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Active Tuberculosis Prevented by New Drug that Kills Latent Bacteria

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A new chemical that can prevent active tuberculosis in people infected with the latent form of the bacterium has been discovered by researchers. The drug could also shorten the recovery time needed, and suggests new ways of combating bacterial infection, increasingly resistant to traditional antibiotics.

"With each new case of antibiotic resistance, doctors are losing ground against Mycobacterium tuberculosis and other infectious diseases," explains the study’s senior author Dr. Carl Nathan, chairman of Microbiology and Immunology and the R.A. Rees Pritchett Professor of Microbiology at Weill Cornell Medical College. "This new approach fights the pathogen in a way that’s different from conventional antibiotics. For what may be the first time, we have found compounds that only kill M. tuberculosis when they are not dividing. This lack of replication is a characteristic of latent bacteria, which are tough to eradicate with existing antibiotics and ultimately play a huge role in the epidemic’s spread."
The World Health Organization reports 1.6 million worldwide die from the lung infection annually. It is also estimated that as many as one-third of the world’s population is infected with latent or non-replicating M tuberculosis. The latent bacteria begins to replicate in 5% – 10% of these people, resulting in active disease, while experts opinion states that each person with active TB is estimated to infect 9 and 20 other people.
"That means that killing latent M. tuberculosis is one of the keys to curtailing or eliminating TB as a disease," Dr. Nathan says. "Antibiotic research has typically focused on killing rapidly dividing bacteria. But with antibiotic resistance rising, that no longer seems like a winning strategy. The long duration of treatment required for curing TB may reflect the fact that some of the bacteria remain non-dividing even during clinically active disease."
It can take 6 months to wipe out most non-dividing bacteria using present drugs, but if this difficult regime is stopped too early, drug-resistant bacteria can appear. The focus of the Weill Cornell researchers was a bacterial enzyme called dihydrolipoamide acetyltransferase (DlaT).
"DlaT’s main job is to help M. tuberculosis get energy from nutrients. But when the bacterium is under stress, it also uses the enzyme to defend itself against oxidative damage from human immune cells, such as macrophages," explains study lead author Dr. Ruslana Bryk, assistant research professor in the Department of Microbiology and Immunology at Weill Cornell Medical College.
DlaT is vital to initiating active TB disease, the team discovered. "So we screened 15,000 compounds to find chemicals that might inhibit DlaT," Dr. Bryk says. The researchers discovered one such compound from a class of chemicals called rhodanines. Their collaborators at deCODE Chemistry then synthesized over 1,000 different variants until the Weill Cornell team found several that can enter and selectively kill non-dividing M. tuberculosis.
"We believe that these DlaT inhibitors probably target additional mechanisms that non-dividing M. tuberculosis needs to survive, and we are currently investigating that possibility," Dr. Nathan says. "We also believe that these compounds work in synergy with human immune responses and the chemical environment inside the host to kill latent bacteria."
The inhibitors described in the paper are surely not the only ones with the ability to kill non-dividing M. tuberculosis selectively. "This was really a proof-of-principle effort to show that targeting non-dividing bacteria was feasible," Dr. Nathan explains. "In recent work supported by the Bill and Melinda Gates Foundation, we have since found additional compounds that appear to kill non-dividing M. tuberculosis selectively."
"As a parent, a citizen and an occasional patient, I worry about losing the hard-fought gains we’ve made against infectious disease," Dr. Nathan says. "When traditional antibiotics work, treating TB, pneumonia and other bacterial diseases seems routine. When they don’t work — as is happening now with growing frequency — these infections become emergencies. The growing crisis of microbial resistance demands innovative new approaches. We hope this work will encourage more scientists that such innovations are worth seeking."
The new findings are published in the March 12, 2008 online issue of the journal Cell Host & Microbe.

Teen Pregnancy May Be Reduced by Sex Education in Schools, Says Study

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Sex education may reduce teen pregnancy without increasing the amount of sexual intercourse among teens, or the incidence of sexually transmitted diseases among them, according to new research.

"It is not harmful to teach teens about birth control in addition to abstinence," said study lead author Pamela Kohler, a program manager at the University of Washington in Seattle.

Which approach will postpone sexual experience? Instruction on birth control, or advice on how to say No. That’s the longstanding debate between sex educators and parents. The findings of a study analyzing the response from 1,719 teens, heterosexual and aged between 15 and 19, and the 2002 national survey, found that one in four teens received abstinence-only education, 9%—primarily those living in rural areas and the poor%—received no sex education at all, while the remaining two-thirds received comprehensive instruction with discussion of birth control.

Predictably, those teens receiving comprehensive sex education were 60% less likely to become pregnant or impregnating someone than those receiving no sex education at all. The one in four teens receiving abstinence-only education were 30% less likely to become pregnant than those receiving no sex education at all, although this number was dismissed as statistically insignificant by the researchers because so few teens fit the categories researchers analyzed.

The findings support comprehensive sex education, Kohler said. "There was no evidence to suggest that abstinence-only education decreased the likelihood of ever having sex or getting pregnant." Don Operario, Ph.D., a professor at Oxford University in England, said the study provides "further compelling evidence" about the value of comprehensive sex education and the "ineffectiveness" of the abstinence-only approach.

Still, the study does not show how educators should implement comprehensive sex education in the classroom, said Operario, who studies sex education. "We need a better understanding of the most effective ways of delivering this type of education in order to maximize audience comprehension and community acceptability."


The study appeared in the April, 2008 issue of the Journal of Adolescent Health.

Insulin Research May Lead to Longer, Healthier Life

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Insulin can affect aging and lifespan, a previously unknown outcome which could provide a means of gene manipulation capable of lengthening lives and making people healthier.

In a recent paper, researchers from the Joslin Diabetes Center note that Insulin inhibits a master gene regulator protein called SKN-1, whose activity increases lifespan. SKN-1 also controls what is called the Phase 2 detoxification pathway, a network of genes that defends cells and tissue against oxidative stress—damage caused by elevated levels of free radicals (byproducts of metabolism)—and various environmental toxins. This new research result was validated in experiments on the digestive system of C.elegans, a microscopic worm often used as a model organism.

"We’ve found something new that insulin does and it has to be considered when we think about how insulin is affecting our cells and bodies," said Dr. T. Keith Blackwell, senior investigator at Joslin and author of the paper. "This has implications for basic biology since under some circumstances insulin may reduce defense against the damaging effects of oxidative stress more than we realize."

Enhancing the activity of SKN-1 may lead to increased resistance to chronic diseases and influence longevity, said Dr. Keith, and the work could be important as it relates to diabetes and the many problems associated with the disease, particularly vascular and renal complications.

"The major implication is that we have found something new that affects lifespan and aging, and an important new effect that insulin and/or a related hormone called insulin-like growth factor-1 may have in some tissues," said Blackwell. "The implications go far beyond diabetes."

A gene regulator protein called FOXO is important in diabetes metabolism, tumor suppression and stem cell maintenance, a fact known since the 1990’s. FOXO controls a number of genes involved in stress resistance, and studies in C.elegans demonstrated that diminished insulin signaling increased activity of a FOXO protein called DAF-16, leading to greater stress resistance and longer life.

The Joselin research adds to knowledge about insulin and its effects on gene pathways, while putting SKN-1 next to FOXO as a second master gene regulator that is inhibited by insulin signaling. According to the paper, insulin’s effect on SKN-1 occurs independently of its effect on DAF-16.

The paper was published in the March 21, 2008 issue of Cell.

Many Gulf War Veterans’ Health Problems Traceable to Toxic Chemicals

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The high incidence of illness in Persian Gulf War veterans can be traced to their exposure to toxic chemicals such as nerve agents and pesticides, say researchers at the University of California, San Diego School of Medicine.

Symptoms reported by deployed personnel include fatigue, muscle pain, memory problems, trouble sleeping, rash and breathing problems. These personnel had a higher rate of chronic, multi-symptom health problems than non-deployed personnel, or those deployed elsewhere.

"This evidence suggests that exposure to this certain class of chemical may be linked to elevated risk of health problems," said Beatrice Golomb, M.D., Ph.D., associate professor of medicine at the UC San Diego School of Medicine.

"Health issues among Gulf War veterans have been a concern for nearly two decades. Now, enough studies have been conducted, and results shared, to be able to say with considerable confidence that there is a link between chemical exposure and chronic, multi-symptom health problems," said Golomb. "Furthermore, the same chemicals affecting Gulf War veterans may be involved in similar cases of unexplained, multi-symptom health problems in the general population."

Chemicals known as acetylcholinesterase inhibitors (AChEis) and organophosphates (OP), nerve gas chemicals, sarin and pesticides were included in the study, together with carbamate pyridostigmine bromide (PB) pills originally given to service members to protect against potential nerve-agent exposure. (Note: As a result of an earlier RAND corporation report by Golomb outlining the risks of using such pills, military policy has been changed.)

The study linked exposure to each of these chemicals with the chronic, multi-symptom health problems in 25 to 33 percent of returning Gulf War veterans.
"There is evidence that genetics have something to do with how a body handles exposure to these chemicals," said Golomb. "Some people are genetically less able to withstand these toxins and evidence shows that these individuals have higher chance of suffering the effects of exposure."

Specifically, illness is linked to lower activity of enzymes that detoxify AChEis, due to genetic variants The enzymes known to be involved are paraoxonase (PON) for OPs, including sarin, and butyrylcholinesterase (BChE) for PB.

Source: Proceedings of the National Academy of Sciences (PNAS), March 18, 2008, vol. 105, no. 11, pp. 4295-4300

Concerns Voiced Over Long-Term Effects of Synthetic Progestins

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In a study done at the University of Oregon, the widely used synthetic progestin medroxyprogesterone acetate (MPA) decreased endothelial function in premenopausal women. The finding, researchers said, raises concerns about the long-term effects of MPA and possibly other synthetic hormones on vascular health in young women.

The vascular endothelium lines the inside of blood vessels. In recent years, it has been found to be a dynamic organ that serves an important role in the prevention of atherosclerosis. "The logical conclusion of this study is that over a long period of time it would not be good to have exposure to an agent that is reducing blood vessel flexibility, because it could be associated with the development of heart disease or related problems," said co-author Dr. Paul F. Kaplan, a long-time Eugene gynecologist and senior researcher in the UO’s human physiology department. He stressed, however, that a longer, larger study is needed.

MPA is the active ingredient of Provera, used to treat abnormal uterine bleeding, induce menstrual cycles and relieve symptoms of menopause. Depo/Provera, an injectible long-lasting contraceptive in common use by many young women, contains MPA as an active ingredient. MPA was also used in the Women’s Health Initiative (WHI) including a clinical study on hormone replacement. This was stopped because of health concerns in post menopausal women. Millions of women use hormone therapies with a variety of progestin types for contraception.

The UO study is among the first to target the impact of MPA in premenopausal women. Fourteen women, 19-27 years old, participated in the study after exams to screen out various health conditions. The five-member UO team—led by Jessica R. Meendering, a former UO doctoral student now a professor of exercise science at the University of Nebraska in Omaha—studied the effects of the sex hormone estradiol by itself and in combination with MPA on endothelial function of the brachial artery. The health of the endothelium in this artery has been shown to be a telling proxy for the coronary arteries and a good predictor of cardiovascular risk.

When researchers gave an oral version of MPA to determine its impact, they found that it wiped out the positive effects on endothelial function that estradiol had provided. MPA reduced the function by reducing the brachial artery’s ability to dilate—grow bigger in diameter—in response to the stress of changing blood flow, Kaplan said.

Source: Journal of Physiology: Heart and Circulatory Physiology

What Can Birds Teach Us About Raising Our Own Young?

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Are younger siblings at a competetive disadvantage to their older brothers or sisters? What wisdom can a bird study provide to us about human sibling relationships?

Common wisdom holds that the first-laid birds in a clutch have a better chance of surviving to leave the nest. But Keith Sockman, an assistant biology professor in UNC’s College of Arts and Sciences, has discovered that first-laid eggs are, in fact, the least likely to hatch at all. His findings, based on studying a population of Lincoln’s sparrows in a remote stretch of Colorado’s San Juan Mountains, were published in the March 12,2008 issue of PLoS ONE. "I believe this is the first study to follow siblings from laying through fledging and demonstrate that the effect of laying order on hatching is very different from its effect post-hatching," said Sockman.

It is well-known that because the youngest hatchlings are too small to compete with their stronger brood-mates for the food provided by their parents, they often die. This pattern is often repeated in other animals, from beetles to marsupials to humans. But these observations have so far not allowed for whathappens to eggs before they hatch.

Female Lincoln’s sparrows usually produce three to five eggs, laying one egg a day. Monitoring the birds for three breeding seasons, Sockman and his researchers noticed that the mothers did not start incubating the eggs right away, since they had other things claiming their attention, such as foraging for food. Sockman thinks this makes it probable that first-laid eggs won’t hatch at all, besides helping ensure that a greater number of healthy, strong birds will hatch and mature into young birds.

"At these elevations, conditions can be fairly harsh even during the summer when Lincoln’s sparrows breed," said Sockman. "It’s often freezing at night, which is hard on an un-incubated egg, while daytime temperatures are warm enough to foster the growth of harmful microbes. As a result, since the mother sparrow isn’t keeping them at the most optimal incubating temperature from day one, first-laid eggs can be exposed to environmental conditions that lower the chance those embryos will ever see the world outside their shell."

"If the female did start incubating all her eggs as soon as she laid them, it would increase the probability they’d all hatch. But it would also give a huge head start to those first-laid eggs and the chicks that emerge from them, putting their younger siblings at even more of a competitive disadvantage once they begin battling for food and their mother’s attention," said Sockman.

"It may also reduce the number of eggs she is capable of laying.The mother’s careful balancing of this trade-off enables her to end up with three or four relatively equally robust offspring, instead of one or two strong hatchlings and several "runts of the litter."

Sockman plans to examine what, if any repercussions laying order has once young birds reach adulthood. "The severely competitive environment in the nest may have consequences on the individual’s ability to compete for resources and mates the following year when it is reproductively mature," said Sockman.

Keep these findings in mind as you raise your own young!

Genetic Markers Identify Probability of Lung Cancers Recurrence

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Genetic alterations in tumors and tissue taken from early-stage lung cancer patients are clear pointers to which cancers might recur. Researchers say the findings could change the approach to treating even the smallest lung cancers—the size of a pea—which are known to recur within five years in 30 to 40 percent of patients.

"This is DNA forensics for cancer," says Malcolm Brock, M.D., associate professor of surgery at Johns Hopkins. "While there may be no trace of cancer that we can spot after surgery with a microscope, the DNA evidence from these tumors may have been left at the scene, especially in lymph nodes."

The research team from Johns Hopkins Kimmel Cancer Center identified methyl groups that connect with the DNA structure of a gene. The development of cancers signals cells to switch certain genes on or off, and methylation is a common phenomenon in this process. Disruption to these signals may create abnormal proteins that lead to cancer or its recurrence.

In the study, Brock and his team checked more than 700 surgical samples from 167 early stage non-small lung cancer patients, looking for specific methylation patterns linked o cancer. For 51 patients, whose cancers recurred within 40 months, tumor and lymph node tissue was compared with samples from the remaining 116 patients whose cancer did no recur. The scientists tested all the samples for methylation on seven genes linked to the development of lung cancer. Four of them—p16, H-cadherin, APC and RASSF1A—showed the highest amounts of methylation in patients who had a recurrence of the cancer.

For many of the genes, the study revealed a twofold difference in methyl marks between recurrent cancers and those that did not return.

"The DNA evidence we see for many of the recurring cases suggests it may be wise if our work is confirmed to reclassify such cancers as advanced disease instead of early stage," says Brock.

Higher than normal methylation, combining two genes known as p16 and H-cadherin located in both tumor tissue and a lymph node remote from the tumor area, meant that cancers returned faster than average in 11 patients. For 8 of them this methylation pattern had cancers returning within a year; for the remaining 3 it took 30 months for the cancers to recur.

When analyzing the results to quantify the odds on a patient’s cancer returning, they noted a 5 to 25-fold in risk depending on the particular methylation pattern. While the small sample size meant that some of the gene markers lacked statistical significance, they believed that odds predictions were valid for p16 and H-cadherin.

Kimmel Cancer Center medical oncologist James Herman, M.D. says if these results are confirmed, it may lead doctors to consider treating high-risk patients more aggressively with chemotherapy after surgery. He also believes that therapies which target these gene patterns by stripping off methyl groups hold promise as well. "These marks of aggressive disease also are themselves targets for therapy."

The study appeared in the March 13 issue of the New England Journal of Medicine.

Researchers Find that Head and Neck Cancers May Be Different Diseases

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Different risk factors for head and neck cancer have been identified by researchers at Johns Hopkins Kimmel Cancer Center, raising the possibility that they are different forms of these diseases.

Head and neck tumors caused by the human papillomavirus (HPV) were generally associated with sexual behaviors and smoking marijuana, rather than tobacco and alcohol. It was also found that people with the viral-linked cancer were mostly white, younger, married, and college-educated with income of $50,000 or more. Those not attributable to HPV were associated with tobacco, alcohol and poor oral hygiene, most generally listed as the causes of head and neck cancer. The findings are to be published in the March 12 issue of the Journal of the National Cancer Institute.

"Our results indicate that HPV-positive and HPV-negative head and neck cancers have different risk-factor profiles and should be considered two distinct diseases," says Maura L. Gillison, M.D., Ph.D., an associate professor of oncology and epidemiology at Hopkins. "They just happen to occur in the same place."

HPV infection has been seen in up to 72% of patients, and is associated with the development of some neck and head cancers, mostly in the upper throat and back of the tongue. Gillison noted that the incidence of HPV-linked cancer has nearly doubled over the past 30 years, and that head and neck cancer patients with HPV-positive tumors are mlore responsive to treatment and survive longer than HPV-negative patients.

According to Gillison, the American Joint Committee on Cancer is now considering incorporating HPV status in its guidelines for determining clinical stages of head and neck cancer.

For this study, 240 patients at the Johns Hopkins Hospital with head and neck squamous cell carcinomas were studied between 2000 and 2006, to identify HPV-positive or negative tumors. All study participants completed a computerized interview that asked questions about their risk factors.

Source: Journal of the National Cancer Institute, March 12, 2008

Ayuverdic Natural Medicine Balances Health And Life

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Comprising yoga, massage, meditation and much more, Ayuverdic medicine is among the world’s oldest, and reputedly balances life and health. It originated in India more than 5,000 years ago, and is still practiced there alongside Western medicine.

Ayuverdic medicine is based on the belief that balance in life starts at birth, where a person’s innate qualities help to frame the person’s physical and mental patterns, to create the state known as praktiki. A person’s present state is known as vikruti, which is praktiki incorporating everything affecting one’s life—work, diet, hobbies and friends, for example. The closer one is to praktiki the better. Discord in life, or divergence from self, leads to dosha imbalance. Dosha refers to energy patterns.

To identify diseases, practitioners of ayurvedic medicine must evaluate what dosha is the greatest influence in the patient and seek to understand if there’s discourse between the innate and current self. Individuals can apply ayurvedic medicine to everyday situations, too. For example, dry skin may require more than lotion. One may need to look at emotions and consider how to heal emotional dryness.

An overview of ayuverdic medicine is published in the March, 2008 issue of Mayo Clinic Health Letter.

Not Enough Doctors to Treat Increasing Number of Obese and Diabetic Children

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The number of diabetic and obese children is growing so rapidly that there aren’t enough doctors to treat the kids. According to a recent study by University of Michigan’s C.S. Mott Hospital, there is only one board-certified pediatric endocrinologist per 290 children with diabetes. The ratio of obese children to board-certified endocrinologists is 17,000 to 1. The rate if childhood obesity in the United States meanwhile has more than doubled in the past 20 years, with a corresponding increase in the number of children at risk for type 1and type 2 diabetes.

"Although the American Diabetes Association recommends that all children with diabetes be cared for by a pediatric endocrinologist as part of a diabetes team, there is a current shortage of pediatric endocrinologists in this country," says study lead author Joyce Lee, M.D., MPH, a pediatric endocrinologist and member of the Child Health Evaluation and Research (CHEAR) Unit in the U-M Division of General Pediatrics. "This problem will likely only worsen due to the recent epidemic of childhood obesity."

The 16.5% of American children aged 6 to 19 who are obese are at risk for ‘adult’ diseases such as type 2 diabetes, elevated blood pressure and high cholesterol. As a result more children than ever are being referred to pediatric endocrinologists for screening, evaluation and management. "But even if just a small fraction of obese children are referred to a pediatric endocrinologist for evaluation", says Lee, " the overall ratio of one pediatric endocrinologist to 17,000 obese children makes providing the necessary care extremely challenging." Dr. Lee is assistant professor in the Department of Pediatrics and Communicable Diseases at the U-M Medical School.

Available pediatric endocrinologists are so few in relation to the number of children at risk that they cannot see even a fraction of the children with diabetes or at risk for the disease. "The epidemic of childhood obesity has undoubtedly created new challenges for our health care, and we need to reassess the current system to ensure children with diabetes or at risk for diabetes receive appropriate care," Lee notes.

Pediatric endocrinologists currently do not have the capabilities to see even a fraction of the large number of children with diabetes or at risk for diabetes. "The epidemic of childhood obesity has undoubtedly created new challenges for our health care, and we need to reassess the current system to ensure children with diabetes or at risk for diabetes receive appropriate care," Lee notes.

Using data from the American Board of Pediatrics and the National Survey of Children’s Health, Lee and her colleagues compared the number of board certified pediatric endocrinologists by region to obese children and children with diabetes in those same areas.

Their research revealed that there are an estimated 229,249 children with diabetes, and only 790 board-certified pediatric endocrinologists in the country. And, in two states—Montana and Wyoming—there are no board-certified pediatric endocrinologists.

The study was published in the March, 2008 issue of The Journal of Pediatrics.