Focusing on a rare, genetic and disabling disease known as fibrodysplasia ossificans progressiva, or FOP, researchers designed the study as an examination of the frequency of misdiagnosis and the complications associated with it.

Their findings are reported in the November issue of the journal Pediatrics.

FOP is a disorder of connective tissue that ultimately results in massive bone formation across the body’s major joints, eventually rendering movement impossible. The disorder affects one in two million people worldwide, and there are 200 known cases in the U.S.

The study found that FOP is misdiagnosed 87 percent of the time, takes an average of four years to be accurately diagnosed, and often is inaccurately identified as cancer. The inaccurate diagnoses have led to painful biopsies and incorrect treatments that in themselves often worsened the condition of the patient, speeding permanent loss of mobility.

"It is unfortunate that individuals afflicted with this rare disabling disease have suffered further serious problems due to incorrect diagnoses by their physicians," said Joseph Kitterman, MD, lead investigator and professor of pediatrics at the University of California, San Francisco.

In addition to Kitterman, the team included researchers from the University of Pennsylvania, the International FOP Association, and the University of California, Davis.

Based on study findings, the researchers estimate that only 10 percent of doctors have ever heard of FOP.Only eight percent of the 184 medical textbooks that they reviewed contained adequate descriptions of FOP.

An accurate diagnosis of the disease can be made based on the clinical findings of tumor-like swellings on the head, neck, back or shoulders in association with malformations of the great (big) toes, according to Kitterman. However, the study showed that physicians often misdiagnosed the condition because the patient was not fully examined or the physician was not aware of FOP.

The disease is distinguished by the unique characteristics of toe malformations and missing joints which are present at birth, but their significance is almost never appreciated, Kitterman noted.

"The irony here is that diagnosis of FOP has distinguishing features and is obvious just by asking a few simple questions," he said. "Instead, with misdiagnosis of this rare disease, the result was anxiety and pain for the patient."

The study found that patients often endured painful deep muscle biopsies and permanent complications due to misdiagnosis, with almost half reporting permanent loss of mobility that resulted from invasive procedures.

No condition other than FOP is associated with malformed toes and rapid tissue swellings during childhood, Kitterman said.

"FOP can look like cancer. Inspection of the toes, however, would instantly reveal a different disease," said co-investigator Frederick Kaplan, MD, an international FOP expert at the University of Pennsylvania and director of one of the few research centers in the world investigating the disease.

"The disease is easy to diagnose once the physician knows what to look for," he added.

The study findings showed that it took an average of six physicians to accurately diagnose FOP. Those consulted most frequently were orthopedic surgeons, pediatricians, general practitioners, oncologists, rheumatologists and internists.

The research team reviewed the experiences of 138 patients with FOP from around the world. The extremely high rate of misdiagnoses was worldwide, with cancer cited most often. Sixty-seven percent of the study patients had unnecessary invasive procedures, and 68 percent received inappropriate therapies.

The next steps in finding a cure for FOP are to define the metabolic pathways that influence the disease and identify the gene that causes it, according to the researchers.

In addition to Kitterman and Kaplan, the study team included Sharon Kantanie, MAT, of the International FOP Association, and David Rocke, PhD, of the University of California, Davis.

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UCSF is a leading university that consistently defines health care worldwide by conducing advanced biomedical research, educating graduate students in the life sciences, and providing complex patient care.

Nearly all patients in the NICU require some method of oxygen supplementation, according to background information in the article. Oxygen is most often delivered to infants through an endotracheal tube, nasal cannula (slender tubes inserted into the nose) or nasal continuous positive airway pressure (CPAP, which delivers pressurized air through the nose to help keep breathing passages open). Nasal CPAP is a good alternative for many newborns because it avoids complications associated with long-term use of tracheal tubes, including narrowing of the airways under the vocal cords (subglottic stenosis).

However, some reports have linked CPAP devices to nasal complications. To investigate the potential effects, Kris R. Jatana, M.D., of The Ohio State University Medical Center and Nationwide Children’s Hospital, Columbus, and colleagues studied 100 patients younger than one year who received at least seven days of nasal CPAP or oxygen supplementation with cannula in the NICU in 2007 or 2008. All patients underwent an external examination of the nose and then nasal endoscopy to identify any internal complications.

Nasal complications were observed in 12 of the 91 patients (13.2 percent) with at least seven days of nasal CPAP use, whereas no complications were seen in the nine patients with only nasal cannula use. Complications inside the nose included ulceration in six of 182 nasal cavities (3.3 percent), granulation or the formation of healing tissue in three nasal cavities (1.6 percent) and vestibular stenosis (narrowing of the front portion of the nasal passage) in four nasal cavities (2.2 percent).

The primary external complication was columellar necrosis, or tissue death at the end of the nasal septum, which was observed in five of 91 patients (5.5 percent). "Once this occurs, it is difficult to repair surgically, and adverse cosmetic results may ensue," the authors write. "In our series, columellar necrosis was found as early as 10 days after placement of nasal CPAP, but columellar necrosis has been reported as early as after only three days of nasal CPAP use in very-low-birthweight infants."

All nasal complications from CPAP were associated with lower Apgar scores — an overall measure of newborn health — at one and five minutes after birth.

"Nasal CPAP is gaining popularity as a preferred means of ventilatory support in the NICU, and its potential complications will be encountered more frequently," the authors write. "Close surveillance for potential complications should be considered during nasal CPAP use."

According to the study by Richard Frankel, Ph.D., professor of medicine at the Indiana University School of Medicine and a research scientist at the Regenstrief Institute and the Center for Implementing Evidence Based Practice at the Indianapolis VA Medical Center, and colleagues from Johns Hopkins and Northeastern universities and the Fetzer Institute, nonverbal behavior can be an important diagnostic tool increasing the physician’s comprehension of words spoken or thoughts left unsaid.

On the other hand, the nonverbal behavior of the physician can influence the patient’s satisfaction with his clinic visit and affect his compliance with the doctor’s instructions.

The study on this under-recognized communication tool, entitled "The Expression of Emotion Through Nonverbal Behavior in Medical Visits," was presented at the Ninth Biannual Regenstrief Conference and appears in the supplement to the January 2006 issue of the Journal of General Internal Medicine.

"Nonverbal behavior conveys the meaning of words," says Dr. Frankel, a medical sociologist. "The way someone gestures tells you the speaker’s stance; words alone don’t convey the full picture. Nonverbal behavior can be a duplication of the words or it can contradict what an individual is saying.

"To put it more eloquently, if the words are the musical notes on a Tchaikovsky score, then nonverbal behavior is the interpretation of those notes. A computer always plays the music in the same way without any nonverbal behavior, but Jascha Heifetz would play that score differently than Itzhak Perlman, each violinist conveying a different interpretation of Tchaikovsky’s original intent," he said.

Nonverbal communication is a clue to the emotions underlying feelings. Does the patient look at the physician when describing symptoms or does he look down at his feet? Does another patient wring her hands and refuse to meet the doctor’s gaze? Either or both patients may be exhibiting signs of humiliation or anxiety.

Does the physician repeatedly glance at her watch or answer his cell phone? Both actions send nonverbal messages to patients, probably messages the physician did not intend to transmit. Those scenarios are in contrast to yet another doctor who makes eye contact and tilts his head while the patient explains complaints of concern; that physician appears empathetic, said Dr. Frankel.

"From studies outside of medicine — in the business world, for example – we know we can improve nonverbal sensitivity — altering nonverbal cues from ourselves and others," he said. "Our own studies have shown that patients who are satisfied with their physicians perceive their visits were two minutes longer than they actually were and these patients are better at following the physician’s instructions. We also found that patients who felt their physician was not empathetic, perceived their visit to be two minutes shortly than it actually was."

This study and the Regenstrief Conference where it was presented developed from the Regenstrief Institute’s focus on relationship-centered care. "The mutual influence of patients on physicians and physicians on patients is part of a relationship rather than individual actions or behaviors," said Dr. Frankel.

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In addition to Dr. Frankel, the authors of the new study are Debra L. Roter, Dr.Ph. of Johns Hopkins; Judith Hall, Ph.D. of Northeastern, and David Sluyter, Ed.D. of Fetzer. The study was funded by the Fetzer Institute of Kalamazoo, MI.

Several studies have documented increased survival when androgen (male sex hormone) suppression therapy (AST) is combined with external beam radiation therapy (RT) compared with RT alone in the treatment of unfavorable localized and locally advanced prostate cancer. However, comorbid (co-existing) illnesses may increase the negative effects of specific anti-cancer treatments such as AST, altering the survival benefit observed when AST is added to RT.

Anthony V. D’Amico, M.D., Ph.D., of Brigham and Women’s Hospital and Dana Farber Cancer Institute, Boston, and colleagues performed an analysis of overall survival of 206 men with localized but unfavorable–risk prostate cancer in subgroups defined by their level of comorbidity at the time of their randomization to AST and RT vs. RT alone. During a median follow-up of 7.6 years, 74 deaths occurred.

Estimates of overall survival were significantly higher for men who were randomized to RT and AST compared with RT. The cumulative incidence estimates of prostate cancer–specific mortality significantly favored the RT and AST group, with an increased risk of prostate cancer–specific mortality (14 vs. 4 deaths) that translated into an increased risk of all-cause mortality (44 vs. 30 deaths) in men randomized to RT compared with RT and AST.

A significant interaction was noted between comorbidity score and treatment. For the 157 men with no or minimal comorbidity scores, treatment with RT and AST compared with RT was associated with a significantly higher survival (31 vs. 11 deaths). Among the 49 men with moderate or severe comorbidity, those randomized to RT alone vs. RT and AST did not have an increased risk of all-cause mortality (13 vs. 19 deaths).

"The clinical significance of this finding is that pre-existing comorbid illness may increase the negative effects of specific anti-cancer treatments such as AST," the authors write.

"In conclusion, the addition of 6 months of AST to RT resulted in increased overall survival in men with localized but unfavorable–risk prostate cancer. This result may pertain only to men without moderate or severe comorbidity, but this requires further assessment in a clinical trial specifically designed to assess this interaction."

Journal reference: JAMA. 2008;299[3]:289-295.

For the study, researchers surveyed 79 pairs of identical twins with the same genetic risk for MS in which only one twin had MS. The twins were asked to specify whether they or their twin spent more time outdoors during hot days, cold days, and summer, and which one spent more time sun tanning, going to the beach and playing team sports as a child.

The study found the twin with MS spent less time in the sun as a child than the twin who did not have MS. Depending on the activity, the twin who spent more hours outdoors had a 25 to 57 percent reduced risk of developing MS. For example, the risk of developing MS was 49 percent lower for twins who spent more time sun tanning than their siblings.

"Sun exposure appears to have a protective effect against MS," said study authors Talat Islam, MBBS, PhD, and Thomas Mack, MD, MPH, with the Keck School of Medicine of the University of Southern California in Los Angeles. "Exposure to ultra violet rays may induce protection against MS by alternative mechanisms, either directly by altering the cellular immune response or indirectly by producing immunoactive vitamin D."

The study also found the protective effect of sun exposure was seen only among female twin pairs, but Mack says this novel finding must be viewed with caution since only a few male twins were involved in the study.

"Our findings note the importance of sun exposure among people with identical genetic risk for MS," said Mack. "High priority should be given to research into how sun exposure reduces MS risk if we are to unravel the mystery of what causes MS."

The study was supported by grants from the Multiple Sclerosis Society of Canada, the National Institute of Neurological Disorders and Stroke, the National Cancer Institute, and the National Institute of Environmental Health Sciences.

The urine test measures if patients are still making their own insulin even if they take insulin injections. Researchers have shown that the test can be used to differentiate Type 1 diabetes from Type 2 diabetes and rare genetic forms of diabetes. Making the correct diagnosis can result in important changes in treatment and the discontinuation of insulin in some cases.

Jillian, 35 has recently benefited from the home urine test. She was diagnosed with diabetes aged 19 and put on insulin injections. The urine test identified that she is still making her own insulin 14 years after being diagnosed and a DNA test confirmed that she has a genetic type of diabetes. After 14 years of insulin treatment, Jillian is now off her insulin injections.

"Being told I don’t have to take insulin injections any more has changed my life," she said.

The key studies, led by Dr Rachel Besser and Dr Angus Jones and were funded by Diabetes UK and the National Institute of Health Research, are published in the diabetes journals, Diabetes Care and Diabetic Medicine.

Dr Rachel Besser, who has led the studies on over 300 patients, commented: "The urine test offers a practical alternative to blood testing. As the urine test can be done in the patients own home we hope that it will be taken up more readily, and more patients can be correctly diagnosed and be offered the correct treatment."

As described in the February 4, 2011 edition of the journal Science, when the team attached a specific oligomeric array of sugars called a "glycan" to proteins having a defined structure, the proteins were up to 200 times more stable in the test tube. In the body, this stability may translate into longer half-lives for therapies, possibly lowering the overall cost of treatment for certain protein-based drugs and requiring patients to have fewer injections during a course of treatment.

The work may have major implications for the drug industry because there are a large number of protein-based drugs on the market, more in clinical trials, and many more under development worldwide. Nearly all of these protein-based drugs have glycans attached to them and are therefore called "glycoproteins." Glycoprotein-based drugs can be quite expensive to produce and usually need to be administered intravenously.

One of the challenges in producing these drugs has been increasing their stability, which generally extends their half-life in the bloodstream — issues that the new discovery appears to address directly.

"We’ve now provided engineering guidelines for glycoprotein stability," said Scripps Research Professor Jeffery W. Kelly, who is chair of the Department of Molecular and Experimental Medicine, Lita Annenberg Hazen Professor of Chemistry, and member of The Skaggs Institute for Chemical Biology at Scripps Research. Kelly led the study with Scripps Research Associate Professor Evan Powers and Staff Scientist Sarah R. Hanson, in collaboration with Research Associates Elizabeth K. Culyba, Joshua Price, and colleagues.

In Search of Stability

Making therapeutic proteins more stable by attaching glycans to them is nothing new. Scientists have known for many years that the human body widely modifies proteins in this way after they are made inside cells. By some estimates, as many as a third of all types of proteins in the human body are "glycosylated," the scientific name for the process whereby glycans are attached to proteins. Scientists also know that these modifications can be directly linked to protein stability.

Attaching a glycan to one part of a protein can have a dramatic stabilizing effect, accounting for the difference between it lasting in the bloodstream for a few minutes or a few days. But attaching the same glycan to another part of the same protein can have a distinctly different destabilizing effect, turning it into the microscopic equivalent of a cooked egg — unfolded and worthless as a medicine.

Scientists who work on these sorts of drugs often try to stabilize their therapeutic proteins with glycans, but until now nobody understood the rules that govern the process — nobody even knew for sure if there were general rules governing it. Researchers have always made such modifications through trial-and-error — more of a time-consuming art than an exact science.

But now, predicts Powers, "Having a rational design approach will streamline protein drug optimization quite a bit."

Simple Engineering Rules

The new research shows simple engineering rules do exist for achieving stability of glycoproteins in the test tube. In the new paper, the Scripps Research team showed that scientists could dramatically stabilize proteins by integrating the standard N-glycan into a particular part of the protein — a structure known as a "reverse turn" containing a certain combination of amino acids. Reverse turns are found in the vast majority of proteins, making this methodology broadly applicable.

The scientists tested their ability to increase the stability of proteins by creating glycoproteins from proteins that are not normally glycosylated — leading to increased stabilization in the test tube. These scientists have not yet looked at how long the proteins survive in the bloodstream — that work is currently under way. But the team is confident that the principles they discovered will now give scientists a new way to predictably stabilize proteins by design.

Kelly added that this portable stabilizing structural module called the "enhanced aromatic sequon" also leads to more efficient production of glycoproteins by cells, a result that is potentially very important, since glycoproteins remain difficult to produce and purify.

In addition to Kelly, Powers, Hanson, Culyba, and Price, the article, "Protein Native-State Stabilization by Placing Aromatic Side Chains in N-Glycosylated Reverse Turns" is authored by Apratim Dhar, Chi-Huey Wong, and Martin Gruebele.

This work was supported in part by the Skaggs Institute for Chemical Biology and the Lita Annenberg Hazen Foundation, and funded through grants from the National Institutes of Health and the National Science Foundation.

The mutator hypothesis, which states that normal human cells increase their rate of genetic change as a mechanism for speeding up the transformation to cancer cells, has been a pivotal concept in cancer biology for over 30 years, influencing our ideas both of how cancer arises and of the challenges of developing cancer therapies.

According to this hypothesis, an early step in becoming a cancer cell is a "mutator mutation", which causes the developing cancer to become genetically unstable. This accelerates the transformation of normal cells to cancer cells. It means that cancer cells are constantly changing, making them an elusive target for therapy.

However as a general concept applicable to all cancer, the mutator hypothesis has been debated on several grounds. Firstly, an increased mutation rate due to a mutator mutation could lead to an increased rate of random mutations that might reduce the fitness of the cell and its daughter cells (the "cell lineage") to compete for survival, dooming it to extinction before it could become malignant. Secondly, rates of cancer appearance in people can possibly be explained without a mutator mutation, just by continuing mutation at normal rates, and growth and selection of cell lineages with increased fitness; that is, by normal evolution occurring in populations of cells.

In an article published in the open-access journal PLoS ONE, Robert A. Beckman, a Visitor in the Simons Center for Systems Biology at the Institute for Advanced Study in Princeton, New Jersey, mathematically analyses the mutator hypothesis and compares the cancer-generating efficiency of mutator and non-mutator pathways to cancer, taking into account representative fitness changes a cell might experience as it potentially evolves to cancer. These fitness changes can be represented as pathways through a "fitness landscape", the equivalent of a topographic map of pathways to cancer.

Beckman had previously introduced the concept of efficiency in evaluating pathways to cancer. In previous work, he defined efficiency as the number of new cancer lineages expected to be created in the typical time it takes to develop cancer. He reasoned that, since most cancer cell lineages are eliminated by the body’s defenses, or fail to establish a blood supply, the most efficient pathways to cancer would likely be the ones responsible for most cancers in people. He then showed that in the special circumstance where there are no fitness changes, mutator pathways are the most efficient path to cancer, even though getting the mutator mutation is itself an extra step.

In the current work, he shows more generally that mutator pathways are in most cases the most efficient path to cancer, even in the presence of fitness changes from a variety of fitness landscapes, addressing the previous objections to the mutator hypothesis. He also shows that the mutation rate which most efficiently evolves normal cells to cancer cells is likely to be higher than the mutation rate which is most efficient for driving the evolution of species. These findings provide strong support for the mutator hypothesis.

If the mutator hypothesis is true, there may be implications for cancer therapy. Genetic instability may enable cancer cells to rapidly evolve resistance to therapy, or may even mean that minority cell populations within a cancer are already primed to resist therapy. Cancers which show more genetic instability may more readily evade any given therapy, and may require different strategies for treatment.

Robert A. Beckman is a stockholder in Merck & Co., Inc. and Johnson & Johnson, Inc.

At the time, Tyska knew that the core bundle traveling up the center of the microvillus was an array of the structural protein actin, and that the ladder-like "rungs" connecting the actin bundle to the cell membrane were composed of the motor protein myosin-1a. This myosin, though related to the myosin involved in muscle cell contraction, was thought to serve a purely structural role. "The textbook thinking for decades was that microvilli serve as a passive scaffold, a way to amplify the membrane surface area," said Tyska, assistant professor of Cell and Developmental Biology at Vanderbilt University.

In the intestines, an expanded cell surface increases the space for nutrient-processing enzymes and transporters, offering greater capacity for nutrient handling. But it didn’t make sense to Tyska that a motor protein — a protein with the potential to generate force and move cargo around in cells — would play a passive structural role. "When I looked at that image, the near crystalline arrangement reminded me of actin and myosin in a muscle fiber," Tyska said. "I kept returning to the same question: why would the microvillus have this beautiful structure packed with motor proteins. The concentration of myosin motors in a single microvillus is very high; there’s serious force-generating potential there."

Tyska and Russell McConnell, a student in his laboratory, tested the idea that these motor proteins are more than molecular glue binding the cell membrane to the actin bundle" The investigators purified the intestinal "brush border" — the layer of densely packed microvilli — from the intestines of rats or mice, and added ATP, the chemical fuel for myosin-1a. Through the microscope, they watched the cell membrane move toward the tips of the microvilli and pop off the ends in the form of vesicles, tiny bubble-like packets.

Their findings, reported in the May 21 Journal of Cell Biology, have implications for nutrient processing and other aspects of gastrointestinal physiology. Tyska is excited about the group’s unexpected discovery. "What we’re showing is that the microvillus is more than just a scaffold to increase the amount of cell membrane," Tyska said. "It’s a little machine that can shed membrane from the tips." The team confirmed that myosin-1a is the motor that moves membrane up the microvillus. Brush borders isolated from knockout mice lacking the myosin-1a gene shed membrane at only five percent of the level of brush borders from wild-type animals.

The investigators are working now to understand why intestinal cells might launch vesicles from their microvilli. They know from ongoing vesicle sorting and mass spectrometry studies that the vesicles contain nutrient-processing enzymes and transporters, like the microvillar membrane. "One idea is that these vesicles operate remotely to speed nutrient processing, before the nutrients even get to the brush border to be absorbed by the (intestinal epithelial cell)," Tyska said.

The team is also exploring other possibilities for the role of membrane shedding: that it offers protection against microbes and pathogens by expelling them from the surface before they can enter the cell; that it provides a mechanism for altering the composition of the microvillar surface to handle changes in "what comes down the pipe;" and that it serves a role in cell-cell communication by launching vesicles that contain signaling proteins. Tyska and his team also plan to explore whether myosin-1a is serving a similar membrane-moving role in its other known location: the hair cells of the inner ear, and if other microvilli also use myosin motors to jettison vesicles from their tips.

Research in the Tyska laboratory is supported by the Crohn’s and Colitis Foundation of America, the March of Dimes, the National Institutes of Health, the VUMC Digestive Disease Research Center, and the VUMC Training Program in Developmental Biology.

The discovery represents a further step in the ever-expanding field of understanding the ways in which stem cells develop into specific cells, a necessary prelude towards the use of stem cell therapy as a means to reverse the consequences of disease and disability.

The identification of the gene, known as Chd1, was made by Dr. Eran Meshorer of the Alexander Silberman Institute of Life Sciences at the Hebrew University and Dr. Miguel Ramalho-Santos (UCSF), together with their graduate students Adi Alajem (the Hebrew University) and Alexandre Gaspar-Maia (UCSF).

Embryonic stem (ES) cells, which are primary cells derived from the early developing embryo, are capable of giving rise, according to their environment and conditions, to any cell type — a trait known as pluripotency.

It was assumed that the ES cells have a relatively high degree of open chromatin, which is thought to enable their pluripotency, a theory which awaited proof. Chromatin, which is found in all cells, is composed of DNA and its surrounding proteins and can be found in one of two conformations: closed chromatin (heterochromatin) — when the genetic material is packed in a way that prevents the expression of the genes — and open chromatin (euchromatin) — when chromatin is accessible to the gene expression machinery. Different cells display varying degrees of open and closed chromatin as a function of the genes required for their function.

In their current study, which was published recently in the journal Nature, the researchers from the Hebrew University and UCSF showed, using mouse ES cells, that Chd1 regulates open chromatin in ES cells. The open chromatin conformation, maintained by Chd1, enabled the expression of a wide variety of genes, leading to proper differentiation into all types of specific cells. Depletion of Chd1 in embryonic stem cells led to formation of heterochromatin (closed chromatin) and prevented the ability of the cells to generate all types of tissues.

The study, therefore, showed a proven link between open chromatin in ES cells and their pluripotency — an important finding on the road to the implementation of stem cell applications in future medical treatment.