As the science of genetics advances, the task of informing patients has grown both more complicated and more essential. Good communication must reflect the science of the genetic situation and the attitudes and beliefs of patients and their families, says Roxanne Parrott, professor of communication arts and sciences, and health policy, at Penn State.

Photo: futurowoman

This child may one day choose to know the genetic risks passed down from her parents.

In starting a new study, Parrott used a survey to elicit attitudes and beliefs from family members and patients with three genetic conditions: Down syndrome, Marfan syndrome and neurofibromatosis. The results, she says, confirm the idea that communication must reflect the audience: “There is not a one-size-fits-all notion of how to communicate about genetic conditions, but there are enough patterns that we don’t have to adapt to each individual or family member.”

Although some genetic mutations always cause disease, more raise the risk without spelling doom — and that’s often a hard concept to get across, she adds. “There is so much media attention to genetic determinism,” so those who would communicate with patients must realize that many people assume that having a gene means getting a disease, when in fact more disease genes raise the odds of getting that disease, but are also affected by environmental and behavioral factors.

Talking genes blues

Communications researchers “have focused on the threat, and on trying to motivate people to take action,” says Parrott, “and this is correct, as long as we package the message in ways that can help them change their behavior and reduce the threat.”

A fearsome genetic test

Huntington’s disease, a hereditary neurological disorder, was one of the first diseases linked to a single gene. Huntington’s progressively attacks motor, mental and emotional abilities.

Photo: Library of Congress Prints and Photographs Division, Digital ID: cph 3c30859

American folk singer Woody Guthrie died from Huntington’s disease in 1967. His son Arlo Guthrie chose to be tested for HD and found that he does not carry the mutation.

HD is caused by a dominant mutation in the Huntington gene, so any child of a parent with HD has a 50 percent risk of inheriting the disease. Huntington’s is the archetype of genetic determinism: if you have the mutation, HD is inevitable.

Once the genetic test became available, a child of a parent with HD could be tested for the mutated gene. This is a difficult decision: Would you rather live in uncertainty, or get tested and possibly learn you will develop a fatal, incurable disease?

Messages about the genetic contribution to heart disease, cancer and diabetes should reflect the needs of patients with disparate beliefs, says Parrott. She and co-author Kathryn Peters, a genetic counselor, found that each group was about equally common among family members and diagnosed patients. “When we think about communication, these four frameworks represent quite different things to listen for, ideas to probe for, and a different approach to communication.”

In an online survey of 541 patients and family members, Parrott and Peters found that some beliefs were misconceptions while others were accurate, and that despite the media emphasis on single mutations as causing disease, not everybody thought “that genes alone determine health.”

Genes are relative

One interesting result came from the “integrated relativists,” who talked about how behavior, religious faith and social support “could come together to predict health,” Parrott says. That is a rather sophisticated attitude concerning genomic information, she adds.

Unfortunately, “The integrated folks were the most uncertain about their future, and how things would work out with their diagnoses,” says Parrott. “That’s probably a good indication of having almost too much information, conflicting information. Their integrated perspective puts them in a situation where they … believe that a lot of things contribute to their health, and they don’t know what to do about it.”

Learning what’s inside your genes can have a psychological impact, Parrott adds. “How do you know who to tell? How could this affect your personal relationships? When do you start having these conversations? Does your identity become a package of genes?”

Poke deep inside an insect cell, and you may be in for a shock. At least we were startled to learn that bacteria live inside many insects, including the fruit fly, one of the workhorses of biology.

Photo: Biodiversity Institute of Ontario

The star of the study, Drosophila mauritiana.

Today, we hear how bacteria of the genus Wolbachia boost egg production in certain fruit flies. The mechanism, says Horacio Frydman, an assistant professor of biology at Boston University, involves a two-step: first the fly makes more egg cells, and then it blocks a process that would normally prune away extra eggs.

Insects, like other animals, are frequently “married” to bacteria in a relationship that benefits one or both parties. This is common: Bacteria in the cow’s rumen break down cellulose eaten by the cow. Bacteria in the human gut form vitamin K, necessary for blood clotting.

And bacteria in aphids synthesize essential amino acids that the aphids cannot make by themselves.
Wolbachia are not essential to the fruit flies, but their presence can quadruple egg production.

Speeding breeding

Producing four times as many offspring “is a powerful driver of infection,” Frydman says. “Wolbachia manipulate their host reproduction to favor their own spread in nature,” noting that in less than 20 years after Wolbachia was detected in fruit flies in southern California, the infection had spread as far as Canada. “It’s considered one of the largest pandemics in the recent evolution of life. Because Wolbachia influence their host reproduction, they also impact the evolutionary history of innumerable hosts.”

Wolbachia have been linked with a wide variety of effects in the insect realm. Wolbachia “lives in at least 20 percent of the world’s arthropods, including insects, spiders, mites, and crustaceans,” according to the Wolbachia project, making them an active area of investigation.

How could this symbiosis work to increase the number of offspring?

Using sophisticated microscopy, Frydman, Ph.D. student Eva Fast and colleagues tracked the location of Wolbachia in fruit flies. In D. mauritiana, a species native to the Mauritius Islands in the Indian Ocean, the bacteria congregate in the germline stem cell niche — a structure that supports stem cells that develop into eggs. In D. melanogaster, the bacteria accumulate in the niche that harbors a different type of stem cell, which produces the eggshell.

In the germline stem cell niche, the bacteria actually outnumber mitochondria, organelles involved in making energy for the fly.

Having the bacteria in the germline stem cell niche doubled the rate of division among those stem cells. Further investigation showed that the bacteria later also halved the rate of programmed cell death.
So the bottom line was a four-fold increase in egg production.

The virtue of pruning

“It’s remarkable that there are two mechanisms being manipulated by the bacteria, the rate of egg production and the rate of programmed cell death,” says Frydman.

Hitting both systems makes sense, Frydman adds, although the mechanisms remain unclear. “It is not surprising that Wolbachia would evolve to manipulate those two process, because they are key in controlling the rate of egg production, and therefore it has a profound impact in the reproductive success of the infected host and in spreading of bacteria in nature.”

Anything that increases the number of eggs and offspring is likely to be favored by natural selection, Frydman adds.

Photo: CDC, #373

Parasitic worms cause elephantiasis, which afflicts this man from the Philippines. Could killing Wolbachia prevent this disfiguring disease?

A healthy thing?

Beyond an insight into the fascinating biology of symbiosis, the finding could also have health implications. Parasitic worms that cause diseases like elephantiasis seem to benefit from Wolbachia infection.

And Wolbachia can affect insect immunity: Tests have shown that infected fruit flies are more resistant to some viruses, for example. And a recent paper in Nature found that mosquitoes in Australia could not transmit dengue fever if they carried a Wolbachia strain derived from Drosophila.

Mosquitoes also transmit malaria. Conceivably, better knowledge of the interaction between Wolbachia and insects might convert mosquitoes from a carrier of this ancient scourge into a defense against it.

– David J. Tenenbaum

With little notice until recently, a shortage of medicine is starting to impair treatment at America’s hospitals. Common, cheap and necessary drugs needed to fight bacteria or cancer, to ease pain or to nourish premature infants are running out.

Many of these meds are injectables, which must be made under sterile conditions. All are generics, which sell for pennies compared to the buck-buster drugs that feed the bottom lines at the big-name drug companies.

Most shortages are unnanounced until a wholesaler’s shipment arrives lacking an ordered drug. “It’s unbelievable,” says Sara Shull, manager of the drug policy program at the University of Wisconsin Hospitals and Clinics in Madison. “Today I was trying figure out alternatives to papaverin,” an old drug used to prevent spasm in the many surgeries that involve grafting a blood vessel. “We have identified some alternatives, and I am now I working with the surgeon to figure out how to dose them, how to apply them. Is it bathed on? Sprayed on? He’s busy, we’re all busy, and sorting this all out takes a lot of time. The continual need to find replacements gives me a headache.”

Shortage-induced substitution played a role in Alabama, where nine hospital patients were killed by intravenous nutrients this summer, says Allen Vaida, executive vice president of the Institute for Safe Medication Practices, a non-profit that targets medicine hazards. “Because of a shortage, this compounding pharmacy was making a product from raw material, and it got a bacterial contamination.” (The maker of the nutrient solution, Meds IV pharmacy in Birmingham, Ala., is apparently out of business.)

Medications on this rack will restock a robot that fills individual patient envelopes that will be sent tomorrow to nurses’ stations in the hospital. Actually, the robot restocks itself in its 24/7 delivery of thousands of prescription drugs.

Photo: The Why Files

ENLARGE

Source: U.S. House of Representatives

Shortages are growing, especially for injectable medicines.

Running long on shortages

Pharmacists have always had to find substitute medicines, as patients keep coming through the door, but Vaida cites Food and Drug Administration numbers to argue that shortages are now at “crisis” proportions. “The FDA shows 70 shortages in 2006, 129 in 2007 and last year, there were 211. So far this year, we are already above 200 shortages, and the year isn’t done. Shortages have been around forever, but they have never reached this number.”

Some drugs can be substituted, says Vaida, but “especially with chemotherapy and nutritional products, it’s not like are three alternatives for some medications, as there are with blood-pressure drugs. Some chemotherapies are specific for certain cancers, and if they are not available, you may have no alternative or [you] may have to use a third-line alternative.”

The pharmaceutical situation has never been more complicated, with more than 45,000 prescription drug products on the market, from about 1,400 manufacturers. Although we could not easily find numbers, drug shortages are also rising in the United Kingdom, where the supply situation is complicated by the restriction on exports within the European Union.

Shortages have many possible causes, but because manufacturers tend to be closed-mouthed, it’s not clear which problems are most momentous or easiest to solve:

How short is short?

A drug is considered “short” if a specific dosage and formulation is unavailable, and in some cases, a similar item can be substituted. But Shull says that’s still a problem in a big hospital. If a product that is normally purchased in a pre-loaded syringe is only available in a vial, University of Wisconsin Hospitals and Clinics can no longer send a “unit of dose” to the nurse, and “that’s what the nurses are expecting,” Shull says.

Changing procedures complicate care and raise costs, Shull adds. “All our people are working in a complex system, with lives on the line. These shortages can be a recipe for increased errors.” Her hospital must dedicate one staffer to securing supplies of the common blood-thinner heparin, she says. Searching for alternate sources is less rewarding than studying the efficacy of various medication treatments, she adds. “It’s not what I was taught in pharmacy school, but when your back is up against the wall, you have no other options.”

Beyond impairing patient care, shortages have also become a major burden in medical research. Tests of new medicines, often set up to run at several hospitals nationwide, must give standardized meds to the treatment and control groups, and chaos can result when the drugs become unavailable. “These shortages are now affecting clinical trial options for patients with cancer,” Robert DiPaola, director of the Cancer Institute of New Jersey, told the House Energy and Commerce Subcommittee on Health on Sept. 23. “Due to the uncertainty of being able to obtain many of these drugs, enrollment of patients on clinical trials has been delayed or stopped in several of our trials.”

Howard Koh, assistant secretary of health and human services, reinforced that message to the committee: “Many of the cancer drugs in short supply … are mainstays of the anti-cancer arsenal, and were largely developed through federally funded research begun 20, 30, even 40 years ago. They are still essential to treatment and research,” he said. The National Cancer Institute is currently sponsoring 349 clinical trials that require these drugs, Koh added. “Taken together, these studies represent thousands of patients, as well as a significant federal investment in clinical trials research.”

At the same hearing, Mike Alkire, chief operating officer of Premier healthcare alliance, told Congress how widespread the shortages have become. In a recent Premier survey, 53 percent of hospital pharmacists said they had faced at least six shortages “that had the potential to cause a medication safety issue or an error in patient care.” And 34 percent of respondents said at least six shortages had “resulted in a delay or cancellation of a patient-care intervention.”

Premier estimates that the 2,500-plus non-profit U.S. hospitals in its membership pay an extra $66 million per year due to these shortages — which translates to $415 million at all U.S. hospitals.

Market going gray?

When the usual sources run dry, hospital pharmacists often get emails, faxes and phone calls from the “gray market,” sources outside the usual supply chain. In the summer of 2011, the Institute for Safe Medication Practices surveyed 549 hospitals and found that:

Alkire, of the Premier alliance, told Congress that the gray market is “appalling,” with an average markup of 650 percent. Forty-five percent of the offers were marked up at least 1,000 percent above normal price, and drugs for leukemia and non-Hodgkin’s lymphoma were marked up 4,000 percent. “We saw similar markups for medicines for sedation during surgeries; to dilate veins and prevent brain or heart spasms; and to prevent damage during a heart attack,” Alkire said.

For these reasons, University Hospital at UW-Madison does not buy gray, says Shull, although it does buy from a wholesaler that seems to have supplies of drugs when nobody else does.

The gray market arouses suspicion: How do some firms know about shortages before anybody else? How do they obtain drugs when normal sources are short?

“There is speculation going on,” says Vaida. “Some secondary wholesalers may try to buy up some available drugs and sell them for higher prices. Often times, they are looking for people who need the product, and try to obtain it from whatever sources. Some are playing it almost like Wall Street, anticipating what may go on shortage — if two manufacturers have just consolidated, and there’s a generic product that is only going to be made by one of them.”

Cures for missing meds

Many measures have been proposed to ease the medication shortage:

Photo: Armin Kübelbeck

Generic, injectable drugs comprise the majority of shortages.

The FDA seems to be getting the message. In testimony to the subcommittee on Sept. 23, Koh claimed that the agency had already headed off 99 looming shortages in 2011, compared to 38 for all of 2010. But Koh added that today’s shortages “include standard therapies for the treatment of lung, breast, ovarian, testicular and colorectal cancers, as well as several types of lymphomas and leukemias.”

Sometimes, Koh said, common-sense, proven measures can sidestep shortages. “… the FDA was able to mitigate a shortage by allowing the use of a filter to safely remove foreign particles contained within vials of injectable drugs, averting the obvious risk to patients of having metal shavings or other particulate matter injected into their veins.”

A pessimist, of course, could say the higher number of averted shortages simply reflects the greater number of shortages overall.

At any rate, organizations concerned with shortages say they are in a vise. “From our members’ perspective, it’s become [a] crisis,” says Hill. “We are seeing shortages nationwide. We have been tracking this for about 10 years, but in the last few years, we’ve seen a spike in the numbers.”

Given the problem’s multiple and sometimes obscure, roots, Hill sees “no single solution, and that’s the troublesome part. Unfortunately we will be dealing with this for a while. But there are some things we can do. We’d like to establish a mandatory early-warning system, so a manufacturer that has a problem has to notify the FDA. The FDA says it has avoided 99 shortages in the past year when it had that information. When there are multiple sources, the FDA can reach out to other manufacturers and urge them to ramp up production.”

David J. Tenenbaum

Each year, as influenza season approaches, medical authorities must scramble to predict which strains of flu will be most important, and then grow enough vaccine to inoculate the population. Why does this take so much time, and what are some alternative strategies that might speed the process?

Photo: National Archives

During the 1918 flu pandemic, New York City residents took all the precautions they could against the deadly virus that ultimately killed over 50 million people globally, or roughly 3 percent of the world’s population.

Find the article:

Discussion Questions

1. Discuss: How does the influenza virus benefit from having so many strains?
2. What are the key steps in the process for identifying a seasonal strain of flu and then making a vaccine for it?
3. How have scientists proposed speeding up the process?
4. What is the meaning of the “H” and “N” in the virus designations, and how do they help explain the activity of a virus?
5. How is a virus different from a bacterium?
6. Why is influenza so deadly in some years, and not others?

Lesson Plans/Activities

1. Bird flu, swine flu, ferret flu? The flu can be spread between all sorts of creatures. Explore the NCBI Influenza database to find out what kinds of animals have been the source of flu outbreaks. What factors cause diseases to spread from animals to humans?
2. Facebook status: Outbreak! Follow this lesson plan that teaches about epidemiology and contagious diseases using social media.
3. The flu through time. Have students research previous flu pandemics such as the deadly 1918 “Spanish flu” pandemic. Have students identify the similarities and differences between these pandemics, including the specific strains of influenza and the symptoms they produced. Aside from vaccines, how can people help prevent the spread of flu?

You see them, and you sniff. Apples are as boring, as generic as a fruit can get. They lack the cachet of red grapes, oozing life-extending resveratrol. Unlike blueberries or pomegranates, they are not celebrated for supplying palate-pleasing megadoses of antioxidants.

So why did some wit observe, “An apple a day keeps the doctor away”? That question has been on the mind of Bahram Arjmandi, professor and chair of the department of nutrition, food and exercise sciences at Florida State University.

His answer, presented at the Experimental Biology 2011 meeting in Washington this week, admittedly seems too good to be true: Apples have a profound effect on total cholesterol, and also on the “good” and “bad” types of cholesterol. They caused a major reduction in inflammatory proteins that are implicated in a number of serious diseases.

Not only does this “medicine” taste good, but unlike cholesterol-control pills, it does not attack the liver. And last we heard, you can buy them without a prescription.

“An apple a day” or a “fateful fruit”?

In the Bible, “the apple was an evil food in the story of Adam and Eve,” Arjmandi says, “then someone said, ‘An apple a day…’ and that gave them a positive image. I thought, if there is that saying, there might be a reason for it, but you’d be amazed at how little has been done in clinical studies.”

Animals were apparently eating apples long before Adam and Eve. Photo: LASZLO ILYES

To get answers, Arjmandi rounded up 100 women who had just passed menopause — a time when dropping levels of estrogen lead to unhealthy changes in cholesterol levels that allow women to catch up with the male rate of cardiovascular disease.

Randomly dividing his volunteers, Arjmandi asked one group to supplement their normal diet with dried prunes. The treatment group got one-a-day packages containing 75 grams — about 2.5 ounces — of dried apple.

Arjmandi used dry apples rather than the equivalent one or two fresh apples as a way to standardize the “dose,” but he says fresh fruit is likely to be even more healthy.

If the object of these tests was a pill, the results after one year would certainly boost the stock of the drugmaker: among the apple-eaters, total cholesterol fell by 14 percent and low-density lipoprotein (LDL, the harmful fraction of cholesterol) fell 23 percent. High levels of both total cholesterol and LDL are linked to damage to blood vessels, heart attacks and strokes.

Meanwhile, the level of a protective type of cholesterol called high-density lipoprotein (HDL) rose 3 to 4 percent.

(Anti-) inflammatory results

Moving beyond cholesterol, the level of C-reactive protein fell 32 percent. “This is significant, and not just in a statistical sense but in clinical relevance,” says Arjmandi. “CRP is associated with inflammation, and is considered a marker for cardiovascular disease, cancer and Alzheimer’s disease.”

Does 'an apple a day...' translate into Japanese? Photo: Luca Moglia

Seeing such a major reduction from such a simple “treatment” is “amazing,” Arjmandi said.

And although the women in the test group were eating about 240 calories of dry apple each day, they lost an average of about three pounds over the year — perhaps because apple makes people feel full.

The study was partly funded by the United States Department of Agriculture, and got no funding from the apple industry. Although the report, as far as we know, has not been peer reviewed, talks at scientific meetings are routinely used to introduce new studies and new concepts.

And the active ingredient is…

What makes apples so healthy? Although both pectin, a soluble fiber, and chemicals called polyphenols are thought to confer health benefits, Arjmandi says, “an apple is more than these compounds. I’ve been working on functional foods [which give health benefits] for 20 years, and I find it’s not good to approach whole fruit or whole vegetables like drugs. If you isolate the component chemicals and take them, you get some benefits, but you will deprive yourself of greater benefits.”

Are some apples better than others? “For pectin, the firmer the better,” says Arjmandi. “Otherwise, most varieties, from jonathan to red delicious, give more or less the same benefit.”

Polyphenols are concentrated in the peel; pectin is found throughout the apple, he adds.

Last question: Did the study participants get sick of snacking on dry apple day after day? Some did, and quit the study, but “those who like them became addicted,” says Arjmandi. “The longer they were on it, the more they liked apple. Afterwards, some contacted us to ask if we can provide them with apple.”

Supermarkets, actually, carry apples side-by-side with other non-prescription produce.

Based on these results, Arjmandi would like to test the apple-a-day prescription more broadly. “I’d like to do a multi-state trial. Eating 75 grams of apple is not that difficult, and finding people with moderately high cholesterol is not that difficult.”

– David J. Tenenbaum

Step on a jetliner. Sit in a doctor’s waiting room. Take your kid to day care. If it’s flu season, we’re wagering you’re wondering: Am I inhaling enough influenza virus to get sick?

“Yes, if you stick around for an hour.” That’s our bare-bones summary of a new measurement of airborne influenza A virus in these three locations. The study calculated how long virus particles would remain aloft and therefore be subject to inhalation.

Influenza A is the most common and dangerous genus of influenza virus.

Bigger particles can carry more virus, but they also settle far faster than tiny ones.

Among the half of the samples that contained influenza A, the average cubic meter of air contained 16,000 influenza A particles. Since we breathe roughly one liter per inspiration, this means that when influenza is present, one would inhale 16 pieces of flu virus with each breath.

Breathing that air for an hour would be enough to make half of us sick, says Linsey Marr, an associate professor of civil and environmental engineering at Virginia Tech, the study’s corresponding author.

The study sorted the flu-carrying aerosol particles by size, Marr says, which “allows us to say how long the virus particles will stay suspended in the air. We found virus in aerosols small enough to remain suspended for hours.”

About 64 percent of the virus particles were held in aerosols no more than 2.5 millionths of a meter across.

Because few previous studies of influenza A measured the size of the aerosols that carried them, Marr says, “We did not know if they were held in very large droplets that would fall out in a few seconds or minutes,” and thus be less likely to transmit disease.

Understanding the movement of influenza became critical in the late 1990s, when deadly avian influenza arose in Southeast Asia, and again after the 2009 “swine flu” epidemic.

Photo: June 2009, Roger Schultz

Passengers flying from Washington to Buenos Aires during the swine flu epidemic hoped masks could intercept the virus.

Virus: Just another pollutant?

Marr, an air-pollution engineer who says she became interested in viral transmission after her three-year-old came home sick from day care “about every two weeks,” says hunks of influenza A virus are about one-tenth of a micron across, and thus difficult to identify.

Using a version of polymerase chain reaction that detects viral RNA, Marr and her collaborators, including Elankumaran Subbiah, an assistant professor of virology at the Virginia-Maryland Regional College of Veterinary Medicine, examined air samples during flu season.

Half of the samples were influenza free, a strong indication that nobody in the area had the flu. But when influenza A was present, the researchers calculated that the air would contain enough to infect 50 percent of the people after one hour, Marr says.

Such an estimate is necessarily rough, as many factors can affect the health consequences of any exposure to the virus:

“We detected total virus RNA, but that does not tell us whether the particles are infectious,” says Marr, since they could have been inactivated due to ultraviolet light or another cause. Previous studies, many of them decades old, suggest that influenza A can remain infective for two to three hours, but those estimates vary widely, Marr says.

Furthermore, although in general smaller particles can go deeper, and cause more disease, the body is also “pretty good at removing virus in the nasal tract,” she points out.

Making sense

“The research is an important step in better understanding the nature of influenza transmission,” says Jonathan Temte, a professor of family medicine at University of Wisconsin-Madison, and a specialist on immunization. “Influenza continues to be a very significant respiratory pathogen which can spread significantly and almost without abatement, especially when there is little immunity such as we saw during the pandemic of influenza A(H1N1) last year.”

However, Temte says, “This study is limited” because it relied on only 16 air samples, and was performed “when there was almost no transmission of influenza in North America. Hence, the researchers were able to detect influenza at a time when very few individuals were getting sick. From a clinician’s viewpoint, it is necessary to show that viable influenza viruses can be carried in an airborne form and that transmission can occur in this mode and this occurs at a high enough rate to be of significance.” Although the study is an interesting application of technology, “Making the translation from technology to real patient care in the next and necessary step,” Temte says.

Now that the study has confirmed with measurement what we’ve long known — that flu virus can float in the air — we wondered whether we are more likely to catch flu by breathing or by touching our schnozz after shaking hands with an infected person. The answer is not yet clear, says Marr, “but we have showed that the airborne aerosol route is possible.”

Will this intensify fear of flying? Perhaps. “This fear has always been there — if someone is sick, it’s possible that virus is floating around,” says Marr. Face masks could help contain influenza, “But without a proper fit, you short-circuit the mask, and it doesn’t do much good. What would be even better is if infected people wore masks….”

– David J. Tenenbaum

In Haiti, the body blows just keep coming. About 200,000 died in the January earthquake. Then the recovery was hampered by poverty, an ineffective and corrupt government, and a long tradition of class antagonism and social chaos.

And now Haiti is stricken by a cholera epidemic that has already killed about 1,300.

Cholera is a fast-moving bacterial disease that causes intense diarrhea and can kill within hours. Despite efforts to contain it, Haiti’s epidemic is spreading from its epicenter north of Port au Prince, the capital, and has reached the vast tent cities that still house earthquake survivors.

In cholera, the Vibrio cholerae bacterium multiplies in the intestines, forcing the patient to release vast quantities of highly infectious watery stool. Lacking proper disposal and treatment, the diarrhea can pollute drinking water and start new infections.
Cholera is vanishingly scarce in the developed world, and cholera thrives on poverty, disorganization and under-development.

Photo: PAHO

Drinking water contaminated with the cholera bacterium is the major cause of new infections. The Artibonite river, a source of drinking water for many Haitians, is suspected to be transmitting the cholera epidemic.

Haiti, where cholera had not been seen for a century, has been rocked by controversy about the source of the bacterium. Some angry Haitians blame United Nations peacekeeping troops for bringing it from Nepal, but at this point, treating patients and providing clean drinking water seems more pressing than doing genetic forensics to track the disease to its origin.

From the viewpoint of V. cholerae, chaotic, post-earthquake Haiti may be paradise, but outbreaks have also occurred in Latin America, Africa and India in recent years. The World Health Organization estimates that cholera annually infects three to five million people and kills 100,000 to 120,000.

Prompt treatment with electrolytes dissolved in clean water can prevent death in 99 percent of cases.

A violent announcement

Cholera announces itself with a sudden, violent outbreak of diarrhea – a “rice-water stool” named for its semblance of water used to cook rice. Diarrhea — and sometimes vomiting — can cause massive water loss and electrolyte imbalance. Muscles cramp and eyes recede into the skull.

Falling blood pressure and oxygen starvation cause a state of shock that can kill within minutes. A graphic description of cholera is mortifying: “A mid-nineteenth-century English newspaper report described cholera victims who were ‘one minute warm, palpitating, human organisms-the next a sort of galvanized corpse, with icy breath, stopped pulse, and blood congealed-blue, shriveled up, convulsed.’”

Saint Nicolas Hospital, St. Marc, Haiti; PAHO

Haiti’s hospitals, like this one north of Port au Prince, are being tested by the cholera outbreak, but most patients can be treated at an early stage with oral rehydration salts.

An incubation period as short as two hours is one reason for cholera’s dreadful reputation, but its efficient spread through contaminated water is another. As Haiti demonstrates, the conditions of poverty, filth and social chaos that help spread cholera also hinder prevention and treatment efforts.

At present, health organizations in Haiti are focusing on sanitation, clean water, hand washing, and other tactics to interrupt the chain of infection. Treatment is taking place in dedicated wards.

To restore the body’s electrolyte balance, patients with moderate to severe diarrhea need treatment with an oral rehydration mixture — essentially a medical-grade sports drink containing sodium and glucose dissolved in clean water. Treatment is simple and many patients need no hospitalization if treated promptly.

In severe cases, antibiotics are used to kill V. cholerae, although the main benefit is often a faster return to health and a reduction in the load of bacteria released in the feces.

Photo: PAHO

A patient in Saint Nicolas Hospital, St. Marc, Haiti, during the cholera outbreak. That hole in the bed accommodates the violent diarrhea that is cholera’s trademark.

Very versatile vermin

The cholera bacterium, like any self-respecting microbe, has evolved genetic tricks for optimizing its survival in changing circumstances. Once it passes through the human mouth, V. cholerae:

Photo: Dartmouth Electron Microscope Facility

The cholera culprit Vibrio cholerae infects its host quickly and spreads easily via diarrhea.

Cholera’s big gifts

Like an execution in the morning, fast-spreading cholera has served to concentrate the medical mind. Cholera was first seen for sure in 1817 in India; the disease then traveled with people and their commerce around the world and eventually gave humanity two durable gifts.

The first gift came when a mid-19th-century outbreak of cholera in London spawned the science of epidemiology — the study of epidemics. The story is often told of how, in 1854, physician John Snow marked where cholera cases lived, and realized that they all had gotten water from the same pump.

Even though the germ theory of disease was yet nascent, authorities removed the handle from the pump and the epidemic subsided. Although that removal is credited with ending the epidemic, it may have already been waning.

Images: Map; Snow: UCLA Department of Epidemiology

This map, drawn by Dr. John Snow (1813-1858), correlated London cholera cases (each marked by a dash) with drinking water from the Broad St. pump. Mouseover image for a photo of Snow, the founder of epidemiology.

Photo: Madison Metropolitan Sewerage District

Sewage treatment is essential for dozens of reasons, but many countries cannot afford expensive treatment systems.

Snow’s achievement is especially awesome considering that the bacteria that causes cholera would not be identified until 1883, by the great German microbiologist Robert Koch.
By correlating a disease with foul water, Snow showed that epidemics could be understood by analyzing the timing and location of the illnesses — two rudiments of epidemiology. And that led to a second gift: As epidemiologists realized that drinking feces was dangerous, not just disgusting, the health-giving revolution of sanitation got under way.

Virtuous vaccines?

Antibiotics kill cholera bacteria. But carpet-bombing with antibiotics (“mass chemoprophylaxis” in medico-lingo) is inadvisable because it stimulates bacteria to resist the drugs.

Vaccines must be given before an epidemic gets under way, and thus are most suitable in regions where cholera is endemic, like South Asia. But oral cholera vaccines are showing progress:

Breaking the chain

Infections are contained by interrupting the chain of infection; and no fundamental scientific or social hurdles prevent this from being done with cholera. Unlike HIV, cholera is not spread by sexual contact. Unlike tuberculosis or influenza, it is not spread by coughing.
Instead, cholera prevention requires attention to boring, even repulsive, topics like safe drinking water and sewage treatment. Granted, the technology can be expensive, but water and sanitation are also the primary defense against microbes, viruses and parasites that cause dozens of other waterborne diseases.

The United Nations’s Millennium Development Goals aim to raise the proportion of people getting clean water and adequate sanitation, but Unicef says progress is mixed: “Two and half billion people are still without access to improved sanitation – including 1.2 billion who have no facilities at all and are forced to engage in the hazardous and demeaning practice of open defecation. The news is better for water: the number of people without an improved source has dropped below one billion for the first time in history.”

Map: Unicef

Improved sanitation parallels national wealth. In Latin America and the Caribbean, 117 million people live without adequate sanitation.

In 2010, 884 million people have no access to “improved” drinking water, including 330 million in Sub-Saharan Africa, 222 million in Southern Asia and 151 million in Eastern Asia.
India and China account for the lion’s share of progress in both water and sanitation. Globally, city folks usually score higher in these basic barometers of human development.
So do rich people.

In terms of public health, clean water, clean air and sanitation are the big three environmental goals. By themselves, diarrhea diseases cause 4 percent of all time lost to illness, when measured by disability-adjusted life years.
The cholera question is scientifically straightforward, and is quickly solved when resources and social organization are available. Yet even if the victims of cholera are poor and powerless, the benefits of clean water and sanitation are so manifold that it’s hard to accept that these basic requisites for health are not for everybody.

But as the population soars, as people continue flooding into shantytowns around megacities, and as income inequality remains a fact of life, we anticipate this is not the last article you’ll read about such an avoidable epidemic.

Semi-starve a rat, monkey or yeast, and it’s likely to outlive its free-feeding friends. It’s weird but true: caloric restriction produces longer, healthier lives, although people who restrict their calories do report feeling cold, listless and a certain obsession with food.

But here’s the billion-dollar question: Why does cutting calories by roughly 30 percent produce such benefits if the rest of the diet is sufficient? The best answer is that the lo-cal regime reduces free radicals — molecules and fragments that damage genes, fats and proteins.

A better understanding of this radical-reduction mechanism could support drug discovery. Not to over-dramatize, but the Holy Grail of this research is to find a shortcut to the many benefits of caloric restriction while avoiding that void in the pit of the stomach.

In a study published today in the journal Cell, scientists firmly identified the gene Sirt-3 as essential to some of the benefits of caloric restriction. Sirt-3 is among a group of genes that were already associated with anti-oxidant mechanisms.

Proof in the pudding

“This study is the first direct proof for a mechanism underlying the anti-aging effects we observe under caloric restriction,” says Tomas A. Prolla, a professor of genetics at the University of Wisconsin-Madison, and a senior author of the new study. “We’re getting closer and closer to a good understanding of how caloric restriction works.”

Aging is as hard on mice as it is on people. Both these mice are the same age, but the one in front was genetically engineered to age rapidly for a study led by Tomas Prolla. Photo: Jeff Miller/University of Wisconsin-Madison

The study focuses on mechanisms that control free radicals produced by mitochondria, units in cells that process chemicals so cells can move and perform chemical reactions. Because mitochondria also produce free radicals, the very mechanism that keeps us going in the short run also spells doom in the long run.

But cells have also evolved anti-oxidant mechanisms to defang free radicals, and caloric restriction may be the best way to trigger those defenses.

Bring on the mice

The Cell study focused on age-related hearing loss, a common problem caused by cellular suicide among sensory cells in the inner ear. The scientists compared a control group, which reliably has this loss, to another that lacked the Sirt-3 gene.

Starting at age two months, the mice either stayed on the normal lab diet, or got a 25 percent reduction in calories. At two and 12 months, the mice got hearing tests. As expected, at 12 months, the normal-diet mice, but not the caloric restriction mice, had lost some hearing.

But check this out: the hungry mice without the Sirt-3 gene got absolutely no benefit from the low-cal diet.

The finding was clear, says John Denu, of UW-Madison’s Wisconsin Institute for Discovery. “Caloric restriction no longer prevents age-dependent hearing loss in mice that do not have Sirt-3, and there is thus a clear link between this protein and prevention of age-dependent hearing loss.”

And because hearing loss is considered a legit indicator of the anti-oxidant power of caloric restriction, the study shows that Sirt-3 plays an essential role in the only proven way to retard aging.

Links in the chain

Looking further, the researchers, who included Wei Yu in Denu’s lab and Shinichi Someya in Prolla’s research group, found that Sirt-3 activates an enzyme inside the mitochondria that also participates in a chain reaction that makes the crucial anti-oxidant glutathione, which destroys free radicals.

Even the yeast that fermented this beer live longer if raised under caloric restriction. Photo: cyclonebill

Caloric restriction has many effects, and many genes and proteins are likely to be involved, but Sirt-3 is the first gene proven essential to preserving age-related hearing loss, says Denu, a professor of biomolecular chemistry. “In the mouse, Sirt-3 is one part of the solution.”

Now that Sirt-3 is known to play an essential role, the search is on for a drug that can stimulate it. Finding a key link in caloric restriction is inherently interesting, but the new results may help capture the benefits of caloric restriction, such as better hearing and a longer lifespan, without the pit-of-the-stomach price.

A second approach would be to artificially induce the Sirt-3 stimulating mechanism that caloric restriction uses.

These questions become more pressing now that Sirt-3 is known to be crucial to some of the metabolic benefits of caloric restriction, Denu adds.

Which is just as well, considering that few people can successfully cut calories by 25 percent. “In American culture, it’s more palatable to take a pill than chronically starve yourself,” Denu observes.

We concur. And as the feasts of Thanksgiving approach, we can only say, “Amen. And pass the stuffing!”

Strokes — bleeding or blocked blood vessels in the brain — are a major cause of disability, and most neuroscientists say the brain has little or no ability to repair itself afterwards: Dead neurons do not spring to life. They are not replaced, and losing the ability to talk to each other is irrevocable.

Photo: University of Cincinnati

Relearning the activities of daily life can be a struggle after a stroke. The University of Cincinnati has tested a robotic brace to aid recovery. A drug that restores brain cells could reduce the need for this kind of retraining.

When a stroke cannot be prevented, damage is irreversible. Or so went the neuroscientific dogma.

But a mouse study being published today in Nature shows that suppressing a common brain chemical can boost neuronal repair after a stroke. The treatment focuses not on restoring neurons, but rather on restoring connections, so neurons located at the edge of the dead zone can talk to each other and go back to work.

Based on tests of walking ability, the mice regained 30 to 50 percent of their motor coordination. If this result can be repeated, it could represent a major step forward, as no drug is approved for helping restore communication between nerve cells after a stroke.

“Basically, we are upsetting a lot of dogma that says the brain does not repair itself or recover, that there is no formation of new connections,” says study leader S. Thomas Carmichael, a professor of neurology and stroke specialist at the University of California at Los Angeles. “My lab is one of those that has showed that this is not true, and that has opened interesting molecular and cellular questions about what happens to regenerate the brain.”

Begging for an explanation

The research was rooted in some facts that did not jibe with the “no repair” dogma, Carmichael says. “Most strokes get a little better, and some get quite a bit better, in the weeks after the stroke. So our question is what events lead to this repair and recovery in the brain, and why they are limited.”

Several processes could explain these small recoveries, Carmichael says:

Brain cells are under both positive and negative controls; some chemicals make them more excitable, and others dampen their excitation. The study reported today was designed to test whether blocking a major inhibitory chemical would help neurons return to work after a stroke.

Just as two negatives make a positive, blocking an inhibitory chemical can stimulate a nerve cell.

The study concerned GABA, the major inhibitory compound in the brain. GABA released at a synapse, where neurons connect with each other, causes other neurons to briefly be less excitable. In the 1990s, an “extra-synaptic” receptor for the same compound, GABA, was found elsewhere on the nerve cell. “This is a whole separate group of GABA receptors that are on the cell body,” says Carmichael. “They don’t respond to GABA released into the synapse, but to GABA that spills over.”

Because these receptors are built differently, they can be blocked without affecting the synaptic GABA, says Carmichael.

During the experiment, Carmichael and colleagues used chemical or genetic mechanisms to block extra-synaptic GABA, and found that the mice recovered 30 to 50 percent of their motor coordination in various tests.

Neurons in the area around the injury started conversing once again, but only if they had been treated with the GABA inhibitor.

Courtesy S. Thomas Carmichael, UCLA

After a stroke, mice received three treatments. “Foot faults” measured their coordination; mice that got the experimental drug L655,708 were more coordinated than untreated mice.

Red: Stroke alone.

Blue: Stroke + GABA-inhibiting compound

Green: GABA-inhibiting compound (no stroke)

A promising drug?

Many drugs cannot enter the brain, but Carmichael says the oddly-named L655,708 can do so. And since it’s in early-stage human trials, it has already satisfied preliminary safety standards. More important, no other drug treatment has been able to put intact, but “stunned,” neurons back to work following a stroke, Carmichael says.

In essence, the treatment seems to “change the set point of neurons,” Carmichael says, making them more excitable — without affecting the synapse. “Inhibiting or blocking all inhibition of synaptic signaling would put you to sleep or give you a seizure, and neither is desirable after a stroke. The nice thing about this receptor is that it is involved in a completely different situation.”

“The research is both important and relevant,” commented Matthew B. Jensen, an assistant professor in the Comprehensive Stroke Program at the University of Wisconsin-Madison. “Post-stroke disability is a major public health problem, and we need to better understand the limitations for recovery of the nervous system after injury to be able to design effective treatments.”

“The study matters because it suggests a new target for treatments to improve stroke recovery,” Jensen added, although it is not completely clear that the drug acted solely in the area near the stroke, or also elsewhere in the nervous system.

The 30 to 50 percent improvement is “dramatic, an impressive recovery,” says Carmichael. Treatment for strokes focuses on restoring blocked blood flow, but “If you look at stroke literature, there are no drugs that promote recovery” of lost function.

But this is only one study, as Carmichael admits. “We have done this in one lab, and somebody has to replicate these findings.”

Once that happens, it should be time to test the drugs in stroke patients. Although mice are not people, “At that point, we will have done all we can with a non-human model.”

– David J. Tenenbaum