overall survival in KRAS-mutated lung cancer. This P3 failure demonstrates once again the challenges in corroborating positive P2 data and joins a series of disappointing news for MEK inhibitors. In 2015, selumetinib failed another P3 study in uveal melanoma and earlier this year, Array terminated a P3 study for its wholly-owned MEK inhibitor, binimetinib, in ovarian cancer. Recent P3 data for binimetinib in NRAS+ melanoma was technically a success but benefit was underwhelming (improvement in PFS without a survival benefit).

MEK inhibitors are still being explored in multiple indications that may enable developers to expand their use beyond BRAF+ melanoma. At ASCO 2016, Roche and Exelixis reported an intriguing efficacy signal with Cotellic in KRAS+ colon cancer. Another indication that is not discussed much is neurofibromatosis type 1 where selumetinib demonstrated strong efficacy but timelines and registration strategy are not clear. Later in 2016, Array will report data for binimetinib in BRAF+ melanoma, where two other MEK inhibitors (Mekinist and Cotellic) are already approved. Array hopes to demonstrate a differentiated safety profile but penetrating the BRAF+ market is going to be challenging.

Aurinia Aurinia reported results from a P2b evaluating two doses of its calcineurin inhibitor (voclosporin) in lupus nephritis. While voclosporin demonstrated superiority over the control arm at the low dose in inducing remission (32.6% vs. 19.3%), there was no effect with the high dose and there was an alarming imbalance in deaths between the low dose cohort (13 cases overall, 10 of which occurred in the lower dose arm). The fact the active arm had such a high mortality obviously raises safety concerns but also casts a shadow on the efficacy signal and trial design.

SAGE SAGE reported a strong efficacy signal for its lead program, SAGE-547, in a placebo- controlled P2 in postpartum depression (PPD). Despite the typically high placebo response in depression trials, the drug led to a clinically meaningful reduction in depression with a ~12 point reduction from placebo on the HAM-D scale. Importantly, the effect had a quick onset and appears durable almost a month following treatment cessation.

These results are very significant for SAGE-547 becausethey validate the initial signal observed to date in single arm open label trials or case studies, which are rightfully viewed as unreliable (especially in CNS indications). Despite the small sample size, the strength and consistency of the PPD data imply the drug is active and de-risk the program.

Going forward, SAGE decided to focus on SRSE with SAGE-547 (P3 data pushed out to 1H:2017) while pursuing PPD as well as other CNS diseases (essential tremor, Parkinsons) with a next-generation oral drug (SAGE-217). This decision makes sense in light of the different clinical settings (SRSE patients are hospitalized and need immediate solution for their seizures whereas PPD may require more prolonged treatment). SAGE-217 appears more potent and selective than SAGE-547 with good pharmacologic profile based on P1, but it is still not validated in the clinic.

Momentum continues to build around gene therapy

There have been some notable news in the gene therapy space including three data readouts and an acquisition. This gradual but consistent progress helps to build confidence around gene therapy and makes it one of the most important segments in the industry.

The combined recent data set from all gene therapy companies still comprises less than 100 patients with limited follow up, but for the first time in more than25years, we are starting to get positive answers on three major questions: Efficacy, durability and safety. With tens of active clinical programs, strong data across multiple domains (liver, CNS, retina, bone marrow) and an armamentarium of tissue-specific vectors, gene therapy may be ready for primetime. The field will surely see its share of failures but the path to commercial success with gene therapy is finally visible.

Biomarin

Biomarin (BMRN) made a big splash with its hemophilia A treatment, BMN-270, demonstrating that gene therapy can lead to a functional cure (at least for a period of time). Results from 7 patients treated at the highest dose demonstrated quick and robust expression of factor VIII (hemophilia A is caused by low factor VIII activity). Strikingly, all but one patient achieved normal levels and this was accompanied by a dramatic reduction in bleeding events despite taking patients off prophylactic FVIII treatment. Follow up is still limited (up to 20 weeks) but Factor VIII production appears to be stabilizing or even increasing in some cases.

The study was a major win but there were two safety signals: ALT elevation (marker for liver damage) and an above normal FVIII levels in two patients.

ALT elevations are closely watched in every liver-targeted gene therapy study because earlier products led to ALT elevations (probably an immunogenic response against the viral vector) that led to clinically relevant elevations and were associated with loss of transgene expression. There is still not enough follow up to rule out any chronic liver toxicity but according to Biomarin, the ALT elevations were not clinically meaningful and appear to be manageable with steroids (in some cases patients were taken off steroids and liver functions returned to normal). Fortunately, the ALT elevations do not seem to correlate with loss FVIII expression as production continued to rise or stabilized during these events.

The excessive FVIII levels in two patients are troubling on paper (especially if production keeps going up) because elevated levels of FVIII are associated with higher risk of thrombotic complications according to several studies, reviewed here. This demonstrates a primary concern with gene therapy its irreversible and cannot be switched off. While the company disclosed patients are not experiencing any thrombosis-related events, they will have to be monitored and potentially treated in case FVIII continue to climb or any abnormalities emerge. Going forward Biomarin plans to evaluate a lower dose to avoid such cases.

Overall, Biomarins hem A data are impressive and together with data from hemophilia B programs from Spark (ONCE)/Pfizer (PFE) and UniQure (QURE), they lay the groundwork for registration programs in hemophilia potentially next year.

Avexis

While Biomarins gene therapy for hemophilia demonstrated both protein production (FVIII in the blood) and clinical improvement (bleeding incidence), Avexis (AVXS) AVXS-101 demonstrated only the latter. Nevertheless, the dramatic clinical signal coupled with the fact that the target tissue are neurons make AVXS-101 one of the most important gene therapies in development (and personally speaking, the most intriguing one).

Last month, Avexis provided an update from a clinical trial evaluating AVXS-101 for SMA1, a fatal disease in infants that affects the motor neurons and is invariably fatal by 2 years of age. Following the previous data readout (which I discussed here), the clinical effect appears to hold with unprecedented functional and survival improvements over historical data. All but one patient on the high dose cohort had a dramatic functional improvement vs. the expected persistent decline that is the hallmark of SMA1. Importantly, none of the patients had an event (defined as ventilation or death) despite crossing 8 months of age where a recent study showed an event rate of 50%. Duration of the effect is still unknown due to limited follow up (appears to be at least 1 year).

The trial did not have a control arm but the difference is so dramatic that I find it hard to believe it is just a statistical artifact. The recent breakthrough therapy designation the FDA granted to AVXS-101 is another testament to the robustness of the data. Biogen (BIIB) and Ionis (IONS) reported P3 success for nusinersen in SMA1, which validates the signal observed in a previous single-arm study and this strengthens the notion that single-arm trials in SMA1 can generate a reliable signal. Although nusinersen can theoretically be seen as a competitive threat to AVXS-101, if both drugs are approved, nusinersen will probably be used on top of a one-time gene therapy like AVXS-101.

AVXS-101s effect, if real, implies that AAV9 vectors Avexis utilizes can cross the blood-brain-barrier and reach the central nervous system. This could have dramatic implications for many rare genetic diseases (and down the road more prevalent diseases like Parkinsons and Alzheimers disease) where the nerve system is damaged but cannot be modulated by existing drugs. In this perspective, companies like REGENXBIO (RGNX) and Abeona (ABEO) are very interesting opportunities as both target neurologic diseases (or ones with neurologic manifestations) with AAV9-based gene therapies.

Spark

Spark reported updated results from its pivotal trial for its RPE65 gene therapy (Voretigene neparvovec) for inherited retinal disease. The study was overwhelmingly positive and will likely be the basis of the first ever FDA approval for gene therapy next year. In contrast to other gene therapy programs in development, Sparks program has up to 3 years of follow-up and so far the effect appears to hold.

RPE65 gene therapy is to retinal diseases what hemophilia gene therapy is to liver diseases a proof of concept that paves the way for other genetic retinal diseases like XLRS, XLRP, achromatopsia and choroideremia. Spark will have first clinical data for its choroideremia program later in 2016. AGTC (AGTC) is expected to report initial clinical data in XLRS and achromatopsia also in 2016.

Spark also has a Hemophilia A program (SPK-8011), which is about to enter P1. Despite being more than a year behind Biomarin, recent results for Sparks Hemophilia B program (partnered with Pfizer) were very encouraging and may point to some advantages with Sparks vectors. These include better potency and lower immunogenicity that could translate to a more compelling clinical profile (i.e achieving the required protein levels with limited immune reaction, and down the road better durability and dosing flexibility).

Pfizer acquires Bamboo

One item that went relatively unnoticed is the acquisition of Bamboo by Pfizer. Bamboo is developing gene therapies for neuronal and neuromuscular indications with a program in P1 for Giant Axonal Neuropathy. Despite the modest deal size ($150M upfront), it is an important milestone in big pharmas venture into gene therapy, which historically has not been aligned with the pharma business model (one time genetic treatment vs. recurring sales of small molecules or biologics). The title of Pfizers press release (Pfizer aims to become industry leader in gene therapy with aquisition of bamboo therapeutics) clearly demonstrates this trend.

If gene therapy is indeed going to become a central component of the biopharma industry, the demand for validated platforms with clinical data and CMC capabilities could grow dramatically in the near future. In contrast to cell therapies such as CARs and TCRs, gene therapy may be more palatable to pharma because the end product is still a drug in a vial and not a process.

Portfolio updates

Given the early stage and inherent risk in gene therapy, I intend to build a diversified portfolio with the goal of starting 2017 with 7-8 stocks that will comprise a third of the portfolio. Today I am starting with Spark, Avexis, REGENXBIO and Abeona (Next on the list is Bluebird going into ASH 2016)

I am selling Array Biopharma, Aurinia, Genocea (GNCA) and Conatus (CNAT). In addition, I am selling part of my ArQule (ARQL) and Foundation Medicine (FMI) position.

Lastly, I am initiating a small position in Kura Oncology (KURA) following an early signal in HRAS+ H&N cancer.

Portfolio holdings September 4th, 2016

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Read the original:
Biotech portfolio update Jumping into gene therapy ...

Recommendation and review posted by simmons

Triple X syndrome, also known as trisomy X and 47 XXX, is characterized by the presence of an extra X chromosome in each cell of a female.[1] Those affected are often taller than average. Usually there is no other physical differences and normal fertility. Occasionally there are learning difficulties, decreased muscle tone, seizures, or kidney problems.[1]

Triple X is due to a random event.[1] Triple X can result either during the division of the mother's reproductive cells or during division of cells during early development.[2] It is not typically inherited from one generation to the next. A form where only a percentage of the body cells contain XXX can also occur.[1] Diagnosis is by chromosomal analysis.[3]

Treatment may include speech therapy, physical therapy, and counseling.[3] It occurs in about one in every 1,000 female births.[2] It is estimated that 90% of those affected are not diagnosed as they either have no or only few symptoms.[2] It was first identified in 1959.[4]

Because the vast majority of triple X females are never diagnosed, it may be very difficult to make generalizations about the effects of this syndrome. The samples that were studied were small and may be nonrepresentative. Because of the lyonization, inactivation, and formation of Barr bodies in all female cells, only one X chromosome is active at any time. Thus, triple X syndrome most often has only mild effects or has no effects. The symptoms vary from person to person, with some women being more affected than others.

Symptoms may include tall stature, vertical skin folds that may cover the inner corners of the eyes (epicanthal folds), poor muscle tone, and a curve in the 5th finger towards the 4th.[2] There may also be a small head (microcephaly).[5] There are seldom any observable physical anomalies in triple X females, other than being taller than average.

Poor coordination may be present.[6] Those affected appear to have higher rates of scoliosis.[6]

Epicanthal folds and increased distance between the eyes in 2-year-old girl with trisomy X[2]

The type of finger curvature frequently seen in triple X syndrome

Females with triple X syndrome often have delayed language development.[6] On average those affected have IQs that are 20 points lower.[6] Poor self-esteem, anxiety, and depression are also common.[2][6]

Triple X syndrome is not inherited, but usually, occurs as an event during the formation of reproductive cells (ovum and sperm). An error in cell division called nondisjunction can result in reproductive cells with additional chromosomes. For example, an oocyte or sperm cell may gain an extra copy of the X chromosome as a result of the non-disjunction. If one of these cells contributes to the genetic makeup of a child, the child will have an extra X chromosome in each of her cells. In some cases, trisomy X occurs during cell division in early embryonic development.

Some females with triple X syndrome have an extra X chromosome in only some of their cells. These cases are called 46,XX/47,XXX mosaics.

The vast majority of triple X women are never diagnosed, unless they undergo tests for other medical reasons later in life. Triple X can be diagnosed by a blood test which is able to look at a persons chromosomes (karyotype). Abnormalities on the electroencephalography may be present.[6]

Triple X syndrome can be diagnosed prenatally through amniocentesis or chorionic villus sampling. In Denmark, between 1970 and 1984, 76% of the prenatally diagnosed fetuses with triple-X were aborted. Between 1985-1987, this figure dropped to 56%. With improved information, the number of abortions diminished. In the Netherlands, between 1991 and 2000, 33% (18/54) of the couples that were confronted with a prenatal diagnosis of 47, XXX elected to abort. If balanced information is provided to prospective parents, prenatally, the incidence of voluntary termination (abortion) is reduced.[7]

A stable home environment can improve some of the symptoms.[6]

Triple X syndrome occurs in around 1 in 1,000 girls. On average, five to ten girls with triple X syndrome are born in the United States each day.[8]

The first published report of a woman with a 47,XXX karyotype was by Patricia A. Jacobs, et al. at Western General Hospital in Edinburgh, Scotland, in 1959. It was found in a 35year-old, 5ft. 9 in. (176cm) tall, 128lb. (58.2kg) woman who had premature ovarian failure at age 19; her mother was age 41 and her father was 40 at the time of her conception.[9] Jacobs, et al. called the 47,XXX woman a "superfemale", a term which was immediately criticized, did not gain acceptance, and was based on the incorrect assumption that the sex-determination system in mammals was the same as in the fruit fly Drosophila.[10] British pathologist and geneticist Bernard Lennox, the principal consultant on medical terms for the Oxford English Dictionary, suggested the term "XXX syndrome".[11]

Read more here:
Triple X syndrome - Wikipedia

Recommendation and review posted by Bethany Smith

Stem cells have tremendous promise to help us understand and treat a range of diseases, injuries and other health-related conditions. Their potential is evident in the use of blood stem cells to treat diseases of the blood, a therapy that has saved the lives of thousands of children with leukemia; and can be seen in the use of stem cells for tissue grafts to treat diseases or injury to the bone, skin and surface of the eye. Important clinical trials involving stem cells are underway for many other conditions and researchers continue to explore new avenues using stem cells in medicine.

There is still a lot to learn about stem cells, however, and their current applications as treatments are sometimes exaggerated by the media and other parties who do not fully understand the science and current limitations, and also by clinics looking to capitalize on the hype by selling treatments to chronically ill or seriously injured patients. The information on this page is intended to help you understand both the potential and the limitations of stem cells at this point in time, and to help you spot some of the misinformation that is widely circulated by clinics offering unproven treatments.

It is important to discuss these Nine Things to Know and any research or information you gather with your primary care physician and other trusted members of your healthcare team in deciding what is right for you.

See more here:
Nine Things to Know About Stem Cell Treatments

Recommendation and review posted by simmons

While a number of companies have dabbled in this space, the following players are facilitating the development of iPS cell therapies: Cellular Dynamics International (CDI), RIKEN, Cynata Therapeutics, and Astellas (previously Ocata Therapeutics).

While each iPS cell therapy group is considered in detail below, Cellular Dynamics International (CDI) is featured first, because it dominates the iPSC industry. CDI also recently split into two business units, a Life Science Unit and a Therapeutics Unit, demonstrating a commercial strategy for its iPS cell therapy development.

Cellular Dynamics International (CDI) is headquartered in Madison, Wisconsin, although it provides technical support and sales information from both the United States and Japan. CDI was founded in 2004 and listed on NASDAQ in July 2013. The company had global revenues of $16.7 million in 2014 and currently has 150+ employees. It also has an extremely robust patent portfolio containing more than 800 patents, of which 130 pertain to iPSCs.

According to the company, CDI is the worlds largest producer of fully functional human cells derived from induced pluripotent stem (iPS) cells.[1] Their trademarked, iCell Cardiomyocytes, derived from iPSCs, are human cardiac cells used to aid drug discovery, improve the predictability of a drugs worth, and screen for toxicity. In addition, CDI provides: iCell Endothelial Cells for use in vascular-targeted drug discovery and tissue regeneration, iCell Hepatocytes, and iCell Neurons for pre-clinical drug discovery, toxicity testing, disease prediction, and cellular research.[2] As such, CDIs main role with regard to iPCS therapy development is the production of industrial-scale, clinical-grade iPSCs.

As mentioned previously, induced pluripotent stem cells were first produced in 2006 from mouse cells and in 2007 from human cells, by Shinya Yamanaka at Kyoto University,[3] who also won the Nobel Prize in Medicine or Physiology for his work on iPSCs.[4] Yamanaka has ties toCellular Dynamics International as a member of the scientific advisory board of iPS Academia Japan.

IPS Academia Japan was originally established to manage the patents and technology of Yamanakas work, and is now the distributor of several of Cellular Dynamics products, including iCell Neurons, iCell Cardiomyocytes, and iCell Endothelial Cells.[5] Importantly, in 2010 Cellular Dynamics became the first foreign company to be granted rights to use Yamanakas iPSC patent portfolio.Not only has CDI licensed rights to Yamanakas patents, but it also has a license to use Otsu, Japan-based Takara Bios RetroNectin product, which it uses as a tool to produce its iCell and MyCell products.[6] Through its licenses and intellectual property, CDI currently uses induced pluripotent stem cells to produce human heart cells (cardiomyocytes), brain cells (neurons), blood vessel cells (endothelial cells), and liver cells (hepatocytes), manufacturing them in high quantity, quality, and purity.

These human cells produced by the company are used for both in vitro and in vivo applications that range from basic and applied research to drug discovery research that includes target identification and validation, toxicity testing, safety and efficacy testing, and more. As such, CDI has emerged as a global leader with the ability to generate iPSCs that have the potential to be used for a wide range of research and possibly therapeutic purposes.

In a landmark event with the iPSC market, the company had an initial public offering (IPO) in July of 2013, in which it sold 38,460,000 shares of common stock to the public at $12.00 per share, to raise proceeds of approximately $43 million.[7] This event secured the companys position as the global leader in producing high-quality human iPSCs and differentiated cells in industrial quantities.

In addition, in March of 2013, Celullar Dynamics International and the Coriell Institute for Medical Research announced receiving multi-million dollars grants from the California Institute for Regenerative Medicine (CIRM) for the creation of iPSC lines from 3,000 healthy and diseased donors, a result that will create the worlds largest human iPSC bank.

Not surprisingly, Cellular Dynamics International has continued its innovation, announcing in February of 2015 that it would be manufacturing cGMP HLA Superdonor stem cell lines that will support cellular therapy applications through genetic matching.[8] Currently, CDI has two HLA superdonor cell lines that provide a partial HLA match to approximately 19% of the population within the U.S., and it aims to expand its master stem cell bank by collecting more donor cell lines that will cover 95% of the U.S. population.[9]

The HLA superdonor cell lines were manufactured using blood samples, and used to produce pluripotent iPSC lines, giving the cells the capacity to differentiate into nearly any cell within the human body.

CDI also leads the iPSC market in terms of supporting drug development and discovery. For example, CDIs MyCell products are created using custom iPSC reprogramming and differentiation methods, thereby providing biologically relevant human cells from patients with unique disease-associated genotypes and phenotypes.[10] The companys iCell and MyCell cells can also be adapted to screening platforms and are matched to function with common readout technologies.[11] CDIs products are also used for high-throughput screening,[12] and have been used as supporting data for Investigational New Drug (IND) applications submitted to the Federal Drug Administration (FDA).[13]

On March 30, 2015, Fujifilm Holdings Corporation announced that it was acquiring CDI, in which Fujifilm will acquire CDI through all-cash offer followed by a second step merger. Specifically, Fujifilm will acquire all issued and outstanding shares of CDIs common stock for $16.5 per share or approximately $ 307 million, after which CDI will continue to run its operations in Madison, Wisconsin, and Novato, California as a consolidated subsidiary of Fujifilm.[14]

CDIs technology platform enables the production of high-quality fully functioning iPSCs (and other human cells) on an industrial scale, while Fujifilm has developed highly-biocompatible recombinant peptidesthat can be shaped into a variety of forms for use as a cellular scaffoldin regenerative medicinewhen used in conjunction with CDIs products.[15] Fujifilm has been strengthening its presence in the regenerative medicine field over several years, including by acquiring a majority of shares of Japan Tissue Engineering Co. in December 2014, so while the acquisition was unexpected, it as not fully suprising.

In summary, the acquisition of CDI will allow Fujifilm to gaindominance in the areaof iPS cell-based drug discovery services and will position it to strategically combine CDIs iPS cell technologywithFujifilms expertise in material science and engineering systems, creating a powerhouse within the iPSC market. It is yet to be seen whether Fujifilm will try to commercialize CDIs iPS cell production technologies by making the cells available for clinical use or whether they will choose to focus their attention on iPS cell-based drug discovery services.

In November 2015 Astellas Pharma announced it was acquiring Ocata Therapeutics for $379M. Ocata Therapeutics is a biotechnology company that specializes in the development of cellular therapies, using both adult and human embryonic stem cells to develop patient-specific therapies. The companys main laboratory and GMP facility is in Marlborough, Massachusetts, and its corporate offices are in Santa Monica, California.

When a number of private companies began to explore the possibility of using artificially re-manufactured iPSCs for therapeutic purposes, one such company that was ready to capitalize on the breakthrough technology was Ocata Therapeutics (at the time called Advanced Cell Technology or ACT). In 2010, the company announced that it had discovered several problematic issues while conducting experiments for the purpose of applying for U.S. Food and Drug Administration approval to use iPSCs in therapeutic applications. Concerns such as premature cell death, mutation into cancer cells, and low proliferation rates were some of the problems that surfaced. [16]

As a result, the company has since shifted its induced pluripotent stem cell approach to producingiPS cell-derived human platelets, as one of the benefits of a platelet-based product is that platelets do not contain nuclei, and therefore, cannot divide or carry genetic information. Although nothing is completely safe, iPS cell-derived platelets are likely to be much safer than other iPSC therapies, in which uncontrolled proliferation is a major concern.

While the companys Induced Pluripotent Stem Cell-Derived Human Platelet Program received a great deal of media coverage in late 2012, including being awarded the December 2012 honor of being named one of the 10 Ideas that Will Shape the Yearby New Scientist Magazine,[17] unfortunately the company did not succeed in moving the concept through to clinical testing in 2013.

Nonetheless, in a November 2015 presentation by Astellas President and CEO, Yoshihiko Hatanaka, he indicated that the company will aim to develop an Ophthalmic Disease Cell Therapy Franchise based around its embryonic stem cells (ESCs) and induced pluripotent stem cell (iPS cells) technology. [18]

On June 22, 2016, RIKEN announced that it is resuming its retinal induced pluripotent stem cell (iPSC) study in partnership with Kyoto University.

2013 was the first time in which clinical research involving transplant of iPSCs into humans was initiated, led by Masayo Takahashi of the RIKEN Center for Developmental Biology (CDB)in Kobe, Japan. Dr. Takahashi and her team wereinvestigating the safety of iPSC-derived cell sheets in patients with wet-type age-related macular degeneration. Althoughthe trial was initiated in 2013 and production of iPSCs from patients began at that time, it was not until August of 2014 that the first patient, a Japanese woman, was implanted with retinal tissue generated using iPSCs derived from her own skin cells.

A team of three eye specialists, led by Yasuo Kurimoto of the Kobe City Medical Center General Hospital, implanted a 1.3 by 3.0mm sheet of iPSC-derived retinal pigment epithelium cells into the patients retina.[19]Unfortunately, the study was suspended in 2015 due to safety concerns. As the lab prepared to treat the second trial participant, Yamanakas team identified two small genetic changes in the patients iPSCs and the retinal pigment epithelium (RPE) cells derived from them. Therefore, it is major news that theRIKEN Institute will now be resuming the worlds first clinical study involving the use of iPSC-derived cells in humans.

According to the Japan Times, this attempt at the clinical studywill involve allogeneic rather than autologous iPSC-derived cells for purposes of cost and time efficiency.Specifically,the researchers will be developing retinal tissues from iPS cells supplied by Kyoto Universitys Center for iPS Cell Research and Application, an institution headed by Nobel prize winner Shinya Yamanaka. To learn about this announcement, view this article fromAsahi Shimbun, aTokyo- based newspaper.

Australian stem cell company Cynata Therapeutics (ASX:CYP) is taking a unique approach. It is creating allogeneic iPS cell derived mesenchyal stem cell (MSCs).Cynatas Cymerus technology utilizes iPSCs originating from an adult donor as the starting material for generating mesenchymoangioblasts (MCAs), and subsequently, for manufacturing clinical-gradeMSCs.

One of the key inventors of the approach is Igor Slukvin, who has released more than 70 publications about stem cell topics, including the landmark article in Cell describing the now patented Cymerus technique. Dr. Slukvins co-inventor is James Thomson, the first person to isolate an embryonic stem cell (ESC) and one of the first people to create a human-induced, pluripotent stem cell (hiPSC).

Recently, Cynata received advice from the UK Medicines and Healthcare products Regulatory Agency (MHRA) that its Phase I clinical trial application has been approved, titledAn Open-Label Phase 1 Study to Investigate the Safety and Efficacy of CYP-001 for the Treatment of Adults With Steroid-Resistant Acute Graft Versus Host Disease. It will be the worlds first clinical trial involving a therapeutic product derived from allogeneic (unrelated to the patient) induced pluripotent stem cells (iPSCs).

Participants for Cynatas upcoming Phase I clinical trial will be adults who have undergone an allogeneic haematopoietic stem cell transplant (HSCT) to treat a haematological disorder and subsequently been diagnosed with steroid-resistant Grade II-IV GvHD.The primary objective of the trial is to assess safety and tolerability, while the secondary objective is to evaluate the efficacy of two infusions of CYP-001 in adults with steroid-resistant GvHD.

There are four key advantages of Cynatas proprietary Cymerus MSC manufacturing platform, as described below.

Unlimited Quantities Cynatas Cymerus technology utilizes iPSCs originating from an adult donor as the starting material for generating mesenchymoangioblasts (MCAs), and subsequently, for manufacturing clinical-gradeMSCs. According to Cynatas Executive Chairman Stewart Washer who was recently interviewed by The Life Sciences Report, The Cymerus technology gets around the loss of potency with the unlimited iPS cellor induced pluripotent stem cellwhich is basically immortal.

Uniform Batches Because the proprietary Cymerus technology allows nearly unlimited production of MSCs from a single iPSC donor, there is batch-to-batch uniformity. Utilizing a consistent starting material allows for a standardized cell manufacturing process and a consistent cell therapy product.

Single Donor As described previously, Cynatas Cymerus technology creates iPSC-derived mesenchymoangioblasts (MCAs), which are differentiated into MSCs. Unlike other companies involved with MSC manufacturing, Cynata does not require a constant stream of new donors in order to source fresh stem cells for its cell manufacturing process, nor does it require the massive expansion of MSCs necessitated by reliance on freshly isolated donations.

Economic Manufacture at Commercial Scale (Low Cost) Finally, Cynata has achieved a cost-savings advantage through its uniqueapproach to MSCmanufacturing. Its proprietary Cymerus technology addresses a critical shortcoming in existing methods of production of MSCs for therapeutic use, which is the ability to achieve economic manufacture at commercial scale.

Footnotes [1] CellularDynamics.com (2014). About CDI. Available at: http://www.cellulardynamics.com/about/index.html. Web. 1 Apr. 2015. [2] Ibid. [3] Takahashi K, Yamanaka S (August 2006).Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors.Cell126(4): 66376. [4] 2012 Nobel Prize in Physiology or Medicine Press Release. Nobelprize.org. Nobel Media AB 2013. Web. 7 Feb 2014. Available at: http://www.nobelprize.org/nobel_prizes/medicine/laureates/2012/press.html. Web. 1 Apr. 2015. [5] Striklin, D (Jan 13, 2014). Three Companies Banking on Regenerative Medicine. Wall Street Cheat Sheet. Retrieved Feb 1, 2014 from, http://wallstcheatsheet.com/stocks/3-companies-banking-on-regenerative-medicine.html/?a=viewall. [6] Striklin, D (2014). Three Companies Banking on Regenerative Medicine. Wall Street Cheat Sheet [Online]. Available at: http://wallstcheatsheet.com/stocks/3-companies-banking-on-regenerative-medicine.html/?a=viewall. Web. 1 Apr. 2015. [7] Cellular Dynamics International (July 30, 2013). Cellular Dynamics International Announces Closing of Initial Public Offering [Press Release]. Retrieved from http://www.cellulardynamics.com/news/pr/2013_07_30.html. [8] Investors.cellulardynamics.com,. Cellular Dynamics Manufactures Cgmp HLA Superdonor Stem Cell Lines To Enable Cell Therapy With Genetic Matching (NASDAQ:ICEL). N.p., 2015. Web. 7 Mar. 2015. [9] Ibid. [10] Cellulardynamics.com,. Cellular Dynamics | Mycell Products. N.p., 2015. Web. 7 Mar. 2015. [11]Sirenko, O. et al. Multiparameter In Vitro Assessment Of Compound Effects On Cardiomyocyte Physiology Using Ipsc Cells.Journal of Biomolecular Screening18.1 (2012): 39-53. Web. 7 Mar. 2015. [12] Sciencedirect.com,. Prevention Of -Amyloid Induced Toxicity In Human Ips Cell-Derived Neurons By Inhibition Of Cyclin-Dependent Kinases And Associated Cell Cycle Events. N.p., 2015. Web. 7 Mar. 2015. [13] Sciencedirect.com,. HER2-Targeted Liposomal Doxorubicin Displays Enhanced Anti-Tumorigenic Effects Without Associated Cardiotoxicity. N.p., 2015. Web. 7 Mar. 2015. [14] Cellular Dynamics International, Inc. Fujifilm Holdings To Acquire Cellular Dynamics International, Inc.. GlobeNewswire News Room. N.p., 2015. Web. 7 Apr. 2015. [15] Ibid. [16] Advanced Cell Technologies (Feb 11, 2011). Advanced Cell and Colleagues Report Therapeutic Cells Derived From iPS Cells Display Early Aging [Press Release]. Available at: http://www.advancedcell.com/news-and-media/press-releases/advanced-cell-and-colleagues-report-therapeutic-cells-derived-from-ips-cells-display-early-aging/. [17] Advanced Cell Technology (Dec 20, 2012). New Scientist Magazine Selects ACTs Induced Pluripotent Stem (iPS) Cell-Derived Human Platelet Program As One of 10 Ideas That Will Shape The Year [Press Release]. Available at: http://articles.latimes.com/2009/mar/06/science/sci-stemcell6. Web. 9 Apr. 2015. [18] Astellas Pharma (2015). Acquisition of Ocata Therapeutics New Step Forward in Ophthalmology with Cell Therapy Approach. Available at: https://www.astellas.com/en/corporate/news/pdf/151110_2_Eg.pdf. Web. 29 Jan. 2017. [19]Cyranoski, David. Japanese Woman Is First Recipient Of Next-Generation Stem Cells. Nature (2014): n. pag. Web. 6 Mar. 2015.

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Companies Developing Induced Pluripotent Stem Cell (iPS ...

Recommendation and review posted by simmons

The XY sex-determination system is the sex-determination system found in humans, most other mammals, some insects (Drosophila), and some plants (Ginkgo). In this system, the sex of an individual is determined by a pair of sex chromosomes (gonosomes). Females have two of the same kind of sex chromosome (XX), and are called the homogametic sex. Males have two distinct sex chromosomes (XY), and are called the heterogametic sex.

This system is in contrast with the ZW sex-determination system found in birds, some insects, many reptiles, and other animals, in which the heterogametic sex is female.

A temperature-dependent sex determination system is found in some reptiles.

All animals have a set of DNA coding for genes present on chromosomes. In humans, most mammals, and some other species, two of the chromosomes, called the X chromosome and Y chromosome, code for sex. In these species, one or more genes are present on their Y-chromosome that determine maleness. In this process, an X chromosome and a Y chromosome act to determine the sex of offspring, often due to genes located on the Y chromosome that code for maleness. Offspring have two sex chromosomes: an offspring with two X chromosomes will develop female characteristics, and an offspring with an X and a Y chromosome will develop male characteristics.

In humans, half of spermatozoons carry X chromosome and the other half Y chromosome.[1] A single gene (SRY) present on the Y chromosome acts as a signal to set the developmental pathway towards maleness. Presence of this gene starts off the process of virilization. This and other factors result in the sex differences in humans.[2] The cells in females, with two X chromosomes, undergo X-inactivation, in which one of the two X chromosomes is inactivated. The inactivated X chromosome remains within a cell as a Barr body.

Humans, as well as some other organisms, can have a chromosomal arrangement that is contrary to their phenotypic sex; for example, XX males or XY females (see androgen insensitivity syndrome). Additionally, an abnormal number of sex chromosomes (aneuploidy) may be present, such as Turner's syndrome, in which a single X chromosome is present, and Klinefelter's syndrome, in which two X chromosomes and a Y chromosome are present, XYY syndrome and XXYY syndrome.[2] Other less common chromosomal arrangements include: triple X syndrome, 48, XXXX, and 49, XXXXX.

In most mammals, sex is determined by presence of Y. "Female" is the default sex; due to the absence of the Y.[3] In the 1930s, Alfred Jost determined that the presence of testosterone was required for Wolffian duct development in the male rabbit.[4]

SRY is a sex-determining gene on the Y chromosome in the therians (placental mammals and marsupials).[5] Non-human mammals use several genes on the Y-chromosome. Not all male-specific genes are located on the Y-chromosome. Other species (including most Drosophila species) use the presence of two X chromosomes to determine femaleness. One X chromosome gives putative maleness. The presence of Y-chromosome genes is required for normal male development.

Birds and many insects have a similar system of sex determination (ZW sex-determination system), in which it is the females that are heterogametic (ZW), while males are homogametic (ZZ).

Many insects of the order Hymenoptera instead have a system (the haplo-diploid sex-determination system), where the males are haploid individuals (which have just one chromosome of each type), while the females are diploid (with chromosomes appearing in pairs). Some other insects have the X0 sex-determination system, where just one chromosome type appears in pairs for the female but alone in the males, while all other chromosomes appear in pairs in both sexes.[citation needed]

For a long time, biologists believed that the female form was the default template for the mammalian fetuses of both sexes. After the discovery of the testis-determining gene SRY, many scientists shifted to the theory that the genetic mechanism that determines a fetus to develop into a male form was initiated by the SRY gene, which was thought to be responsible for the production of testosterone and its overall effects on body and brain development. This perspective still shared the classical way of thinking; that in order to produce two sexes, nature has developed a default female pathway and an active pathway by which male genes would initiate the process of determining a male sex, as something that is developed in addition to and based on the default female form. This view is no longer considered accurate by most scientists who study the genetics of sex. In an interview for the Rediscovering Biology website,[6] researcher Eric Vilain described how the paradigm changed since the discovery of the SRY gene:

For a long time we thought that SRY would activate a cascade of male genes. It turns out that the sex determination pathway is probably more complicated and SRY may in fact inhibit some anti-male genes.

The idea is instead of having a simplistic mechanism by which you have pro-male genes going all the way to make a male, in fact there is a solid balance between pro-male genes and anti-male genes and if there is a little too much of anti-male genes, there may be a female born and if there is a little too much of pro-male genes then there will be a male born.

We [are] entering this new era in molecular biology of sex determination where it's a more subtle dosage of genes, some pro-males, some pro-females, some anti-males, some anti-females that all interplay with each other rather than a simple linear pathway of genes going one after the other, which makes it very fascinating but very complicated to study.

In mammals, including humans, the SRY gene is responsible with triggering the development of non-differentiated gonads into testes, rather than ovaries. However, there are cases in which testes can develop in the absence of an SRY gene (see sex reversal). In these cases, the SOX9 gene, involved in the development of testes, can induce their development without the aid of SRY. In the absence of SRY and SOX9, no testes can develop and the path is clear for the development of ovaries. Even so, the absence of the SRY gene or the silencing of the SOX9 gene are not enough to trigger sexual differentiation of a fetus in the female direction. A recent finding indicates that ovary development and maintenance is an active process,[7] regulated by the expression of a "pro-female" gene, FOXL2. In an interview[8] for the TimesOnline edition, study co-author Robin Lovell-Badge explained the significance of the discovery:

We take it for granted that we maintain the sex we are born with, including whether we have testes or ovaries. But this work shows that the activity of a single gene, FOXL2, is all that prevents adult ovary cells turning into cells found in testes.

Looking into the genetic determinants of human sex can have wide-ranging consequences. Scientists have been studying different sex determination systems in fruit flies and animal models to attempt an understanding of how the genetics of sexual differentiation can influence biological processes like reproduction, ageing[9] and disease.

In humans and many other species of animals, the father determines the sex of the child. In the XY sex-determination system, the female-provided ovum contributes an X chromosome and the male-provided sperm contributes either an X chromosome or a Y chromosome, resulting in female (XX) or male (XY) offspring, respectively.

Hormone levels in the male parent affect the sex ratio of sperm in humans.[10] Maternal influences also impact which sperm are more likely to achieve conception.

Human ova, like those of other mammals, are covered with a thick translucent layer called the zona pellucida, which the sperm must penetrate to fertilize the egg. Once viewed simply as an impediment to fertilization, recent research indicates the zona pellucida may instead function as a sophisticated biological security system that chemically controls the entry of the sperm into the egg and protects the fertilized egg from additional sperm.[11]

Recent research indicates that human ova may produce a chemical which appears to attract sperm and influence their swimming motion. However, not all sperm are positively impacted; some appear to remain uninfluenced and some actually move away from the egg.[12]

Maternal influences may also be possible that affect sex determination in such a way as to produce fraternal twins equally weighted between one male and one female.[13]

The time at which insemination occurs during the oestrus cycle has been found to affect the sex ratio of the offspring of humans, cattle, hamsters, and other mammals.[10] Hormonal and pH conditions within the female reproductive tract vary with time, and this affects the sex ratio of the sperm that reach the egg.[10]

Sex-specific mortality of embryos also occurs.[10]

Since ancient times, people have believed that the sex of an infant is determined by how much heat a man's sperm had during insemination. Aristotle wrote that:

...the semen of the male differs from the corresponding secretion of the female in that it contains a principle within itself of such a kind as to set up movements also in the embryo and to concoct thoroughly the ultimate nourishment, whereas the secretion of the female contains material alone. If, then, the male element prevails it draws the female element into itself, but if it is prevailed over it changes into the opposite or is destroyed.

Aristotle claimed that the male principle was the driver behind sex determination,[14] such that if the male principle was insufficiently expressed during reproduction, the fetus would develop as a female.

Nettie Stevens and Edmund Beecher Wilson are credited with independently discovering, in 1905, the chromosomal XY sex-determination system, i.e. the fact that males have XY sex chromosomes and females have XX sex chromosomes.[15][16][17]

The first clues to the existence of a factor that determines the development of testis in mammals came from experiments carried out by Alfred Jost,[18] who castrated embryonic rabbits in utero and noticed that they all developed as female.[citation needed]

In 1959, C. E. Ford and his team, in the wake of Jost's experiments, discovered[19] that the Y chromosome was needed for a fetus to develop as male when they examined patients with Turner's syndrome, who grew up as phenotypic females, and found them to be X0 (hemizygous for X and no Y). At the same time, Jacob & Strong described a case of a patient with Klinefelter syndrome (XXY),[20] which implicated the presence of a Y chromosome in development of maleness.[21]

All these observations lead to a consensus that a dominant gene that determines testis development (TDF) must exist on the human Y chromosome.[21] The search for this testis-determining factor (TDF) led a team of scientists[22] in 1990 to discover a region of the Y chromosome that is necessary for the male sex determination, which was named SRY (sex-determining region of the Y chromosome).[21]

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XY sex-determination system - Wikipedia

Recommendation and review posted by Bethany Smith

Organisms of many species are specialized into male and female varieties, each known as a sex,[1] with some falling in between being intersex. Sexual reproduction involves the combining and mixing of genetic traits: specialized cells known as gametes combine to form offspring that inherit traits from each parent. Gametes can be identical in form and function (known as isogamy), but in many cases an asymmetry has evolved such that two sex-specific types of gametes (heterogametes) exist (known as anisogamy).

Among humans and other mammals, males typically carry XY chromosomes, whereas females typically carry XX chromosomes, which are a part of the XY sex-determination system. Other animals have a sex-determination system as well, such as the ZW sex-determination system in birds, and the X0 sex-determination system in insects.

The gametes produced by an organism are determined by its sex: males produce male gametes (spermatozoa, or sperm, in animals; pollen in plants) while females produce female gametes (ova, or egg cells); individual organisms which produce both male and female gametes are termed hermaphroditic. Frequently, physical differences are associated with the different sexes of an organism; these sexual dimorphisms can reflect the different reproductive pressures the sexes experience. For instance, mate choice and sexual selection can accelerate the evolution of physical differences between the sexes.

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One of the basic properties of life is reproduction, the capacity to generate new individuals, and sex is an aspect of this process. Life has evolved from simple stages to more complex ones, and so have the reproduction mechanisms. Initially the reproduction was a replicating process that consists in producing new individuals that contain the same genetic information as the original or parent individual. This mode of reproduction is called asexual, and it is still used by many species, particularly unicellular, but it is also very common in multicellular organisms.[2] In sexual reproduction, the genetic material of the offspring comes from two different individuals. As sexual reproduction developed by way of a long process of evolution, intermediates exist. Bacteria, for instance, reproduce asexually, but undergo a process by which a part of the genetic material of an individual (donor) is transferred to an other (recipient).[3]

Disregarding intermediates, the basic distinction between asexual and sexual reproduction is the way in which the genetic material is processed. Typically, prior to an asexual division, a cell duplicates its genetic information content, and then divides. This process of cell division is called mitosis. In sexual reproduction, there are special kinds of cells that divide without prior duplication of its genetic material, in a process named meiosis. The resulting cells are called gametes, and contain only half the genetic material of the parent cells. These gametes are the cells that are prepared for the sexual reproduction of the organism.[4] Sex comprises the arrangements that enable sexual reproduction, and has evolved alongside the reproduction system, starting with similar gametes (isogamy) and progressing to systems that have different gamete types, such as those involving a large female gamete (ovum) and a small male gamete (sperm).[5]

In complex organisms, the sex organs are the parts that are involved in the production and exchange of gametes in sexual reproduction. Many species, particularly animals, have sexual specialization, and their populations are divided into male and female individuals. Conversely, there are also species in which there is no sexual specialization, and the same individuals both contain masculine and feminine reproductive organs, and they are called hermaphrodites. This is very frequent in plants.[6]

Sexual reproduction first probably evolved about a billion years ago within ancestral single-celled eukaryotes.[7] The reason for the evolution of sex, and the reason(s) it has survived to the present, are still matters of debate. Some of the many plausible theories include: that sex creates variation among offspring, sex helps in the spread of advantageous traits, that sex helps in the removal of disadvantageous traits, and that sex facilitates repair of germ-line DNA.

Sexual reproduction is a process specific to eukaryotes, organisms whose cells contain a nucleus and mitochondria. In addition to animals, plants, and fungi, other eukaryotes (e.g. the malaria parasite) also engage in sexual reproduction. Some bacteria use conjugation to transfer genetic material between cells; while not the same as sexual reproduction, this also results in the mixture of genetic traits.

The defining characteristic of sexual reproduction in eukaryotes is the difference between the gametes and the binary nature of fertilization. Multiplicity of gamete types within a species would still be considered a form of sexual reproduction. However, no third gamete is known in multicellular animals.[8][9][10]

While the evolution of sex dates to the prokaryote or early eukaryote stage,[11] the origin of chromosomal sex determination may have been fairly early in eukaryotes (see Evolution of anisogamy). The ZW sex-determination system is shared by birds, some fish and some crustaceans. XY sex determination is used by most mammals,[12] but also some insects,[13] and plants (Silene latifolia).[14]X0 sex-determination is found in certain insects.

No genes are shared between the avian ZW and mammal XY chromosomes,[15] and from a comparison between chicken and human, the Z chromosome appeared similar to the autosomal chromosome 9 in human, rather than X or Y, suggesting that the ZW and XY sex-determination systems do not share an origin, but that the sex chromosomes are derived from autosomal chromosomes of the common ancestor of birds and mammals. A paper from 2004 compared the chicken Z chromosome with platypus X chromosomes and suggested that the two systems are related.[16]

Sexual reproduction in eukaryotes is a process whereby organisms form offspring that combine genetic traits from both parents. Chromosomes are passed on from one generation to the next in this process. Each cell in the offspring has half the chromosomes of the mother and half of the father.[17] Genetic traits are contained within the deoxyribonucleic acid (DNA) of chromosomesby combining one of each type of chromosomes from each parent, an organism is formed containing a doubled set of chromosomes. This double-chromosome stage is called "diploid", while the single-chromosome stage is "haploid". Diploid organisms can, in turn, form haploid cells (gametes) that randomly contain one of each of the chromosome pairs, via meiosis.[18] Meiosis also involves a stage of chromosomal crossover, in which regions of DNA are exchanged between matched types of chromosomes, to form a new pair of mixed chromosomes. Crossing over and fertilization (the recombining of single sets of chromosomes to make a new diploid) result in the new organism containing a different set of genetic traits from either parent.

In many organisms, the haploid stage has been reduced to just gametes specialized to recombine and form a new diploid organism; in others, the gametes are capable of undergoing cell division to produce multicellular haploid organisms. In either case, gametes may be externally similar, particularly in size (isogamy), or may have evolved an asymmetry such that the gametes are different in size and other aspects (anisogamy).[19] By convention, the larger gamete (called an ovum, or egg cell) is considered female, while the smaller gamete (called a spermatozoon, or sperm cell) is considered male. An individual that produces exclusively large gametes is female, and one that produces exclusively small gametes is male. An individual that produces both types of gametes is a hermaphrodite; in some cases hermaphrodites are able to self-fertilize and produce offspring on their own, without a second organism.[20]

Most sexually reproducing animals spend their lives as diploid organisms, with the haploid stage reduced to single cell gametes.[21] The gametes of animals have male and female formsspermatozoa and egg cells. These gametes combine to form embryos which develop into a new organism.

The male gamete, a spermatozoon (produced within a testicle), is a small cell containing a single long flagellum which propels it.[22] Spermatozoa are extremely reduced cells, lacking many cellular components that would be necessary for embryonic development. They are specialized for motility, seeking out an egg cell and fusing with it in a process called fertilization.

Female gametes are egg cells (produced within ovaries), large immobile cells that contain the nutrients and cellular components necessary for a developing embryo.[23] Egg cells are often associated with other cells which support the development of the embryo, forming an egg. In mammals, the fertilized embryo instead develops within the female, receiving nutrition directly from its mother.

Animals are usually mobile and seek out a partner of the opposite sex for mating. Animals which live in the water can mate using external fertilization, where the eggs and sperm are released into and combine within the surrounding water.[24] Most animals that live outside of water, however, must transfer sperm from male to female to achieve internal fertilization.

In most birds, both excretion and reproduction is done through a single posterior opening, called the cloacamale and female birds touch cloaca to transfer sperm, a process called "cloacal kissing".[25] In many other terrestrial animals, males use specialized sex organs to assist the transport of spermthese male sex organs are called intromittent organs. In humans and other mammals this male organ is the penis, which enters the female reproductive tract (called the vagina) to achieve inseminationa process called sexual intercourse. The penis contains a tube through which semen (a fluid containing sperm) travels. In female mammals the vagina connects with the uterus, an organ which directly supports the development of a fertilized embryo within (a process called gestation).

Because of their motility, animal sexual behavior can involve coercive sex. Traumatic insemination, for example, is used by some insect species to inseminate females through a wound in the abdominal cavitya process detrimental to the female's health.

Like animals, plants have developed specialized male and female gametes.[26] Within seed plants, male gametes are contained within hard coats, forming pollen. The female gametes of plants are contained within ovules; once fertilized by pollen these form seeds which, like eggs, contain the nutrients necessary for the development of the embryonic plant.

Female (left) and male (right) cones are the sex organs of pines and other conifers.

Many plants have flowers and these are the sexual organs of those plants. Flowers are usually hermaphroditic, producing both male and female gametes. The female parts, in the center of a flower, are the pistils, each unit consisting of a carpel, a style and a stigma. One or more of these reproductive units may be merged to form a single compound pistil. Within the carpels are ovules which develop into seeds after fertilization. The male parts of the flower are the stamens: these consist of long filaments arranged between the pistil and the petals that produce pollen in anthers at their tips. When a pollen grain lands upon the stigma on top of a carpel's style, it germinates to produce a pollen tube that grows down through the tissues of the style into the carpel, where it delivers male gamete nuclei to fertilize an ovule that eventually develops into a seed.

In pines and other conifers the sex organs are conifer cones and have male and female forms. The more familiar female cones are typically more durable, containing ovules within them. Male cones are smaller and produce pollen which is transported by wind to land in female cones. As with flowers, seeds form within the female cone after pollination.

Because plants are immobile, they depend upon passive methods for transporting pollen grains to other plants. Many plants, including conifers and grasses, produce lightweight pollen which is carried by wind to neighboring plants. Other plants have heavier, sticky pollen that is specialized for transportation by insects. The plants attract these insects or larger animals such as humming birds and bats with nectar-containing flowers. These animals transport the pollen as they move to other flowers, which also contain female reproductive organs, resulting in pollination.

Most fungi reproduce sexually, having both a haploid and diploid stage in their life cycles. These fungi are typically isogamous, lacking male and female specialization: haploid fungi grow into contact with each other and then fuse their cells. In some of these cases the fusion is asymmetric, and the cell which donates only a nucleus (and not accompanying cellular material) could arguably be considered "male".[27]

Some fungi, including baker's yeast, have mating types that create a duality similar to male and female roles. Yeast with the same mating type will not fuse with each other to form diploid cells, only with yeast carrying the other mating type.[28]

Fungi produce mushrooms as part of their sexual reproduction. Within the mushroom diploid cells are formed, later dividing into haploid sporesthe height of the mushroom aids the dispersal of these sexually produced offspring.

The most basic sexual system is one in which all organisms are hermaphrodites, producing both male and female gametes[citation needed] this is true of some animals (e.g. snails) and the majority of flowering plants.[29] In many cases, however, specialization of sex has evolved such that some organisms produce only male or only female gametes. The biological cause for an organism developing into one sex or the other is called sex determination.

In the majority of species with sex specialization, organisms are either male (producing only male gametes) or female (producing only female gametes). Exceptions are commonfor example, the roundworm C. elegans has an hermaphrodite and a male sex (a system called androdioecy).

Sometimes an organism's development is intermediate between male and female, a condition called intersex. Sometimes intersex individuals are called "hermaphrodite"; but, unlike biological hermaphrodites, intersex individuals are unusual cases and are not typically fertile in both male and female aspects.

In genetic sex-determination systems, an organism's sex is determined by the genome it inherits. Genetic sex-determination usually depends on asymmetrically inherited sex chromosomes which carry genetic features that influence development; sex may be determined either by the presence of a sex chromosome or by how many the organism has. Genetic sex-determination, because it is determined by chromosome assortment, usually results in a 1:1 ratio of male and female offspring.

Humans and other mammals have an XY sex-determination system: the Y chromosome carries factors responsible for triggering male development. The "default sex," in the absence of a Y chromosome, is female-like. Thus, XX mammals are female and XY are male. In humans, biological sex is determined by five factors present at birth: the presence or absence of a Y chromosome (which alone determines the individual's genetic sex), the type of gonads, the sex hormones, the internal reproductive anatomy (such as the uterus in females), and the external genitalia.[30]

XY sex determination is found in other organisms, including the common fruit fly and some plants.[29] In some cases, including in the fruit fly, it is the number of X chromosomes that determines sex rather than the presence of a Y chromosome (see below).

In birds, which have a ZW sex-determination system, the opposite is true: the W chromosome carries factors responsible for female development, and default development is male.[31] In this case ZZ individuals are male and ZW are female. The majority of butterflies and moths also have a ZW sex-determination system. In both XY and ZW sex determination systems, the sex chromosome carrying the critical factors is often significantly smaller, carrying little more than the genes necessary for triggering the development of a given sex.[32]

Many insects use a sex determination system based on the number of sex chromosomes. This is called X0 sex-determinationthe 0 indicates the absence of the sex chromosome. All other chromosomes in these organisms are diploid, but organisms may inherit one or two X chromosomes. In field crickets, for example, insects with a single X chromosome develop as male, while those with two develop as female.[33] In the nematode C. elegans most worms are self-fertilizing XX hermaphrodites, but occasionally abnormalities in chromosome inheritance regularly give rise to individuals with only one X chromosomethese X0 individuals are fertile males (and half their offspring are male).[34]

Other insects, including honey bees and ants, use a haplodiploid sex-determination system.[35] In this case diploid individuals are generally female, and haploid individuals (which develop from unfertilized eggs) are male. This sex-determination system results in highly biased sex ratios, as the sex of offspring is determined by fertilization rather than the assortment of chromosomes during meiosis.

For many species, sex is not determined by inherited traits, but instead by environmental factors experienced during development or later in life. Many reptiles have temperature-dependent sex determination: the temperature embryos experience during their development determines the sex of the organism. In some turtles, for example, males are produced at lower incubation temperatures than females; this difference in critical temperatures can be as little as 12C.

Many fish change sex over the course of their lifespan, a phenomenon called sequential hermaphroditism. In clownfish, smaller fish are male, and the dominant and largest fish in a group becomes female. In many wrasses the opposite is truemost fish are initially female and become male when they reach a certain size. Sequential hermaphrodites may produce both types of gametes over the course of their lifetime, but at any given point they are either female or male.

In some ferns the default sex is hermaphrodite, but ferns which grow in soil that has previously supported hermaphrodites are influenced by residual hormones to instead develop as male.[36]

Many animals and some plants have differences between the male and female sexes in size and appearance, a phenomenon called sexual dimorphism. Sex differences in humans include, generally, a larger size and more body hair in men; women have breasts, wider hips, and a higher body fat percentage. In other species, the differences may be more extreme, such as differences in coloration or bodyweight.

Sexual dimorphisms in animals are often associated with sexual selection the competition between individuals of one sex to mate with the opposite sex.[37] Antlers in male deer, for example, are used in combat between males to win reproductive access to female deer. In many cases the male of a species is larger than the female. Mammal species with extreme sexual size dimorphism tend to have highly polygynous mating systemspresumably due to selection for success in competition with other malessuch as the elephant seals. Other examples demonstrate that it is the preference of females that drive sexual dimorphism, such as in the case of the stalk-eyed fly.[38]

Other animals, including most insects and many fish, have larger females. This may be associated with the cost of producing egg cells, which requires more nutrition than producing spermlarger females are able to produce more eggs.[39] For example, female southern black widow spiders are typically twice as long as the males.[40] Occasionally this dimorphism is extreme, with males reduced to living as parasites dependent on the female, such as in the anglerfish. Some plant species also exhibit dimorphism in which the females are significantly larger than the males, such as in the moss Dicranum[41] and the liverwort Sphaerocarpos.[42] There is some evidence that, in these genera, the dimorphism may be tied to a sex chromosome,[42][43] or to chemical signalling from females.[44]

In birds, males often have a more colourful appearance and may have features (like the long tail of male peacocks) that would seem to put the organism at a disadvantage (e.g. bright colors would seem to make a bird more visible to predators). One proposed explanation for this is the handicap principle.[45] This hypothesis says that, by demonstrating he can survive with such handicaps, the male is advertising his genetic fitness to femalestraits that will benefit daughters as well, who will not be encumbered with such handicaps.

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Diagnosis of the classic form of Graves disease is easy and depends on the recognition of the cardinal features of the disease and confirmation by tests such as TSH and FTI. The differential diagnosis includes other types of thyrotoxicosis, such as that occurring in a nodular gland, accompanying certain tumors of the thyroid, or thyrotoxicosis factitia, and nontoxic goiter. Types of hypermetabolism that imitate symptoms of thyrotoxicosis must also enter the differential diagnosis. Examples are certain cases of pheochromocytoma, polycythemia, lymphoma, and the leukemias. Pulmonary disease, infection, parkinsonism, pregnancy, or nephritis may stimulate certain features of thyrotoxicosis. Treatment of Graves disease cannot yet be aimed at the cause because it is still unknown. One seeks to control thyrotoxicosis when that seems to be the major indication, or the ophthalmopathy when that aspect of the disease appears to be more urgent. The available forms of treatment, including surgery, drugs, and 131-I therapy, are reviewed. There is a difference of opinion as to which of these modalities is best, but to a large degree guidelines governing choice of therapy can be drawn. Antithyroid drugs are widely used for treatment on a long- term basis. About one-third of the patients undergoing long-term antithyroid therapy achieve permanent euthyroidism. Drugs are the preferred initial therapy in children and young adults. Subtotal thyroidectomy is a satisfactory form of therapy, if an excellent surgeon is available, but is less used in 2016. The combined use of antithyroid drugs and iodine makes it possible to prepare patients adequately before surgery, and operative mortality is approaching the vanishing point. Many young adults, are treated by surgery if antithyroid drug treatment fails. Currently, most endocrinologists consider RAI to be the best treatment for adults, and consider the associated hypothyroidism to be a minor problem. Evidence to date after well over five decades of experience indicates that the risk of late thyroid carcinoma must be near zero. The authors advise this therapy in most patients over age 40, and believe that it is not contraindicated above the age of about 15. Dosage is calculated on the basis of 131-I uptake and gland size. Most patients are cured by one treatment. Hypothyroidism.occurs with a fairly constant frequency for many years after therapy and may be unavoidable if cure of the disease is to be achieved by 131-I.. Many therapists accept this as an anticipated outcome of treatment. Thyrotoxicosis in children is best handled initially by antithyroid drug therapy. If this therapy does not result in a cure, surgery may be performed. Treatment with 131-I is accepted as an alternative form of treatment by some physicians, especially as age increase toward 15 years. Neonatal thyrotoxicosis is a rarity. Antithyroid drugs, propranolol and iodide may be required for several weeks until maternally-derived antibodies have been metabolized. The physician applying any of these forms of therapy to the control of thyrotoxicosis should also pay heed to the patients emotional needs, as well as to his or her requirements for rest, nutrition, and specific antithyroid medication. Consult our FREE web-book http://WWW.ENDOTEXT.ORG for complete coverage on this and related topics.

We note that there are currently available 2 very extensive Guidelines on Diagnosis and Treatment of Graves DiseaseThe 2016 ATA guideline http://online.liebertpub.com/doi/pdfplus/10.1089/thy.2016.0229 (270 pages), and the AACE 2011 version on Hyperthyroidism and other Causes of Thyrotoxicosis (65 pages)https://www.aace.com/files/hyperguidelinesapril2013.pdf. Both are well worth reviewing.

The diagnosis of Graves disease is usually easily made. The combination of eye signs, goiter, and any of the characteristic symptoms and signs of hyperthyroidism forms a picture that can hardly escape recognition (Fig -1). It is only in the atypical cases, or with coexisting disease, or in mild or early disease, that the diagnosis may be in doubt. The symptoms and signs have been described in detail in the section on manifestations of Graves disease. For convenience, the classic findings from the history and physical examination are grouped together in Table 1a and 1b.These occur with sufficient regularity that clinical diagnosis can be reasonably accurate. Scoring the presence or absence and severity of particular symptoms and signs can provide a clinical diagnostic index almost as reliable a diagnostic measure as laboratory tests(1).

Occasionally diagnosis is not at all obvious.In patients severely ill with other disease, in elderly patients with apathetic hyperthyroidism, or when the presenting symptom is unusual, such as muscle weakness, or psychosis, the diagnosis depends on clinical alertness and laboratory tests.

The diagnosis of Graves Disease does not only depend on thyrotoxicosis. Ophthalmopathy, or pretibial myxedema may occasionally occur without goiter and thyrotoxicosis, or even with spontaneous hypothyroidism. While proper classification can be debated, these patients seem to represent one end of the spectrum of Graves Disease. Thus we are usually making two coincident diagnoses:1)- Is the patient hyperthyroid? and 2)- Is the cause of the problem Graves disease ?.

Family history of any thyroid disease, especially Graves disease

TSH and FT4 assay-Once the question of thyrotoxicosis has been raised, laboratory data are required to verify the diagnosis, help estimate the severity of the condition, and assist in planning therapy. A single test such as the TSH or estimate of FT4 (free T4) may be enough, but in view of the sources of error in all determinations, most clinicians prefer to assess two more or less independent measures of thyroid function. For this purpose, an assessment of FT4 and sensitive TSH are suitable. As an initial single test, a sensitive TSH assay may be most cost-effective and specific. TSH should be 0 .1 U/ml in significant thyrotoxicosis, although values of .1 .3 are seen in patients with mild illness, especially with smoldering toxic multinodular goiter in older patients(1.1). TSH can be low in some elderly patients without evidence of thyroid disease. TSH can be normal or elevated only if there are spurious test results from heterophile antibodies or other cause, or the thyrotoxicosis is TSH-driven, as in a pituitary TSH-secreting adenoma or pituitary resistance to thyroid hormone. Measurement of FT4 or FTI (Free thyroxine index)is also usually diagnostic.The degree of elevation of the FT4 above normal provides an estimate of the severity of the disease. During replacement therapy with thyroxine the range of both FTI and fT4 values tend to be about 20% above the normal range, possibly because only T4, rather than T4 and T3 from the thyroid, is providing the initial supply of hormone. Thus many patients will have an fT4 or FTI above normal when appropriately replaced and while TSH is in the normal range. Except for this, elevations of fT4 not due to thyrotoxicosis are unusual, and causes are given in Table 3.

Of course the Total T4 level may normally be as high as 16 or 20 g/dl in pregnancy, and can be elevated without thyrotoxicosis in patients with familial hyperthyroxinemia due to abnormal albumin, the presence of hereditary excess TBG, the presence of antibodies binding T4 , the thyroid hormone resistance syndrome, and other conditions listed in Table 3. The T4 level may be normal in thyrotoxic patients who have depressed serum levels of T4 -binding protein or because of severe illness, even though they are toxic. Thus, thyrotoxicosis may exist when the total T4 level is in the normal range. However measurement of FT4, FT3 (Free T3), or FTI (Free Thyroxine Index) usually obviates this source of error and is the best test. In the presence of typical symptoms, one measurement of suppressed TSH or elevated fT4 is sufficient to make a definite diagnosis, although it does not identify a cause. If the fT4 is normal, repetition is in order to rule out error, along with a second test such as serum FT3. And it should be noted that in much of Europe FT3 is the preferred test, rather than FT4, and serves very well.

A variety of methods for FT4 determination have become available, including commercial kits. Although these methods are usually reliable, assays using different kits do not always agree among themselves or with the determination of FT4 by dialysis. Usually T4 and T3 levels are both elevated in thyrotoxicosis, as is the FTI (Free Thyroxin Index), or an index constructed using the serum T3 and rT3U levels, and the newer measures of FT3.

T3 and FT3 ASSAY-The serumT3 level determined by RIA is almost always elevated in thyrotoxicosis and is a useful but not commonly needed secondary test. Usually the serum T3 test is interpreted directly without use of a correction for protein binding, since alterations of TBG affect T3 to a lesser extent than T4. Any confusion caused by alterations in binding proteins can be avoided by use of a FT3 assay or T3 index calculated as for the FTI. Generally the FT3 assay is as diagnostically effective as the FT4. In patients with severe illness and thyrotoxicosis, especially those with liver disease or malnutrition or who are taking steroids or propranolol, the serum T3 level may not be elevated, since peripheral deiodination of T4 to T3 is suppressed (T4 toxicosis). A normal T3 level has also been observed in thyrotoxicosis combined with diabetic ketoacidosis. Whether or not these patients actually have tissue hypermetabolism at the time their serum T3 is normal is not entirely certain. In these patients the rT3 level may be elevated. If the complicating illness subsides, the normal pattern of elevated T4 , FTI, and T3 levels may return(5,6). Elevated T4 levels with normal serum T3 levels are also found in patients with thyrotoxicosis produced by iodine ingestion(7).

T3 Toxicosis Since 1957, when the first patient with T3 thyrotoxicosis was identified, a number of patients have been detected who had clinical thyrotoxicosis, normal serum levels of T4 and TBG, and elevated concentrations of T3 and FT3[8]. Hollander et al [9] found that approximately 4% of patients with thyrotoxicosis in the New York area fit this category. These patients often have mild disease but otherwise have been indistinguishable clinically from others with thyrotoxicosis. Some have had the diffuse thyroid hyperplasia of Graves disease, others toxic nodular goiter, and still others thyrotoxicosis with hyperfunctioning adenomas. Interestingly, in Chile, a country with generalized iodine deficiency, 12.5% of thyrotoxic subjects fulfilled the criteria for T3 thyrotoxicosis [10]. Asymptomatic hypertriiodothyronemia is an occasional finding several months before the development of thyrotoxicosis with elevated T4 levels [11]. Since T4 is normally metabolized to T3, and the latter hormone is predominantly the hormone bound to nuclear receptors, it makes sense that elevation of T3 alone is already indicative of thyrotoxicosis.

Thyroid Isotope uptake-In patients with thyrotoxicosis the RAIU (Radioactive Iodine Uptake) at 24 hours is characteristically above normal. In the United States, which has had an increasing iodine supply in recent years, the upper limit of normal is now about 25% of the administered dose. This value is higher in areas of iodine deficiency and endemic goiter. The uptake value at a shorter time interval, for example 6 hours, is as valid a test and may be more useful in the infrequent cases having such a rapid isotope turnover that uptake has fallen to normal by 24 hours. If there is reason to suspect that thyroid isotope turnover is rapid, it is wise to do both a 6- and a 24-hour RAIU determination during the initial laboratory study. As noted below, rapid turnover of 131-I can seriously reduce the effectiveness of 131-I therapy. Similar studies can be done with 123-I and also technetium. Because of convenience, and since serum assays of thyroid hormones and TSH are reliable and readily available, the RAIU is now infrequently determined unless 131-I therapy is planned.. It is however useful in patients who are mildly thyrotoxic for factitia thyrotoxicosis, subacute thyroiditis and painless thyroiditis in whom RAIU is low, thus confirming thyrotoxicosis in the absence of elevated RAIU. This may include patients with brief symptom duration, small goiter, or lacking eye signs, absent family history, or negative antibody test result. Obviously other causes of a low RAIU test need to be considered and excluded. Tests measuring suppressibility of RAIU are of historical interest(13-15)

Thyroid IsotopeScanning-Isotope scanning of the thyroid has a limited role in the diagnosis of thyrotoxicosis. It is useful in patients in whom the thyroid is difficult to feel or in whom nodules (single or multiple) are present that require evaluation, or rarely to prove the function of ectopic thyroid tissue. Nodules may be incidental, or may be the source of thyrotoxicosis (toxic adenoma), or may contribute to the thyrotoxicosis that also arises from the rest of the gland. Scanning should usually be done with 123-I in this situation, in order to combine it with an RAIU measurement.

Thyroid Ultrasound- US exam of the thyroid is sometimes of value in diagnosis. For example, if a possible nodule is detected on physical exam. It also may confirm hypoechogenicity or intense vascularity of Graves disease if a color Doppler flow exam is done.

Antithyroid Antibodies Determination of antibody titers provides supporting evidence for Graves disease. More than 95% of patients have positive assays for TPO (thyroperoxidase or microsomal antigen), and about 50% have positive anti-thyroglobulin antibody assays. In thyroiditis the prevalence of positive TG antibody assays is higher. Positive assays prove that autoimmunity is present, and patients with causes of thyrotoxicosis other than Graves disease usually have negative assays. During therapy with antithyroid drugs the titers characteristically go down, and this change persists during remission. Titers tend to become more elevated after RAI treatment.

Antibodies to TSH-Receptor-Thyrotrophin receptor antibody (TRAb) assays have become readily available, and a positive result strongly supports the diagnosis of Graves disease(15.1). Determination of TRAb is not required for the diagnosis, but the implied specificity of a positive test provides security in diagnosis, and for this reason the assay is now widely used. The assay is valuable as another supporting fact in establishing the cause of exophthalmos, in the absence of thyrotoxicosis. High maternal levels suggest possible fetal or neonatal thyrotoxicosis. TRAb assays measure any antibody that binds to the TSH-R. Assays for Thyroid Stimulating Antibodies (TSAb,TSI) are less available, but are more specific for the diagnosis. Using current tests, both are positive in about 90% of patients with Graves disease who are thyrotoxic. Second generation assays becoming available use monoclonal anti-TSH-R antibodies and biosynthetic TSH-R in coated tube assays, are reported to reach 99% specificity and sensitivity(15.2,15.3,3). Although rarely required, serial assays are of interest in following a patients course during antithyroid drug therapy, and a decrease predicts probable remission(15.4).

Other Assays Rarely Used-General availability of assays that can reliably measure suppressed TSH has made this the gold standard to which other tests must be compared, and has effectively eliminated the need for most previously used ancillary tests. There are only rare causes of confusion in the TSH assay. Severe illness, dopamine and steroids, and hypopituitarism, can cause low TSH, but suppression below 0.1 /ml is uncommon and below 0.05 /ml is exceptional, except in thyrotoxicosis. Thyrotoxicosis is associated with normal or high TSH in patients with TSH producing pituitary tumors and selective pituitary resistance to thyroid hormone. If TSH, FT4, TRAb, and other tests noted above do not establish the diagnosis, it may be wise to do nothing further except to observe the course of events. In patients with significant thyroid hyperfunction, the symptoms and signs will become clearer, and the laboratory measurements will fall into line. Measurement of BMR, T3 suppression of RAIU, TRH testing, and clinical response to KI are of historical interest.

Graves disease must be differentiated from other conditions causing thyrotoxicosis. (Table -4).

Thyrotoxicosis factitia-Thyrotoxicosis may be caused by taking T4 or its analogs, most commonly due to administration of excessive replacement hormone by the patients physician. Hormone may be taken surreptitiously by the patient for weight loss or psychologic reasons. The typical findings are a normal or small thyroid gland, a low131-I uptake, a low serum TG, and, of course, a striking lack of response to antithyroid drug therapy. The problem can easily be confused with painless thyroiditis, but in thyrotoxicosis factitia, the gland is typically small.

Toxic nodular goiter is usually distinguished by careful physical examination and a history of goiter for many years before symptoms of hyperthyroidism developed. The thyrotoxicosis comes on insidiously, and often, in the older people usually afflicted, symptoms may be mild, or suggest another problem such as heart disease. The thyroid scan may be diagnostic, showing areas of increased and decreased isotope uptake. The results of assays for antithyroid antibodies, including TRAb, are usually negative. TMNG is typically produced by activating somatic mutations in TSH-R in one or more nodules, allowing them to enlarge and become functional even in the absence of TSH stimulation. (Interestingly, cats are well known to develop hyperthyroidism, with thyroid autonomy, often due to TSH-R gene mutations as seen in humans.(16))

Hyperfunctioning solitary adenoma is suggested on the physical finding of a palpable nodule in a otherwise normal gland, and is proved by a scintiscan demonstrating preferential radioisotope accumulation in the nodule. This type of adenoma must be differentiated from congenital absence of one of the lobes of the thyroid. Toxic nodules typically present in adults with gradually developing hyperthyroidism and a nodule > 3 cm in size. These nodules are usually caused by activating somatic mutations in the TSH-R, which endows them with mildly increased function, compared to normal tissue, even in the absence of TSH. These nodules are usually, but not always, monoclonal(17). In adults toxic nodules are very rarely malignant. Rarely, functioning thyroid carcinomas produce thyrotoxicosis. The diagnosis is made by the history, absence of the normal thyroid, and usually widespread functioning metastasis in lung or bones. Invasion of the gland by lymphoma has produced thyrotoxicosis, presumably due to thyroid destruction (18).

Thyrotoxicosis associated with subacute thyroiditis is usually mild and transient, and the patient lacks the physical findings of long-standing thyrotoxicosis. If thyrotoxicosis is found in conjunction with a painful goiter and low or absent 131-I uptake, this diagnosis is likely. Usually the erythrocyte sedimentation rate (ESR) and CRP are greatly elevated, and the leukocyte count may also be increased. Occasionally the goiter is non-tender. Antibody titers are low or negative. Many patients have the HLA-B35 antigen, indicating a genetic predisposition to the disease. The rare TSH secreting pituitary adenoma will be missed unless one measures the plasma TSH level, or until the enlargement is sufficient to produce deficiencies in other hormones, pressure symptoms, or expansion of the sella turcica(19). These patients have thyrotoxicosis with inappropriately elevated TSH levels and may/or may not secrete more TSH after TRH stimulation. The characteristic finding is a normal or elevated TSH, and an elevated TSH alpha subunit level in blood, measured by special RIA. TRAbs are not present. Exophthalmos, and antibodies of Graves disease are absent. Family history is sometimes positive for a similar condition. Demonstration of a suppressed TSH level excludes these rare cases.

The category of patients with thyrotoxicosis and inappropriately elevated TSH levels also includes the rare persons with pituitary T3 resistance as a part of the Resistance to Thyroid Hormone syndrome caused by TH Receptor mutations. The syndrome of Pituitary Thyroid Hormone Resistance is usually marked by mild thyrotoxicosis, mildly elevated TSH levels, absence of pituitary tumor, a generous response to TRH, no excess TSH alpha subunit secretion [19,20, 21],and by TSH suppression if large doses of T3 are administered. Final diagnosis depends on laboratory demonstration of a mutation in the TR gene, if possible. Hyperthyroidism caused by excess TRH secretion is a theoretical but unproven possibiity.

Administration of large amounts of iodide in medicines, for roentgenographic examinations, or in foods can occasionally precipitate thyrotoxicosis in patients with multinodular goiter or functioning adenomas. This history is important to consider since the illness may be self-limiting. Induction of thyrotoxicosis has also been observed in apparently normal individuals following prolonged exposure to organic iodide containing compounds such as antiseptic soaps and amiodarone. Amiodarone is of special importance since the clinical problem often is the presentation of thyrotoxicosis in a patient with serious cardiac disease including dysrythmia. Amodarone can induce thyrotoxicosis in patients without known prior thyroid disease, or with multinodular goiter. The illness appears to come in two forms. In one the RAIU may be low or normal. In the second variety , which appears to be more of a thyroiditis-like syndrome, the RAIU is very suppressed, and IL-6 may be elevated. In either case TSH is suppressed, FTI may be normal or elevated, but T3 is elevated if the patient is toxic. Antibodies are usually negative.

An increasingly recognized form of thyrotoxicosis is the syndrome described variously as painless thyroiditis, transient thyrotoxicosis, or hyperthyroiditis. Its hallmarks are self-limited thyrotoxicosis, small painless goiter, and low or zero RAIU(22,23). The patients usually have no eye signs, a negative family history, and often positive antibody titers. This condition is due to autoimmune thyroid disease, and is considered a variant of Hashimotos Thyroiditis. It occurs sporadically, usually in young adults. It frequently occurs 3 12 weeks after delivery, sometimes representing the effects of immunologic rebound from the immunosuppressive effects of pregnancy in patients with Hashimotos thyroiditis or prior Graves Disease, and is called Post Partum Thyroiditis(22-25). The course typically includes development of a painless goiter, mild to moderate thyrotoxicosis, no eye signs, remission of symptoms in 3 -20 weeks, and often a period of hypothyroidism before return to euthyroid function. The cycle may be repeated several times. Histologic examination shows chronic thyroiditis, but it is not typical of Hashimotos disease or subacute thyroiditis and may revert to normal after the attack(26). In most patients, the thyrotoxic episode occurs in the absence of circulating TSAb. This finding suggests that the pathogenesis is quite distinct from that in Graves disease. The thyrotoxicosis is caused by an inflammation-induced discharge of preformed hormone due to the thyroiditis. The T4/T3 ratio is higher than in typical Graves disease,and thyroid iodine stores are depleted. Since the thyrotoxicosis is due to an inflammatory process, therapy with antithyroid drugs or potassium iodide is usually to no avail, and RAI treatment of course cannot be given when RAIU is suppressed. Propranolol is usually helpful for symptoms. Glucocorticoids may be of help if the process often transient and mild requires some form of therapy. Propylthiouracil and/or ipodate can be used to decrease T4 to T3 conversion and will ameliorate the illness. Repeated episodes may be handled by surgery or by RAI therapy during a remission. Occasionally painless post-partum thyroiditis is followed by typical Graves Disease(27-29.1).

Hyperemisis gravidarum is frequently associated with elevated serum T4 , FTI, and variably elevated T3, and suppressed TSH. The abnormalities in thyroid function are caused by high levels of hCG. This molecule, or a closely related form, share enough homology with TSH so that it has about 1/1000 the thyroid stimulating activity of TSH, and can produce thyroid stimulation or thyrotoxicosis(29.12-29.14). It is typically self limited without specific treatment, disappears with termination of pregnancy, but may occasionally require anti-thyroid treatment temporarily or throughout pregnancy(29.3). Patients with minimal signs and symptoms, small or no goiter, and elevation of FTI up to 50 % above normal probably do not require treatment. Rarely those with goiter, moderate or severe clinical evidence of thyrotoxicosis, highly elevated T4 and T3 and suppressed TSH are best treated with antithyroid drugs. If antibodies are positive or eye signs are present, the picture is usually interpreted as a form of Graves disease. Familial severe hyperemesis gravidarum with fetal loss has been reported with an activating germline mutation in the TSH-R, which made it specifically more sensitive to activation by hCG(.29.2,29.3). Hyperthyroidism can be induced by hyperplacentosis, which is characterized by increased placental weight and circulating hCG levels higher than those in normal pregnancy(29.4). After hysterotomy, hCG levels declined in the one case reported and hyperthyroidism was corrected.

Congenital hyperthyroidism caused by a germ-line activating mutation in the TSH-R has recently been recognized . The mutations are usually single aminoacid transitions in the extracellular loops or transmembrane segments of the receptor trans-membrane domain. The diagnosis may be difficult to recognize in the absence of a family history. However the patients lack eye signs, and have negative assays for antibodies(29.2, 29.3)

Hydatidiform moles, choriocarcinomas, and rarely seminomas secrete vast amounts of hCG. hCG, with an alpha subunit identical to TSH , and beta subunit related to TSH , that binds to and activates the thyroid TSH receptor with about 1/1,000th the efficiency of TSH itself (Fig.-3)(30-33). Current evidence indicates that very elevated levels of native hCG or perhaps desialated hCG, cause the thyroid stimulation. Many patients have goiter or elevated thyroid hormone levels or both, but little evidence of thyrotoxicosis, whereas others are clearly thyrotoxic. Diagnosis rests on recognizing the tumor (typically during or after pregnancy) and measurement of hCG. Therapy is directed at the tumor.

Hyperthyroidism also is seen as one manifestation of autoimmune thyroid disease induced by interferon-alpha treatment of chronic hepatitis C. It can be self limiting, or severe enough to require cessation of IFN, or in some cases continue on after INF is stopped(33.1).

Hyperthyroidism also occurs during immune reconstitution seen after effective anti-viral therapy of patients with HIV(33.2), has occurred during recovery of low lymphocyte levels induced by therapy with CAMPATH in patients with Multiple sclerosis, has occurred after cessation of immune-suppressive treatment in patients with T1DM.

It should be remembered that thyrotoxicosis is today not only a clinical but also a laboratory diagnosis. Consistent elevation of the fT4 , and the T3 level, and suppressed TSH, or only suppression of TSH, can indicate that thyrotoxicosis is present even in the absence of clear-cut signs or symptoms These elevations themselves are a sufficient indication for therapy, especially in elderly patients with coincident cardiac disease(33a,b). Antithyroid drug treatment of patients with subclinical hyperthyroidism was found to result in a decrease in heart rate, decrease in number of atrial and ventricular premature beats, a reduction of the left ventricular mass index, and left ventricular posterior wall thickness, as well as a reduction in diastolic peak flow velocity. These changes are considered an argument for early treatment of subclinical hyperthyroidism. Subclinical hyperthyroidism may disappear or evolve into Graves hyperthyroidism, or when caused by MNG, persist for long periods unchanged. Individuals of any age with consistent suppression of TSH should be fully evaluated to determine if evidence of hyperthyroidism is present, or there is coincident disease that might be aggrevated by hyperthyroidism. SCH with TSH of 0.2-0.3.5 may not need treatment. Individuals with TSH at or below 0.1uU/ml most likely will require treatment by one of the methods described below.

Apathetic hyperthyroidism designates a thyrotoxic condition characterized by fatigue, apathy, listlessness, dull eyes, extreme weakness, often congestive heart failure, and low-grade fever.[ 34, 35] Often such patients have small goiters, modest tachycardia, occasionally cool and even dry skin, and few eye signs. The syndrome may, in some patients, represent an extreme degree of fatigue induced by long-standing thyrotoxicosis. Once the diagnosis is considered, standard laboratory tests should confirm or deny the presence of thyrotoxicosis even in the absence of classical symptoms and signs.

Other diagnostic problems Two common diagnostic problems involve (1) the question of hyperthyroidism in patients with goiter of another cause, and (2) mild neuroses such as anxiety, fatigue states, and neurasthenia. Most patients with goiter receive a battery of examinations to survey their thyroid function at some time. Usually these tests are done more for routine assessment than because there is serious concern over the possibility of thyrotoxicosis. In the absence of significant symptoms or signs of hyperthyroidism and ophthalmologic problems, a normal FTI or TSH determination is sufficiently reassuring to the physician and the patient. Of course, the most satisfactory conclusion of such a study is the identification of an alternate cause for enlargement of the thyroid. Some patients complain of fatigue and palpitations, weight loss, nervousness, irritability, and insomnia. These patients may demonstrate brisk reflex activity, tachycardia (especially during examinations), perspiration, and tremulousness. In the abscence of thyrotoxicosis, the hands are more often cool and damp rather than warm and erythematous. Serum TSH assay should be diagnostic.

Mild and temporary elevation of the FTI may occur if there is a transient depression of TBG production for example, when estrogen administration is omitted. This problem is occasionally seen in hospital practice, usually involving a middle-aged woman receiving estrogen medication that is discontinued when the patient is hospitalized. Estrogen withdrawal leads to decreased TBG levels and a transiently elevated FTI. After two to three weeks, both the T4 level and the FTI return to normal ( Table -3). In the differential diagnosis of heart disease, the possibility of thyrotoxicosis must always be considered. Some cases of thyrotoxicosis are missed because the symptoms are so conspicuously cardiac that the thyroid background is not perceived. This is especially true in patients with atrial fibrillation. Many disorders may on occasion show some of the features of hyperthyroidism or Graves disease. In malignant disease, especially lymphoma, weight loss, low grade fever, and weakness are often present. Parkinsonism in its milder forms may initially suggest thyroid disease. So also do the flushed countenance, bounding pulse, thyroid hypertrophy, and dyspnea of pregnancy. Patients with chronic pulmonary disease may have prominent eyes, tremor, tachycardia, weakness, and even goiter from therapeutic use of iodine. One should remember the weakness, fatigue, and jaundice of hepatitis and the puffy eyes of trichinosis and nephritis. Cirrhotic patients frequently have prominent eyes and lid lag, and the alcoholic patient with tremor, prominent eyes, and flushed face may be initially suspected of having thyrotoxicosis. Distinguishing between Graves disease with extreme myopathy and myopathies of other origin can be clinically difficult. The term chronic thyrotoxic myopathy is used to designate a condition characterized by weakness, fatigability, muscular atrophy, and weight loss usually associated with severe thyrotoxicosis. Occasionally fasciculations are seen. The electromyogram result may be abnormal. If the condition is truly of hyperthyroid origin, the thyroid function tests are abnormal and the muscular disorder is reversed when the thyrotoxicosis is relieved. Usually a consideration of the total clinical picture and assessment of TSH and FTI are sufficient to distinguish thyrotoxicosis from polymyositis, myasthenia gravis, or progressive muscular atrophy. True myasthenia gravis may coexist with Graves disease, in which case the myasthenia responds to neostigmine therapy. (The muscle weakness of hyperthyroidism may be slightly improved by neostigmine, but never relieved.) Occasionally electromyograms, muscle biopsy, neostigmine tests, and ACH-receptor antibody assays must be used to settle the problem.

No treatment is ideal and thus indicated in all patients ( 35.1).Three forms of primary therapy for Graves disease are in common use today: (1) destruction of the thyroid by 131-I; (2) blocking of hormone synthesis by antithyroid drugs; and (3) partial or total surgical ablation of the thyroid. Iodine alone as a form of treatment was widely used in the past, but is not used today because its benefits may be transient or incomplete and because more dependable methods became available. Iodine is primarily used now in conjunction with antithyroid drugs to prepare patients for surgical thyroidectomy when that plan of therapy has been chosen. There is, however, some revival of interest in use of iodine treatment as described subsequently. Roentgen irradiation was also used in the past, but is not currently [36]. Suppression of the autoimmune response is being attempted, and currently new treatments blocking the action of Thyroid Stimulating Immunoglobulins are being investigated.

Selection of therapy depends on a multiplicity of considerations [36.1]. Availability of a competent surgeon, for example, undue emotional concern about the hazards of 131-I irradiation, or the probability of adherence to a strict medical regimen might govern ones decision regarding one program of treatment as opposed to another. More than 90% of patients are satistactorly treated cumulating the effects of these treatment.(36.2) Fig. 2

Antithyroid drug therapy offers the opportunity to avoid induced damage to the thyroid (and parathyroids or recurrent nerves), as well as exposure to radiation and operation. In recent studies patients with thyroids under 40 gm weight, with low TRAb levels, and age over 40, were most likely to enter remission (in up to 80%) (36.3, 36.31). The difficulties are the requirement of adhering to a medical schedule for many months or years, frequent visits to the physician, occasional adverse reactions, and, most importantly, a disappointingly low permanent remission rate. Therapy with antithyroid drugs is used as the initial modality in most patients under age 18, in many adults through age 40, and in most pregnant women(36.31). Remission is most likely in young patients, with small thyroids, and mild disease. ATDs may be preferred in elderly patients, those with serious co-morbidities and who have been previously operated upon.

Iodine-131 therapy is quick, easy, moderatly expensive, avoids surgery, and is without significant risk in adults and probably teenagers. The larger doses required to give prompt and certain control generally induce hypothyroidism, and low doses are associated with a frequent requirement for retreatment or ancillary medical management over one to two years. 131-I is used as the primary therapy in most persons over age 40 and in most adults above age 21 if antithyroid drugs fail to control the disease. Treatment of children with 131-I is less common, as discussed later. It can be used in the elderly and those with co-morbidities with precautions.

Surgery, which was the main therapy until 1950, has been to a large extent replaced by 131-I treatment. As the high frequency of 131-I induced hypothyroidism became apparent, some revival of interest in thyroidectomy occurred. The major advantage of surgery is that definitive management is often obtained over an 8- to 12-week period, including preoperative medical control, and many patients are euthyroid after operation. Its well-known disadvantages include expense, surgery itself, and the risks of recurrent nerve and parathyroid damage, hypothyroidism, and recurrence. Nevertheless, if a skillful surgeon is available, surgical management may be used as the primary or secondary therapy in many young adults, as the secondary therapy in children poorly controlled on antithyroid drugs, in pregnant women requiring excessive doses of antithyroid drugs, in patients with significant exophthalmos, and in patients with coincident suspicious thyroid nodules. Early total thyroidectomy has been recommended for treating older, chronically ill patients with thyrotoxic storm if high-dose thionamide treatment, iopanoic acid, and glucocorticoids fail to improve the patients condition within 12 24 hours (36.4).

Two recent surveys reporting trends in therapeutic choices made by thyroidologists have been published [37]. In Europe, most physicians tended to treat children and adults first with antithyroid drugs, and adults secondarily with 131-I or less frequently surgery. Surgery was selected as primary therapy for patients with large goiters. 131-I was selected as the primary treatment in older patients. Most therapists attempted to restore euthyroidism by use of 131-I or surgery. In the United States, 131-I is the initial modality of therapy selected by members of the American Thyroid Association for management of uncomplicated Graves disease in an adult woman [38]. Two-thirds of these clinicians attempt to give 131-I in a dosage calculated to produce euthyroidism, and one-third plan for thyroid ablation.

Introduction-In many thyroid clinics 131-I therapy is now used for most patients with Graves disease who are beyond the adolescent years. It is used in most patients who have had prior thyroid surgery, because the incidence of complications, such as hypoparathyroidism and recurrent nerve palsy, is especially high in this group if a second thyroidectomy is performed. Likewise, it is the therapy of choice for any patient who is a poor risk for surgery because of complicating disease. Surgery may be preferred in patients with significant ophthalmopathy, often combined with prednisone prophylaxis.

Treatment of children-The question of an age limit below which RAI should not be used frequently arises. With lengthening experience these limits have been lowered. Several studies with average follow-up periods of 12 15 years attest to the safety of 131-I therapy in adults [ 39- 41]. In two excellent studies treated persons showed no tendency to develop thyroid cancer, leukemia, or reproductive abnormalities, and their children had no increase in congenital defects or evidence of thyroid damage [ 42- 44]. Franklyn and co workers recently reported on a population based study of 7417 patients treated with 131-I for thyrotoxicosis in England [44.1]. They found an overall decrease in incidence of cancer mortality, but a specific increase in mortality from cancer of the small bowel (7 fold) and of the thyroid (3.25) fold. The absolute risk remains very low, and it is not possible to determine whether the association is related to the basic disease, or to radioiodine treatment. Although there is much less data on long term results in children, there is a increased use of this treatment in teenagers age 15-18, as discussed below. The epidemic of thyroid cancer apparently induced by radioactive iodine isotopes in infants and children living around Chernobyl suggests caution in use of 131-I in younger children. Since the possibility of a general induction of cancer by 131-I is of central concern, it is interesting to calculate the risk in children using the data presented by Rivkees et al (44.2) who are proponents of use of RAI for therapy in young children..The risk of death from any cancer due specifically to radiation exposure is noted by these authors to be 0.16%/rem for children, and the whole body radiation exposure from RAI treatment at age 10 to be 1.45 rem/mCi administered. Rivkees et al advise treatment with doses of RAI greater then 160 uCi/gram thyroid, to achieve a thyroidal radiation dose of at least 150Gy (about 15000 rads). Assuming a reasonable RAIU of 50% and gland size of 40 gm, the administered dose would thus be 40(gm) x 160uCi/gm x 2 (to account for 50% uptake) =12.8 mCi. Thus the long term cancer death risk would be 12.8 (mCi) x 1.45 rem (per mCi) x 0.16% (per rem) = 3%. For a dose of 15mCi the theoretical incremental risk of a later radiation-induced cancer mortality would be 4% at age 5, 2% at age 10, and 1% at age 15. Whether or not accepting a specific 2-4% risk of death from any cancer because of this treatment is of course a matter of judgment by the physician and family. However, this would seem to many persons to constitute a significant risk that might be avoided. We note that this is a thoretical risk, based on known effects of ioniing radiation to induce malignancies, but not so far proven in this setting.

Low 131-I uptake-Certain other findings may dictate the choice of therapy. Occasionally, the 131-I uptake is significantly blocked by prior iodine administration. The effect of iodide dissipates in a few days after stopping exposure, but it may take 3-12 weeks for the effect of amiodarone or IV contrast dyes to be lost. One may either wait for a few days to weeks until another 131-I tracer indicates that the uptake is in a treatable range or use an alternative therapeutic approach such as antithyroid drugs. Coincident nodule(s)-Sometimes a patient with thyrotoxicosis harbors a thyroid gland with a configuration suggesting the presence of a malignant neoplasm. These patients probably should have surgical exploration. While FNA may exclude malignancy, the safety of leaving a highly irradiated nodule in place for many years is not established. Currently few patients who will have RAI therapy are subjected to ultrasonagraphy or scintiscaning. However Stocker et al. found that 12% of Graves patients had cold defects on scan, and among these half were referred for surgery. Six of 22, representing 2% of all Graves patients, 15% of patients with cold nodules, 25% of patients with palpable nodules, and 27% of those going to surgery, had papillary cancer in the location corresponding to the cold defect. Of these patients, one had metastasis to bone and two required multiple treatments with radioiodine. They argue for evaluating patients with a thyroid scintigram and further diagnostic evaluation of cold defects(44.3). Certainly any patient with GD in whom a thyroid nodule is detected, deserves consideration for surgical treatment

Ophthalmopathy-131-I therapy causes an increase in titers of TSH-R Abs, and anti-TG or TPO antibodies, which reflects an activation of autoimmunity. It probably is due to release of thyroid antigens by cell damage, and possibly destruction of intrathyroidal T cells. Many thyroidologists are convinced that 131-I therapy can lead to exacerbation of infiltrative ophthalmopathy, perhaps because of this immunologic response. Tallstedt and associates published data indicating that 131-I therapy causes exacerbation of ophthalmopathy in nearly 25% of patients, while surgery is followed by this response in about half as many.The same group conducted a second randomized trial (44.3) with a follow-up of 4 yr. Patients with a recent diagnosis of Graves hyperthyroidism were randomized to treatment with iodine-131 (163 patients) or 18 months of medical treatment (150 patients). Early substitution with L-T4 was given in both groups.: Worsening or development of eye problems was significantly more common in the iodine-131 treatment group (63 patients; 38.7%) compared with the medical treatment group (32 patients; 21.3%) (P < 0.001). This adverse effect of RAI therapy has since been confirmed in multiple meta-analyses of randomized studies (44.4-44.7) Thus, as described below, patients with significant ophthalmopathy may receive corticosteroids along with131-I, or may be selected for surgical management. The indications and contraindications for 131-I therapy are given in Table 5.

There are two basically different goals in 131-I dose selection. The traditional approach has been to attempt to give the thyroid 1) sufficient radiation to return the patient to euthyroidism, but not induce hypothyroidism. An alternative approach is to intend to 2) induce hypothyroidism, or euthyroidism and avoid any possible return of hyperthyroidism.

BackgroundThe dosage initially was worked out by a trial-and-error method and by successive approximations. By 1950, the standard dose was 160 uCi 131-I per gram of estimated thyroid weight. Of course, estimating the weight of the thyroid gland by examination of the neck is an inexact procedure, but can now be made more accurate by use of ultrasound. Also, marked variation in radiation sensitivity no doubt exists and cannot be estimated at all. It was gratifying that in practice this dosage scheme worked well enough. In the early 1960s, it was recognized that a complication of RAI therapy was a high incidence of hypothyroidism. This reached 20 40% in the first year after therapy and increased about 2.5% per year, so that by 10 years 50 80% of patients had low function [45,46]. In an effort to reduce the incidence of late hypothyroidism, Hagen and colleagues reduced the quantity of 131-I to 0.08 mCi per gram of estimated gland weight [48]. No increase was reported in the number of patients requiring retreatment, and there was a substantial reduction in the incidence of hypothyroidism. Most of these patients were maintained on potassium iodide for several months after therapy, in order to ameliorate the thyrotoxicosis while the radioiodine had its effect [ 49, 50]. Patients previously treated with 131-I are sensitive to and generally easily controlled by KI. However KI often precipitates hypothyroidism in these patients, which may revert to hyperthyroidism when the KI is discontinued.

Over the years some effort was made to refine the calculation. Account was taken of uptake, half-life of the radioisotope in the thyroid, concentration per gram, and so on, but it is evident that the result in a given instance depends on factors that cannot be estimated precisely [47,]. One factor must be the tendency of the thyroid to return to normal if a dose of radiation is given that is large enough to make the gland approach, for a time, a normal functional state. In many patients, cure is associated with partial or total thyroid ablation. Although we, and many endocrinologists, attempt to scale the dose to the particular patient, some therapists believe it is futile, advocate giving up this attempt, and provide a standard dose giving up to 10000 rads to the thyroid(47.1). Leslie et al reported a comparison of fixed dose treatment and treatment adjusted for 24 hour RAIU, using low or high doses, and found no difference in outcome in either rate of control or induction of hypothyroidism on comparison of the methods. They favor the use of a fixed dose treatment with a single high or low dose (47.2).

Many attempts have been made to improve the therapeutic program by giving the RAI in smaller doses. Reinwein et al [51]. studied 334 patients several years after they had been treated with serial doses of less than 50 uCi 131-I per gram of estimated thyroid weight. One-third of these patients had increased levels of TSH, although they were clinically euthyroid. Only 3% were reported to be clinically hypothyroid.

Dosage adjustmentsmade to induce euthyroidism usually include a factor inc reassing with gland size, a standard dose in microCuries per gram, and a correction to account for 131-I uptake [52]. ALow Dose Protocol was designed to compensate for the apparent radiosensitivity of small glands and resistance of larger glands [53]. Using this approach, after one year, 10% of patients were hypothyroid, 60% are euthyroid, and 30% remained intrinsically toxic [53], although euthyroid by virtue of antithyroid drug treatment. At ten year follow-up, 40% were euthyroid and 60% hypothyroid. A problem with low-dose therapy is that about 25% of patients require a second treatment and 5% require a third. Although this approach reduces early hypothyroidism, it does so at a cost in time, money and patient convenience (Fig. 2). To answer these problems, patients can be re-treated, if need be, within six months, and propranolol and antithyroid drugs can be given between 131-I doses if needed. Unfortunately, experience shows that even low-dose 131-Itherapy is followed by a progressive development of hypothyroidism in up to 40 50% of patients ten years after therapy[ 54- 57].

Thyroid rads, avg.

Impressed by the need to retreat nearly a third of patients, a Moderate Dose Protocol was developed Table -6). This is a fairly conventional program with a mean dose of about 9 mCi. The 131-I dosage is related to gland weight and RAIU, and is increased as gland weight increases. The calculation used is as follows:

uCi given = (estimated thyroid weight in grams) X (uCi/g for appropriate weight from Table 6) / (fractional RAIU at 24 hours) (For readers who may find difficult the conversion of older units in Curies, rads, and rems to newer units of measurement, see Table -7.)

Thyroid rads, avg.

Probably it is wise to do uptakes and treatment using either capsules or liquid isotope for both events. Rini et al have reported that RAIU done with isotope in a capsule appears to give significantly lower values (25 30% lower) than when the isotope is administered in liquid form, and this can significantly influence the determination of the dosage given for therapy(57.1). Berg et al report using a relatively similar protocol (absorbed doses of 100-120 Gy) and that 93% of their patients required replacement therapy after 1-5 years [57.2]. Many studies have presented methods for more accurately delivering a specific radiation dose to the thyroid, and report curing up to 90% of patients, with low incidence of recurrence or hypothyroidism(57.3, 57.4). Franklyn and co-workers analyzed their data on treatment of 813 hyperthyroid patients with radioactive iodide and corroborate many of the previously recognized factors involved in response. Lower dose (in this case 5 mCi), male gender, goiters of medium or large size and severe hyperthyroidism were factors that were associated with failure to cure after one treatment. They suggest using higher fixed initial doses of radioiodine for treating such patients (58.2), as do Leslie et al(58.4). Santos et al (58.4) compared fixed doses of 10 and 15mCi and found no difference in outcome at 12 months post treatment. These authors suggest a standard 10mCi dose, with the larger dose reserved for larger glands.

Planned thyroid partial or complete ablation-All attempts to induce euthyroidism by a calculated moderate dose protocol end up with some patients hypothyroid, and others with persistent hyperthyroidism requiring further treatment. At this time many physicians giving 131-I therapy make no attempt to achieve euthyroidism, and instead use a dose sufficient to largely destroy the thyroid, followed by L- T4 replacement therapy [58]. For example, a dose is given that will result in 7-20 mCi retained at 24 hrs, which is intended to induce hypothyroidism, accepting that in some (or many) patients this will ablate the thyroid completely. A dose of 30 Mci was found to offer a slightly higher cure rate, not surprisingly, at one year than 15 Mci (95 vs 74% (58.1), They argue that this is realistic and preferable since it offers 1) near certainty of prompt control, 2) avoids any chance of persistent or recurrent disease, 3)there is no benefit in having residual thyroid tissue, and 4) hypothyroidism is inevitable in most patients given RAI. Probably many patients given this treatment do in fact have some residual thyroid tissue that is either heavily damaged or reduced in amount so that it can not produce normal amounts of hormone. So far there is no evidence, in adults, that this residual radiated tissue will develop malignant change. There is no certainty at this time that one approach is better than the other. It may be worth remembering that over 50% of patients given calculated moderate dose therapy remain euthyroid after ten years and can easily be surveyed at yearly intervals for hypothyroidism. When giving large doses of 131-I it is prudent to calculate the rads delivered to the gland (as above), which can reach 40-50,000rads. Such large doses of radiation can cause clinically significant radiation thyroiditis, and occasionally damage surrounding structures. And lastly, a speculation. Practitioners comment that the incidence of serious ophthalmopathy seems to be less that in former decades. Prompt diagnosis and therapy might contribute to such a change. Another factor could be the more common ablation of the thyroid during therapy for Graves disease, since this should over time reduce exposure of patients immune system to thyroid antigens.

Lithium with RAI therapy- Although rarely used, RAI combined with lithium is safe and more effective than RAI alone in the cure of hyperthyroidism due to Graves disease, probably because it it causes greater retention of RAI within the thyroid gland.. Bogazzi et al (58.5)reported a study combining lithium with RAI therapy. MMI treatment was withdrawn 5 days prior to treatment, Two hundred ninety-eight patients were treated with RAI plus lithium (900 mg/d for 12 d starting 5 days prior to 131-I treatment) and 353 with RAI alone. RAI dosage was 260mCi/g estimated thyroid weight, corrected for RAIU (done on lithium).. All patients receive prednisone 0.5mg/kg/day, beginning on day 7 after RAI, tapering over 2 months. Patients treated with RAI plus lithium had a higher cure rate (91.0%) than those treated with RAI alone (85.0%, P = 0.030). In addition, patients treated with RAI plus lithium were cured more rapidly (median 60 d) than those treated with RAI alone (median 90 d, P = 0.000). Treatment with lithium inhibited the serum FT4 increase seen after methimazole withdrawal and RAI therapy.

Pretreatment with antithyroid drugsPatients are often treated directly after diagnosis, without prior therapy with antithyroid drugs. This is safe and common in patients with mild hyperthyroidsm and especially those without eye problems. However often physicians give antithyroid drugs before 131-I treatment in order to deplete the gland of stored hormone and to restore the FTI to normal before 131-I therapy. This offers several benefits. The possibility of 131-I induced exacerbation of thyrotoxicosis is reduced, the patient recovers toward normal health, and there is time to reflect on the desired therapy and review any concerns about the use of radioisotope for therapy. If the patient has been on antithyroid drug, it is discontinued two days before RAIU and therapy. Patients can be treated while on antithyroid drug, but this reduces the dose retained, reduces the post-therapy increment in hormone levels, and reduces the cure rate, so seems illogical(58.6) . When antithyroid drugs are discontinued the patients disease may exacerbate, and this must be carefully followed. Beta blockers can be given in this interim, but there is no reason for a prolonged interval between stopping antithyroid drug, and 131-I therapy, unless there is uncertainty about the need for the treatment. Pretreatment with antithyroid drug does not appear in most studies to reduce the efficacy of 131-I treatment. [59] but the debate about the effect of antithyroid drug pretreatment on the efficacy of radioactive iodine therapy continues. In recent studies in which patients were on or off antithyroid therapy, which was discontinued four days, or 1-2 days before treatment, there was no effect on the efficacy of treatment at a one year endpoint (59.1,59.2, 59,3). In another study Bonnema et al found that PTU pretreatment , stopped 4 days prior to 131-I, reduced the efficacy of 131-I(59.6).

Pretreatment is usually optional but is logical in patients with large glands and severe hyperthyroidism. Antithyroid drug therapy does reduce the pretreatment levels of hormone and reduces the rise in thyroid hormone level that may occur after radioactive iodide treatment. This certainly could have a protective effect in individuals who have coincident serious illness such as coronary artery disease, or perhaps individuals who have very large thyroid glands (59.3). It is indicated in two circumstances. In patients with severe heart disease, an 131-I- induced exacerbation of thyrotoxicosis could be serious or fatal. Pretreatment may reduce exacerbation of eye disease (see below), and it does reduce the post-RAI increase in antibody titers(59.1,59.31). The treatment dose of 131-I is best given as soon as possible after the diagnostic RAIU in order to reduce the period in which thyrotoxicosis may exacerbate without treatment, and since any intake of iodine (from diet or medicines or tests) would alter uptake of the treatment dose (59.4), and 2 days seems sufficient.

Post 131-I treatment managementMany patients remain on beta-blockers but require no other treatment after 131-I therapy. Antithyroid drugs can be reinstituted after 5 ( or preferably 7 ) days, with minimal effect on retention of the treatment dose of 131-I.

Alternatively, one may prescribe antithyroid drug (typically 10 mg methimazole q8h) beginning one day after administration of 131-I and add KI (2 drops q8h) after the second dose of methimazole. KI is continued for two weeks, and antithyroid drug as needed. This promotes a rapid return to euthyroidism, but by preventing recirculation of 131-I it can lower the effectiveness of the treatment. This method has been employed in a large number of patients, and is especially useful in patients requiring rapid control- for example, with CHF. A typical response is shown in Fig -3. It also has provided the largest proportion of patients remaining euthyroid at 10 years after therapy, in comparison to other treatment protocols. Glinoer and Verelst also report successful use of this strategy [59.1]. As noted, antithyroid drugs may be given starting 7-10 days after RAI without significantly lowering the radiation dose delivered to the gland.

Treatment using 125-I was tried as an alternative to 131-I, because it might offer certain advantages [60]. 125-I is primarily a gamma ray emitter, but secondary low-energy electrons are produced that penetrate only a few microns, in contrast to the high-energy beta rays of 131-I. Thus, it might theoretically be possible to treat the cytoplasm of the thyroid cell with relatively little damage to the nucleus. Appropriate calculations indicated that the radiation dose to the nucleus could be perhaps one-third that to the cytoplasm, whereas this difference would not exist for 131-I. Extensive therapeutic trials have nonetheless failed to disclose any advantage thus far for 125I. Larger doses 10-20 mCi are required, increasing whole body radiation considerably [ 61, 62].

Doses of 131-I up to 33 mCi can be given to an outpatient basis, and this level is rarely exceeded in treatment of Graves disease. However patients must be given advice (written if possible) on precautions to be followed to prevent unneccessary or excessive exposure of other individuals by radiaactivity administered to the patient. For maximum safety, patients who have received 20 mCi should avoid extended time in public places for 1 day, maximize distance (6 feet) from children and pregnant women for 2 days, may return to work after 1 day, sleep in a separate (6-feet separation) bed from adults for 8 days, sleep in a separate bed from pregnant partners, infant, or child for 20 days, and avoid contact with body fluids (saliva, urine) for at least one week. Lower therapeutic doses require proportionally more moderate precautions. The basic NRC rule is that patients may be released from hospital when (1) the 131I measured dose rate is 7mrem/hr at 1m, or (2) when the expected total dose another person would receive is unlikely to exceed 500mrem (5mSv). Written precaution instructions are required If 100mrem (1mSv) may be exceeded in any person. This topic is well covered in articles by Sisson et al (http://www.ncbi.nlm.nih.gov/pubmed/21417738) andLiu et al (62.1).

If adequate treatment has been given, the T4 level falls progressively, beginning in one to three weeks.. Labeled thyroid hormones, iodotyrosines, and iodoproteins appear in the circulation [63,63.1]. TG is released, starting immediately after therapy. Another iodoprotein, which seems to be an iodinated albumin, is also found in plasma. This compound is similar or identical to a quantitatively insignificant secretion product of the normal gland. It comprises up to 15% or more of the circulating serum 131-I in thyrotoxic patients [64]. It is heavily labeled after 131-I therapy, and its proportional secretion is probably increased by the radiation. Iodotyrosine present in the serum may represent leakage from the thyroid gland, or may be derived from peripheral metabolism of TG or iodoalbumin released from the thyroid.

The return to the euthyroid state usually requires at least two months, and often the declining function of the gland proceeds gradually over six months to a year. For this reason, it is logical to avoid retreating a patient before six months have elapsed unless there is no evidence of control of the disease. While awaiting the response to131-I the symptoms may be controlled by propranolol, antithyroid drugs, or iodide. Hypothyroidism develops transiently in 10 20% of patients, but thyroid function returns to normal in most of these patients in a period ranging from three to six months. These patients rarely become toxic again. Others develop permanent hypothyroidism and require replacement therapy. It is advantageous to give the thyroid adequate time to recover function spontaneously before starting permanent replacement therapy. This can be difficult for the patient unless partial T4 replacement is given. Unfortunately, one of the common side effects of treating hyperthyroidism is weight gain, averaging about 20 lbs through four years after treatment (64.1).

Patients may develop transient increases in FTI and T3 at 2-4 months after treatment [63.1], sometimes associated with enlargement of the thyroid. This may represent an inflammatory or immune response to the irradiationinduced thyroid damage, and the course may change rapidly with a dramatic drop to hypothyroidism in the 4-5th month.

Hypothyroidism may ultimately be inescapable after any amount of radiation that is sufficient to reduce the function of the hyperplastic thyroid to normal [65]. Many apparently euthyroid patients (as many as half) have elevated serum levels of TSH long after 131-I therapy, with normal plasma hormone levels [66]. An elevated TSH level with a low normal T4level is an indicator of changes progressing toward hypothyroidism [67]. The hypothyroidism is doubtless also related to the continued autoimmune attack on thyroid cells. Hypofunction is a common end stage of Graves disease independent of 131-I use; it occurs spontaneously as first noted in 1895(!) [68] and in patients treated only with antithyroid drugs [69]. Just as after surgery, the development of hypothyroidism is correlated positively with the presence of antithyroid antibodies.

During the rapid development of postradiation hypothyroidism, the typical symptoms of depressed metabolism are evident, but two rather unusual features also occur. The patients may have marked aching and stiffness of joints and muscles. They may also develop severe centrally located and persistent headache. The headache responds rapidly to thyroid hormone therapy. Hair loss can also be dramatic at this time.

In patients developing hypothyroidism rapidly, the plasma T4 level and FTI accurately reflect the metabolic state. However, it should be noted that the TSH response may be suppressed for weeks or months by prior thyrotoxicosis; thus, the TSH level may not accurately reflect hypothyroidism in these persons and should not be used in preference to the FTI or FT4.

If permanent hypothyroidism develops, the patient is given replacement hormone therapy and is impressed with the necessity of taking the medication for the remainder of his or her life. Thyroid hormone replacement is not obligatory for those who develop only temporary hypothyroidism, although it is possible that patients in this group should receive replacement hormone, for their glands have been severely damaged and they are likely to develop hypothyroidism at a later date. Perhaps these thyroids, under prolonged TSH stimulation, may tend to develop adenomatous or malignant changes, but this has not been observed. Many middle-aged women gain weight excessively after radioactive iodide treatment of hyperthyroidism. Usually such patients are on what is presumed to be appropriate T4 replacement therapy. Tigas et al note that such weight gain is less common after ablative therapy for thyroid cancer, in which case larger doses of thyroxine are generally prescribed. Thus they question whether the excessive weight gain after radioactive iodide treatment of Graves disease is due to the fact that insufficient thyroid hormone is being provided, even though TSH is within the normal range. They suggest that restoration of serum TSH to the reference range by T4 alone may not constitute adequate hormone replacement [ 69a}. We noted above that the correct reference range for TT4 and FT4, when the patient is on replacement T4, should be 20% higher than normal.

Permanent replacement therapy (regardless of the degree of thyroid destruction) for children who receive 131-I has a better theoretical basis. In these cases, it is advisable to prevent TSH stimulation of the thyroid and so mitigate any possible tendency toward carcinoma formation.

Exacerbation of thyrotoxicosis-During the period immediately after therapy, there may be a transient elevation of the T4 or T3 level [70], but usually the T4 level falls progressively toward normal. Among treated hyperthyroid patients with Graves disease, only rare exacerbations of the disease are seen. These patients may have cardiac problems such as worsening angina pectoris, congestive heart failure, or disturbances of rhythm such as atrial fibrillation or even ventricular tachycardia. Radiation-induced thyroid storm and even death have unfortunately been reported [71- 73]. These untoward events argue for pretreatment of selected patients who have other serious illness, especially cardiac disease, with antithyroid drugs prior to 131-I therapy.

The immediate side effects of 131-I therapy are typically minimal. As noted above, transient exacerbation of thyrotoxicosis can occur, and apparent thyroid storm has been induced within a day (or days) after 131-I therapy. A few patients develop mild pain and tenderness over the thyroid and, rarely, dysphagia. Some patients develop temporary hair loss, but this condition occurs two to three months after therapy rather than at two to three weeks, as occurs after ordinary radiation epilation. Hair loss also occurs after surgical therapy, so that it is a metabolic rather than a radiation effect. If the loss of hair is due to the change in metabolic status, it generally recovers in a few weeks or months. However hair thinning, patchy alopecia, and total alopecia, are all associated with Graves Disease, probably as another auto-immune processes. In this situation the prognosis for recovery is less certain, and occasionally some other therapy for the hair loss (such as steroids) is indicated. Permanent hypoparathyroidism has been reported very rarely as a complication of RAI therapy for heart disease and thyrotoxicosis[ 74- 76]. Patients treated for hyperthyroidism with 131-I received approximately 39 microGy/MBq administered (about 0.144rad/mCi) of combined beta and gamma radiation to the testes. This is reported to cause no significant changes in FSH. Nevertheless, testosterone declines transiently for several months, but there is no variation in sperm motility or % abnormal forms (76.1). Long term studies of patients after RAI treatment by Franklyn et al (76.2) show a slight increase in mortality which appears to be related to cardiovascular disease, possibly related to periods of hypothyroidism.

Worsening of ophthalmopathy after RAIIn contrast to the experience with antithyroid drugs or surgery, antithyroid antibodies including TSAb levels increase after RAI [ 77, 78]. (Fig. 11-4, above). Coincident with this condition, exophthalmos may be worsened [79].(Fig. 11-5, below). This change is most likely an immunologic reaction to discharged thyroid antigens.The relationship of radiation therapy to exacerbation of exophthalmos has beem questioned], but much recent data indicates that there is a definite correlation[ 79, 80, 80.1, 80.2, 80.3]. Many therapists consider bad eyes to be a relative contraindication to RAI. Induction of hypothyroidism, with elevation of TSH, may contribute to worsening of ophthalmopathy. This offers support for early induction of T4 replacement (80.3). Pretreatment with antithyroid drugs has been used empirically in an attempt to prevent this complication. Its benefit, if any, may be related to an immunosuppressive effect of PTU, described below. Treatment with methimazole before and for three months after I-131 therapy has been shown to help prevent the treatment-induced rise in TSH-R antibodies which is otherwise seen[81].

Prophylaxis with prednisone after 131-I helps prevent exacerbation of exophthalmos, and this approach is now the standard approach in patients who have significant exophthalmos at the time of treatment [ 82, 82.1]. (Fig. 6, below) The recommended dose is 30 mg/day for one month, tapering then over 2-3 months. Of course prednisone or other measures can be instituted at the time of any worsening of ophthalmopathy. In this instance doses of 30-60 mg/day are employed, and usually are required over several months. While treatment with prednisone helps prevent eye problems, it does not appear to reduce the effectiveness of RAI in controlling the hyperthyroidism(82.2). Thyroidectomy, with total removal of the gland, should be considered for patients with serious active eye disease. Operative removal of the thyroid is followed by gradual diminution is TSH-R antibodies.(82.3 ), and as shown by Tallstedt is associated with a lower incidence of worsening eye problems than is initial RAI treatment. Several studies document better outcomes of ophthalmopathy in patients with GD who have total thyroidectomy vs those treated by other means(82.4, 82.5, 82.6).

Failure of 131-I to cure thyrotoxicosis occurs occasionally even after 2 or 3 treatments, and rarely 4 or 5 therapies are given. The reason for this failure is usually not clear. The radiation effect may occur slowly. A large store of hormone in a large gland may be one cause of a slow response. Occasional glands having an extremely rapid turnover of 131-I requiring such high doses of the isotope that surgery is preferable to continued 131-I therapy and its attendant whole body radiation. If a patient fails to respond to one or two doses of 131-I, it is important to consider that rapid turnover may reduce the effective radiation dose. Turnover can easily be estimated by measuring RAIU at 4, 12, 24, and 48 hours, or longer. The usual combined physical and biological half-time of 131-I retention is about 6 days. This may be reduced to 1 or 2 days in some cases, especially in patients who have had prior therapy or subtotal thyroidectomy. If this rapid release of 131-I is found, and 131-I therapy is desired, the total dose given must be increased to compensate for rapid release. A rough guide to this increment is as follows:

Increased dose = usual dose X ( (usual half time of 6 days) / (observed half time of X days) )

Most successfully treated glands return to a normal or cosmetically satisfactory size. Some large glands remain large, and in that sense may constitute a treatment failure. In such a situation secondary thyroidectomy could be done, but it is rarely required in practice.

Long term care- Patients who have been treated with RAI should continue under the care of a physician who is interested in their thyroid problem for the remainder of their lives. The first follow-up visit should be made six to eight weeks after therapy. By this time, it will often be found that the patient has already experienced considerable improvement and has begun to gain weight. The frequency of subsequent visits will depend on the progress of the patient. Symptoms of hypothyroidism, if they develop, are usually not encountered until after two to four months, but one of the unfortunate facts of RAI therapy is that hypothyroidism may occur almost any time after the initial response.

In the early days of RAI treatment for Graves disease, only patients over 45 years of age were selected for treatment because of the fear of ill effects of radiation. This age limit was gradually lowered, and some clinics, after experience extending over nearly 40 years, have now abandoned most age limitation. The major fear has been concern for induction of neoplasia, as well as the possibility that 131-I might induce undesirable mutations in the germ cells that would appear in later generations.

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Thyroid Disease Manager : Diagnosis and Treatment of Graves

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NHGRI-ASHG fellowships fulfill critical need in science policy and education

For several years, NHGRI and the American Society of Human Genetics (ASHG) have provided a pathway for scientists who want to pursue careers in science policy or education. The Genetics and Public Policy Fellowship and the Genetics and Education Fellowship offer effective experiences in the public, private and non-profit arenas to those with graduate education in genetics. These fellowships help build the skills required to inform science policy and education. Our 2016-2017 fellows share what they've accomplished.

Geared to students grade 9-12 worldwide, the American Society of Human Genetics (ASHG) DNA Day Essay Contest celebrates National DNA Day by asking students to examine, question and reflect on important concepts in genetics. This year's question asks students to describe a disease or condition researchers are attempting to treat and how gene therapy might repair the underlying cause of the disease or condition. Deadline: March 10, 2017, at 5 p.m. U.S. Eastern Time. See: DNA Day Essay Contest

Your family health history can identify whether you are at a higher risk for some diseases. But people don't necessarily know their entire family's health history. A new study shows that asking multiple family members for family health histories can improve the accuracy of both the family's health history and personalized risk assessments. NHGRI intramural researchers published the study in the American Journal of Preventive Medicine on January 4, 2016.

On June 5-7, 2017, the conference Genomics and Society: Expanding the ELSI Universe will gather ethical, legal and social implications researchers to reflect on current research and discuss future directions. With keynote speakers, plenary panels, workshops, and a wide range of paper, panel, and poster presentations, the Congress will provide an opportunity for scholars to reflect on current research and envision future directions for ELSI research. For more information and to register: elsicon2017.org.

Through a simple blood test, physicians will soon be able to map the fetus' entire collection of genes (the whole genome) using fetal DNA that floats in the mother's blood. But a survey of 1,000 physicians says that ethical guidelines must be developed first. Researchers with the National Human Genome Research Institute published their findings in the December 6th issue of the journal Prenatal Diagnosis.

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National Human Genome Research Institute

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This article is about the family of polycyclic chemical compounds. For the drugs, also used as performance-enhancing substances, see Anabolic steroid. For the scientific journal, see Steroids (journal).

A steroid is an organic compound with four rings arranged in a specific configuration. Examples include the dietary lipid cholesterol, the sex hormones estradiol and testosterone[2]:1019 and the anti-inflammatory drug dexamethasone.[3] Steroids have two principal biological functions: certain steroids (such as cholesterol) are important components of cell membranes which alter membrane fluidity, and many steroids are signaling molecules which activate steroid hormone receptors.

The steroid core structure is composed of seventeen carbon atoms, bonded in four "fused" rings: three six-member cyclohexane rings (rings A, B and C in the first illustration) and one five-member cyclopentane ring (the D ring). Steroids vary by the functional groups attached to this four-ring core and by the oxidation state of the rings. Sterols are forms of steroids with a hydroxyl group at position three and a skeleton derived from cholestane.[1]:1785f[4] They can also vary more markedly by changes to the ring structure (for example, ring scissions which produce secosteroids such as vitamin D3).

Hundreds of steroids are found in plants, animals and fungi. All steroids are manufactured in cells from the sterols lanosterol (animals and fungi) or cycloartenol (plants). Lanosterol and cycloartenol are derived from the cyclization of the triterpene squalene.[5]

Space-filling representation

Ball-and-stick representation

Gonane, also known as steran or cyclopentaperhydrophenanthrene, the simplest steroid and the nucleus of all steroids and sterols,[6][7] is composed of seventeen carbon atoms in carbon-carbon bonds forming four fused rings in a three-dimensional shape. The three cyclohexane rings (A, B, and C in the first illustration) form the skeleton of a perhydro derivative of phenanthrene. The D ring has a cyclopentane structure. When the two methyl groups and eight carbon side chains (at C-17, as shown for cholesterol) are present, the steroid is said to have a cholestane framework. The two common 5 and 5 stereoisomeric forms of steroids exist because of differences in the side of the largely planar ring system where the hydrogen (H) atom at carbon-5 is attached, which results in a change in steroid A-ring conformation.

Examples of steroid structures are:

In addition to the ring scissions (cleavages), expansions and contractions (cleavage and reclosing to a larger or smaller rings)all variations in the carbon-carbon bond frameworksteroids can also vary:

For instance, sterols such as cholesterol and lanosterol have an hydroxyl group attached at position C-3, while testosterone and progesterone have a carbonyl (oxo substituent) at C-3; of these, lanosterol alone has two methyl groups at C-4 and cholesterol (with a C-5 to C-6 double bond) differs from testosterone and progesterone (which have a C-4 to C-5 double bond).

The following are some common categories of steroids. In eukaryotes, steroids are found in fungi, animals, and plants. Fungal steroids include the ergosterols.

Animal steroids include compounds of vertebrate and insect origin, the latter including ecdysteroids such as ecdysterone (controlling molting in some species). Vertebrate examples include the steroid hormones and cholesterol; the latter is a structural component of cell membranes which helps determine the fluidity of cell membranes and is a principal constituent of plaque (implicated in atherosclerosis). Steroid hormones include:

Plant steroids include steroidal alkaloids found in Solanaceae,[8] the phytosterols, and the brassinosteroids (which include several plant hormones). In prokaryotes, biosynthetic pathways exist for the tetracyclic steroid framework (e.g. in mycobacteria)[9] where its origin from eukaryotes is conjectured[10] and the more-common pentacyclic triterpinoid hopanoid framework.[11]

Steroids can be classified based on their chemical composition.[12] One example of how MeSH performs this classification is available at the Wikipedia MeSH catalog. Examples of this classification include:

The gonane (steroid nucleus) is the parent 17-carbon tetracyclic hydrocarbon molecule with no alkyl sidechains.[13]

Secosteroids (Latin seco, "to cut") are a subclass of steroidal compounds resulting, biosynthetically or conceptually, from scission (cleavage) of parent steroid rings (generally one of the four). Major secosteroid subclasses are defined by the steroid carbon atoms where this scission has taken place. For instance, the prototypical secosteroid cholecalciferol, vitamin D3 (shown), is in the 9,10-secosteroid subclass and derives from the cleavage of carbon atoms C-9 and C-10 of the steroid B-ring; 5,6-secosteroids and 13,14-steroids are similar.[14]

Norsteroids (nor-, L. norma; "normal" in chemistry, indicating carbon removal)[15] and homosteroids (homo-, Greek homos; "same", indicating carbon addition) are structural subclasses of steroids formed from biosynthetic steps. The former involves enzymic ring expansion-contraction reactions, and the latter is accomplished (biomimetically) or (more frequently) through ring closures of acyclic precursors with more (or fewer) ring atoms than the parent steroid framework.[16]

Combinations of these ring alterations are known in nature. For instance, ewes who graze on corn lily ingest cyclopamine (shown) and veratramine, two of a sub-family of steroids where the C- and D-rings are contracted and expanded respectively via a biosynthetic migration of the original C-13 atom. Ingestion of these C-nor-D-homosteroids results in birth defects in lambs: cyclopia from cyclopamine and leg deformity from veratramine.[17] A further C-nor-D-homosteroid (nakiterpiosin) is excreted by Okinawan cyanobacteriosponges Terpios hoshinota leading to coral mortality from black coral disease.[18] Nakiterpiosin-type steroids are active against the signaling pathway involving the smoothened and hedgehog proteins, a pathway which is hyperactive in a number of cancers.

Steroids and their metabolites often function as signalling molecules (the most notable examples are steroid hormones), and steroids and phospholipids are components of cell membranes. Steroids such as cholesterol decrease membrane fluidity.[19] Similar to lipids, steroids are highly concentrated energy stores. However, they are not typically sources of energy; in mammals, they are normally metabolized and excreted.

Steroids play critical roles in a number of disorders, including malignancies like Prostate Cancer, where steroid production inside and outside the tumour promotes cancer cell aggressiveness.[20]

Two classes of drugs target the mevalonate pathway: statins (used to reduce elevated cholesterol levels) and bisphosphonates (used to treat a number of bone-degenerative diseases).

The hundreds of steroids found in animals, fungi, and plants are made from lanosterol (in animals and fungi; see examples above) or cycloartenol (in plants). Lanosterol and cycloartenol derive from cyclization of the triterpenoid squalene.[5]

Steroid biosynthesis is an anabolic pathway which produces steroids from simple precursors. A unique biosynthetic pathway is followed in animals (compared to many other organisms), making the pathway a common target for antibiotics and other anti-infection drugs. Steroid metabolism in humans is also the target of cholesterol-lowering drugs, such as statins.

In humans and other animals the biosynthesis of steroids follows the mevalonate pathway, which uses acetyl-CoA as building blocks for dimethylallyl pyrophosphate (DMAPP) and isopentenyl pyrophosphate (IPP).[21][bettersourceneeded] In subsequent steps DMAPP and IPP join to form geranyl pyrophosphate (GPP), which synthesizes the steroid lanosterol. Modifications of lanosterol into other steroids are classified as steroidogenesis transformations.

The mevalonate pathway (also called HMG-CoA reductase pathway) begins with acetyl-CoA and ends with dimethylallyl pyrophosphate (DMAPP) and isopentenyl pyrophosphate (IPP).

DMAPP and IPP donate isoprene units, which are assembled and modified to form terpenes and isoprenoids[22] (a large class of lipids, which include the carotenoids and form the largest class of plant natural products.[23] Here, the isoprene units are joined to make squalene and folded into a set of rings to make lanosterol.[24]

Lanosterol can then be converted into other steroids, such as cholesterol and ergosterol.[24][25]

Steroidogenesis is the biological process by which steroids are generated from cholesterol and changed into other steroids.[27] The pathways of steroidogenesis differ among species. The major classes of steroid hormones, with prominent members and examples of related functions, are:

Human steroidogenesis occurs in a number of locations:

In plants and bacteria, the non-mevalonate pathway uses pyruvate and glyceraldehyde 3-phosphate as substrates.[22][30]

During diseases pathways otherwise not significant in healthy humans can become utilized. For example, in one form of congenital adrenal hyperplasia an deficiency in the 21-hydroxylase enzymatic pathway leads to an excess of 17-Hydroxyprogesterone (17-OHP) this pathological excess of 17-OHP in turn may be converted to dihydrotestosterone (DHT, a potent androgen) through among others 17,20 Lyase (a member of the cytochrome P450 family of enzymes), 5-Reductase and 3-Hydroxysteroid dehydrogenase.[31]

Steroids are primarily oxidized by cytochrome P450 oxidase enzymes, such as CYP3A4. These reactions introduce oxygen into the steroid ring, allowing the cholesterol to be broken up by other enzymes into bile acids.[32] These acids can then be eliminated by secretion from the liver in bile.[33] The expression of the oxidase gene can be upregulated by the steroid sensor PXR when there is a high blood concentration of steroids.[34] Steroid hormones, lacking the side chain of cholesterol and bile acids, are typically hydroxylated at various ring positions or oxidized at the 17 position, conjugated with sulfate or glucuronic acid and excreted in the urine.[35]

Steroid isolation, depending on context, is the isolation of chemical matter required for chemical structure elucidation, derivitzation or degradation chemistry, biological testing, and other research needs (generally milligrams to grams, but often more[36] or the isolation of "analytical quantities" of the substance of interest (where the focus is on identifying and quantifying the substance (for example, in biological tissue or fluid). The amount isolated depends on the analytical method, but is generally less than one microgram.[37][pageneeded] The methods of isolation to achieve the two scales of product are distinct, but include extraction, precipitation, adsorption, chromatography, and crystallization. In both cases, the isolated substance is purified to chemical homogeneity; combined separation and analytical methods, such as LC-MS, are chosen to be "orthogonal"achieving their separations based on distinct modes of interaction between substance and isolating matrixto detect a single species in the pure sample. Structure determination refers to the methods to determine the chemical structure of an isolated pure steroid, using an evolving array of chemical and physical methods which have included NMR and small-molecule crystallography.[2]:1019Methods of analysis overlap both of the above areas, emphasizing analytical methods to determining if a steroid is present in a mixture and determining its quantity.[37]

Microbial catabolism of phytosterol side chains yields C-19 steroids, C-22 steroids, and 17-ketosteroids (i.e. precursors to adrenocortical hormones and contraceptives).[38][39][40][41] The addition and modification of functional groups is key when producing the wide variety of medications available within this chemical classification. These modifications are performed using conventional organic synthesis and/or biotransformation techniques.[42][43]

The semisynthesis of steroids often begins from precursors such as cholesterol,[41]phytosterols,[40] or sapogenins.[44] The efforts of Syntex, a company involved in the Mexican barbasco trade, used Dioscorea mexicana to produce the sapogenin diosgenin in the early days of the synthetic steroid pharmaceutical industry.[36]

Some steroidal hormones are economically obtained only by total synthesis from petrochemicals (e.g. 13-alkyl steroids).[41] For example, the pharmaceutical Norgestrel begins from Methoxy-1-tetralone, a petrochemical derived from phenol.

A number of Nobel Prizes have been awarded for steroid research, including:

Steroid signaling

Agonists

Antagonists

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Medicine (British English i; American English i) is the science and practice of the diagnosis, treatment, and prevention of disease.[1][2] The word medicine is derived from Latin medicus, meaning "a physician".[3][4] Medicine encompasses a variety of health care practices evolved to maintain and restore health by the prevention and treatment of illness. Contemporary medicine applies biomedical sciences, biomedical research, genetics, and medical technology to diagnose, treat, and prevent injury and disease, typically through pharmaceuticals or surgery, but also through therapies as diverse as psychotherapy, external splints and traction, medical devices, biologics, and ionizing radiation, amongst others.[5]

Medicine has existed for thousands of years, during most of which it was an art (an area of skill and knowledge) frequently having connections to the religious and philosophical beliefs of local culture. For example, a medicine man would apply herbs and say prayers for healing, or an ancient philosopher and physician would apply bloodletting according to the theories of humorism. In recent centuries, since the advent of modern science, most medicine has become a combination of art and science (both basic and applied, under the umbrella of medical science). While stitching technique for sutures is an art learned through practice, the knowledge of what happens at the cellular and molecular level in the tissues being stitched arises through science.

Prescientific forms of medicine are now known as traditional medicine and folk medicine. They remain commonly used with or instead of scientific medicine and are thus called alternative medicine. For example, evidence on the effectiveness of acupuncture is "variable and inconsistent" for any condition,[6] but is generally safe when done by an appropriately trained practitioner.[7] In contrast, treatments outside the bounds of safety and efficacy are termed quackery.

Medical availability and clinical practice varies across the world due to regional differences in culture and technology. Modern scientific medicine is highly developed in the Western world, while in developing countries such as parts of Africa or Asia, the population may rely more heavily on traditional medicine with limited evidence and efficacy and no required formal training for practitioners.[8] Even in the developed world however, evidence-based medicine is not universally used in clinical practice; for example, a 2007 survey of literature reviews found that about 49% of the interventions lacked sufficient evidence to support either benefit or harm.[9]

In modern clinical practice, doctors personally assess patients in order to diagnose, treat, and prevent disease using clinical judgment. The doctor-patient relationship typically begins an interaction with an examination of the patient's medical history and medical record, followed by a medical interview[10] and a physical examination. Basic diagnostic medical devices (e.g. stethoscope, tongue depressor) are typically used. After examination for signs and interviewing for symptoms, the doctor may order medical tests (e.g. blood tests), take a biopsy, or prescribe pharmaceutical drugs or other therapies. Differential diagnosis methods help to rule out conditions based on the information provided. During the encounter, properly informing the patient of all relevant facts is an important part of the relationship and the development of trust. The medical encounter is then documented in the medical record, which is a legal document in many jurisdictions.[11] Follow-ups may be shorter but follow the same general procedure, and specialists follow a similar process. The diagnosis and treatment may take only a few minutes or a few weeks depending upon the complexity of the issue.

The components of the medical interview[10] and encounter are:

The physical examination is the examination of the patient for medical signs of disease, which are objective and observable, in contrast to symptoms which are volunteered by the patient and not necessarily objectively observable.[12] The healthcare provider uses the senses of sight, hearing, touch, and sometimes smell (e.g., in infection, uremia, diabetic ketoacidosis). Four actions are the basis of physical examination: inspection, palpation (feel), percussion (tap to determine resonance characteristics), and auscultation (listen), generally in that order although auscultation occurs prior to percussion and palpation for abdominal assessments.[13]

The clinical examination involves the study of:

It is to likely focus on areas of interest highlighted in the medical history and may not include everything listed above.

The treatment plan may include ordering additional medical laboratory tests and medical imaging studies, starting therapy, referral to a specialist, or watchful observation. Follow-up may be advised. Depending upon the health insurance plan and the managed care system, various forms of "utilization review", such as prior authorization of tests, may place barriers on accessing expensive services.[14]

The medical decision-making (MDM) process involves analysis and synthesis of all the above data to come up with a list of possible diagnoses (the differential diagnoses), along with an idea of what needs to be done to obtain a definitive diagnosis that would explain the patient's problem.

On subsequent visits, the process may be repeated in an abbreviated manner to obtain any new history, symptoms, physical findings, and lab or imaging results or specialist consultations.

Contemporary medicine is in general conducted within health care systems. Legal, credentialing and financing frameworks are established by individual governments, augmented on occasion by international organizations, such as churches. The characteristics of any given health care system have significant impact on the way medical care is provided.

From ancient times, Christian emphasis on practical charity gave rise to the development of systematic nursing and hospitals and the Catholic Church today remains the largest non-government provider of medical services in the world.[15] Advanced industrial countries (with the exception of the United States)[16][17] and many developing countries provide medical services through a system of universal health care that aims to guarantee care for all through a single-payer health care system, or compulsory private or co-operative health insurance. This is intended to ensure that the entire population has access to medical care on the basis of need rather than ability to pay. Delivery may be via private medical practices or by state-owned hospitals and clinics, or by charities, most commonly by a combination of all three.

Most tribal societies provide no guarantee of healthcare for the population as a whole. In such societies, healthcare is available to those that can afford to pay for it or have self-insured it (either directly or as part of an employment contract) or who may be covered by care financed by the government or tribe directly.

Transparency of information is another factor defining a delivery system. Access to information on conditions, treatments, quality, and pricing greatly affects the choice by patients/consumers and, therefore, the incentives of medical professionals. While the US healthcare system has come under fire for lack of openness,[18] new legislation may encourage greater openness. There is a perceived tension between the need for transparency on the one hand and such issues as patient confidentiality and the possible exploitation of information for commercial gain on the other.

Provision of medical care is classified into primary, secondary, and tertiary care categories.

Primary care medical services are provided by physicians, physician assistants, nurse practitioners, or other health professionals who have first contact with a patient seeking medical treatment or care. These occur in physician offices, clinics, nursing homes, schools, home visits, and other places close to patients. About 90% of medical visits can be treated by the primary care provider. These include treatment of acute and chronic illnesses, preventive care and health education for all ages and both sexes.

Secondary care medical services are provided by medical specialists in their offices or clinics or at local community hospitals for a patient referred by a primary care provider who first diagnosed or treated the patient. Referrals are made for those patients who required the expertise or procedures performed by specialists. These include both ambulatory care and inpatient services, emergency rooms, intensive care medicine, surgery services, physical therapy, labor and delivery, endoscopy units, diagnostic laboratory and medical imaging services, hospice centers, etc. Some primary care providers may also take care of hospitalized patients and deliver babies in a secondary care setting.

Tertiary care medical services are provided by specialist hospitals or regional centers equipped with diagnostic and treatment facilities not generally available at local hospitals. These include trauma centers, burn treatment centers, advanced neonatology unit services, organ transplants, high-risk pregnancy, radiation oncology, etc.

Modern medical care also depends on information still delivered in many health care settings on paper records, but increasingly nowadays by electronic means.

In low-income countries, modern healthcare is often too expensive for the average person. International healthcare policy researchers have advocated that "user fees" be removed in these areas to ensure access, although even after removal, significant costs and barriers remain.[19]

Working together as an interdisciplinary team, many highly trained health professionals besides medical practitioners are involved in the delivery of modern health care. Examples include: nurses, emergency medical technicians and paramedics, laboratory scientists, pharmacists, podiatrists, physiotherapists, respiratory therapists, speech therapists, occupational therapists, radiographers, dietitians, and bioengineers, surgeons, surgeon's assistant, surgical technologist.

The scope and sciences underpinning human medicine overlap many other fields. Dentistry, while considered by some a separate discipline from medicine, is a medical field.

A patient admitted to the hospital is usually under the care of a specific team based on their main presenting problem, e.g., the Cardiology team, who then may interact with other specialties, e.g., surgical, radiology, to help diagnose or treat the main problem or any subsequent complications/developments.

Physicians have many specializations and subspecializations into certain branches of medicine, which are listed below. There are variations from country to country regarding which specialties certain subspecialties are in.

The main branches of medicine are:

In the broadest meaning of "medicine", there are many different specialties. In the UK, most specialities have their own body or college, which have its own entrance examination. These are collectively known as the Royal Colleges, although not all currently use the term "Royal". The development of a speciality is often driven by new technology (such as the development of effective anaesthetics) or ways of working (such as emergency departments); the new specialty leads to the formation of a unifying body of doctors and the prestige of administering their own examination.

Within medical circles, specialities usually fit into one of two broad categories: "Medicine" and "Surgery." "Medicine" refers to the practice of non-operative medicine, and most of its subspecialties require preliminary training in Internal Medicine. In the UK, this was traditionally evidenced by passing the examination for the Membership of the Royal College of Physicians (MRCP) or the equivalent college in Scotland or Ireland. "Surgery" refers to the practice of operative medicine, and most subspecialties in this area require preliminary training in General Surgery, which in the UK leads to membership of the Royal College of Surgeons of England (MRCS). At present, some specialties of medicine do not fit easily into either of these categories, such as radiology, pathology, or anesthesia. Most of these have branched from one or other of the two camps above; for example anaesthesia developed first as a faculty of the Royal College of Surgeons (for which MRCS/FRCS would have been required) before becoming the Royal College of Anaesthetists and membership of the college is attained by sitting for the examination of the Fellowship of the Royal College of Anesthetists (FRCA).

Surgery is an ancient medical specialty that uses operative manual and instrumental techniques on a patient to investigate and/or treat a pathological condition such as disease or injury, to help improve bodily function or appearance or to repair unwanted ruptured areas (for example, a perforated ear drum). Surgeons must also manage pre-operative, post-operative, and potential surgical candidates on the hospital wards. Surgery has many sub-specialties, including general surgery, ophthalmic surgery, cardiovascular surgery, colorectal surgery, neurosurgery, oral and maxillofacial surgery, oncologic surgery, orthopedic surgery, otolaryngology, plastic surgery, podiatric surgery, transplant surgery, trauma surgery, urology, vascular surgery, and pediatric surgery. In some centers, anesthesiology is part of the division of surgery (for historical and logistical reasons), although it is not a surgical discipline. Other medical specialties may employ surgical procedures, such as ophthalmology and dermatology, but are not considered surgical sub-specialties per se.

Surgical training in the U.S. requires a minimum of five years of residency after medical school. Sub-specialties of surgery often require seven or more years. In addition, fellowships can last an additional one to three years. Because post-residency fellowships can be competitive, many trainees devote two additional years to research. Thus in some cases surgical training will not finish until more than a decade after medical school. Furthermore, surgical training can be very difficult and time-consuming.

Internal medicine is the medical specialty dealing with the prevention, diagnosis, and treatment of adult diseases. According to some sources, an emphasis on internal structures is implied.[20] In North America, specialists in internal medicine are commonly called "internists." Elsewhere, especially in Commonwealth nations, such specialists are often called physicians.[21] These terms, internist or physician (in the narrow sense, common outside North America), generally exclude practitioners of gynecology and obstetrics, pathology, psychiatry, and especially surgery and its subspecialities.

Because their patients are often seriously ill or require complex investigations, internists do much of their work in hospitals. Formerly, many internists were not subspecialized; such general physicians would see any complex nonsurgical problem; this style of practice has become much less common. In modern urban practice, most internists are subspecialists: that is, they generally limit their medical practice to problems of one organ system or to one particular area of medical knowledge. For example, gastroenterologists and nephrologists specialize respectively in diseases of the gut and the kidneys.[22]

In the Commonwealth of Nations and some other countries, specialist pediatricians and geriatricians are also described as specialist physicians (or internists) who have subspecialized by age of patient rather than by organ system. Elsewhere, especially in North America, general pediatrics is often a form of Primary care.

There are many subspecialities (or subdisciplines) of internal medicine:

Training in internal medicine (as opposed to surgical training), varies considerably across the world: see the articles on Medical education and Physician for more details. In North America, it requires at least three years of residency training after medical school, which can then be followed by a one- to three-year fellowship in the subspecialties listed above. In general, resident work hours in medicine are less than those in surgery, averaging about 60 hours per week in the USA. This difference does not apply in the UK where all doctors are now required by law to work less than 48 hours per week on average.

The followings are some major medical specialties that do not directly fit into any of the above-mentioned groups.

Some interdisciplinary sub-specialties of medicine include:

Medical education and training varies around the world. It typically involves entry level education at a university medical school, followed by a period of supervised practice or internship, and/or residency. This can be followed by postgraduate vocational training. A variety of teaching methods have been employed in medical education, still itself a focus of active research. In Canada and the United States of America, a Doctor of Medicine degree, often abbreviated M.D., or a Doctor of Osteopathic Medicine degree, often abbreviated as D.O. and unique to the United States, must be completed in and delivered from a recognized university.

Since knowledge, techniques, and medical technology continue to evolve at a rapid rate, many regulatory authorities require continuing medical education. Medical practitioners upgrade their knowledge in various ways, including medical journals, seminars, conferences, and online programs.

In most countries, it is a legal requirement for a medical doctor to be licensed or registered. In general, this entails a medical degree from a university and accreditation by a medical board or an equivalent national organization, which may ask the applicant to pass exams. This restricts the considerable legal authority of the medical profession to physicians that are trained and qualified by national standards. It is also intended as an assurance to patients and as a safeguard against charlatans that practice inadequate medicine for personal gain. While the laws generally require medical doctors to be trained in "evidence based", Western, or Hippocratic Medicine, they are not intended to discourage different paradigms of health.

In the European Union, the profession of doctor of medicine is regulated. A profession is said to be regulated when access and exercise is subject to the possession of a specific professional qualification. The regulated professions database contains a list of regulated professions for doctor of medicine in the EU member states, EEA countries and Switzerland. This list is covered by the Directive 2005/36/EC.

Doctors who are negligent or intentionally harmful in their care of patients can face charges of medical malpractice and be subject to civil, criminal, or professional sanctions.

Medical ethics is a system of moral principles that apply values and judgments to the practice of medicine. As a scholarly discipline, medical ethics encompasses its practical application in clinical settings as well as work on its history, philosophy, theology, and sociology. Six of the values that commonly apply to medical ethics discussions are:

Values such as these do not give answers as to how to handle a particular situation, but provide a useful framework for understanding conflicts. When moral values are in conflict, the result may be an ethical dilemma or crisis. Sometimes, no good solution to a dilemma in medical ethics exists, and occasionally, the values of the medical community (i.e., the hospital and its staff) conflict with the values of the individual patient, family, or larger non-medical community. Conflicts can also arise between health care providers, or among family members. For example, some argue that the principles of autonomy and beneficence clash when patients refuse blood transfusions, considering them life-saving; and truth-telling was not emphasized to a large extent before the HIV era.

Prehistoric medicine incorporated plants (herbalism), animal parts, and minerals. In many cases these materials were used ritually as magical substances by priests, shamans, or medicine men. Well-known spiritual systems include animism (the notion of inanimate objects having spirits), spiritualism (an appeal to gods or communion with ancestor spirits); shamanism (the vesting of an individual with mystic powers); and divination (magically obtaining the truth). The field of medical anthropology examines the ways in which culture and society are organized around or impacted by issues of health, health care and related issues.

Early records on medicine have been discovered from ancient Egyptian medicine, Babylonian Medicine, Ayurvedic medicine (in the Indian subcontinent), classical Chinese medicine (predecessor to the modern traditional Chinese Medicine), and ancient Greek medicine and Roman medicine.

In Egypt, Imhotep (3rd millennium BC) is the first physician in history known by name. The oldest Egyptian medical text is the Kahun Gynaecological Papyrus from around 2000 BCE, which describes gynaecological diseases. The Edwin Smith Papyrus dating back to 1600 BCE is an early work on surgery, while the Ebers Papyrus dating back to 1500 BCE is akin to a textbook on medicine.[24]

In China, archaeological evidence of medicine in Chinese dates back to the Bronze Age Shang Dynasty, based on seeds for herbalism and tools presumed to have been used for surgery.[25] The Huangdi Neijing, the progenitor of Chinese medicine, is a medical text written beginning in the 2nd century BCE and compiled in the 3rd century.[26]

In India, the surgeon Sushruta described numerous surgical operations, including the earliest forms of plastic surgery.[27][dubious discuss][28][29] Earliest records of dedicated hospitals come from Mihintale in Sri Lanka where evidence of dedicated medicinal treatment facilities for patients are found.[30][31]

In Greece, the Greek physician Hippocrates, the "father of western medicine",[32][33] laid the foundation for a rational approach to medicine. Hippocrates introduced the Hippocratic Oath for physicians, which is still relevant and in use today, and was the first to categorize illnesses as acute, chronic, endemic and epidemic, and use terms such as, "exacerbation, relapse, resolution, crisis, paroxysm, peak, and convalescence".[34][35] The Greek physician Galen was also one of the greatest surgeons of the ancient world and performed many audacious operations, including brain and eye surgeries. After the fall of the Western Roman Empire and the onset of the Early Middle Ages, the Greek tradition of medicine went into decline in Western Europe, although it continued uninterrupted in the Eastern Roman (Byzantine) Empire.

Most of our knowledge of ancient Hebrew medicine during the 1stmillenniumBC comes from the Torah, i.e.the Five Books of Moses, which contain various health related laws and rituals. The Hebrew contribution to the development of modern medicine started in the Byzantine Era, with the physician Asaph the Jew.[36]

After 750 CE, the Muslim world had the works of Hippocrates, Galen and Sushruta translated into Arabic, and Islamic physicians engaged in some significant medical research. Notable Islamic medical pioneers include the Persian polymath, Avicenna, who, along with Imhotep and Hippocrates, has also been called the "father of medicine".[37] He wrote The Canon of Medicine, considered one of the most famous books in the history of medicine.[38] Others include Abulcasis,[39]Avenzoar,[40]Ibn al-Nafis,[41] and Averroes.[42]Rhazes[43] was one of the first to question the Greek theory of humorism, which nevertheless remained influential in both medieval Western and medieval Islamic medicine.[44]Al-Risalah al-Dhahabiah by Ali al-Ridha, the eighth Imam of Shia Muslims, is revered as the most precious Islamic literature in the Science of Medicine.[45] The Persian Bimaristan hospitals were an early example of public hospitals.[46][47]

In Europe, Charlemagne decreed that a hospital should be attached to each cathedral and monastery and the historian Geoffrey Blainey likened the activities of the Catholic Church in health care during the Middle Ages to an early version of a welfare state: "It conducted hospitals for the old and orphanages for the young; hospices for the sick of all ages; places for the lepers; and hostels or inns where pilgrims could buy a cheap bed and meal". It supplied food to the population during famine and distributed food to the poor. This welfare system the church funded through collecting taxes on a large scale and possessing large farmlands and estates. The Benedictine order was noted for setting up hospitals and infirmaries in their monasteries, growing medical herbs and becoming the chief medical care givers of their districts, as at the great Abbey of Cluny. The Church also established a network of cathedral schools and universities where medicine was studied. The Schola Medica Salernitana in Salerno, looking to the learning of Greek and Arab physicians, grew to be the finest medical school in Medieval Europe.[48]

However, the fourteenth and fifteenth century Black Death devastated both the Middle East and Europe, and it has even been argued that Western Europe was generally more effective in recovering from the pandemic than the Middle East.[49] In the early modern period, important early figures in medicine and anatomy emerged in Europe, including Gabriele Falloppio and William Harvey.

The major shift in medical thinking was the gradual rejection, especially during the Black Death in the 14th and 15th centuries, of what may be called the 'traditional authority' approach to science and medicine. This was the notion that because some prominent person in the past said something must be so, then that was the way it was, and anything one observed to the contrary was an anomaly (which was paralleled by a similar shift in European society in general see Copernicus's rejection of Ptolemy's theories on astronomy). Physicians like Vesalius improved upon or disproved some of the theories from the past. The main tomes used both by medicine students and expert physicians were Materia Medica and Pharmacopoeia.

Andreas Vesalius was the author of De humani corporis fabrica, an important book on human anatomy.[50] Bacteria and microorganisms were first observed with a microscope by Antonie van Leeuwenhoek in 1676, initiating the scientific field microbiology.[51] Independently from Ibn al-Nafis, Michael Servetus rediscovered the pulmonary circulation, but this discovery did not reach the public because it was written down for the first time in the "Manuscript of Paris"[52] in 1546, and later published in the theological work for which he paid with his life in 1553. Later this was described by Renaldus Columbus and Andrea Cesalpino. Herman Boerhaave is sometimes referred to as a "father of physiology" due to his exemplary teaching in Leiden and textbook 'Institutiones medicae' (1708). Pierre Fauchard has been called "the father of modern dentistry".[53]

Veterinary medicine was, for the first time, truly separated from human medicine in 1761, when the French veterinarian Claude Bourgelat founded the world's first veterinary school in Lyon, France. Before this, medical doctors treated both humans and other animals.

Modern scientific biomedical research (where results are testable and reproducible) began to replace early Western traditions based on herbalism, the Greek "four humours" and other such pre-modern notions. The modern era really began with Edward Jenner's discovery of the smallpox vaccine at the end of the 18th century (inspired by the method of inoculation earlier practiced in Asia), Robert Koch's discoveries around 1880 of the transmission of disease by bacteria, and then the discovery of antibiotics around 1900.

The post-18th century modernity period brought more groundbreaking researchers from Europe. From Germany and Austria, doctors Rudolf Virchow, Wilhelm Conrad Rntgen, Karl Landsteiner and Otto Loewi made notable contributions. In the United Kingdom, Alexander Fleming, Joseph Lister, Francis Crick and Florence Nightingale are considered important. Spanish doctor Santiago Ramn y Cajal is considered the father of modern neuroscience.

From New Zealand and Australia came Maurice Wilkins, Howard Florey, and Frank Macfarlane Burnet.

In the United States, William Williams Keen, William Coley, James D. Watson, Italy (Salvador Luria), Switzerland (Alexandre Yersin), Japan (Kitasato Shibasabur), and France (Jean-Martin Charcot, Claude Bernard, Paul Broca) and others did significant work. Russian Nikolai Korotkov also did significant work, as did Sir William Osler and Harvey Cushing.

As science and technology developed, medicine became more reliant upon medications. Throughout history and in Europe right until the late 18th century, not only animal and plant products were used as medicine, but also human body parts and fluids.[54]Pharmacology developed in part from herbalism and some drugs are still derived from plants (atropine, ephedrine, warfarin, aspirin, digoxin, vinca alkaloids, taxol, hyoscine, etc.).[55]Vaccines were discovered by Edward Jenner and Louis Pasteur.

The first antibiotic was arsphenamine (Salvarsan) discovered by Paul Ehrlich in 1908 after he observed that bacteria took up toxic dyes that human cells did not. The first major class of antibiotics was the sulfa drugs, derived by German chemists originally from azo dyes.

Pharmacology has become increasingly sophisticated; modern biotechnology allows drugs targeted towards specific physiological processes to be developed, sometimes designed for compatibility with the body to reduce side-effects. Genomics and knowledge of human genetics is having some influence on medicine, as the causative genes of most monogenic genetic disorders have now been identified, and the development of techniques in molecular biology and genetics are influencing medical technology, practice and decision-making.

Evidence-based medicine is a contemporary movement to establish the most effective algorithms of practice (ways of doing things) through the use of systematic reviews and meta-analysis. The movement is facilitated by modern global information science, which allows as much of the available evidence as possible to be collected and analyzed according to standard protocols that are then disseminated to healthcare providers. The Cochrane Collaboration leads this movement. A 2001 review of 160 Cochrane systematic reviews revealed that, according to two readers, 21.3% of the reviews concluded insufficient evidence, 20% concluded evidence of no effect, and 22.5% concluded positive effect.[56]

Traditional medicine (also known as indigenous or folk medicine) comprises knowledge systems that developed over generations within various societies before the era of modern medicine. The World Health Organization (WHO) defines traditional medicine as "the sum total of the knowledge, skills, and practices based on the theories, beliefs, and experiences indigenous to different cultures, whether explicable or not, used in the maintenance of health as well as in the prevention, diagnosis, improvement or treatment of physical and mental illness."[57]

In some Asian and African countries, up to 80% of the population relies on traditional medicine for their primary health care needs. When adopted outside of its traditional culture, traditional medicine is often called alternative medicine.[57] Practices known as traditional medicines include Ayurveda, Siddha medicine, Unani, ancient Iranian medicine, Irani, Islamic medicine, traditional Chinese medicine, traditional Korean medicine, acupuncture, Muti, If, and traditional African medicine.

The WHO notes however that "inappropriate use of traditional medicines or practices can have negative or dangerous effects" and that "further research is needed to ascertain the efficacy and safety" of several of the practices and medicinal plants used by traditional medicine systems.[57] The line between alternative medicine and quackery is a contentious subject.

Traditional medicine may include formalized aspects of folk medicine, that is to say longstanding remedies passed on and practised by lay people. Folk medicine consists of the healing practices and ideas of body physiology and health preservation known to some in a culture, transmitted informally as general knowledge, and practiced or applied by anyone in the culture having prior experience.[58] Folk medicine may also be referred to as traditional medicine, alternative medicine, indigenous medicine, or natural medicine. These terms are often considered interchangeable, even though some authors may prefer one or the other because of certain overtones they may be willing to highlight. In fact, out of these terms perhaps only indigenous medicine and traditional medicine have the same meaning as folk medicine, while the others should be understood rather in a modern or modernized context.[59]

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Bone marrow is a soft, spongy material found in your large bones. It makes more than 200 billion new blood cells every day, including red blood cells, white blood cells, and platelets. But for people with bone marrow disease, including several types of cancer, the process doesnt work properly. Often, a bone marrow transplant is a persons best chance of survival and a possible cure. The good news is that donating bone marrow can be as easy and painless as giving blood.

A bone marrow transplant replaces diseased bone marrow with healthy tissue, usually stem cells found in the blood. Thats why bone marrow transplants are also called stem cell transplants. In an allogeneic transplantation (ALLO transplant), blood stem cells from the bone marrow are transplanted from a donor into the patient. The donor stem cells can come from either the blood that circulates throughout another persons body or from umbilical cord blood.

But theres a catch. Before a person receives an ALLO transplant, a matching donor must be found using human leukocyte antigen (HLA) typing. This special blood test analyzes HLAs, which are specific proteins on the surface of white blood cells and other cells that make each persons tissue type unique. HLA-matched bone marrow is less likely to cause a possible side effect of transplantation called graft vs. host disease (GVHD). GVHD is when immune cells in the transplanted tissue recognize the recipients body as foreign and attack it.

Only about 30% of people who need a transplant can find an HLA-matched donor in their immediate family. For the remaining 70% of people, doctors need to find HLA-matched bone marrow from other donors. In 2016, that equals about 14,000 people from very young children up to older adults in the United States who need to find a donor outside of their close family.

The National Marrow Donor Program (NMDP) has a registry of potential donors that might be the match a patient needs. Heres how the donation process works:

You register with the NMDP online or in person at a donor center. You can find a center by calling the toll-free number 1-800-MARROW2.

You collect cells from your cheek with a cotton swab or provide a small blood sample. This is done by following directions in a mail-in kit or at a donor center. The sample is analyzed to determine your HLA type, which is recorded in the NMDP national database.

If an HLA match is made with a patient in need, the NMDP contacts you. A donor center takes a new sample of your blood, which is sent to the patients transplant center to confirm the HLA match. Once doctors confirm the match, youd meet with a counselor from the NMDP to talk about the procedures, benefits, and risks of the donation process. You then decide whether youre comfortable with donating.

If you agree to donate bone marrow, youll likely do whats called a peripheral blood stem cell (PBSC) collection. Heres how it works:

For 5 days leading up to the donation, youll get a daily 5-minute injection of granulocyte colony-stimulating factor (G-CSF), a white blood cell growth hormone.

On day 5, a trained health care provider will place a needle in each of your arms. One needle will remove blood, and a machine circulates the blood and collects the stem cells. Your blood then is returned to your body through the second needle. The process takes about 3 hours and may be repeated on a second donation day. Side effects include headaches, bone soreness, and discomfort from the needles during the process.

Although less common, some donors may be asked to undergo a bone marrow harvest, during which doctors take bone marrow from the back of a donors hip bone during surgery. Donors usually go home the same day of the surgery and can return to normal activity within 1 week. Common side effects include nausea, headache, and fatigue, most often related to the anesthesia. Bruising or discomfort in the lower back is also common.

The end result? You could help cure someones disease.

Read the rest here:
Donating Bone Marrow | Cancer.Net

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What is a bone marrow transplant?

Bone marrow transplant (BMT) is a special therapy for patients with certain cancers or other diseases. A bone marrow transplant involves taking cells that are normally found in the bone marrow (stem cells), filtering those cells, and giving them back either to the donor (patient) or to another person. The goal of BMT is to transfuse healthy bone marrow cells into a person after their own unhealthy bone marrow has been treated to kill the abnormal cells.

Bone marrow transplant has been used successfully to treat diseases such as leukemias, lymphomas, aplastic anemia, immune deficiency disorders, and some solid tumor cancers since 1968.

What is bone marrow?

Bone marrow is the soft, spongy tissue found inside bones. It is the medium for development and storage of most of the body's blood cells.

The blood cells that produce other blood cells are called stem cells. The most primitive of the stem cells is called the pluripotent stem cell, which is different than other blood cells with regards to the following properties:

It is the stem cells that are needed in bone marrow transplant.

Why is a bone marrow transplant needed?

The goal of a bone marrow transplant is to cure many diseases and types of cancer. When the doses of chemotherapy or radiation needed to cure a cancer are so high that a person's bone marrow stem cells will be permanently damaged or destroyed by the treatment, a bone marrow transplant may be needed. Bone marrow transplants may also be needed if the bone marrow has been destroyed by a disease.

A bone marrow transplant can be used to:

The risks and benefits must be weighed in a thorough discussion with your doctor and specialists in bone marrow transplants prior to procedure.

What are some diseases that may benefit from bone marrow transplant?

The following diseases are the ones that most commonly benefit from bone marrow transplant:

However, patients experience diseases differently, and bone marrow transplant may not be appropriate for everyone who suffers from these diseases.

What are the different types of bone marrow transplants?

There are different types of bone marrow transplants depending on who the donor is. The different types of BMT include the following:

How are a donor and recipient matched?

Matching involves typing human leukocyte antigen (HLA) tissue. The antigens on the surface of these special white blood cells determine the genetic makeup of a person's immune system. There are at least 100 HLA antigens; however, it is believed that there are a few major antigens that determine whether a donor and recipient match. The others are considered "minor" and their effect on a successful transplant is not as well-defined.

Medical research is still investigating the role all antigens play in the process of a bone marrow transplant. The more antigens that match, the better the engraftment of donated marrow. Engraftment of the stem cells occurs when the donated cells make their way to the marrow and begin producing new blood cells.

Most of the genes that "code" for the human immune system are on one chromosome. Since we only have two of each chromosome, one we received from each of our parents, a full sibling of a patient in need of a transplant has a one in four chance of having gotten the same set of chromosomes and being a "full match" for transplantation.

The bone marrow transplant team

The group of specialists involved in the care of patients going through transplant is often referred to as the transplant team. All individuals work together to provide the best chance for a successful transplant. The team consists of the following:

An extensive evaluation is completed by the bone marrow transplant team. The decision for you to undergo a bone marrow transplant will be based on many factors, including the following:

For a patient receiving the transplant, the following will occur in advance of the procedure:

Preparation for the donor

How are the stem cells collected?

A bone marrow transplant is done by transferring stem cells from one person to another. Stem cells can either be collected from the circulating cells in the blood (the peripheral system) or from the bone marrow.

If the donor is the person himself or herself, it is called an autologous bone marrow transplant. If an autologous transplant is planned, previously collected stem cells, from either peripheral (apheresis) or harvest, are counted, screened, and ready to infuse.

The bone marrow transplant procedure

The preparations for a bone marrow transplant vary depending on the type of transplant, the disease requiring transplant, and your tolerance for certain medications. Consider the following:

The days before transplant are counted as minus days. The day of transplant is considered day zero. Engraftment and recovery following the transplant are counted as plus days. For example, a patient may enter the hospital on day -8 for preparative regimen. The day of transplant is numbered zero. Days +1, +2, etc., will follow. There are specific events, complications, and risks associated with each day before, during, and after transplant. The days are numbered to help the patient and family understand where they are in terms of risks and discharge planning.

During infusion of bone marrow, the patient may experience the following:

After infusion, the patient may:

After leaving the hospital, the recovery process continues for several months or longer, during which time the patient cannot return to work or many previously enjoyed activities. The patient must also make frequent follow-up visits to the hospital or doctor's office.

When does engraftment occur?

Engraftment of the stem cells occurs when the donated cells make their way to the marrow and begin producing new blood cells. Depending on the type of transplant and the disease being treated, engraftment usually occurs around day +15 or +30. Blood counts will be checked frequently during the days following transplant to evaluate initiation and progress of engraftment. Platelets are generally the last blood cell to recover.

Engraftment can be delayed because of infection, medications, low donated stem cell count, or graft failure. Although the new bone marrow may begin making cells in the first 30 days following transplant, it may take months, even years, for the entire immune system to fully recover.

What complications and side effects may occur following BMT?

Complications may vary, depending on the following:

The following are complications that may occur with a bone marrow transplant. However, each individual may experience symptoms differently. These complications may also occur alone, or in combination:

Long-term outlook for a bone marrow transplantation

Prognosis greatly depends on the following:

As with any procedure, in bone marrow transplant the prognosis and long-term survival can vary greatly from person to person. The number of transplants being done for an increasing number of diseases, as well as ongoing medical developments, have greatly improved the outcome for bone marrow transplant in children and adults. Continuous follow-up care is essential for the patient following a bone marrow transplant. New methods to improve treatment and to decrease complications and side effects of a bone marrow transplant are continually being discovered.

More here:
Bone Marrow Transplantation | Hematology and Oncology

Recommendation and review posted by sam

Index Copernicus Value: 5.12

NLMID: 101550241

The Journal of Cell Science & Therapy is an Open Access, peer-reviewed, academic journal with a wide range of fields within the discipline creates a platform for the authors to publish their comprehensive and most reliable source of information on the discoveries and current developments in the mode of original articles, review articles, case reports, short communications, etc, making them freely available through online without any restrictions or any other subscriptions to researchers worldwide.

The journal is using Editorial Manager System for quality in peer review process. Editorial Manager is an online manuscript submission, review and tracking systems. Review processing is performed by the editorial board members of Journal of Cell Science & Therapy 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.

Journal of Cell Science & Therapy is a peer reviewed scientific journal known for rapid dissemination of high-quality research. This Cell Science journal with highest impact factor offers an Open Access platform to the authors in academia and industry to publish their novel research. It serves the International Scientific Community with its standard research publications.

Cells are small compartments that hold the biological equipment necessary to keep an organism alive and successful. Living things may be unicellular or multicellular such as a human being. According to cell theory, cells are the fundamental unit of structure and function in all living organisms and come from preexisting cells, and that all cells contain the hereditary information necessary for regulating cell functions and for transmitting information to the next generation of cells.

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The cytokines produced by expression from suitable cloning vectors containing the desired cytokine gene, can be expressed in yeast (Saccharomyces cerevisiae expression system), bacteria (Escherichia coli expression system), mammalian cells (BHK, CHO, COS, Namalwa), or insect cell systems. Cytokines are designed for demanding applications such as cell culture, differentiation studies, and functional assays mainly in the fields of immunology, neurology, and stem cell research.

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Hematology is the investigation of blood, the blood-framing organs, and blood diseases in which the specialists deal with the diagnosis, treatment and overall management of people with blood disorders ranging from anemia to blood cancer. Some of the diseases treated by haematologists include Iron deficiency anaemia, Sickle cell anemia, Polycythemia or excess production of red blood cells, Myelofibrosis, Leukemia, hemophilia, myelodysplastic syndromes, Malignant lymphomas, Blood transfusion and bone marrow stem cell transplantation

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Cell biology (cytology) is a branch of biology that studies cells their physiological properties, their structure, the organelles they contain, interactions with their environment, their life cycle, division, death and cell function. Research in cell biology is closely related to genetics, biochemistry, molecular biology, immunology, and developmental biology.

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A hair follicle is part of the skin that grows hair by packing old cells together. Attached to the follicle is a sebaceous gland, a tiny sebum-producing gland found everywhere except on the palms, lips and soles of the feet. The follicle cells that extrude hairs from just below the surface of the skin are simply too hard to bring back to life, and even preventative therapies didnt seem to be able to do much to keep them alive. But research on inducing stem cells to grow into follicle cells could change that forever.

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Mesenchymal stem cells (MSCs), the major stem cells for cell therapy. From animal models to clinical trials, MSCs have afforded promise in the treatment of numerous diseases, mainly tissue injury and immune disorders. Cell sources for MSC administration in clinical applications, and provide an overview of mechanisms that are significant in MSC-mediated therapies. Although MSCs for cell therapy have been shown to be safe and effective, there are still challenges that need to be tackled before their wide application in the clinical research field.

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Ovation Cell Therapy Hair Treatment nourishes hair and scalp with proteins and amino acids that bind and absorb into the hair shaft for hair that is noticeably thicker, stronger, and longer. The Ovation Cell Therapy is the heart of the system and is often where the system draws occasional criticism for its claims to accelerate hair growth and reduce breakage and hair loss.

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The external effects of degenerative processes inside the body which manifest especially in the face, hands, dcollet, and by hair loss are also psychically stressful. There are promising therapeutic approaches with stem cells and growth factors for both skin regeneration and hair growth regeneration. To dispense with hair transplants and surgical procedures such as facelifts and eyelid correction, in which the skin is pulled back and the excess tissue is excised. To treat the root cause and restore lost volume in a tissue-conserving, natural manner and regenerate both the subcutaneous tissue and the skin.

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Somatic cell therapy is viewed as a more conservative, safer approach because it affects only the targeted cells in the patient, and is not passed on to future generations. Somatic gene therapy represents mainstream basic and clinical research, in which therapeutic DNA (either integrated in the genome or as an external episome or plasmid) is used to treat disease. Most focus on severe genetic disorders, including immunodeficiencies, haemophilia, thalassaemia and cystic fibrosis. Such single gene disorders are good candidates for somatic cell therapy.

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Rejuvenation and regeneration are two key processes that define cell therapy. Cellular Therapy is a form of non-toxic, holistic medicine in which the entire organism is being treated. Cellular Therapies are an integral part of complimentary treatment regimens. They are extremely versatile and can be used for a wide range of disorders.

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Dendritic cells (DCs) cells are the most potent antigen-producing cells, represent unique antigen-producing cells capable of sensitizing T cells to both new and recall antigens. Dendritic Cell Vaccines, or Dendritic cell therapy, is another Alternative Cancer Therapy or newly emerging and potent form of immune therapy used to treat cancer.

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The cells are most commonly immune-derived, with the goal of transferring immune functionality and characteristics along with the cells. Transferring autologous cells minimizes GVHD issues. The adaptive transfer of autologous tumor infiltrating lymphocytes (TIL) or genetically re-directed peripheral blood mononuclear cells has been used to treat patients with advanced solid tumors, including melanoma and colorectal carcinoma, as well as patients with CD19-expressing hematologic malignancies. As of 2015 the technique had expanded to treat cervical cancer, lymphoma, leukemia, bile duct cancer and neuroblastoma.

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The ability to convert one cell type into another has caused great excitement in the stem cell field. iPS Reprogramming and transdifferentiation are the two approaches which makes cells in to another type of cells. In iPS procedure, it make possible to convert essentially any cell type in the body back into pluripotent stem cells that are almost identical to embryonic stem cells. And another approach uses transcription factors to convert a given cell type directly into another specialized cell type, without first forcing the cells to go back to a pluripotent state.

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Advance Cell & Gene Thearpy practical, experienced guidance in development, GMP/GTP manufacturing, and regulatory compliance, as well as comprehensive scientific and technical strategic analysis of business opportunities in cell therapy, gene therapy and tissue therapies.

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Immunotherapy involves engineering patients own immune cells to recognize and attack their tumors. And although this approach, called adoptive cell transfer (ACT), has been restricted to small clinical trials so far, treatments using these engineered immune cells have generated some remarkable responses in patients with advanced cancer. .Adoptive T cell therapy for cancer is a form of transfusion therapy consisting of the infusion of various mature T cell subsets with the goal of eliminating a tumor and preventing its recurrence.

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Journal of Cell Science and Therapy is associated with our international conference "6th World Congrss on Cell & Stem Cell Research" during Feb 29- March 2, 2016 Philadelphia, USA with a theme "Novel Therapies in Cell Science and Stem Cell Research. Stem Cell Therapy-2016 will encompass recent researches and findings in stem cell technologies, stem cell therapies and transplantations, current understanding of cell plasticity in cancer and other advancements in stem cell research and cell science.

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Cell Science & Therapy - omicsonline.org

Recommendation and review posted by Bethany Smith

The breast is made up of glands called lobules that can make milk and thin tubes called ducts that carry the milk from the lobules to the nipple. Breast tissue also contains fat and connective tissue, lymph nodes, and blood vessels.

The most common type of breast cancer is ductal carcinoma, which begins in the cells of the ducts. Breast cancer can also begin in the cells of the lobules and in other tissues in the breast. Ductal carcinoma in situ is a condition in which abnormal cells are found in the lining of the ducts but they haven't spread outside the duct. Breast cancer that has spread from where it began in the ducts or lobules to surrounding tissue is called invasive breast cancer. In inflammatory breast cancer, the breast looks red and swollen and feels warm because the cancer cells block the lymph vessels in the skin.

In the U.S., breast cancer is the second most common cancer in women after skin cancer. It can occur in both men and women, but it is rare in men. Each year there are about 100 times more new cases of breast cancer in women than in men.

Key statistics about breast cancer from the SEER Cancer Statistics Review, 1975-2010.

Excerpt from:
Breast CancerPatient Version - National Cancer Institute

Recommendation and review posted by simmons

Gene Therapy Phone: 617-632-5064

From the first attempt at modifying human DNA in the early 1980s to the first clinical trials based on genetic engineering of the mid 1990s to the first commercialization of a genetically engineered cell product in 2002 gene therapy has moved from being a pioneering research field to becoming one of the most technologically advanced and promising clinical realities for the treatment of a wide spectrum of diseases and tumors.

Founded in 2010, our Gene Therapy Program has been at the forefront of the fight against rare genetic disorders affecting children. The success of our gene therapy clinical trials is due to our programs unique combination of basic research and clinical care and our ability to translate what we learn at the laboratory bench to the bedside care of the patients we treat.

Through our research capabilities and partnerships, we strive to excel in every step of the gene therapy process. Our research includes:

We work closely with industrial and translational academic partners, such as the Translab and Cell Manipulation cores at Dana-Farber Cancer Institute, to:

Learn more

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Gene Therapy Research - Dana-Farber/Boston Children's ...

Recommendation and review posted by simmons

In amyotrophic lateral sclerosis (ALS), gene therapy may help if it can deliver a beneficial protein to salvage dying nerve cells. Gene therapy can be simply a means to boost on site production of a helpful factor, at places where nerve cells are in trouble. Researchers can disarm many types of viruses, and put in the genetic instructions to make therapeutic protein. The redesigned viruses are called vectors. They are simply carriers for therapeutic genes. Knowledge of the SOD1 mutations linked to some forms of ALS has produced a vast body of evidence, pointing to a general strategy for the disease that might be successfully implemented through gene therapy.

Gene therapy is the use of genetic instructions to produce a protein to treat a disorder or deficiency. It can aid in a disease even if the therapy is not directly targeting a gene defect that causes the disease. In amyotrophic lateral sclerosis (ALS), gene therapy may help if it can deliver a beneficial protein, to salvage dying nerve cells. The gene therapy simply is a means to boost on site production of a trophic (growth enhancing) factor, at places where nerve cells are in trouble.

Genes are the molecules in all cells of our bodies that carry the instructions to make all of the materials that comprise the body. In the 1950s, scientists determined that genes code precisely for proteins, with a sequence that specifies the order of the building blocks of proteins, the amino acids. Each gene corresponds to a protein. Each base in a gene codes for an amino acid. The order of bases in a gene produces the ordered chain of amino acids that produce a working protein.

At the turn of the current century, scientists determined, in rough draft form, the sequence of all of the human genes. By this time, they also knew how to create a gene construct, and move that construct into cells, to get the cells to make the corresponding protein.

In some diseases, researchers already know that a defective gene is not able to work. They have the potential means to cure the disease, by replacing the defective gene with a correct, working copy. In ALS, only a few percent of patients have a known gene defect. For the rest, it may be one undiscovered gene that is the problem, or it may be several. But gene therapy can still be designed to aid patients with ALS by providing supportive proteins for nerve cells.

Genes normally reside in the nucleus, the core of a cell, separated from the surrounding materials by a membrane. The chromosomes are the structures within the cell nucleus that contain the DNA that comprises the genes. It is very challenging to get a gene made in the lab to cross both the outer envelope of a cell, and the nuclear membrane as well, to reach the chromosomes.

Scientists studying viruses have discovered natures own solution to the problem of moving genes. Viruses are essentially genes that have evolved to hijack cells, instead of forming cells for themselves. So viruses have strategies to enter cells and take over the protein production process, to produce instead, the virus. Researchers have figured out how to use viruses as Trojan horses, to bring in genes that can then carry out genetic repairs, replacing defective DNA.

For many viruses, researchers can disarm the genes responsible for the damaging properties and put in, instead, genetic instructions to make therapeutic proteins. These viruses, redesigned by researchers, are called vectors. They are simply a means to smuggle in therapeutic genes.

Investigators must demonstrate that the viral vector is not going to revert back to an infectious form, or cause any side effects.

Genes normally are read out only when a protein is needed, and operate under feedback control. If adequate amounts of protein are already there, then the gene is turned off. Scientists have to be able to devise the proper switch elements to accompany a therapeutic gene, to make sure that a gene is expressed in proper amounts, and only in an intended target tissue.

To gauge adequate delivery of the vector, and sufficient levels of gene expression, researchers have to have animal models that reflect the key manifestations of a human disease. Despite preclinical work with animals, it is not always possible to extrapolate to patients.

A patients immune system may mount an attack on viral vectors (after all, that is what the immune system is primed to do), or on the newly introduced therapeutic gene product.

In ALS, a few percent of patients have a known defect in a gene. This genetic mistake, in the gene coding for the SOD1 protein, produces disease no different from any other form of ALS, inherited or not. Gene therapy might be designed for a particular SOD1 defect, but that therapy may or may not work for other ALS patients.

What is encouraging is that the knowledge of the SOD1 mutations has produced a vast body of evidence for what does go wrong in other cases of ALS. And that evidence is pointing to a general strategy that might be successfully implemented through gene therapy.

ALS research has produced the notion that the neighborhood surrounding the motor neurons can be nurturing or detrimental to these crucial cells affected in ALS. Even if a neuron carries a mutated SOD1 gene, that nerve cell can survive if neighboring support cells, the glia, have the normal gene (see section on Cell Targets).

Glial cells surround neurons. Some glial functions produce the hallmarks of damage in the nervous system, either inflammation or scarring. Other glial actions are protective, for instance, sweeping away excess excitatory signal molecules before they can do damage. Gene therapy in ALS may be able to target the glial cells as well as neurons, to produce positive effects.

Studies in animal models of ALS show increased survival after treatment with trophic factors (see section on trophic factors), small proteins that support the growth and metabolic activities of nerve cells, most recently with IGF-1 and also after vascular endothelial growth factor (VEGF). However, clinical trials of trophic factors in ALS patients have been disappointing. The challenge of delivering these proteins to the site of damage is likely the underlying cause of the failures in the clinic.

Gene therapy may be the way to provide a steady supply of trophic factors to neurons damaged in ALS, directly at the place where the damage exists. The ALS Association is supporting various avenues of research that seek to implement gene therapies to deliver trophic factors, and is encouraging entry into clinical trials as quickly as possible.

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Gene Therapy - alsa.org

Recommendation and review posted by Bethany Smith

3D printing may seem a little unfathomable to some, especially when you apply biomedical engineering to 3D printing. In general, 3D printing involves taking a digital model or blueprint created via software, which is then printed in successive layers of materials like glass, metal, plastic, ceramic and assembled one layer at a time. Many major manufacturers use them to manufacture airplane parts or electrical appliances.

Some of the most incredible uses for 3D printing are developing within the medical field. Some of the following ways this futuristic technology is being developed for medical use might sound like a Michael Crichton novel, but are fast becoming reality.

Bioprinting is based on bio-ink, which is made of living cell structures. When a particular digital model is input, specific living tissue is printed and built up layer by cell layer. Bioprinting research is being developed to print different types of tissue, while 3D inkjet printing is being used to develop advanced medical devices and tools.

While an entire organ has yet to be successfully printed for practical surgical use, scientists and researchers have successfully printed kidney cells, sheets of cardiac tissue that beat like a real heart and the foundations of a human liver, among many other organ tissues. While printing out an entire human organ for transplant may still be at least a decade away, medical researchers and scientists are well on their way to making this a reality.

Stem cells have amazing regenerative properties already they can reproduce many different kinds of human tissue. Now, stem cells are being bioprinted in several university research labs, such as the Heriot-Watt University of Edinburgh. Stem cell printing was the precursor to printing other kinds of tissues, and could eventually lead to printing cells directly into parts of the body.

Imagine the uses that printing skin grafts could do for burn victims, skin cancer patients and other kinds of afflictions and diseases that affect the epidermis. Medical engineers in Germany have been developing skin cell bioprinting since 2010, and researcher James Yoo from Wake Forest Institute is developing skin graft printing that can be applied directly onto burn victims.

Hod Lipson, a Cornell engineer, prototyped tissue bioprinting for cartilage within the past few years. Though Lipson has yet to bioprint a meniscus that can withstand the kind of pressure and pounding that a real one can, he and other engineers are well on their way to understanding how to apply these properties. Additionally, the same group from Germany who bioprinted stem cells is also working toward the same results for bioprinting bone and others parts of the skeletal system.

Just six months ago, bioengineering students from the University of British Columbia won a prestigious award for their engineering and 3D printing of a new and extremely effective type of surgical smoke evacuator. Other surgical tools that have been 3D printed include forceps, hemostats, scalpel handles and clamps and best of all, they come out of the printer sterile and cost a tenth as much as the stainless steel equivalent.

In the same way that tissue and types of organ cells are being printed and studied, disease cells and cancer cells are also being bioprinted, in order to more effectively and systematically study how tumors grow and develop. Such medical engineering would allow for better drug testing, cancer cell analyzing and therapy development. With developments in 3D and bioprinting, it may even be a possibility within our lifetime that a cure for cancer is discovered.

Another German institute has created blood vessels using artificial biological cells, a 3D inkjet printer and a laser to mold them into shape. Likewise, researchers at the University of Rostock in Germany, Harvard Medical Institute and the University of Sydney are developing methods of heart repair, or types of a heart patch, made with 3D printed cells.

The human cell heart patches have gone through successful testing on rats, and have also included development of artificial cardiac tissues that successfully mimic the mechanical and biological properties of a real human heart.

There are plenty of other developments being made with 3D and bioprinting, but one of the biggest obstacles is finding software that is advanced or sophisticated enough to meet the challenge of creating the blueprint. While creating the blueprint for an ash tray, and subsequently producing it via 3D printing is a fairly simple and quick process, there is no equivalent for creating digital models of a liver or heart at this point.

However, with the quick developments and advancements researchers and biomedical engineers have made in a short few years, this obstacle will soon be one of many that are overcome on the way to successful complex bioprinting.

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Recommendation and review posted by Bethany Smith

Male hypogonadism is the result of deficiency of the male sex hormone testosterone. It leads to loss of sex drive and function, delayed puberty, osteoporosis, and there can also be associated failure of the testes to produce sperm.

Testosterone deficiency syndrome; testosterone deficiency; primary hypogonadism; secondary hypogonadism; hypergonadotrophic hypogonadism; hypogonadotrophic hypogonadism.

Male hypogonadism describes a state of low levels of the male hormone testosterone in men. Testosterone is produced in the testes and is important for the formation of male characteristics such as deepening of the voice, development of facial and pubic hair and growth of the penis and testes during puberty. Gonadotrophin-releasing hormone made in the hypothalamus stimulates the pituitary gland to produce luteinising hormone and follicle stimulating hormone (gonadotrophins), which then act on the testes causing them to produce testosterone.Low levels of testosterone can occur due to disease of the testes or from conditions affecting the hypothalamus or pituitary gland. Men can be affected at any age and present with different symptoms depending on the timing of the disease in relation to the start of puberty.

Male hypogonadism can be divided into two groups.Classical hypogonadism is where the low levels of testosterone are caused by an underlying specific medical condition, for example Klinefelter's syndrome, Kallmanns syndrome or a pituitary tumour.Late-onset hypogonadism is where the decline in testosterone levels is linked to general ageing and/or age-related diseases, particularly obesity.It is estimated that late-onset hypogonadism only affects a small number of men over the age of 40.

There are two types of classical male hypogonadism primary and secondary.Primary hypogonadism occurs when the low level of testosterone is due to conditions affecting the testes.Primary hypogonadism is also referred to as hypergonadotrophic hypogonadism, whereby the pituitary produces too much luteinising hormone and follicle stimulating hormone (gonadotrophins) to try and stimulate the testes to produce more testosterone. However, as the testes are impaired or missing, they are not able to respond to the increased levels of gonadotrophins and little or no testosterone is produced.

Examples of conditions affecting the testes, which lead to low levels of testosterone, include:

Secondary hypogonadism results from conditions affecting the function of the hypothalamus and/or pituitary gland.It is also known as hypogonadotrophic hypogonadism due to low levels of luteinising hormone and follicle stimulating hormone resulting in decreased testosterone production.Secondary hypogonadism often occurs as part of a wider syndrome of hypopituitarism.Examples of causes can include:

The signs and symptoms depend on the stage at which the patient presents with hypogonadism in relation to sexual maturity.If testosterone deficiency occurs before or during puberty, signs and symptoms are likely to include:

Around the time of puberty, boys with too little testosterone may also have less than normal strength and endurance, and their arms and legs may continue to grow out of proportion with the rest of their body.

In men who have already reached sexual maturity, symptoms are likely to include:

As some of these symptoms (e.g. tiredness, mood changes) can have multiple causes, diagnosis of male hypogonadism may sometimes get missed initially.

Male hypogonadism is more common in ageing men. The levels of testosterone in men start to fall after the age of 40. It has been estimated that 8.4% of men aged 50-79 years have testosterone deficiency.Male hypogonadism is also linked with type 2 diabetes: approximately 17% of men with type 2 diabetes are estimated to have low testosterone levels.

Male hypogonadism does not run in families.There are genetic causes of hypogonadism which include Klinefelters syndrome and Kallmanns syndrome; however, these conditions occur sporadically, they are not inherited from the parents.

A detailed medical history should be taken.In particular, it is important to find out if virilisation was complete at birth, whether the testes descended and to see if the patient went through puberty at the same time as his peers. The patient should be thoroughly examined and the presence and size of the testes recorded and whether they are correctly positioned in the scrotum.

Many of the symptoms of male hypogonadism are non-specific and can be caused by a range of conditions. Therefore, when diagnosing hypogonadism, it is important that biochemical tests are performed to assess the levels of testosterone in the blood to confirm diagnosis. Blood tests will be carried out to measure testosterone levels.The blood sample should be collected preferably at 9am (this is because levels of testosterone change throughout the day) and can be carried out as an outpatient appointment.If the result of the first test shows a low level of testosterone, the test should be repeated after two or three weeks to confirm the result. Other hormones are also tested along with the second blood sample. These hormones include luteinising hormone, follicle stimulating hormone and prolactin (produced by the pituitary gland).The results of these blood tests will help distinguish between primary (low testosterone and high gonadotrophins) and secondary (low testosterone and normal or low gonadotrophins) hypogonadism.

Depending on the findings of the above tests, other investigations may be carried out. These include: a bone densitometry test to assess the impact of testosterone deficiency on bone; semen analysis; genetic studies; and an ultrasound of the testes to check for nodules or growths.

Treatment of classical hypogonadism involves replacement of testosterone with the aim of raising the level of testosterone in the blood to normal levels.Exact treatment will vary between patients and be tailored to their individual needs.Different preparations of testosterone are available:

All these are outpatient treatments. All of these options should be discussed with a medical professional and the most appropriate treatment option chosen.During treatment with testosterone replacement, regular blood tests should be carried out to monitor testosterone levels and if necessary, the dose adjusted to ensure levels return to the normal range.Tablet forms of testosterone taken by mouth are not recommended due to a link with liver damage.

Testosterone should not be given if the patient has prostate cancer. Before starting treatment with testosterone, a blood test to measure a hormone produced by the prostate called PSA (prostate-specific antigen) is carried out (PSA levels are elevated in prostate cancer).The prostate may also be examined (via the back passage) to rule out prostate cancer.

For patients who have been diagnosed with late-onset hypogonadism, there is currently not enough evidence for us to know whether treatment with testosterone is safe and effective over the long-term.While there are some short-term studies that indicate it may benefit these patients over a short period of time, there is a need for longer-term clinical trials in this area, following a large number of patients, to assess the long-term impact of testosterone treatment on patients with late-onset hypogonadism. Areas that particularly require focus are assessing the effects of treatment on the likelihood of developing cardiovascular disease, prostate cancer and secondary polycythaemia (a condition where too many red blood cells are present in the blood).

If patients have any concerns about their health, they should contact their GP in the first instance.

There can be mild side-effects of testosterone replacement depending on the form used: injectable forms can cause pain and bruising at site of injection; the gel form can cause skin irritation; and the buccal form can cause gum irritation.

Treatment with testosterone can cause an increase in red blood cells (known as polycythaemia) which increases the risk of thrombosis.Regular blood tests should be carried out during treatment to check for an increase in red blood cells.Enlargement of the prostate is another serious side-effect that should be monitored.Prostate examination and a blood test for PSA should be performed every three months for the first year and then annually in men over the age of 40 years after starting treatment.If patients have any concerns about these possible side-effects, they should discuss them with their doctor.

Symptoms of male hypogonadism such as lack of sex drive, inadequate erections and infertility can lead to low self-esteem and cause depression. Professional counselling is available to help deal with these side-effects; patients should talk to their doctor for more information.Patients generally see an improvement in their sex drive and self-esteem following testosterone replacement therapy.

Male hypogonadism has been linked with an increased risk of developing heart disease (low testosterone can cause an increase in cholesterol levels). Studies have shown that testosterone levels can be lower in men with type 2 diabetes and in men with excess body weight.Lifestyle changes to reduce weight and increase exercise can raise testosterone levels in men with diabetes.

Testosterone levels in men decline naturally as they age.In the media, this is sometimes referred to as the male menopause (andropause).Low testosterone levels can also cause difficulty with concentration, memory loss and sleep difficulties.Current research suggests that this effect occurs in only a small group of ageing men.However, there is a lot of research in progress to find out more about the effects of testosterone in older men and also whether the use of testosterone replacement therapy would have any benefits.

Reviewed: December 2014

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Drosophila melanogaster is a species of fly (the taxonomic order Diptera) in the family Drosophilidae. The species is known generally as the common fruit fly or vinegar fly. Starting with Charles W. Woodworth's proposal of the use of this species as a model organism, D. melanogaster continues to be widely used for biological research in studies of genetics, physiology, microbial pathogenesis, and life history evolution. It is typically used because it is an animal species that is easy to care for, has four pairs of chromosomes, breeds quickly, and lays many eggs.[2]D. melanogaster is a common pest in homes, restaurants, and other occupied places where food is served.[3]

Flies belonging to the family Tephritidae are also called "fruit flies". This can cause confusion, especially in Australia and South Africa, where the Mediterranean fruit fly Ceratitis capitata is an economic pest.

Wildtype fruit flies are yellow-brown, with brick-red eyes and transverse black rings across the abdomen. They exhibit sexual dimorphism: females are about 2.5 millimeters (0.098in) long; males are slightly smaller with darker backs. Males are easily distinguished from females based on colour differences, with a distinct black patch at the abdomen, less noticeable in recently emerged flies (see fig.), and the sexcombs (a row of dark bristles on the tarsus of the first leg). Furthermore, males have a cluster of spiky hairs (claspers) surrounding the reproducing parts used to attach to the female during mating. There are extensive images at FlyBase.[4]

Egg of D. melanogaster

The D. melanogaster lifespan is about 30 days at 29C (84F).

The developmental period for D. melanogaster varies with temperature, as with many ectothermic species. The shortest development time (egg to adult), 7 days, is achieved at 28C (82F).[5][6] Development times increase at higher temperatures (11 days at 30C or 86F) due to heat stress. Under ideal conditions, the development time at 25C (77F) is 8.5 days,[5][6][7] at 18C (64F) it takes 19 days[5][6] and at 12C (54F) it takes over 50 days.[5][6] Under crowded conditions, development time increases,[8] while the emerging flies are smaller.[8][9] Females lay some 400 eggs (embryos), about five at a time, into rotting fruit or other suitable material such as decaying mushrooms and sap fluxes. The eggs, which are about 0.5mm long, hatch after 1215 hours (at 25C or 77F).[5][6] The resulting larvae grow for about 4 days (at 25C) while molting twice (into second- and third-instar larvae), at about 24 and 48 h after hatching.[5][6] During this time, they feed on the microorganisms that decompose the fruit, as well as on the sugar of the fruit itself. The mother puts feces on the egg sacs to establish the same microbial composition in the larvae's guts which has worked positively for herself.[10] Then the larvae encapsulate in the puparium and undergo a four-day-long metamorphosis (at 25C), after which the adults eclose (emerge).[5][6]

Females become receptive to courting males at about 812 hours after emergence.[11] Specific neuron groups in females have been found to affect copulation behavior and mate choice. One such group in the abdominal nerve cord allows the female fly to pause her body movements to copulate.[12] Activation of these neurons induces the female to cease movement and orient herself towards the male to allow for mounting. If the group is inactivated, the female remains in motion and does not copulate. Various chemical signals such as male pheromones often are able to activate the group.[12]

The female fruit fly prefers a shorter duration when it comes to sex. Males, on the other hand, prefer it to last longer.[13] Males perform a sequence of five behavioral patterns to court females. First, males orient themselves while playing a courtship song by horizontally extending and vibrating their wings. Soon after, the male positions itself at the rear of the female's abdomen in a low posture to tap and lick the female genitalia. Finally, the male curls its abdomen and attempts copulation. Females can reject males by moving away, kicking, and extruding their ovipositor.[14] Copulation lasts around 1520 minutes,[15] during which males transfer a few hundred, very long (1.76mm) sperm cells in seminal fluid to the female.[16] Females store the sperm in a tubular receptacle and in two mushroom-shaped spermathecae; sperm from multiple matings compete for fertilization. A last male precedence is believed to exist in which the last male to mate with a female sires about 80% of her offspring. This precedence was found to occur through both displacement and incapacitation.[17] The displacement is attributed to sperm handling by the female fly as multiple matings are conducted and is most significant during the first 12 days after copulation. Displacement from the seminal receptacle is more significant than displacement from the spermathecae.[17] Incapacitation of first male sperm by second male sperm becomes significant 27 days after copulation. The seminal fluid of the second male is believed to be responsible for this incapacitation mechanism (without removal of first male sperm) which takes effect before fertilization occurs.[17] The delay in effectiveness of the incapacitation mechanism is believed to be a protective mechanism that prevents a male fly from incapacitating its own sperm should it mate with the same female fly repetitively. Sensory neurons in the uterus of female D. melanogaster respond to a male protein, sex peptide, which is found in sperm.[12] This protein makes the female reluctant to copulate for about 10 days after insemination. The signal pathway leading to this change in behavior has been determined. The signal is sent to a brain region that is a homolog of the hypothalamus and the hypothalamus then controls sexual behavior and desire[12]

D. melanogaster is often used for life extension studies, such as to identify genes purported to increase lifespan when mutated.[18]

D. melanogaster females exhibit mate choice copying. When virgin females are shown other females copulating with a certain type of male, they tend to copulate more with this type of male afterwards than naive females (which have not observed the copulation of others). This behavior is sensitive to environmental conditions, and females copy less in bad weather conditions.[19]

D. melanogaster males exhibit a strong reproductive learning curve. That is, with sexual experience, these flies tend to modify their future mating behavior in multiple ways. These changes include increased selectivity for courting only intraspecifically, as well as decreased courtship times.

Sexually nave D. melanogaster males are known to spend significant time courting interspecifically, such as with D. simulans flies. Nave D. melanogaster will also attempt to court females that are not yet sexually mature, and other males. D. melanogaster males show little to no preference for D. melanogaster females over females of other species or even other male flies. However, after D. simulans or other flies incapable of copulation have rejected the males advances, D. melanogaster males are much less likely to spend time courting nonspecifically in the future. This apparent learned behavior modification seems to be evolutionarily significant, as it allows the males to avoid investing energy into futile sexual encounters.[20]

In addition, males with previous sexual experience will modify their courtship dance when attempting to mate with new females the experienced males spend less time courting and therefore have lower mating latencies, meaning that they are able to reproduce more quickly. This decreased mating latency leads to a greater mating efficiency for experienced males over nave males.[21] This modification also appears to have obvious evolutionary advantages, as increased mating efficiency is extremely important in the eyes of natural selection.

Both male and female D. melanogaster act polygamously (having multiple sexual partners at the same time).[22] In both males and females, polygamy results in a decrease in evening activity compared to virgin flies, more so in males than females.[22] Evening activity consists of the activities that the flies participate in other than mating and finding partners, such as finding food.[23] The reproductive success of males and females varies, due to the fact that a female only needs to mate once to reach maximum fertility.[23] Mating with multiple partners provides no advantage over mating with one partner, and therefore females exhibit no difference in evening activity between polygamous and monogamous individuals.[23] For males, however, mating with multiple partners increases their reproductive success by increasing the genetic diversity of their offspring.[23] This benefit of genetic diversity is an evolutionary advantage because it increases the chance that some of the offspring will have traits that increase their fitness in their environment.

The difference in evening activity between polygamous and monogamous male flies can be explained with courtship. For polygamous flies, their reproductive success increases by having offspring with multiple partners, and therefore they spend more time and energy on courting multiple females.[23] On the other hand, monogamous flies only court one female, and expend less energy doing so.[23] While it requires more energy for male flies to court multiple females, the overall reproductive benefits it produces has kept polygamy as the preferred sexual choice.[23]

It has been shown that the mechanism that affects courtship behavior in Drosophila is controlled by the oscillator neurons DN1s and LNDs.[24] Oscillation of the DN1 neurons was found to be effected by socio-sexual interactions, and is connected to mating-related decrease of evening activity.[24]

D. melanogaster was among the first organisms used for genetic analysis, and today it is one of the most widely used and genetically best-known of all eukaryotic organisms. All organisms use common genetic systems; therefore, comprehending processes such as transcription and replication in fruit flies helps in understanding these processes in other eukaryotes, including humans.[25]

Thomas Hunt Morgan began using fruit flies in experimental studies of heredity at Columbia University in 1910 in a laboratory known as the Fly Room. The Fly Room was cramped with eight desks, each occupied by students and their experiments. They started off experiments using milk bottles to rear the fruit flies and handheld lenses for observing their traits. The lenses were later replaced by microscopes, which enhanced their observations. Morgan and his students eventually elucidated many basic principles of heredity, including sex-linked inheritance, epistasis, multiple alleles, and gene mapping.[25]

D. melanogaster is one of the most studied organisms in biological research, particularly in genetics and developmental biology. The several reasons include:

Genetic markers are commonly used in Drosophila research, for example within balancer chromosomes or P-element inserts, and most phenotypes are easily identifiable either with the naked eye or under a microscope. In the list of example common markers below, the allele symbol is followed by the name of the gene affected and a description of its phenotype. (Note: Recessive alleles are in lower case, while dominant alleles are capitalised.)

Drosophila genes are traditionally named after the phenotype they cause when mutated. For example, the absence of a particular gene in Drosophila will result in a mutant embryo that does not develop a heart. Scientists have thus called this gene tinman, named after the Oz character of the same name.[27] This system of nomenclature results in a wider range of gene names than in other organisms.

The genome of D. melanogaster (sequenced in 2000, and curated at the FlyBase database[26]) contains four pairs of chromosomes: an X/Y pair, and three autosomes labeled 2, 3, and 4. The fourth chromosome is so tiny, it is often ignored, aside from its important eyeless gene. The D. melanogaster sequenced genome of 139.5 million base pairs has been annotated[28] and contains around 15,682 genes according to Ensemble release 73. More than 60% of the genome appears to be functional non-protein-coding DNA[29] involved in gene expression control. Determination of sex in Drosophila occurs by the X:A ratio of X chromosomes to autosomes, not because of the presence of a Y chromosome as in human sex determination. Although the Y chromosome is entirely heterochromatic, it contains at least 16 genes, many of which are thought to have male-related functions.[30]

A March 2000 study by National Human Genome Research Institute comparing the fruit fly and human genome estimated that about 60% of genes are conserved between the two species.[31] About 75% of known human disease genes have a recognizable match in the genome of fruit flies,[32] and 50% of fly protein sequences have mammalian homologs. An online database called Homophila is available to search for human disease gene homologues in flies and vice versa.[33]Drosophila is being used as a genetic model for several human diseases including the neurodegenerative disorders Parkinson's, Huntington's, spinocerebellar ataxia and Alzheimer's disease. The fly is also being used to study mechanisms underlying aging and oxidative stress, immunity, diabetes, and cancer, as well as drug abuse.

Embryogenesis in Drosophila has been extensively studied, as its small size, short generation time, and large brood size makes it ideal for genetic studies. It is also unique among model organisms in that cleavage occurs in a syncytium.

During oogenesis, cytoplasmic bridges called "ring canals" connect the forming oocyte to nurse cells. Nutrients and developmental control molecules move from the nurse cells into the oocyte. In the figure to the left, the forming oocyte can be seen to be covered by follicular support cells.

After fertilization of the oocyte, the early embryo (or syncytial embryo) undergoes rapid DNA replication and 13 nuclear divisions until about 5000 to 6000 nuclei accumulate in the unseparated cytoplasm of the embryo. By the end of the eighth division, most nuclei have migrated to the surface, surrounding the yolk sac (leaving behind only a few nuclei, which will become the yolk nuclei). After the 10th division, the pole cells form at the posterior end of the embryo, segregating the germ line from the syncytium. Finally, after the 13th division, cell membranes slowly invaginate, dividing the syncytium into individual somatic cells. Once this process is completed, gastrulation starts.[34]

Nuclear division in the early Drosophila embryo happens so quickly, no proper checkpoints exist, so mistakes may be made in division of the DNA. To get around this problem, the nuclei that have made a mistake detach from their centrosomes and fall into the centre of the embryo (yolk sac), which will not form part of the fly.

The gene network (transcriptional and protein interactions) governing the early development of the fruit fly embryo is one of the best understood gene networks to date, especially the patterning along the anteroposterior (AP) and dorsoventral (DV) axes (See under morphogenesis).[34]

The embryo undergoes well-characterized morphogenetic movements during gastrulation and early development, including germ-band extension, formation of several furrows, ventral invagination of the mesoderm, and posterior and anterior invagination of endoderm (gut), as well as extensive body segmentation until finally hatching from the surrounding cuticle into a first-instar larva.

During larval development, tissues known as imaginal discs grow inside the larva. Imaginal discs develop to form most structures of the adult body, such as the head, legs, wings, thorax, and genitalia. Cells of the imaginal disks are set aside during embryogenesis and continue to grow and divide during the larval stagesunlike most other cells of the larva, which have differentiated to perform specialized functions and grow without further cell division. At metamorphosis, the larva forms a pupa, inside which the larval tissues are reabsorbed and the imaginal tissues undergo extensive morphogenetic movements to form adult structures.

Drosophila flies have both X and Y chromosomes, as well as autosomes. Unlike humans, the Y chromosome does not confer maleness; rather, it encodes genes necessary for making sperm. Sex is instead determined by the ratio of X chromosomes to autosomes. Furthermore, each cell "decides" whether to be male or female independently of the rest of the organism, resulting in the occasional occurrence of gynandromorphs.

Three major genes are involved in determination of Drosophila sex. These are sex-lethal, sisterless, and deadpan. Deadpan is an autosomal gene which inhibits sex-lethal, while sisterless is carried on the X chromosome and inhibits the action of deadpan. An AAX cell has twice as much deadpan as sisterless, so sex-lethal will be inhibited, creating a male. However, an AAXX cell will produce enough sisterless to inhibit the action of deadpan, allowing the sex-lethal gene to be transcribed to create a female.

Later, control by deadpan and sisterless disappears and what becomes important is the form of the sex-lethal gene. A secondary promoter causes transcription in both males and females. Analysis of the cDNA has shown that different forms are expressed in males and females. Sex-lethal has been shown to affect the splicing of its own mRNA. In males, the third exon is included which encodes a stop codon, causing a truncated form to be produced. In the female version, the presence of sex-lethal causes this exon to be missed out; the other seven amino acids are produced as a full peptide chain, again giving a difference between males and females.[35]

Presence or absence of functional sex-lethal proteins now go on to affect the transcription of another protein known as doublesex. In the absence of sex-lethal, doublesex will have the fourth exon removed and be translated up to and including exon 6 (DSX-M[ale]), while in its presence the fourth exon which encodes a stop codon will produce a truncated version of the protein (DSX-F[emale]). DSX-F causes transcription of Yolk proteins 1 and 2 in somatic cells, which will be pumped into the oocyte on its production.

Unlike mammals, Drosophila flies only have innate immunity and lack an adaptive immune response. The D. melanogaster immune system can be divided into two responses: humoral and cell-mediated. The former is a systemic response mediated through the Toll and imd pathways, which are parallel systems for detecting microbes. The Toll pathway in Drosophila is known as the homologue of Toll-like pathways in mammals. Spatzle, a known ligand for the Toll pathway in flies, is produced in response to Gram-positive bacteria, parasites, and fungal infection. Upon infection, pro-Spatzle will be cleaved by protease SPE (Spatzle processing enzyme) to become active Spatzle, which then binds to the Toll receptor located on the cell surface (Fat body, hemocytes) and dimerise for activation of downstream NF-B signaling pathways. The imd pathway, though, is triggered by Gram-negative bacteria through soluble and surface receptors (PGRP-LE and LC, respectively). D. melanogaster has a "fat body", which is thought to be homologous to the human liver. It is the primary secretory organ and produces antimicrobial peptides. These peptides are secreted into the hemolymph and bind infectious bacteria, killing them by forming pores in their cell walls. Years ago[when?] many drug companies wanted to purify these peptides and use them as antibiotics. Other than the fat body, hemocytes, the blood cells in Drosophila, are known as the homologue of mammalian monocyte/macrophages, possessing a significant role in immune responses. It is known from the literature that in response to immune challenge, hemocytes are able to secrete cytokines, for example Spatzle, to activate downstream signaling pathways in the fat body. However, the mechanism still remains unclear.

In 1971, Ron Konopka and Seymour Benzer published "Clock mutants of Drosophila melanogaster", a paper describing the first mutations that affected an animal's behavior. Wild-type flies show an activity rhythm with a frequency of about a day (24 hours). They found mutants with faster and slower rhythms, as well as broken rhythmsflies that move and rest in random spurts. Work over the following 30 years has shown that these mutations (and others like them) affect a group of genes and their products that comprise a biochemical or biological clock. This clock is found in a wide range of fly cells, but the clock-bearing cells that control activity are several dozen neurons in the fly's central brain.

Since then, Benzer and others have used behavioral screens to isolate genes involved in vision, olfaction, audition, learning/memory, courtship, pain, and other processes, such as longevity.

The first learning and memory mutants (dunce, rutabaga, etc.) were isolated by William "Chip" Quinn while in Benzer's lab, and were eventually shown to encode components of an intracellular signaling pathway involving cyclic AMP, protein kinase A, and a transcription factor known as CREB. These molecules were shown to be also involved in synaptic plasticity in Aplysia and mammals.[citation needed]

Male flies sing to the females during courtship using their wings to generate sound, and some of the genetics of sexual behavior have been characterized. In particular, the fruitless gene has several different splice forms, and male flies expressing female splice forms have female-like behavior and vice versa. The TRP channels nompC, nanchung, and inactive are expressed in sound-sensitive Johnston's organ neurons and participate in the transduction of sound.[36][37]

Furthermore, Drosophila has been used in neuropharmacological research, including studies of cocaine and alcohol consumption. Models for Parkinson's disease also exist for flies.[38]

Stereo images of the fly eye

The compound eye of the fruit fly contains 760 unit eyes or ommatidia, and are one of the most advanced among insects. Each ommatidium contains eight photoreceptor cells (R1-8), support cells, pigment cells, and a cornea. Wild-type flies have reddish pigment cells, which serve to absorb excess blue light so the fly is not blinded by ambient light.

Each photoreceptor cell consists of two main sections, the cell body and the rhabdomere. The cell body contains the nucleus, while the 100-m-long rhabdomere is made up of toothbrush-like stacks of membrane called microvilli. Each microvillus is 12 m in length and about 60 nm in diameter.[39] The membrane of the rhabdomere is packed with about 100 million rhodopsin molecules, the visual protein that absorbs light. The rest of the visual proteins are also tightly packed into the microvillar space, leaving little room for cytoplasm.

The photoreceptors in Drosophila express a variety of rhodopsin isoforms. The R1-R6 photoreceptor cells express rhodopsin1 (Rh1), which absorbs blue light (480nm). The R7 and R8 cells express a combination of either Rh3 or Rh4, which absorb UV light (345nm and 375nm), and Rh5 or Rh6, which absorb blue (437nm) and green (508nm) light, respectively. Each rhodopsin molecule consists of an opsin protein covalently linked to a carotenoid chromophore, 11-cis-3-hydroxyretinal.[40]

As in vertebrate vision, visual transduction in invertebrates occurs via a G protein-coupled pathway. However, in vertebrates, the G protein is transducin, while the G protein in invertebrates is Gq (dgq in Drosophila). When rhodopsin (Rh) absorbs a photon of light its chromophore, 11-cis-3-hydroxyretinal, is isomerized to all-trans-3-hydroxyretinal. Rh undergoes a conformational change into its active form, metarhodopsin. Metarhodopsin activates Gq, which in turn activates a phospholipase C (PLC) known as NorpA.[41]

PLC hydrolyzes phosphatidylinositol (4,5)-bisphosphate (PIP2), a phospholipid found in the cell membrane, into soluble inositol triphosphate (IP3) and diacylglycerol (DAG), which stays in the cell membrane. DAG or a derivative of DAG causes a calcium-selective ion channel known as transient receptor potential (TRP) to open and calcium and sodium flows into the cell. IP3 is thought to bind to IP3 receptors in the subrhabdomeric cisternae, an extension of the endoplasmic reticulum, and cause release of calcium, but this process does not seem to be essential for normal vision.[41]

Calcium binds to proteins such as calmodulin (CaM) and an eye-specific protein kinase C (PKC) known as InaC. These proteins interact with other proteins and have been shown to be necessary for shut off of the light response. In addition, proteins called arrestins bind metarhodopsin and prevent it from activating more Gq. A sodium-calcium exchanger known as CalX pumps the calcium out of the cell. It uses the inward sodium gradient to export calcium at a stoichiometry of 3 Na+/ 1 Ca++.[42]

TRP, InaC, and PLC form a signaling complex by binding a scaffolding protein called InaD. InaD contains five binding domains called PDZ domain proteins, which specifically bind the C termini of target proteins. Disruption of the complex by mutations in either the PDZ domains or the target proteins reduces the efficiency of signaling. For example, disruption of the interaction between InaC, the protein kinase C, and InaD results in a delay in inactivation of the light response.

Unlike vertebrate metarhodopsin, invertebrate metarhodopsin can be converted back into rhodopsin by absorbing a photon of orange light (580nm).

About two-thirds of the Drosophila brain is dedicated to visual processing.[43] Although the spatial resolution of their vision is significantly worse than that of humans, their temporal resolution is around 10 times better.

The wings of a fly are capable of beating up to 220 times per second.[citation needed] Flies fly via straight sequences of movement interspersed by rapid turns called saccades.[44] During these turns, a fly is able to rotate 90 in less than 50 milliseconds.[44]

Characteristics of Drosophila flight may be dominated by the viscosity of the air, rather than the inertia of the fly body, but the opposite case with inertia as the dominant force may occur.[44] However, subsequent work showed that while the viscous effects on the insect body during flight may be negligible, the aerodynamic forces on the wings themselves actually cause fruit flies' turns to be damped viscously.[45]

Drosophila is commonly considered a pest due to its tendency to infest habitations and establishments where fruit is found; the flies may collect in homes, restaurants, stores, and other locations.[3] Removal of an infestation can be difficult, as larvae may continue to hatch in nearby fruit even as the adult population is eliminated.

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