Neuroscience

Articles and news from the latest research reports.

Posts tagged medicine

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To Advance Care for Patients with Brain Metastases: Reject Five Myths A blue-ribbon team of national experts on brain cancer says that professional pessimism and out-of-date “myths,” rather than current science, are guiding — and compromising — the care of patients with cancers that spread to the brain. In a special article published in the July issue of Neurosurgery, the team, led by an NYU Langone Medical Center neurosurgeon, argues that many past, key clinical trials were designed with out-of-date assumptions and the tendency of some physicians to “lump together” brain metastases of diverse kinds of cancer, often results in less than optimal care for individual patients. Furthermore, payers question the best care when it deviates from these misconceptions, the authors conclude. “It’s time to abandon this unjustifiable nihilism and think carefully about more individualized care,” says lead author of the article, Douglas S. Kondziolka, M.D., MSc, FRCSC, Vice Chair of Clinical Research and Director of the Gamma Knife Program in the Department of Neurosurgery at NYU Langone. The authors — who also say medical insurers help perpetuate the myths by denying coverage that deviates from them — identify five leading misconceptions that often lead to poorer care: All tumor cell types act the same way once they spread to the brain. This oversimplification means that doctors assume that histologically diverse cancers respond the same way to chemotherapy and are equally sensitive (or insensitive) to radiation. It also means that patients are all assumed to be at the same risk of subsequent brain cancer relapses, and development of additional metastatic lesions; and that survival rates are similar as well. The authors point out that this type of thinking overlooks important biological differences in brain metastases resulting from different types of cancer, such as those originating in the lung, breast or skin. The number of brain metastases is the best indicator for guiding management of the disease. Such strict adherence to quantity, the authors say, can wrongly limit treatment options. Physicians should look at total tumor burden, including the size and scope of metastases, rather than just how many metastases occur. All cancers detectable in the brain already reflect the presence of micrometastases, or  smaller, newly formed tumors too miniscule to detect. Evidence, the authors say, suggests otherwise, and aggressively monitoring for, and treating, individual brain metastases can, in fact, improve tumor control and patient survival. Whole brain radiation (WBR) is generally unjustified because it will cause disabling cognitive dysfunction if a patient lives long enough. Dr. Kondziolka and his co-authors say the risks and benefits of WBR should be evaluated for each patient, and that new studies examining the cognitive impact of WBR on thinking and learning are underway. Most brain metastases cause obvious symptoms, making regular screening for them unnecessary, and unlikely to affect survival. The authors counter that advances in screening allow metastases to be detected earlier, and treated sooner, before symptoms occur. “We are in an era of personalized medicine,” Dr. Kondziolka says, “and we need to begin thinking that way.” The authors further write: “It is time for fresh thinking and new critical analyses,” urging consideration of updated clinical trial designs that include comparison of matched cohorts and cost effectiveness factors. In addition to research that pays more attention to specific cell types and overall tumor burden, investigators should focus on tools available from advances in molecular biology and genetic subtyping and on efforts to learn “why some patients with a given primary cancer develop brain tumors and others do not.” Ultimately, the authors hope better stratifying patients will improve care for patients with diverse brain metastases.

To Advance Care for Patients with Brain Metastases: Reject Five Myths

A blue-ribbon team of national experts on brain cancer says that professional pessimism and out-of-date “myths,” rather than current science, are guiding — and compromising — the care of patients with cancers that spread to the brain.

In a special article published in the July issue of Neurosurgery, the team, led by an NYU Langone Medical Center neurosurgeon, argues that many past, key clinical trials were designed with out-of-date assumptions and the tendency of some physicians to “lump together” brain metastases of diverse kinds of cancer, often results in less than optimal care for individual patients. Furthermore, payers question the best care when it deviates from these misconceptions, the authors conclude.

“It’s time to abandon this unjustifiable nihilism and think carefully about more individualized care,” says lead author of the article, Douglas S. Kondziolka, M.D., MSc, FRCSC, Vice Chair of Clinical Research and Director of the Gamma Knife Program in the Department of Neurosurgery at NYU Langone.

The authors — who also say medical insurers help perpetuate the myths by denying coverage that deviates from them — identify five leading misconceptions that often lead to poorer care:

  1. All tumor cell types act the same way once they spread to the brain. This oversimplification means that doctors assume that histologically diverse cancers respond the same way to chemotherapy and are equally sensitive (or insensitive) to radiation. It also means that patients are all assumed to be at the same risk of subsequent brain cancer relapses, and development of additional metastatic lesions; and that survival rates are similar as well. The authors point out that this type of thinking overlooks important biological differences in brain metastases resulting from different types of cancer, such as those originating in the lung, breast or skin.
  2. The number of brain metastases is the best indicator for guiding management of the disease. Such strict adherence to quantity, the authors say, can wrongly limit treatment options. Physicians should look at total tumor burden, including the size and scope of metastases, rather than just how many metastases occur.
  3. All cancers detectable in the brain already reflect the presence of micrometastases, or  smaller, newly formed tumors too miniscule to detect. Evidence, the authors say, suggests otherwise, and aggressively monitoring for, and treating, individual brain metastases can, in fact, improve tumor control and patient survival.
  4. Whole brain radiation (WBR) is generally unjustified because it will cause disabling cognitive dysfunction if a patient lives long enough. Dr. Kondziolka and his co-authors say the risks and benefits of WBR should be evaluated for each patient, and that new studies examining the cognitive impact of WBR on thinking and learning are underway.
  5. Most brain metastases cause obvious symptoms, making regular screening for them unnecessary, and unlikely to affect survival. The authors counter that advances in screening allow metastases to be detected earlier, and treated sooner, before symptoms occur.

“We are in an era of personalized medicine,” Dr. Kondziolka says, “and we need to begin thinking that way.” The authors further write: “It is time for fresh thinking and new critical analyses,” urging consideration of updated clinical trial designs that include comparison of matched cohorts and cost effectiveness factors. In addition to research that pays more attention to specific cell types and overall tumor burden, investigators should focus on tools available from advances in molecular biology and genetic subtyping and on efforts to learn “why some patients with a given primary cancer develop brain tumors and others do not.”

Ultimately, the authors hope better stratifying patients will improve care for patients with diverse brain metastases.

Filed under brain cancer tumor cells medicine science

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Vitamin D Can Lower Weight, Blood Sugar via the Brain

Vitamin D treatment acts in the brain to improve weight and blood glucose (sugar) control in obese rats, according to a new study being presented Saturday at the joint meeting of the International Society of Endocrinology and the Endocrine Society: ICE/ENDO 2014 in Chicago.

“Vitamin D deficiency occurs often in obese people and in patients with Type 2 diabetes, yet no one understands if it contributes to these diseases,” said Stephanie Sisley, MD, the study’s principal investigator and an assistant professor at Baylor College of Medicine, Houston. “Our results suggest that vitamin D may play a role in the onset of both obesity and Type 2 diabetes by its action in the brain.”

“The brain is the master regulator of weight,” Sisley said. A region of the brain called the hypothalamus controls both weight and glucose, and has vitamin D receptors there.

In this study funded by the National Institutes of Health, Sisley and partners at the University of Cincinnati delivered vitamin D directly to the hypothalamus. The investigators administered the active, potent form of vitamin D—called 1,25-dihydroxyvitamin D3—to obese male rats through a cannula (thin tube) surgically inserted using anesthesia into the brain’s third ventricle. This narrow cavity lies within the hypothalamus. Rats recovered their presurgery body weight, and the researchers verified the correct cannula placement.

The animals received nothing to eat for four hours, so they could have a fasting blood sugar measurement. Afterward, 12 rats received vitamin D dissolved in a solution acting as a vehicle for drug delivery. Another 14 rats, matched in body weight to the first group, received only the vehicle, thus serving as controls. One hour later, all rats had a glucose tolerance test, in which they received an injection of dextrose, a sugar, in their abdomen, followed by measurement of their blood sugar levels again.

Compared with the control rats, animals that received vitamin D had improved glucose tolerance, which is how the body responds to sugar. In a separate experiment, these treated rats also had greatly improved insulin sensitivity, the body’s ability to successfully respond to glucose. When this ability decreases—called insulin resistance—it eventually leads to high blood sugar levels. Two of insulin’s main effects are to clear glucose from the bloodstream and decrease glucose production in the liver. In this study, vitamin D in the brain decreased the glucose created by the liver.

In a separate experiment of long-term vitamin D treatment, the researchers gave three rats vitamin D and four rats vehicle alone for four weeks. They observed a large decrease in food intake and weight in rats receiving vitamin D compared with the group that did not get vitamin D. Over 28 days, the treated group ate nearly three times less food and lost 24 percent of their weight despite not changing the way they burned calories, study data showed. The control group did not lose any weight.

“Vitamin D is never going to be the silver bullet for weight loss, but it may work in combination with strategies we know work, like diet and exercise,” Sisley commented.

She said more research is necessary to determine if obesity alters vitamin D transport into the brain or its action in the brain.

(Source: newswise.com)

Filed under vitamin D obesity weight loss blood glucose hypothalamus medicine science

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How a new approach to funding Alzheimer’s research could pay off More than 5 million Americans suffer from Alzheimer’s disease, the affliction that erodes memory and other mental capacities, but no drugs targeting the disease have been approved by the U.S. Food and Drug Administration since 2003. Now a paper by an MIT professor suggests that a revamped way of financing Alzheimer’s research could spur the development of useful new drugs for the illness. “We are spending tremendous amounts of resources dealing with this disease, but we don’t have any effective therapies for it,” says Andrew Lo, the Charles E. and Susan T. Harris Professor of Finance and director of the Laboratory for Financial Engineering at the MIT Sloan School of Management. “It really imposes a tremendous burden on society, not just for the afflicted, but also for those who care for them.” Lo and three co-authors propose creating a public-private partnership that would fund research for a diverse array of drug-discovery projects simultaneously. Such an approach would increase the chances of a therapeutic breakthrough, they say, and the inclusion of public funding would help mitigate the risks and costs of Alzheimer’s research for the private sector. There would be a long-term public-sector payoff, according to the researchers: Government funding for Alzheimer’s research would pale in comparison to the cost of caring for Alzheimer’s sufferers in public health-care programs. The paper’s model of the new funding approach calls for an outlay of $38.4 billion over 13 years for research; the costs of Medicare and Medicaid support for Alzheimer’s patients in 2014 alone is estimated to be $150 billion. “Having parallel development would obviously decrease the waiting time, but it increases the short-run need for funding,” Lo says. “Given how much of an urgent need there is for Alzheimer’s therapies, it has to be the case that if you develop a cure, you’re going to be able to recoup your costs and then some.” In fact, the paper’s model estimates a double-digit return on public investment over the long run. Lo adds: “Can we afford it? I think a more pressing question is, ‘Can we afford not to do something about this now?’” Modeling the odds of success The paper, “Parallel Discovery of Alzheimer’s Therapeutics,” was published today in Science Translational Medicine. Along with Lo, the co-authors of the piece are Carole Ho of the biotechnology firm Genentech, Jayna Cummings of MIT Sloan, and Kenneth Kosik of the University of California at Santa Barbara. The main hypothesis on the cause of Alzheimer’s involves amyloid deposition, the buildup of plaques in the brain that impair neurological function; most biomedical efforts to tackle the disease have focused on this issue. For the study, Ho and Kosik, leading experts in Alzheimer’s research, compiled a list of 64 conceivable approaches to drug discovery, addressing a range of biological mechanisms that may be involved in the disease. A fund backing that group of research projects might expand the chances of developing a drug that could, at a minimum, slow the progression of the disease. On the other hand, it might not increase the odds of success so much that pharmaceutical firms and biomedical investment funds would plow money into the problem. “Sixty-four projects are a lot more than what’s being investigated today, but it’s still way shy of the 150 or 200 that are needed to mitigate the financial risks of an Alzheimer’s-focused fund,” Lo says. The model assumes 13 years for the development of an individual drug, including clinical trials, and estimates the success rates for drug development. Given 150 trials, the odds of at least two successful trials are 99.59 percent. Two successful trials, Lo says, is what it would take to make the investment — a series of bonds issued by the fund — profitable and attractive to a broad range of investors. “With a sufficiently high likelihood of success, you can issue debt to attract a large group of bondholders who would be willing to put their money to work,” Lo says. “The enormous size of bond markets translates into enormous potential funding opportunities for developing these therapeutics.” Stakeholders everywhere To be clear, Lo says, Alzheimer’s drug development is a very difficult task, since researchers often have to identify a pool of potential patients well before symptoms occur, in order to see how well therapies might work on delaying the onset of the disease. Compared with the development of new drugs to treat other diseases, “Alzheimer’s drug development is more expensive, takes longer, and needs a larger sample of potential patients,” Lo acknowledges. However, since the number of Americans suffering from Alzheimer’s is projected to double by 2050, according to the Alzheimer’s Association, an advocacy group, Lo stresses the urgency of the task at hand.”

How a new approach to funding Alzheimer’s research could pay off

More than 5 million Americans suffer from Alzheimer’s disease, the affliction that erodes memory and other mental capacities, but no drugs targeting the disease have been approved by the U.S. Food and Drug Administration since 2003. Now a paper by an MIT professor suggests that a revamped way of financing Alzheimer’s research could spur the development of useful new drugs for the illness.

“We are spending tremendous amounts of resources dealing with this disease, but we don’t have any effective therapies for it,” says Andrew Lo, the Charles E. and Susan T. Harris Professor of Finance and director of the Laboratory for Financial Engineering at the MIT Sloan School of Management. “It really imposes a tremendous burden on society, not just for the afflicted, but also for those who care for them.”

Lo and three co-authors propose creating a public-private partnership that would fund research for a diverse array of drug-discovery projects simultaneously. Such an approach would increase the chances of a therapeutic breakthrough, they say, and the inclusion of public funding would help mitigate the risks and costs of Alzheimer’s research for the private sector.

There would be a long-term public-sector payoff, according to the researchers: Government funding for Alzheimer’s research would pale in comparison to the cost of caring for Alzheimer’s sufferers in public health-care programs. The paper’s model of the new funding approach calls for an outlay of $38.4 billion over 13 years for research; the costs of Medicare and Medicaid support for Alzheimer’s patients in 2014 alone is estimated to be $150 billion.

“Having parallel development would obviously decrease the waiting time, but it increases the short-run need for funding,” Lo says. “Given how much of an urgent need there is for Alzheimer’s therapies, it has to be the case that if you develop a cure, you’re going to be able to recoup your costs and then some.” In fact, the paper’s model estimates a double-digit return on public investment over the long run.

Lo adds: “Can we afford it? I think a more pressing question is, ‘Can we afford not to do something about this now?’”

Modeling the odds of success

The paper, “Parallel Discovery of Alzheimer’s Therapeutics,” was published today in Science Translational Medicine. Along with Lo, the co-authors of the piece are Carole Ho of the biotechnology firm Genentech, Jayna Cummings of MIT Sloan, and Kenneth Kosik of the University of California at Santa Barbara.

The main hypothesis on the cause of Alzheimer’s involves amyloid deposition, the buildup of plaques in the brain that impair neurological function; most biomedical efforts to tackle the disease have focused on this issue. For the study, Ho and Kosik, leading experts in Alzheimer’s research, compiled a list of 64 conceivable approaches to drug discovery, addressing a range of biological mechanisms that may be involved in the disease.

A fund backing that group of research projects might expand the chances of developing a drug that could, at a minimum, slow the progression of the disease. On the other hand, it might not increase the odds of success so much that pharmaceutical firms and biomedical investment funds would plow money into the problem.

“Sixty-four projects are a lot more than what’s being investigated today, but it’s still way shy of the 150 or 200 that are needed to mitigate the financial risks of an Alzheimer’s-focused fund,” Lo says.

The model assumes 13 years for the development of an individual drug, including clinical trials, and estimates the success rates for drug development. Given 150 trials, the odds of at least two successful trials are 99.59 percent. Two successful trials, Lo says, is what it would take to make the investment — a series of bonds issued by the fund — profitable and attractive to a broad range of investors.

“With a sufficiently high likelihood of success, you can issue debt to attract a large group of bondholders who would be willing to put their money to work,” Lo says. “The enormous size of bond markets translates into enormous potential funding opportunities for developing these therapeutics.”

Stakeholders everywhere

To be clear, Lo says, Alzheimer’s drug development is a very difficult task, since researchers often have to identify a pool of potential patients well before symptoms occur, in order to see how well therapies might work on delaying the onset of the disease.

Compared with the development of new drugs to treat other diseases, “Alzheimer’s drug development is more expensive, takes longer, and needs a larger sample of potential patients,” Lo acknowledges.

However, since the number of Americans suffering from Alzheimer’s is projected to double by 2050, according to the Alzheimer’s Association, an advocacy group, Lo stresses the urgency of the task at hand.”

Filed under alzheimer's disease drug development health medicine neuroscience science

131 notes

Hearing protein required to convert sound into brain signals A specific protein found in the bridge-like structures that make up part of the auditory machinery of the inner ear is essential for hearing. The absence of this protein or impairment of the gene that codes for this protein leads to profound deafness in mice and humans, respectively, reports a team of researchers in the journal EMBO Molecular Medicine. “The goal of our study was to identify which isoform of protocadherin-15 forms the tip-links, the essential connections of the auditory mechanotransduction machinery within mature hair cells that are needed to convert sound into electrical signals,” remarks Christine Petit, the lead author of the study and Professor at the Institut Pasteur in Paris and at Collège de France. Three types of protocadherin-15 are known to exist in auditory sensory cells of the inner ear but it was not clear which of these protein isoforms was essential for hearing. “Our work pinpoints the CD2 isoform of protocadherin-15 as an essential component of the tip-link and reveals that the absence of protocadherin-15 CD2 in mouse hair cells results in profound deafness.” Within the hair bundle, the sensory antenna of auditory sensory cells, the tip-link is a bridge-like structure that when stretched can activate the ion channel responsible for generating electrical signals from sound. Tension in the tip-link created by sound stimulation opens this channel of unknown molecular composition thus generating electrical signals and, ultimately, the perception of sound. The researchers engineered mice that lack only the CD2 isoform of protocadherin-15 exclusively during adulthood. While the absence of this isoform led to profound deafness, the lack of the other protocadherin-15 isoforms in mice did not affect their hearing. Patients who carry a mutation in the gene encoding protocadherin-15 are affected by a rare devastating disorder, Usher syndrome, which is characterized by profound deafness, balance problems and gradual visual loss due to retinitis pigmentosa. In a separate approach, the scientists also sequenced the genes of 60 patients who had profound deafness without balance and visual impairment. Three of these patients were shown to have mutations specifically affecting protocadherin-15 CD2. “The demonstration of a requirement for protocadherin-15 CD2 for hearing not only in mice but also in humans constitutes a major step in the objective of deciphering the components of the auditory mechanotransduction machinery. This isoform can be used as a starting point to identify the other components of the auditory machinery. By focusing our attention on the CD2 isoform of protocadherin-15, we can now consider developing gene therapy strategies for deafness caused by defects in this gene,” says EMBO Member Christine Petit.

Hearing protein required to convert sound into brain signals

A specific protein found in the bridge-like structures that make up part of the auditory machinery of the inner ear is essential for hearing. The absence of this protein or impairment of the gene that codes for this protein leads to profound deafness in mice and humans, respectively, reports a team of researchers in the journal EMBO Molecular Medicine.

“The goal of our study was to identify which isoform of protocadherin-15 forms the tip-links, the essential connections of the auditory mechanotransduction machinery within mature hair cells that are needed to convert sound into electrical signals,” remarks Christine Petit, the lead author of the study and Professor at the Institut Pasteur in Paris and at Collège de France.

Three types of protocadherin-15 are known to exist in auditory sensory cells of the inner ear but it was not clear which of these protein isoforms was essential for hearing. “Our work pinpoints the CD2 isoform of protocadherin-15 as an essential component of the tip-link and reveals that the absence of protocadherin-15 CD2 in mouse hair cells results in profound deafness.”

Within the hair bundle, the sensory antenna of auditory sensory cells, the tip-link is a bridge-like structure that when stretched can activate the ion channel responsible for generating electrical signals from sound. Tension in the tip-link created by sound stimulation opens this channel of unknown molecular composition thus generating electrical signals and, ultimately, the perception of sound.

The researchers engineered mice that lack only the CD2 isoform of protocadherin-15 exclusively during adulthood. While the absence of this isoform led to profound deafness, the lack of the other protocadherin-15 isoforms in mice did not affect their hearing.

Patients who carry a mutation in the gene encoding protocadherin-15 are affected by a rare devastating disorder, Usher syndrome, which is characterized by profound deafness, balance problems and gradual visual loss due to retinitis pigmentosa. In a separate approach, the scientists also sequenced the genes of 60 patients who had profound deafness without balance and visual impairment. Three of these patients were shown to have mutations specifically affecting protocadherin-15 CD2. “The demonstration of a requirement for protocadherin-15 CD2 for hearing not only in mice but also in humans constitutes a major step in the objective of deciphering the components of the auditory mechanotransduction machinery. This isoform can be used as a starting point to identify the other components of the auditory machinery. By focusing our attention on the CD2 isoform of protocadherin-15, we can now consider developing gene therapy strategies for deafness caused by defects in this gene,” says EMBO Member Christine Petit.

Filed under hair cells inner ear usher syndrome hearing protocadherin-15 medicine science

354 notes

Researchers identify new compound to treat depression There is new hope for people suffering from depression. Researchers have identified a compound, hydroxynorketamine (HNK), that may treat symptoms of depression just as effectively and rapidly as ketamine, without the unwanted side effects associated with the psychoactive drug, according to a study in the July issue of Anesthesiology, the official medical journal of the American Society of Anesthesiologists® (ASA®).  Interestingly, use of HNK may also serve as a future therapeutic approach for treating neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases, the authors note. “The clinical use of ketamine therapy for depression is limited because the drug is administered intravenously and may produce adverse effects such as hallucinations and sedation to the point of anesthesia,” said Irving Wainer, Ph.D., senior investigator with the Intramural Research Program at the National Institute on Aging, Baltimore. “We found that the HNK compound significantly contributes to the anti-depressive effects of ketamine in animals, but doesn’t produce the sedation or anesthesia, which makes HNK an attractive alternative as an antidepressant in humans.” HNK is one of several different compounds produced when ketamine, an anesthesia medicine-turned-antidepressant, is broken down (metabolized) in the body. Using a rat model, researchers tested HNK to see if the compound alone could produce the same beneficial effects attributed to ketamine without ketamine’s unwanted side effects.  In the study, rats were given intravenous doses of ketamine, HNK and another compound produced by ketamine metabolism known as norketamine. The effect each had on stimulating certain cellular pathways of the rats’ brains was examined after 20, 30 and 60 minutes.  Brain tissue from drug-free rats was used as a control. Researchers found the compound HNK, like ketamine, not only produced potent and rapid antidepressant effects, but also stimulated neuro-regenerative pathways and initiated the regrowth of neurons in rats’ brains. HNK also appears to have several advantages over ketamine in that it is 1,000 times more potent, does not act as an anesthetic agent, and can be taken by mouth, the authors report.  Surprisingly, HNK was also found to reduce the production of D-serine, a chemical found in the body, overproduction of which is associated with neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases. HNK’s ability to reduce the production of D-serine, while stimulating the regeneration of neuron connections in the brain, may present a potential new therapeutic approach to the treatment of these disorders.  “HNK’s unique properties increase the possibility of the development of a self-administered, daily treatment that works quickly and can be taken at home for a variety of central nervous system diseases,” said Dr. Wainer.  “This is a very exciting discovery and we hope that the results of this study will enable future investigations into this potentially therapeutic and important compound.” Dr. Wainer and several of the study’s authors are listed as co-inventors on a patent application for the use of ketamine compounds in the treatment of bipolar disorder and major depression. 

Researchers identify new compound to treat depression

There is new hope for people suffering from depression. Researchers have identified a compound, hydroxynorketamine (HNK), that may treat symptoms of depression just as effectively and rapidly as ketamine, without the unwanted side effects associated with the psychoactive drug, according to a study in the July issue of Anesthesiology, the official medical journal of the American Society of Anesthesiologists® (ASA®).  Interestingly, use of HNK may also serve as a future therapeutic approach for treating neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases, the authors note.

“The clinical use of ketamine therapy for depression is limited because the drug is administered intravenously and may produce adverse effects such as hallucinations and sedation to the point of anesthesia,” said Irving Wainer, Ph.D., senior investigator with the Intramural Research Program at the National Institute on Aging, Baltimore. “We found that the HNK compound significantly contributes to the anti-depressive effects of ketamine in animals, but doesn’t produce the sedation or anesthesia, which makes HNK an attractive alternative as an antidepressant in humans.”

HNK is one of several different compounds produced when ketamine, an anesthesia medicine-turned-antidepressant, is broken down (metabolized) in the body. Using a rat model, researchers tested HNK to see if the compound alone could produce the same beneficial effects attributed to ketamine without ketamine’s unwanted side effects. 

In the study, rats were given intravenous doses of ketamine, HNK and another compound produced by ketamine metabolism known as norketamine. The effect each had on stimulating certain cellular pathways of the rats’ brains was examined after 20, 30 and 60 minutes.  Brain tissue from drug-free rats was used as a control.

Researchers found the compound HNK, like ketamine, not only produced potent and rapid antidepressant effects, but also stimulated neuro-regenerative pathways and initiated the regrowth of neurons in rats’ brains. HNK also appears to have several advantages over ketamine in that it is 1,000 times more potent, does not act as an anesthetic agent, and can be taken by mouth, the authors report. 

Surprisingly, HNK was also found to reduce the production of D-serine, a chemical found in the body, overproduction of which is associated with neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases. HNK’s ability to reduce the production of D-serine, while stimulating the regeneration of neuron connections in the brain, may present a potential new therapeutic approach to the treatment of these disorders. 

“HNK’s unique properties increase the possibility of the development of a self-administered, daily treatment that works quickly and can be taken at home for a variety of central nervous system diseases,” said Dr. Wainer.  “This is a very exciting discovery and we hope that the results of this study will enable future investigations into this potentially therapeutic and important compound.”

Dr. Wainer and several of the study’s authors are listed as co-inventors on a patent application for the use of ketamine compounds in the treatment of bipolar disorder and major depression. 

Filed under hydroxynorketamine ketamine depression neurodegenerative diseases norketamine medicine science

115 notes

Strokefinder quickly differentiates bleeding strokes from clot-induced strokes The results from the initial clinical studies involving the microwave helmet Strokefinder confirm the usefulness of microwaves for rapid and accurate diagnosis of stroke patients. This is shown in a scientific article published on Monday. Strokefinder enables earlier diagnosis than current methods, which improves the possibility to counteract brain damage. In the article, researchers from Chalmers University of Technology, Sahlgrenska Academy and Sahlgrenska University Hospital present results from the initial patient studies completed last year. The study included 45 patients, and the results show that the technique can with great certainty differentiate bleeding strokes from clot-induced strokes in patients with acute symptoms. Strokefinder is placed on the patient’s head where it examines the brain tissue by using microwaves. The signals are interpreted by the system to determine if the stroke is caused by a blood clot or bleeding. “The results of this study show that we will be able to increase the number of stroke patients who receive optimal treatment when the instrument makes a diagnosis already in the ambulance,” says Mikael Persson, professor of biomedical engineering at Chalmers University of Technology. “The possibility to rule out bleeding already in the ambulance is a major achievement that will be of great benefit in acute stroke care. Equally exciting is the potential application in trauma care. Diagnosis and treatment already in the ambulance The initial patient studies have been performed inside hospitals, and this autumn the research groups at Chalmers and Sahlgrenska Academy will test a mobile stroke helmet on patients in ambulances. “Our goal with Strokefinder is to diagnose and initiate treatment of stroke patients already in the ambulance,” says Mikael Elam, professor of clinical neurophysiology at Sahlgrenska University Hospital. “Since time is a critical factor for stroke treatment, the use of the instrument leads to patients suffering less extensive injury. This in turn can shorten the length of stay at hospitals and reduce the need for rehabilitation, thus providing a number of other positive consequences for both the patient and the health care system.” Studies involving Strokefinder are currently being conducted at Sahlgrenska University Hospital and Södra Älvsborg Hospital in Borås. The research is being conducted in close collaboration between Chalmers University of Technology, Sahlgrenska Academy, Sahlgrenska University Hospital, Södra Älvsborg Hospital and MedTech West, which is a platform for collaboration in medical device R&D, with premises at Sahlgrenska University Hospital. A new product, based on the results of the present study, has been developed, and further studies will be conducted in several countries in preparation for the CE approval that Medfield Diagnostics, a spin-off from Chalmers, expects to obtain later this year. (Illustration: Boid) How Strokefinder differentiates bleeding strokes from clot-induced strokes The antennas of the helmet sequentially transmit weak microwave signals into the brain. At the same time, the receiving antennas listen for reflected signals. The brain’s different structures and substances affect the microwave scattering and reflections in different ways. The received signals give a complex pattern, which is interpreted with the help of advanced algorithms. Based on these data, the system can diagnose bleeding or a clot. Bleeding is particularly pronounced, but an area with a clot and oxygen deficiency can also be distinguished. (Watch the video).

Strokefinder quickly differentiates bleeding strokes from clot-induced strokes

The results from the initial clinical studies involving the microwave helmet Strokefinder confirm the usefulness of microwaves for rapid and accurate diagnosis of stroke patients. This is shown in a scientific article published on Monday. Strokefinder enables earlier diagnosis than current methods, which improves the possibility to counteract brain damage.

In the article, researchers from Chalmers University of Technology, Sahlgrenska Academy and Sahlgrenska University Hospital present results from the initial patient studies completed last year. The study included 45 patients, and the results show that the technique can with great certainty differentiate bleeding strokes from clot-induced strokes in patients with acute symptoms.

Strokefinder is placed on the patient’s head where it examines the brain tissue by using microwaves. The signals are interpreted by the system to determine if the stroke is caused by a blood clot or bleeding.

“The results of this study show that we will be able to increase the number of stroke patients who receive optimal treatment when the instrument makes a diagnosis already in the ambulance,” says Mikael Persson, professor of biomedical engineering at Chalmers University of Technology. “The possibility to rule out bleeding already in the ambulance is a major achievement that will be of great benefit in acute stroke care. Equally exciting is the potential application in trauma care.

Diagnosis and treatment already in the ambulance

The initial patient studies have been performed inside hospitals, and this autumn the research groups at Chalmers and Sahlgrenska Academy will test a mobile stroke helmet on patients in ambulances.

“Our goal with Strokefinder is to diagnose and initiate treatment of stroke patients already in the ambulance,” says Mikael Elam, professor of clinical neurophysiology at Sahlgrenska University Hospital. “Since time is a critical factor for stroke treatment, the use of the instrument leads to patients suffering less extensive injury. This in turn can shorten the length of stay at hospitals and reduce the need for rehabilitation, thus providing a number of other positive consequences for both the patient and the health care system.”

Studies involving Strokefinder are currently being conducted at Sahlgrenska University Hospital and Södra Älvsborg Hospital in Borås. The research is being conducted in close collaboration between Chalmers University of Technology, Sahlgrenska Academy, Sahlgrenska University Hospital, Södra Älvsborg Hospital and MedTech West, which is a platform for collaboration in medical device R&D, with premises at Sahlgrenska University Hospital.

A new product, based on the results of the present study, has been developed, and further studies will be conducted in several countries in preparation for the CE approval that Medfield Diagnostics, a spin-off from Chalmers, expects to obtain later this year.

(Illustration: Boid)

How Strokefinder differentiates bleeding strokes from clot-induced strokes

The antennas of the helmet sequentially transmit weak microwave signals into the brain. At the same time, the receiving antennas listen for reflected signals. The brain’s different structures and substances affect the microwave scattering and reflections in different ways. The received signals give a complex pattern, which is interpreted with the help of advanced algorithms. Based on these data, the system can diagnose bleeding or a clot. Bleeding is particularly pronounced, but an area with a clot and oxygen deficiency can also be distinguished. (Watch the video).

Filed under brain damage stroke strokefinder microwaves medicine science

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Fungal protein found to cross blood-brain barrier

In a remarkable series of experiments on a fungus that causes cryptococcal meningitis, a deadly infection of the membranes that cover the spinal cord and brain, investigators at UC Davis have isolated a protein that appears to be responsible for the fungus’ ability to cross from the bloodstream into the brain.

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The discovery — published online June 3 in mBio, the open-access, peer-reviewed journal of the American Society for Microbiology — has important implications for developing a more effective treatment for Cryptococcus neoformans, the cause of the condition, and other brain infections, as well as for brain cancers that are difficult to treat with conventional medications. 

“This study fills a significant gap in our understanding of how C. neoformans crosses the blood-brain barrier and causes meningitis,” said Angie Gelli, associate professor of pharmacology at UC Davis and principal investigator of the study. “It is our hope that our findings will lead to improved treatment for this fungal disease as well as other diseases of the central nervous system.”

Normally the brain is protected from bacterial, viral and fungal pathogens in the bloodstream by a tightly packed layer of endothelial cells lining capillaries within the central nervous system — the so-called blood-brain barrier. Relatively few organisms — and drugs that could fight brain infections or cancers — can breach this protective barrier.

The fungus studied in this research causes cryptococcal meningoencephalitis, a usually fatal brain infection that annually affects some 1 million people worldwide, most often those with an impaired immune system. People typically first develop an infection in the lungs after inhalation of the fungal spores of C. neoformans in soil or pigeon droppings. The pathogen then spreads to the brain and other organs.

Unique protein identified

In an effort to discover how C. neoformans breaches the blood-brain barrier, the investigators isolated candidate proteins from the cryptococcal cell surface. One was a previously uncharacterized metalloprotease that they named Mpr1. (A protease is an enzyme — a specialized protein — that promotes a chemical reaction; a metalloprotease contains a metal ion — in this case zinc — that is essential for its activity.) The M36 class of metalloproteases to which Mpr1 belongs is unique to fungi and does not occur in mammalian cells.

The investigators next artificially generated a strain of C. neoformans that lacked Mpr1 on the cell surface. Unlike the normal wild-type C. neoformans, the strain without Mpr1 could not cross an artificial model of the human blood-brain barrier.

They next took a strain of common baking yeast — Saccharomyces cerevisiae — that does not cross the blood-brain barrier and does not normally express Mpr1, and modified it to express Mpr1 on its cell surface. This strain then gained the ability to cross the blood-brain barrier model.

Investigators then infected mice with either the C. neoformans that lacked Mpr1 or the wild-type strain by injecting the organisms into their bloodstream. Comparing the brain pathology of mice 48 hours later, they found numerous cryptococci-filled cysts throughout the brain tissue of mice infected with the wild-type strain; these lesions were undetectable in those infected with the strain lacking Mpr1. In another experiment, after 37 days of being infected by the inhalation route, 85 percent of the mice exposed to the wild-type C. neoformans had died, while all of those given the fungus without Mpr1 were alive.

“Our studies are the first clear demonstration of a specific role for a fungal protease in invading the central nervous system,” said Gelli. “The details of exactly how it crosses is an important new area under investigation.”

New targeted therapies possible

According to Gelli, their discovery has significant therapeutic potential via two important mechanisms. Either Mpr1 — or an aspect of the mechanism by which it crosses the blood-brain barrier — could be a target of new drugs for treating meningitis caused by C. neoformans. In a person who develops cryptococcal lung infection, such a treatment would ideally make the fungus less likely to enter the brain and lead to a rapidly fatal meningitis.

Secondly, Mpr1 could be developed as part of a drug-delivery vehicle for brain infections and cancers. An antibiotic or cancer-fighting drug that is unable to cross the blood-brain barrier on its own could be attached to a nanoparticle containing Mpr1, allowing it to hitch a ride and deliver its goods to where it is needed.

“The biggest obstacle to treating many brain cancers and infections is getting good drugs through the blood-brain barrier,” said Gelli. “If we could design an effective delivery system into the brain, the impact would be enormous for treating some of these terrible diseases.”

Gelli’s group is currently pursuing such a nanoparticle drug-delivery system using Mpr1. They are also further investigating the exact molecular mechanism by which Mpr1 breaches the blood-brain barrier.

(Source: ucdmc.ucdavis.edu)

Filed under blood brain barrier meningitis CNS drug delivery Mpr1 medicine science

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Immune response affects sleep and memory

Fighting off illness- rather than the illness itself- causes sleep deprivation and affects memory, a new study has found.

University of Leicester biologist Dr Eamonn Mallon said a common perception is that if you are sick, you sleep more.

But the study, carried out in flies, found that sickness induced insomnia is quite common.

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(Image credit)

The research has been published in the journal PeerJ.

Dr Mallon said: “Think about when you are sick. Your sleep is disturbed and you’re generally not feeling at your sharpest. Previously work has been carried out showing that being infected leads to exactly these behaviours in fruit flies.

“In this paper we show that it can be the immune system itself that can cause these problems. By turning on the immune system in flies artificially (with no infection present) we reduced how long they slept and how well they performed in a memory test.

“This is an interesting result as these connections between the brain and the immune system have come to the fore recently in medicine. It seems to be because the two systems speak the same chemical language and often cross-talk. Having a model of this in the fly, one of the main systems used in genetic research will be a boost to the field.

“The key message of this study is that the immune response, sleep and memory seem to be intimately linked. Medicine is beginning to study these links between the brain and the immune system in humans. Having an easy to use insect model would be very helpful.”

(Source: www2.le.ac.uk)

Filed under fruit flies immune system memory sleep medicine science

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Embryonic Stem Cells Offer Treatment Promise for Multiple Sclerosis Scientists in the University of Connecticut’s Technology Incubation Program have identified a novel approach to treating multiple sclerosis (MS) using human embryonic stem cells, offering a promising new therapy for more than 2.3 million people suffering from the debilitating disease. The researchers demonstrated that the embryonic stem cell therapy significantly reduced MS disease severity in animal models, and offered better treatment results than stem cells derived from human adult bone marrow. The study was led by ImStem Biotechnology Inc. of Farmington, Conn., in conjunction with UConn Health Professor Joel Pachter, Assistant Professor Stephen Crocker, and Advanced Cell Technology (ACT) Inc. of Massachusetts. ImStem was founded in 2012 by UConn doctors Xiaofang Wang and Ren-He Xu, along with Yale University doctor Xinghua Pan and investor Michael Men. “The cutting-edge work by ImStem, our first spinoff company, demonstrates the success of Connecticut’s Stem Cell and Regenerative Medicine funding program in moving stem cells from bench to bedside,” says Professor Marc Lalande, director of the UConn’s Stem Cell Institute. The research was supported by a $1.13 million group grant from the state of Connecticut’s Stem Cell Research Program that was awarded to ImStem and Professor Pachter’s lab. “Connecticut’s investment in stem cells, especially human embryonic stem cells, continues to position our state as a leader in biomedical research,” says Gov. Dannel P. Malloy. “This new study moves us one step closer to a stem cell-based clinical product that could improve people’s lives.” The researchers compared eight lines of adult bone marrow stem cells to four lines of human embryonic stem cells. All of the bone marrow-related stem cells expressed high levels of a protein molecule called a cytokine that stimulates autoimmunity and can worsen the disease. All of the human embryonic stem cell-related lines expressed little of the inflammatory cytokine. Another advantage of human embryonic stem cells is that they can be propagated indefinitely in lab cultures and provide an unlimited source of high quality mesenchymal stem cells – the kind of stem cell needed for treatment of MS, the researchers say. This ability to reliably grow high quality mesenchymal stem cells from embryonic stem cells represents an advantage over adult bone marrow stem cells, which must be obtained from a limited supply of healthy donors and are of more variable quality. “Groundbreaking research like this furthering opportunities for technology ventures demonstrates how the University acts as an economic engine for the state and regional economy,” says Jeff Seemann, UConn’s vice president for research. The findings also offer potential therapy for other autoimmune diseases such as inflammatory bowel disease, rheumatoid arthritis, and type-1 diabetes, according to Xu, a corresponding author on the study and one of the few scientists in the world to have generated new human embryonic stem cell lines. There is no cure for MS, a chronic neuroinflammatory disease in which the body’s immune system eats away at the protective sheath called myelin that covers the nerves. Damage to myelin interferes with communication between the brain, spinal cord, and other areas of the body. Current MS treatments only offer pain relief, and slow the progression of the disease by suppressing inflammation. “The beauty of this new type of mesenchymal stem cells is their remarkable higher efficacy in the MS model,” says Wang, chief technology officer of ImStem. The group’s findings appear in the current online edition of Stem Cell Reports, the official journal of the International Society for Stem Cell Research. ImStem is currently seeking FDA approval necessary to make this treatment available to patients.

Embryonic Stem Cells Offer Treatment Promise for Multiple Sclerosis

Scientists in the University of Connecticut’s Technology Incubation Program have identified a novel approach to treating multiple sclerosis (MS) using human embryonic stem cells, offering a promising new therapy for more than 2.3 million people suffering from the debilitating disease.

The researchers demonstrated that the embryonic stem cell therapy significantly reduced MS disease severity in animal models, and offered better treatment results than stem cells derived from human adult bone marrow.

The study was led by ImStem Biotechnology Inc. of Farmington, Conn., in conjunction with UConn Health Professor Joel Pachter, Assistant Professor Stephen Crocker, and Advanced Cell Technology (ACT) Inc. of Massachusetts. ImStem was founded in 2012 by UConn doctors Xiaofang Wang and Ren-He Xu, along with Yale University doctor Xinghua Pan and investor Michael Men.

“The cutting-edge work by ImStem, our first spinoff company, demonstrates the success of Connecticut’s Stem Cell and Regenerative Medicine funding program in moving stem cells from bench to bedside,” says Professor Marc Lalande, director of the UConn’s Stem Cell Institute.

The research was supported by a $1.13 million group grant from the state of Connecticut’s Stem Cell Research Program that was awarded to ImStem and Professor Pachter’s lab.

“Connecticut’s investment in stem cells, especially human embryonic stem cells, continues to position our state as a leader in biomedical research,” says Gov. Dannel P. Malloy. “This new study moves us one step closer to a stem cell-based clinical product that could improve people’s lives.”

The researchers compared eight lines of adult bone marrow stem cells to four lines of human embryonic stem cells. All of the bone marrow-related stem cells expressed high levels of a protein molecule called a cytokine that stimulates autoimmunity and can worsen the disease. All of the human embryonic stem cell-related lines expressed little of the inflammatory cytokine.

Another advantage of human embryonic stem cells is that they can be propagated indefinitely in lab cultures and provide an unlimited source of high quality mesenchymal stem cells – the kind of stem cell needed for treatment of MS, the researchers say. This ability to reliably grow high quality mesenchymal stem cells from embryonic stem cells represents an advantage over adult bone marrow stem cells, which must be obtained from a limited supply of healthy donors and are of more variable quality.

“Groundbreaking research like this furthering opportunities for technology ventures demonstrates how the University acts as an economic engine for the state and regional economy,” says Jeff Seemann, UConn’s vice president for research.

The findings also offer potential therapy for other autoimmune diseases such as inflammatory bowel disease, rheumatoid arthritis, and type-1 diabetes, according to Xu, a corresponding author on the study and one of the few scientists in the world to have generated new human embryonic stem cell lines.

There is no cure for MS, a chronic neuroinflammatory disease in which the body’s immune system eats away at the protective sheath called myelin that covers the nerves. Damage to myelin interferes with communication between the brain, spinal cord, and other areas of the body. Current MS treatments only offer pain relief, and slow the progression of the disease by suppressing inflammation.

“The beauty of this new type of mesenchymal stem cells is their remarkable higher efficacy in the MS model,” says Wang, chief technology officer of ImStem.

The group’s findings appear in the current online edition of Stem Cell Reports, the official journal of the International Society for Stem Cell Research. ImStem is currently seeking FDA approval necessary to make this treatment available to patients.

Filed under MS stem cells cytokine mesenchymal stem cells autoimmune diseases medicine science

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Breakthrough Study Sheds New Light on Best Medication for Children with Seizures

A recently published clinical study in the Journal of the American Medical Association has answered an urgent question that long puzzled ER pediatricians: Is the drug lorazepam really safer and more effective than diazepam – the U.S. Food and Drug Administration-approved medication as first line therapy most often used by emergency room doctors to control major epileptic seizures in children?

The answer to that question – based on a double-blind, randomized clinical trial that compared outcomes in 273 seizure patients, about half of whom were given lorazepam – is a clear-cut “no,” said Prashant V. Mahajan, M.D., M.P.H., M.B.A, one of the authors of the study.

“The results of our clinical trial were very convincing, and they showed clearly that the two medications are just about equally effective and equally safe when it comes to treating status epilepticus [major epileptic brain seizures in children],” Dr. Mahajan said. “This is an important step forward for all of us who frequently treat kids in the ER for [epilepsy-related] seizures, since it answers the question about the best medication to use in ending the convulsions and getting these patients back to normal brain functioning.”

Describing the brain convulsions that were targeted by the study, its authors pointed out that status epilepticus occurs when an epilepsy-related seizure lasts more than 30 minutes. Such seizures – which occur in more than 10,000 U.S. pediatric epilepsy patients every year – can cause permanent brain damage or even death, if allowed to persist.

Published in JAMA, the study, “Lorazepam vs Diazepam for Pediatric Status Epilepticus: A Randomized Clinical Trial,” was designed to test earlier assertions by many clinicians that lorazepam was more effective at controlling pediatric seizures. The study-authors wrote, “Potential advantages proposed in some studies of lorazepam include improved effectiveness in terminating convulsions, longer duration of action compared with diazepam, and lower incidence of respiratory depression. Specific pediatric data comparing diazepam with lorazepam suggest that lorazepam might be superior, but they are limited to reports from single institutions or retrospective studies with small sample sizes, thus limiting generalizability.”

Based on data collected over four years at 11 different U.S. pediatric emergency departments, the new study found that “treatment with lorazepam [among pediatric patients with convulsive status epilepticus] did not result in improved efficacy or safety, compared with diazepam.”

That determination led the study authors to conclude: “These findings do not support the preferential use of lorazepam for this condition.”

Dr. Mahajan, a nationally recognized researcher in pediatric emergency medicine and a Wayne State University School of Medicine pediatrics professor recently appointed chair of the American Academy of Pediatrics Executive Committee of the Section on Emergency Medicine, said the JAMA study provides “a compelling example of how effective research in pediatric medicine, based on treatment of patients right in the clinical setting, can play a major role in improving outcomes.”

Children’s Hospital of Michigan Chief of Pediatrics Steven E. Lipshultz, M.D., said this recent breakthrough will “undoubtedly result in better care for pediatric patients who present in the emergency room with seizures related to epilepsy.

“There’s no doubt that combining excellent research with excellent treatment is the key to achieving the highest-quality outcomes for patients – and Dr. Mahajan’s cutting-edge study is a terrific example of how kids are benefiting from the research that goes on here at Children’s every single day,” said Dr. Lipshultz.

(Source: media.wayne.edu)

Filed under epilepsy epileptic seizures lorazepam diazepam medicine science

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