Since vacations are good for Congress and the President, we figured why not this Blog. See you after Labor Day.

 

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Experts Redesign Common Microbe to Fight Drug-Resistant Bacteria

 

 

E. coli bacteria is seen in an image taken by an electron microscope. REUTERS/USDA/Handout

 

Researchers in Singapore have re-engineered a harmless strain of bacteria to fight another common, drug-resistant microbe that spreads in hospitals and is deadly to patients with weak 1) ___ systems. To fight the Pseudomonas aeruginosa bacterium, the scientists used a strain of the E.coli bacteria that is normally present in the human 2) ___. They inserted into E.coli foreign 3) ___ fragments that empowered it to sense the offending pathogen and quickly produce and release a deadly toxin. “Once it (re-engineered E.coli) detects the presence of the aeruginosa, it produces a 4) ___ and the killing molecule will be released to kill the pathogen,” said assistant professor Chueh Loo Poh, a member of the research team at the Nanyang Technological University’s School of Chemical and Biomedical Engineering.

 

“Our engineered 5) ___ inhibited the growth of the (pathogen) by 90%,” said lead author of the paper, assistant professor Matthew Wook Chang. The team published their findings in the journal Molecular Systems Biology on Tuesday. While many 6) ___ unleash a blanket attack on both good and bad bacteria, the re-engineered E.coli targets specific invaders, in this case, the P. aeruginosa. The same formula can be used to redesign other 7) ___ to fight other infective agents, such as the Vibrio cholerae which causes cholera, said Chang. “We can easily change the sensing 8) ___,” he said.

 

Apart from offering possible new therapies, the team believes re-engineered bacteria can be made into probiotics and consumed in food such as yoghurt. 9) ___ are live bacteria that are beneficial to their hosts. The team is now testing its re-engineered E.coli on animals and hope to carry out clinical 10) ___ in people infected with Pseudomonas aeruginosa later.

 

ANSWERS: 1) immune; 2) gut; 3) DNA; 4) toxin; 5) bacteria; 6) antibiotics; 7) microbes; 8) device; 9) Probiotics; 10) trials

Epidemics Helped Shape the Modern Metropolis

 

 

Photo: New York Historical Society

 

Horatio Bartley, an apothecary, put together a pamphlet of illustrations and descriptions of cholera cases at one of the city’s cholera hospitals. Of the 410 patients admitted to this hospital, 179 died. The attempted remedies included pouring boiling water on the victims. Marinus Willet Jr., the physician-in-chief, recounted, “We soon abandoned this remedy, because we derived no benefit from it, and its application produced great agitation in the mind of the patient.” From Bartley’s pamphlet: “J.G. aged thirty-one, admitted six o’clock, P.M. July 17th, 1832, in the stage of collapse. Was rubbed with camphorated mercurial ointment, until reaction was produced; he was then put under hospital treatment. 22d. Ptyalism [excessive salivation] being induced, was ordered small doses of sulphur, and a wash of the same for the mouth. At six o’clock P.M. diarrhea increasing, was ordered an anodyne enema. He was under medical treatment until 24th, when he died, at three o’clock, P.M.”

 

Cholera is an acute illness characterized by watery diarrhea. The toxin released by the bacteria causes increased secretion of water and chloride ions in the intestine, which can produce massive diarrhea. Death can result from the severe dehydration brought on by the diarrhea.

 

The New York City epidemic of cholera, cause unknown and prognosis dire, reached its peak in July 1832. The upper classes escaped to their country houses. The New York Evening Post reported, “The roads, in all directions, were lined with well-filled stagecoaches, livery coaches, private vehicles and equestrians, all panic-struck, fleeing the city, as we may suppose the inhabitants of Pompeii fled when the red lava showered down upon their houses.”

 

An assistant to the painter Asher B. Durand described the scene near the center of the outbreak. “There is no business doing here if I except that done by Cholera, Doctors, Undertakers, Coffinmakers, &c,” he wrote. “Our bustling city now wears a most gloomy & desolate aspect — one may take a walk up & down Broadway & scarce meet a soul.” The epidemic left 3,515 dead out of a population of 250,000. (The equivalent death toll in today’s city of eight million would exceed 100,000.)

 

The outbreak, highlighted the vulnerabilities of life in overcrowded cities in a time of deplorable sanitation and before medical science recognized the role of germs in disease. Cities were growing faster in population than in understanding what it took to make them fit places to live – an urban problem probably as old as the Sumerians of Mesopotamia. The initial response to the epidemic, Kenneth T. Jackson, a professor of history at Columbia University, said recently, exposed more than ever the city’s divisions of class, race and religion. The disease hit hardest in the poorest neighborhoods, particularly the slum known as Five Points, where African-Americans and immigrant Irish Catholics were crowded in squalor and stench. “Other New Yorkers looked down on the victims,” said Dr. Jackson, editor of The Encyclopedia of New York City. “If you got cholera, it was your own fault.”

 

Unlike most upper-class residents, John Pintard, the respected civic leader who was the historical society’s founder, remained in the stricken city. The epidemic, he wrote in an attitude typical of his peers, “is almost exclusively confined to the lower classes of intemperate dissolute & filthy people huddled together like swine in their polluted habitations.” In another letter, his judgment was even harsher. “Those sickened must be cured or die off, & being chiefly of the very scum of the city, the quicker [their] dispatch the sooner the malady will cease.”

 

Science and medicine advanced more slowly in the 19th century. It was 1883 before the bacterium Vibrio cholerae was discovered to be the agent causing the gastrointestinal disease. But a turning point in prevention came in 1854, when a London physician, Dr. John Snow, established the connection between contaminated water and cholera. Dr. Snow tested the idea by plotting cholera cases on a map of Soho. This showed that most of the victims drew their water from a public pump on Broad (now Broadwick) Street. An infected baby’s diapers had been dumped into a cesspool near the well. A recent book, “Ghost Map,” by Steven Johnson, recounts the discovery.

 

The cholera research was an early application of mapping in medical investigations, a technique that has become widespread now that computers facilitate the display and analysis of such data. Historians of medicine credit Dr. Snow with advancing the modern germ theory of disease and laying the foundations of scientific epidemiology.

 

The cholera menace thus prompted cities to begin cleaning up their fouled nests. This came too late for victims of the 1832 epidemic in New York, or one that followed in 1849. By then, the city’s population had doubled, to 500,000, and deaths by cholera rose to 5,071. The city in 1832 had expanded as far north as 14th Street. People were squeezed out of the lower wards by the influx of immigrants. Some, escaping earlier outbreaks of malaria and yellow fever, had sought a haven in the clean air and open land of the village called Greenwich. Walking in Greenwich Village today, one is struck by the number of small brick houses bearing markers with dates immediately after 1832. It may be no coincidence that John Blauvelt, a carter working the piers, built his on West 10th Street (then Amos Street) the year after the cholera epidemic.

 

New Yorkers should have suspected that the scourge was on its way. Cholera, originally confined to South Asia, had started spreading in 1817 from seaport to seaport, presumably carried by infected sailors. The disease struck London in 1831 and reached New York the next June.

No one was prepared, not even doctors. They generally believed that miasmas, the noxious vapors from rotting organic matter, carried infections, an idea inspiring literature of death in Rome and Venice. The cholera in Five Points seemed to bear out the hypothesis.

 

Five Points was a slum that had metastasized from an intersection of five streets north of City Hall through the area that is now Foley Square and Chinatown. “All that is loathsome, drooping and decayed is here,” Charles Dickens wrote after a visit. Martin Scorsese’s movie “Gangs of New York” captures the lowlife there later in the 19th century, when it was still an urban sinkhole.

 

The exhibition includes illustrations of the thugs and gamblers, the stray dogs and pigs that inhabited the streets of mud and manure. The pigs at least were useful as garbage collectors and sources of food. For victims, the onset of cholera was sudden: an attack of diarrhea and vomiting, followed by abdominal cramps and then acute shock, signaling

 

The collapse of the circulatory system. Some survived the illness, despite the lack of effective remedies. Posters from the time described recommended treatments, including laudanum (morphine), calomel (mercury) as a binding laxative, and camphor as an anesthetic. High doses sometimes did more harm than good. Poultices of mustard, cayenne pepper and hot vinegar were also applied, as well as opium suppositories and tobacco enemas.

 

Many victims, nearly half the cases at one hospital, died within a day of admission. After private hospitals began turning away patients, the city set up emergency public hospitals in schools and other buildings. One, on Rivington Street, bore the brunt, and sketches of its patients’ faces contorted in the throes of death look down from the exhibition walls.

 

In stark contrast, Asher Durand, who had escaped with his family to their country home in New Jersey, painted his children happily eating apples in a sunny orchard. The idyllic canvas hangs a few feet, and a world, away from the scenes of Five Points. While many Protestants sat out the epidemic at safe distances, the city’s Catholics, many of whom were poor immigrants, mostly Irish, had no choice but to stay. Their nuns and priests also remained to offer comfort and some help, and they emerged as the few heroes in the ordeal. “The Sisters of Charity performed heroic service, and many of them died,” said Stephen R. Edidin, co-curator of the exhibition, with Joseph Ditta. “As a result, there was some reduction of anti-Catholic sentiments and a new respect for the Catholic clergy, who risked their lives in the epidemic. The feeling didn’t last, of course.”

 

Despite the epidemics of ’32 and ’49, people still flocked to New York and other teeming cities. But the first outbreak bolstered support for the Croton Aqueduct system to bring clean upstate water to the city, a project, completed in 1842, that led to the phasing out of private and neighborhood wells that were often polluted with human and animal waste. In 1849, the municipal government banished more than 20,000 pigs to the outer reaches of the city. A similar effort in previous years had provoked riots, but this time a public chastened by epidemic complied.

 

Finally, after the work of Dr. Snow in London and a lesser cholera outbreak in New York in 1866, the Metropolitan Board of Health was established with doctors in commanding roles and broad powers to clean up the city. Inspectors went to houses and burned clothing of people who had just died. They cleared the filth, spread lime and instructed survivors in proper sanitation.

 

Cities had learned, or should have, that epidemics as a consequence of urbanization were their responsibility to prevent and control.

Cholera is still a threat wherever drinking water is polluted. But Dr. Ho says that people should no longer die of it, if they are treated promptly and properly with rehydration fluids to restore their ravaged bodies. (From John Noble Wilford, The New York Times)

ONCOLOGY

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Cigarette Smoking Implicated in Half of Bladder Cancers in Women

 

In 2011, approximately 69,250 people will be diagnosed with bladder cancer in the US, and 14,990 will die from the disease.

 

Previous studies indicate that the population attributable risk (PAR) of bladder cancer for tobacco smoking is 50% to 65% in men and 20% to 30% in women and that current cigarette smoking triples bladder cancer risk relative to never smoking. During the last 30 years, incidence rates have remained stable in the United States in men (123.8 per 100 000 person-years to 142.2 per 100 000 person-years) and women (32.5 per 100,000 person-years to 33.2 per 100,000 person-years).

 

Although there have been reductions in the concentrations of tar and nicotine in cigarette smoke, there have been apparent increases in the concentrations of certain carcinogens associated with bladder cancer. A 2009 NCI/DCEG study was the first to suggest a higher risk for smoking-induced bladder cancer than previously reported. That report, based on data from the New England Bladder Cancer Study, found that the association between cigarette smoking and risk of bladder cancer appeared to be stronger than it was in the mid-1990s.

 

According to an article published in the Journal of the American Medical Association (2011;306:737-745), it was shown that current cigarette smokers have a higher risk of bladder cancer than previously reported, and the risk in women is now comparable to that in men. The study used data from over 450,000 participants in the NIH-AARP Diet and Health Study, a questionnaire-based study that was initiated in 1995, with follow-up through the end of 2006.

 

While previous studies showed that only 20 to 30% of bladder cancer cases in women were caused by smoking, these new data indicate that smoking is responsible for about half of female bladder cancer cases – similar to the proportion found in men in current and previous studies. The increase in the proportion of smoking-attributable bladder cancer cases among women may be a result of the increased prevalence of smoking by women, so that men and women are about equally likely to smoke, as observed in the current study and in the U.S. population overall, according to surveillance by the CDC. The majority of the earlier studies were conducted at time periods or in geographic regions where smoking was much less common among women.

 

In the current study, former smokers were twice as likely to develop bladder cancer as never smokers, and current smokers were four times more likely than those who never smoked. As with many other smoking-related cancers, smoking cessation was associated with reduced bladder cancer risk. Participants who had been smoke-free for at least 10 years had a lower incidence of bladder cancer compared to those who quit for shorter periods of time or who still smoked.

 

According to the authors, even though smoking carries the same risk for men and women, men are still about four times more likely to be diagnosed with bladder cancer, and that the study results suggest that difference in smoking rates explain only part of the higher incidence rates in American men. The authors added that occupational exposures, as well as physiologic differences, may contribute to the gender disparity.

Nasal Spray Flu Vaccine Works in Kids

 

Influenza vaccinations for young children are provided in a two-dose, prime-boost combination. The first vaccine dose is designed to prime the immune system to produce a favorable antibody response, and the second vaccine dose is the “boost” designed to spur an immune response.

 

According to a study published online in The Journal of Infectious Diseases (DOI: 10.1093/infdis/JIR436; 15 August 2011), children younger than 3 years old receive the same protective antibody response from the recommended two doses of licensed seasonal influenza vaccines regardless of whether the two doses are injected by needle, inhaled through a nasal spray or provided through one dose of each in any order. In addition, the study found that young children who received at least one dose of the nasal spray vaccine – a live, attenuated influenza virus vaccine (LAIV) – made a wide array of immune T cells which may be important for protection against many diverse flu strains.

 

The study took place during the 2005-2006 and the 2006-2007 flu seasons and involved 53 children aged 6 to 35 months. Study participants were divided into four groups of roughly equal size. None of the children had received an influenza vaccine before. During the study, all children received an initial dose of licensed seasonal flu vaccine and a booster dose one month later. In two groups, the vaccines matched, with children receiving two injections of a trivalent, inactivated vaccine (TIV) injection or two LAIV nasal spray vaccines. Children in the other two groups received a combination of vaccines, with a dose of LAIV given either before or after TIV.

 

According to the authors, kids who have never been immunized against flu are generally advised to receive two doses of inactivated or live, attenuated vaccine to ensure adequate antibody responses, and vaccination schedules combining one dose of TIV with one dose of LAIV have not been recommended because clinical studies of these combinations have not been done previously.

 

The study found that all four dosing patterns were safe and induced similar levels of protective antibodies. However, when the study looked at responses from the T-cell arm of the immune system, a striking difference emerged. They could not detect influenza-specific T cells in children who received only TIV. But the kids who received at least one dose of LAIV nasal spray vaccine produced significant amounts of three important T-cell subtypes that are likely to confer additional protection beyond that afforded by antibodies alone.

 

Previous studies have demonstrated that children are better protected against influenza infection and disease by LAIV than by TIV. However, few studies have examined the T-cell responses elicited by LAIV when given to very young children who have little prior natural exposure to seasonal influenza viruses. Distinguishing T-cell responses due to vaccination from those arising after natural exposure to influenza virus becomes more difficult as a child ages. Because the children in the trial were all younger than 3 years old, the investigators were be confident that spikes in levels of the three T-cell subtypes that were detected were likely due to the vaccinations.

 

Children who received only one dose of LAIV had T-cell responses similar to those who received two, and the order of vaccine types did not make a significant difference in the size of the T-cell response. However, because LAIV has sometimes been associated with increased incidence of wheezing in the youngest recipients, the results of this trial suggest that the best regimen for kids younger than 24 months may be TIV followed by LAIV. However, larger clinical trials are required to confirm the safety and efficacy of such an approach.

 

In a separate series of experiments using influenza virus-infected cells grown in the laboratory, the authors showed that LAIV, but not TIV, induces T cells that recognize genetic sequences shared by a diverse set of influenza viruses. In contrast to currently used flu vaccines – which must be given annually because circulating influenza viruses change from season to season – a vaccine capable of eliciting broad T-cell responses aimed at a portion of virus shared by multiple strains could provide decades-long protection against many or all flu strains.

DIABETES

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Red Meat Consumption and Risk of Diabetes

 

Since the relationship between consumption of different types of red meats and risk of type 2 diabetes (T2D) remains uncertain, a study published online (10 August 2011) in the American Journal of Clinical Nutrition (doi: 10.3945/ajcn.111.018978), was performed to evaluate the association between unprocessed and processed red meat consumption and incident T2D in US adults.

 

The study followed 37,083 men in the Health Professionals Follow-Up Study (1986–2006), 79,570 women in the Nurses’ Health Study I (1980-2008), and 87,504 women in the Nurses’ Health Study II (1991–2005). Diet was assessed by validated food-frequency questionnaires, and data were updated every 4 years. Incident T2D was confirmed by a validated supplementary questionnaire.

 

Results showed that during 4,033,322 person-years of follow-up, 13,759 incident T2D cases were documented. After adjustment for age, BMI, and other lifestyle and dietary risk factors, both unprocessed and processed red meat intakes were positively associated with T2D risk in each cohort (all P-trend <0.001). The pooled hazards ratios (HRs) for a one serving/day increase of unprocessed, processed, and total red meat consumption were 1.12, 1.32, and 1.14, respectively. The results were confirmed by a meta-analysis (442,101 participants and 28,228 diabetes cases): the RRs were 1.19 and 1.51 for 100 g of unprocessed red meat and for 50 g of unprocessed red meat, respectively. The authors estimated that substitutions of one serving of nuts, low-fat dairy, and whole grains per day for one serving of red meat per day were associated with a 16–35% lower risk of T2D.

 

The authors concluded that the results suggest that red meat consumption, particularly processed red meat, is associated with an increased risk of T2D.

TARGET HEALTH excels in Regulatory Affairs and Public Policy issues. Each week we highlight new information in these challenging areas.

 

Finally a Deal in Place for Inspecting Foreign Drugs

 

The following is based on an article published in the New York Times.

 

At its present pace, the FDA would need more than 13 years to inspect every foreign drug plant exporting to the US. Some plants have never been inspected, which saves them huge sums in cleanup and other compliance costs – an important reason that drug manufacturing is disappearing from the US and that tainted-drug scandals occur.

 

In one infamous case, Chinese manufacturers deliberately substituted a cheap fake for the dried pig intestines used to make the blood-thinning drug heparin. The tainted drug was linked to 81 deaths and exposed tens of thousands of people to danger. The FDA had never inspected the plants making the crucial ingredients, a larger problem that only now, more than three years later, may be fixed.

 

After decades of failed attempts, the federal government and the generic drug industry have reached an agreement that is almost certain to pass Congress and that will lead to routine inspections of these overseas plants, potentially transforming the enormous global medicine trade. Under the landmark agreement, expected to be completed within weeks, generic drug companies – which make 75% of the prescription medicines sold in the United States – would pay $299 million in annual fees to underwrite inspections of foreign manufacturing plants every two years, the same frequency required of domestic plants. Self-interest helped drive the agreement because the industry will not only get speedier approvals of new products as part of the deal but also may avoid scandals involving tainted medicines, which tend to hurt confidence in the entire industry.

 

Dr. Margaret Hamburg, commissioner of the F.D.A., said she was pleased with the generic drug fee proposals. “If a program along the lines of what the parties are working on is enacted by Congress, it would represent a real breakthrough,” Dr. Hamburg said. “FDA’s entire generic drug program would be placed on a much more stable footing.”

 

The agreement will not affect the making of over-the-counter medicines or vitamins, whose global supply chains are even more vulnerable to tampering since government inspectors almost never visit their makers. Aspirin and vitamin C supplements, among others, are now made almost entirely in uninspected plants in China. Nor will the agreement change the FDA’s oversight of name-brand prescription medicines. Although branded drugs usually have more secure supply chains than those of generics, major pharmaceutical companies have moved aggressively into China in recent years and often rely on rarely inspected suppliers.

 

Federal officials for years have expressed concerns about the nation’s growing reliance on sometimes mysterious foreign drug suppliers, but they had largely despaired of fixing the problem. Congress has never given the FDA the money needed to inspect these plants, and for nearly two decades the generic drug industry resisted proposals to pay inspection fees. The industry changed its stance for several reasons. First, the heparin scandal scared everyone. The fake ingredient was good enough to pass a sophisticated test, so the conspirators probably knew that deaths would result, reflecting a callous level of greed. And the Chinese government refused to allow the FDA to investigate, suggesting that the perpetrators were not only smart but politically well connected. Second, the generic drug industry is no longer a motley collection of struggling mom-and-pop companies. Years of consolidation have created giants like Israel-based Teva Pharmaceuticals that understand that their businesses depend on winning the confidence of patients and regulators alike, and they can afford to pay the fees needed to achieve that confidence.