Mayo Clinic: Add bone deterioration to diabetes complications

The list of complications from Type 2 diabetes is long: vascular and heart disease, eye problems, nerve damage, kidney disease, hearing problems and Alzheimer’s disease. Physicians have long thought of osteoporosis as another complication.

Based on a Mayo Clinic study published in the Journal of Bone and Mineral Research, that’s confirmed: You can definitely add skeletal problems to the list.
“This is the first demonstration – using direct measurement of bone strength in the body – of compromised bone material in patients with Type 2 diabetes,” says Sundeep Khosla, M.D., Mayo Clinic endocrinologist and senior author of the study. “Clearly, the skeleton needs to be recognized as another important target of diabetes complications.”

Previous studies in the field showed that patients with diabetes experienced fractures at levels of bone density above that of the regular population, hinting that something was different about the “quality” of their bone.

The Mayo researchers validated that assumption in a clinical study of 60 postmenopausal women, 30 of whom had Type 2 diabetes. Using a new tool (Osteo- Probe), the researchers performed micro indentation testing of the tibia (actually causing a microscopic crack) to measure bone material strength. Compared to the control group of women, aged 50 to 80, the group with Type 2 diabetes had significantly lower bone material strength.

There was no difference between the microarchitecture of the bone or bone density between the two groups. The study showed that diabetic women with lower bone material strength had also experienced higher levels of hypoglycaemia over the previous 10 years, suggesting potential detrimental effects of poor glucose control on bone quality.

The resounding message: Conventional measurements under-estimated the risk of fracture among patients with Type 2 diabetes and loss of bone material strength, or bone quality, is a clear, downstream consequence of the disease.

The new technology may help in studying other conditions where fractures occur at higher than expected bone density, says co-author and rheumatologist Shreyasee Amin, M.D. She says this will be especially relevant to many forms of auto-immune arthritis where glucocorticoids are used, such as in rheumatoid arthritis. The team says more research needs to be done, as this was a small study in a limited population.



Musical training influences brain anatomy and function

New findings show that extensive musical training affects the structure and function of different brain regions, how those regions communicate during the creation of music, and how the brain interprets and integrates sensory information. The findings were presented at Neuroscience 2013, the annual meeting of the Society for Neuroscience and the world’s largest source of emerging news about brain science and health.

These insights suggest potential new roles for musical training including fostering plasticity in the brain, an alternative tool in education, and treating a range of learning disabilities. The new findings show that: l Long-term high level musical training has a broader impact than previously thought.

Researchers found that musicians have an enhanced ability to integrate sensory information from hearing, touch, and sight. l The age at which musical training begins affects brain anatomy as an adult; beginning training before the age of seven has the greatest impact. l Brain circuits involved in musical improvisation are shaped by systematic training, leading to less reliance on working memory and more extensive connectivity within the brain.

Some of the brain changes that occur with musical training reflect the automation of task (much as one would recite a multiplication table) and the acquisition of highly specific sensorimotor and cognitive skills required for various aspects of musical expertise. “Playing a musical instrument is a multi-sensory and motor experience that creates emotions and motions – from finger tapping to dancing – and engages pleasure and reward systems in the brain.

It has the potential to change brain function and structure when done over a long period of time,” said press conference moderator Gottfried Schlaug, MD, PhD, of Harvard Medical School/Beth Israel Deaconess Medical Center, an expert on music, neuro-imaging and brain plasticity. “As these findings show, intense musical training generates new processes within the brain, at different stages of life, and with a range of impacts on creativity, cognition, and learning.”



High-voltage electric fields may aid scar tissue research

High voltage, short-pulsed electric fields, used for disinfection and solid tumour destruction, selectively damage cell membranes, while preserving overall tissue structure, a phenomenon that may be a key factor in scarless tissue regeneration.

Any organ or tissue after serious injury forms a scar, an enigma which has puzzled humans for thousands of years. The mechanism by which scars form is not known, and there are very limited therapies available to block scar formation. Now, a team based at the Center for Engineering in Medicine at the Massachusetts General Hospital report that high-voltage short electric fields appear to destroy all cells in skin tissue but lead to full regeneration with no scars.

These strong but short-pulsed electric fields selectively kill the cells, while preserving the extracellular matrix tissue structure including the local blood supply, which are needed for healthy tissue growth and functional regeneration.

“It is a fascinating finding,” says Alexander Golberg, PhD of MGH, the paper’s first author. “We compared this technique with thermal burns and found many different aspects post-injury both in terms of the extent of damage and the dynamics of recovery”.

Currently, pulsed electric fields are primarily used for disinfection and solid tumour ablation. Pulsed fields selectively kill cells in the tissue presumably by a mechanism called irreversible electroporation. After exposure to the fields, large pores appear in cell membranes that eventually lead to cell death.

“Previously, scarless regeneration has only been observed in adult amphibians and early in mammalian fetuses, both of which do not have an adaptive immune response.

Even though our rodents had an intact adaptive immune system, we were able to generate scarless skin regeneration in these adult mammals. Further study of this technique will help us better understand the mechanism of scarring,” says Martin L. Yarmush, MD, PhD, director of the MGH Center for Engineering in Medicine, the senior author of the paper. “This development not only holds a great promise for unravelling many aspects of the complex wound healing process but also to potentially lead to new therapies,” Golberg says.

“We believe that this model will enable other laboratories to learn and uncover new aspects of adult tissue growth and development.” The paper is published in the inaugural issue of the new journal Technology. l doi: 10.1142/S233954781320001X



Drug interactions cause significant impact on statin use

A new study has found that many people who stopped taking cholesterol-lowering statin drugs were also taking an average of three other drugs that interfered with the normal metabolism of the statins. The other drugs can contribute to a common side-effect of taking statins – muscle pain – and often led people to discontinue use of a medication that could otherwise help save their lives, researchers learned.

The interactions of many drugs with statins have been known of for some time, researchers said, but are not being adequately managed by physicians and pharmacists, who could often choose different medications or adjust dosages to retain the value of statin drugs without causing this side-effect.

The research, done as part of a survey of more than 10,000 current and former statin users, found that use of medications which interfere with statin metabolism almost doubles the chance that a person will discontinue statin use due to muscle pain.

The issue is of growing importance because statin drugs are some of the most widely used medications in the world, proven to lower LDL, or “bad” cholesterol, and decrease the risk of heart attacks, heart disease, strokes and death. About 20 million people in the US now take statins, and new guidelines have just been issued to further expand the types of health conditions for which statins may be of benefit.

Based on those guidelines, the number of statin users could increase to more than 30 million. The findings were published in the Journal of Clinical Lipidology by scientists from Oregon State University and four other universities or research institutes.

“We’ve known for some time of many medications that can interact with statins, but only now is it becoming clear that this is a significant contributor to the side-effects, and often the reason some patients stop taking statins,” said Matt Ito, a professor in the OSU College of Pharmacy and president of the National Lipid Association, which funded this study. “This issue is something physicians, pharmacists and patients all need to be more aware of,” Ito said.

“There’s a lot we can do besides discontinue use of these valuable medications. You can change dosages, use drugs that don’t cause interactions, use different types of statins. Patients need to be proactive in understanding this issue and working with their health care providers to address it.” Besides drug interactions, statin side-effects are also more common in women and associated with increasing age, history of cardiovascular disease, and some other conditions. Statin discontinuation has also been associated with increased cardiovascular morbidity and death.



New research findings may aid early detection of Alzheimer’s

Using scores obtained from cognitive tests, Johns Hopkins researchers think they have developed a model that could help determine whether memory loss in older adults is benign or a step on the way to Alzheimer’s disease.

The risk of developing dementia increases markedly when a person is diagnosed with mild cognitive impairment, a noticeable and measurable decline in intellectual abilities that does not seriously interfere with daily life. But physicians have no reliable way to predict which people with mild cognitive impairment are likely to be in the 5 to 10% a year who progress to dementia. In a proof-of-concept study, the Johns Hopkins investigators analyzed records of 528 people age 60 and over, who were referred to the Johns Hopkins Medical Psychology Clinic for cognitive testing as part of a dementia work-up between 1996 and 2004.

The results were compared to those of 135 healthy older adults who participated in a study of normal aging. Both groups completed tests of memory, language, attention, processing speed and drawing abilities from which 13 scores were recorded. Since each person is naturally more skilful in some areas than in others, the scores of healthy adults showed a symmetrical, bell-shaped range.

Most of their scores were high, some were a bit lower, and a few were even lower. By grouping the patients into cohorts based on the severity of their dementia, the researchers found a trend in the test scores that is likely to mimic the deterioration of an individual’s scores over time. At the outset, he says, Alzheimer’s disease subtly disrupts some mental abilities, while leaving others intact.

Thus, well before a person develops clear cognitive impairment, his or her performance declines slightly on a few measures. When shown on a graph, these changes cause the healthy symmetric, bell-shaped curve to shift and become asymmetrical. Regardless of how low a person’s test scores were, the researchers determined that lopsidedness in their score distribution correlated with dementia.

They predicted that people with low scores that were evenly distributed were not likely to develop dementia. But those with clearly lopsided test score distributions on the 13 measures administered were already experiencing varying levels of dementia.

“Departures from the normal bell-shaped pattern of variability on cognitive tests might determine which people with low scores develop dementia,” says David J. Schretlen, Ph.D., a professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine and leader of a study published online in the November 2013 issue of the journal Neuropsychology. Since these declines can be subtle, the researchers also increased the precision of cognitive testing by accounting for the effects of age, sex, race and education on test performance.

The challenge for doctors, Schretlen explains, is that most normal, healthy people will produce a few low scores on cognitive testing. That makes it nearly impossible to know at the outset whether a patient who reports forgetfulness and produces one or two low scores has a benign form of mild cognitive impairment, or is in the earliest stage of dementia. As a result, doctors often tell such patients to return for followup testing in a year or two.

But if future research confirms it, this new statistical model could help doctors get the prognosis right earlier in the disease, at the first visit, and start treating patients accordingly.



New research finds Mediterranean diet without breakfast best for diabetics

For patients with diabetes, it is better to eat a single large meal than several smaller meals throughout the day. This is the result of a current dietary study done at Link?ping University in Sweden. In the study, the effect on blood glucose, blood lipids and different hormones after meals were compared using three different macronutrient compositions in patients with Type 2 diabetes.

The three diets were a low-fat diet, a low-carbohydrate diet and a Mediterranean diet. The scientists observed 21 patients that tested all three diets in a randomized order. During each test day, blood samples were collected at six time points.

The low-fat diet had a nutrient composition that has traditionally been recommended in the Nordic countries, with about 55% of the total energy from carbohydrates. The low-carbohydrate diet had a relatively low content of carbohydrate; approximately 20% of the energy was from carbohydrates and about 50% of the total energy came from fat.

The Mediterranean diet was composed of only a cup of black coffee for breakfast, and with all the caloric content corresponding to breakfast and lunch during the other two test days accumulated to one large lunch. Furthermore, the total caloric content included energy from 150 ml (women) to 200 ml (men) of French red wine to ingest with the lunch. The food in the Mediterranean diet had an energy content from carbohydrates that was intermediate between the low-fat and the low-carbohydrate meals, and sources of fat were mainly olives and fatty fish.

“We found that the low-carbohydrate diet increased blood glucose levels much less than the low-fat diet but that levels of triglycerides tended to be high compared to the low-fat diet,” says Dr Hans Guldbrand, who, together with Professor Fredrik Nystrom, was the principal investigator of the study.

“It is very interesting that the Mediterranean diet, without breakfast and with a massive lunch with wine, did not induce higher blood glucose levels than the lowfat diet lunch, despite such a large single meal,” says Professor Nystr?m. “This suggests that it is favourable to have a large meal instead of several smaller meals when you have diabetes, and it is surprising how often one today refers to the usefulness of the so-called Mediterranean diet but forgets that it also traditionally meant the absence of a breakfast.

Our results give reason to reconsider both nutritional composition and meal arrangements for patients with diabetes,” says Professor Nystrom. l doi: 10.1371/journal.pone.0079324



NIH launches trial of investigational genital herpes vaccine

Researchers have launched an early-stage clinical trial of an investigational vaccine designed to prevent genital herpes disease. The US National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, is sponsoring the Phase I trial, which is being conducted at the NIH Clinical Center in Bethesda, Maryland.

Genital herpes is one of the most common sexually transmitted infections in the United States. Most genital herpes cases are caused by infection with herpes simplex virus type 2 (HSV-2); however, herpes simplex virus type 1 (HSV-1) can also cause genital herpes. An estimated 776,000 people in the United States are infected with HSV-2 or HSV-1 each year. There is no vaccine to prevent genital herpes.

“Although genital herpes is treatable, it is a lifelong infection that can exact a substantial psychological and physical toll on infected individuals and places them at higher risk of acquiring HIV,” said NIAID Director Anthony S. Fauci, M.D.

“Furthermore, mothers with active genital herpes infection at time of delivery can transmit the virus to their newborns, which can lead to severe illness and death.” “A protective vaccine would help to reduce significantly the spread of this alltoo- common sexually transmitted infection,” Fauci added.

Led by principal investigator Lesia K. Dropulic, M.D., of NIAID’s Laboratory of Infectious Diseases, the trial will test an investigational HSV-2 vaccine candidate, called HSV529, for safety and the ability to generate an immune system response.

The investigational vaccine manufactured by Sanofi Pasteur was developed by David Knipe, Ph.D., professor of microbiology and immunobiology at Harvard Medical School, Boston. Pre-clinical testing of the candidate vaccine involved a 10-year collaborative effort between Dr. Knipe and Jeffrey Cohen, M.D., chief of NIAID’s Laboratory of Infectious Diseases. The experimental product is a replication-defective vaccine, meaning that scientists have removed two key proteins from the vaccine virus so that it cannot multiply to cause genital herpes.

The clinical trial is expected to enrol 60 adults ages 18 to 40, who will be divided into three groups of 20 participants each. The first group will be of people who have been previously infected with HSV-2 and HSV-1 or solely with HSV-2; the second will have individuals who had been infected with HSV-1 only; and the third will consist of those who have not been infected with HSV-1 or HSV-2. The investigational vaccine is being tested among study participants who have previously been infected with HSV to determine if it may pose any safety issues.

Within each of the three groups, researchers will randomly assign participants to receive three doses (0.5 milliliters each) of the investigational HSV529 vaccine (15 participants) or a saline-based placebo vaccine (five participants). The three vaccinations will occur at study enrollment and again one month and six months later. Participant safety will be monitored throughout the course of the trial, and researchers will follow participants for six months after they have received their last dose of vaccine.

Blood samples will be used to evaluate the candidate vaccine’s ability to stimulate immune system responses to HSV-2, including production of virusspecific antibodies and T-cell responses. The study is expected to be completed by October 2016. HSV-2 is generally transmitted through sexual contact and can spread even when the infected individual shows no symptoms.

Although HSV-1 commonly infects the mouth and lips, it can also cause genital herpes. Once in the body, HSV migrates to nerve cells and remains there permanently, where it can reactivate to cause painful sores and blisters.



New way to grow neural stem cells may aid brain therapy

Researchers have discovered a new, highly efficient way to produce neural stem cells from human pluripotent stem cells that can then go on to form neurons in the brain.

The discovery, reported in the November 2013 issue of Stem Cells Translational Medicine, could greatly accelerate the development of new drug and cell therapies for people suffering from brain injuries or disease. Human pluripotent stem cells (hPSCs), including human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs), show great promise in regenerative medicine due to their ability to be “coaxed” into becoming different specific types of cells.

These cells can theoretically then go on to help the body heal itself by replacing or repairing damaged or dead cells. However, the current methods for inducing neural stem cells involve time-consuming, multiple labor-intensive steps that cannot be easily automated or made GMP (good manufacturing practice) compliant for clinical grade manufacture.

In addition, not many of the neural stem cells produced this way can be expanded and coaxed into becoming different neural subtypes specific to the brain regions responsible for controlling different functions.

“Towards this critical need, we have developed a simple one-step protocol with a GMP-manufactured medium that is rapid and efficient in the derivation of neural stem cells (from hPSCs) that retain the cues to differentiate into different disease relevant neurons. By starting with a million pluripotent stem cells, it is possible to get approximately 40 to 50 million neural stem cells in seven days,” said Mohan C. Vemuri, Ph.D., director of research and development for Cell Biology and Stem Cell Systems at Life Technologies, Frederick, Md.

He was lead author of the study done in conjunction with researchers from Buck Institute for Age Research, Novato, California, the Methodist Hospital Research Institute in Houston and the National Institutes of Health, Bethesda, Maryland. “This method sets the stage for producing neural cells that potentially could lead to new therapies for diseases such as Parkinson’s,” he added.

“Whether the intended use is drug discovery or cell therapies for neurological diseases, it is essential to develop efficient and reproducible differentiation methods for neurons,” said Anthony Atala, M.D., editor of Stem Cells Translational Medicine and director of the Wake Forest Institute for Regenerative Medicine. “This study reports on a new method for the robust and reproducible production of neural stem cells.” l doi: 10.5966/sctm.2013-0080



Newly discovered brown fat cells may help treat diabetes, obesity

Obesity and diabetes have become a global epidemic leading to severe cardiovascular disease. Researchers at the University of Utah believe their recent identification of brown fat stem cells in adult humans may lead to new treatments for heart and endocrine disorders, according to a new study published in the peer-reviewed journal Stem Cells.

The study was led by Amit N. Patel, M.D. M.S., director of Clinical Regenerative Medicine and Tissue Engineering, and associate professor in the Division of Cardiothoracic Surgery at the University of Utah School of Medicine. Prior to Patel’s study, it was thought that brown fat stem cells did not exist in adults.

Children have large amounts of brown fat that is highly metabolically active, which allows them to eat large amounts of food and not gain weight. Patel notes, adults generally have an abundance of white fat in their bodies, which leads to weight gain and cardiovascular disease but this is not seen in brown fat.

As people age, the amount of white fat increases and brown fat decreases which contributes to diabetes and high cholesterol. “If you have more brown fat, you weigh less, you’re metabolically efficient, and you have fewer instances of diabetes and high cholesterol. The unique identification of human brown fat stem cells in the chest of patients aged from 28 to 84 years is profound.

We were able to isolate the human stem cells, culture and grow them, and implant them into a pre-human model which has demonstrated positive effects on glucose levels,” said Patel. The new discovery of finding brown fat stem cells may help in identifying potential drugs that may increase the body’s own ability to make brown fat or find novel ways to directly implant the brown fat stem cells into patients.



Researchers find two forms of Parkinson’s

Why can the symptoms of Parkinson’s disease vary so greatly from one patient to another? A consortium of researchers, headed by a team from the Laboratoire CNRS d’Enzymologie et Biochimie Structurales, is well on the way to providing an explanation.

Parkinson’s disease is caused by a protein known as alpha-synuclein, which forms aggregates within neurons, killing them eventually. The researchers have succeeded in characterizing and producing two different types of alpha-synuclein aggregates. Better still, they have shown that one of these two forms is much more toxic than the other and has a greater capacity to invade neurons.

This discovery takes account, at the molecular scale, of the existence of alphasynuclein accumulation profiles that differ from one patient to the next. These results, published October 10 in Nature Communications, represent a notable advance in our understanding of Parkinson’s Disease and pave the way for the development of specific therapies targeting each form of the disease.

Parkinson’s Disease, which is the second most frequent neurodegenerative disease after Alzheimer’s, affects some 150,000 people in France. According to those suffering from the disease, it can manifest itself in the form of uncontrollable shaking (in 60% of patients) or by less localized symptoms such as depression, behavioural and motor disorders.

These differences in symptoms point to different forms of Parkinson’s disease. This condition, for which no curative treatment currently exists, is caused by the aggregation in the form of fibrillar deposits of alpha-synuclein, a protein that is naturally abundant at neuron junctions.

These misfolded alpha-synuclein aggregates propagate between neurons. When they invade a new neuron, they are capable of recruiting normal alpha-synuclein and adding it to the deposit. For this reason, many researchers advocate that the alpha-synuclein of the aggregates should be considered as an infectious protein, in other words a prion.

Highly toxic, the alpha-synuclein deposits end up by triggering a process of apoptosis, i.e. cell death. The researchers have shown that there is not just one single type of aggregate. They succeeded in producing two types of aggregate that only differ in how the protein stacks up. At the millionth of a millimetre scale, the first form of aggregate resembles spaghetti, whereas the second form is long and flat, recalling the shape of wider pasta such as linguine. The team of scientists then tried to determine whether these structural differences result in functional differences.

To find out, they placed the two types of aggregates in contact with neuronal cells in culture. They discovered that the capacity of the “spaghetti” form to bind to and penetrate cells is notably greater than that of the “linguine” form. The “spaghetti” form is also considerably more toxic and rapidly kills the infected cells.

This form has shown itself to be capable of resisting the cell mechanisms responsible for eliminating it, whereas the “linguine” form is, to a certain extent, controlled by the cell. The researchers are convinced that the existence of at least two forms of alphasynuclein aggregates explains why doctors are faced with different Parkinson’s Diseases depending on the patient. Experiments on mice are currently under way to confirm this hypothesis.

Furthermore, the scientists consider that analysis of the type of aggregate could lead to an efficient diagnosis method, which would make it possible, in particular, to assess the virulence of the disease for each patient. Finally, they hope that by refining the characterization of the structure of the aggregates, it will be possible to develop targeted therapeutic strategies for each variant in order to slow down the propagation of abnormal alpha-synuclein within the brain.

                                  
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