Early Diagnosis and treatment of Parkinson’s Disease

Researchers at Flinders University have made new discoveries about Parkinson’s disease that may help in the diagnosis and treatment of this neurodegenerative disease. They found that a protein called VAMP2 is involved not only in communication between neurons, but also in cell death. Although the mechanism by which VAMP2 interferes with Parkinson disease is still under investigation, this new protein may become in the future a new therapeutic target in the treatment of Parkinson’s disease. It must be noted that Parkinson’s disease is one of the most common neurodegenerative disease that usually occurs in patients aged between 40 and 70 years.

The disease is caused by loss of dopaminergic neurons ( involved in voluntary movements) in substantia nigra. It is an incurable disease and unfortunately, most symptoms occur when most dopaminergic neurons have already died. In other words, current treatment can only improve symptoms of Parkinson’s disease. Therefore, researchers are now focused to discover markers to diagnose disease in an early stage when treatment can stop the disease.

Parkinson’s Disease

Dr Wei-Ping Gai from the University’s Human Physiology Department, explained that VAMP2 protein is involved in neuronal transmission but it was discovered that it is also involved in Parkinson’s disease. “It’s the second most common neurodegenerative disorder in older populations and it’s extremely prevalent in countries like Australia, which is why it must be a research priority.” he said. Now  researchers hope to find out wth the use of an analytical method called mass spectrometry why these protein aggregates in brain cells. Dr. Gai said that if they could find the cause of these protein aggregates, they could find new markers for early diagnosis and treatment of Parkinson’s disease.

Parkinson’s disease is a condition characterized by hypertonia and hypokinesia.  One hallmark of the disease is bradykinesia which refers to the slowness of voluntary movements. Parkinson patients have a characteristic  walking (small steps), postural instability, tremor (which is emphasized by emotions and diminishes during voluntary movements), and other motor symptoms. Besides these motor symptoms, patients also have other symptoms such as sleep disturbances (most commonly insomnia), behavioral disorders,  depression, urination disturbances(dysuria), digestive disorders (constipation), etc.

There are several drugs to keep control of Parkinson’s disease but not all patients are responsive to treatment. The most important medication is levo-dopa or dopamine agonists, such as pramipexole and ripinorole. Other drugs are inhibitors of COMT, MAO B ( rasagiline), amantadine, anticholinergics etc. In selected cases deep brain stimulation may be performed, and involves implanting a brain pacemaker, which sends impulses to specific regions of the brain.

New Drug Target For Lupus Revealed by Researchers

A new study led by a research team from TSRI (The Scripps Research Institute), in the United States, managed to identify the key events that are involved in lupus. The findings of the study suggest that if this specific pathway is blocked, a potential new therapy for the autoimmune diseases could be developed. The study was published a couple of days ago in the online journal Proceedings of the National Academy of Sciences.

According to the scientists, the absence of a certain molecule with signalling  properties found inside immune cells, can be linked to a slower developing process of autoimmunity in laboratory mice suffering from lupus. Researchers report that these mice suffered less damage to their immune systems, compared to normal laboratory mice. Argyrios Theofilopoulos, the senior author of the study, says that their research could lead to the development of an inhibitory drug capable of treating not only lupus, but other autoimmune diseases as well.

There are various therapies available for the condition known as SLE (systemic lupus erythematosus), however none of them are able to target the causes of the disease. Precedent studies suggest that environmental and genetic factors are responsible for the complex autoimmune reaction that triggers the onset of SLE. One of the main immune interaction is that of the autoantibodies. These are antibodies turned against the “self” nucleic acids and proteins. SLE is one of the numerous conditions that mimic the symptoms of other diseases. Its symptoms vary from one patient to another and can appear and disappear unpredictably. The most common symptoms accused by SLE patients include rash, fever, joint pains, fatigue and myalgias. If left untreated, the complications that arise with the onset and progression of lupus are fatal.

Lupus Rash

One of the most commonly used therapies for SLE patients are immunosupressives. However, these drugs can raise the risks for other diseases, such as infectious diseases and cancer. Theofilopoulos and his research team have been the vanguard of SLE research for many years. Recently, they discovered a more powerful class of immunostimulatory compounds, known as type 1 interferons. These compounds are closely related to lupus and its autoimmunity cycle.

The autoimmunity cycle in lupus begins when immune cells are unable to recognize different nucleic acids and proteins as “self” molecules and consider them to be “non-self”. Subsequently, the immune cells start releasing type 1 interferons. This upregulates the antibody response with the formation of autoantibodies, which are responsible for presenting the so-considered “non-self” molecules to the cells that produce type 1 interferon. Investigations performed in an enclosed laboratory environment, on a  Petri dish suggests that the cells responsible for producing type 1 interferons are pDCs (plasmacytoid dendritic cells). In the current study, Theofilopoulos and his team further investigated the role of these cells in laboratory mice that suffered from SLE.

The leader of the experiments, and first author of the study was associate professor Roberto Baccala. Bacalla and Theofilopoulos have been working on research regarding lupus for the past 20 years. In collaboration with Keiko Ozato, one of the experts on immune cell genetics, the research team was able to investigate if a pDC deficit can stop lupus from developing. Professor Ozator created a strain of laboratory mice with no pDCs, due to the lack of the gene responsible for their development. “When we watched the animals for the usual development of lupus, we found that autoantibodies were practically non-existent, and all the other lupus-like manifestations were drastically reduced”, reported Baccala.

The next objective of the research team was to find out exactly how pDCs influence the onset and development of SLE. For this step, with the help of collaborator Bruce Beutler, the team created another strain of laboratory mice that were lacking the gene SLC15A4. This gene is responsible only for the ability of pDCs to produce type 1 interferon, whilst growing normally in all other aspects. The next step of their study was to detect whether the specially designed strain of mice would still develop SLE. Researchers report that normally, in lupus patients, two toll-like receptors (TLRs) – TLR7 and TLR9, are responsible for mistaking nucleic acids and proteins as “non-self”, instead of “self”. However, the absence of the SLC15A4 gene, caused the laboratory mice to be unresponsive to stimuli that would normally cause an autoimmune response. “The usual lupus-like signs significantly decreased, and survival was extended”, reported Baccala.

Theofilopoulos and Baccala are confident that SLC15A4 is a potential target for a new SLE therapy. A drug that would target SLC15A4 could potentially suppress only the immune cells directly responsible for SLE, without affecting the rest of the immune system. The research team is currently trying to develop a new pharmacological compound capable of inhibiting the production of type 1 interferon. This inhibition would be possible if the expression of the SLC15A4 gene could be blocked.

Scientists Discover Novel Potential Therapy for Cancer Patients

Researchers from the UPCI (University of Pittsburgh Cancer Institute) have discovered a new method to stop the proliferation of cancerous cells, thus leading them to uncover new therapy against cancer. Their research is funded by a grant received from the NIH (National Institutes of Health). The paper was published in the recently published issue of the Journal of Cell Science, revealing that if cancerous cells are deprived of a certain protein, they lose the ability to divide properly.

According to Bennett Van Houten, senior author and professor of molecular pharmacology at the University of Pittsburgh Cancer Institute, the study he seniors is the first one to explain the process through which this specific protein stops the growth of cancerous cells. Professor Van Houten says that the current study should be the starting point of a novel type of cancer medication. Every cell in the human organism contains a variable number of mitochondria. These are structures that generate energy and are essential for the metabolism. The protein called Drp1 (dynamin-related protein 1) is responsible for mitochondrial fission, a process responsible for the formation of new mitochondria.

Chemotherapy

Researchers investigated both lung and breast cancer. The cells that were deprived of Drp1 were observed to halt their growth in the G2/M cellular division stage. Thus, the proliferation of the cancerous cells was stopped as well. Wei Qian, the lead author of the study managed to capture an image of a Drp1 deficient cell that stopped during the process of separating its chromosomes by using a confocal microscope. “Once we revealed this process for halting cancer cell growth by knocking out Drp1, we began looking into existing compounds that might utilize a similar mechanism”, said professor Van Houten. The research team also discovered a compound (Mdivi-1) that can cause cancerous cells to react in a similar manner to that of a Drp1 deficit. If this compound is used together with cisplatin (a platinum-containing anti-cancer drug that bind to the cell DNA and cause its cross-linking of DNA, thus triggering apoptosis.

Currently, the effects of Mdivi-1 on cisplatin are being studied in the laboratory. Professor Van Houten and his research team are trying to discover the mechanisms through which Mdivi-1 acts similar to a Drp1 deficit. “We were on the hunt for a drug that could make cancer cells deficient in Drp1 and, instead, we found a new cancer therapy that seems to work really well”, concluded Van Houten.

Researchers Find Common Pathways Between Autism-Related Genetic Mutations

From a statistical point of view, autism and other diseases included in ASDs (Autism Spectrum Disorders) affect approximately 1 in 90 children. Symptoms of these diseases can range from moderate personality issues to seizures and even severe intellectual disabilities. One of the critical aspects of diagnostic and medication is the understanding of how the genetic pathways are altered. A new study on the responsibility of genes in autism spectrum disorders is going to be presented during the 57th Annual Meeting of the BPS (Biophysical Society), held in early February this year.

According to Rajini Rao, from the Johns Hopkins University, in Baltimore, autism is “the most inheritable of neurodevelopmental disorders”. She adds that it’s difficult for scientists to identify the genes responsible for autism since there is a great variety of genes that contribute to the onset of autism, each gene having a very small contribution. However, she adds that all these genes affect several common pathways.

A team of researchers from Johns Hopkins University teamed up with Tel Aviv University from Israel investigated the genetic sequence variations of the NHE9 ion transporter. They found out that the variants of NHE9 found in autism spectrum diseases causes an important loss of its transporter function. Professor Rao notes that if the levels of this transporter is altered it may result into the modulation of glutamate attracting proteins on the cell membrane. According to professor Rao, high levels of glutamate levels are associated with seizures, thus being a possible explanation of why some autistic patients suffer from seizures.

Scientists used a particular approach in which they studied multiple decades of research done on yeast and bacteria and used it towards understanding this complicated neurological disorder. The research group from the Tel Aviv University created structural models of the NHE9 through the use of a bacterial template. These models allowed the research team from the Johns Hopkins University to use baker’s yeast in order to screen any developed mutation. If genomic information becomes available for the general public in the near future, it would mean that patients would have access to a fast, cheap and efficient method of screening, thus allowing the evaluation of genetic variants in autism spectrum diseases and other genetic disorders to be conducted on a larger number of patients.

“These findings add a new candidate for genetic screening of at-risk patients that may lead to better diagnosis or treatment of autism”, concluded professor Rao.

Androgenic hormones – A new treatment for multiple sclerosis

According to an article published in the journal Brain, androgenic hormones could be the basis of a new treatment for multiple sclerosis and other demyelinating neurological diseases. Multiple sclerosis, the most common demyelinating disease of the central nervous system, is an autoimmune inflammatory disease, that generally evolves with attacks and remissions.

Multiple sclerosis is a neurodegenerative disease that occurs due to autoimmune attack on myelinated axons in the central nervous system. This progressive demyelination leads over time to neurological deficits that can seriously affect the patient’s life. MS can give virtually any neurological deficit, but more often the disease begins with retrobulbar optic neuritis (which leads to vision problems), diplopia, ataxia (difficulty in walking), motor deficits, impaired urinate (urinary incontinence, urinary retention ) etc..  General symptoms may also be present such as myalgia, arthralgia, weight loss, disturbed cognition, depression etc. There is no cure for multiple sclerosis, there is only symptomatic treatment. There are used corticosteroids as acute treatment, and as chronic treatment, the medication includes interferon, monoclonal antibodies, immunosuppressants (methotrexate, cyclophosphamide, etc.).

Multiple Sclerosis

It is not clear what triggers the autoimmune attack on myelinated axons, although there have been put into question  several factors, such as infectious factors, environmental factors, etc.. What was observed was that treatment with contraceptives and pregnancy lower the risk of relapse. Conversely, postpartum period increases the risk, so it is believed that androgens play an important role in disease pathogenesis.

The study led by Dr Said Ghandour shows that androgen receptors may be new therapeutic targets for neurodegenerative demyelinating diseases such as multiple sclerosis. Researchers at the Laboratoire d’Imagery et de Neurosciences Cognitives, have done many experiments on animals and showed that testosterone and a synthetic analog help regenerate oligodendrocytes, the cells of the nervous system with a role in myelination of axons. The researchers first induced demyelination in mice by adding  cuprizone in their diet, a molecule that sequesters copper. Then they administered testosterone to mice for 6 or 9 weeks and found that axons began to myelinate. In addition, it seems that the synthetic testosterone analogue, 7-alpha-methyl-19-nortestosterone (MENT), has the same effect.

What the researchers discovered was that androgens induce transformation of neural stem cells into oligodendrocytes, which in turn induce myelination of axons. Moreover, it seems that remyelinization is dependent on testosterone. In mice in which there were selectively inactivated receptors for androgenic hormones, or in those with mutated androgen receptors, testosterone was not effective, meaning it did not cause remyelinization of axons.

Researchers investigate the difference between belly fat and thigh fat

A study published in the Journal of Clinical Endocrinology and Metabolism, found that there are genetic differences between the two types of fat: belly fat and thigh fat. Although it is known that belly fat is associated with cardiovasculare disease, it is not very clear how this type of fat affects health. Now researchers at Sanford-Burnham Translational Research Institute for Metabolism and Diabetes made new researchers on this type of obesity.

Men usually deposit fat in the abdominal area, while women accumulate fat predominantly in the thighs. Abdominal obesity is more harmful to health than tight obesity because it increases the risk of cardiovacular disease ( heart attack, stroke etc). In fact, waist size over 94 cm in men (80 cm in women) is one of the criteria for metabolic syndrome, according to International Diabetes Federation. The researchers wanted to investigate the differences between the two types of obesity to better understand the mechanisms underlying these processes. Also, investigators intend to develop treatments that target the most harmful type of health obesity (abdominal obesity).

Obesity

The team, led by Steven R. Smith, MD, director of the Florida Hospital – Sanford-Burnham Translational Research Institute for Metabolism and Diabetes, took samples from both women and men and compared the most active genes from belly fat and from tight fat. They found significant differences between the types of obesity. It seems that men have 125 genes that are expressed differenttly, while women have 218 such genes, most of which are specific to them. What is interesting is that the researchers found that some genes that differ are the homebox genes that play a role in embryonic development and are influenced by estrogen.

Also, investigators took stem cells from belly and thigh and grew them in vitro to see their evolution. Although in laboratory dishes the cells were not influenced by any endogenous factor, as are influenced in the body (nerves, hormones, etc.), these cells grew equally, that is the fat had the same pattern. This growth model shows that these cells are preprogrammed. Smith says it is important to understand the differences between the types of fat in order to develop new treatments to prevent or reverse complications of obesity. He added that belly fat is just one of the problems: “Most people want to stop belly fat. But the problem is not just the fat”it’s the location. Belly fat is just a marker of the problem. The real issue is in inability to store that fat on the hips and thighs.”

New gene that affects clearance of hepatitis C virus discovered

Researchers at the National Cancer Institute (NCI), along with investigators from other institutions, have made further progress on hepatitis C virus infection. In their studies, they found that the clearance of hepatitis C virus is genetically determined and that  there is also a gene variant,  called interferon gamma 4 (IFNL4), which predicts treatment response. The study results were published in Nature Genetics.

Hepatitis C is a major health problem that affects approximately 3% of the world population. Hepatitis C is one of the most serious infections because of the risk of liver cirrhosis and hepatocellular carcinoma. It seems that up to 80% of those infected with the virus C fail to eliminate the virus and progresses to chronic hepatitis. Of these, about 5% develop liver cancer. Even though recently there have been made advances in virus C infection treatment, what is remarkable is that not all patients respond in the same way to treatment. There is a difference between African patients and European or Asian patients regarding treatment response.

Studies so far have shown that there is a genetic component that determines the response to virus infection C. Using genome-wide association studies (GWAS) there has been shown that there are genetic markers located on chromosome 9 (near the interferon gene, IFNL3) that influence response to treatment.

To discover the new gene, the researchers used a different technique involving RNA sequencing on human liver cells that were infected with virus C. Co-lead investigator Ludmila Prokunina-Olsson, Ph.D., of the Laboratory of Translational Genomics in NCI’s Division of Cancer Epidemiology and Genetics (DCEG), was excited about this approach and said that it is possible to find other genes with RNA sequencing.

It seems that IFNL4 region has two variants. One of them, called deltaG, is the deletion variant and it seems that it is more common in patients from Africa, patients that do not respond to treatment so well as those from Europe or Asia. The deletion variant refers to an abnormality in DNA structure leading to the formation of a protein called IFNL4 protein,  protein that is associated with a poorer clearance and poorer response to treatment. However, the mechanism by which protein IFNL4 interfere with the clearance of hepatitis C virus is unknown.

NCI’s Thomas R. O’Brien, MD, Infections and Immunoepidemiology Branch, DCEG, said that these findings  may lead in the future to personalized medicine. In other words, it is a step forward to more effective therapies. He also said that INFL4 protein may be a new therapeutic target  not only for C virus infection treatment but also for other diseases.

 Dark chocolate improves blood circulation

A new study by researchers at the University of Aberdeen Rowett Institute of Nutrition and Health shows that eating dark chocolate is good for health because it protects against cardiovascular disease. This protective effect was demonstrated especially in men.

Cardiovascular disease is one of the most common diseases worldwide. According to the World Health Organization, chronic diseases are responsible for 63% of deaths, and of these, cardiovascular disease is the leading cause of mortality. Cardiovascular disease refers to damage of the heart and blood vessels and a feature of this is impaired blood flow, that is blood clots. Atherosclerosis contributes to impaired blood flow and this is one of the precipitating factors for stroke and myocardial infarction.

Dark Chocolate

Besides atherosclerosis, an important  role in forming blood clots is played by blood platelets, which normally bind to stop the bleeding. In cardiovascular disease platelets become overactive and accumulates around a atheromatous plaque . Thus increases the risk of artery blockage and so stroke or myocardial infarction appear.

Platelet function may be influenced by various medications or food. There are certain compounds found in green tea, fruits, vegetables, herbs, spices and others, which seems to improve the function of platelets. Latest studies show that   flavanols, which are found in cocoa have major benefit in improving blood circulation.

To prove this,  researchers conducted a study: they assess platelet function in healthy individuals after they consumed dark chocolate and white chocolate. They took blood and urine samples at two and six hours after they ate chocolate.

Dr Baukje of Roos, from the University of Aberdeen Rowett Institute of Nutrition and Health, said that the role of platelets in healthy individuals is to heal wounds and stop bleeding, but under certain conditions, such as obesity, diabetes or smoking, platelets become overactive and lead to thrombosis, ie blood clots that can block arteries. In other words, the risk of heart attack or stroke greatly increases. She added that it was long known that flavonols prevent platelets to aggregate but how they did it was not clear.

It was found that specially enriched dark chocolate greatly decreases the risk of platelet activation and aggregation, especially in men and the effect is maximal at 2 hours after consumption. In women it seems that flavonols only decreases the risk of platelet aggregation. However, Dr De Roos emphasized that this study should not encourage individuals to consume excessive amounts of chocolate, because chocolate is high in sugar and fat, but it would be good for people to choose dark chocolate with 70% cocoa.

Genetic Clues to insulin production

A study published in the journal Nature Genetics shows that there are three new genetic variants underlying diabetes. These gene variants -called TBC1D30, KANK1 and EAP-are associated with insulin production and individuals that  carry these variants are more prone  to develop diabetes than the non-carriers.

The researchers reached these conclusions by exome genotyping array, a method less expensive than genetic sequencing and efficient in studying rare variants. Karen Mohlke, PhD, one of the study’s senior authors and associate professor of genetics at the University of North Carolina School of Medicine, said that exome genotyping array helps to analyze a large number of individuals efficiently. She also said she hopes by this method to discover new findings about other common diseases such as cancer and obesity.

Insulin

The sample of 8229 Finnish males which researchers used for this study was selected from another large health study conducted by scientists at University of Eastern Finland. Now researchers want to see how these gene variants lead to diabetes. Mohlke added that studying variants of genes helps scientists understand how they affect health.

Diabetes, which affects more than 25 million people living in the United States, is characterized by a lack of insulin production. Researchers believe that the behind  this disease is not a single gene, but many genes that, through interaction with environmental factors, lead to diabetes.

There are two major types of diabetes: type I diabetes, which usually occurs in lean and young  individuals, and type II diabetes, which usually occurs in individuals over the age of 45 years and obese or overweight. It should be mentioned that type II diabetes represents over 80% of cases of diabetes. There are also other types: gestational diabetes, diabetes induced by drugs (corticosteroids, for example), MODY (maturity onset diabetes to the young) etc., but these are relatively rare.

Although it is a disease that does not hurt, diabetes is a severe condition because over time  leads to serious complications: retinopathy, nephropathy, diabetic gangrene, diabetic neuropathy etc.. For example, retinopathy is the leading cause of blindness in individuals aged between 20 and 65 years. Retinopathy is one of the microvascular complications of diabetes along with renal disease and cardiovascular disease.

Kidney disease or diabetic nephropathy, which is manifested by microalbuminuria, that is loss of albumin in the urine, and decreased glomerular filtration rate, finally leads to dialysis. Another serious complication is cardiovascular disease. It should be noted that cardiovascular disease is the leading cause of mortality in individuals with diabetes. It is therefore very important screening the patients at risk and treating the disease before the occurrence of these complications.