Observations of a blown mind

Health

Scientists discover a natural molecule to treat type 2 diabetes


Image (c) Allan Miller - used with thanks.

Image (c) Allan Miller – used with thanks.

Researchers at the Université Laval Faculty of Medicine, the Quebec Heart and Lung Institute Research Center, and the Institute of Nutrition and Functional Foods have discovered a natural molecule that could be used to treat insulin resistance and type 2 diabetes. The molecule, a derivative of omega-3 fatty acids, mimics some of the effects of physical exercise on blood glucose regulation. The details of the discovery made by Professor André Marette and his team are published today in Nature Medicine.

It has been known for some time that omega-3 fatty acids can help reduce insulin resistance caused by a diet high in saturated fat. In their earlier work, André Marette and his colleagues had linked these effects to a bioactive lipid called protectin D1. In investigating further, they discovered that another member of the same family named protectin DX (PDX) triggers the production and release of interleukin 6 (IL-6) in muscle cells, a response that also occurs during physical exercise. “Once in the bloodstream, IL-6 controls glucose levels in two ways: it signals to the liver to reduce glucose production and acts directly on the muscles to increase glucose uptake,” explains the researcher who is also Scientific Director of Université Laval’s Institute of Nutrition and Functional Foods.

The researchers used transgenic mice lacking the IL-6 gene to demonstrate the link between PDX and IL-6. PDX had very little effect on the control of blood glucose in these animals. In similar tests conducted on obese diabetic rats, PDX was shown to dramatically improve responsiveness to insulin, the hormone which regulates blood glucose. “The mechanism of action described for PDX represents a new therapeutic strategy for improving glucose control,” proposes the researcher. “Its efficacy may be comparable with that of certain drugs currently prescribed to control glycemia.”

Even though PDX appears to mimic the effect of physical exercise by triggering IL-6 secretion in the muscles, André Marette warns that it is not a substitute for physical activity. “Exercise has cardiovascular and other hormonal benefits that go well beyond its metabolic effects on the muscles,” adds the researcher whose work is supported by the Canadian Institutes of Health Research (CIHR) and the Canadian Diabetes Association.

Professor Marette and Université Laval have filed a patent application for PDX and its therapeutic applications. “For us, the next step is to demonstrate the antidiabetic effects in humans and determine the receptor through which PDX acts.”

NOTES;

In addition to André Marette, the study is authored by Phillip White, Philippe St-Pierre, Alexandre Charbonneau, Patricia Mitchell, Emmanuelle St-Amand, and Bruno Marcotte.

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Breaking bad mitochondria


Mitochondria in hepatitis C-infected cells (bottom row) are self-destructing. The self-annihilation process explains the persistance and virulence of the virus in human liver cells. Credit: UC San Diego School of Medicine

Mitochondria in hepatitis C-infected cells (bottom row) are self-destructing. The self-annihilation process explains the persistance and virulence of the virus in human liver cells.
Credit: UC San Diego School of Medicine

Researchers at the University of California, San Diego School of Medicine have identified a mechanism that explains why people with the hepatitis C virus get liver disease and why the virus is able to persist in the body for so long.

The hard-to-kill pathogen, which infects an estimated 200 million people worldwide, attacks the liver cells’ energy centers – the mitochondria – dismantling the cell’s innate ability to fight infection. It does this by altering cells mitochondrial dynamics.

The study, published in today’s issue of the Proceedings of the National Academy of Sciences, suggests that mitochondrial operations could be a therapeutic target against hepatitis C, the leading cause of liver transplants and a major cause of liver cancer in the U.S.

“Our study tells us the story of how the hepatitis C virus causes liver disease,” said Aleem Siddiqui, PhD, professor of medicine and senior author. “The virus damages mitochondria in liver cells. Cells recognize the damage and respond to it by recruiting proteins that tell the mitochondria to eliminate the damaged area, but the repair process ends up helping the virus.”

Mitochondria are organelles in a cell that convert energy from food (glucose) into a form of energy that can be used by cells called adenosine triphosphate.

Specifically, the researchers discovered that the virus stimulates the production of a protein (Drp 1) that induces viral-damaged mitochondria to undergo asymmetric fragmentation. This fragmentation (fission) results in the formation of one healthy mitochondrion and one damaged or bad mitochondrion, the latter of which is quickly broken down (catabolized) and dissolved in the cell’s cytoplasm.

Although the fragmentation serves to excise the damaged area from the mitochondrion, the formation of a healthy mitochondrion also helps keep the virus-infected cell alive. Moreover, the virus is able to use the mitochondrial remains (all the amino acids and lipids from the catabolized mitochondrion) to help fuel its continued replication and virulence.

“It’s like the bad part of the house is demolished to the benefit of the virus,” Siddiqui said.

In their experiments, the researchers showed that hepatitis C-infected cells with higher Drp 1 protein levels also produced less interferon, the body’s natural immune booster. These cells were also less likely to undergo apoptosis, a process that would encourage damaged cells to essentially kill themselves.

The reverse was also observed: When the Drp 1 protein was “silenced,” interferon production and apoptotic activity increased.

“Mitochondrial processes are at the center of understanding the persistence of the virus and how it flies under the radar of the body’s natural immune response,” he said. “The trick is to find a way to deliver a drug that could target the Drp 1 protein specifically in hepatitis C-infected liver cells, maybe through nanotechnology.


Nanoparticles to probe mystery sperm defects behind infertility


 

This is boar sperm mixed with mesoporous silica nanoparticles that have been tagged with fluorescent green dye for identification. These nanoparticles were developed by Oxford University researchers to investigate 'mystery' cases of infertility. They can be loaded with any compound to identify, diagnose or treat the causes of infertility. Credit: Natalia Barkalina/Oxford University

This is boar sperm mixed with mesoporous silica nanoparticles that have been tagged with fluorescent green dye for identification. These nanoparticles were developed by Oxford University researchers to investigate ‘mystery’ cases of infertility. They can be loaded with any compound to identify, diagnose or treat the causes of infertility.
Credit: Natalia Barkalina/Oxford University

A way of using nanoparticles to investigate the mechanisms underlying ‘mystery’ cases of infertility has been developed by scientists at Oxford University.

The technique, published in Nanomedicine: Nanotechnology, Biology and Medicine, could eventually help researchers to discover the causes behind cases of unexplained infertility and develop treatments for affected couples. The method involves loading porous silica nanoparticle ‘envelopes’ with compounds to identify, diagnose or treat the causes of infertility.

The researchers demonstrated that the nanoparticles could be attached to boar sperm with no detrimental effects on their function.

‘An attractive feature of nanoparticles is that they are like an empty envelope that can be loaded with a variety of compounds and inserted into cells,’ says Dr Natalia Barkalina, lead author of the study from the Nuffield Department of Obstetrics and Gynaecology at Oxford University. ‘The nanoparticles we use don’t appear to interfere with the sperm, making them a perfect delivery vessel.

‘We will start with compounds to investigate the biology of infertility, and within a few years may be able to explain or even diagnose rare cases in patients. In future we could even deliver treatments in a similar way.’

Sperm are difficult to study due to their small size, unusual shape and short lifetime outside of the body. Yet this is a vital part of infertility research, as senior author Dr Kevin Coward explains: ‘To discover the causes of infertility, we need to investigate sperm to see where the problems start. Previous methods involved complicated procedures in animals and introduced months of delays before the sperm could be used.

‘Now, we can simply expose sperm to nanoparticles in a petri dish. It’s so simple that it can all be done quickly enough for the sperm to survive perfectly unharmed.’

This is a cluster of mesoporous silica nanoparticles under a scanning electron microscope. These nanoparticles, developed at Oxford University, can be inserted into sperm to investigate unexplained infertility cases. They can be loaded with compounds to identify, diagnose or treat infertility. Credit: Natalia Barkalina/Oxford University

This is a cluster of mesoporous silica nanoparticles under a scanning electron microscope. These nanoparticles, developed at Oxford University, can be inserted into sperm to investigate unexplained infertility cases. They can be loaded with compounds to identify, diagnose or treat infertility.
Credit: Natalia Barkalina/Oxford University

The team, based at the Institute of Reproductive Sciences, used boar sperm because of its similarities to human sperm, as study co-author Celine Jones explains: ‘It is similar in size, shape and activity. Now that we have proven the system in boar sperm, we hope to replicate our findings in human sperm and eventually see if we can use them to deliver compounds to eggs as well.’

The research was an interdisciplinary effort, involving reproductive biologists from the Nuffield Department of Obstetrics & Gynaecology and nanoscientists from the Department of Engineering Science led by Dr Helen Townley.

The study was funded by the Nuffield Department of Obstetrics & Gynaecology at Oxford University and the Engineering and Physical Sciences Research Council (EPSRC). This technique is the subject of patent applications held by Isis Innovation, Oxford University’s technology transfer arm.

 


Drug offers to improve outcome for children with high-risk leukemia


St. Jude Children’s Research Hospital leads study showing that a drug withdrawn from the market in 2010 may enhance the effectiveness of bone marrow transplants for select pediatric leukemia patients.

Jeffrey Rubnitz, M.D., Ph.D., of St. Jude Children's Research Hospital, led a study that suggests some pediatric AML patients may benefit from drugs designed to kill cells that carry a particular protein on their surface. Credit: St. Jude Biomedical Communications

Jeffrey Rubnitz, M.D., Ph.D., of St. Jude Children’s Research Hospital, led a study that suggests some pediatric AML patients may benefit from drugs designed to kill cells that carry a particular protein on their surface.
Credit: St. Jude Biomedical Communications

Combining the drug gemtuzumab ozogamicin (GO) with conventional chemotherapy may improve the outcome of bone marrow transplantation for some children battling high-risk acute myeloid leukemia (AML), according to a study led by St. Jude Children’s Research Hospital. The results appear in the current edition of the journal Cancer.

For young AML patients with suitable bone marrow donors, transplantation offers the best chance of a cure. Being free of even low levels of detectable cancer cells prior to transplantation is associated with better patient survival. This analysis found that combination therapy helped to eliminate minimal residual disease (MRD) in young AML patients who initially had a poor response to chemotherapy. By reducing MRD levels prior to transplantation, it is likely that GO contributed to the excellent outcome of these patients, researchers said.

The drug, trade named Mylotarg, received accelerated approval from the U.S. Food and Drug Administration in 2000 for treatment of AML in adults. The drug was voluntarily withdrawn in 2010 following questions about its safety and efficacy. Since then several studies conducted while the drug was authorized reported promising results in adults with AML. Those reports prompted this analysis of pediatric AML patients who received GO in a clinical trial conducted while the drug was available.

Researchers said the results add to evidence that both adults and children battling AML may benefit from treatments that use a similar mechanism as GO to combat AML. The drug was not associated with severe toxicity in this or other recent studies.

Unlike traditional chemotherapy that kills rapidly dividing cells, both malignant and healthy, GO was designed to kill more selectively. The drug works by targeting a protein carried on the surface of about 90 percent of AML cells. Work has begun on new strategies, including antibody-based therapies, that target the same AML surface protein, said the study’s senior author Jeffrey Rubnitz, M.D., Ph.D., a member of the St. Jude Department of Oncology.

AML is diagnosed in about 500 children annually and accounts for about 20 percent of childhood leukemia. The disease affects white blood cells.

“Currently there are few options for AML patients who relapse or do not respond to conventional therapy,” said first author Carol O’Hear, M.D., Ph.D., a St. Jude postdoctoral oncology fellow. Added Rubnitz: “Without new agents, it is unlikely we will be able to improve pediatric AML survival beyond current levels of about 70 percent. The results of this and earlier studies make a strong case that some patients benefit from this targeted therapy, which has us looking for new ways to take aim at the same protein.”

This study involved a subset of patients enrolled in a clinical trial of pediatric AML called AML02. Altogether, 232 children with AML enrolled in the six-year, multicenter trial that ended in 2008. A total of 46 patients received GO alone or in combination with conventional chemotherapy.

For this analysis, researchers wanted to know if GO was associated with reduced MRD. Patients were considered free of MRD if less than one cancer cell could be detected in 1,000 normal bone marrow cells.

Seventeen patients received GO alone when MRD was detected after two rounds of chemotherapy with the drugs cytarabine, daunorubicin and etoposide. After GO treatment, leukemia declined in 14 of the 17 patients and fell to undetectable levels in 13 patients.

An additional 29 patients received GO as part of their second round of three-drug chemotherapy. All had levels of residual disease that indicated a poor initial response to chemotherapy alone, including nine with MRD levels of 25 percent or more. Residual disease fell to undetectable levels in four of the nine patients following combination therapy.

Malignant cells fell to undetectable levels in 45 percent, or nine of the remaining 20 patients whose second round of treatment included GO plus chemotherapy. The patients all had MRD of between 1 and 25 percent after the first round of chemotherapy.

The overall five-year survival level of the 20 patients was 55 percent, compared to 36 percent for 22 patients with similar MRD who received chemotherapy alone. The survival difference between the two groups was not statistically significant, but investigators said the results point to a possible benefit of GO treatment for some pediatric AML patients whose cancer remained following chemotherapy. The 22 patients were treated early in AML02 before the protocol was revised to expand the use of GO. The revision followed evidence that the drug was well tolerated by the young AML patients.

Notes –

The other authors are Hiroto Inaba, Stanley Pounds, Lei Shi, Ching-Hon Pui and Raul Ribeiro, all of St. Jude; Gary Dahl, Packard Children’s Hospital and Stanford Cancer Center, Palo Alto, Calif.; W. Paul Bowman, Cook Children’s Medical Center, Fort Worth, Texas; Jeffrey Taub, Children’s Hospital of Michigan, Detroit; and Elaine Coustan-Smith and Dario Campana, National University of Singapore.


New SARS-like coronavirus discovered in Chinese horseshoe bats


10 years after SARS outbreak – Ecohealth Alliance finds plausible evidence for direct bat to human transmission

Rhinolophus sinicus is the host of the newly discovered SL-CoV. Credit: Dr. Libiao Zhang, Guangdong Entomological Institute/South China Institute of Endangered Animals

Rhinolophus sinicus is the host of the newly discovered SL-CoV.
Credit: Dr. Libiao Zhang, Guangdong Entomological Institute/South China Institute of Endangered Animals

EcoHealth Alliance, a nonprofit organization that focuses on local conservation and global health issues, announced the discovery of a new SARS-like coronavirus (CoV) in Chinese horseshoe bats. Ten years after the SARS outbreak, EcoHealth Alliance scientists and an international group of collaborators have uncovered genome sequences of a new virus closely related to the SARS coronavirus that erupted in Asia in 2002 – 2003, which caused a global pandemic crisis. For the first time ever, the group was able to isolate the live SARS-like virus from bats allowing scientists to conduct detailed studies to create control measures to thwart outbreaks and provide opportunities for vaccine development. The research team involved scientists from China, Australia, Singapore, and the U.S. and the results were published today in the journal Nature. “Our discovery that bats may directly infect humans has enormous implications for public health control measures,” stated co-senior author Peter Daszak, PhD, President of EcoHealth Alliance. Dr. Daszak is also principal investigator on a National Institutes of Health (NIH)/National Science Foundation (NSF) Ecology and Evolution of Infectious Diseases (EEID) grant, and leads EcoHealth Alliance’s work on the USAID PREDICT project, both of which funded the current work. “Since 2003 there has been disagreement about the origin of the virus that directly evolved into human SARS-CoV, the causative agent of the first emerging pandemic threat of the 21st century. Even though our team reported that bats are natural reservoirs of SARS-like coronaviruses in 2005, we have been searching for this missing link for 10 years, and finally we’ve found it,” said Dr. Zhengli Shi, Director of Emerging Infectious Diseases at the Wuhan Institute of Virology, Chinese Academy of Sciences and co-senior author on the paper.

The research team isolated and cultured a live virus that binds to the human SARS receptor ACE2 and can therefore be transmitted directly from bats to people. During the original outbreak of SARS in the wet markets of Guangdong province in China over 10 years ago, it was thought that bat viruses first infected civets, and then the virus evolved to infect people by this intermediate wildlife host. The current breakthrough suggests that SARS may have originated from one of these viruses, precluding civets from playing a part in the transmission process. “This paper hasn’t resolved the provenance of SARS CoV; nonetheless, it does provide compelling evidence that an intermediate host was not necessary,” commented W. Ian Lipkin, MD, John Snow Professor and Director, Center for Infection and Immunity of Columbia University.

“EcoHealth Alliance continues to work on predicting and preventing the next pandemic crisis. Our research uncovered a wide diversity of potentially pandemic viruses present, right now, in bats in China that could spillover into people and cause another SARS-like outbreak. Even worse, we don’t know how lethal these viruses would be if such an outbreak erupted,” said Dr. Daszak. “The results point out the importance of continuing surveillance of viruses in bats, with the goals of identifying other viruses, including coronaviruses, that could cross species and potentially cause serious disease in humans or domesticated animals,” conveyed Stanley Perlman, M.D., Ph.D.
Professor
in the Department of Microbiology University of Iowa.

“There are lessons here for the recent outbreak of Middle East Respiratory Syndrome coronavirus that likely originated in Saudi Arabian bats. We need to protect bat habitats from severe human-induced changes to the environment as well as create public health measures to reduce the risk of transmission,” continued Daszak. It is not uncommon for bats to be used as a food source for many people in China and other parts of Asia so the risk is substantial. EcoHealth Alliance is working to help find alternative measures to decrease the hunting of bats for food and sport as well as monitoring the global wildlife trade. Bats are vitally important to the health of ecosystems providing seed dispersal and pollination services while also controlling insect populations and agricultural pests.

EcoHealth Alliance’s contribution to the USAID-funded PREDICT program targets pathogen discovery in high-risk wildlife species in emerging disease global hotspots. This is a completely new approach for pandemic diseases – most of which originate in wildlife – in this case EcoHealth Alliance scientists are identifying the wildlife host and cataloging both known and previously unknown viruses before spillover events could infect people.

The results published in Nature, are based on genetic analyses of samples taken over the course of a year from members of a horseshoe bat colony in Kunming, China. At least seven different strains of SARS-like CoVs were found to be circulating within the single group of bats. The findings highlight the importance of research programs targeting high-risk wildlife groups in emerging disease hotspots to predict, prepare for, and prevent pandemics.

PREDICT is part of USAID’s Emerging Pandemic Threats (EPT) program, designed to target surveillance of wildlife populations and identify potential pandemic viruses before they emerge. “This work validates our assumption that we should be searching for viruses of pandemic potential before they spillover to humans. That USAID has designed and implemented such an innovative approach through their EPT program is very forward thinking. We may finally begin to get ahead of the curve and prevent pandemics,” said University of California, Davis, School of Veterinary Medicine, One Health Institute Director, Professor Jonna Mazet, Co-Director of PREDICT.

“The paradigm setting study provides the most compelling information to date that zoonotic coronaviruses, like SARS-CoV and perhaps the MERS-CoV, are preprogrammed to transmit directly between species. Clearly, SARS-CoV is not extinct, but rather, the virus is hiding out in animal reservoirs-poised to recolonize the human host at the first opportunity. The study further demonstrates the critical importance of continued surveillance and the development of public health preparedness platforms to control these important and deadly emerging human coronaviruses,” said Ralph Baric, Professor, Department of Epidemiology, School of Public Health, University of North Carolina at Chapel Hill.

Notes –

Dr. Daszak’s EEID grant (R01TW005869)—managed by the Fogarty International Center at NIH—is part of a joint NIH-NSF initiative that supports efforts to understand the underlying ecological and biological mechanisms that govern relationships between human-induced environmental changes and the emergence and transmission of infectious diseases. Additional U.S. government funding for the research came from the National Institute of Allergy and Infectious Diseases at NIH (R01AI079231), a Fogarty award supported with International Influenza Funds from the Department of Health and Human Services (R56TW009502) and the United States Agency for International Development (USAID) Emerging Pandemic Threats PREDICT initiative. The State Key Program for Basic Research and the National Natural Science Foundation of China also provided support.

 


Preventable risk factors pose serious threat to heart health of childhood cancer survivors


A Childhood Cancer Survivors Study led by St. Jude Children’s Research Hospital suggests that reducing risk factors like hypertension might lower the risk of heart disease for survivors as they age

For childhood cancer survivors, risk factors associated with lifestyle, particularly hypertension, dramatically increase the likelihood of developing serious heart problems as adults, according to a national study led by St. Jude Children’s Research Hospital. The findings appear in the current issue of the Journal of Clinical Oncology.

The Childhood Cancer Survivor Study (CCSS) is one of the first to focus on how hypertension, diabetes, obesity and elevated blood lipids contribute to cardiovascular disease in childhood cancer survivors. The research concentrated on risk factors that can often be modified with diet, exercise and other lifestyle changes. The federally funded CCSS follows survivors of childhood cancer treated at 26 medical centers in the U.S. and Canada. St. Jude is its coordinating center.

The risk was greatest for survivors whose cancer treatment had included therapies associated with heart damage. The findings suggest that risk factors linked to lifestyle, particularly hypertension, intensify the impact of those childhood cancer treatments and accelerate development of heart disease.

The findings raise hope that prevention or treatment of such risk factors might help reduce heart-related death and disability among the nation’s growing population of childhood cancer survivors. For survivors, treatment-related heart disease is a leading cause of non-cancer death and disability.

The results reinforce the importance of survivors receiving annual medical screenings to check blood pressure, weight, cholesterol and other health indicators, said the study’s first and corresponding author Greg Armstrong, M.D., an associate member of the St. Jude Department of Epidemiology and Cancer Control. Screenings have a track record of reducing heart disease in the general population and are recommended for childhood cancer survivors. “For doctors who are caring for survivors, the key message from this study is that aggressive management of hypertension is especially important for this population,” Armstrong said.

Nationwide, there are an estimated 395,000 survivors of childhood cancer. With overall pediatric cancer survival rates now 80 percent, the number of survivors will continue to grow.

The study included 10,724 childhood cancer survivors, half younger than 34 years old and 3,159 siblings whose average age was 36 and who had not been diagnosed with childhood cancer. The survivors were all at least five years from their cancer diagnosis and half had survived for more than 25 years.

Research led by Greg Armstrong, M.D., of St. Jude Children's Research Hospital suggests that reducing risk factors like hypertension might lower the risk of heart disease for childhood cancer survivors as they age. Credit: St. Jude Biomedical Communications

Research led by Greg Armstrong, M.D., of St. Jude Children’s Research Hospital suggests that reducing risk factors like hypertension might lower the risk of heart disease for childhood cancer survivors as they age.
Credit: St. Jude Biomedical Communications

While similar percentages of survivors and siblings reported at least two preventable risk factors, by age 45 survivors were far more likely than the siblings to report severe, life threatening or fatal heart problems. For example, 5.3 percent of survivors, but 0.9 percent of siblings, reported a diagnosis of coronary artery disease and, 4.8 percent of survivors, but just 0.3 percent of siblings, reported suffering from heart failure.

The difference was even more dramatic when investigators focused on survivors whose cancer treatment included either chest irradiation or a class of chemotherapy drugs known as anthracyclines. Both are associated with an increased risk of serious heart problems. While treatments have changed since survivors in this study battled cancer in the 1970s and mid-1980s, anthracyclines and chest irradiation still play essential roles in childhood cancer treatments.

Such treatment-related risk left survivors with normal blood pressure at a five-fold increased risk of coronary artery disease. Researchers found survivors with the same treatment history but who had also developed hypertension were at a 37-fold increased risk. Researchers found similarly dramatic differences in the likelihood of heart failure, heart valve disease or arrhythmia depending on whether the at-risk survivors reported treatable risk factors in addition to their cancer-treatment-related risk.

“For survivors whose cancer treatment included cardio-toxic therapy, we found that preventable factors, particularly hypertension, resulted in a risk beyond what is likely from a simple additive effect,” Armstrong said. Having both treatment-associated risk and hypertension resulted in double-digit excess risk of coronary artery disease, heart failure and other serious heart problems.

Hypertension, diabetes, obesity and high blood lipid levels significantly increase the risk that childhood cancer survivors will develop serious cardiovascular disease as adults. Credit: Betsy Williford of St. Jude Biomedical Communications

Hypertension, diabetes, obesity and high blood lipid levels significantly increase the risk that childhood cancer survivors will develop serious cardiovascular disease as adults.
Credit: Betsy Williford of St. Jude Biomedical Communications

The study’s other authors are Kevin Oeffinger and Charles Sklar, both of Memorial Sloan-Kettering Cancer Center, New York; Yan Chen and Yutaka Yasui, both of University of Alberta, Edmonton; Toana Kawashima, Wendy Leisenring and Eric Chow, all of Fred Hutchinson Cancer Research Center, Seattle; Marilyn Stovall and Jean-Bernard Durand, both of the University of Texas M.D. Anderson Cancer Center, Houston; Daniel Mulrooney and Leslie Robison, both of St. Jude; and Ann Mertens, William Border and Lillian Meacham, all of Emory University, Atlanta.


New urine test could diagnose eye disease


You might not think to look to a urine test to diagnose an eye disease.

But a new Duke University study says it can link what is in a patient’s urine to gene mutations that cause retinitis pigmentosa, or RP, an inherited, degenerative disease that results in severe vision impairment and often blindness. The findings appear online in the Journal of Lipid Research.

“My collaborators, Dr. Rong Wen and Dr. Byron Lam at the Bascom Palmer Eye Institute in Florida first sought my expertise in mass spectrometry to analyze cells cultured from a family in which three out of the four siblings suffer from RP,” said Ziqiang Guan, an associate research professor of biochemistry in the Duke University Medical School and a contributing author of the study.

Guan’s collaborators had previously sequenced the genome of this family and found that the children with RP carry two copies of a mutation at the dehydrodolichol diphosphate synthase (DHDDS) gene, which makes the enzyme that synthesizes organic compounds called dolichols. In humans, dolichol-19, containing 19 isoprene units, is the most abundant species.

The DHDDS mutation, which was found in 2011, is the latest addition to more than 60 gene mutations that have been implicated in RP. This mutation appears to be prevalent in RP patients of the Ashkenazi Jewish origin, and 1 in 322 Ashkenazi carries one copy of the mutation.

“I knew from my previous experience in analyzing urine samples from liver disease patients that I can readily detect dolichols by liquid chromatography and mass spectrometry,” Guan said. Using these techniques, he analyzed urine and blood samples from the six family members and found that instead of dolichol-19, the profiles from the three siblings with RP showed dolichol-18 as the dominant species. The parents, who each carry one copy of the mutated DHDDS gene, showed intermediate levels of dolichol-19 and higher levels of dolichol-18 than their healthy child. Guan believes dolichol profiling could effectively distinguish RP caused by DHDDS mutation from that caused by other mutations.

Guan and his collaborators hope to develop the dolichol profiling method as a first-line diagnostic test to identify RP patients with abnormal dolichol metabolism. They think this mass spectrometry-based detection method will help physicians provide more personalized care to RP patients, especially to young children whose retinal degeneration has not fully developed.

“Since the urine samples gave us more distinct profiles than the blood samples, we think that urine is a better clinical material for dolichol profiling,” he said. Urine collection is also easier than a blood draw and the samples can be conveniently stored with a preservative. The team is now pursuing a patent for this newl diagnostic test for the DHDDS mutation.

There are currently no treatments for RP, but Guan hopes his research will shed light on potential drug design strategies for treating RP caused by DHDDS mutation. “We are now researching ways to manipulate the dolichol synthesis pathway in RP patients with the DHDDS mutation so that the mutated enzyme can still produce enough dolichol-19, which we believe may be important for the rapid renewal of retinal tissue in a healthy individual.”

 

A composite image of the human retina shows diffused pigmentary retinal degeneration. Credit: Ziqiang Guan, Duke University Medical Center

A composite image of the human retina shows diffused pigmentary retinal degeneration.
Credit: Ziqiang Guan, Duke University Medical Center


Study identifies possible biomarker for Parkinson’s disease


Researchers discover that an important clue to diagnosing Parkinson’s disease may lie just beneath the skin.

Although Parkinson’s disease is the second most prevalent neurodegenerative disorder in the U.S., there are no standard clinical tests available to identify this widespread condition. As a result, Parkinson’s disease often goes unrecognized until late in its progression, when the brain’s affected neurons have already been destroyed and telltale motor symptoms such as tremor and rigidity have already appeared.

Now researchers from Beth Israel Deaconess Medical Center (BIDMC) have discovered that an important clue to diagnosing Parkinson’s may lie just beneath the skin.

In a study scheduled to appear in the October 29 print issue of the journal Neurology and currently published on-line, the investigators report that elevated levels of a protein called alpha-synuclein can be detected in the skin of Parkinson’s patients, findings that offer a possible biomarker to enable clinicians to identify and diagnose PD before the disease has reached an advanced stage.

Parkinson’s disease affects more than 1 million individuals throughout the U.S. Diagnosis is currently made through neurological history and examination, often by a patient’s primary care physician.

“Even the experts are wrong in diagnosing Parkinson’s disease a large percentage of the time,” says senior author Roy Freeman, MD, Director of the Autonomic and Peripheral Nerve Laboratory at BIDMC and Professor of Neurology at Harvard Medical School. “A reliable biomarker could help doctors in more accurately diagnosing Parkinson’s disease at an earlier stage and thereby offer patients therapies before the disease has progressed.”

Alpha-synuclein is a protein found throughout the nervous system. Although its function is unknown, it is the primary component of protein clumps known as Lewy bodies, which are considered the hallmark of Parkinson’s disease. There is accumulating evidence that the protein plays a role in Parkinson’s disease development.

“Alpha-synuclein deposition occurs early in the course of Parkinson’s disease and precedes the onset of clinical symptoms,” explains Freeman, who with his coauthors suspected that the protein was elevated in the skin’s structures with autonomic innervation.

“Symptoms related to the autonomic nervous system, including changes in bowel function, temperature regulation, and blood pressure control may antedate motor symptoms in Parkinson’s patients,” he explains. “Skin-related autonomic manifestations, including excessive and diminished sweating and changes in skin color and temperature, occur in almost two-thirds of patients with Parkinson’s disease. The skin can provide an accessible window to the nervous system and based on these clinical observations, we decided to test whether examination of the nerves in a skin biopsy could be used to identify a PD biomarker.”

To test this hypothesis, the research team enrolled 20 patients with Parkinson’s disease and 14 control subjects of similar age and gender. The participants underwent examinations, autonomic testing and skin biopsies in three locations on the leg. Alpha-synuclein deposition and density of cutaneous sensory, sudomotor and pilomotor nerve fibers were measured.

As predicted, their results showed that alpha-synuclein was increased in the cutaneous nerves supplying the sweat glands and pilomotor muscles in the Parkinson’s patients. Higher alpha-synuclein deposition in the nerves supplying the skin’s autonomic structures was associated with more advanced Parkinson’s disease and worsening autonomic function.

“There is a strong and unmet need for a biomarker for Parkinson’s disease,” says Freeman. “Alpha-synuclein deposition within the skin has the potential to provide a safe, accessible and repeatable biomarker. Our next steps will be to test whether this protein is present in the cutaneous nerves of individuals at risk for Parkinson’s disease, and whether measurement of alpha-synuclein deposition in the skin can differentiate Parkinson’s disease from other neurodegenerative disorders.”

Notes –  

Study coauthors include BIDMC investigators Ningshan Wang, PhD and Christopher Gibbons, MD (co-first authors) and Jacob Lafo.

This study was supported by National Institutes of Health grant K23NS020509 and grants from the Langer Family Foundation and the RJG Foundation.


Feeling blue?


fugates

You may well have seen the above image before, if you haven’t then settle down comfortably and I’ll relate to you a sad story of strong family ties and good reasons why inbreeding really isn’t a good idea.

As I understand it, our story begins when French orphan Martin Fugate settled on the banks of Troublesome Creek, (near Hazard, Kentucky), sometime after 1800 to claim a land grant and married a red-haired woman named Elizabeth Smith. She had a very pale complexion – and their union brought on the ‘methaemoglobinaemia’ genetic mutation, also known as met-H, which reduces an individual’s ability to carry oxygenated blood.  There were no railroads and few roads outside the region, so the community remained small and isolated. The Fugates married other Fugate cousins and families who lived nearby, with names like Combs, Smith, Ritchie and Stacy.

The most detailed account, Blue People of Troublesome Creek,” was published in 1982 by the University of Indiana’s Cathy Trost. The Fugates’ story still offers a window into a medical mystery that was solved through modern genetics and the sleuth-like energy of Dr. Madison Cawein III, a hematologist at the University of Kentucky’s Lexington Medical Clinic.  Cawein died in 1985, but his family charts and blood samples led to a sharper understanding of the recessive diseases that only surface if both parents carry a defective gene. The Fugate progeny had a genetic condition called methemoglobinemia, which was passed down through a recessive gene and blossomed through intermarriage. None of Martin and Mary Fugate’s descendants would have been blue had they not intermarried with a nearby clan, the Smiths. The Smiths were descendants of Richard Smith and Alicia Combs, one of whom apparently was also a met-H carrier. According to the family historian the first known blue Fugate was born in 1832. 

So what causes it?

Methemoglobinemia is a blood disorder in which an abnormal amount of methemoglobin — a form of hemoglobin — is produced, according to the National Institutes for Health. Hemoglobin is responsible for distributing oxygen to the body and without oxygen, the heart, brain and muscles can die.  With methemoglobinemia, the hemoglobin is unable to carry oxygen and it also makes it difficult for unaffected hemoglobin to release oxygen effectively to body tissues. Patients’ lips are purple, the skin looks blue and the blood is “chocolate colored” because it is not oxygenated. 

The disorder can be inherited, as was the case with the Fugate family, or caused by exposure to certain drugs and chemicals such as anesthetic drugs like benzocaine and xylocaine. The carcinogen benzene and nitrites used as meat additives can also be culprits, as well as certain antibiotics, including dapsone and chloroquine. Recently Paul Karason who appeared on TODAY to discuss methemoglobinemia passed away (click here), however, Karason started turning blue about 15 years ago after he began using a special silver-based preparation to treat a skin condition. He also had been drinking colloidal silver, a product consisting of silver particles suspended in liquid.

The genetic form of methemoglobinemia is caused by one of several genetic defects. The Fugates probably had a deficiency in the enzyme called cytochrome-b5 methemoglobin reductase, which is responsible for recessive congenital methemoglobinemia.

Normally, people have less than about 1 percent of methemoglobin, a type of hemoglobin that is altered by being oxidized so is useless in carrying oxygen in the blood. When those levels rise to greater than 20 percent, heart abnormalities and seizures and even death can occur. But at levels of between 10 and 20 percent a person can develop blue skin without any other symptoms. Most of blue Fugates never suffered any health effects and lived into their 80s and 90s.

If you are between 1 percent and 10 percent, no one knows you have an abnormal level and this might be the case in a lot of unsuspecting patients.  Many other recessive gene diseases, such as sickle cell anemia, Tay Sachs and cystic fibrosis can be lethal. 

For example if I carried a bad recessive gene with a rare abnormality and married, the child probably wouldn’t be sick, because it’s very rare to meet another person with the same bad gene, therefore the most frequent cause is in-breeding,

Such was the case with the Fugates.

Other mentionings of blue skinned folks 

Picts of Scotland

They are thought to have tattooed themselves. The name Pict derives from the Latin pictor, painter. Tattoos often have a bluish cast; still, there’s no definite evidence that the Picts were blue. Learn more here.

The Ainu

An indigenous people living in Japan whose skin hue is often described as blue. However, in anthropological literature their skin is described as brown. However, an 1891 Smithsonian report comments, “It is difficult to speak with confidence, for they do not bathe or wash, and the natural color of the skin is not often seen.” Learn more here.

Others

In Irish-Scottish Gaeilge (or Gaelic), people of African descent were historically referred to as the fir gorum, or blue men. People of this race were described as “blue” rather than as “black.” However a little research shows that the true blue men are the Tuareg, a nomadic group of people in the Sahara whose traditional territories included Mali and parts of Niger, Morocco, Algeria, and so on. They get their nickname from the blue robes they wear. Originally their clothing was deeply dyed with natural indigo. This was absorbed by the skin, which also took on a blue tinge. I have read that even babies were born with blue skin because of the indigo in their mothers’ blood, of this though I am skeptical.

Krishna is traditionally shown with blue skin in almost all the art of India. This is part of the mythology of Krishna. The story goes that some demons wanted to kill every living being on the earth, so they dumped poison in the rivers. Krishna prevented mass mortality by drinking up all the poison. Being a god, naturally Krishna didn’t die from the poison, but it did turn his skin blue for the rest of time.

NB. I’ve heard that blue is the standard depiction of all Hindu gods.


Setting blurred images in motion improves perception


‘Optic flow’ is especially important for people with low vision, says study in optometry and vision science

 

Wikimedia Commons Image

Wikimedia Commons Image

Blurred images that are unidentifiable as still pictures become understandable once the images are set in motion. That’s because of a phenomenon called “optic flow”—which may be especially relevant as a source of visual information in people with low vision, reports a study ‘With an Eye to Low Vision: Optic Flow Enables Perception Despite Image Blur(published online ahead of print, September 3, 2013) in the October issue of Optometry and Vision Science official journal of the American Academy of Optometry. The journal is published by Lippincott Williams & Wilkins, a part of Wolters Kluwer Health.

The concept of optic flow “has important implications for understanding of the daily functioning of observers with low vision,” according to the report by Jing Samantha Pan, MA, and Geoffrey P. Bingham, PhD, of Indiana University, Bloomington. “For low-vision observers, static image information is not the only (or perhaps even the primary) source of information about [their] surroundings.”

Despite Blur, Motion Improves Perception of Events

The researchers designed a study to assess the contributions of static images and optic flow to identifying events in the environment. They took short videos of everyday activities, such as a woman pouring a drink, a man bowling, and two people dancing. The black-and-white videos were then blurred—similar to what might be seen by a person with low vision—and split into 20 frames.

Volunteers with normal vision were then presented with the blurred images and asked to describe what they saw. First, static images were presented one at a time. Next, the images were set in motion by playing the frames in sequence.

When viewing the blurred, static images, the volunteers were usually unable to perceive what was going on. They correctly identify the event pictured in less than 30 percent of attempts.

In contrast, when participants viewed the moving images, the rate of correct identification increased to nearly 90 percent. For an example, see the video illustration at http://links.lww.com/OPX/A137. In the moving images, it’s much easier to perceive the dancing couple—despite the blurring.

Optic Flow Aids Functioning in People with Low Vision

“Our results showed that motion-generated optic flow information compensates for the lack of image details and enables effective event perception,” Pan and Bingham write. The effects of optic flow also appeared to be persistent—when participants viewed the static images again five days later, they could still “see” the activities depicted.

The results illustrate the importance of optic flow as a source of information for perceiving everyday events. Optic flow may be especially vital for the millions of people worldwide with low vision—usually defined as visual acuity of 20/60 or less, even with the best possible correction. In the United States, the main causes of low vision are cataract, glaucoma, age-related macular degeneration, and diabetic eye disease.

In the study, once blurred images were “calibrated” by motion, the depicted events could be easily recognized. The concept of optic flow might help to explain how people with even poor visual acuity can function well even in unfamiliar environments. Optic flow may be generated by the motion of objects around them, or even by their own motions.

The information provided by optic flow contributes to perception not only immediately but also several days later “When the motions stop, the blurry images may continue to inform low vision observers about the surround objects and their layout,” Pan and Bingham write.

“When visual acuity is poor, moving images can become important and make the otherwise imperceptible static images meaningful,” comments Anthony Adams, OD, PhD, Editor-in-Chief of Optometry and Vision Science. “Our authors demonstrate the surprisingly powerful effect of moving images despite blur making the static image unrecognizable. They suggest that in low vision as in normal vision, both static and moving images are probably very important sources of information.”