Typhoid fever kills 10-30% of untreated people. It has been controlled by vaccination and use of antibiotics: however, antibiotic resistance is an emerging problem, especially in south-east Asia.Typhoid has claimed the lives of millions: among the more well known are Queen Victoria’s husband, Albert, English author Arnold Bennett, Wilbur Wright of the Wright brothers and Leland Stanford, for whom the US university is named.

One of the best-known cases is that of Mary Mallon, a healthy carrier of typhoid, who worked for many years in the food industry in New York and is thought to have infected almost 50 people. She was eventually forcibly quarantined by authorities.

For the first time, next-generation DNA sequencing technologies have been turned on typhoid fever - a disease that kills 600,000 people each year. The results will help to improve diagnosis, tracking of disease spread and could help to design new strategies for vaccination.

The study sets a new standard for analysing the evolution and spread of a disease-causing bacterium: it is the first study of multiple samples of any bacterial pathogen at this level of detail. It uncovers previously hidden genetic signatures of the evolution of individual lineages of Salmonella Typhi.

The team developed methods that are being used to type outbreaks, allowing researchers to identify individual organisms that are spreading in the population: using Google Earth, the outbreaks can be easily visualized. The team hope that these mapping data can be used to target vaccination campaigns more successfully with the aim of eradicating typhoid fever.

Unlike most related Salmonella species, and in contrast to many other bacteria, Typhi is found only in humans and the genomes of all isolates are superficially extremely similar, hampering attempts to track infections or to type more prevalent variants. The detail of the new study transforms the ability of researchers to tackle Typhi.

“Modern genomic methods can be used to develop answers to diseases that have plagued humans for many years,” explains Professor Gordon Dougan from the Wellcome Trust Sanger Institute and senior author on the study. “Genomes are a legacy of an organism’s existence, indicating the paths it has taken and the route it is on. This analysis suggests we may have found Typhi’s Achilles’ heel: in adapting to an exclusively human lifestyle, it has become complacent, its genome is undergoing genetic decay and it’s heading up an evolutionary dead end in humans.

“We believe that concerted vaccination programmes, combined with epidemiological studies aiming to track down and treat carriers, could be used to eradicate typhoid as a disease.”

There are 17 million cases of Typhoid fever each year - although the World Health Organization cautions that this is a ‘very conservative’ estimate. Young people are most at risk: in Indonesia, nine out of ten cases occur in 3-19-year-olds.

“A key to survival of Salmonella Typhi is its ability to lie dormant in carriers, who show no symptoms but remain able to infect others,” says Kathryn Holt, a PhD student at the Wellcome Trust Sanger Institute and first author on the study. “Our new tools will assist us in tracing the source of typhoid outbreaks, potentially even to infected carriers, allowing those individuals to be treated to prevent further spread of the disease.

“Using the genomic biology of this study, we can now type Typhi, identify the strain that is causing infection, identify carriers and direct vaccination programmes most efficiently. It is a remarkable step forward.”

The study is a collaboration between researchers at the Wellcome Trust Sanger Institute, University College, Cork, Institut Pasteur in Paris and Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam. The team studied 19 isolates of Typhi from ten countries, using new sequencing methods that meant they could capture the rare signals of genetic variation in this stubborn genome. They produced more than 1.7 billion letters of genetic sequence and found evidence of fewer than 2000 mutation events, suggesting very little evolution since the emergence of Typhi at least 15,000 years ago.

Their analysis shows that the Typhi genome is decaying - as it becomes more closely allied to us, its human host, it is losing genes that are superfluous to life in the human body. More importantly, genes that contain instructions for the proteins on the surface of the bacterium - those most often attacked by our immune system defences - vary much less than do the equivalent genes in most other bacteria, suggesting that Typhi has a strategy to circumvent the selective pressures of our immune system.

“Both the genome and the proteins that make up the surface of Typhi - the targets for vaccines - show amazingly little variation,” says Professor Julian Parkhill, Head of Pathogen Genomics. “We have been able to use novel technologies, developed for the analysis of human genome variation, to identify this variation: this would have been impossible a year ago. The technologies we have developed here could also be used in the battles against other disease-causing bacteria.”

Publication details
Holt KE et al. (2008) High-throughput sequencing provides insights into genome variation and evolution in Salmonella Typhi. Nature Genetics, available online in advance of print publication on Sunday 27 June 2008

Newly developed software will help to allay patients’ fears about who has access to their confidential data. Research published today in the open access journal BMC Medical Informatics and Decision Making describes a computer program capable of deleting details from medical records which may identify patients, while leaving important medical information intact.Patient records that are to be shared within the research community must have any identifying information removed. Manual removal of identifying information is prohibitively expensive and time consuming. Considerable research by many investigators has focussed on developing automated techniques for “de-identifying” medical records. A team from the Massachusetts Institute of Technology (MIT) funded by the National Institutes of Health (NIH) aimed to solve this problem, pointing out that: “Text-based patient medical records are a vital resource in research. The expense of manual de-identification, coupled with the fact that it is time-consuming and prone to error, necessitates automatic methods for large-scale de-identification.”

The MIT team tested their censoring software on a meticulously hand-annotated database of 1836 nursing notes (a total of 296,400 words). According to the authors, “The software successfully deleted more than 94% of the confidential information, while wrongly deleting only 0.2% of the useful content. This is significantly better than one expert working alone, at least as good as two trained medical professionals checking each other’s work and many, many times faster than either.”

The MIT team is also providing access to the fully-scrubbed annotated data together with the software to allow others to improve their systems, and to allow the software to be adapted to other data types that may exhibit different qualities.

Reference

Automated De-Identification of Free-Text Medical Records
Ishna Neamatullah, Margaret M Douglass, Li-wei H Lehman, Andrew Reisner, Mauricio Villarroel, William J Long, Peter Szolovits, George B Moody, Roger G Mark and Gari D Clifford

Researchers at the Burnham Institute for Medical Research, led by Josh Luis Millhn, Ph.D., have demonstrated in mice the first successful use of enzyme replacement therapy to prevent hypophosphatasia (HPP), a primary skeletal disease of genetic origin. This discovery lays the foundation for future clinical trials for HPP patients.

Rickets is a softening of the bones that most commonly results from a lack of vitamin D or calcium and from insufficient exposure to sunlight. Hypophosphatasia is a rare, heritable form of rickets caused by mutations in a gene called TNAP, which is essential for the process that causes minerals such as calcium and phosphorus to be deposited in developing bones and teeth. The physical presentations of this disorder can vary depending on the specific mutation, with more severe symptoms occurring at a younger age of onset. The most severe form of the disease occurs at birth, which can present with absence of bone mineralization in utero, resulting in stillbirth.

Using a mouse model, Josh Luis Millhn, Ph.D. tested the hypothesis that, when administered from birth, a bone-targeted form of the TNAP gene would ease the skeletal defects of HPP. The Millhn laboratory, in collaboration with scientists from Enobia Pharma in Montreal, Canada and from the Shriners Hospitals for Children in St. Louis, Missouri, created a soluble form of human TNAP that had been shown to display a strong attraction to bone tissue. Upon injecting the enzyme into the fat layer under the skin of the mice, the treated mice maintained a healthy rate of growth and apparent well being, as well as normal bone mineral density (BMD) of the skull, femur and spine. In fact, complete preservation of skeletal and dental structures were observed after 15 days, and bone lesions were still not seen after 52 days of treatment.

“While the biochemical mechanism that leads to skeletal and dental defects of HPP is now generally understood,” said Dr. Millhn, “there is currently no established medical treatment.”

Given the success of this therapy in preventing HPP, current efforts in Dr. Millhn’s laboratory are focused on reversing the bone defects in mice once the disease is quite advanced. Future clinical trials may reveal this as the first promising therapy for patients with this genetic disorder.

A puzzling medical condition, identified more than 2,000 years ago by Hippocrates, has finally been explained by researchers at the University of Leeds.The phenomenon of “finger clubbing”, a deformity of the fingers and fingernails, has been known for thousands of years, and has long been recognized to be a sign of a wide range of serious diseases – especially lung cancer.

“It’s one of the first things they teach you at medical school,” explained Professor David Bonthron of the Leeds Institute of Molecular Medicine. “You shake the patient by the hand, and take a good look at their fingers in the process.”

Lung cancer, heart disease, hyperthyroidism, various gastrointestinal diseases and many other conditions all result in finger clubbing. But exactly why swollen, reddened fingers should be an indicator of serious illness has remained a mystery – until now.

“There are benign cases of clubbing, where it isn’t associated with other illnesses, but particularly because of the link to lung cancer, it is generally regarded as rather sinister,” said Bonthron. “You look at the range of conditions connected to finger clubbing and wonder what on earth they could have in common.”

The researchers found clues in the medical literature, detailing past cases and previous research. “We knew that in cystic fibrosis patients who have undergone a lung transplant, their finger clubbing goes away. The same goes for empyema patients who have had their lungs drained. It suggested that impaired lung function was somehow crucial to finger clubbing – but we didn’t understand how.”

Prof Bonthron, Dr Chris Bennett of the Yorkshire Regional Genetics Service and their colleagues studied a group of patients suffering from inherited primary hypertrophic osteoarthropathy (PHO), a genetic disorder in which the finger clubbing is accompanied by painful joint enlargement and a thickening of the bone.

Their findings implicated a fatty compound called PGE2, which is produced naturally by the body to mediate the effects of internal inflammation. Crucially, once it has done its work, PGE2 is broken down by an enzyme 15-HPGD, produced in the lungs. The patients followed by the Leeds study were found to have a genetic mutation which prevented the production of 15-HPGD, resulting in up to ten times as much of the PGE2 in their systems.

“If you don’t have this enzyme the PGE2 isn’t broken down normally and simply builds up,” said Bonthron, whose findings are published online this week in Nature Genetics.

In lung cancer patients, it is most likely overproduction of PGE2 by the tumour that causes the clubbing. In congenital heart disease, blood bypasses the lungs, where PGE2 is normally broken down by 15-HPGD.

The researchers have suggested that a straightforward urine test for levels of PGE2 may be a useful first step in the diagnosis of individuals with unexplained clubbing, and to understanding whether it is the symptom of something far more serious. The results also suggest that existing drugs such as aspirin, which are already used to prevent PGE2 production, may be effective in reducing the painful symptoms of finger clubbing.

It has taken 2,000 years to make the connection, but Bonthron adds: “Actually, when you look back, it’s rather obvious. When we found this gene, everything else fell neatly into place – it was like a smack on the forehead.”

Johns Hopkins undergraduates have designed and built a device to enable critically ill intensive care unit patients to leave their beds and walk while remaining tethered to essential life-support equipment. The invention allows doctors to better understand whether carefully supervised rehabilitation, as opposed to continuous sedation and bed rest, can improve the recovery of intensive care patients.

Some clinicians believe that allowing ICU patients to get out of bed and walk could avert some of the muscle weakness, bedsores and depression that typically develop when these patients are kept heavily sedated and confined to bed. Because such patients usually must remain connected to an artificial breathing machine, heart monitors and intravenous lines with essential medications, a simple walk down the hall can require four staff members to accompany the patient.

Johns Hopkins biomedical engineering students Erica Jantho, Hanlin Wan and Swarnali Sengupta test their team’s ICU MOVER, a mobility aid designed to safely ambulate critical care patients. Photo by Will Kirk

To reduce this staffing demand and improve this new ICU rehabilitation program, a physician at Johns Hopkins Hospital last year asked students in a biomedical engineering design team course to devise a mobility aid for ICU patients. Over two semesters, the students, supervised by faculty members and graduate students and advised by hospital staff, produced a device called the ICU MOVER Aid. This device has two components: a novel mobility aid that combines the rehabilitative features of a walker and the safety features of a wheelchair, and a separate wheeled tower to which important life-support equipment can be attached.

“The finished product is truly outstanding,” said physician Dale Needham, an assistant professor in the Division of Pulmonary and Critical Care Medicine at the Johns Hopkins School of Medicine. “The most recent version of the MOVER is far beyond a rough prototype. The students exceeded everyone’s expectations in designing a device that we could routinely use in the Medical ICU.”

As demonsrated by students Hanlin Wan and Swarnali Sengupta, the ICU MOVER also can serve as a wheelchair and “catch” a walking patient who needs to sit down immediately because of fatigue or a sudden change in his or her medical condition. Photo by Will Kirk

To help him improve the new Medical ICU rehabilitation program at Johns Hopkins, Needham had challenged the students to produce a device that would meet three key criteria. First, it had to provide physical support for the patient during walking. Second, it had to safely house all necessary monitoring and therapeutic equipment for critically ill patients. Finally, it needed a safety backup system for patients who must immediately sit down because of fatigue or a sudden change in their medical condition.

“We ended up building three versions,” said Joshua Lerman, a senior biomedical engineering student who served as team leader. “First, we used PVC pipes to work on the basic design. Then, we made an aluminum version. We made the final prototype mostly of steel. All through the process we got feedback from the hospital’s ICU staff, who told us what we needed to change to make it better suit patients’ needs. All of the staff involved in the ICU rehabilitation program were very happy with the final version.”

This final version features a walker type framework, similar to devices that some frail or elderly people use to get around. Immediately behind the patient, however, a fabric seat is attached to the frame so that a tired patient can sit down. The seat can also “catch” a patient who abruptly collapses because of a medical problem. “We made the seat out of ballistic nylon because we didn’t want it to rip,” said Lerman, 22, from Delray Beach, Fla. “It’s durable, and it’s easy to clean for infection-control purposes.”

The student-designed ICU MOVER includes a wheeled tower that carries important medical equipment. The devices, top to bottom, are a cardiac monitor, an intravenous infusion pump and a portable ventilator. Photo by Will Kirk

As a separate component, the prototype features a tower designed to accommodate two oxygen tanks and three medical devices: a cardiac monitor, intravenous infusion pumps to provide medications, and a ventilator to support breathing. Despite all of the equipment attached to it, the MOVER prototype was small enough to maneuver through the Medical ICU’s narrow hallways, although using it in the ICU patient rooms, which are particularly small, proved to be more challenging. In terms of improved efficiency, the inventors said, the MOVER requires only two hospital staff members to accompany the walking patient, compared with four staff under the earlier system.

Needham, the project’s faculty sponsor, said, “We’ve tried this device on one MICU patient so far, and we are certainly keen to continue using it as part of our physical medicine and rehabilitation program in the Medical ICU at Johns Hopkins. The MOVER worked as well with the real patient as it did when we tested it with the biomedical engineering students serving as simulated patients.”

At a recent competition for Johns Hopkins biomedical engineering design projects, the MOVER’s team took second-place honors. The student inventors and their faculty mentors have obtained a provisional patent for the device and are exploring commercialization opportunities. Needham said much will depend on how quickly other hospitals adopt new therapies in the ICU setting to improve patient recovery. “With the increasing interest in early mobility for ICU patients and the emerging scientific evidence supporting the benefit of this approach,” he said, “I think there is a strong commercial future for the MOVER device.”

In addition to Lerman, the undergraduates who worked on this project were Ravy Vajravelu, Derrick Kuan, Jeremy Elser, Erica Jantho, Jinjie Chen, Hanlin Wan and Swarnali Sengupta. The design course is taught by Robert Allen, an associate research professor and senior lecturer in the Department of Biomedical Engineering.

Color images of the device and the student inventors available; contact Phil Sneiderman.

Significant numbers of female high school athletes and non-athletes suffer from one or more components of the female athlete triad, a combination of three conditions that can lead to cardiovascular disease, according to a new study by Medical College of Wisconsin researchers in Milwaukee.

The study results were presented today at the American College of Sports Medicine at Indianapolis, by Anne Z. Hoch, D.O., associate professor of orthopedic surgery and physical medicine and rehabilitation at the Medical College, and director of the Froedtert & Medical College Sports Medicine Program. She is also a member of the Medical College’s Cardiovascular Center.

Dr. Hoch found that 78 percent of female high school athletes and 65 percent of female high school non-athletes display one or more components of the female athlete triad. The triad is a combination of three conditions – low energy availability, menstrual abnormalities and low bone mineral density – that often leads to the same steroid and hormonal profiles as postmenopausal women.

“We are concerned that non athletic girls have some of the same components of the female athlete triad as athletes and are in fact at greater risk for low bone density,” says Dr. Hoch. “These young women are under great pressure to conform to society’s standards of body image. In an effort to lose weight, they are restricting their caloric intake and adapting unhealthy nutrition habits.”

The study, conducted at Froedtert Hospital, examined eighty varsity athletes and eighty non-athletes at an all-girls school in Milwaukee. Ninety-three percent of non-athletes were found to have calcium deficiencies, compared to 74 percent of athletes.

“Most important and alarming is that 30 percent of the non athletes versus 16 percent of athletes were found to have low bone mineral density putting them at greater risk for developing osteoporosis earlier in life,” says Dr. Hoch.

Both groups showed little difference in low energy availability, with 39 percent of non-athletes and 36 percent of athletes reporting this condition. The athletes reported 33 percent more menstrual abnormalities than the non-athletes. Women who have normal periods, and hence normal estrogen levels, are less likely to display changes in the function of the layer of cells that line the interior of blood vessels, called the endothelium.

“Change in endothelial function is the seminal event in cardiovascular disease,” says Dr. Hoch.

Dr. Hoch began her studies in the late 1990s to see if young women who have menstrual abnormalities as a result of participating in intense sports are likely to develop cardiovascular disease similar to that seen in postmenopausal women. She and her colleagues were able to show that young women who had the triad also had early vascular change that is a precursor to cardiovascular disease.

“We not only need to educate athletes about the consequences of the triad, now we must educate all students about the harmful effects of a restrictive diet in the adolescent period,” says Dr. Hoch.

A monkey has successfully fed itself with fluid, well-controlled movements of a human-like robotic arm by using only signals from its brain, researchers from the University of Pittsburgh School of Medicine report in the journal Nature. This significant advance could benefit development of prosthetics for people with spinal cord injuries and those with “locked-in” conditions such as Lou Gehrig’s disease, or amyotrophic lateral sclerosis.“Our immediate goal is to make a prosthetic device for people with total paralysis,” said Andrew Schwartz, Ph.D., senior author and professor of neurobiology at the University of Pittsburgh School of Medicine. “Ultimately, our goal is to better understand brain complexity.”

Previously, work has focused on using brain-machine interfaces to control cursor movements displayed on a computer screen. Monkeys in the Schwartz lab have been trained to command cursor movements with the power of their thoughts.

“Now we are beginning to understand how the brain works using brain-machine interface technology,” said Dr. Schwartz. “The more we understand about the brain, the better we’ll be able to treat a wide range of brain disorders, everything from Parkinson’s disease and paralysis to, eventually, Alzheimer’s disease and perhaps even mental illness.”

Using this technology, monkeys in the Schwartz lab are able to move a robotic arm to feed themselves marshmallows and chunks of fruit while their own arms are restrained. Computer software interprets signals picked up by probes the width of a human hair. The probes are inserted into neuronal pathways in the monkey’s motor cortex, a brain region where voluntary movement originates as electrical impulses. The neurons’ collective activity is then evaluated using software programmed with a mathematic algorithm and then sent to the arm, which carries out the actions the monkey intended to perform with its own limb. Movements are fluid and natural, and evidence shows that the monkeys come to regard the robotic device as part of their own bodies.

The primary motor cortex, a part of the brain that controls movement, has thousands of nerve cells, called neurons, which fire together as they contribute to the generation of movement. Because of the massive number of neurons that fire at the same time to control even the simplest of actions, it would be impossible to create probes that capture the firing pattern of each. Pitt researchers developed a special algorithm that uses limited information from about 100 neurons to fill in the missing signals.

“In our research, we’ve demonstrated a higher level of precision, skill and learning,” explained Dr. Schwartz. “The monkey learns by first observing the movement, which activates his brain cells as if he were doing it. It’s a lot like sports training, where trainers have athletes first imagine that they are performing the movements they desire.”