Posts tagged medicine
Articles and news from the latest research reports.
We’ve all heard about circadian rhythm, the roughly 24-hour oscillations of biological processes that occur in many living organisms. Yet for all its influence in many aspects of our lives — from sleep to immunity and, particularly, metabolism — relatively little is understood about the mammalian circadian rhythm and the interlocking processes that comprise this complex biological clock.
Through intensive analysis and computer modeling, researchers at UC Santa Barbara have gained insight into factors that affect these oscillations, with results that could lend themselves to circadian regulation and pharmacological control. Their work appears in the early edition of the Proceedings of the National Academy of Sciences.
“Our group has been fascinated with circadian rhythms for over 10 years now, as they represent a marvelous example of robust control at the molecular scale in nature,” said Frank Doyle, chair of UCSB’s Department of Chemical Engineering and the principal investigator for the UCSB team. “We are constantly amazed by the mechanisms that nature uses to control these clocks, and we seek to unravel their principles for engineering applications as well as shed light on the underlying cellular mechanisms for medical purposes.”
“Focus is often given to metabolism, cell division and other generic cell processes, but circadian oscillations are just as central to how life is organized,” said Peter St. John, a researcher in the Department of Chemical Engineering and lead author of the study.
Blood pressure, he noted, varies with time of day, as do visual acuity, smell and taste. Certain hormones are released at certain times to do their tasks. We get sleepy or become more alert at different hours. All these various highs and lows, rises and falls are the result of our circadian rhythm.
“There are genes and proteins that are expressed in a cell and their activity, or expression level, changes with time of day,” explained St. John. “These oscillations are caused by genetic circuits. So you’ll have a gene that’s produced, and when it’s in its finished form, it will turn itself off.” The proteins and genes get cleared away, after which production starts all over again, in a cycle that takes roughly 24 hours to complete.
While genetics plays a role in these rhythms — for instance if your parents were night owls, it’s likely you will be one too — environment, habits and lifestyles also affect the clock.
“It’s not just this free-running oscillator,” said St. John. “It gets these inputs from light. For instance if you get light early in the morning, it’ll speed up something so your phase is adjusted to the time of day.” Other influences include food (not so much what you eat but when), drugs, shift work and frequent travel across time zones.
The healthiest circadian rhythms are the ones that are considered to be “high-amplitude” — where different and complementary processes occur in the body during distinct and regular daytime and nighttime phases.
“We’re very different animals during the night and the day,” said St. John. “If you’re fasting at night and you’re asleep, the demands on your cells will be very different than if you’re awake and running around. There’s this temporal separation between the genes that you need during the day and those you need at night.”
Problems occur when the amplitude gets repressed, often because of modern-day schedules and lifestyles. Too much light at night, insufficient or irregular sleep hours, and eating or exercising too late in the evening are all habits that don’t allow for the necessary nighttime-phase cellular activity. This in turn can lead to disorders such as diabetes, heart disease and obesity. In very preliminary studies, Alzheimer’s disease and certain liver conditions are also associated with low-amplitude rhythms.
Establishing high-amplitude circadian rhythms could be as simple as modifying our schedules, but for some people — those with sleep disorders, for example, or those whose work requires long and irregular hours — it can be difficult, if not impossible.
By studying the regulation of the clock proteins called Period (PER) and Cryptochrome (CRY) — proteins that are thought to be involved with metabolism — St. John and Doyle were able to model the mechanisms of two small-molecule drugs — Longdaysin and KL0001 — that regulate the expression of the clock proteins. The insight they gained could lead to therapies that can help those with repressed circadian rhythms.
“Everybody thought that these were very similar proteins,” said St. John. “They bind to each other. They enter the nucleus together.” The assumption was that perturbations to those proteins would produce similar results. “But when we analyzed the data,” St. John continued, “it turned out that when you stabilize PER you get these higher-amplitude rhythms, but when you stabilize CRY you get these lower-amplitude rhythms.”
These results — obtained by studying cultured human cells that glow depending on their circadian phase, as well as through computer modeling — shed light on the mechanisms behind the metabolic aspect of circadian rhythms and pave the way for drug therapies that could decrease the risk of disease for those with disrupted rhythms. The UCSB researchers worked in collaboration with experimental scientists Tsuyoshi Hirota and Steve Kay from UC San Diego and USC, respectively.
“These collaborative partnerships with life scientists are crucial to the success of a project like this,” said Doyle, “and this kind of collaborative research team can implement the paradigm of systems biology with combined mathematical modeling and high-throughput experimental biology.”
Future modeling studies will try to determine if there is an optimal phase for taking one drug or the other to improve the amplitude of circadian rhythms. Experimental work will focus on improving specificity and bioavailability — the amount of drug that actually reaches the target tissues before being discharged by the body.
Alzheimer’s drugs fail, but lessons are learned
After the failure of two novel drugs using antibodies to fight the buildup of brain plaque in Alzheimer’s patients, scientists said on Wednesday they have learned lessons for the future.
The biologic drugs solanezumab, by pharmaceutical giant Eli Lilly, and bapineuzumab, by Johnson and Johnson, made it to phase III trials and were taken by thousands of patients, according to a full report on the research published in the New England Journal of Medicine.
Breakthrough in Understanding the Secret Life of Prion Molecules
New research from David Westaway, PhD, of the University of Alberta and Jiri Safar, MD, Case Western Reserve University School of Medicine has uncovered a quality control mechanism in brain cells that may help keep deadly neurological diseases in check for months or years.
Image credit: STEVE GSCHMEISSNER / SPL
The findings, published in The Journal of Clinical Investigation, “present a breakthrough in understanding the secret life of prion molecules in the brain and may offer a new way to treat prion diseases,” said Westaway, Director of the Centre for Prions and Protein Folding Diseases and Professor of Neurology in the Faculty of Medicine and Dentistry at the University of Alberta.
Global first: easing cannabis withdrawal
A world-first study led by the National Cannabis Prevention and Information Centre (NCPIC) at UNSW has revealed a breakthrough for dependent cannabis users, employing a cannabis-based medication, Sativex (nabiximols), that has been shown to provide significant relief from withdrawal symptoms.
“One in ten people who try cannabis go on to become dependent. As cannabis use increases around the world and more people seek treatment to help them quit, it is surprising there is no approved medication to alleviate symptoms of withdrawal. The success of this study offers considerable hope for those struggling to get through a cannabis withdrawal and remain abstinent into the future,” said Professor Jan Copeland, Director of NCPIC and Chief Investigator of the study.
“One of the greatest barriers to quitting cannabis is withdrawal and while symptoms aren’t life-threatening, they are of a severity level that causes marked distress. For many people, symptoms including irritability, depression, cannabis cravings and sleep problems, can overcome their strong desire to quit and they find themselves using again.”
The study was conducted at inpatient services of South Eastern Sydney and Hunter New England Local Health Districts.
Associate Professor Nicolas Lintzeris, Director of Drug and Alcohol Services at South Eastern Sydney Local Health District and a trial investigator said: “The study found patients treated with Sativex stayed in treatment longer, and experienced a shorter and milder withdrawal than patients receiving placebo.”
Administered as an oral spray, Sativex is only licensed in Australia for the treatment of spasticity and pain in Multiple Sclerosis (MS) patients when other medications have failed. The spray contains the cannabis extracts, cannabidiol (CBD) and delta-9-tetrahydrocannabinol (THC), which is the substance primarily responsible for the psychoactive effects of cannabis.
The lead author of the paper and study investigator Dr David Allsop noted, “While most people who use cannabis do not become dependent, those who use regularly or for an extended period run that risk. Sativex is not licensed or available for treating cannabis users at this time. Our hope is that this study will lead to further research, and possibly approval of the drug for use as a treatment for people experiencing problematic cannabis use.”
The full findings of this study have been published in international psychiatry journal, JAMA Psychiatry.
(Source: newsroom.unsw.edu.au)
Breast cancer spreads to brain by masquerading as neurons
Often, several years can pass between the time a breast cancer patient successfully goes into remission and a related brain tumor develops. During that time, the breast cancer cells somehow hide, escaping detection as they grow and develop. Now City of Hope researchers have found out how.
Breast cancer cells disguise themselves as neurons, becoming “cellular chameleons,” the scientists found. This allows them to slip undetected into the brain and, from there, develop into tumors.
The discovery is being heralded as “a tremendous advance in breast cancer research.”
Although breast cancer is a very curable disease – with more than 95 percent of women with early-stage disease surviving after five years – breast cancer that metastasizes to the brain is difficult to fight. In fact, only about 20 percent of patients survive a year after diagnosis.
"There remains a paucity of public awareness about cancer’s relentless endgame," said Rahul Jandial, M.D., Ph.D., a City of Hope neurosurgeon who headed the breast-cancer-and-brain-tumor study, published online ahead of print this week in the Proceedings of the National Academy of Sciences.
"Cancer kills by spreading. In fact, 90 percent of all cancer mortality is from metastasis," Jandial said. "The most dreaded location for cancer to spread is the brain. As we have become better at keeping cancer at bay with drugs such as Herceptin, women are fortunately living longer. In this hard-fought life extension, brain metastases are being unmasked as the next battleground for extending the lives of women with breast cancer."
He added: “I have personally seen my neurosurgery clinic undergo a sharp rise in women with brain metastases years – and even decades – after their initial diagnosis.”
Jandial and other City of Hope scientists wanted to explore how breast cancer cells cross the blood-brain barrier – a separation of the blood circulating in the body from fluid in the brain – without being destroyed by the immune system.
“If, by chance, a malignant breast cancer cell swimming in the bloodstream crossed into the brain, how would it survive in a completely new, foreign habitat?” said Jandial in a recent interview with New Scientist.
Jandial and his team’s hypothesis: Given that the brain is rich in many brain-specific types of chemicals and proteins, perhaps breast cancer cells that could exploit these resources by assuming similar properties would be the most likely to flourish. These cancer cells could deceive the immune system by blending in with the neurons, neurotransmitters, other types of proteins, cells and chemicals.
Taking samples from brain tumors resulting from breast cancer, Jandial and his team found that the breast cancer cells were exploiting the brain’s most abundant chemical as a fuel source. This chemical, GABA, is a neurotransmitter used for communication between neurons.
When compared to cells from nonmetastatic breast cancer, the metastasized cells expressed a receptor for GABA, as well as for a protein that draws the transmitter into cells. This allowed the cancer cells to essentially masquerade as neurons.”Breast cancer cells can be cellular chameleons (or masquerade as neurons) and spread to the brain,” Jandial said.
Jandial says that further study is required to better understand the mechanisms that allow the cancer cells to achieve this disguise. He hopes that ultimately, unmasking these disguised invaders will result in new therapies.
Scientists Develop Promising Drug Candidates for Pain, Addiction
Scientists from the Florida campus of The Scripps Research Institute (TSRI) have described a pair of drug candidates that advance the search for new treatments for pain, addiction and other disorders.
The two new drug scaffolds, described in a recent edition of The Journal of Biological Chemistry, offer researchers novel tools that act on a demonstrated therapeutic target, the kappa opioid receptor (KOR), which is located on nerve cells and plays a role in the release of the neurotransmitter dopamine. While compounds that activate KOR are associated with positive therapeutic effects, they often also recruit a molecule known as βarrestin2 (beta arrestin), which is associated with depressed mood and severely limits any therapeutic potential.
“Compounds that act at kappa receptors may provide a means for treating addiction and for treating pain; however, there is the potential for the development of depression or dysphoria associated with this receptor target,” said Laura Bohn, a TSRI associate professor who led the study. “There is evidence that the negative feelings caused by kappa receptor drugs may be, in part, due to receptor actions through proteins called beta arrestins. Developing compounds that activate the receptors without recruiting beta arrestin function may serve as a means to improve the therapeutic potential and limit side effects.”
The new compounds are called “biased agonists,” activating the receptor without engaging the beta arrestins.
Research Associate Lei Zhou, first author of the study with Research Associate Kimberly M. Lovell, added, “The importance of these biased agonists is that we can manipulate the activation of one particular signaling cascade that produces analgesia, but not the other one that could lead to dysphoria or depression.”
The researchers note that the avoidance of depression is particularly important in addiction treatment, where depressed mood can play a role in relapse.
The two drug candidates also have a high affinity and selectivity for KOR over other opioid receptors and are able to pass through the blood-brain barrier. Given these promising attributes, the scientists plan to continue developing the compounds.
(Source: scripps.edu)
Medical implants, complex interfaces between brain and machine or remotely controlled insects: Recent developments combining machines and organisms have great potentials, but also give rise to major ethical concerns. In their review entitled “Chemie der Cyborgs – zur Verknüpfung technischer Systeme mit Lebewesen” (The Chemistry of Cyborgs – Interfacing Technical Devices with Organisms), KIT scientists discuss the state of the art of research, opportunities, and risks. The review is published now by the renowned journal “Angewandte Chemie Int. Ed.”
They are known from science fiction novels and films – technically modified organisms with extraordinary skills, so-called cyborgs. This name originates from the English term “cybernetic organism”. In fact, cyborgs that combine technical systems with living organisms are already reality. The KIT researchers Professor Christof M. Niemeyer and Dr. Stefan Giselbrecht of the Institute for Biological Interfaces 1 (IBG 1) and Dr. Bastian E. Rapp, Institute of Microstructure Technology (IMT), point out that this especially applies to medical implants.
In recent years, medical implants based on smart materials that automatically react to changing conditions, computer-supported design and fabrication based on magnetic resonance tomography datasets or surface modifications for improved tissue integration allowed major progress to be achieved. For successful tissue integration and the prevention of inflammation reactions, special surface coatings were developed also by the KIT under e.g. the multidisciplinary Helmholtz program “BioInterfaces”.
Progress in microelectronics and semiconductor technology has been the basis of electronic implants controlling, restoring or improving the functions of the human body, such as cardiac pacemakers, retina implants, hearing implants, or implants for deep brain stimulation in pain or Parkinson therapies. Currently, bioelectronic developments are being combined with robotics systems to design highly complex neuroprostheses. Scientists are working on brain-machine interfaces (BMI) for the direct physical contacting of the brain. BMI are used among others to control prostheses and complex movements, such as gripping. Moreover, they are important tools in neurosciences, as they provide insight into the functioning of the brain. Apart from electric signals, substances released by implanted micro- and nanofluidic systems in a spatially or temporarily controlled manner can be used for communication between technical devices and organisms.
BMI are often considered data suppliers. However, they can also be used to feed signals into the brain, which is a highly controversial issue from the ethical point of view. “Implanted BMI that feed signals into nerves, muscles or directly into the brain are already used on a routine basis, e.g. in cardiac pacemakers or implants for deep brain stimulation,” Professor Christof M. Niemeyer, KIT, explains. “But these signals are neither planned to be used nor suited to control the entire organism – brains of most living organisms are far too complex.”
Brains of lower organisms, such as insects, are less complex. As soon as a signal is coupled in, a certain movement program, such as running or flying, is started. So-called biobots, i.e. large insects with implanted electronic and microfluidic control units, are used in a new generation of tools, such as small flying objects for monitoring and rescue missions. In addition, they are applied as model systems in neurosciences in order to understand basic relationships.
Electrically active medical implants that are used for longer terms depend on reliable power supply. Presently, scientists are working on methods to use the patient body’s own thermal, kinetic, electric or chemical energy.
In their review the KIT researchers sum up that developments combining technical devices with organisms have a fascinating potential. They may considerably improve the quality of life of many people in the medical sector in particular. However, ethical and social aspects always have to be taken into account.
Scientists discover new causes of diabetes
The research, published today in the journal Cell Metabolism, provides further insights on how the insulin-producing beta cells are formed in the pancreas. The team discovered that mutations in two specific genes which are important for development of the pancreas can cause the disease. These findings increase the number of known genetic causes of neonatal diabetes to 20. The study was funded by the Wellcome Trust, Diabetes UK, European Community’s Seventh Framework Programme, with some of the authors supported by the National Institute for Health Research (NIHR).
Dr Sarah Flanagan, lead author on the paper, said: “We are very proud to be able to give answers to the families involved on why their child has diabetes. Neonatal diabetes is diagnosed when a child is less than six months old, and some of these patients have added complications such as muscle weakness and learning difficulties with or without epilepsy.
“Our genetic discovery is critical to the advancement of knowledge on how insulin-producing beta cells are formed in the pancreas, which has implications for research into manipulating stem cells, which could one day lead to a cure.”
Dr Alasdair Rankin, Diabetes UK Director of Research, said: “As well as shedding further light on the genetic causes of neonatal diabetes and providing answers for parents of children with this rare condition, this work helps us understand how the pancreas develops. Many people with diabetes can no longer make insulin and would benefit from therapies that replace the insulin producing beta cells of the pancreas. The results of this study are critical to bringing the day closer when this type of treatment is possible.”
Neonatal diabetes is caused by a change in a gene which affects insulin production. This means that levels of blood glucose (sugar) in the body rise dangerously high.
The Exeter team is the leading centre for neonatal diabetes having recruited over 1200 patients from more than 80 countries. This specific study focussed on 147 young people with neonatal diabetes, a rare condition which affects approximately 1 in 100,000 births. Following a systematic screen, 110 patients received a genetic diagnosis. For the remaining 37 patients, mutations in genes important for human pancreatic development were screened. Mutations were found in 11 patients, four of which were in one of two genes not previously known to cause neonatal diabetes (NKX2-2 and MNX1).
For many of the 121 (82%) patients who received a genetic diagnosis, knowing the cause of the diabetes will result in improved treatment, and for all the patients it will provide important information on risk of neonatal diabetes in future pregnancies. These patients also provide important scientific insights into pancreatic development.
(Source: exeter.ac.uk)
Racism May Accelerate Aging in African American Men
A new University of Maryland-led study reveals that racism may impact aging at the cellular level. Researchers found signs of accelerated aging in African American men who reported high levels of racial discrimination and who had internalized anti-Black attitudes. Findings from the study, which is the first to link racism-related factors and biological aging, are published in the American Journal of Preventive Medicine.
Racial disparities in health are well-documented, with African Americans having shorter life expectancy, and a greater likelihood of suffering from aging-related illnesses at younger ages compared to whites. Accelerated aging at the biological level may be one mechanism linking racism and disease risk.
“We examined a biomarker of systemic aging, known as leukocyte telomere length,” explained Dr. David H. Chae, assistant professor of epidemiology at UMD’s School of Public Health and the study’s lead investigator. Shorter telomere length is associated with increased risk of premature death and chronic disease such as diabetes, dementia, stroke and heart disease. “We found that the African American men who experienced greater racial discrimination and who displayed a stronger bias against their own racial group had the shortest telomeres of those studied,” Chae explained.
Telomeres are repetitive sequences of DNA capping the ends of chromosomes, which shorten progressively over time – at a rate of approximately 50-100 base pairs annually. Telomere length is variable, shortening more rapidly under conditions of high psychosocial and physiological stress. “Telomere length may be a better indicator of biological age, which can give us insight into variations in the cumulative ‘wear and tear’ of the organism net of chronological age,” said Chae. Among African American men with stronger anti-black attitudes, investigators found that average telomere length was 140 base pairs shorter in those reporting high vs. low levels of racial discrimination; this difference may equate to 1.4 to 2.8 years chronologically.
Participants in the study were 92 African American men between 30-50 years of age. Investigators asked them about their experiences of discrimination in different domains, including work and housing, as well as in getting service at stores or restaurants, from the police, and in other public settings. They also measured racial bias using the Black-White Implicit Association Test. This test gauges unconscious attitudes and beliefs about race groups that people may be unaware of or unwilling to report.
Even after adjusting for participants’ chronological age, socioeconomic factors, and health-related characteristics, investigators found that the combination of high racial discrimination and anti-black bias was associated with shorter telomeres. On the other hand, the data revealed that racial discrimination had little relationship with telomere length among those holding pro-black attitudes. “African American men who have more positive views of their racial group may be buffered from the negative impact of racial discrimination,” explained Chae. “In contrast, those who have internalized an anti-black bias may be less able to cope with racist experiences, which may result in greater stress and shorter telomeres.”
The findings from this study are timely in light of regular media reports of racism facing African American men. “Stop-and-frisk policies, and other forms of criminal profiling such as ‘driving or shopping while black’ are inherently stressful and have a real impact on the health of African Americans,” said Chae. Researchers found that racial discrimination by police was most commonly reported by participants in the study, followed by discrimination in employment. In addition, African American men are more routinely treated with less courtesy or respect, and experience other daily hassles related to racism.
Chae indicated the need for additional research to replicate findings, including larger studies that follow participants over time. “Despite the limitations of our study, we contribute to a growing body of research showing that social toxins disproportionately impacting African American men are harmful to health,” Chae explained. “Our findings suggest that racism literally makes people old.”
(Image: Shutterstock)
How fat might be controlled through the body clock
Australian researchers have shed more light on an underexplored aspect of the important brain-signaling system that controls appetite, body composition and energy use. Their findings suggest that a specific gene regulating our body clock may play a central role in determining how fat we become.
Evolution has preserved the ‘neuropeptide Y (NPY) system’, as it is known, in most species – indicating its importance – and much of our understanding comes from studying it in mice. There is one important difference, however, between the NPY system in mouse and man.
In man, the neurotransmitter NPY communicates with four well-known ‘cell surface receptors’ in the brain (Y1, Y2, Y4 and Y5), which in turn trigger the system’s effects.
The new study has shown that mice have an additional receptor, Y6, which has profound effects on their body composition. Y6 is produced in a very small region of the brain that regulates the body clock, as well as growth hormone production.
PhD student Ernie Yulyaningsih, Dr Kim Loh, Dr Shu Lin and Professor Herbert Herzog from Sydney’s Garvan Institute of Medical Research, together with Associate Professor Amanda Sainsbury-Salis, now at the University of Sydney, deleted the Y6 gene from mice to understand its effects. Their study showed that mice without the Y6 gene were smaller, and had less lean tissue, than normal mice. On the other hand, as they aged, these ‘knockout mice’ grew fatter than the normal mice, especially when fed a high-fat diet. In that case, they became obese and developed metabolic problems similar to diabetes. These findings are now published online in the prestigious international journal, Cell Metabolism.
While the gene encoding the Y6 receptor is altered in man, Professor Herzog believes it would be unwise to ignore it because the development of anti-obesity drugs relies heavily on mouse studies.
“It is now clear to us that signaling through the Y6 receptor system is critical for the ways in which energy is used at different times of the day,” said Professor Herbert Herzog.
“Our work shows that Pancreatic Polypeptide has a very high affinity for Y6 in mice. It’s a satiety signal, and probably controls the circadian aspect of food intake – because the same amount of calories eaten at different times of the day has different effects on body weight.”
“The Y6 gene is highly expressed in a part of the brain called the ‘hypothalamic suprachiasmatic nucleus’, which is known to control the body’s circadian rhythm and may also critically modulate metabolic processes in response to food. The gene stimulates higher levels of certain peptides, including vasoactive intestinal peptide (VIP) – which controls growth hormone release.”
“While it is not clear whether the Y6 receptor is fully active in humans, Pancreatic Polypeptide is highly expressed – even more so than in mice – and it’s possible that another receptor to which the peptide has high affinity, such as Y4, could have taken over this function.”
Associate Professor Amanda Sainsbury-Salis expressed surprise at the impact of the Y6 gene deletion on mice, commenting “I find it amazing that one gene, which is expressed in the small part of the brain that controls the body clock, has such a profound impact on how much fat is stored on the body, and how much lean tissue is maintained.”
“Importantly, we use mice as models of human beings in research, and so when looking for anti-obesity drugs, we need to fully understand the function of the NPY system in this animal model to understand how similar circuits in humans connect with the body clock.”
(Source: garvan.org.au)