How Neurons Generate Movement

When the eye tracks a bird's flight across the sky, the visual experience is normally smooth, without interruption. But underlying this behavior is a complex coordination of neurons that has remained mysterious to scientists. Now, UCSF scientists have broken ground in understanding how the brain generates this tracking motion, a finding that offers a window, they say, into how neurons orchestrate all of the body's movements.

The study, published in the April 24 issue of Neuron, reveals that individual neurons do not fire independently across the entire duration of a motor function as traditionally thought. Rather, they coordinate their activity with other neurons, each firing at a particular moment in time.

"Researchers have known that neurons that connect to muscles initiate movement in a coordinated fashion. But they have not known how the neurons we are studying - which coordinate these front-line neurons -- commit the brain to move the eyes,"says co-lead author David Schoppik, PhD, who conducted the study while a doctoral candidate in the laboratory of senior author Stephen Lisberger, PhD, at the University of California, San Francisco.

"For decades, researchers have been asking, 'Do the signals involve a handful of neurons or thousands? What is the nature of the commands?' The classical understanding has been that one class of neuron is responsible for one movement, such as generating eye movement to the left, and that it remains active across the entire duration of a behavior," he says.

"The new findings suggest a totally different way of looking at how movement is controlled across time," says Lisberger, a Howard Hughes Medical Institute Investigator at UCSF, where he is professor of physiology, director of the W.M. Keck Foundation Center for Integrative Neuroscience, and co-director of the Sloan Center for Theoretical Neurobiology.

The findings, the scientists say, could inform efforts to develop neural prosthetics to treat paralysis and motor dysfunctions, such as those resulting from stroke. "The brain's messages don't reach the muscles in these conditions," says Schoppik, "so it's critical that the drive to these prosthetics reflect what the brain is trying to do to move muscles. Understanding how multiple neurons work together could influence the type of software created to drive these devices".

The investigation of how neurons give rise to motor behaviorshas been stymied until now, says Schoppik, by the difficulties inherent in studying more than one neuron in action at a time during the course of a behavior. In the current study, the researchers overcame this obstacle in a study of macaque monkeys that had been trained to track a moving object with their eyes.

Basing their approach on two key pieces of information -- first, that when a neuron responds to a stimulus there is always a slight variation in its performance, a phenomenon that neuroresearchers traditionally refer to as "noise," and, second, that each attempt of the eye to pursue a moving target is also unique - they proposed that some aspects of neural variation may reflect behavioral variation.

They used this inherent variability as a probe. Using a formula from financial securities market analysis that looks at how individual stocks behave at a given time within the context of fluctuations in the larger financial market, they explored how individual neurons would behave relative to their neighbors.

They compared the deviations from the average spiking activity of single neurons and simultaneous deviations from the mean eye velocity. They also measured the degree to which variation shared across two pairs of concurrently active neurons.

The data demonstrated that individual neurons encode different aspects of behavior, controlling eye velocity fluctuations at particular moments during the course of eye movement, while the population of neurons collectively tiles the entire duration of the movement.

The analysis also revealed the strength of correlations in the eye movement predictions derived from pairs of simultaneously recorded neurons, and suggests, the researcher say, either that a small number of neurons are sufficient to drive the behavior at any given time or that a number of neurons operate collectively at each moment.

The finding, says Lisberger, underscores the importance of recording for more than one neuron at a time. "There is a lot that we can learn from how multiple neurons interact."

Source

New Treatment Target for Asthma

An enzyme released by mast cells in the lungs appears to play a key role in the tightening of airways that is a hallmark of asthma - pointing to a potential new target for therapy against the illness.

Reporting in the online edition of Proceedings of the National Academy of Sciences, a team at Weill Cornell Medical College explains that during an immune response, mast cells release the enzyme - called renin - which in turn produces angiotensin, a potent constrictor of the smooth muscle that lines airways.

Mast cells are normally present in small numbers in all organs, and are best known for their role in allergy, shock, wound healing and defense against pathogens.

"Back in 2005, our team was the first to discover that mast cells in the heart released renin locally, which elicited heart arrhythmias by triggering angiotensin production within the heart," explained co-senior author Dr. Roberto Levi, professor of pharmacology at Weill Cornell Medical College.

"Now, we've expanded those findings to the lungs, where similar mechanisms appear to work locally to help trigger constriction in the airway," he says.

Renin is no stranger to medical research - for decades, doctors have known that the enzyme is produced by the kidney in relatively large quantities for systemic use throughout the body. But the Weill Cornell team was the first to discover that mast cells also produced their own "local" supply of the enzyme, at a variety of body sites.

"In the heart and now the lungs, this localized production of renin appears to have a profound effect on nearby tissues," says co-senior author Dr. Randi Silver, associate professor of physiology and biophysics at Weill Cornell.

"More study is needed, of course, but our finding suggests that drugs that target renin might prove effective agents in dampening asthma or other respiratory diseases," she says. "These types of 'renin inhibitors' are, in fact, currently being developed by the pharmaceutical industry right now".

The genesis of the new study came through the efforts of the study's lead author, Arul Veerappan, now a postdoctoral researcher in Dr. Silver's laboratory. He looked closely at rings of bronchial tissue from rodents, discovering that mast cells in these rings released renin along with other substances.

"You ended up getting the same biochemical cascade that we had seen elsewhere - newly produced renin bringing about a local rise in angiotensin in tissues," Veerappan says.

Research led by co-author Alicia Reid, also a postdoctoral associate in Dr. Silver's lab, led to another first. Using a technology Reid developed, the scientists confirmed for the first time that mast cells from human lung tissue release a form of renin that is nearly identical to renin found in human mast cells grown in culture or human kidney renin.

"That's a big achievement, because it supports the notion that the mechanism we have discovered is not just a laboratory phenomenon - it's actually occurring in the living human lung," Dr. Levi notes.

New research suggests that local renin production may also be crucial in diseases marked by tissue fibrosis (stiffening). In fact, Dr. Silver's lab is now looking at the role locally produced renin might play in a rare, deadly illness called idiopathic pulmonary fibrosis (IPF), where lung tissue becomes increasingly inflexible over time.

"We're interested in any disease in which we can also detect local renin/angiotensin production because it appears to be associated with fibrosis, vasoconstriction, and now bronchoconstriction," Dr. Silver explains.

The goal of all this research: new therapy targets for a range of illnesses.

"Of course, we already have antihypertensive medicines - such as ACE inhibitors and angiotensin receptor blockers -- that focus on curbing angiotensin in a more systemic way," says Dr. Levi. "But if we could find agents that dampen this renin-angiotensin cascade locally - in the heart or the lung, for example - that could prove to be a formidable new weapon against disease".

This work was funded by grants from the U.S. National Institutes of Health.

Source.

LASIK works well in highly myopic patients

Laser surgery to correct vision problems has been in use since the early part of 1990s. Photorefractive Keratotomy (PRK) is typically used to correct low to moderate myopia, while laser in-situ keratomileusis (LASIK) is preferred for high myopia corrections. Eventhough over 18 million LASIK procedures have been performed worldwide, there is still some controversy regarding the maximum correction possible and efficacy with this technique. In an article reported in the January 2008 issue of the American Journal of Ophthalmology, scientists from Miguel Hernandez University, Medical School, Alicante, Spain; and Ankara University School of Medicine, Ankara, Turkey; report on a study of high myopia patients ten years after LASIK surgery. The findings show that LASIK for myopia over -10 D is a safe and effective procedure in the long-term.

196 high myopic eyes of 118 patients, preoperatively needing at least 10 diopter (10 D) corrections to achieve 20/20 vision, were reviewed ten years following surgery. Uncorrected vision was 77% of best-corrected vision (BSCVA) before surgery. BSCVA improved 1 line. Only 5% of eyes lost more than 2 lines of BSCVA and 40% avoided the use of glasses. 119 (61 %) of eyes were within 2.00 Diopters at 10 years. Only 2 eyes (1%) developed corneal ectasia. The retreatment rate was 27%.

As per lead investigator Jorge L. Ali, These results are extremely encouraging considering that this refractive correction implies the maximum limit of application of this technique. This study has allowed us to demonstrate that, in spite of the prejudices about the limits of LASIK technique, the results regarding predictability, efficacy and safety for high myopic patients are very good in the long term. The optimum limit of predictability for this technique is around 10 D of myopia. This reference study, with a long time perspective, allows us to know the safety, precision and limits of LASIK in highly myopic eyes.

Source from:Medicine World.

Why are doctors so unhappy?

Doctors are unhappy. They are not all unhappy all the time, but when doctors gather, their conversation turns to misery and talk of early retirement. The unhappiness has been illustrated in a plethora of surveys and manifests itself in talk of a mass resignation by general practitioners from the NHS.The British government is rattled by the unhappiness of doctors, recognising that a health service staffed by demoralised doctors cannot flourish. It has responded by trying to hand more control of the service to front­line staff.2 3 But is this the right treatment? Treatment must, of course, follow diagnosis, and the causes of doctors' unhappiness may be many and deep. The most obvious cause of doctors' unhappiness is that they feel overworked and undersupported. They hear politicians make extravagant promises but then must explain to patients why the health service cannot deliver what is promised. Endless initiatives are announced, but on the ground doctors find that operat­ing lists are cancelled, they cannot admit or discharge patients, and community services are disappearing. They struggle to respond, but they feel as though they are battling the system rather than being supported by it. Those in the NHS are the last survivors of a social­ist inspired system. In a society that pays a businessman £500 000 a year and many public servants £10 000, they try to patch up the social and health damage that accompanies such divisions. It's difficult, if not impossi­ble, work. And, worse, it is undertaken against a backcloth of negative media coverage. Dr Kildare has been replaced by Dr Shipman, and stories of errors outnumber tales of triumph. Government ministers look down on the health service and don't quite understand. Resources are being increased in real terms. General practitioners have more time with patients than they had 20 years ago. Doctors are more and more involved in running the service—as czars, medical or clinical directors, or members of primary care groups. Dozens of initiatives—national service frameworks and health action zones—are being developed to counter problems that doctors have been highlighting for years. And the ministers work harder than anybody—criss crossing the country, chairing task forces, doing their ministerial work in the morning, answering parliamentary questions in the afternoon, and conducting surgeries on Saturday mornings. Ministers are thus likely to diagnose doctors'unhappiness in terms of diminished control, more change, and increased accountability. It's impossible to reverse the increasing accountability. This is a
worldwide phenomenon that affects not only doctors. Similarly, ministers cannot imagine slowing the pace of change. They live in a world where escalation of promises is routine. Ministers thus fall back on “sweeping away bureaucracy and giving more control to frontline staff,” not least because nobody wants more bureaucracy. Health workers might, however, want better management of the service, and they themselves might not be the best people to do this. And here we come to something deeper—the mis­match between what doctors were trained for and what they are required to do. Julian Tudor Hart, a general practitioner who retired recently, observed that what he learnt at medical school didn't serve him well for hospital medicine, which in turn didn't serve him well for general practice. In other words, he started three times as a doctor. But maybe now it's more extreme.

Trained in pathophysiology, diagnosis, and treatment, doctors find themselves spending more time thinking about issues like management, improvement, finance, law, ethics, and communication. Luke Filde's 19th century painting of a contemplative doctor alone with a sick child might now be replaced by a harassed doctor trying to park his car to get to a meeting on time. The gratification that comes from curing a sick child is different from that which comes from being part of the meeting that agrees to take an abused child into care. Christian Koeck—a doctor, professor of health policy, and member of the BMJ editorial board—thinks the problem goes deeper. He thinks the intellectual model of medicine is wrong and that instead of being trained simply to apply the natural sciences to peoples' health problems doctors should also be trained as change managers. That way they can help people adjust to the sickness, pain, and death that are central to being human. Another way to think about doctors' unhappiness is to think of the change in the contract between doctors and patients. We hear much about doctors changing from being authorities to being partners with patients, and some find this transition unsettling. But perhaps the change is deeper still. Maybe we are changing from what has become a bogus contract between doctors and patients to something more real. Doctors are often acutely aware of the limitations of what they can do, whereas patients—partly through the exaggeration of doctors—have inflated ideas of the power of medicine. Negative media coverage might represent the world's waking up to the limitations of doctors and medicine, and—though it's uncomfortable now—it may lead to a much more honest, adult, and comfortable, relationship.

Written by Richard Smith from:BMJ.

The Run on Tamiflu — Should Physicians Prescribe on Demand?

"Doctor, I need a prescription for that bird flu drug". If recent newspaper headlines are any indication, 1 this request has been repeated tens of thousands of times around the country this fall. So much oseltamivir (Tamiflu) has been prescribed — presumably for personal stockpilingin case of an avian influenza pandemic, given that the human influenza season has not yet begun— that at the end of October, the drug’s manufacturer stopped shipping it to the United States.

A busy outpatient office is no place to think through complicated ethical dilemmas. But a request for oseltamivir is just that, and it must be examined from both the perspective of individual patient–physician encounters and that of public health. From the first perspective, such requests raise a more general question: What is the physician’s obligation to grant patients’ requests for specific interventions? As an outgrowth of the patient-autonomy movement, patients’ preferences have come to play an important role in clinical decision making. It is widely accepted that, in nearly all clinical circumstances, patients may refuse unwanted interventions proposed by physicians. Less straightforward, however, are clinical encounters in which patients insist on interventions that are deemed inappropriate by physicians. These encounters have been discussed both in the context of common problems in primary care (e.g., when patients demand antibiotics for viral infections) and in the context of lifesustaining treatment near the end of life (in cases in which physicians have deemed further treatment to be futile). The literature on ethics in the clinical setting and professional guidelines generally support the conclusion that physicians are not obligated to honor requests for nonbeneficial tests and treatments — although what should count as nonbeneficial or inappropriate may remain problematic.

Physicians are trained and licensed to practice medicine according to scientific evidence and professional standards. When there is at least a modicum of benefit from the perspective of conventional medicine, physicians should generally defer to patients’ requests, and a patient’s weighing of benefits and harms should drive the decision. But if a patient requests an intervention that falls outside the boundaries established by scientific evidence, a physician is not obligated to provide it.

In the case of avian influenza, a human outbreak in any given geographic area is currently a purely hypothetical concern; physicians are not required to dispense medications for hypothetical scenarios when it is not yet possible to determine who is at risk. If a human outbreak occurred, it is unclear whether the virus would be generally susceptible to oseltamivir and whether this drug would still be the treatment of choice. Moreover, in an epidemic, any indicated drug could be used in several different ways — for preexposure prophylaxis, postexposure prophylaxis, or treatment after symptoms have appeared. If oseltamivir were dispensed well in advance of an outbreak, patients would probably use their stockpiles in a chaotic fashion, rather than optimally for any of these indications. Indeed, some or most of it would no doubt be wasted on viral illnesses other than influenza.

From the perspective of the individual patient–physician encounter, these factors suggest that physicians have no obligation to prescribe oseltamivir to patients who request it for a hypothetical outbreak of avian influenza: the threshold for a modicum of benefit has not been reached. The relative lack of side effects does not constitute a sufficient reason for prescribing oseltamivir.

From a public health perspective, preventive or therapeutic interventions should be optimally allocated across a population. Accordingly, a major focus of public health ethics is maximizing the health of the population while minimizing infringements on individual liberty.2 Ethical dilemmas arising from the tension between the two are typically posed by cases in which a person refuses to comply with a public health imperative (such as mandatory vaccination or quarantine). Less common are cases in which a person demands an intervention that is perceived as conferring individual benefit but that might contribute to net harm to the public health. The personal stockpiling of oseltamivir for a potential avian influenza pandemic represents just such a case. The current supply of oseltamivir is inadequate to meet the demand that would arise in the event of an avian influenza pandemic. Moreover, personal stockpiling of oseltamivir depletes the supply available for patients who could benefit from the drug during the usual human influenza season: a person who is assertive enough to ask for a prescription does not necessarily need the drug more than unassertive people do.The likely confusion about whether to use stockpiled oseltamivir for prophylaxis or treatment and the probability that much will be used for illnesses other than influenza are relevant from the public health perspective as well. Finally, the inappropriate or chaotic use of oseltamivir will increase the risk that resistant strains of influenza virus will develop. These considerations strongly suggest that random stockpiling of oseltamivir would confer no benefit to the overall population and would probably confer harm.

Thus, an individual physician has no obligation to prescribe oseltamivir in response to a patient’s request — a position that discourages prescribing of the drug but does not prohibit it. In contrast, the public health perspective clearly suggests that the physician has an obligation not to prescribe oseltamivir — a position that is tantamount to a prohibition against prescribing it. The public health perspective need not always trump the individual perspective, but since both point in the same direction in this instance, the prohibition should prevail.

As in 2001, when physicians were besieged with demands for ciprofloxacin after the anthrax attacks, this year’s run on oseltamivir should stimulate public health experts to consider more generally the dilemma encountered by physicians who have simultaneous obligations to individual patients and to public health. Physicians who faced demands for oseltamivir in the early fall of 2005 would have welcomed explicit directives from public health institutions such as the Centers for Disease Control and Prevention and state departments of health. Such directives were helpful in the fall of 2004 when physicians were forced to ration influenza vaccine.3 In the absence of formal guidelines from the government, some professional societies4 and private medical groups5 have stepped in to issue statements that are consistent with our conclusion: physicians should decline any request for a prescription for the purpose of stockpiling oseltamivir, optimally with an explanation that reflects the reasoning here.

Source from: n engl j med.

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