Human Immunodeficiency Virus
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NIAID
“What we saw today was a more complete presentation of different types of analyses that were done, [and] the scientific conclusions are as they were described earlier,” said virologist Gary Nabel, director of the Vaccine Research Center (VRC) at the National Institute of Allergy and Infectious Diseases in Bethesda, Md., who did not participate in the research. “This really is a landmark study for HIV vaccine research.”

After the preliminary results were released late last month, many raised concerns about whether the 31% decrease in HIV infection risk shown by the vaccine candidate was genuine or a statistical anomaly. The doubts were in part fueled by hints of additional analyses that yielded weaker and non-significant effects.

The full data, presented at the meeting and published today in the New England Journal of Medicine (NEJM), alleviated some of those uncertainties by showing the same trend in three different analyses — the intent to treat (ITT), which included all 16,402 subjects; the modified intent to treat (MITT), which excluded seven individuals who were infected with HIV before the trial even began (and was the only analysis made public last month); and the per protocol analysis, which excluded any subject who did not receive all six doses of the vaccine within the correct time periods (about 25% of subjects) as well as any individuals who became infected over the course of the study (about 31% of subjects).

Although the MITT analysis was the only one that reached statistical significance, it “was the most appropriate,” and “all three analyses are qualitatively similar,” said infectious disease epidemiologist Seth Berkley, CEO of the International AIDS Vaccine Initiative (IAVI), who was not involved in the study. “It’s unfortunate that the controversy occurred, [but] now with all the data in front of us, [we can see that] there is a signal there.”

What’s important now, researchers agree, is learning as much as possible from the results of this trial. Two “intriguing” trends in particular that emerged during today’s meeting deserve a closer look, Berkley said. First, the vaccine seemed to provide a higher level of protection early that waned over time, and second, that protection appeared to be stronger for low and moderate risk groups, as opposed to the high risk group.

“All those things make sense if you think about the pathogenesis of HIV,” said viral immunologist Barney Graham of the VRC, who was not involved in the research. “Typically in an HIV infection you’re only infected with one virus. [These results suggest] we may be right on the threshold of being able to control a single virion, but we may not be close to controlling a group of virions — for example, in IV drug users, or people with genital ulcers.”

Another area that warrants further investigation is the mechanism behind the vaccine’s effectiveness. The vaccine is a combination of two HIV vaccine candidates — one that showed no effect and another that was never tested in an efficacy trial. “The combination of the two worked,” Berkley said, “and so the question is why? What’s the mechanism?”

“I think this has inspired the field and given hope that it is possible to give protection in human,” Berkley said. “If a poor vaccine and a weakly immunogenic vaccine together can provide protection, then [developing an effective vaccine] may be easier than we originally thought.”

In addition, the trial revealed no difference in viral load or CD4 counts of infected individuals, suggesting that “those immune responses that might be able to initially prevent HIV infection and those that modulate [the virus] once you have become infected might be quite different,” Colonel Nelson Michael of the Walter Reed Army Institute of Research and the US Military HIV Research Program (MHRP) said during a press conference this morning.

The trial’s collaborators are assembling four advisory committees “to interpret the results and plan future [vaccine trials],” said Michael, who is a coauthor on the NEJM paper. “We’re looking forward to the rich discussion [about the results] that has already begun.”

A few years ago, when she moved into a retirement home, she became the de facto social director and drove her new friends to movies and plays. You should have seen her amble out to the car using her walker, then open the trunk and heave the walker inside, one handed.

Whenever she had a health problem, she could be counted on to charge ahead and go for the fix — no matter how difficult the surgery and rehab, or how intransigent the drugs. Until now.

She has recently been diagnosed with a condition called atrial fibrillation. I hoped my experience as a health journalist could help my mother sift through her different treatment options and once again go for the fix. But now my family and I are questioning whether the available treatments are worse than the illness. Should she try to treat the problem, and suffer side effects and new risks? Or should she opt to live with her illness, and all the complications it presents?

Atrial fibrillation is primarily an age-related disease in a much-used heart. The smaller, upper chambers of the heart start to beat irregularly, causing palpitations, fatigue, faintness and sometimes chest pain. The disease affects 1 percent of all adults. It won’t kill you by itself, but it can decrease your quality of life — and dramatically increases the risk of a stroke from blood clots.

After my mother learned of her diagnosis, she was immediately put on a blood thinner by her doctors, as recommended in guidelines, to reduce the risk of stroke. I felt better. But she felt a lot more tired.

Next, she tried a treatment called cardioversion — an electrical jolt to shock the heart back into rhythm. For 10 days, she felt great. Then the atrial fibrillation returned, and she felt lousy again.

Next up came a powerful and controversial drug called amiodarone, to improve the odds that another cardioversion would last longer. Side effects may include problems with the eyes, thyroid, lungs and nervous system, including possible loss of balance. She fell. Seven times in seven days. Not good, especially for someone on a blood thinner, which raises the risk of hemorrhage. She stopped taking the drug.

Now, she’s usually in a wheelchair, too weak and worried about falling to use her walker, though that is her goal. She’s going to physical therapy and walking 10 or 15 minutes a day. She’s waiting to
be sure all the side effects go away and trying to decide what to do next. She sounds and feels better than she did on the drug, but worse than her old self.

I stumbled across news about a new drug last month in The New England Journal of Medicine. It’s called dronedarone, or Multaq, and made by the pharmaceutical company Sanofi-Aventis. The drug is apparently slightly less effective than amiodarone but has fewer side effects.

Trouble is, while the Food and Drug Administration reviews the drug later this month, it probably won’t be approved until much later this year. Will it be too late for my mother? Will it work for her? We can’t know. But I do have a new appreciation of the drug companies’ complaints that the F.D.A. takes too long to approve drugs.

There is another procedure called ablation, which threads a catheter through a vein right into the heart to scar some tissue in hopes of blocking arrhythmic signals. Should she try it? It can be a cure. But in people her age, it has a high rate of serious complications like stroke or shock, and the procedure takes hours under anesthesia and often needs repeating.

My brother lives in the small town near my mother and bears disproportionate responsibility for her care. But he also has the pleasure of her company. He, my sister and I consult regularly. Then we all talk to her. Our mother listens to us and her doctors, and confesses to moments of despair, interspersed with periods of equanimity.

My sister and I have joined her for a trip to a favorite spot in Hawaii for a short stay right now. She’ll mostly be in the wheelchair and no doubt wondering if she’ll ever be able to travel again. It’s no fun getting old. And it’s confusing to see how opinions differ on the best course of treatment.

For now, my mother has decided that accepting her new ailment is better than dealing with the side effects of a risky drug or complications of a more invasive heart procedure. She’s still asking questions about pacemakers and other drugs. But for now, anyway, her plan is to live with atrial fibrillation rather than try to fix it.

Anyone concerned about themselves or a loved one developing prostate cancer should know the basics about the first symptoms that are typically seen.
What Are the Most Common Symptoms of Prostate Cancer?

Because of its location in the body, prostate cancer is often accompanied by a number of unique symptoms. The prostate is located just below the bladder in the lower pelvis. As urine empties out of the bladder it travels through a thin tube called the urethra. At the very beginning of the urethra, just as it exits the bladder, it passes directly through the prostate. As the prostate enlarges due to cancer or another problem, the urethra is pinched tighter and tighter within the prostate. As the tube narrows, urine has a much harder time making its way through the urethra and out of the body.

This results in four primary urinary symptoms:

* Frequency – urinating much more often than normal.
* Urgency – having a sensation that you need to urinate immediately.
* Nocturia – getting up to urinate multiple times during the night.
* Hesitancy – difficulty starting the urine stream.

All of these symptoms are a direct result of the urethra being pinched closed by the enlarged prostate.

Prostate cancer is not the only disease that can cause the prostate to swell, however. In fact, BPH (benign prostatic hyperplasia) is a much more common cause of an enlarged prostate and, thus, of urinary symptoms. BPH is not cancer, but is still an important condition that should be treated by a physician.
What Are Other Less Common Symptoms of Prostate Cancer?

The urinary symptoms discussed above are undoubtedly the most common symptoms experienced by men with prostate cancer. However, they are not the only ones. Other less common symptoms include:

* Blood in the urine.
* Blood in the semen.
* New-onset erectile dysfunction (impotence).
* Bone pain (especially in the lower back, hips, or ribs).
* Loss of bladder control.

These symptoms are less specific to problems with the prostate (meaning that problems with other organs such as the bladder can also cause them). However, they are important symptoms of which to be aware.
When Should I Go to See My Doctor?

The answer to this question is simple. Visit your physician and explain your situation whenever you first begin to experience any of these symptoms. This is especially true for any men that are over the age of 40 because the vast majority of prostate cancers are diagnosed after that age. It is also especially important for African-American men and those with a family history of prostate cancer to see their physicians as these two groups have much higher rates of prostate cancer.

The symptoms listed above are almost always abnormal and all need to be evaluated by a physician. This is especially true if these symptoms appear suddenly. Very simple examinations and laboratory tests can be put to use by your doctor to determine whether or not your symptoms are due to prostate cancer, another serious disease, or a less dangerous condition.
Are Most Men Diagnosed With Prostate Cancer After They Have Symptoms?

Many people are surprised to learn that the majority of men diagnosed with prostate cancer today have no symptoms when it is first detected. Because of the PSA (prostate specific antigen) test, most men have their prostate cancer detected before they have any significant symptoms. The PSA test is a simple blood test that detects a specific protein produced by the prostate. As the prostate enlarges, more of this protein is produced and more is detected by the PSA test.

Despite this fact, it is still vitally important that you see your physician if you begin experiencing any of the symptoms discussed above. Thousands of men are still diagnosed every year after they develop symptoms.

An interesting and helpful website that can be used to evaluate your own symptoms is Symptom Checker.

My mother understood that he was busy helping other patients. But seeing him one last time would have given her great comfort and the chance to say goodbye to a man she truly cared for. The issue of patient abandonment at the end of life is the topic of a recent University of Washington study, as well as this week’s Doctor and Patient column by Dr. Pauline Chen.

Dr. Chen reflects on the ramifications of the new research, as well as her own experiences dealing with dying patients and their families.

While John ended up living far longer than any of his doctors expected, in the week before his death — which he predicted to the day — he remembered every one of us. He wrote us notes and sent me two handmade, wooden Mandarin ducks. In nature, Mandarin ducks mate for life. John had never found a partner but made it clear from his very first clinic visit that he hoped I, single at the time, eventually would.

The oncologist wrote back to John’s niece, thanking her for all the work she had done caring for her uncle and telling her of the wonderful impression John had left on him and his staff. I, on the other hand, never wrote back. Or called.

An endocrinologist is a doctor who specializes in treating disorders of the endocrine system, such as diabetes, hyperthyroidism, and many others (see list of diseases below). A disease due to a disorder of the endocrine system is often called a “hormone imbalance,” but is technically known as an endocrinopathy or endocrinosis.

Background

All multicellular organisms need “Coordinating systems to regulate and integrate the function of differentiating cells.” Two mechanisms perform this function in higher animals: the nervous system and the endocrine system. The endocrine system acts through the release (generally into the blood) of chemical agents and is vital to the proper development and function of organisms. As Hadley notes the integration of developmental events such as proliferation, growth, and differentiation (including histogenesis and organogenesis) and the coordination of metabolism, respiration, excretion, movement, reproduction, and sensory perception depend on “chemical cues, substances synthesised and secreted by the specialised cells within the animal.”

Endocrinology is concerned with the study of the biosynthesis, storage, chemistry, and physiological function of hormones and with the cells of the endocrine glands and tissues that secrete them. The study of endocrinology began when Berthold noted that castrated cockerels did not develop combs and wattles or exhibit overtly male behaviour. He found that replacement of testes back into the abdominal cavity of the same bird or another castrated bird resulted in normal behavioural and morphological development, and he concluded (erroneously) that the testes secreted a substance that “conditioned” the blood that, in turn, acted on the body of the cockerel. In fact, one of two other things could have been true: that the testes modified or activated a constituent of the blood or that the testes removed an inhibitory factor from the blood. It was not proven that the testes released a substance that engenders male characteristics until it was shown that the extract of testes could replace their function in castrated animals. Pure, crystalline testosterone was isolated in 1935.

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

Hormones

Overview

The endocrine system consists of several glands, in different parts of the body, that secrete hormones directly into the blood rather than into a duct system. Hormones have many different functions and modes of action; one hormone may have several effects on different target organs, and, conversely, one target organ may be affected by more than one hormone.
Amine hormones, norepinephrine and triiodothryonine
Amine hormones, norepinephrine and triiodothryonine
Steroid hormones, cortisol and vitamin D3
Steroid hormones, cortisol and vitamin D3

In 1902 Bayliss and Starling performed an experiment in which they observed that acid instilled into the duodenum caused the pancreas to begin secretion, even after they had removed all nervous connections between the two. The same response could be produced by injecting jejunal mucosa, showing that some factor in the mucosa was responsible. They named this substance “secretin” and coined the term “hormone” for chemicals that act in this way. They specified that, to be classified as a hormone, a chemical must be produced by an organ, be released (in small amounts) into the blood, and be transported by the blood to a distant organ to exert its specific function. This definition holds for most ‘classical’ hormones, but there are also paracrine mechanisms (chemical communication between cells within a tissue or organ), autocrine signals (a chemical that acts on the same cell), and intracrine signals (a chemical that acts within the same cell). A neuroendocrine signal is a ‘classical’ hormone that is released into the blood by a neurosecretory neuron (see article on Neuroendocrinology).

Hormones act by binding to specific receptors in the target organ. As Baulieu notes, a receptor has at least two basic constituents: a recognition site, to which the hormone binds, and an effector site, which precipitates the modification of cellular function. Between these is a “transduction mechanism” in which hormone binding induces allosteric modification that, in turn, produces the appropriate response.

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

Amines

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

Peptide and Protein

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

Steroid

Steroid hormones are derivatived from cholesterol and are subdivided into those with an intact steroid nucleus (gonadal and adrenal steroids) and those with a broken steroid nucleus (vitamin D). Steroid horomones include estrogen and progesterone from the ovary, testosterone from the testes, and cortisol and aldosterone from the adrenal gland.

Work

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

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

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

Endocrinology involves caring for the person as well as the disease. Most endocrine disorders are chronic diseases that need life-long care. The most common of these is diabetes mellitus. Care of diabetes and other chronic diseases necessitates understanding the patient at the personal and social level as well as the molecular, and the physician-patient relationship can be an important therapeutic process.

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

Training

There are roughly 7,000 to 8,000 endocrinologists in the United States. Endocrinologists are specialists of internal medicine or pediatrics. Reproductive endocrinologists deal primarily with problems of fertility and menstrual function – often training first in obstetrics. Most qualify as an internist, pediatrician, or gynecologist for a few years before specializing, depending on the local training system. In the U.S. and Canada, training for board certification in internal medicine, pediatrics, or gynecology after medical school is called residency. Further formal training to subspecialize in adult, pediatric, or reproductive endocrinology is called a fellowship. Typical training for a North American endocrinologist involves 4 years of college, 4 years of medical school, 3 years of residency, and 3 years of fellowship.

Professional organizations

In North America the principal professional organizations of endocrinologists include The Endocrine Society (www.endo-society.org), the American Association for Clinical Endocrinology (www.aace.com), the American Diabetes Association (www.diabetes.org), the Lawson Wilkins Pediatric Endocrine Society (www.lwpes.org), American Thyroid association ( www.thyroid.org), and the Academy of Clinical Thyroidologists,(www.thyroidologists.com). In the United Kingdom, the Society for Endocrinology (www.endocrinology.org) and the British Society of Paediatric Endocrinology and Diabetes (www.bsped.org.uk) are the main professional organisations. The European Society of Paediatric Endocrinology is the largest international professional association dedicated solely to paediatric endocrinology.

There are numerous similar associations around the world.