Wednesday, August 27, 2014

HIV and Nutrition

HIV and nutrition are intimately linked. HIV infection can lead to malnutrition, while poor diet can in turn speed the infection’s progress. As HIV treatment becomes increasingly available in the poorest parts of the world, critical questions are emerging about how well the drugs work in people if they are short of food. Uncertainty also surrounds the role of vitamins and other supplements. And for those already receiving treatment, side effects such as body fat changes are a daily concern.

Understandably, HIV positive people and those who care for them are interested in whatever might benefit their health.
 HIV and AIDS is well known for causing severe weight loss known as wasting. In Africa, the illness was at first called “slim” because sufferers became like skeletons. Yet body changes are not only seen during AIDS, less dramatic changes often occur in earlier stages of HIV infection.

Whereas starving people tend to lose fat first, the weight lost during HIV infection tends to be in the form of lean tissue, such as muscle. This means there may be changes in the makeup of the body even if the overall weight stays the same.

In children, HIV is frequently linked to growth failure. One large European study found that children with HIV were on average around 7 kg (15 lbs) lighter and 7.5 cm (3 inches) shorter than uninfected children at ten years old. One factor behind HIV-related weight loss is increased energy expenditure. Though no one knows quite why, many studies have found that people with HIV tend to burn around 10% more calories while resting, compared to those who are uninfected. People with advanced infection or AIDS (particularly children) may expend far more energy.

But faster metabolism is not the only problem. In normal circumstances, a small rise in energy expenditure may be offset by eating slightly more food 4 or taking less exercise.  There are two other important reasons why people with HIV may lose weight or suffer childhood growth failure.

The first factor is decreased energy intake or, to put it simply, eating less food. Once HIV has weakened the immune system, various infections can take hold, some of which can affect appetite and ability to eat. For example, sores in the mouth or throat may cause pain when swallowing, while diarrhea or nausea may disturb normal eating patterns. Someone who is ill may be less able to earn money, shop for food or prepare meals. Stress and psychological issues may also contribute.

Secondly, weight loss or growth failure can occur when the body is less able to absorb nutrients – particularly fat – from food, because HIV or another infection (such as cryptosporidium) has damaged the lining of the gut. Diarrhea is a common symptom of such malabsorption. Current antiviral drug treatments control HIV infection and prevent severe wasting, as well as other AIDS-related conditions. Emaciated people tend to regain weight once they begin treatment, and stunted children start to grow faster. Nevertheless, the drugs do not eliminate wasting.

Studies have found that relatively small weight loss (between 5% and 10% over six months) is quite common among people with HIV who are taking treatment and not trying to lose weight. Although this might not seem like much, losses of this size have been linked to an increased risk of illness or death, as discussed below.  In addition, some antiretroviral drugs have been linked to a problem called lipodystrophy. Whereas HIV-related wasting tends to deplete lean tissue, lipodystrophy involves changes in fat distribution. Prolonged treatment is sometimes associated with losing fat from the face, limbs or buttocks, or gaining fat deep within the abdomen, between the shoulder blades, or on the breasts.

Antiretroviral treatment can also contribute to lipid abnormalities by raising LDL cholesterol, lowering HDL cholesterol, and raising triglyceride levels in the blood. This may result in higher risks of heart disease, stroke and diabetes. Other side effects of antiretroviral treatment include insulin resistance, which can occasionally lead to diabetes.

Tuesday, August 19, 2014

Antibody Building and HIV Infection

Scientists at the National Institutes of Health have identified long-sought and elusive broadly neutralizing antibodies to HIV in a pair of papers. These proteins produced by the immune system are crucial for creating a preventive vaccine, and could also have therapeutic uses developed in the coming years or decades.

Variations in individuals' immune systems can dramatically affect responses to infection—HIV is no exception. The result generally can be shown as a bell curve, with a group of people whose disease progresses rapidly, a broad middle segment who progress typically, and a small group of "elite controllers" whose immune systems are quite effective at containing HIV viral replication.

The quest to figure out why has focused primarily on the adaptive immune system, because CD4+ and CD8+ T cells have a clearly demonstrated capacity to kill cells infected with HIV. But that response only arises some days, weeks and even months after a person has been exposed to HIV and the virus has integrated itself into cellular DNA, establishing lifelong infection. The adaptive immune response can only contain an established infection, it cannot prevent that infection from occurring at its onset.

B cells are the first line of defense against infection. They attack at the initial exposure to a pathogen, and can prevent the establishment of infection—and HIV is no exception. But there are a number of reasons why it has proved difficult to identify their contribution to neutralizing the deadly virus.

HIV transmission is not very efficient. Exposed persons may avoid infection for a variety of mechanical (barrier) and biological reasons, such as the virus's failure to penetrate to the surface of mucosal tissue or dendritic cell difficulties in latching onto the virus to carry it to a lymph node. So it is challenging to conclusively identify the contribution of a specific immune response that can prevent an initial infection.

Over the years, it has become clear that there are factors other than CD4+ and CD8+ T cells that help to control the virus in at least a portion of those infected with HIV.

Researchers have identified several antibodies that can neutralize the virus. Most of them bind weakly to small, often deep, pockets on the virus. In most instances, once infection becomes established rapidly mutating HIV evolves resistance to those narrowly focused antibodies, often by adding glycans or sugars to its outer envelope, which shields or blocks antibody access to the binding site.

What is needed is an antibody that binds strongly to a surface site on the virus, and which cannot be easily blocked. It is also important that the binding site is greatly conserved across the many strains of HIV.

Researchers at NIH Vaccine Research Center (VRC) decided to look at neutralizing antibodies in the blood of persons who are able to better control HIV infection. Elite controllers were not part of the mix because they seem to control HIV through their adaptive immunological system T cell mechanisms.

Using sophisticated reverse-engineering techniques, the researchers identified three proteins that are broadly neutralizing, which they labeled VRC01, VRC02 and VRC03. They also isolated the B cells that produced them.

The first two antibodies have very similar chemical structures and bind to HIV's gp120 trimer spike on its surface. The virus uses the trimer to link up with a CD4 receptor, which is the first of many steps taken to enter and infect a host cell. The antibody and gp120 spike bind in a way that is, in part, similar to the way that the spike and CD4 receptor bind.

As a result, VRC01 and VRC02 binding is particularly long and strong compared with the bonds formed by other antibodies. Further, the binding site on the gp120 spike is well exposed and not likely to become blocked by the addition of sugars to the viral envelope.

The two antibodies neutralized 91 percent of the 190 different HIV isolates that the team tested. Those isolates represent all of the various clades or strains of HIV present worldwide, says John Mascola, one of the VRC research team leaders. Also, the antibodies were able to neutralize all of the limited number of HIV variants that are transmitted sexually—a key point, because 80 percent of all new infections result from sexual activity.

VRC01 and VRC02 occur naturally and are produced by what are called RSC3 memory-specific B cells, an extremely rare component of the immune system. Using flow cytometry, the NIH team could isolate only 29 of those cells from among the 25 million cells that they screened. Furthermore, the proteins produced by those B cells often are immature and it appears that the proteins must undergo a series of combinations before they become functional VRC01 or VRC02.

X-ray crystallography allowed the researchers "to identify the [antibody's] binding site down to the atomic level structure…. It is a particularly invariant part of the CD4 binding site, which is exposed," Mascola says. He calls that knowledge "a blueprint from which to design new vaccines. It allows us to try to design a protein that mimics and presents that specific site to the immune system" to stimulate B cells "to crank out the antibody."

Mascola acknowledges the complex nature of the VRC01 and VRC02 antibodies and their low naturally occurring numbers may prove to be an obstacle to developing a vaccine. It is too early to understand all of the issues surrounding the stimulation of antibody production and the concentration necessary to afford protection from infection.

The VRC research team has designed vaccine antigens that already are in preclinical study in small animals. If those prove successful, the work may advance into a monkey model, although it is not completely clear how monkeys can control the simian version of HIV and not progress to advanced disease. The identification of VRC01 and VRC02 may also help to advance a better understanding of the disease in monkeys.

Mascola says these discoveries also may lead to development of a "therapeutic vaccine" or immune-based therapy that helps train the immune system of an HIV-infected person to better control the virus without the use of drugs.

It may be possible to mass-produce these antibodies for passive administration as an adjunct or substitute for current small molecule drugs used to treat HIV. And if production costs can be reduced sufficiently there may be a role for them in topical microbicides as a preventative for HIV exposure.

Tuesday, August 12, 2014

Oxymetholone drug effect

Anadrol (Oxydrol) is the U.S. brand name for Oxymetholone, a very potent oral androgen. This compound was first made available in 1960, by the international drug firm Syntex. Since Oxymetholone is quite reliable in its ability to increase red blood cell production (and effect characteristic of most anabolic/androgenic steroids), it showed great promise in treating cases of severe anemia. It turned out to be well suited for this purpose, and was popular for quite some time. But recent years have brought fourth a number of new treatments, most notably the non-steroidal hormone Epogen (erythropoietin). Many Athletes feared Anadrol 50 might be on the way out for good. But new HIV/AIDS studies have shown a new light on oxymetholone. These studies are finding (big surprise) exceptional anti-wasting properties to the compound and believe it can be used safely in many such cases. Interest has been peaked and as of 1998 Anadrol 50 is again being sold in the United States.
Oxydrol is the only oral anabolic-androgenic steroid indicated in the treatment of anemias caused by deficient red cell production. Oxymetholone is contraindicated in: male patients with carcinoma of the prostate or breast, females with hyperglycemia with carcinoma of the breast, women who are or may become pregnant, ipatients with nephrosis or the nephrotic phase of nephritis, patients with hypersensitivity to the drug or with severe hepatic dysfunction.
Anadrol (Oxydrol) is considered by many to be the most powerful steroid available, with results of this compound being extremely dramatic. A steroid novice experimenting with Oxymetholone is likely to gain 20 to 30 pounds of massive bulk, and it can often be accomplished in less than 6 weeks, with only 50-100mg a day. This steroid produces a lot of trouble with water retention, so let there be little doubt that much of this gain is simply bloat. But for the user this is often little consequence, feeling bigger and stronger on Anadrol 50 than any steroid they are likely to cross. Although the smooth look that results from water retention is often not attractive, it can aid quite a bit to the level of size and strength gained. The muscle is fuller, will contract better and is provided a level of protection in the form of "lubrication" to the joints as some of this extra water is held into and around connective tissues. This will allow for more elasticity, and will hopefully decrease the chance for injury when lifting heavy. It should be noted however, that on the other hand the very rapid gain in mass might place too much stress on your connective tissues for this to compensate. The tearing of pectoral and biceps tissue is commonly associated with heavy lifting while massing up on heavy androgens. There is such a thing as gaining too fast. Pronounced estrogen trouble also puts the user at risk for developing gynecomastia. Individuals sensitive to the effects of estrogen, or looking to retain a more quality look, will therefore often add Nolvadex to each cycle.

It is important to note however, that this drug does not directly convert to estrogen in the body. Oxymetholone is a derivative of dihydrotestosterone, which gives it a structure that cannot be aromatized. As such, many have speculated as to what makes this hormone so troublesome in terms of estrogenic side effects. Some have suggested that it has progestational activity, similar to nandrolone, and is not actually estrogenic at all. Since the obvious side effects of both estrogens and progestins are very similar, this explanation might be a plausible one. However we do find medical studies looking at this possibility. One such tested the progestational activity of various steroids including nandrolone, norethandrolone, methandrostenolone, testosterone and oxymetholone. It reported no significant progestational effect inherent in oxymetholone or methandrostenolone, slight activity with testosterone and strong progestational effect inherent in nandrolone and norethandrolone. With such findings it starts to seem much more likely that Oxymetholone can intrinsically activate the estrogen receptor itself, similar to but more profoundly than the estrogenic androgen methAndriol. If this is the case we can only combat the estrogenic side effects of oxymetholone with estrogen receptor antagonists such as Nolvadex or Clomid, and not with an aromatase inhibitor. The strong anti-aromatase compounds such as Arimidex, Femara, or Aromasin would prove to be totally useless with this steroid, as aromatase is not involved.

Anadrol (Oxydrol) is also a very potent androgen. This factor tends to produce many pronounced, unwanted androgenic side effects. Oily skin, acne and body/facial hair growth can be seen very quickly with this drug. Many individuals respond with severe acne, often requiring medication to keep it under control. Some of these individuals find that Accutaine works well, which is a strong prescription drug that acts on the sebaceous glands to reduce the release of oils. Those with a predisposition for male pattern baldness may want to stay away from Anadrol 50 completely, as this is certainly a possible side effect during therapy. And while some very adventurous female athletes do experiment with this compound, it is much too androgenic to recommend. Irreversible virilization symptoms can be the result and may occur very quickly, possibly before you have a chance to take action.

It is interesting to note that Anadrol 50 does exhibit some tendency to convert to dihydrotestosterone, although this does not occur via the 5-alpha reductase enzyme (responsible for altering testosterone to form DHT) as it is already a dihydrotestosterone based steroid. Aside from the added c-17 alpha alkylation, oxymetholone differs from DHT only by the addition of a 2-hydroxymethylene group. This grouping can be removed metabolically however, reducing oxymetholone to the potent androgen l7alpha-methyl dihydrotestosterone (mesterolone; methyldihydrotestosterone). There is little doubt that this biotransformation contributes at least at some level to the androgenic nature of this steroid, especially when we note that in its initial state Anadrol 50 has a notably low binding affinity for the androgen receptor. So although we have the option of using the reductase inhibitor finasteride (Proscar) to reduce the androgenic nature of testosterone, it would be of no benefit with Anadrol 50 as this enzyme is not involved.

The principle drawback to Anadrol 50 (Oxydrol) is that it is a 17alpha alkylated compound. Although this design gives it the ability to withstand oral administration, it can be very stressful to the liver. Anadrol (Oxydrol) is particularly dubious because we require such a high milligram amount per dosage. The difference is great when comparing it to other oral steroids like Dianabol or Winstrol, which have the same chemical alteration. Since they have a slightly higher affinity for the androgen receptor, they are effective in much smaller doses. Anadrol 50 has a lower affinity, which may be why we have a 50mg tablet dosage. When looking at the medical requirements, the recommended dosage for all ages has been 1 - 5 mg/kg of body weight. This would give a 220lb person a dosage as high as 10 Anadrol 50 tablets (500mg) per day. There should be little wonder why when liver cancer has been linked to steroid use, Anadrol 50 (Oxydrol) is generally the culprit. Athletes actually never need such a high dosage and will take in the range of only 1-3 tablets per day. Many happily find that one tablet is all they need for exceptional results, and avoid higher amounts. Cautious users will also limit the intake of this compound to no longer than 4-6 weeks and have their liver enzymes checked regularly with a doctor. Kidney functions may also need to be looked after during longer use, as water retention/high blood pressure can take a toll on the body. Before starting a cycle, one should know to give Anadrol 50 the respect it is due. It is a very powerful drug, but not always a friendly one.

When discontinuing Anadrol 50, the crash can be equally powerful. To begin with, the level of water retention will quickly diminish, dropping the user's body weight dramatically. This should be expected, and not of much concern. What is of great concern is restoring endogenous testosterone production. Anadrol 50 will quickly and effectively lower natural levels during a cycle, so HCG and Clomid/Nolvadex are a must when discontinuing a cycle.