“Better diagnostic tools and new methods of surveillance provide more affordable and realistic opportunities to improve the planning, monitoring, and evaluation of NTD control,” write authors Dr. Peter Hotez, President of the Sabin Vaccine Institute and Distinguished Research Professor of The George Washington University Medical Center, Dr. Simon Brooker, Reader in Tropical Epidemiology and Disease Control at the London School of Hygiene and Tropical Medicine and Research Fellow at KEMRI-Wellcome Trust Research Programme in Nairobi, Kenya and Professor Donald Bundy, Coordinator of the Africa Program for Onchocerciasis Control (APOC) and Program Leader in Maternal and Child Health, Population and Nutrition, Africa Region, The World Bank.

The authors assert that, in the past, NTD control has been incomplete and unreliable because of weak disease surveillance systems, and that a “new generation of diagnostics provides a sound foundation for developing reliable, up-to-date maps of the distribution of different NTDs to guide and target resources efficiently. Without such maps, the journey of NTD control will be difficult.”

New mapping technologies utilize electronic data entry at the point of collection and rapid transmission of information to a central database using mobile phone technology. Once the data have been compiled, geographical information systems (GIS) simultaneously manage and display the data and include estimates of such variables as temperature, vegetation, and humidity, which affect NTD distribution.

Although many surveys of NTDs have been conducted, the most detailed maps are for onchocerciasis, lymphatic filariasis, and schistosomiasis. These maps are an important resource, but much of their data are old and not easily accessible to policy-makers and managers of public health programs.

The authors highlight a project, the Global Atlas of Helminth Infection (GAHI), which will provide open-access information on the distribution of soil-transmitted helminthiases and schistosomiasis. The GAHI will also highlight the geographical areas where further survey information is required via the GAHI website (http://www.thiswormyworld.org.)

The authors conclude that the development of an integrated Global NTD Atlas for all NTDs would increase the reliability of estimates of disease burden, measure the impact of NTD control efforts, and provide an important planning tool for national control programs.

Troy, N.Y. – Researchers have found that an enzyme in the bacteria that causes cholera uses a previously unknown mechanism in providing the bacteria with energy. Because the enzyme is not found in most other organisms, including humans, the finding offers insights into how drugs might be created to kill the bacteria without harming humans.

Blanca Barquera, a Rensselaer associate professor of biology, led a team (including research professor Joel Morgan and postdoctoral fellow Oscar Juarez) whose findings were published in the June 28 edition of theProceedings of the National Academy of Sciences.

The team studied Na+-NQR, an enzyme that is essentially two linked machines to create energy from food and electrically charge the cell membrane of Vibrio cholerae, powering many cellular functions.

Vibrio cholerae causes cholera, a disease transmitted primarily through contaminated drinking water. Cholera, in which severe diarrhea and vomiting lead to rapid dehydration, is a major cause of death in the developing world, and in the aftermath of catastrophes that compromise water systems.

The Rensselaer team found that the way in which the two machines are linked in Na+-NQR is different from other respiratory enzymes and likely involves much more movement of the protein than has been observed in other enzymes.

Their work stems from an interest in cellular respiration. Cellular respiration carries electrons from food to oxygen, in what amounts to a controlled burn. This process releases energy.

“Cellular respiration is remarkable,” Barquera said. “It is one of the most efficient energy conversion processes known, and nevertheless, does not require high temperatures. This efficiency has drawn the attention of researchers.”

In more complex organisms, like humans, the process of creating energy for a cell – respiration – takes place in specialized organelles within the cell called mitochondria.

But in bacteria, which lack mitochondria, respiration occurs in the cell membrane. Na+-NQR is a respiratory enzyme found on the cell membrane of Vibrio Cholerae.

The enzyme creates energy through respiration and uses that energy to pump ions out of the cell, electrically charging the cell membrane and providing power for all the functions of the cell. Unlike similar enzymes found in many animals and bacteria, Na+-NQR pumps sodium ions out of the cell, rather than protons.

Barquera’s paper in PNAS describes the mechanism the enzyme uses to convert energy using sodium ions.

“Na+-NQR plays the same role as human respiratory proteins but it is much smaller,” Barquera said. “We want to understand how it works, how it produces energy. If we understand how Na+-NQR works, we can learn the basic principles used by living organisms to convert energy and transport ions.”

Researchers studied the enzyme by removing it from the inner cell membrane and studying it in a solution. Na+-NQR, which prefers an environment of water and oil, flourished in a solution similar to detergent, which mimics the bacterial membrane.

“We have the enzyme off of the membrane with all of its components,” Barquera said. Once isolated, the researchers observed the enzyme as it moved sodium from the inside to the outside of the cell.

Their study revealed the protein itself is moving the ions along a path through the cell membrane.

“It works in a very different way from enzymes in other bacteria and mitochondria. The catch and release of ions is done by movement of the protein,” Barquera said.

Barquera said that, by modifying the protein in various ways, the researchers had identified the site on the protein where the ions begin and end their travel along the protein.

Next they want to map the route the ion takes along the protein.

“We can see the in and out site. Now we want to know the path,” Barquera said.

Tuberculous lymphadenopathy in children can be safely treated with six months of INH and RMP with PZA given for the first two months and accompanied by EMB in areas with a high prevalence of drug resistance. Every effort should be made to confirm the diagnosis and possible relapses microbiologically.
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In high-risk adults with type 2 diabetes, researchers have found that two therapies may slow the progression of diabetic retinopathy, an eye disease that is the leading cause of vision loss in working-age Americans.

Intensive blood sugar control reduced the progression of diabetic retinopathy compared with standard blood sugar control, and combination lipid therapy with a fibrate and statin also reduced disease progression compared with statin therapy alone. However, intensive blood pressure control provided no additional benefit to patients compared with standard blood pressure control.

Results of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Eye Study, supported by the National Institutes of Health, were recently published in the New England Journal of Medicine (NEJM) and presented at the 70th Scientific Sessions of the American Diabetes Association.

“This is the largest study to date examining the effects of blood sugar, combination lipid therapy, and blood pressure control on the prevention of diabetic retinopathy progression using retinal photographs,” said Walter T. Ambrosius, Ph.D., a professor of biostatistical sciences in the Division of Public Health Sciences at Wake Forest University Baptist Medical Center, and principal investigator of the ACCORD Eye study’s coordinating center. “Many people with diabetes have microvascular problems, which can result in problems with the kidneys and amputation of toes and feet, and the only place that you can directly observe the microvasculature is in the back of the eyes. What we have seen in the eyes is potentially an indicator of what is happening in other parts of the body.”

Wake Forest Baptist was involved in many ways with the multi-site ACCORD study serving as the coordinating center, a clinical site, and as the head of the study’s southeastern clinical center network, under the leadership of David C. Goff, Jr., Ph.D., a professor and chair of epidemiology and prevention, also in the Division of Public Health Sciences.

“The ACCORD Eye Study clearly indicates that intensive glycemic control and fibrate treatment added to statin therapy separately reduce the progression of diabetic retinopathy,” said Emily Chew, M.D., chair of the Eye Study and chief of the Clinical Trials Branch of the Division of Epidemiology and Clinical Applications at the National Eye Institute (NEI). “The main ACCORD findings showed that fibrate treatment added to statin therapy is safe for patients like those involved in the study. However, intensive blood sugar control to near normal glucose levels increased the risk of death and severe low blood sugar, so patients and their doctors must take these potential risks into account when implementing a diabetes treatment plan.”

The ACCORD study was a landmark clinical trial that included 10,251 adults with type 2 diabetes who were at especially high risk for heart attack, stroke or cardiovascular death. The study evaluated three intensive strategies compared with standard treatments for lowering cardiovascular risks associated with diabetes.

Intensive treatments included control of blood sugar to near normal levels, control of blood pressure to normal levels, and combination treatment of blood lipids with fenofibrate and simvastatin compared to standard treatment with simvastatin alone. Fenofibrate treatment lowers triglycerides and raises the “good” high density lipoprotein (HDL) cholesterol levels, while simvastatin lowers the “bad” low density lipoprotein (LDL) cholesterol levels. All participants were enrolled in the blood sugar trial and in either the blood pressure or lipid trial.

The ACCORD Eye Study involved a subset of 2,856 participants. Researchers analyzed the effects of the treatment strategies on blood vessels in the eye by identifying diabetic retinopathy progression over four years. Diabetic retinopathy is a disease in which blood vessels in the eye’s light-sensitive retinal tissue are damaged by diabetes. Blood vessels can begin to leak, causing swelling in the retina, and abnormal new blood vessels can develop, both causing vision loss. In the study, disease progression was identified through retinal photographs that indicated blood vessel changes or by the need for laser or eye surgery to treat abnormal blood vessels.

Compared with standard blood sugar control, intensive control decreased the progression of diabetic retinopathy by about one-third, from 10.4 percent to 7.3 percent, over four years. Participants in the intensive control group had a median blood sugar level of 6.4 percent hemoglobin A1c – a level close to values in people without diabetes. The standard blood sugar control group maintained a median level of 7.5 percent.

“Previous clinical trials have shown the beneficial effects of intensive blood sugar control on slowing the progression of diabetic retinopathy in people with type 1 diabetes or newly diagnosed type 2 diabetes,” said NEI director Paul A. Sieving, M.D., Ph.D. “The ACCORD Eye Study expands these findings to a larger population of adults who had type 2 diabetes for an average of 10 years, and demonstrates that the eye benefits from the reduction of glucose below previously established levels.”

In addition, compared with simvastatin treatment alone, combination lipid therapy with fenofibrate plus simvastatin also reduced disease progression by about one-third, from 10.2 percent to 6.5 percent, over four years. No prior clinical trial has shown that the combination of fenofibrate and simvastatin reduces diabetic eye disease progression.

There were no differences in diabetic retinopathy progression among participants treated to an intensive systolic blood pressure (top number in a reading) target of less than 120 mm Hg compared with those treated to a standard target of less than 140 mm Hg.

“The results of the ACCORD Eye Study are exciting, and have provided new and useful information to ophthalmologists managing patients with diabetic retinopathy,” said Craig M. Greven, M.D., professor and chair of the Department of Ophthalmology at Wake Forest Baptist and consultant to the ACCORD Eye Study. “We look forward to using these findings to improve outcomes and prevent visual loss in our patients.”

In the main ACCORD study, none of the three treatment strategies resulted in a significant decrease in the combined rates of heart attack, stroke or cardiovascular death compared with standard treatments. However, over about three-and-a-half years of follow up, participants in the intensive blood sugar group had a 22 percent higher risk of death (5.0 percent versus 4.0 percent) and a three times higher risk of seriously low blood sugar (10.5 percent versus 3.5 percent) compared with participants in the standard blood sugar control group.

The ACCORD study began in 2001, and participants were treated and monitored for an average of five years. Results of the blood sugar clinical trial were reported in 2008, when the intensive blood sugar therapy was stopped 18 months early due to an increased risk of death in that treatment group compared with the standard blood sugar control group. Findings from the blood pressure and lipid clinical trials appeared in the April 29, 2010 edition of NEJM.

“A key question in the main ACCORD study was whether intensive glucose control, previously demonstrated to reduce risk of microvascular disease – including eye problems – in diabetes, would reduce large vessel disease that causes problems like heart attacks. Investigators are continuing to evaluate the risks and benefits of the treatment strategies in these high-risk patients with type 2 diabetes,” said Susan B. Shurin, M.D., acting director of the National Heart, Lung, and Blood Institute, the primary sponsor of the ACCORD study. “Clinicians should individualize treatment for each patient to prevent complications, also incorporating information about conditions such as cardiovascular or visual problems. Lifestyle interventions, including physical activity, weight loss and healthy diets, can improve diabetes control and reduce onset of diabetes.”

The Rab1 protein in its "normal " form (left) and following modification with adenosine monophosphate (AMP; right) using the bacterial enzyme DrrA. The green area shows the contact surface for proteins...

When it infects the lungs, the Legionnaire’s bacterium Legionella pneumophila causes acute pneumonia. The pathogen’s modus operandi is particularly ingenious: it infiltrates deliberately into cells of the human immune system and injects a host of proteins which then interfere in the normal cellular processes. Scientists from the Max Planck Institute of Molecular Physiology in Dortmund have now discovered how Legionella reprogrammes the cells to ensure its own survival and to propagate. They examined a protein used by the pathogen to divert the material transport within the cells for its own purposes. (Science, July 22, 2010)

During a Legionella infection, the bacteria are engulfed by immune cells and bound by a membrane in the cell interior.Legionella protects itself against destruction by releasing proteins that reprogramme the human cell and exploit it for its own purposes. One of these proteins is DrrA. Previous studies succeeded in demonstrating that DrrA diverts the material transport in human cells in the direction of the pathogen, using what are known as Rab proteins for this purpose.

Rab proteins are switch molecules that coordinate transport vesicles within cells. In this capacity, they ensure that these membrane-bound vesicles reach the correct destination at the right time. Of the total of 60 different Rab proteins, DrrA specifically uses the Rab1 molecule for its own purposes: it deposits Rab1 on the membrane enclosing the bacteria and activates it. As a result, part of the material transport of the human cell is diverted to the vesicle containing the bacterium.

The structural and biochemical analysis of DrrA led the Dortmund-based scientists to make an astonishing discovery: DrrA is not only capable of activating Rab1, it also appears to be able to extend its activated state. To this end, DrrA blocks the switching-off of Rab1 and the necessary recognition site for regulatory proteins by attaching an AMP molecule to Rab1. “The permanent activation of Rab1 by DrrA could ensure increased material transport in the direction of the Legionella containing compartment and hence support its survival,” concludes Aymelt Itzen from the Max Planck Institute of Molecular Physiology.

“These results represent an example of how the molecular analysis of bacterial diseases can help us not only to understand the cellular mechanisms involved in an infection, but also the functioning of healthy cells,” explains Roger Goody from the Dortmund Institute. In the case of Legionnaire’s disease, the study of the bacterial protein DrrA reveals how a human regulatory protein (Rab1) is activated in a targeted way and maintained in an active state. This raises the question as to whetherLegionella devised this kind of regulation or whether healthy cells can also control material transport in a similar but hitherto unknown way.

Summary: While we wait for improved new anti-tuberculosis drugs, the main aim for improving current treatment should be to optimize the use of the two current drugs, rifampicin and the pro-drug pyrazinamide, which are responsible to a similar extent for the entire sterilizing activity of current therapy. The rifamycin activity could be improved by increasing the dose size of rifampicin or by daily dosing with long acting rifapentine. Increasing the dose size of pyrazinamide is limited by toxicity but an alternative approach is to use inhalation with pyrazinoic acid, as an adjunct to standard oral therapy. This would acidify pulmonary lesions, thus increasing the bactericidal activity of the orally administered pyrazinamide. Because pyrazinoic acid is the active moiety, it should also increase overall pyrazinamide activity and, because most resistance arises in the pncA gene that converts pyrazinamide to pyrazinoic acid, it should act on most pyrazinamide resistant strains. Inhalation technology allows delivery of drug to lesions rapidly and without first pass toxicity. The properties of drug containing microparticles and nanoparticles during inhalation and storage are reviewed. Spray-dried larger Trojan particles in which the smaller encapsulated particles can reside should be able to improve localisation within alveoli and avoid some storage problems.
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Summary: In spite of having effective, safe treatment for tuberculosis, the prevalence, incidence and mortality remain high. One of the ways to improve control of the disease is to reduce treatment duration either with currently used drugs or with the development of new drugs. These will all require clinical testing for safety and efficacy. The increasing complexity of regulations governing the conduct of clinical trials poses a threat to the very indications for which they are intended. There is an urgent need to review and harmonise the guidelines so that they can be administered in a way that does not compromise the safety and well-being of the trial subjects.
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Author Summary

Infections with parasitic worms (e.g., Schistosoma mansoni, hookworm, roundworm, whipworm, and threadworm) are still widespread in the developing world. Accurate diagnosis is important for better patient management and for monitoring of deworming programs. Unfortunately, methods to detect parasite eggs or larvae in stool samples lack sensitivity, particularly when infection intensities are low. The most widely used method for the diagnosis of S. mansoni, hookworm, roundworm and whipworm in epidemiological surveys is the Kato-Katz technique. Recently, the FLOTAC technique has shown a higher sensitivity than the Kato-Katz method for the diagnosis of hookworm, roundworm and whipworm, but no data are available for S. mansoni. We compared the diagnostic accuracy of the FLOTAC with the Kato-Katz, ether-concentration and Koga agar plate techniques for S. mansoni and other parasitic worm infections using stool samples from 112 school children from Côte d’Ivoire. FLOTAC showed the highest sensitivity for S. mansoni diagnosis. Egg counts, however, were lower when using FLOTAC, an issue which needs further investigations. The FLOTAC, Kato-Katz and ether-concentration techniques failed to accurately detect threadworm larvae, and hence, the Koga agar plate remains the method of choice for this neglected parasite.

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