Testosterone deficiency is frequently seen in both men and women with HIV. Endocrine abnormalities, which can affect testosterone production, have long been recognized as a complication of HIV since the earliest days of the pandemic (although it has generally been associated with late stage disease).

However, recent research has shown that nearly one out of every five men with HIV has documented testosterone deficiency, irrespective of CD4 count, viral load, or treatment status.

Similarly, testosterone deficiency is seen in one in four HIV-positive women, most often in the context of severe, unexplained weight loss (HIV wasting).

Testosterone is the steroid hormone which is central to the development of the testes (testicles) and prostate in men as well as the promotion of secondary male sexual characteristics (e.g., lean muscle mass, bone mass, hair growth). Testosterone is also important to women in maintaining normal muscle and bone mass, although at levels around 10% less than men.

In both men and women, testosterone is essential to a person's overall health and well-being, contributing to an individual's strength, energy levels, and libido.

By contrast, testosterone depletion is associated with:

Testosterone deficiency in men with HIV is largely associated with an endocrine abnormality called male hypogonadism in which the function of the male gonads (testes) is impaired, resulting in the diminished production of sex hormones beyond what would be expected of a man's specific age.

In the general population, hypogonadism is known to occur in about one in 25 men between the ages of 30 and 50, increasing to one in 14 between the ages of 50 to 79. By contrast, the incidence among men with HIV is as much as five times greater.

Hypogonadism can be caused by either a defect in the testes themselves (primary) or a dysfunction occurring outside of the testes (secondary). In adult males with HIV:

Hypogonadism can also be caused by childhood mumps or the abuse of anabolic steroids. HIV medications have not been shown to contribute to hypogonadism.

Hypogonadism in adult males is characterized by low serum (blood) testosterone levels, as well as one or several of following symptoms:

Diagnosis is made by measuring the amount of testosterone in the blood, of which there are three different subtypes. When a test is performed, the results will reveal both a person's total testosterone (all subtypes) and one of the three subtypes called free testosterone.

Free testosterone is simply a type of testosterone to which no protein is attached, allowing it enter cells and activate receptors that other subtypes can't. It is considered the most accurate measure of testosterone deficiency, despite representing only 2-3% of the total population. On its own, total testosterone is considered less accurate since results can appear normal if other non-free subtypes are elevated.

Testing should be performed early in the morning since levels can fluctuate by up to 20% during the course of a day. "Normal" levels are simply those within the reference range of the lab. These ranges can vary, but, for illustrative purposes, are roughly between

However, an assessment of "normal" cannot be made by numbers alone. Testosterone levels tend to drop by about 1-2% every year after the age of 40. Therefore, what may be "normal" for a 60-year-old male won't be the same for a 30-year-old. Assessments need to be made on an individual basis with your treating doctor.

If a diagnosis of hypogonadism is confirmed, testosterone replacement therapy may be indicated. Intramuscular testosterone injections are usually recommended, which offer low side effects if physiological doses are used and adjusted by the treating doctor. FDA-approved options include Depo-testosterone (testosterone cypionate) and Delatestryl (testosterone enanthate).

On average, injections are given every two to four weeks. To avoid the effects of fluctuating testosterone levelswhich can cause sometimes dramatic swings in mood, energy, and sexual functionlower doses and shorter dosing intervals are often used.

Side effects of treatment can include:

Testosterone replacement therapy can also cause the acceleration of pre-existing prostate cancer. Because of this, a patient's prostate-specific antigen (PSA) levels will be tested and monitored during the course of therapy.

All told, intramuscular injections offer a cost-effective option for treating hypogonadism, with associative increases in alertness, well-being, libido, lean muscle mass, and erection ability. Disadvantages include regular doctor's visits and dosing administration.

Oral, transdermal, and topical gel agents are also available, and may be applicable in certain cases. Discuss these with your doctor.

In women, testosterone is produced in the ovaries and adrenal glands. As with men, it is an important hormone for maintaining normal muscle and bone mass, as well as energy, strength, and libido.

While hypogonadism is far less common in women with HIV, it can occur and is most often in the context of HIV wasting and advanced disease. The implementation of ART can reverse wasting and the hypogonadal state in many cases.

There are currently no fixed guidelines for the treatment of female hypogonadism, and treatment options are limited. Hormone replacement therapy (HRT) may be appropriate for some, while the short-term use of testosterone may improve sex drive, lean muscle mass, and energy levels.

However, data is still incomplete on the use of testosterone to treat hypogonadism in pre-menopausal women with HIV. Speak with your health care provider about possible side effects. Testosterone is not recommended for women who are pregnant or wish to become pregnant.

Rietschel, P.; Corcoran, C.; Stanley T.; et al. "Prevalence of hypogonadism among men with weight loss related to human immunodeficiency virus infection who were receiving highly active antiretroviral therapy." Clinical Infectious Diseases. November 2, 2000; 31(5):1240-1244.

Hugh Jones, T. "Late Onset Hypogonadism." British Medical Journal. February 13, 2009; 338:b352.

Huang, J.; Wilkie, S.; Dolan, S.; et al. "Reduced testosterone levels in human immunodeficiency virus-infected women with weight loss and low weight." Clinical Infectious Diseases. January 28, 2003; 36(4):499-506.

Grinspoon, S. "The Use of Androgens in HIV-Infected Men and Women." Physicians Research Network Notebook. March 2005.

Kalyani, R.; Gavini, S.; and Dobs. A. "Male Hypogonadism in systemic disease." Endocrinology Metabolism Clinics of North America Journal. June 2007; 36(2):333-48.

Carnegie, C. "Diagnosis of Hypogonadism: Clinical Assessment and Laboratory Tests." Review in Urology. 2004; 6(6):s3-8.

Kumar, P.; Kumar, N.; Patidar, A.; et al. "Male Hypogonadism: Symptoms and treatment." Journal of Advanced Pharmacological Technology and Research. July-September 2010; 1(3): 297-302.

Mylonakis, E.; Koutkia, P.; and Grinspoon, S. "Diagnosis and treatment of androgen deficiency in human immunodeficiency virus-infected men and women." Clinical Infectious Diseases. September 15, 2001; 33(6):857-64.

Read this article:
HIV and Testosterone Deficiency - verywell.com

Recommendation and review posted by Bethany Smith

Hypogonadism is a medical term for a defect of the reproductive system which results in lack of function of the gonads (ovaries or testes).

Hypogonadism may occur if the hypothalamic-pituitary-gonadal axis is interrupted at any level. Hypergonadotropic hypogonadism (primary hypogonadism) results if the gonad does not produce the amount of steroid sufficient to suppress secretion of LH and FSH at normal levels. Hypogonadism resulting from defects of the gonads is traditionally referred to as primary hypogonadism. Examples include Klinefelter syndrome and Turner syndrome. Hypogonadism resulting from hypothalamic or pituitary defects are termed secondary hypogonadism or central hypogonadism (referring to the central nervous system). Hypogonadism can affect men of any age, from fetal development, through puberty and adulthood. Hypogonadism is one of the main causes of male infertility. It is estimated that 13 million men in the United States alone are affected by hypogonadism. Hypogonadism is caused by deficient testosterone secretion by the testes. The two basic types of male hypogonadism are Primary and Secondary.

Hypogonadism Primary, also known as primary testicular failure, originates from an abnormality in the testicles. Hypogonadism may be induced by chronic use of anabolic/androgenic steroids (AAS). The Secondary type of hypogonadism is caused by defects in the pituitary gland connected to the brain that controls hormone production. If chemical messages from the pituitary gland to the testicles aren't sent, impaired testicular function occurs. This condition can be a result from defects in development of the pituitary gland, certain inflammatory diseases, and the use of certain drugs used in the treatment of psychiatric disorders and gastroesophageal reflux disease. Mental and emotional changes can also accompany hypogonadism. As testosterone decreases, some men may experience signs and symptoms similar to those of menopause in women. These may include hot flashes, decreased drive, irritability, depression and fatigue.

Hypogonadism is most often treated by replacement of the appropriate hormones.

Gonadotropin or GnRH replacement is offered to the patient when fertility is desired. Oral testosterone is no longer used in the U.S. because it is broken down in the liver and rendered inactive. In boys, testosterone replacement therapy (TRT) can stimulate puberty and the development of secondary characteristics, such as increased muscle mass, beard and pubic hair growth. Also available is a topical 1% testosterone gel. It is applied once daily to clean, dry skin of the shoulders, upper arms, or abdomen. Another alternative is testosterone patches. The testosterone may be mixed with the adhesive with a new patch applied daily to a different site; this system leaves a sticky residue but causes little skin irritation. Injections of pituitary hormone may be used to help male patients produce sperm. In others, surgery and radiation therapy may be needed. In adult men, TRT can restore function and muscle strength and prevent bone loss.

Treatment for Hypogonadism

Read more:
Hypogonadism - Definition, Causes, Symptoms and Treatment

Recommendation and review posted by Bethany Smith

Definition

Hypogonadism occurs when the body's sex glands produce little or no hormones. In men, these glands (gonads) are the testes. In women, these glands are the ovaries.

Gonadal deficiency

The cause of hypogonadism can be primary or central. In primary hypogonadism, the ovaries or testes themselves do not function properly. Causes of primary hypogonadism include:

The most common genetic disorders that cause primary hypogonadism are Turner syndrome (in women) and Klinefelter syndrome (in men).

If you already have other autoimmune disorders you may be at higher risk of autoimmune damage to the gonads. These can include disorders that affect the liver and adrenal and thyroid glands as well as type 1 diabetes.

In central hypogonadism, the centers in the brain that control the gonads (hypothalamus and pituitary) do not function properly. Causes of central hypogonadism include:

A genetic cause of central hypogonadism is Kallmann syndrome. Many people with this condition also have a decreased sense of smell.

Girls who have hypogonadism will not begin menstruating. Hypogonadism can affect their breast development and height. If hypogonadism occurs after puberty, symptoms in women include:

In boys, hypogonadism affects muscle, beard, genital and voice development. It also leads to growth problems. In men the symptoms are:

If a pituitary or other brain tumor is present (central hypogonadism), there may be:

The most common tumors affecting the pituitary are craniopharyngioma in children and prolactinoma adenomas in adults.

You may need to have tests to check:

Other tests may include:

Sometimes imaging tests are needed, such as a sonogram of the ovaries. If pituitary disease is suspected, an MRI or CT scan of the brain may be done.

You may need to take hormone-based medicines. Estrogen and progesterone are used for girls and women. The medicines comes come in the form of a pill or skin patch. Testosterone is used for boys and men. The medicine can be given as a skin patch, skin gel, a solution applied to the armpit, a patch applied to the upper gum, or by injection.

For women who have not had their uterus removed, combination treatment with estrogen and progesterone may decrease the chance of developing endometrial cancer. Women with hypogonadism who have low sex drive may also be prescribed low-dose testosterone.

In some women, injections or pills can be used to stimulate ovulation. Injections of pituitary hormone may be used to help men produce sperm. Other people may need surgery and radiation therapy.

Many forms of hypogonadism are treatable and have a good outlook.

In women, hypogonadism may cause infertility. Menopause is a form of hypogonadism that occurs naturally and can cause hot flashes, vaginal dryness, and irritability as a woman's estrogen levels fall. The risk of osteoporosis and heart disease increase after menopause.

Some women with hypogonadism take estrogen therapy, especially those who have early menopause. But long-term used of hormone therapy can increase the risk of breast cancer, blood clots and heart disease. Women should talk with their health care provider about the risks and benefits of hormone replacement therapy with your doctor.

In men, hypogonadism results in loss of sex drive and may cause:

Men normally have lower testosterone as they age. However, the decline in hormone levels is not as dramatic as it is in women.

Talk to your health care provider if you notice:

Both men and women should call their provider if they have headaches or vision problems.

Maintain normal body weight and healthy eating habits may help in some cases. Other causes may not be preventable.

Ali O, Donohoue PA. Hypofunction of the testes. In: Kliegman RM, Stanton BF, St. Geme JW III, et al., eds. Nelson Textbook of Pediatrics. 19th ed. Philadelphia, PA: Elsevier Saunders; 2011:chap 577.

Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone therapy in adult men with androgen deficiency syndromes: An Endocrine Society Clinical Practice guideline. J Clin Endocrinol Metab. 2010;95:2536-59. PMID: 20525905 http://www.ncbi.nlm.nih.gov/pubmed/20525905

Kansra AR, Donohoue PA. Hypofunction of the ovaries. In: Kliegman RM, Stanton BF, St. Geme JW III, et al, eds. Nelson Textbook of Pediatrics. 19th ed. Philadelphia, PA: Elsevier Saunders; 2011:chap 580.

Swerdloff RS, Wang C. The testis and male sexual function. In: Goldman L, Schafer AI. Goldman's Cecil Medicine. 24th ed. Philadelphia, PA: Elsevier Saunders; 2012:chap 242.

Review Date: 10/25/2014 Reviewed By: Brent Wisse, MD, Associate Professor of Medicine, Division of Metabolism, Endocrinology & Nutrition, University of Washington School of Medicine, Seattle, WA. Also reviewed by David Zieve, MD, MHA, Isla Ogilvie, PhD, and the A.D.A.M. Editorial team.

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Hypogonadism - UT Medical Center

Recommendation and review posted by Bethany Smith

Testosterone levels in men decline with age, at a rate of about 1% per year beginning at about 40 years old.3 Epidemiological studies have determined that total testosterone follows an age-related decline with mean serum concentration at the age of 75 years approximately two thirds that at 25 years.4

According to reports, approximately 74% of chronic opioid users5, 50% of AIDS patients6, 52% of obese men7, 50% of diabetic men7,8 have low testosterone.

Other causes of lowered testosterone levels include: injury, infection, or loss of the testicles; chemotherapyor radiation treatment for cancer; genetic abnormalities such as Klinefelter's Syndrome (extra X chromosome); hemochromatosis(too much iron in the body); dysfunction of the pituitary gland; inflammatory diseases such as sarcoidosis (a condition that causes inflammation of the lungs); chronic illness; chronic kidney failure; liver cirrhosis; stress; and, alcoholism.

3Feldman HA, et al. J. Clin Endocrinol Metab 2002; 87 (2):589-98 4Myers et al. Rev Urol 2003; 5 (4) 216-226 5Daniell HW., J Pain. 2002; 3:377-384 6Dobs AS. Baillires Clin Endocrinol Metab. 1998; 12:379-390 7Mulligan T, et al. Int J Clin Pract. 2006;60:762-769 8Bodie J, et al. J Urol. 2003;169:22622264 9Jackson JA et al., AM. J. Med. Sci. 1992,304 (1) 4-8

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Lipocine - Hypogonadism

Recommendation and review posted by simmons

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Hypogonadism - Risks, Symptoms and Leading Causes | Treato

Recommendation and review posted by Bethany Smith

Loss of gonadal function of any cause. Diagnosis requires testing of sex hormone and gonadotropin levels. This section includes absent or delayed puberty, primary testicular failure, premature ovarian failure, and secondary hypogonadotropic hypogonadism.

Detailed history,including pubertal development,is mandatory in all patients as this may reduce the list of differential diagnoses considerably.

Specific lines of questioning are indicated according to the exact problem, as below.

The list of differential diagnoses will be different in a patient with multiple medical problems or an obvious congenital condition.

Serious systemic illness of any cause is associated with pubertal delay. Specific conditions associated with abnormal pubertal develoment include the intersex disorders, pseudopseudohypoparathyroidism, Cushing's syndrome andcongenital hypothyroidism.

Pubertal delay is defined by theabsence of thelarche by age 13, or menarche by age 16.

Assess thetiming ofpuberty in as much detail as possible: timing of secondary hair development, breast development and menarche in females, increase in testicular and penile volume, early morning erections and voice breaking in males.

Loss of secondary sexual characteristics such as body hair,and aninability to build new muscle mayoccur withgonadotropin deficiency of any cause.

Weight loss may indicate the development of hypopituitarism or hyperthyroidism. Hypogonadotropic hypogonadism may also occur with Cushing's syndrome and in obesity.

Tall stature and a feminine or 'eunucoid' body shape may be associated with absent puberty in males.

Gynaecomastia may indicate gonadotropin deficiency but in the absence of other symptoms other causes should be considered. Gynaecomastia occurring in conjunction with weight loss should alert to the possibility of malignancy and other systemic diseases.

Absent libido occurs with primary hypogonadism.

New onset loss of libido may be associated with hypogonadism though may be multifactorial.

This may indicate sex hormone deficiency.

Differential diagnoses differ between primary and secondary amenorrhoea.

For secondary amenorrhoea or oligomenorrhoea, specifically assess for symptoms ofpolycystic ovarian syndromeas well as hyperprolactinaemia and thyroid dysfunction below.

Previous pregnancies may help define the duration of disease.

Amenorrhoea and breast swelling are signs of early pregnancy which may not be noticed in the oligomenorrhoeic patient.

Post partum haemorrhage leading to Sheehans syndrome as a cause of hypopituitarism is possible if the patient was unable to breast feed and developed secondary amenorrhoea.

Frequency of shaving varies widely but is usually constant within an individual adult.

Loss of early morning erections is usually important though erectile dysfunction is frequently multifactorial. Symptoms of erectile dysfunction may not be forthcoming unless specifically asked about.

These are all causes of gonadal failure, though orchitis is frequently asymptomatic.

Maldescent may be associated with gonadal dysfunction as well as an increased risk of malignancy.

Hyperprolactinaemia of any cause usually causes hypogonadotropic hypogonadism.

Ask about headache, visual disturbance, breast swelling and galactorrhoea.

Hypothyroidism is a common cause ofdelayed puberty.

Also ask whether the patient hasdeveloped increased sweating, palpitations, tremor, weight loss or diarrhoea, as thyrotoxicosis may also cause gynaecomastia andoligomenorrhoea.

Patients presenting with infertility can on rare occasion befound to havehypopituitarism.

Anorexia nervosa and very low BMI of any cause may cause hypothalamic dysfunction.

Soyacontains large amounts of phytoestrogens which may interfere with the hypothalamic-pituitary-gonadal axis and may be associated with reversible gyncecomastia.

Steroids also interact with the hypothalamic-pituitary-gonadal axis and may occasionally be found in preparations thought by the patient to be 'natural' or 'herbal'.

Excessive exercise may lead to hypothalamic dysfunction.

Various agents associated with hypogonadism are listed below (although it is not exhaustive):

Opiates and recreational drugs, for examplediamorphine, morphine sulphate,heroin, marijuana and alcohol.

Steroids, for examplehydrocortisone, beclamethasone, fluticasone interfere with the hypothalamo-pituitary axis.

Exogenous testosterone,for exampleused forfitness, body building or other sports, will alsoenhance estrogen synthesis.

Estrogens and drugs with estrogen-like activity, such as diethylstilbestrol anddigoxin will also cause gynaecomastia in some cases.

Phenytoin alsoenhances estrogen synthesis, as dogonadotropins.

A range of drugs can inhibit testosterone synthesis or action, includingketoconazole, metronidazole, alkylating agents,spironolactone, cimetidine, flutamide, finasteride, and etomidate.

Other agentssuch asmethyldopa,tricyclic antidepressants, diazepam, penicillamine, omeprazole, phenothiazines, calcium channel blockers, angiotensin-converting enzyme (ACE) inhibitors have all been reported as causing gynaecomastia, though themechanisms underlying this are unclear.

Patients may not report anosmia unless specifically questioned. Kallmanns syndrome is typified by anosmia and hypogonadotropic hypogonadism.

Dental aplasia, cleft palate and dental malalignment requiring orthodontic treatment may not be obvious and are associated with Kallmanns syndrome.

Congenital abnormalities of the urogenital system may occur with Kallmanns and Turners syndromes.

Specifically ask if any family members, for example cousins,have had late or absent puberty,infertility or simply never had children.

Ask also if any family members have had dental or palatal problems, kidney abnormalities or anosmia which might suggest a family history of Kallmanns syndrome.

Congenital hypothyroidism is associated with delayed puberty.

Hypothyroidismis also associated with Turner's syndrome.

These may be associated with Turner's syndrome.

Deafness may be associated with Turner's syndrome.

Patients with Klinefelter's syndrome have an increased incidence of psychiatric problems.

Multiple congenital conditions includeabnormalities of sexual development. Examples includepseudopseudohypoparathyroidism, Russell Silver syndrome, congenital hypothyroidism.

Specificdisorders of sexual development may also be encountered: congenital adrenal hyperplasia,androgen insensitivity syndrome, 5-alpha reductase deficiency, aromatase deficiency, gonadal dysgenesis, Kallmann's syndrome, Turner's syndrome, Klinefelter's syndrome, and other rarer conditions.

Loss of acuity or failing vision at night are worrying features suggesting optic nerve involvement.

Visual field loss, for examplehomonymous hemianopia,is common indicating chiasmal impingement.

It is worth specifically asking whether patients drive and, if so, whether they have had trouble noticing street signs on either side of the road as this may be the first instance in which field loss is noticed.

Assess for red flag symptoms: headaches present on waking, whichworsen on coughing or leaning forward, are more suggestive of increased intracranial pressure.

Headaches or lancing pain across one section of the head or face only are more suggestive of cranial nerve involvement particularly with disease in the cavernous sinus.

Vague symptoms of tiredness, nausea and dizziness may indicate the development of hypopituitarism with ACTH or TSH deficiency.

Diabetes insipidusis uncommon with intrinsic pituitary disease and suggests para sellar pathology.

Pituitary metastases are common and may be the first presentation of malignant disease.

Ask specifically about change of bowel habit, new prostatic symptoms andbreast lumps.

Ask the patient whetherthere has been a change in their weight or body shape. New bruising, redness, acne, hirsuitism, oligomenorrhoea, diabetes, hypertension, depression, osteoporosisor muscle weakness are all associated with Cushing's syndrome, which leads to pubertal delay and hypogonadotropic hypogonadism.

A detailed history of gynaecomastia will help elucidate likely causes.

Peripubertal breast swelling is common and usually requires no treatment. Long standing obesity may be associated with bilateral non-glandular breast swelling. Sudden onset and unilateral gynaecomastia should alert to the possibility of breast cancer.

Sudden onset and unilateral gynaecomastia should alert to the possibility of breast cancer.

Changes in the skin, nipple or unilateral discharge is highly suspicious for breast cancer.

Bilateral galactorrhoea is suggestive of elevated prolatin.

Weight loss and malaise occur with hypopituitarism but may indicate malignancy.

Hyperthyroidism may be associated with gynaecomastia: ask about sweating, palpitations, tremor, weight loss ordiarrhoea.

Hypothyroidism may be associated with delayed puberty.

Cirrhosis, haemachromatosis and congestive cardiac failure are frequently associated with gynaecomastia.

Various agents associated with hypogonadism are listed below (although it is not exhaustive):

Opiates and recreational drugs, for examplediamorphine, morphine sulphate,heroin, marijuana and alcohol.

Steroids, for examplehydrocortisone, beclamethasone, fluticasone interfere with the hypothalamo-pituitary axis.

Exogenous testosterone,for exampleused forfitness, body building or other sports -will alsoenhance estrogen synthesis.

Estrogens and drugs with estrogen-like activity, such as diethylstilbestrol anddigoxin will also cause gynaecomastia in some cases.

Phenytoin alsoenhances estrogen synthesis, as dogonadotropins.

A range of drugs can inhibit testosterone synthesis or action, includingketoconazole, metronidazole, alkylating agents,spironolactone, cimetidine, flutamide, finasteride, and etomidate.

Other agentssuch asmethyldopa,tricyclic antidepressants, diazepam, penicillamine, omeprazole, phenothiazines, calcium channel blockers, angiotensin-converting enzyme (ACE) inhibitors have all been reported as causing gynaecomastia, though themechanisms underlying this are unclear.

Follow this link:
Hypogonadism diagnosis - history - Endobible

Recommendation and review posted by Bethany Smith

Male hypogonadism is a deficiency of testosterone in men. About 5 percent to 6 percent of men experience male hypogonadism, and the condition becomes more common as a man ages.

Hypogonadism may be congenital or may be acquired as the result of aging, disease, drugs or other factors. Symptoms include low sperm count, decreased libido, erectile dysfunction, fatigue, sleep disturbances and depression.

In primary hypogonadism, the testes fail to make testosterone because of infection or injury to the testes. Common causes of testicular dysfunction include cancer treatment, excessive alcohol consumption, Klinefelter syndrome, mumps orchitis and autoimmune disorders.

In secondary hypogonadism, which is more common, the hypothalamus or the pituitary gland fails to produce enough hormones. These hormones are needed to trigger the testes to produce testosterone. Secondary hypogonadism can be caused by Kallmann syndrome, pituitary or hypothalamic tumors or disorders, obesity, diabetes and Prader-Willi syndrome.

Following a complete medical history and physical, tests will be done to measure the man's testosterone level. Because testosterone levels naturally fall off during the day, a testosterone blood test is done between 7:00 am and 10:00 am.

If the test shows a low testosterone level, additional tests may be ordered to check for a pituitary gland disorder. A blood test to check serum follicle-stimulating hormone (FSH), luteinizing hormone (LH) and prolactin levels can help determine the cause. If needed, specialized testing may be performed in the Endocrine Diagnostic Unit, based at Froedtert Hospital.

Other tests may be used to measure sperm count, check for testicle or gland tumors, or identify a genetic (congenital) cause.

For men with primary hypogonadism, treatment typically involves lifelong testosterone replacement therapy. Options for replacement therapy include:

Too much testosterone can place a man at a higher risk for blood clots. As with any hormonal therapy, its important to monitor patients as treatment progresses. Men receiving hormone replacement therapy are seen for blood tests and a prostate exam at one, three and six months after beginning treatment. They continue to be seen every six months.

Secondary hypogonadism is treated by addressing the root cause - a disorder with the hypothalamus or pituitary gland.

Treatment may also be needed for conditions related to hypogonadism, including:

Infertility related to secondary hypogonadism may respond to hormonal replacement therapy. Infertility related to primary hypogonadism, however, does not respond to hormonal therapy. In these cases, a man and his partner can be referred to the Reproductive Medicine Center for help conceiving a child.

Link:
Testosterone Deficiency, Hypogonadism | Froedtert Hospital ...

Recommendation and review posted by sam

Early symptoms of low testosterone in men include low libido (sex drive). As levels become very low, sexual dysfunction (also called "erectile dysfunction (ED)" or "impotence") often develops. Other signs and symptoms of low testosterone may include depression, fatigue, osteoporosis, loss of muscle mass, an increase in abdominal fat, development of breast tissue (gynecomastia) and infertility.

Symptoms of low testosterone in women may include low libido (sex drive), sexual dysfunction, fatigue, loss of muscle mass, an increase in body fat and bone loss.

Pituitary Symptoms

There are many causes of low testosterone. These can be differentiated with hormone testing. Pituitary dysfunction is one cause of low testosterone and can result from compression of the pituitary gland by a large pituitary tumor. In addition, excess hormone secretion by a pituitary tumor can cause low testosterone either directly or indirectly. For example, elevated prolactin, cortisol or GH levels can cause low testosterone. Testosterone levels normalize with treatment of the tumor in some, but not all, cases. There are other causes of low testosterone that are not related to pituitary tumors. These include anabolic steroid use (for body building or athletic enhancement), obesity, depression, and testicular failure.

Research Studies

The complications of low testosterone in men include infertility, sexual dysfunction, osteoporosis, loss of muscle mass, depression and fatigue.

Research Studies

You're likely to start by seeing your family doctor or a general practitioner. However, in some cases when you call to set up an appointment, you may be referred immediately to an endocrinologist, a doctor who specializes in endocrine (hormonal) disorders.

Special Instructions (If available, please bring):

Our clinic assistants will help you update your hospital registration and insurance information.

Thank you.

Appointments

Testosterone levels can be measured directly. An endocrinologist can test for causes of low testosterone, including elevated prolactin levels. Sometimes other blood tests are indicated to make the diagnosis or determine the cause, including free testosterone, sex hormone binding globulin, leutinizing hormone (LH) or evaluation for Cushing's disease or acromegaly.

Newsletter Archive

If the underlying cause of the low testosterone can be determined and corrected, testosterone levels often rise to normal levels. Medical treatment to lower prolactin levels from a prolactinoma often results in normalization of testosterone level. In addition, resection of large nonfunctioning pituitary tumors that are causing low testosteorne by compressing the pituitary gland results in restoration of normal testosterone levels in approximately 50% of cases. Cure of acromegaly or Cushing's disease also often results in normalization of testosterone levels. In patients for whom the cause cannot be determined or addressed, testosterone replacement therapy can be prescribed by an endocrinologist with expertise in this area. There are a number of different preparations available, including gels, creams, patches, and injections. Your endocrinologist can discuss the pros and cons of the different options with you. S/he will also check lab results to make sure it is safe to prescribe the medication and that your testosterone levels on the medication are appropriate. If bone density does not improve when testosterone has been normalized, additional medications may be necessary.

There are no FDA-approved testosterone preparations for women, who make 10 to 20 times less testosterone than men and therefore need much lower replacement doses than men.

Appointments

Research is ongoing in the Neuroendocrine Unit on the effects of low testosterone and testosterone treatment in both men and women.

Research Studies

Originally posted here:
Hypogonadism and Hypogonadism Resources - What is ...

Recommendation and review posted by simmons

At a microscopic level, we are all composed of cells. Look at yourself in a mirror -- what you see is about 10 trillion cells divided into about 200 different types. Our muscles are made of muscle cells, our livers of liver cells, and there are even very specialized types of cells that make the enamel for our teeth or the clear lenses in our eyes!

If you want to understand how your body works, you need to understand cells. Everything from reproduction to infections to repairing a broken bone happens down at the cellular level. If you want to understand new frontiers like biotechnology and genetic engineering, you need to understand cells as well.

Anyone who reads the paper or any of the scientific magazines (Scientific American, Discover, Popular Science) is aware that genes are BIG news these days. Here are some of the terms you commonly see:

Gene science and genetics are rapidly changing the face of medicine, agriculture and even the legal system!

In this article, we'll delve down to the molecular level to completely understand how cells work. We'll look at the simplest cells possible: bacteria cells. By understanding how bacteria work, you can understand the basic mechanisms of all of the cells in your body. This is a fascinating topic both because of its very personal nature and the fact that it makes these news stories so much clearer and easier to understand. Also, once you understand how cells work, you will be able to answer other related questions like these:

All of these questions have obvious answers once you understand how cells work -- so let's get started!

Original post:
How Cells Work | HowStuffWorks

Recommendation and review posted by Bethany Smith

For 26 years, doctors could not piece together the medical puzzle of Stewart Altman's symptoms -- as a child growing up on Long Island, he was uncoordinated and slurred his speech. Later, as a volunteer fireman, he kept falling down and had trouble climbing the ladders.

It seemed unrelated at the time, but his older sister, who had a history of psychological symptoms, was hospitalized in a mental institution. Her psychiatrist suspected a physical disorder and consulted a geneticist who eventually connected the dots.

In 1978, Altman and his sister Roslyn Vaccaro were given a stunning diagnosis: Tay-Sachs -- an inherited neurological disease that typically affects babies, killing them between the ages of 3 and 5. Only several hundred cases exist in the United States.

Altman, now 58, has a non-fatal, adult form of the disease, late onset Tay-Sachs (LOTS), and depends on his wife and a service dog to perform most daily tasks.

"I am devastated," Altman said of the disease that has robbed him of much of his speech and muscle strength, confining him to a wheelchair. "But the alternative is much worse."

His sister died in 2000 after battling LOTS-related bipolar disorder and schizophrenia -- which occurs in 50 to 60 percent of all adult cases -- and Altman and his wife raised her two sons.

Now scientists are hopeful that gene therapy may help late-onset patients like Altman and look forward to human trials.

Tay-Sachs is caused by gene mutation results in the absence or insufficient levels of the enzyme, hexosamindase A or Hex A. Without it, a fatty substance or lipids accumulates in the cells, mostly in the brain. It comes in three forms: infantile, juvenile or adult onset.

Doctors say there can be great variations in the presentation of Tay-Sachs, even in the same family with the same mutations. Babies born with Tay-Sachs appear normal at first, but by 3 or 4 years old, their nerve cells deteriorate and they eventually die. Those with LOTS can live a long life, but, like Altman, are progressively disabled.

The story of Tay-Sachs is a miraculous one. It was first identified in the late 1800s by British ophthalmologist Warren Tay and New York neurologist Bernard Sachs, who noticed the disease was prevalent in Jews of Eastern European origin.

In the 1970s and 1980s, when genetic testing became available, synagogues launched public education campaigns encouraging prospective parents to be tested, and the disease was virtually eliminated in those of Jewish ancestry.

Now, mostly non-Jews, though their risk is not as great, are among the 100 American children who have the disease, according to the National Tay-Sachs and Allied Diseases Association (NTSAD), which leads the fight for a cure.

Altman's speech is difficult to understand, so his wife Lorrie said her husband of 37 years wanted the public to know, "it's not just an infant's disease."

"Tay-Sachs is also in the general population and people don't know," she said. "He thinks we need to get the word out. One in 250 Americans carries the gene."

French Canadians, Louisiana Cajuns and even those of English-Irish ancestry have a greater chance of carrying the recessive gene that causes the disease.

Tay-Sachs is an autosomal recessive disorder, which means each parent must carry the gene. Their children have a 25 percent chance of developing Tay-Sachs, 50 percent chance of being a carrier and a 25 percent chance of being free of that recessive gene.

Altman was born in 1952, before genetic testing was available. Both his parents were carriers of the recessive gene that causes Tay-Sachs and both he and sister were stricken with the mildest form of the disease. Two of their brothers were unaffected, although one is a carrier.

The Massapequa, N.Y., couple have two healthy sons, who are carriers, but whose wives are not, and four healthy grandchildren.

For years, Altman was able to get around with a walker until he had to drop out of a clinical trial for a new drug because of debilitating side effects. After that, he said he lost 40 pounds and so much muscle that he could no longer stand on his own.

"Between the two of us we handle it and we lead kind of a normal life," said Lorrie. "But we have no idea what the future will bring."

Altman works at Nassau University Medical Center in the security monitoring department. He raises funds for about 11 different non-profit organizations, including NTSAD, and has given presentations to the Boy Scouts and senior citizens.

Much of the public work has now ended, as his speech has become more incomprehensible because the degeneration of the nerves that control his respiratory muscles.

"Stewart has a good way of just living in the moment," said his wife, who met Altman in college. "But the worst part for him is his speech. He is such a social, outgoing person."

He has faced discrimination along the way, especially after leaving a Manhattan engineering job because he couldn't climb the subway stairs.

"He has such a hard time getting a job -- it was devastating," said Lorrie Altman. "On paper, he looked so good, but his speech was terrible. He has a college degree and isn't stupid, but all people see is the wheelchair."

Doctors say that many with the milder adult form of Tay-Sachs can lead full lives, despite their disability. And science is getting closer to finding treatments for this devastating disease.

Dr. Edwin Kolodny, former department chair and now professor of neurology at New York University School of Medicine, has been a leader in the field for 30 years. He first helped identify the role of the enzyme Hex-A and later tested more than 30,000 young adults in the 1970s and 1980s.

Today, he and others are involved in the promising gene therapy studies involving first mice, then cats and now sheep. Injecting genes into the brains of Jacob lambs has doubled their life span.

Clinical trials on humans are set to begin as soon as researchers can raise another $700,000 -- in addition to a grant from the National Institutes of Health -- to manufacture the vectors required to insert the genes into the body.

"It seems like every parent in the world would like to be part of the trial," said Kolodny. "And there are reasons to think there will be success here, especially for children who have a slightly later onset and not the classic form Tay-Sachs."

In the past, infantile Tay-Sachs has seen most of the medical attention. "These children have zero quality of life," he said.

Those with mild mutations, like Altman, who have 5 to 10 percent of Hex A enzyme activity, "sometimes lead full lives," according to Kolodny. "Intellectually, most of their cognitive function is retained. We have patients who are lawyers and accountants."

Pre-conception testing is still the gold standard for fighting the disease. "If your parents don't have the same recessive genes, you are home free," he said.

Those identified as at risk for having a child with Tay-Sachs can decide to adopt or conceive through in vitro fertilization, where geneticists can test the embryos before implantation to ensure the child will be disease-free.

Doctors can also do prenatal genetic testing and if the fetus is affected, the decision is up to the parents whether or not they want to terminate the pregnancy. "Three out of four times, they are reassured they have a normal child," said Kolodny.

Doctors say such testing -- at a cost of around $100 -- should be done routinely for 18 autosomal recessive disorders, including the gene for cystic fibrosis, which occurs in one in 20 caucasians, said Kolodny. Even with advances in Tay-Sachs testing in the Jewish community, public education must continue.

"The problem is each generation forgets what happened in the prior generation -- the grandmothers die out, " said Kolodny. "We need to educate health care professionals. Each new group of students graduating from medical school isn't prepared to ask the right questions."

Susan Kahn, NTSAD's executive director, who is involved in fundraising for research, agrees that along with a fight for a cure, genetic testing is critical.

"When there is a genetic disease, it's not just about that person, there is a whole implication for the rest of the family and how they deal with it," she said.

Stewart Altman sits on the association's board of directors and is a tireless crusader for a cure.

"He's got some disabilities that make it difficult for him to do certain things, but of all the board members asking for money to support, he is probably the boldest in our group," said Kahn. "He does have a lot of limitations, but he is still very energetic and wants to do something important. Not everyone responds with the same attitude."

His wife Lorrie backed that up with a laugh. "He is persistent," she said. "He carries these little envelopes around and will ask anyone he meets for a donation. It's almost embarrassing. He's not afraid to ask."

Link:
Gene Therapy in Sheep May Bring Hope to Adults With Tay ...

Recommendation and review posted by Bethany Smith

Morbidity for men and women with hypogonadism includes infertility and an increased risk of osteoporosis; there is no increase in mortality.

Hypogonadotropic hypogonadism (see the image below) is one of several types of hypogonadism.

History

Considerations in the evaluation of males with hypogonadism include the following:

For postpubertal males, the rate of beard growth, libido and sexual function, muscle strength, and energy levels

Possible causes of acquired testicular failure (eg, mumps orchitis, trauma, radiation exposure of the head or testes, and chemotherapy)

Drugs that may interrupt testicular function: Including agents that interfere with testosterone synthesis, such as spironolactone, cyproterone, marijuana, heroin, and methadone

Considerations in the evaluation of females with hypogonadism include the following:

Signs associated with Turner syndrome (eg, lymphedema, cardiac or renal congenital anomalies, and short growth pattern)

Age of menarche

Physical examination

Considerations in the physical examination of males with hypogonadism include the following:

Evaluation of the testes: This is the most important feature of the physical examination; determine whether both testes are palpable, their position in the scrotum, and their consistency; testes size can be quantitated by comparison with testicular models (orchidometer), or their length and width may be measured

Examination of the genitalia for hypospadias

Examination of the scrotum to see if it is completely fused

Evaluation of the extent of virilization

Staging of puberty: Use the Tanner criteria for genitalia, pubic hair, and axillary hair

Examination for signs of Klinefelter syndrome (eg, tall stature, especially if the legs are disproportionately long, gynecomastia, small or soft testes, and a eunuchoid body habitus)

Considerations in the physical examination of females with hypogonadism include the following:

Examination of the genitalia is important

Determination of the extent of androgenization: May be adrenal or ovarian in origin and is demonstrated in pubic and axillary hair

Determination of the extent of estrogenization: As evidenced by breast development and maturation of the vaginal mucosa

Examination for signs of Turner syndrome (eg, short stature, webbing of the neck [such as pterygium colli], a highly arched palate, short fourth metacarpals, widely spaced nipples, or multiple pigmented nevi)

See Clinical Presentation for more detail.

The following studies may be indicated in males with hypogonadism:

Follicle-stimulating hormone (FSH) levels

Luteinizing hormone (LH) levels

Prolactin levels

Testosterone levels

Thyroid function

Seminal fluid examination

Karyotyping

Testicular biopsy

For males after puberty, the Guidelines of the Endocrine Society[2] require that the diagnosis of hypogonadism be based on symptoms and signs of hypogonadism plus the presence of a low testosterone level measured on at least 2 occasions.

The following studies may be indicated in females with hypogonadism:

Additional tests in the evaluation of patients with hypogonadism include the following:

Adrenocorticotropic hormone (ACTH) stimulation testing: In patients in whom a form of congenital adrenal hyperplasia is suspected, adrenal steroid synthesis is best evaluated by performing a cosyntropin (ACTH 1-24) stimulation test

Luteinizing-hormone releasing hormone (LHRH) stimulation testing: To distinguish between true hypogonadotropic hypogonadism and constitutional delay in growth and maturation

Testicular tissue testing: If the testes are not palpable and if it is not certain whether any testicular tissue is present, administering human chorionic gonadotropin (hCG) and measuring testosterone response may be helpful

See Workup for more detail.

Hormonal replacement

The simplest and most successful treatment for males and females with either hypergonadotropic or hypogonadotropic hypogonadism is replacement of sex steroids, but the therapy does not confer fertility or, in men, stimulate testicular growth.

When fertility is desired, an alternative therapy for men with hypogonadotropic hypogonadism is administration of pulsatile LHRH or injections of hCG and FSH. (In patients with hypergonadotropic hypogonadism, fertility is not possible.)

In a 6-year European study of men being treated for hypogonadism, long-term transdermal testosterone treatment did not increase prostate-specific antigen (PSA) levels or influence prostate cancer risk.[3, 4]

Investigators used data from a 5-year, open-label extension of a 1-year trial of a transdermal testosterone patch (Testopatch) in men with hypogonadism. Study subjects wore two 60 cm2 patches, each of which delivered 2.4 mg of testosterone per day. More than 90% of patients had PSA concentrations below 2 ng/mL during the 6-year study, and no prostate cancer was found in patients over the course of the trial.

See Treatment and Medication for more detail.

Read more:
Hypogonadism - Medscape Reference

Recommendation and review posted by Bethany Smith

By Irvin H. Hirsch, MD

NOTE: This is the Professional Version. CONSUMERS: Click here for the Consumer Version

NOTE: This is the Professional Version. DOCTORS: Click here for the Consumer Version

Hypogonadism is defined as testosterone deficiency with associated symptoms or signs, deficiency of spermatozoa production, or both. It may result from a disorder of the testes (primary hypogonadism) or of the hypothalamic-pituitary axis (secondary hypogonadism). Both may be congenital or acquired as the result of aging, disease, drugs, or other factors. Additionally, a number of congenital enzyme deficiencies cause varying degrees of target organ androgen resistance. Diagnosis is confirmed by hormone levels. Treatment varies with etiology but typically includes gonadotropin-releasing hormone, gonadotropin, or testosterone replacement.

DELATESTRYL

No US brand name

ZOLADEX

ALDACTONE

REGLAN

TAGAMET

NIZORAL

LUPRON

OZURDEX

NOTE: This is the Professional Version. CONSUMERS: Click here for the Consumer Version

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View post:
Male Hypogonadism - Genitourinary Disorders - Merck ...

Recommendation and review posted by simmons

Stem Cell 100 is designed to rejuvenate your body and slow the aging process to help you feel and function more like a young person. This can help you feel better, look younger and improve your health.

Most of the cells in your body lose function with age. Everyone has special cells called adult stem cells which are needed to repair damaged and old tissues, but adult stem cells themselves are also aging.

Until now there was not much you could do about it. Stem Cell 100 rejuvenates adult stem cells and their micro-environments with the proprietary SC100 formula. Stem Cell 100+ is a more powerful and faster acting version of the same nutraceutical.

Developed by experts in the anti-aging field, patent-pending Stem Cell 100 is the only supplement proven to double maximum lifespan of an animal model. No other product or therapy including caloric restriction even comes close.

Harness the Power of Your Own Stem Cells

Millions of people suffer from chronic conditions of aging and disease. Based on international scientific studies in many academic and industry laboratories, there is new hope that many of the conditions afflicting mankind can some day be cured or greatly improved using stem cell regenerative medicine.

Stem Cell 100 offers a way to receive some of the benefits of stem cell therapy today by improving the effectiveness of your own adult stem cells.

Stem Cell 100 Helps to Support:

The statements above have not been reviewed by the FDA. Stem Cell 100 is not a preventive or treatment for any disease.

Help Rejuvenate Your Body by Boosting Your Own Stem Cells

As a child, we are protected from the ravages of aging and can rapidly recover from injury or illness because of the ability of the young regenerative stem cells of children have a superior ability to repair and regenerate most damaged tissues.

As we age, our stem cell populations become depleted and/or slowly lose their capacity to repair. Moreover, the micro-environment (i.e. niches) around stem cells becomes less nurturing with age, so cell turnover and repair are further reduced. This natural progression occurs so slowly that we are barely aware of it, but we start to notice the body changes in our 20s, 30s, 40s, and especially after 50 years of age.

Stem Cell 100 helps adults regain their youthful regenerative potential by stabilizing stem cell function.

Stem Cell 100 works differently than other stem cell products on the market

You may have seen a number of products that are advertised as stimulating or enhancing the number of stem cells. Each person only has a limited number of stem cells so using them up faster may not be a good strategy. Stem Cell 100 is about improving the effectiveness and longevity of your stem cells as well as preserving the stem cell micro-environment. That should be the goal of any effective stem cell therapy and is what Stem Cell 100 is designed to do and what other stem cell products cannot do.

Stem Cell 100 Extends Drosophila (Fruit Fly) Lifespan

In extensive laboratory testing Stem Cell 100 greatly extended both the average and maximum lifespan of Drosophila fruit flies. The study (see Charts below) included three cages of Drosophila fruit flies that were treated with Stem Cell 100 (Cages T1 to T3) and three cages which were untreated controls (Cages C1 to C3). Each cage started with 500 fruit flies including 250 males and 250 females.

The experiment showed that median lifespan more than doubled with a 123% increase.

While fruit flies are not people they are more like us than you might think. Drosophila have a heart and circulatory system, and the most common cause of death is heart failure. Like humans and other mammals (e.g. mice), it is difficult to increase their lifespan significantly.

These observed results outperform every lifespan enhancing treatment ever tested including experiments using genetic modification and dietary restriction.

The longest living fruit fly receiving Stem Cell 100 lived 89 days compared to the longest living untreated control which lived 48 days. It is possible that the single longest living fruit fly lived longer for other reasons such as genetic mutation, however, there were many others that lived almost as long so it was not just an aberation.

The oldest 5% of the treated fruit flies lived 77% longer than the oldest 5% of the control group. It is also important that the study showed an improved ability of the fruit flies to survive stress and illness at all ages not just during old age. Even after the first few days of the study there were already more of the

Stem Cell 100 treated fruit flies alive that survived youth than the control group of untreated fruit flies. For additional information about the study please go to our Longevity page.

SK, Santa Fe, New Mexico

I have been using Stem Cell 100 for about one year. Initially I noticed a boost in energy level, which now remains steady-hence not noticed I have experienced no adverse effects from taking this product. I heartily recommend Stem Cell 100 and plan to continue on it.*

Leslie

Stem Cell 100 has made a noticeable difference in me, including turning my gray hair back to its original color, which supposedly is impossible. The reversal of the gray hair to original color began a couple of months after starting the pill. After about 10 months, the gray hair is mostly gone. At the current rate of improvement, I expect my hair to completely be back to its original color within 1 to 2 months. I think my beard will take longer, but it was the first to gray.

Also, my skin became smoother and younger looking. The skin and hair rely heavily on stem cells, and they seem to benefit strongly from this product. Im so excited about telling people my results because there is nothing that can reverse the graying of hair. It will give me evidence that this supplement thing is really powerful.

Unfortunately, I dont have before and after pictures because I didnt read any claims that the product would affect hair color. I would just say that Im a person who totally believes that it does me no good to imagine things or interpret tings in a way favorable to what I want to believe. When Im convinced enough to make a statement, you can count on it.*

Joey, California

I am a 48 year old working woman. A friend of mine introduced me to Stem Cell 100. After taking Stem Cell 100 for about 4 months my anxiety level has really been diminished. Its a great supplement and I would recommend it to everyone!*

Paul, California

I am an active 61 year old man in excellent health, but had experienced a serious drop in my energy level at the time I enrolled in a 4-month trial of Stem Cell 100. Within a month, my energy increased noticeably and I began to take to my physical activities (running, cycling) with a renewed enthusiasm and intensity level. My mood began to elevate steadily, and soon I had even lost those few stubborn pounds that had eluded me for years. I am very enthusiastic about Stem Cell 100. I look forward to continuing with the new, improved formulation, and would not hesitate to recommend it.*

Mike, Texas

After taking the Stem Cell 100 for the last month my sinuses have also cleared, unplugging my ears for the first time since mid September.*

Tom, Australia

Only after about 2-3 weeks of taking Stem Cell 100 my eye sight returned back to a level where I did not need glasses to work on my computer monitors. My eyes had always been good but had started to deteriorate about a year ago where 50% of the time I had to wear my glasses. I was shocked to find the improvement so quick. I found I was less stressed. No other changes to lifestyle yet a measureable difference.

My fingers would sometimes get stiff in the mornings after long days on the keyboard. This stiffness disappeared. Some of my hair is getting darker. I have a full body of hair that had virtually all turned grey but I noticed that some of my hair was starting regrow brown my original colour. I had some age spots in my left leg that are disappearing. Generally, I feel great.*

Willie, California

As I was sprinting this morning around 6:00am I noticed that I was not hurting anymore! I have been having sore knees, ankles, hamstrings and back for the last couple of years. I usually just ran through it, but I noticed since I have been taking the Stem Cell 100 capsules for about 45 days now, those nagging pains are gone away!*

*DIsclaimer: The testimonials reflect the real life experiences written and voluntarily submitted to us by individuals who used our products. Individual results may vary. We do not claim that any individual experience recounted is typical or representative of what any other consumer might experience.

View More Testimonials

Supplement Facts

Stem Cell 100 and Stem Cell 100+ are Patent-Pending Life Code Nutraceuticals.

All Life Code products arenutraceutical grade and provide the best of science along with the balance of nature. Stem Cell 100+ is vegetarian.

Serving Size: One type O capsule

Servings Per Container: 60 Capsules

Recommended Use: Typical usage of Stem Cell 100 or Stem Cell 100+ is two capsules per day, preferably at meal times. While both capsules can be taken at the same time, it is preferable to separate the two capsules by at least 4 hours. Since Stem Cell 100 is a potent formulation, do not take more than three capsules per day. One capsule per day may be sufficient for those below 110 pounds.

Recommended Users: Anyone from ages 22 and up could benefit from Stem Cell 100 or Stem Cell 100+. Those in their 20s and 30s will like the boost in endurance during sports or exercise, while older users will notice better energy and general health with the potential for some weight loss.

Stem Cell 100 was our first multi-pathway longevity nutraceutical. Stem Cell 100+ is a more advanced, faster acting and powerful version of Stem Cell 100.

Click label to enlarge

Active Stem Cell 100 Ingredients: There are ten herbal components that make up the patent-pending combination in Stem Cell 100. The herbal components are highly extracted natural herbs that are standardized for active components that promote adult stem cells and lower inflammation:

1) Polysaccharides, flavonoids, and astragalosides extracted from Astragalus membranaceus, which has many positive effects on stem cells and the cardiovascular and immune systems.

2) Proprietary natural blueberry flavonoids and other compounds from a stabilized pharmaceutical grade medicinal Vaccinium extract. Activate metabolic PPARS and helps produce healthy levels of cholesterol and inflammation. Also has anti-fungal and anti-viral activity.

3) Flavonoids and oligo-proanthocyanidins (OPCs) extracted from Pine Bark, which greatly reduce oxidative stress, DNA damage, and inflammation.

4) L-Theanine, which is a natural amino acid from Camellia sinesis that reduces mental stress and inflammation while improving cognition and protecting brain cells from ischemic or toxic injury.

5) Pterocarpus Marsupium, which contains two stable resveratrol analogs which promote stem cells, lower inflammation, and stabilized metabolism.

6) Polygonum Multiflorium stem stem is a popular Chinese herbal tonic that fights premature aging and promotes youthfulness. Polygonum is reported to enhance fertility by improving sperm count in men and egg vitality in women. Polygonum is also widely used in Asia to strengthen muscle and is thus used by many athletes as an essential tonic for providing strength and stamina to the body.

Modern research has supported Polygonum multiflorium stem in that animal studies have proven that it can extend lifespan and improve the quality of life. Polygonum appears to protect the liver and brain against damage, perhaps by improving immune and cardiovascular health. The stem sections of Polygonum multiflorium are also calming to the nervous system and promote sounder sleep. Life Code uses a proprietary Polygonum multiflorium stem extract.

7) Schisandra Berry is used by many Chinese women to preserve their youthful beauty. For thousands of years, Schisandra has been prized as an antiaging tonic that increases stamina and mental clarity, while fighting stress and fatigue. In Chinese traditional medicine, Schisandra berry has been used for liver disorders and to enhance resistance to infection and promote skin health and better sleep.

Schisandra berry is classified as an adaptogen, which can stimulate the central nervous system, increase brain efficiency, improve reflexes, and enhance endurance. Modern research indicates that Schisandra berry extracts have a protective effect on the liver and promote immunity. A double-blind human trial suggested that Schisandra berry may help patients with viral hepatitis, which is very prevalent in China.

Recent work indicates that the liver is protected by the enhanced production of glutathione peroxidase, which helps detoxify the liver. Life Code uses a proprietary Schisandra berry extract.

8) Fo-Ti Root (aka He-Shou-Wu) is one of the most widely used Chinese herbal medicines to restore blood, kidney, liver, and cardiovascular health. Fo-Ti is claimed to have powerful rejuvenating effects on the brain, endocrine glands, the immune system, and sexual vigor.

Legend has it that Professor Li Chung Yun took daily doses of Fo-Ti to live to be 256 and is said to have outlived 23 wives and spawned 11 generations of descendents before his death in 1933. While it is unlikely that he really lived to such an old age there is scientific support for Fo-Ti as beneficial for health and longevity.

Like the Indian Keno bark, Fo-ti contains resveratrol analogs and likely acts by various mechanism, which includes liver detoxification and protection of skin from UVB radiation. Life Code uses a proprietary Fo-Ti root extract.

9) Camellia sinensis has many bioactive polyphenols including the potent epigallocatechin-3-gallate (EGCG). A 2006 Japanese study published in the Journal of the American Medical Association reports that adults aged 40 to 79 years of age who drank an average of 5 or more cups of tea per day had a significantly lower risk of dying from all causes (23% lower for females and 12% lower for males). The study tracked more than 40,000 adults for up to 11 years and found dramatically lower rates of cardiovascular disease and strokes in those drinking 5 or more cups of tea.

Many studies have found that adults drinking 3 or more cups of tea per day have significantly less cancer. Other studies have found that green tea helps protect against age-related cognitive decline, kidney disease, periodontal disease, and type 2 diabetes. Green tea also promotes visceral fat loss and higher endurance levels.

Summarizing all of the thousands of studies on tea and tea polyphenols that have been published, it can be concluded that tea polyphenols preserve health and youth. This conclusion is backed up by gene studies showing that tea polyphenols decrease insulin-like growth factor-1 (IGF-1), which is a highly conserved genetic pathway that has been strongly linked to aging in yeast, worms, mice, and humans. If everyone could drink 4 to 5 cups of green tea each day, they could enjoy these important health benefits, but for most people drinking that much green tea can disturb their sleep patterns.

Life Code uses a nutraceutical grade green tea extract that has 98% polyphenols and 50% ESCG that provides the polyphenol and ESCG equivalent of 4 to 5 cups of green tea with only 2% of the caffeine. Thus, most or all of the benefits of green tea are provided without concerns about disturbing sleep.

10) Drynaria Rhizome is used extensively in traditional Chinese medicine as an effective herb for healing bones, ligaments, tendons, and lower back problems. Eastern martial art practitioners have used Drynaria for thousands of years to help in recovering from sprains, bruises, and stress fractures.

Drynaria has also helped in many cases of bleeding gums and tinnitus (ringing in the ears). The active components of Drynaria protect bone forming cells by enhancing calcium absorption and other mechanisms. Drynaria is also reported to act as a kidney tonic and to promote hair growth and wound healing. Life Code uses a proprietary Drynaria rhizome extract.

Safety: The extracts in both versions of Stem Cell 100 are pharmaceutical grade and have been individually tested in both animals and humans without significant safety issues. Those with pre-existing conditions of diabetes or hypertension should coordinate this product with your doctor, as lower blood glucose or reduced blood pressure can result from taking the recommended dose of this product.

Warnings: may lower glucose and/or blood pressure in some individuals. The supplement is not recommended for pregnant, lactating, or hypoglycemic individuals.

References

1. Yu, Q., Y.S. Bai, and J. Lin, [Effect of astragalus injection combined with mesenchymal stem cells transplantation for repairing the Spinal cord injury in rats]. Zhongguo Zhong Xi Yi Jie He Za Zhi, 2010. 30(4): p. 393-7.

2. Xu, C.J., et al., [Effect of astragalus polysaccharides on the proliferation and ultrastructure of dog bone marrow stem cells induced into osteoblasts in vitro]. Hua Xi Kou Qiang Yi Xue Za Zhi, 2007. 25(5): p. 432-6.

3. Xu, C.J., et al., [Effects of astragalus polysaccharides-chitosan/polylactic acid scaffolds and bone marrow stem cells on repairing supra-alveolar periodontal defects in dogs]. Zhong Nan Da Xue Xue Bao Yi Xue Ban, 2006. 31(4): p. 512-7.

4. Zhu, X. and B. Zhu, [Effect of Astragalus membranaceus injection on megakaryocyte hematopoiesis in anemic mice]. Hua Xi Yi Ke Da Xue Xue Bao, 2001. 32(4): p. 590-2.

5. Qiu, L.H., X.J. Xie, and B.Q. Zhang, Astragaloside IV improves homocysteine-induced acute phase endothelial dysfunction via antioxidation. Biol Pharm Bull, 2010. 33(4): p. 641-6.

6. Araghi-Niknam, M., et al., Pine bark extract reduces platelet aggregation. Integr Med, 2000. 2(2): p. 73-77.

7. Rohdewald, P., A review of the French maritime pine bark extract (Pycnogenol), a herbal medication with a diverse clinical pharmacology. Int J Clin Pharmacol Ther, 2002. 40(4): p. 158-68.

8. Koch, R., Comparative study of Venostasin and Pycnogenol in chronic venous insufficiency. Phytother Res, 2002. 16 Suppl 1: p. S1-5.

9. Rimando, A.M., et al., Pterostilbene, a new agonist for the peroxisome proliferator-activated receptor alpha-isoform, lowers plasma lipoproteins and cholesterol in hypercholesterolemic hamsters. J Agric Food Chem, 2005. 53(9): p. 3403-7.

10. Manickam, M., et al., Antihyperglycemic activity of phenolics from Pterocarpus marsupium. J Nat Prod, 1997. 60(6): p. 609-10.

11. Grover, J.K., V. Vats, and S.S. Yadav, Pterocarpus marsupium extract (Vijayasar) prevented the alteration in metabolic patterns induced in the normal rat by feeding an adequate diet containing fructose as sole carbohydrate. Diabetes Obes Metab, 2005. 7(4): p. 414-20.

12. Mao, X.Q., et al., Astragalus polysaccharide reduces hepatic endoplasmic reticulum stress and restores glucose homeostasis in a diabetic KKAy mouse model. Acta Pharmacol Sin, 2007. 28(12): p. 1947-56.

13. Schafer, A. and P. Hogger, Oligomeric procyanidins of French maritime pine bark extract (Pycnogenol) effectively inhibit alpha-glucosidase. Diabetes Res Clin Pract, 2007. 77(1): p. 41-6.

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15. Xue, B., et al., Effect of total flavonoid fraction of Astragalus complanatus R.Brown on angiotensin II-induced portal-vein contraction in hypertensive rats. Phytomedicine, 2008.

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18. Kimura, Y. and M. Sumiyoshi, French Maritime Pine Bark (Pinus maritima Lam.) Extract (Flavangenol) Prevents Chronic UVB Radiation-induced Skin Damage and Carcinogenesis in Melanin-possessing Hairless Mice. Photochem Photobiol, 2010.

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Clin Microbiol Rev. 2008 Oct; 21(4): 583593.

Department of Molecular Genetics and Microbiology, College of Medicine,1 University of Florida Genetics Institute, University of Florida, Gainesville, Florida2

Summary: The unique life cycle of adeno-associated virus (AAV) and its ability to infect both nondividing and dividing cells with persistent expression have made it an attractive vector. An additional attractive feature of the wild-type virus is the lack of apparent pathogenicity. Gene transfer studies using AAV have shown significant progress at the level of animal models; clinical trials have been noteworthy with respect to the safety of AAV vectors. No proven efficacy has been observed, although in some instances, there have been promising observations. In this review, topics in AAV biology are supplemented with a section on AAV clinical trials with emphasis on the need for a deeper understanding of AAV biology and the development of efficient AAV vectors. In addition, several novel approaches and recent findings that promise to expand AAV's utility are discussed, especially in the context of combining gene therapy ex vivo with new advances in stem or progenitor cell biology.

Adeno-associated virus (AAV) vectors are currently among the most frequently used viral vectors for gene therapy. At recent meetings of the American Society for Gene Therapy, nearly half of the presentations involved the use of AAV. This represents a significant turnaround. Historically, AAV has not been of great medical interest, because it has not been identified as a pathogen; thus, the lack of widespread knowledge of the virus initially inhibited its broad use as a vector. Twelve human serotypes of AAV (AAV serotype 1 [AAV-1] to AAV-12) and more than 100 serotypes from nonhuman primates have been discovered to date. The lack of pathogenicity of the virus, the persistence of the virus, and the many available serotypes have increased AAV's potential as a delivery vehicle for gene therapy applications. This review will focus on the biology of AAV and its use as a vector for gene therapy.

AAV is a small (25-nm), nonenveloped virus that packages a linear single-stranded DNA genome. It belongs to the family Parvoviridae and is placed in the genus Dependovirus, because productive infection by AAV occurs only in the presence of a helper virus, either adenovirus or herpesvirus. In the absence of helper virus, AAV (serotype 2) can set up latency by integrating into chromosome 19q13.4, establishing itself as the only mammalian DNA virus known to be capable of site-specific integration.

The AAV-2 genome is a linear, single-stranded DNA of 4.7 kb (Fig. ) (60). Both sense and antisense strands of AAV DNA are packaged into AAV capsids with equal frequency. The genome is structurally characterized by 145-bp inverted terminal repeats (ITRs) that flank two open reading frames (ORFs) (Fig. ).

Map of the wild-type AAV-2 genome. (A) Rep and Cap genes flanked by ITRs. The different Rep and Cap transcripts are produced from their respective promoters (P5, P19, and P40). The star indicates the alternative ACG codon used to produce VP3. (B) Secondary ...

The first 125 nucleotides of the ITR constitute a palindrome, which folds upon itself to maximize base pairing and forms a T-shaped hairpin structure. The other 20 bases, called the D sequence, remain unpaired. The ITRs are important cis-active sequences in the biology of AAV. A key role of the ITRs is in AAV DNA replication. In the current model of AAV replication, the ITR is the origin of replication and serves as a primer for second-strand synthesis by DNA polymerase. The double-stranded DNA formed during the synthesis, called replicating-form monomer, is used for a second round of self-priming replication and forms a replicating-form dimer. These double-stranded DNA intermediates (replicating-form monomer and replicating-form dimer) are processed via a strand displacement mechanism, resulting in single-stranded DNA used for packaging and double-stranded DNA used for transcription. Critical to the replication process are the Rep binding elements (RBEs) (RBE and RBE) and a terminal resolution site (TRS), which is located within the ITR (Fig. ). These features are used by the viral regulatory protein Rep during AAV replication to process the double-stranded intermediates. In addition to their role in AAV replication, the ITR is also essential for AAV genome packaging, transcription, negative regulation under nonpermissive conditions, and site-specific integration.

The left ORF contains the Rep gene, which produces four Rep proteins, Rep78, Rep68, Rep52, and Rep40. The larger Rep proteins (Rep78 and Rep68) are produced from transcripts using the P5 promoter, whereas the smaller Rep proteins (Rep52 and Rep40) are produced from transcripts using the P19 promoter. Rep78 and Rep68 are produced from unspliced and spliced transcripts, respectively, and are important regulatory proteins that act in trans in all phases of the AAV life cycle. Specifically, they positively and negatively regulate AAV gene expression in the presence or absence of helper virus, respectively, and are required for DNA replication (48). The smaller Rep proteins, Rep52 and Rep40, produced from unspliced and spliced transcripts, respectively, are involved in the accumulation of single-stranded viral DNA used for packaging within AAV capsids. All four Rep proteins possess helicase and ATPase activity. In addition, the larger Rep proteins possess strand- and site-specific endonuclease activity (nicking at the TRS) and site-specific DNA binding activity (binding at the RBE).

The right ORF contains the Cap gene, which produces three viral capsid proteins (VP1, VP2, and VP3) using the P40 promoter. Alternative splicing of the P40 transcript is used to produce the three viral proteins from two transcripts. The unspliced transcript produces VP1 (87 kDa), the biggest of the capsid proteins. The spliced transcript produces VP2 (72 kDa) and VP3 (62 kDa). VP2 is produced using a nonconventional ACG start codon, whereas VP3 is produced using a downstream conventional AUG codon. The AAV-2 capsid comprises 60 viral capsid proteins arranged into an icosahedral structure with symmetry equivalent to a triangulation number of 1. The capsid proteins (VP1, VP2, and VP3) are present in a 1:1:10 molar ratio.

There are two stages to the AAV life cycle (Fig. ) after successful infection, a lytic stage and a lysogenic stage. In the presence of helper virus (adenovirus or herpesvirus), the lytic stage ensues. During this period, AAV undergoes productive infection characterized by genome replication, viral gene expression, and virion production. The adenoviral genes that provide helper functions regarding AAV gene expression have been identified and include E1a, E1b, E2a, E4, and VA RNA. Herpesvirus aids in AAV gene expression by providing viral DNA polymerase and helicase as well as the early functions necessary for HSV transcription. Although adenovirus and herpesvirus provide different sets of genes for helper function, they both regulate cellular gene expression, providing a permissive intracellular milieu for AAV productive infection.

AAV life cycle. AAV undergoes productive infection in the presence of adenovirus coinfection. This is characterized by genome replication, viral gene expression, and virion production. In the absence of adenovirus, AAV can establish latency by integrating ...

In the absence of adenovirus or herpesvirus, there is limited AAV replication, viral gene expression is repressed, and the AAV genome can establish latency by integrating into a 4-kb region on chromosome 19 (q13.4), termed AAVS1 (36, 37). The AAVS1 locus is near several muscle-specific genes, TNNT1 and TNNI3 (16). The AAVS1 region itself is an upstream part of a recently described gene, MBS85. The exact function of this gene is not clear, but its product has been shown to be involved in actin organization (64). Whether AAV integration into this site is suitable for human gene therapy applications remains to be evaluated. Tissue culture experiments suggest that the AAVS1 locus is a safe integration site.

One of the features of AAV is its ability to specifically integrate to establish latent infection. Current AAV vectors do not have this ability, and the development of such a vector would ensure long-term transgene expression in tissues without problems associated with insertional mutagenesis.

Some of the viral and cellular requirements for targeted integration have been elucidated. The AAV components that are required have been identified. These include the ITRs (in cis), Rep78 or Rep68 (in trans), and a 138-bp sequence termed the integration efficiency element (IEE), located within the P5 promoter in cis (49). It is unclear if the entire 138-bp IEE in P5 is required, since a recent study showed that a 16-bp RBE in P5 is sufficient (18). Latent infection with wild-type AAV-2 appears to be nonpathogenic in tissue culture, when Rep is expressed under its own promoter. Such expression is regulated by negative feedback. Excess Rep expression has been shown to arrest cell division (75) and induce cellular apoptosis (58).

A 33-bp minimum AAVS1 sequence, which contains an RBE-like and a TRS-like sequence separated by 8 nucleotides, is necessary and sufficient to target AAV integration (26). The intervening sequence may be varied, but a central 5 CTC is required. The actual integration site is somewhat downstream from the target sequence and can be variable. Many RBEs have been identified in the human genome, with AAVS1 being the only site that has an RBE and a TRS in close proximity to one other. Interestingly, the AAV genome and AAVS1 can be tethered to each other via Rep68 in vitro (68). These observations provide a molecular explanation for why AAVS1 is targeted, even though the exact mechanism remains unknown.

The process of site-specific integration is not completely specific even under ideal conditions of Rep78 and Rep68 expression, with approximately 40 to 70% of integrants occurring in AAVS1. Moreover, the mechanism is imprecise, as judged by there not being reproducible breakpoints for vector-AAVS1 junctions; however, clusters of integrants appear within a 2-kb fragment of AAVS1. While the cis- and trans-acting viral factors required for site-specific integration have been identified, much less is known about cellular factors that are required or may be involved. Only recently has a study provided evidence that a cellular protein, human immunodeficiency virus transacting response element-RNA loop binding protein 185 (TRP-185), can promote AAV integration into AAVS1 further downstream from the RBE via interactions with both Rep and AAVS1 (73). Moreover, site-specific integration has been demonstrated in mice and rats transgenic for AAVS1, suggesting that the AAVS1 open-chromatin structure is maintained in vivo and that the cellular factors that mediate site-specific integration are present in nondividing cells (56).

AAV-2 gains entry into target cells by using the cellular receptor heparan sulfate proteoglycan (62). Internalization is enhanced by interactions with one or more of at least six known coreceptors including V5 integrins (63), fibroblast growth factor receptor 1 (53), hepatocyte growth factor receptor (35), v1 integrin (7), and laminin receptor (3). The cellular events that mediate AAV trafficking postentry are not completely characterized. Cells defective for dynamin significantly hindered AAV-2 infection, suggesting that AAV is endocytosed into clathrin-coated vesicles (15). For successful AAV infection, AAV particles need to escape these endocytic vesicles. Infection experiments with bafilomycin A1 (a drug that inhibits the proton pump for endosomes) suggested that the low pH in the endosomes is essential for virus escape and successful infection (9). Moreover, cellular signaling involving the activation of the Rac1 protein and the phosphatidylinositol 3-kinase pathway is necessary for intracellular trafficking of AAV particles using microtubules (57). Interestingly, a conserved phospholipase A2 motif identified in the N terminus of the VP1 protein was reported to be important for successful infection (27). Specifically, the phospholipase A2 motif seemed to be playing a crucial role during AAV trafficking, possibly helping AAV escape the late endosome. Mutational analysis of the AAV capsid structure indicated that the fivefold pore structure may also serve as the site for phospholipase domain presentation during viral infection (10). Moreover, endosomal cysteine proteases, cathepsins B and L, have implied roles in AAV trafficking and capsid disassembly (4). Exactly how AAV enters the nucleus after escaping the endosome is not known and is currently an active area of research. Although AAV is theoretically small enough to enter the nucleus via the nuclear pore complex, an early study suggested that AAV entry may be nuclear pore complex independent (29).

There are several considerations for any viral vector. These include the ability to attach to and enter the target cell, successful transfer to the nucleus, the ability to be expressed in the nucleus for a sustained period of time, and a general lack of toxicity. AAV vectors have been highly successful in fulfilling all of these criteria. Moreover, a variety of modifications have served to enhance their utility. Several considerations have guided the development of current AAV vectors, especially the lack of pathogenicity of the wild-type virus and its persistence.

The small size of the AAV genome and concerns about potential effects of Rep on the expression of cellular genes led to the construction of AAV vectors that do not encode Rep and that lack the cis-active IEE, which is required for frequent site-specific integration. The ITRs are kept because they are the cis signals required for packaging. Thus, current recombinant AAV (rAAV) vectors persist primarily as extrachromosomal elements (1, 59).

rAAV vectors for gene therapy have been based mostly on AAV-2. AAV-2-based rAAV vectors can transduce muscle, liver, brain, retina, and lungs, requiring several weeks for optimal expression. The efficiency of rAAV transduction is dependent on the efficiency at each step of AAV infection: binding, entry, viral trafficking, nuclear entry, uncoating, and second-strand synthesis. Inefficient AAV trafficking (30) and second-strand synthesis (19) have been identified as being rate-limiting factors in AAV gene expression. Interestingly, the binding of cellular protein FKBP52 to the AAV ITR inhibits second-strand synthesis, and this inhibition is dependent on the phosphorylation state of FKBP52 (51, 52, 80). Moreover, epidermal growth factor receptor kinase signaling has been implicated in regulating both AAV trafficking and second-strand synthesis (80).

Several novel AAV vector technologies have been developed to either increase the genome capacity for AAV or enhance gene expression (Fig. ). The idea of trans-splicing AAV vectors has been used to increase AAV vector capacity (74). This system takes advantage of AAV's ability to form head-to-tail concatemers via recombination in the ITRs. In this approach, the transgene cassette is split between two rAAV vectors containing adequately placed splice donor and acceptor sites. Transcription from recombined AAV molecules, followed by the correct splicing of the mRNA transcript, results in a functional gene product. This application becomes useful for using AAV to deliver therapeutic genes up to 9 kb in size. trans splicing has been successfully used for gene expression in the retina (55), the lung (39), and, more recently, muscle (25). trans-Splicing vectors are less efficient than rAAV vectors.

(Left) trans-Splicing approach. The head-to-tail formation of two different AAV vector results in functional product after splicing. (Right) Comparison of scAAV and rAAV vectors.

The design and use of self-complementary AAV (scAAV) vectors to bypass the limiting aspects of second-strand synthesis have been described (44). The rationale underlying the scAAV vector is to shorten the lag time before transgene expression and potentially to increase the biological efficiency of the vector. scAAV vectors can fold upon themselves, immediately forming transcriptionally competent double-stranded DNA. One consequence of the use of scAAV is that the maximal size of the transgene is reduced by 50% (2.4-kb capacity), but up to 3.3 kb of DNA can be encapsidated (71). Rapid transduction has been observed using scAAV in both tissue culture and in vivo experiments.

Many clinically relevant tissues are not susceptible to infection by AAV-2. Greater gene expression was seen in muscle, retina, liver, and heart using AAV serotypes 1, 5, 8, and 9, respectively. The cell surface receptors have been identified for only some of the many AAV serotypes: AAV-3 (heparan sulfate proteoglycan), AAV-4 (O-linked sialic acid), and AAV-5 (platelet-derived growth factor receptor). In addition, a 37-kDa/67-kDa laminin receptor has been identified as being a receptor for AAV serotypes 2, 3, 8, and 9 (3). The attachment receptors for the other serotypes have not yet been identified. All of these serotypes are potential candidates for testing as vectors for gene therapy. To date, most of the testing has involved serotypes 1 to 9, which have considerable differences at the capsid amino acid sequence level, except for AAV-1 and AAV-6 (Table ), and has succeeded in identifying vectors with widely divergent tissue specificities.

Capsid homology among AAV serotypes 1 to 9

The use of the different AAV serotypes in a pseudotyping approach (the genome of one ITR serotype being packaged into a different serotype capsid) has allowed broad tissue tropisms. However, some tissues remain refractory to transduction using available serotypes. This presents a major challenge for AAV-based gene therapy for clinically relevant tissues.

A deeper understanding of the AAV capsid properties has made the rational design of AAV vectors that display selective tissue/organ targeting possible, thus broadening the possible applications for AAV as a gene therapy vector. Two approaches have been used for AAV vector retargeting: (i) direct targeting and (ii) indirect targeting. In direct targeting, vector targeting is mediated by small peptides or ligands that have been directly inserted into the viral capsid sequence. This approach has been used successfully to target endothelial cells (61, 69). Direct targeting requires extensive knowledge of the capsid structure. Important aspects involve the following: peptides or ligands must be positioned at sites that are exposed to the capsid surface, the insertion must not significantly affect capsid structure and assembly, and it is important that the native tropism be ablated to maximize targeting.

In indirect targeting, vector targeting is mediated by an associating molecule that interacts with both the viral surface and the specific cell surface receptor. The use of bispecific antibodies (8) and biotin (6, 50) has been described for AAV vectors. The advantages of this approach are that different adaptors can be coupled to the capsid without significant changes in capsid structure, and the native tropism can be easily ablated. One disadvantage of using adaptors for targeting may involve the decreased stability of the capsid-adaptor complex in vivo. The development of efficient AAV targeting vectors will require a better understanding of all aspects of the AAV infection process: binding and entry, viral processing, and nuclear entry and expression. Significant progress has been made in all these categories, and the development of efficient AAV targeting vectors will expand AAV's use as a vector for many clinical applications.

One of the biggest challenges facing AAV gene delivery is the host immune response. The host defense mechanism at the adaptive level is made up of cell-mediated and humoral immunity. The cell-mediated response functions at the cellular level, eliminating the transduced cells using cytotoxic T cells, whereas the humoral response produces neutralizing antibodies (Nab), preventing the readministration of vector. Almost no innate response is seen in AAV infection (76).

Immune response to AAV is primarily a humoral response (72). Preexisting Nab in patients, because of prior infection, account for the humoral response seen toward AAV. In a study by Chirmule et al. (13), antibodies to AAV were seen in 96% of the subjects (patients with cystic fibrosis [CF] and healthy subjects), and 32% showed neutralizing ability in an in vitro assay. Nab to AAV have been to show limit AAV transduction in liver (47) and lung (28); however, no such effect was seen in muscle (21), brain (43), and retina (5). Interestingly, the humoral response to AAV may be T-cell dependent; the inhibition of T-cell function using anti-CD4 antibodies prevents Nab formation and allows vector readministration (14, 28, 40).

Cell-mediated responses to AAV vectors have been documented, but this response may be dependent on the route of administration (11) and AAV serotype (67). A potent immune response to AAV-ovalbumin was observed when AAV was administered intraperitoneally, intravenously, or subcutaneously but not when administered intramuscularly. Moreover, AAV-2 has been shown to induce a weak cell-mediated immune response. This may be attributed to AAV inefficiently infecting mature dendritic cells (DC); however, a recent study demonstrated an efficient infection of immature DC and generated a cytotoxic-T-lymphocyte (CTL) response when used in adoptive transfer experiments (77). The extent to which mature and immature DC are transduced by AAV in vivo and the mechanism of how AAV induces a cellular immune response are not known.

In a recent clinical trial for hemophilia B, an unexpected liver toxicity was observed and was attributed to a CTL response to AAV-2-transduced hepatocytes (42). Subsequently, it was discovered that the AAV-2 capsid heparin binding motif was responsible for T-cell activation (65). This correlated well with a study in mice that showed that AAV-2 infection can activate a CTL response, whereas AAV-7 and AAV-8 do not (67). Moreover, Wang et al. (67) suggested that the cross-presentation of input AAV capsids via major histocompatibility complex class I presentation may be playing a role in the observed activation of cytotoxic T cells; however, this response does not diminish transgene expression via the targeted destruction of transduced hepatocytes, a finding confirmed by another group (38). Taken together, these studies suggest that immune responses are a major hurdle and that a deeper understanding of AAV-host interactions in humans is required for the efficient use of AAV as a gene transfer vector.

AAV has become increasingly common as a vector for use in human clinical trials; as of now, 38 protocols have been approved by the Recombinant DNA Advisory Committee and the Food and Drug Administration (FDA). The increased popularity of AAV vectors reflects the appreciation of the long-term transgene expression observed in animal models and the relative lack of immune response and other toxicities in the models. Other factors that have played a role in encouraging the use of AAV vectors include the discovery of new serotypes and the appreciation that matching the tissue specificity of the serotype with the presumptive target tissue can greatly enhance the potential effectiveness of therapy. In general, the goal of gene therapy can be classified into one of two categories, the correction of an intracellular defect or the synthesis of a secreted protein, which is active at an extracellular level. In the latter case, the site of protein synthesis would not seem to be critical as long as it has no deleterious intracellular effects and is successfully secreted into blood. This assumption has been tested in clinical trials in which proteins normally synthesized in the liver are now induced to be produced in skeletal muscle. Whether the assumption is correct is still not certain, in part because different vector target sites may induce different host immune responses (41, 42).

Despite the small packaging capacity of AAV vectors, clever investigators have devised ways of engineering transgenes and associated regulatory sequences so that their sizes can be reduced sufficiently to allow packaging into AAV capsids. In general, the expectations with regard to minimal toxicity have been met, although there have been two notable exceptions to this, which will be discussed below. To date, no clinical cures have been effected, although there have been anecdotal data that have kept hopes up. Trials that have been concluded or are in progress are listed in Table . Several of these will be discussed below in some detail to illustrate specific points of interest and concern.

Clinical trials involving AAV vectors

Initial targets for gene therapy included monogenic diseases in which the gene product either was altered to become nonfunctional or was missing. First among these was CF, a lethal, autosomal recessive disease in which the CF transmembrane regulator (CFTR) is inactivated by mutation. CFTR is a component of the Cl channel and the lack of functional CFTR affects the transmembrane electrical potential. This leads to the accumulation of thick secretions in the lung coupled with a loss of the normal respiratory epithelial ciliary activity. The primary difficulty is pulmonary, with an increased incidence of pulmonary infection, especially by Pseudomonas aeruginosa. Additional difficulty occurs with pancreatic secretion, but the loss of the pancreatic enzymes can be treated with supplements. Thirteen protocols have been approved for phase I and phase II clinical trials using an AAV vector (2, 22, 23, 46, 66). Delivery of the vector was achieved by bronchoscope or by aerosol into the lung and in several cases by delivery to the maxillary sinus (to make measurement of the transmembrane potential, which is affected in CF, possible). The primary and most important observation in early trials was the lack of measurable toxicity and a very modest immune response evoked by the route of pulmonary delivery. Serum antibody was evoked but did not affect the subsequent administration of the vector. The measurement of efficacy in the lung is pretty much restricted to measures of pulmonary function; any improvement that was noted in this manner was not statistically significant. However, in those patients who had vector instilled into the maxillary sinus, it was possible to make a somewhat more direct measurement. The most notable effect was an increase in levels of interleukin-10, a cytokine that is anti-inflammatory, and a concomitant decrease in levels of interleukin-8, which has the opposite effect. Major challenges with vector delivery to the lung through the airway included rapid, regular shedding of the respiratory epithelium, which means that cells that have taken up the vector are fairly quickly lost and that the uptake of the AAV-2 vector in cell culture was mostly through the basolateral surface, which is not very accessible via the airway. Thus, consideration must be given to alternative routes of delivery and the possibility of vectors with alternative serotypes.

A second monogenic disease that could be amenable to gene therapy is hemophilia. Although this disease can be lethal, it is functionally chronic with current modes of therapy. The two common forms are hemophilia A and hemophilia B. Clotting requires a complex series of enzymatic reactions. Two of the required enzymes are factors VIII and IX; a lack of the former results in hemophilia A, and a lack of the latter results in hemophilia B. Initial efforts concentrated on the replacement of factor IX, because the coding region and regulatory sequences could readily be encapsidated in the AAV vector. A factor IX AAV vector could be used to cure mice with hemophilia B (31) and, more excitingly, also performed well in a canine model of hemophilia (32). Initial phase I studies were performed by the intramuscular injection of an AAV-2 vector (36, 41). Disappointingly, although no vector toxicity was noted, no transgenic factor IX could be detected in serum. The notion had been that although factor IX is normally expressed in hepatocytes, the expression of factor IX, which could be excreted, in muscle cells could raise serum factor IX concentration to a therapeutic level (10% of normal). The consequence of the failure to see a rise in the factor IX serum level was to alter the vector target to the liver, the normal site of synthesis, with administration via the hepatic artery (42). Vector was administered to the patients in increasing amounts. At the first two doses, there was no detectable toxicity nor any detectable transgenic factor IX in the serum. At the highest dose (2 1012 vector genomes/kg), there was detectable transgenic factor IX in the serum for 4 to 9 weeks in the two subjects. However, in contrast to what was observed in animal models, the serum concentration went back to baseline levels. More troublesome was a rise in liver transaminases in the serum, a sign of liver inflammation. Subsequently, the inflammatory response was shown to be caused by the induction of a CTL response (45). The first question was whether the immune response was due to the transgene product or the vector. It turned out to be due to the AAV capsid. While an antibody response to capsid had been anticipated, the CTL response to AAV proteins had not been anticipated, because all AAV genes had been deleted from the vector. The working hypothesis is that at the highest dose, where the inflammatory response had occurred, the multiplicity of infection (MOI) was sufficiently high that degradation products of the capsid were displayed on the surface of the transduced hepatocytes in sufficient quantity to induce the CTL response. Thus, there is a conundrum: with the vectors used, the dose required to produce a detectable level of factor IX was also sufficient to induce a CTL response, which destroyed the cells expressing factor IX. Possible solutions to this problem include being able to induce tolerance to the AAV capsid fragments displayed on the surface of the hepatocytes or developing a more efficient vector, which would enable a much lower MOI or dose so that a CTL response would not be evoked. The latter may be able to be achieved by use of alternative AAV serotypes such as AAV-8 or by modification of the surface of the AAV capsid to render trafficking of the ingested AAV particle to the cell nucleus, with ensuing expression of the transgene being much more efficient. An example of the latter approach will be described below in the section on future prospects for AAV vectors.

A much more serious problem arose in a clinical trial involving rheumatoid arthritis (33, 70). Rheumatoid arthritis is a disabling inflammatory disease in which the immune system reacts against the body's joint tissue. Current therapy involves blocking the host response against itself. One way of achieving this inhibition is to counteract the effects of the cytokine tumor necrosis factor alpha (TNF-) by use of the drug adalimumab (Humira). Repeated use of the drug is required whenever there is an exacerbation of the disease in a particular joint. An alternative approach would be to design an AAV vector that could express a TNF inhibitor for an extended period of time, with expression located primarily in the joint that had the vector injected. Promising data were achieved in the animal model of disease. Unfortunately, in the phase I clinical trial, one patient became extremely ill the day after the administration of the AAV vector and died within 4 days. Subsequent investigation established that the patient had died of an overwhelming Histoplasmosis capsulatum fungal infection. The patient had also been treated with adalimumab, one of whose side effects is known to be sepsis. Thus, the question was what role, if any, that the AAV vector played in the demise of the patient. While this was studied, the clinical trial was put on hold by the FDA. The study showed that the patient had already had a systemic histoplasmosis infection before the injection of the vector and that this infection was not controlled, most probably because of adalimumab, which is a systemic drug. Among the conclusions of the investigation was that the AAV vector carrying the transgene had not contributed to any toxicity. The possibility remained that the TNF- inhibitor expressed from the transgene might have contributed to a reduction in the ability of the host immune system to combat the infection; this was deemed to be highly unlikely because little, if any, of the vector was able to be detected outside of the joint that had been injected. Thus, in a relatively short period of time, the FDA essentially exonerated the AAV vector and permitted the clinical trial to resume.

Parkinson's disease, a chronic neurodegenerative disease, has also been an area in which there has been an AAV clinical trial. In Parkinson's disease, a loss of dopaminergic neurons leads to the loss of inhibitory gamma aminobutyric acid-sensitive input to the subthalamic nucleus. Kaplitt et al. (34) and Feigin et al. (17) described a study in which 12 patients with advanced Parkinson's disease had an AAV vector carrying a transgene encoding glutamic acid decarboxylase injected into the subthalamic nucleus on one side. The therapy was well tolerated, with no adverse effects attributable to gene therapy noted for any of the patients, who had been divided into three groups that received low, moderate, or high doses of the vector. The clinical impression was that motor activity on the treated side was improved significantly relative to the untreated side regardless of dose. No change in cognition was noted. The clinical impression was supported by position emission tomography scan data, which measured the reduced metabolic activity on the treated side, consistent with enhanced inhibition. Of particular interest was that motor improvement was not noted until 3 months postinjection so that it did not seem directly related to trauma associated with the injection. Also very encouraging was that the observed improvement in motor activity persisted for at least 1 year. Although the trial involved an open surgical procedure, the dramatic improvements noted, if consistent and reproducible, suggest that AAV gene therapy for chronic, degenerative neurological diseases has great promise. Additional clinical trials for Parkinson's disease, Alzheimer's disease, and Batten disease have been approved.

From these three examples of the 38 clinical trials that have been approved, two approaches can be noted. On one hand, the original notion of replacing a defective gene in a monogenic disease is exemplified by the trials involving patients with CF or hemophilia B. The second approach is demonstrated in the Parkinson's disease trial, in which the intention was to block the consequences of a chronic disease characterized more by a metabolic defect caused by the lack of dopaminergic neurons rather than a cure of the primary lesion.

Two inferences can be drawn from those clinical trials that have already been done. The first is that there has been relatively little toxicity that can be directly attributed to the AAV vector platform. The one area of potential toxicity appears to arise from an inflammatory response involving cytotoxic T cells responding to fragments of the coat proteins from input vector that are presented on the cell surface as major histocompatibility complexes. This has been observed when very high doses of vector were given via the hepatic artery or by intramuscular injection. It is a particularly complex reaction, because dosage, location of injection, and the possibility of induction of tolerance all have to be taken into consideration. Humoral immunity seems to play a role in some instances when the subsequent administration of a vector may be blocked, but toxicity per se has not been a significant observation. Again, the route of administration seems to be important; little humoral immunity has been noted when the pulmonary route is used. The ability of humoral antibody to block vector activity is significant because the seropositivity of the population to AAV is high (80 to 90% for AAV-2). However, the discovery of many new AAV serotypes and the ability to package the AAV-2-based vector DNA into many, if not most, of them suggest that preexisting humoral immunity will not pose a significant barrier to therapy.

Although significant progress has been made in the use of AAV vectors for human gene therapy, several developments are likely to enhance the potential utility of the system. The host immune response remains of concern so that approaches to mitigate the response would constitute a definite advance. One such approach would be to reduce the vector dose required for a therapeutic response. The discovery of additional AAV serotypes is one possibility (24). Another is to modify the surface of the vector capsid to include specific ligands for attachment to target tissues (see Rational Design of AAV Capsids). Recently, an alternative approach was described by Srivastava et al. (79). The particle-to-infectivity ratio of AAV vector preparations usually ranges from 10:1 to 100:1. These ratios reflect, in part, incomplete or empty vector particles. However, an additional reason for the high ratios includes trafficking from the endocytoplasmic vesicle to the nucleus. In the course of trafficking, the vector particle may become ubiquitinated and thus directed to a proteasome for degradation rather than to the nucleus, where the transgene may be expressed. Srivastava's group found that ubiquitinylation and direction to the proteasome require the phosphorylation of tyrosine residues on the surface of the vector capsid. There are seven tyrosines on the surface of the AAV-2 capsid, and Srivastava et al. (A. Srivastava et al., unpublished data) systematically replaced each of these tyrosine residues with phenylalanine. The consequence of these modifications is that the MOI required for the detection of transgene expression has been greatly reduced, both in cell culture and in several mouse models of transduction of cells in the liver and eye. This innovation is likely to greatly enhance the ability to increase transgene expression in several diseases to therapeutic levels.

One of the most attractive features of current AAV vectors is the continued expression of the transgene for prolonged periods of time. This is in spite of the extrachromosomal location of the vector. However, the infrequent integration of the vector means that transduction must occur in cells that either do not turn over or do so very slowly. Additionally, the rarity of integration reduces the likelihood of insertional mutagenesis, but the possibility does remain. Recent experience with the induction of leukemia in patients in two clinical trials who were successfully treated for severe combined immunodeficiency disease with retroviral vectors has heightened awareness of the problem (20). Although AAV vectors seem to be highly unlikely to cause such problems in postmitotic tissues, the issue remains of some concern. In contrast to the wild-type AAV genomes, recombinant AAV vector genomes do not integrate site specifically into chromosome 19 in human cells in vitro and have been shown to remain episomal in animal models in vivo. However, all previous studies were carried out with cells and tissues that are postmitotic. In hematopoietic stem cells, which must proliferate and differentiate to give rise to progenitor cells, recombinant AAV genomes would be lost in the absence of stable integration into chromosomal DNA. Srivastava and colleagues, using a murine bone marrow serial transplant model in vivo, documented the stable integration of the proviral genomes, and integration sites were localized to different mouse chromosomes (A. Srivastava et al., unpublished data). None of the integration sites was found to be in a transcribed gene or near a cellular oncogene. All animals monitored for up to 1 year exhibited no pathological abnormalities. Thus, an AAV proviral integration-induced risk of oncogenesis was not found in these studies.

One of the features of AAV is its ability to specifically integrate into chromosome 19q13.4 to establish latent infection. Current AAV vectors do not have this ability because they lack both the cis-active signal in P5 (IEE) and the trans-active proteins (Rep68 and Rep78) required for site-specific integration. The development of such a vector would enable the transduction of germ or progenitor cells and thus help to ensure long-term transgene expression in tissues where cell turnover is a consideration. If transduction were done ex vivo, it would theoretically be possible to clone cells in which site-specific integration had occurred in the absence of significant, additional random integration. Appropriate vector design would allow the rep gene to be expressed during transduction but not itself be incorporated. Two such vectors were described: one is an AAV/adenovirus hybrid (54), and the other is a bipartite AAV vector (78). In the latter case, Rep is expressed from one component, and the second component contains the cis-active IEE. Both systems are promising but in early stages of development.

Another area with great potential for improvement is the route of administration. This is particularly true for the use of AAV vectors in the central nervous system (CNS). Currently, vector administration requires an open neurosurgical procedure. This is true because of the blood-brain barrier and because of the desire to target specific areas of the CNS. The development of vectors that could achieve the required targeting specificity and the ability to penetrate the blood-brain barrier would greatly facilitate CNS gene therapy. A number of different methods have been suggested and tried with limited success to date.

Other possible advances include a better understanding of the host response and the requirements for the induction of tolerance and the development of more efficient systems for the production of AAV vectors (12).

Gene therapy requires three things: the identification of the defect at the molecular level, a correcting gene, and a way to introduce the gene into appropriate host cells (i.e., a vector). We now have a sophisticated understanding of the basic mechanisms of many genetic diseases, and many corresponding genes have been cloned and can be produced at high levels. The major hurdle to be surmounted is the development of adequate vectors. The wide variety of approaches that have been tried, many of which are still being studied, points to the challenge of developing effective vectors. The delivery methods that have been tried include purified DNA under hydrodynamic pressure, the shotgun approach using DNA adhering to gold particles, lipid-DNA complexes, and, finally, virus-based vectors. Although the first three methods have an inherent simplicity that is attractive, in practice, the efficiency of gene delivery and expression has been lower than what is required for therapeutic efficacy. Viruses, on the other hand, represent nature's vectors for the delivery and expression of exogenous genes in host cells. Here, the challenge is to maintain the efficiency of delivery and expression while minimizing any pathogenicity of the virus from which the vector was derived. In practice, the challenge has been significant. In the only clearly documented instance of therapeutic correction of an inborn error, the inherent oncogenic properties of the original virus (Moloney murine leukemia virus) were retained; 4 of 12 patients with X-linked severe combined immunodeficiency disease developed leukemia. In this experiment, bone marrow precursor cells were transduced and allowed to differentiate. Under these conditions, a vector that would integrate was needed.

Among current viral vectors, only those derived from retroviruses have the ability to integrate at a reasonable frequency; retroviruses require cell division for integration to occur, whereas lentiviruses and foamy viruses can enter the nucleus and integrate in nondividing cells. Lentiviral vectors carry the psychological burden of being derived from significant pathogens, but foamy viruses infect a high percentage of humans without having been implicated as the cause of disease. Although there are production challenges, very promising results have been obtained in a canine model of congenital granulomatosis. The overriding theoretical consideration is that retroviruses integrate at many sites in the human genome, so there is always the concern of insertional mutagenesis possibly causing oncogenesis.

AAV-2, and presumably other serotypes, has been reported to integrate at a specific site in the q arm of chromosome 19 (AAVS1). The frequency with which integration occurs in AAVS1 has been reported to be from 60 to 90%. This exceeds the frequency that has been observed, with the most successful vectors being derived from bacteriophage systems. However, current AAV vectors do not have this ability (they lack the sequences required both in trans and in cis), and integration, which has been observed to occur at a low frequency (107), is random. As discussed above (Future Prospects), it is possible to design AAV vectors that can integrate in a site-specific manner; therefore, a DNA virus vector is possible.

AAV was initially considered as a vector by only a few laboratories. This undoubtedly reflected the lack of familiarity with the virus, since it is nonpathogenic and, thus, of interest only to those inherently interested in its distinctive biology. However, as noted above, with time, it has become among the most commonly used viral vectors. This is likely the consequence of several factors. First, almost all other viral vectors lead to an initial burst of transgene expression that commonly disappears after a relatively short time, measured in weeks. AAV transgene expression, on the other hand, frequently persists for years or the life time of the animal model. Second, other viral vectors have a greater capacity with which to insert the transgene(s). However, with time and clever engineering, it has been possible to insert originally very large transgenes into AAV vectors. Interestingly, it has also proved to be feasible to have split vectors in which one construct has slight sequence overlap with a second construct so that recombination after vector nuclear entry leads to the intact transgene product being expressed. Thus, the consequences of the small size of the AAV genome have been overcome to a large extent.

Another significant positive feature of AAV vectors is that they frequently do not elicit a deleterious immune response. This feature is dependent on the site of administration and the effective MOI of the vector used. Another factor is that AAV appears to be taken up poorly by dendritic cells. Finally, the small capacity of the genome has meant that no viral genes remain. In a parallel manner, the latest version of adenovirus vectors is the gutless vectors from which all viral genes have also been removed. Interestingly, the gutless adenovirus vectors still do not perform as well as AAV vectors in terms of expression persistence. It is tempting to speculate that the difference reflects the special structure of the AAV ITR, which could serve both as an insulator and to protect against cellular exonucleases.

Thus, AAV has become appreciated as a good vector for the transduction of postmitotic cells. At this time, retroviral vectors remain the vector of choice for the transduction of stem or progenitor cells despite the inherent concern of possible oncogenesis. These considerations apply for situations in which long-term transgene expression is desired. In cases such as immunization or vector-induced oncolysis, where expression at higher levels for relatively short periods of time is desirable, other viral vectors such as those derived from adenovirus and herpesvirus have more useful characteristics. What has become apparent is that different vectors have characteristics that are advantageous in specific cases. Thus, the notion of best vector depends on the question of what is best for what purpose.

AAV remains a promising delivery system for the realization of the dream of gene therapy. It compares favorably to other viral vectors, especially when sustained transgene expression is desired. Although nonviral vector systems such as lipid-mediated vectors, hydrodynamic delivery, and the gene gun have been advocated and tried, to date, none have approached the efficacy of the viral delivery systems. Whether such development will occur remains unknown. AAV vectors have achieved some success, and it seems likely that some of the advances described above and others not yet envisioned will enable AAV to become an effective therapeutic agent.

We thank A. Srivastava for his helpful suggestions.

The work was supported in part by a grant from the USPHS, grant DK58327.

Articles from Clinical Microbiology Reviews are provided here courtesy of American Society for Microbiology (ASM)

See the article here:
Gene Therapy Using Adeno-Associated Virus Vectors

Recommendation and review posted by simmons

Numerous scientific studies document that people who eat the most fruits and vegetables have a lower incidence of health problems. Few people, however, consistently eat enough plant food to provide vital phyto-protection against common age-related decline. Commercial multivitamins do not contain all of the vital plant components needed to maintain good health.1-3

Life Extension Mix is vastly superior to other multivitamins on the market todaypartly because it provides a remarkably broad array of fruit and vegetable extracts.

Packed into this blend are extracts of fruits ranging from grape and maqui to bilberry and tart cherry. Its standardized vegetable extracts range from broccoli to artichoke. All with known health benefits throughout the body.

Rounding out the superiority of Life Extension Mix is its extensive list of water- and fat-soluble vitamins, minerals, amino acids. Life Extension Mix provides enzymatically-active forms of B vitamins like pyridoxal-5-phosphate that provide immediate antiglycation benefits. This formula is the only multivitamin to contain 5-methyltetrahydrofolate (5-MTHF), the active form of folate that is more bioavailable than folic acid. This greater bioavailability is especially important in people who have a genetic deficiency since it requires no conversion to become metabolically active.

Scientists have identified multiple mechanisms by which green tea extract helps protect against LDL oxidation, neuronal degradation, and a host of other structural and functional age-related changes. Life Extension Mix provides more green tea extract than found in commercial formulations.

Broccoli is one of the vegetables best documented to protect healthy DNA. The broccoli concentrate in Life Extension Mix is standardized to provide sulforaphane and other glucosinolates, compounds responsible for broccolis protective benefits.

Olive polyphenols help protect against LDL oxidation, quench free radicals, and stabilize cell membranes. Life Extension Mix contains an olive extract standardized to provide the best-documented polyphenol called hydroxytyrosol.

Luteolin is a flavonoid found in parsley, artichoke, basil, celery and other foods. It has shown the ability to help protect against DNA oxidative damage. When measured against 27 other citrus flavonoids, luteolin proved one of the most beneficial at maintaining healthy DNA. Luteolin also suppresses excess levels of interleukin-6 and interleukin-1b. Life Extension Mix contains a standardized dose of 8 mg of luteolin.

Lycopene is the red carotenoid in tomatoes that supports a healthy prostate and helps promote healthy lipid profiles for those already within a normal range. Lutein is found in spinach and collard greens and has been shown to help maintain eye macula pigment structure.

Pomegranate may be the most effective plant to help maintain optimal endothelial function. This pomegranate extract is standardized to provide the punicalagins and other polyphenols found in up to 2.6 ounces of pomegranate juice.

Sesame lignans increase tissue levels of vitamin E, including gamma tocopherol, and inhibit the formation of an inflammatory precursor called arachidonic acid.

The wild blueberry extract in Life Extension Mix is standardized to help maintain optimal neuronal function.

Bilberry extract has antioxidative properties that not only are neuroprotective, but help suppress photooxidative processes and have been shown to improve microcapillary circulation.

Cyanidin-3-glucoside is a berry compound that promotes healthy function of the retina to help support night vision.

Pterostilbene is a compound naturally found in blueberries and grapes that has been shown to have beneficial, anti-aging effects on gene expression and to promote healthy cognitive function.

D-glucarate is found in grapefruit, apples, oranges, broccoli, and Brussels sprouts. D-glucarate supports a detoxification process that helps to remove DNA toxins.

Unlike folic acid, 5-MTHFwhich is more bioavailableis able to cross the blood-brain barrier. This is especially important for people with cognitive difficulties to enhance the synthesis of acetylcholine in the brain, the neurotransmitter associated with memory. It also better facilitates maintenance of healthy homocysteine levels.

Vitamin D3 helps maintain healthy bone density and DNA. There is five times more vitamin D in Life Extension Mix compared to conventional multivitamins.

Life Extension Mix utilizes natural mixed tocopherols that provide natural vitamin E from alpha tocopherol and a small amount of gamma tocopherol (40 mg). Compared to synthetic vitamin E, the natural form is far more bioavailable.

N-acetyl-L-cysteine suppresses free radicals inside the cell and maintains healthy glutathione levels. Taurine may protect against free radicals between cells and supports eye health.

Life Extension Mix contains the sodium selenite, selenomethionine, and Se-methyl L-selenocysteine forms of selenium. Some scientific evidence suggests that consumption of selenium may reduce the risk of certain forms of cancer; however, the FDA has determined that this evidence is limited and not conclusive.

Zinc is often poorly absorbed, but Life Extension Mix provides two of the most bioavailable forms of zinc.

Boron is not only needed to maintain healthy bone density but may also help promote healthy prostate cell function.

Life Extension Mix provides a high amount of an optimal form of chromium to help maintain arterial wall structure and already normal glucose levels.

Magnesium helps protect arteries and heart valves, and supports heart and brain cells. Life Extension Mix provides high potencies of six different forms of magnesium to fully saturate the body with this life-saving mineral.

Choline, phosphatidylcholine and inositol help maintain high levels of acetylcholine in the brain to support cognitive function and memory.

A healthy type of dietary fat, medium-chain triglycerides are easily absorbed intact and transported directly to the liver, where they are immediately used for energy.

Due to license restrictions, this product is not for sale to doctors and MLM wholesalers in the USA, Canada or the Philippines.

Original post:
Life Extension Mix Tablets, 315 tablets

Recommendation and review posted by simmons

Uses Insomnia

Studies suggest that melatonin supplements may help people with disrupted circadian rhythms (such as people with jet lag or those who work the night shift), and those with low melatonin levels (such as some seniors and people with schizophrenia) to sleep better. A review of the scientific literature suggests that melatonin supplements may help prevent jet lag, particularly in people who cross 5 or more time zones.

A few clinical studies suggest that, when taken for short periods of time (days to weeks), melatonin is more effective than a placebo in reducing the time it takes to fall asleep, increasing the number of sleeping hours, and boosting daytime alertness. It is not clear how well melatonin works, however. Some studies suggest that it only reduces the amount of time to fall asleep by a few minutes.

Several human studies have measured the effects of melatonin supplements on sleep in healthy people. A wide range of doses has been used, often taken by mouth 30 to 60 minutes prior to sleep time. Results have been mixed. Some evidence suggests that melatonin may work best for people over 55 who have insomnia. One study of 334 people aged 55 and older found that sustained-release melatonin seemed to help people with primary insomnia fall asleep faster, sleep better, be more alert in the morning, and improve quality of life in people with primary insomnia.

Several studies show melatonin has cardioprotective properties, including antioxidant and anti-inflammatory effects. Research also suggests that melatonin may help lower blood pressure levels and improve cholesterol profiles. More research is needed.

Melatonin supplements may improve sleep problems associated with menopause. Other studies suggest it may help restore quality of life and prevent bone loss among perimenopausal women. However, it does not appear to relieve other symptoms of menopause, such as hot flashes. Peri- or postmenopausal women who use melatonin supplements should do so only for a short period of time since long-term effects are not known.

Some research suggests that melatonin may help elderly people with insomnia who are tapering off or stopping benzodiazepines such as diazepam (Valium), alprazolam (Xanax), or lorazepam (Ativan). Taking controlled-release melatonin improved sleep quality in those stopping benzodiazepine use. More research is needed. You should never combine melatonin with sedative medications unless you are under the strict supervision of a health care provider.

Several studies suggest that low melatonin levels may be associated with breast cancer risk. For example, women with breast cancer tend to have lower levels of melatonin than those without the disease. Laboratory experiments have found that low levels of melatonin stimulate the growth of certain types of breast cancer cells, while adding melatonin to these cells slows their growth. Preliminary evidence also suggests that melatonin may strengthen the effects of some chemotherapy drugs used to treat breast cancer. In a study that included a small number of women with breast cancer, melatonin (given 7 days before beginning chemotherapy) prevented the lowering of platelets in the blood. This is a common complication of chemotherapy that can lead to bleeding.

In another small study of women who were taking tamoxifen for breast cancer but seeing no improvement, adding melatonin caused tumors to modestly shrink in more than 28% of the women. Women with breast cancer should ask their doctors before taking melatonin.

Studies show that men with prostate cancer have lower melatonin levels than men without the disease. In test tube studies, melatonin blocks the growth of prostate cancer cells. In one small-scale study, melatonin, combined with conventional medical treatment, improved survival rates in 9 out of 14 men with metastatic prostate cancer. Interestingly, since meditation may cause melatonin levels to rise it appears to be a valuable addition to the treatment of prostate cancer. More research is needed before doctors can make recommendations in this area. Men with prostate cancer should talk to their doctor before taking medication.

Some evidence suggests that melatonin may help promote sleep in children with ADHD or autism, although it does not seem to improve the behavioral symptoms of ADHD or autism.

A randomized, placebo-controlled study found that people with fibromyalgia experienced a significant reduction in their symptoms when they took a melatonin supplement either alone or in conjunction with fluoxetine (Prozac). Other studies suggest that melatonin may play a role in other painful conditions, such as migraines. People with chronic pain should speak to their physicians before using melatonin as it can interact with some medications.

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Serfaty MA, Osborne D, Buszewicz MJ, Blizard R, Raven PW. A randomized double-blind placebo-controlled trial of treatment as usual plus exogenous slow-release melatonin (6 mg) or placebo for sleep disturbance and depressed mood. Int Clin Psychopharmacol. 2010;25(3):132-42.

Shamir E, Barak Y, Shalman I, Laudon M, Zisapel N, Tarrasch R, et al. Melatonin treatment for tardive dyskinesia: a double-blind, placebo-controlled, crossover study. Arch Gen Psych. 2001;58(11):1049-52.

Shamir E, Laudon M, Barak Y, Anis Y, Rotenberg V, Elizur A, et al. Melatonin improves sleep quality of patients with chronic schizophrenia. J Clin Psychiatry. 2000;61(5):373-7.

Simko F, Pechanova O. Potential roles of melatonin and chronotherapy among the new trends in hypertension treatment. J Pineal Res. 2009 Sep;47(2):127-33. Epub 2009 Jun 29. Review.

Smits MG, Nagtegaal EE, van der Heijden J, Coenen AM, Kerkhof GA. Melatonin for chronic sleep onset insomnia in children: a randomized placebo-controlled trial. J Child Neurol. 2001;16(2):86-92.

Srinivasan V, Spence DW, Pandi-Perumal SR, Trakht I, Cardinali DP. Therapeutic actions of melatonin in cancer: possible mechanisms. Integr Cancer Ther. 2008 Sep;7(3):189-203. Review.

Stewart LS. Endogenous melatonin and epileptogenesis: facts and hypothesis. Int J Neurosci. 2001;107(1-2):77-85.

van Wijingaarden E, Savitz DA, Kleckner RC, Cai J, Loomis D. Exposure to electromagnetic fields and suicide among electric utility workers: a nested case-control study. West J Med. 2000;173;94-100.

Vural EM, van Munster BC, de Rooij SE. Optimal dosages for melatonin supplementation therapy in older adults: a systematic review of current literature. Drugs Aging. 2014:31(6):441-51.

Wilhelmsen M, Amirian I, Reiter RJ, Rosenburg J, Gogenur I. Analgesic effects of melatonin: a review of current evidence from experimental and clinical studies. Pineal Res. 51(3):270-7.

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melatonin hormone - University of Maryland Medical Center

Recommendation and review posted by sam

What Do We Make?

Gene Tools makes Morpholino antisense oligos. Morpholino oligos bind to complementary RNA and get in the way of processes; they can knock down gene expression, modify RNA splicing or inhibit miRNA activity and maturation. Morpholinos are the premier knockdown tools used in developmental biology labs, the best RNA-blocking reagents for cells in culture and, as Vivo-Morpholinos, the most specific delivery-enhanced oligos available for other animal models. We are the sole commercial manufacturer selling research quantities of Morpholinos world-wide.

Morpholino oligos are short chains of about 25 Morpholino subunits. Each subunit is comprised of a nucleic acid base, a morpholine ring and a non-ionic phosphorodiamidate intersubunit linkage. Morpholinos do not degrade their RNA targets, but instead act via an RNAse H-independent steric blocking mechanism. With their requirement for greater complementarity with their target RNAs, Morpholinos are free of the widespread off-target expression modulation typical of knockdowns which rely on RISC or RNase-H activity. They are completely stable in cells and do not induce immune responses.

With their high mRNA binding affinity and exquisite specificity, Morpholinos yield reliable and predictable results. Depending on the oligo sequence selected, they either can block translation initiation in the cytosol (by targeting the 5' UTR through the first 25 bases of coding sequence), can modify pre-mRNA splicing in the nucleus (by targeting splice junctions or splice regulatory sites) or can inhibit miRNA maturation and activity (by targeting pri-miRNA or mature miRNA), as well as more exotic applications such as ribozyme inhibition, modifying poly-A tailing, blocking RNA translocation sequences or translational frameshifting. Morpholinos have been shown effective in animals, protists, plants and bacteria.

We are continually developing novel cytosolic delivery systems like our 'Endo-Porter' for cultured cells and our Vivo-Morpholinos for both cultures and in vivo delivery. With established delivery technologies it's easy to deliver Morpholinos into cultures, embryos or animals -- making Morpholinos the best tools for genetic studies and drug target validation programs.

What Sets Us Apart?

Morpholino oligos have excellent antisense properties compared to other gene knockdown systems. Microinjection or electroporation of Morpholino oligos into the embryos of frogs, zebrafish, chicks, sea urchins and other organisms successfully and specifically shuts down the expression of targeted genes, making Morpholinos an indispensable tool of developmental biologists. Morpholinos have also proven their versatility and efficacy in cultures of primary or immortal cells when delivered by Endo-Porter, electroporation or Vivo-Morpholinos. Usually, Vivo-Morpholinos are used to bring the specificity and efficacy of Morpholino oligos to experiments requiring systemic delivery in adult animals. The list of over 7500 publications using Morpholinos is growing daily and is maintained on-line in a browseable database.

Besides providing the best knockdown and splice modification tools, we also provide the best customer support available in the gene silencing industry. Our customer support team includes three Ph.D.-level scientists with hands-on Morpholino experience who are available to: 1) discuss your experiment design, 2) design your oligos for you, and 3) help you troubleshoot your experiments, all at no additional cost.

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What are targeted cancer therapies?

Targeted cancer therapies are drugs or other substances that block the growth and spread of cancer by interfering with specific molecules ("molecular targets") that are involved in the growth, progression, and spread of cancer. Targeted cancer therapies are sometimes called "molecularly targeted drugs," "molecularly targeted therapies," "precision medicines," or similar names.

Targeted therapies differ from standard chemotherapy in several ways:

Targeted therapies are currently the focus of much anticancer drug development. They are a cornerstone of precision medicine, a form of medicine that uses information about a persons genes and proteins to prevent, diagnose, and treat disease.

Many targeted cancer therapies have been approved by the Food and Drug Administration (FDA) to treat specific types of cancer. Others are being studied in clinical trials (research studies with people), and many more are in preclinical testing (research studies with animals).

The development of targeted therapies requires the identification of good targetsthat is, targets that play a key role in cancer cell growth and survival. (It is for this reason that targeted therapies are sometimes referred to as the product of "rational" drug design.)

One approach to identify potential targets is to compare the amounts of individual proteins in cancer cells with those in normal cells. Proteins that are present in cancer cells but not normal cells or that are more abundant in cancer cells would be potential targets, especially if they are known to be involved in cell growth or survival. An example of such a differentially expressed target is the human epidermal growth factor receptor 2 protein (HER-2). HER-2 is expressed at high levels on the surface of some cancer cells. Several targeted therapies are directed against HER-2, including trastuzumab (Herceptin), which is approved to treat certain breast and stomach cancers that overexpress HER-2.

Another approach to identify potential targets is to determine whether cancer cells produce mutant (altered) proteins that drive cancer progression. For example, the cell growth signaling protein BRAF is present in an altered form (known as BRAF V600E) in many melanomas. Vemurafenib (Zelboraf) targets this mutant form of the BRAF protein and is approved to treat patients with inoperable or metastatic melanoma that contains this altered BRAF protein.

Researchers also look for abnormalities in chromosomes that are present in cancer cells but not in normal cells. Sometimes these chromosome abnormalities result in the creation of a fusion gene (a gene that incorporates parts of two different genes) whose product, called a fusion protein, may drive cancer development. Such fusion proteins are potential targets for targeted cancer therapies. For example, imatinib mesylate (Gleevec) targets the BCR-ABL fusion protein, which is made from pieces of two genes that get joined together in some leukemia cells and promotes the growth of leukemic cells.

How are targeted therapies developed?

Once a candidate target has been identified, the next step is to develop a therapy that affects the target in a way that interferes with its ability to promote cancer cell growth or survival. For example, a targeted therapy could reduce the activity of the target or prevent it from binding to a receptor that it normally activates, among other possible mechanisms.

Most targeted therapies are either small molecules or monoclonal antibodies. Small-molecule compounds are typically developed for targets that are located inside the cell because such agents are able to enter cells relatively easily. Monoclonal antibodies are relatively large and generally cannot enter cells, so they are used only for targets that are outside cells or on the cell surface.

Candidate small molecules are usually identified in what are known as "high-throughput screens," in which the effects of thousands of test compounds on a specific target protein are examined. Compounds that affect the target (sometimes called "lead compounds") are then chemically modified to produce numerous closely related versions of the lead compound. These related compounds are then tested to determine which are most effective and have the fewest effects on nontarget molecules.

Monoclonal antibodies are developed by injecting animals (usually mice) with purified target proteins, causing the animals to make many different types of antibodies against the target. These antibodies are then tested to find the ones that bind best to the target without binding to nontarget proteins.

Before monoclonal antibodies are used in humans, they are "humanized" by replacing as much of the mouse antibody molecule as possible with corresponding portions of human antibodies. Humanizing is necessary to prevent the human immune system from recognizing the monoclonal antibody as "foreign" and destroying it before it has a chance to bind to its target protein. Humanization is not an issue for small-molecule compounds because they are not typically recognized by the body as foreign.

What types of targeted therapies are available?

Many different targeted therapies have been approved for use in cancer treatment. These therapies include hormone therapies, signal transduction inhibitors, gene expression modulators, apoptosis inducers, angiogenesis inhibitors, immunotherapies, and toxin delivery molecules.

Cancer vaccines and gene therapy are sometimes considered targeted therapies because they interfere with the growth of specific cancer cells. Information about these treatments can be found in the NCI fact sheets Cancer Vaccines and Biological Therapies for Cancer.

How is it determined whether a patient is a candidate for targeted therapy?

For some types of cancer, most patients with that cancer will have an appropriate target for a particular targeted therapy and, thus, will be candidates to be treated with that therapy. CML is an example: most patients have the BCR-ABL fusion gene. For other cancer types, however, a patients tumor tissue must be tested to determine whether or not an appropriate target is present. The use of a targeted therapy may be restricted to patients whose tumor has a specific gene mutation that codes for the target; patients who do not have the mutation would not be candidates because the therapy would have nothing to target.

Sometimes, a patient is a candidate for a targeted therapy only if he or she meets specific criteria (for example, their cancer did not respond to other therapies, has spread, or is inoperable). These criteria are set by the FDA when it approves a specific targeted therapy.

Targeted therapies do have some limitations. One is that cancer cells can become resistant to them. Resistance can occur in two ways: the target itself changes through mutation so that the targeted therapy no longer interacts well with it, and/or the tumor finds a new pathway to achieve tumor growth that does not depend on the target.

For this reason, targeted therapies may work best in combination. For example, a recent study found that using two therapies that target different parts of the cell signaling pathway that is altered in melanoma by the BRAF V600E mutation slowed the development of resistance and disease progression to a greater extent than using just one targeted therapy (1).

Another approach is to use a targeted therapy in combination with one or more traditional chemotherapy drugs. For example, the targeted therapy trastuzumab (Herceptin) has been used in combination with docetaxel, a traditional chemotherapy drug, to treat women with metastatic breast cancer that overexpresses the protein HER2/neu.

Another limitation of targeted therapy at present is that drugs for some identified targets are difficult to develop because of the targets structure and/or the way its function is regulated in the cell. One example is Ras, a signaling protein that is mutated in as many as one-quarter of all cancers (and in the majority of certain cancer types, such as pancreatic cancer). To date, it has not been possible to develop inhibitors of Ras signaling with existing drug development technologies. However, promising new approaches are offering hope that this limitation can soon be overcome.

What are the side effects of targeted cancer therapies?

Scientists had expected that targeted cancer therapies would be less toxic than traditional chemotherapy drugs because cancer cells are more dependent on the targets than are normal cells. However, targeted cancer therapies can have substantial side effects.

The most common side effects seen with targeted therapies are diarrhea and liver problems, such as hepatitis and elevated liver enzymes. Other side effects seen with targeted therapies include:

Certain side effects of some targeted therapies have been linked to better patient outcomes. For example, patients who develop acneiform rash (skin eruptions that resemble acne) while being treated with the signal transduction inhibitors erlotinib (Tarceva) or gefitinib (Iressa), both of which target the epidermal growth factor receptor, have tended to respond better to these drugs than patients who do not develop the rash (2). Similarly, patients who develop high blood pressure while being treated with the angiogenesis inhibitor bevacizumab generally have had better outcomes (3).

The few targeted therapies that are approved for use in children can have different side effects in children than in adults, including immunosuppression and impaired sperm production (4).

What targeted therapies have been approved for specific types of cancer?

The FDA has approved targeted therapies for the treatment of some patients with the following types of cancer (some targeted therapies have been approved to treat more than one type of cancer):

Adenocarcinoma of the stomach or gastroesophageal junction: Trastuzumab (Herceptin), ramucirumab (Cyramza)

Basal cell carcinoma: Vismodegib (Erivedge), sonidegib (Odomzo)

Bladder cancer: Atezolizumab (Tecentriq)

Brain cancer: Bevacizumab (Avastin), everolimus (Afinitor)

Breast cancer: Everolimus (Afinitor), tamoxifen (Nolvadex), toremifene (Fareston), Trastuzumab (Herceptin), fulvestrant (Faslodex), anastrozole (Arimidex), exemestane (Aromasin), lapatinib (Tykerb), letrozole (Femara), pertuzumab (Perjeta), ado-trastuzumab emtansine (Kadcyla), palbociclib (Ibrance)

Cervical cancer: Bevacizumab (Avastin)

Colorectal cancer: Cetuximab (Erbitux), panitumumab (Vectibix), bevacizumab (Avastin), ziv-aflibercept (Zaltrap), regorafenib (Stivarga), ramucirumab (Cyramza)

Dermatofibrosarcoma protuberans: Imatinib mesylate (Gleevec)

Endocrine/neuroendocrine tumors: Lanreotide acetate (Somatuline Depot)

Head and neck cancer: Cetuximab (Erbitux)

Gastrointestinal stromal tumor: Imatinib mesylate (Gleevec), sunitinib (Sutent), regorafenib (Stivarga)

Giant cell tumor of the bone: Denosumab (Xgeva)

Kaposi sarcoma: Alitretinoin (Panretin)

Kidney cancer: Bevacizumab (Avastin), sorafenib (Nexavar), sunitinib (Sutent), pazopanib (Votrient), temsirolimus (Torisel), everolimus (Afinitor), axitinib (Inlyta), nivolumab (Opdivo),cabozantinib (Cabometyx), lenvatinib mesylate (Lenvima)

Leukemia: Tretinoin (Vesanoid), imatinib mesylate (Gleevec), dasatinib (Sprycel), nilotinib (Tasigna), bosutinib (Bosulif), rituximab (Rituxan), alemtuzumab (Campath), ofatumumab (Arzerra), obinutuzumab (Gazyva), ibrutinib (Imbruvica), idelalisib (Zydelig), blinatumomab (Blincyto), venetoclax (Venclexta)

Liver cancer: Sorafenib (Nexavar)

Lung cancer: Bevacizumab (Avastin), crizotinib (Xalkori), erlotinib (Tarceva), gefitinib (Iressa), afatinib dimaleate (Gilotrif), ceritinib (LDK378/Zykadia), ramucirumab (Cyramza), nivolumab (Opdivo), pembrolizumab (Keytruda), osimertinib (Tagrisso), necitumumab (Portrazza), alectinib (Alecensa)

Lymphoma: Ibritumomab tiuxetan (Zevalin), denileukin diftitox (Ontak), brentuximab vedotin (Adcetris), rituximab (Rituxan), vorinostat (Zolinza), romidepsin (Istodax), bexarotene (Targretin), bortezomib (Velcade), pralatrexate (Folotyn),ibrutinib (Imbruvica), siltuximab (Sylvant), idelalisib (Zydelig), belinostat (Beleodaq), obinutuzumab (Gazyva), nivolumab (Opdivo)

Melanoma: Ipilimumab (Yervoy), vemurafenib (Zelboraf), trametinib (Mekinist), dabrafenib (Tafinlar), pembrolizumab (Keytruda), nivolumab (Opdivo), cobimetinib (Cotellic)

Multiple myeloma: Bortezomib (Velcade), carfilzomib (Kyprolis),panobinostat (Farydak), daratumumab (Darzalex), ixazomib citrate (Ninlaro), elotuzumab (Empliciti)

Myelodysplastic/myeloproliferative disorders: Imatinib mesylate (Gleevec), ruxolitinib phosphate (Jakafi)

Neuroblastoma: Dinutuximab (Unituxin)

Ovarian epithelial/fallopian tube/primary peritoneal cancers: Bevacizumab (Avastin), olaparib (Lynparza)

Pancreatic cancer: Erlotinib (Tarceva), everolimus (Afinitor), sunitinib (Sutent)

Prostate cancer: Cabazitaxel (Jevtana), enzalutamide (Xtandi), abiraterone acetate (Zytiga), radium 223 dichloride (Xofigo)

Soft tissue sarcoma: Pazopanib (Votrient)

Systemic mastocytosis: Imatinib mesylate (Gleevec)

Thyroid cancer: Cabozantinib (Cometriq), vandetanib (Caprelsa), sorafenib (Nexavar), lenvatinib mesylate (Lenvima)

Where can I find information about clinical trials of targeted therapies?

Follow this link:
Targeted Cancer Therapies Fact Sheet - National Cancer ...

Recommendation and review posted by Bethany Smith

Source: http://www.abc57.com By: Vahid Sadrzadeh

Video Link Here: ABC57 News See the Difference Michiana

An unprecedented stem cell procedure was performed today at a veterinary clinic in Michiana. [Click link above to watch video].

The surgery was for5-year-old German Shepherd, Nike, and set anexample of how stem cell therapy is changing modern medicine.

Although it took merely 30 minutes, it was toughfor Jayne Stommel to watch,Nikes owner and trainer.

Stommel traveled from Indianapolis to South Bend hoping the operation would relieve her 5-year-old super dog of arthritic pain and ensure Nike could continue working for many more years.

Stommelslove for training rescue dogs began long before Guinness and Nike came along.

After seeing the devastation of 9/11 firsthand, Stommel says shediscovered her calling.

With a little bit of research and the right dog,that dream became a reality.

Nike, is one of only 150 certified FEMA trained rescue dogs in the nation that actively works to find survivors of fires, building collapses and natural disasters.

While training at only a year old, Nike was in an accident which ultimately led to arthritis in her hips.

Nike is mid-career, she just turned five. If she doesnt have to stop because the pain in her hips, she should be able to go another four or five years, saidStommel.

Stommel knew in order to prolong Nikes career as long as possible, the stem cell procedure, which was affordable and minimally invasive, was necessary.

It takes a lot of work and training and thats after you find the right dog. They are very unique dogs. Being able to keep her working longer, is very important, saidStommel.

Noticing that Nike was favoring her hip during recent training, Stommelwas recommended to and then sought the help of Dr. Chris Persing and the team at Western Veterinary Clinic on the edge of South Bend.

The treatment was divided into two operations, the first was this morning.

We opened up her abdomen; we found a good healthy layer of fat that we pulled out. I handed that over to a staff so that she could prepare that tissue. To extrude the stem cells, to incubate them, to excite them, to get them ready for a job to do. Later on in the day, we went ahead and used those stem cells to inject in to Nikes hips, says Persing, Associate Veterinarian.

The injection went well and hopes are high for a full recovery.

After a two or three week period, she should be pretty much back to her normal activity and doing the things that she needs to for training again, saidPersing.

And in just two monthsStommels other German Shepherd, Guinness, will be joining that exclusive list of certified FEMA trained rescue K9s.

Until then the two train together, waiting for Nike to join the pack again.

Link:
Stem Cell Worx News

Recommendation and review posted by Bethany Smith

Research is ongoing in Japan and overseas with the aim of realizing cell transplantation therapy using iPS cells. One safety issue of concern is the risk of tumor formation. CiRA in particular has focused its resources on this issue.

Broadly speaking, there are two main theories as to the mechanism whereby iPS cells may form tumors. One theory is that iPS cells form tumors in response either to reactivation of the reprogramming factors inserted into the cell or through damage caused to the original cell genome through the artificial insertion of the reprogramming factors. In response, a search was launched for optimal reprogramming factors which do not cause reactivation, and a method of generating iPS cells was developed in which reprogramming factors are not incorporated into the cell chromosomes and damage to the host genome is therefore avoided.

The other theory is that residues of undifferentiated cells - cells which have not successfully completed differentiation to the target cell type - or other factors lead to the formation of teratomas, a kind of benign tumor. This theory requires research on iPS cell proliferation and differentiation.

1. Search for optimal reprogramming factors When Professor Shinya Yamanaka and his research team announced the successful generation of mouse iPS cells, one of the reprogramming factors they used was c-Myc, which is known to be an oncogene, that is a cancer-causing gene. There have been suggestions that this gene may be activated within the cell and cause a tumor to form. However, in 2010, CiRA Lecturer Masato Nakagawa and his team reported that L-Myc was a promising replacement factor for c-Myc. iPS cells created using L-Myc not only display almost no tumor formation, they also have a high rate of successful generation and a high degree of pluripotency.

2. Search for optimal vectors When the reprogramming factors required to generate iPS cells were inserted into the cells of the skin or other body tissues, early methods employed a retrovirus or lentivirus as a "vector," or carrier. In these methods, the target genes are inserted into the viruses with the which the cells were then infected in order to deliver the target genes. When a retrovirus or lentivirus is used as a vector, however, the viruses are incorporated into the cells genomic DNA in a random fashion. This may cause some of the cells original genes to be lost, or in other cases activated, resulting in a risk of cancerous changes.

In 2008, to remedy this risk, CiRA Lecturer Keisuke Okita and his team explored the use of a circular DNA fragment known as a plasmid, which is not incorporated into the cell chromosome, as a substitute to the retrovirus or lentivirus methods. In this way, they developed a method of generating iPS cells in which the reprogramming factors are not incorporated into the cell chromosome. In 2011, Okita and his team further improved the efficiency generation by introducing into a self-replicating episomal plasmid six factors - OCT3/4, SOX2, KLF4, LIN28, L-MYC, and p53shRNA.

3. Establishing a method for generating and screening safe cells Once iPS cells have been induced to differentiate into the target somatic cells using the appropriate genes and gene insertion methods as explained above, the differentiated cells can be relied upon not to revert to the undifferentiated state. However, there may sometimes be a residue of undifferentiated cells which have not completed the process of differentiation into the target cells, and it is possible that these cells, however few, may form a tumor. Scientists had already established that different iPS cell lines, even if generated from the same individual using the same method, might nevertheless display differences in proliferation and differentiation potentials. This meant that, if iPS cells with low differentiation potential were used, there was a risk that a residue of cells in the cell group might fail to fully differentiate and result in the formation of a teratoma. In 2013, a team led by CiRA Lecturer Kazutoshi Takahashi and Dr. Michiyo Aoi, now an assistant professor at Kobe University, developed a simple method to screen for iPS cell lines that have high potential to differentiate into nerve cells. There is also a risk of tumorigenesis from genomic or other damage arising at the iPS cell generation stage or at the subsequent culture stage. CiRA Assistant Professor Akira Watanabe and his team have developed a sensitive method to detect genomic and other damage in iPS cells using the latest equipment.

4. Developing a reliable method of differentiation into the target cell type In cell transplantation therapy, iPS cells are not transplanted directly into the human body. Instead, cells are transplanted after first being differentiated into the target cell type. It is therefore important to develop a reliable method of inducing iPS cells to differentiate into the target cell type. CiRA is currently working to develop technology for differentiation into a range of different cell types from iPS cells. CiRA Professor Jun Takahashi and his team have developed a highly efficient method of inducing iPS cells to differentiate into dopamine-producing nerve cells. In 2014, CiRA Professor Koji Eto and his team reported a method of producing platelets from iPS cells that is both reliable and can yield high volumes. These findings represent a major step toward iPS cell-based regenerative medicine for nerve diseases such as Parkinsons disease and blood diseases such as aplastic anemia.

View post:
What are iPS cells? | For the Public | CiRA | Center for ...

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Recommendation and review posted by simmons

The Wnt/-catenin signaling pathway during hair follicle (HF) morphogenesis and regeneration. (a) Schematic of the canonical Wnt pathway (for more details, see http://www.stanford.edu/%7Ernusse/). In the absence of a Wnt signal, the excess of cytoplasmic -catenin is targeted for degradation through its association with a multiprotein complex. Upon binding Wnt, its activated receptor complex recruits certain key components of the -catenin degradation targeting machinery. Stabilized free cytoplasmic -catenin is now translocated to the nucleus, where it can associate with transcription factors of the LEF/TCF family to transactivate the expression of their target genes. (b) Loss- and gain-of-function studies in mice have highlighted the different functions of Wnt/-catenin signaling during morphogenesis and adult skin homeostasis. During HF morphogenesis, Wnt/-catenin is required to specify the HF (placode) fate in the undifferentiated basal epidermis. During the adult hair cycle, Wnt/-catenin is required to maintain HF stem cell (SC) identity. As judged by a Wnt reporter transgene, an increase in Wnt signaling promotes SC activation to initiate the growth of a new hair during the telogen-to-anagen transition. An even stronger signal appears to be involved later at the transition of matrix cells to commit to terminally differentiate specifically along the hair shaft lineage. (c) When a constitutively active form of -catenin is expressed for sustained periods in skin epidermis, mice develop de novo HFs from the interfollicular epidermis (IFE), outer root sheath (ORS), and sebaceous glands (SGs). Eventually, these mice develop HF tumors called pilomatricoma, which consist of immortalized matrix-like cells at the periphery, and pure hair cells in the centers (no inner root sheath or companion layer cells). Visualization was enhanced by breeding the K14-N mice on a background of K14-GFP mice. (d) The different signal strengths of Wnt reporter gene activity, combined with the -catenin dosage dependency associated with these different outcomes in mice, can be explained by a model whereby the effective strength of Wnt signaling controls the behavior and fate of the follicle SC. Note: The so-called gradient of Wnt activity refers to the status of Tcf/Lef/-catenin transcriptional activity within the cell, which in fact could be achieved as a gradient, without even involving a Wnt per se. DP, dermal papilla.

The rest is here:
Epidermal stem cells of the skin. - National Center for ...

Recommendation and review posted by Bethany Smith

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Recommendation and review posted by sam

This website is an avenue for communicating with my patients. I keep very up to date with health issues, especially to do with aging and hormonal problems. I will share the interesting bits with you. I encourage a two-way conversation so please add your comments and opinions. I have a daily blog dealing with health issues. You can subscribe to this free service by entering your email address in the space provided.

I am a GP working in Caboolture, Queensland. I have a special interest in natural hormone treatments, also known as Bio-identical hormones. The name derives from the fact these hormones are identical to the hormones we produce naturally.

I have been using these hormones for the last 20 years, and have treated nearly 4500 people with them.

Qualifications

I have a MB Bch,(Bachelor of Surgery and Medicine). I also have a Diploma in Obstetrics, obtained from the Royal College of Obstetricians and Gynecologists. As well I have a Diploma in Tropical Medicine and Hygiene, obtained at the Witwatersrand University, South Africa. I am a Fellow of the Royal Australian College of GPs. Over my lifetime I have delivered over 1500 babies, an achievement I value highly. Some of those I delivered are now my patients.

Books written:

Having studied diet, lifestyle, health and positive attitudes, I was frequently asked as to why I did not share this knowledge with others more widely. So with the encouragement of my wife, I would get up at 4 am to research and write Live Well Over 100. The first edition of 5000 sold out very quickly, so more study and earlier am starts led to the second edition, which was a lot bigger and more in-depth. The print run of 20,000 sold out fairly quickly as well. I was invited to speak at various health related conferences, something I really enjoyed, as I got to meet people from various parts of the world. I spoke in conferences in New Zealand, Singapore, Philippines, South Africa and Australia of course. Unfortunately, the book is now out of print, and is no longer current as it was written over 15 years ago.

While touring New Zealand and giving talks at various venues, I met Michail Borrisenko, who had a great interest in Colostrum, and the many health benefits thereof. Michail and I coauthored Microbe Apocalypse- Man Vs Microbe'. Michail Borrisenko, is chief scientist, Institute of Colostrum Research, New Zealand.

I wrote The Medical Vitadiet, which has sold over 25,000 copies to date. This deals with the benefits of the low-calorie diet to produce weight loss. At one stage I had 5 weight loss clinics in Queensland, with very successful results. Having decided to move on to other aspects of health, I sold the business, but allowed the new owners to continue to use the book I wrote as part of the program.

Environmental concerns:

When living in Bargara, near Bundaberg, in the 70s and 80s with my family, I became concerned about the threat developers posed to the famous Mon Repos Turtle Rookery. A meeting was called by concerned locals, at which I found myself elected to a committee to fight the threat to Mon Repos. We ran a campaign mainly around environmental issues and won in a landslide. I did 2 terms on the local council and feel we made a difference to the local environment my family and friends lived in. I continued my general practice during this time, which kept me very busy. I am still keenly interested in politics, as the world we live in will be determined by the actions of our leaders, and we need to be ever vigilant to ensure our freedoms and good governments.

Womens Hormones.

Why should women get artificial hormones that are not the same as the natural hormones women produce? It isobvious that the body will react and have side effects to hormones it does not recognize.

Why not use the natural hormone produced by the body? How can the limited dosages available from the synthetic HRT suit all women? You would not be satisfied with a choice of only 2 sizes when buying a pair of shoes. So how much more important is it to have hormones made to measure.

Some of the motivation for this web site is to present the medical evidence and research to reassure men and women about the science behind what I do and to refute some of the nonsense that is said about Natural (Bio-identical) HRT. The big pharmaceutical companies have a commercial interest in women using their products and not the natural form. To this end they spend vast sums in promoting their products to doctors, and give big grants to the various menopause associations. I ask people to keep an open mind and to look at the research available into using hormones.

Link:
Dr Colin Holloway | Managing hormone imbalances

Recommendation and review posted by Bethany Smith

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Recommendation and review posted by simmons