First investigational treatment for infantile-onset SMA shows promising results in clinical trial

A major milestone was reached when nusinersen, an investigational treatment for spinal muscular atrophy (SMA), was shown to significantly improve achievement of motor milestones in babies with infantile-onset SMA, according to an interim analysis of the double-blind, randomized, placebo controlled Phase 3 clinical trial called ENDEAR. Babies born with SMA, a genetic disorder affecting nerves that control muscle movement, cannot hold up their heads, roll over or sit up independently. They often do not survive beyond 2 years of age. Thirty-six centers around the world participated in the study, including Ann & Robert H. Lurie Children's Hospital of Chicago, which had the highest patient enrollment.

"This landmark study provides the most robust type of evidence that nusinersen, which targets the genetic defect in SMA, safely and effectively helps infants with this condition gain muscle function," said Nancy Kuntz, MD, Principal Investigator (PI) at Lurie Children's, Medical Director of Mazza Foundation Neuromuscular Program and Associate Professor of Pediatrics and Neurology at Northwestern University Feinberg School of Medicine. "This might be a promising therapy for this devastating disorder."

Based on these positive findings and safety profile, the trial will be stopped early and nusinersen will be the first SMA treatment to be filed for FDA approval. Patients in the study will be transitioned into an open label study in which all infants will receive nusinersen. Biogen, the sponsoring company, is working to open a global expanded access program for eligible patients with infantile-onset SMA in the coming months.

"Going forward, we could add SMA to the newborn screening panel and treat infants in the pre-symptomatic phase," said Leon Epstein, MD, Co-PI at Lurie Children's, Division Head of Neurology, Medical Director of the Clinical Research Unit of Stanley Manne Children's Research Institute at Lurie Children's, and Professor of Pediatrics and Neurology at Northwestern University Feinberg School of Medicine.

Due to a genetic defect, infants with SMA do not produce enough survival motor neuron (SMN) protein, which is critical for the maintenance of motor nerve cells. Nusinersen is designed to increase production of fully functional SMN protein by regulating gene expression. The investigational treatment is delivered to the fluid around the spine by lumbar puncture, or spinal tap. Repeated doses are needed.

"The success we saw in the trial is incredibly exciting for families of infants with SMA, as well as for physicians who care for these children," said Kuntz.

Ref : http://www.chemspider.com/Chemical-Structure.34983394.html

Heron Therapeutics Announces FDA Approval of Sustol (granisetron) Extended-Release Injection for the Prevention of Chemotherapy-Induced Nausea and Vomiting

Heron Therapeutics, Inc. (NASDAQ:HRTX), today announced that the U.S. Food and Drug Administration (FDA) has approved Sustol (granisetron) extended-release injection. Sustol is a serotonin-3 (5-HT3) receptor antagonist indicated in combination with other antiemetics in adults for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic chemotherapy (MEC) or anthracycline and cyclophosphamide (AC) combination chemotherapy regimens.

Sustol is an extended-release, injectable 5-HT3 receptor antagonist that utilizes Heron’s Biochronomer® polymer-based drug delivery technology to maintain therapeutic levels of granisetron for ≥5 days, covering both the acute and delayed phases of chemotherapy-induced nausea and vomiting (CINV).

“Despite advances in the management of CINV, up to half of patients receiving chemotherapy can still experience CINV, with delayed CINV being particularly challenging to control,” commented Ralph V. Boccia, MD, FACP, Medical Director, Center for Cancer and Blood Disorders. “In our experience, other 5-HT3 receptor antagonists, including palonosetron, are generally effective for 48 hours or less. Sustol, due to its extended-release profile, represents a novel option that can protect patients from CINV for a full 5 days.”

The Sustol global Phase 3 development program was comprised of two, large, guideline-based clinical trials that evaluated Sustol's efficacy and safety in more than 2,000 patients with cancer. Sustol's efficacy in preventing nausea and vomiting was evaluated in both the acute phase (day 1 following chemotherapy) and the delayed phase (days 2-5 following chemotherapy). "The Sustol clinical trial populations and results are highly representative of cancer patients in our real-world clinical practice,” said Jeffrey Vacirca, MD, FACP, Chief Executive Officer and Director of Clinical Research, North Shore Hematology Oncology Associates and Vice President, Community Oncology Alliance. “Use of MEC regimens is widespread, and AC-based regimens are among the most commonly prescribed highly emetogenic chemotherapy regimens. The most significant challenge for my breast cancer patients receiving AC is chemotherapy-induced nausea and vomiting. Sustol represents a better option to manage this devastating side effect of therapy.”

"We would like to thank the investigators, caregivers and most of all the patients who have helped us to achieve this important milestone,” commented Barry D. Quart, PharmD, Chief Executive Officer of Heron Therapeutics. “In addition to bringing an important product to patients, we are extremely pleased to have obtained the first approval of a product utilizing Heron’s Biochronomer polymer-based drug delivery technology.”

"The approval of Sustol is a major step in Heron’s evolution into a fully-integrated biopharmaceutical company with both development and commercial capabilities," said Robert H. Rosen, President of Heron Therapeutics. “Our focus now turns to ensuring patients have access to this important therapy. We look forward to collaborating with the oncology community to make SUSTOL available in the fourth quarter of this year.”

About Sustol (granisetron) extended-release injection

Sustol is indicated in combination with other antiemetics in adults for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic chemotherapy (MEC) or anthracycline and cyclophosphamide (AC) combination chemotherapy regimens. Sustol is an extended-release, injectable 5-HT3 receptor antagonist that utilizes Heron’s Biochronomer® polymer-based drug delivery technology to maintain therapeutic levels of granisetron for ≥5 days. The Sustol global Phase 3 development program was comprised of two, large, guideline-based clinical trials that evaluated Sustol's efficacy and safety in more than 2,000 patients with cancer. Sustol's efficacy in preventing nausea and vomiting was evaluated in both the acute phase (day 1 following chemotherapy) and the delayed phase (days 2-5 following chemotherapy).

Drugs designed to target nervous system could control inflammation in the gut, study shows

There's a reason it's called a gut feeling. The brain and the gut are connected by intricate neural networks that signal hunger and satiety, love and fear, even safety and danger. These networks employ myriad chemical signals that include dopamine, a powerful neurotransmitter most famous for its role in reward and addiction.

Duke University researchers have shown that manipulating dopamine signaling in the nervous system of the nematode worm C. elegans can control inflammation in the gut.

The study, which appears Aug. 12 in Current Biology, provides a proof of principle that the immune system can be controlled using drugs originally designed to target the nervous system, such as antipsychotics.

"We are talking about an existing set of drugs and drug targets that could open up the spectrum of potential therapeutic applications by targeting pathways that fine-tune the inflammatory response," said Alejandro Aballay, Ph.D., a professor of molecular genetics and microbiology at Duke School of Medicine.

"It is a big leap from worms to humans, but the idea of targeting the nervous system to control the immune system could potentially be used to treat conditions such as rheumatoid arthritis, autoimmune disease, cancer, inflammatory bowel disease, and Crohn's disease," Aballay said.

Recent research suggests that the wiring between the gut and the brain is involved in many other maladies, including autism, anxiety, depression, Alzheimer's disease, and Parkinson's disease.

Aballay believes that C. elegans provides an excellent model for dissecting this complex cross-talk between the nervous system and the immune system. This tiny, transparent worm has a simple nervous system, consisting of only 302 neurons compared to the roughly 100 billion neurons in the human brain. Yet the worm also has a very basic, rudimentary immune system.

Aballay and his team first stumbled upon the gut-brain connection a few years ago when they were studying the immune system of C. elegans. The worms were subjected to a barrage of chemicals in search of immune activators that could protect against bacterial infections. Out of more than a thousand different chemical compounds, they identified 45 that turned on an immune pathway. Curiously, half of those were involved in the nervous system, and a handful blocked the activity of dopamine.

In this study, Aballay decided to examine the effects of dopamine and dopamine signaling pathways on immunity.

Graduate student Xiou Cao blocked dopamine by treating animals with chlorpromazine, a dopamine antagonist drug used to treat schizophrenia and manic depression in humans. He found that these worms were more resistant to infection by the common pathogen Pseudomonas aeruginosa than counterparts that hadn't received the drug.

When Cao then treated the animals with dopamine, it generated the opposite effect, rendering them more susceptible to infection.

The researchers believe their findings indicate that dopamine signaling acts by putting the brakes on the body's inflammatory response so it doesn't go too far.

"Worms have evolved mechanisms to deal with colonizing bacteria," Aballay said. "That is true for us as well. Humans have trillions of microorganisms in our guts, and we have to be careful when activating antimicrobial defenses so that we mainly target potentially harmful microbes, without damaging our good bacteria -- or even our own cells -- in the process."

"The nervous system appears to be the perfect system for integrating all these different physiological cues to keep the amount of damage in check," Aballay said.

Aballay plans continue his studies in C. elegans to identify the different cues involved in fine-tuning the immune response. He also thinks it is worth looking at different analogues or different doses of dopamine antagonists to see if their effects on psychosis can be separated from their effects on immunity.

Drugs designed to target nervous system could control inflammation in the gut, study shows

New class of anti-cancer agents may be promising treatment for multiple myeloma

Australian researchers have discovered that a new class of anti-cancer agents may be effective in treating multiple myeloma, an incurable bone marrow cancer.

The research revealed that the majority of myelomas rely on a protein called MCL-1 to stay alive. Potential drugs that inhibit MCL-1, which are in pre-clinical development, may be a promising new treatment for multiple myeloma.

Each year more than 1700 Australians are diagnosed with multiple myeloma, which is a cancer of immune cells called plasma cells. Currently available treatments are only able to halt the progression of the disease and relieve symptoms, but cannot cure the disease.

Walter and Eliza Hall Institute researchers Dr Jianan Gong, Dr David Segal, Ms Yuan Yao, Professor Andrew Roberts and Professor David Huang, working with researchers at the Australian Centre for Blood Diseases, Monash University and the Alfred Hospital, investigated the 'survival proteins' that keep myeloma cells alive, allowing the cancer to persist.

The survival of many cancer types relies on a family of related survival proteins called BCL-2 family proteins, Professor Huang said. "In the past decade there has been considerable interest in the using anti-cancer agents called 'BH3-mimetics' to kill cancer cells by blocking the BCL-2 family proteins," he said. "Recent clinical trials have demonstrated that a BH3-mimetic that switches off the protein BCL-2 is an effective treatment for certain forms of leukaemia.

"Our latest research has focused on which BH3-mimetics would be the most effective in treating multiple myeloma, a cancer for which new treatments are urgently needed," Professor Huang said.

Dr Gong said the team discovered that the majority of myeloma samples died when MCL-1 was switched off. "In contrast, only around one-quarter were susceptible to inhibiting BCL-2," she said. "This finding is in keeping with earlier research at the Walter and Eliza Hall Institute that pinpointed MCL-1 as the likely protein that keeps myeloma cells alive.

"Our research shows that switching off MCL-1 has the potential to be effective new treatment approach for the majority of patients with myeloma," Dr Gong said.

Professor Roberts said that there had been considerable interest in developing anti-cancer agents that target MCL-1. "As yet, these inhibitors are still in pre-clinical development," he said. "Our results suggest that, once necessary laboratory testing for safety is completed, clinical trials of their effectiveness in treating patients with multiple myeloma that is no longer responding to current therapies would be well justified."

New class of anti-cancer agents may be promising treatment for multiple myeloma

Commonly used anti-inflammatory drug shows potential to treat Alzheimer's disease

A research project has shown that an experimental model of Alzheimer's disease can be successfully treated with a commonly used anti-inflammatory drug.

A team led by Dr David Brough from The University of Manchester found that the anti-inflammatory drug completely reversed memory loss and brain inflammation in mice.

Nearly everybody will at some point in their lives take non-steroidal anti-inflammatory drugs; mefenamic acid, a common Non-Steroidal Anti Inflammatory Drug (NSAID), is routinely used for period pain.

The findings are published today in a paper authored by Dr Brough and colleagues, in the respected journal Nature Communications. Dr Brough and Dr Catherine Lawrence supervised PhD student Mike Daniels, and postdoc Dr Jack Rivers-Auty who conducted most of the experiments.

Though this is the first time a drug has been shown to target this inflammatory pathway, highlighting its importance in the disease model, Dr Brough cautions that more research is needed to identify its impact on humans, and the long-term implications of its use.

The research, funded by the Medical Research Council and the Alzheimer's Society, paves the way for human trials which the team hope to conduct in the future.

Around 500,000 people in the UK have Alzheimer's disease which gets worse over time, affecting many aspects of their lives, including the ability to remember, think and make decisions.

In the study transgenic mice that develop symptoms of Alzheimer's disease were used. One group of 10 mice was treated with mefenamic acid, and 10 mice were treated in the same way with a placebo.

The mice were treated at a time when they had developed memory problems and the drug was given to them by a mini-pump implanted under the skin for one month.

Memory loss was completely reversed back to the levels seen in mice without the disease.

Dr Brough said: "There is experimental evidence now to strongly suggest that inflammation in the brain makes Alzheimer's disease worse.

"Our research shows for the first time that mefenamic acid, a simple Non-Steroidal Anti Inflammatory Drug can target an important inflammatory pathway called the NLRP3 inflammasome , which damages brain cells."

He added: "Until now, no drug has been available to target this pathway, so we are very excited by this result.

"However, much more work needs to be done until we can say with certainty that it will tackle the disease in humans as mouse models don't always faithfully replicate the human disease."Because this drug is already available and the toxicity and pharmacokinetics of the drug is known, the time for it to reach patients should, in theory, be shorter than if we were developing completely new drugs.

"We are now preparing applications to perform early phase II trials to determine a proof-of-concept that the molecules have an effect on neuroinflammation in humans."

Dr Doug Brown, Director of Research and Development at Alzheimer's Society, said: "Testing drugs already in use for other conditions is a priority for Alzheimer's Society - it could allow us to shortcut the fifteen years or so needed to develop a new dementia drug from scratch.

"These promising lab results identify a class of existing drugs that have potential to treat Alzheimer's disease by blocking a particular part of the immune response. However, these drugs are not without side effects and should not be taken for Alzheimer's disease at this stage - studies in people are needed first."

Commonly used anti-inflammatory drug shows potential to treat Alzheimer's disease

Antioxidant compound could be effective to combat immune rejection after islet transplantation

A team of researchers has found that doses of bilirubin help provide suppression of the immune response following islet transplantation in mouse models. Bilirubin also significantly decreased islet cell death after the cells had been isolated and undergone nutrient deprivation and hypoxic (low oxygen) stress. If applied, the results of the study are expected to improve outcomes after allograft (other donated) islet cell transplantation to treat type 1 diabetes.

Carried out by researchers at North Carolina State University, Ohio State University and the University of California Irvine, the study will be published in a future issue of Cell Transplantation  

"Pancreatic islet transplantation has the potential to provide a potentially curative, non-invasive treatment for type 1 diabetes," said Dr. Christopher A. Adin, associate professor, College of Veterinary Medicine, North Carolina State University. "However, stress and injury can cause up to a 70 percent loss of cells in the first 72 hours after transplantation. We hypothesized that bilirubin, an antioxidant, could be used as a supplement to suppress the immune response to allograft islet transplantation. In this study with mice, we administered bilirubin to the pancreas before procurement or added it to a culture after islet isolation."

Bilirubin, a cytoprotectant, has been shown to improve outcomes in cases of sepsis and in solid organ transplantation, said the researchers. The current study, however, is the first to investigate bilirubin as an islet allograft protectant from the immune response and other cell death-causing injury.

The researchers found that bilirubin supplementation could suppress the damage caused by the release of "damage-associated molecular patterns" (DAMPs) that included types of foreign cell-fighting immune cells.

Their studies also revealed that bilirubin also has a direct effect on the phenotype - the physical appearance - of the antigen cells that fight against engraftment, especially macrophages, a type of cell that engulfs and digests cellular debris and foreign substances.

Taken together, that bilirubin can suppress DAMP release, alter cytokine profiles, and affect macrophages, suggests that the use of this natural antioxidant may provide a method for pre-conditioning to improve outcomes after islet allograft transplantation, concluded the researchers.

"With the increasing age of the population, diabetes will increase in prevalence and the demand for new treatment paradigms will become more pressing," said Dr. Camillo Ricordi, Diabetes Research Institute, University of Miami, Miami, FL. "Use of an anti-oxidant compound to combat immune rejection could be an effective method for overcoming obstacles to the advancement of cell therapy for diabetes."

Ref : http://www.ingentaconnect.com/content/cog/ct/pre-prints/content-ct-1616_adin_et_al

Antioxidant compound could be effective to combat immune rejection after islet transplantation

New compound could kill parasites of three neglected diseases

Scientists have identified a compound that can kill the parasites responsible for three neglected diseases: Chagas disease, leishmaniasis and sleeping sickness. These diseases affect millions of people in Latin America, Asia and Africa, but there are few effective treatments available.

A new study, published today in Nature, suggests that a single class of drugs could be used to treat all three. Wellcome-funded researchers at the Genomics Institute of the Novartis Research Foundation (GNF) have identified a chemical that can cure all of these diseases in mice. It also does not harm human cells in laboratory tests, providing a strong starting point for drug development.

Chagas, leishmaniasis and sleeping sickness have different symptoms, but are all caused by parasites called 'kinetoplastids' - a type of single-celled organism. The parasites share similar biology and genetics, which led scientists to think it might be possible to find a single chemical that could destroy all three.

The team at GNF tested over 3 million different chemicals and identified a compound, GNF6702, which was effective against the parasites but did not damage human cells. They refined this starting compound to make it more potent before testing in it mice.

Senior study author Frantisek Supek from GNF said: "We found that these parasites harbour a common weakness. We hope to exploit this weakness to discover and develop a single class of drugs for all three diseases."

Dr Stephen Caddick, Director of Innovation at Wellcome, said: "These three diseases lead to more than 50,000 deaths annually, yet they receive relatively little funding for research and drug development. We hope that our early stage support for this research will provide a basis for the development of new treatments that could reduce suffering for millions of people in the poorest regions of the world."

Existing treatments for the three diseases are expensive, often have side effects and are not very effective. The fact that GNF6702 does not seem to have any adverse effects in mice suggests that it might have fewer side-effects than existing drugs, although this will need to be explored in human studies. GNF6702 is now being tested for toxicity before it can be moved in to clinical trials.

Ref : https://en.wikipedia.org/wiki/GNF6702

New compound could kill parasites of three neglected diseases

Novel compound holds potential for next-generation prostate cancer treatment

In the search for new ways to attack recurrent prostate cancer, researchers at Duke Health report that a novel compound appears to have a unique way of blocking testosterone from fueling the tumors in mice.

The potential foundation for a next-generation therapy, called tetraaryl cyclobutane, or CB, is being studied as an option for prostate tumors that have grown resistant to current anti-androgen drugs, notably enzalutamide. (see below structure)

"Prostate cancer is the most prevalent form of cancer in men, and the principal driver of tumor growth is the androgen receptor," said John D. Norris, Ph.D., associate research professor in the Department of Pharmacology & Cancer Biology at Duke and senior author of a study published online Aug. 8 in the journal Nature Chemical Biology.

"Suppression of androgen receptor function by anti-endocrine therapies is initially effective, but most tumors develop resistance, resulting in a more aggressive cancer," Norris said. "Our research has been focused on finding a new approach to suppressing androgen receptor activity, because even in situations where tumors are resistant to current therapies, the androgen receptor remains a viable target."

  

Norris and colleagues focused on a group of CB compounds developed in collaboration with scientists at the University of Illinois at Urbana-Champaign. The compounds act as competitive inhibitors of androgen receptors, but are structurally different from current anti-androgens such as enzalutamide.

One of the CB compounds, in particular, inhibits mutant forms of the androgen receptors that promote resistance to enzalutamide. It functions by preventing the androgen receptor from entering the nucleus of the cell where it can promote tumor growth.

"It's encouraging that this compound has a different mechanism of action when compared to current therapies, which gives it a good chance of having efficacy in resistant disease," Norris said. "We have shown in animal models that the compound has activity against prostate tumors where enzalutamide fails."

Norris said additional studies are underway in additional animal models and in tests with other forms of cancer, including breast cancer.

Ref: http://www.nature.com/nchembio/journal/vaop/ncurrent/full/nchembio.2131.html#compounds

Novel compound holds potential for next-generation prostate cancer treatment

New drug treatment could reduce body weight in obese patients with rare genetic disorder

As part of a phase II study at Charité - Universitätsmedizin Berlin and the Berlin Institute of Health, two obese patients with a rare genetic disorder were given a drug treatment to stimulate the satiety center in the brain. After only a few weeks, both patients, which were severely hyperphagic before the study start, showed a normalization of their hunger feeling as well as a significant reduction of body weight. Results from this study have been published in the current edition of the New England Journal of Medicine.

Our understanding of the factors involved in the dysregulation of normal body weight remains rudimentary. However it is known that mutations in certain genes play could lead to the development of early onset obesity due to a severe hyperphagia. MC4R is one example; it provides the blueprint for the melanocortin-4 receptor (MC4R) setmelanotide, which regulates energy balance and weight. Activation of the receptor by MSH (melanocyte-stimulating hormone) leads to a reduction in the sensation of hunger. Patients deficient in MSH show severe hyperphagia, and develop obesity within the first months of life.

The study team, led by Dr. Peter Kühnen - a physician at the Institute for Experimental Pediatric Endocrinology -- treated two patients with congenital proopiomelanocortin (POMC) deficiency. POMC is a precursor of the hormone MSH, and is secreted by the hypothalamus; deficiency causes significantly increased hunger. The researchers set out to test whether the new drug might replace the effect of the prohormone through targeted activation of the satiety center. First effects were recorded within a few weeks of the start of treatment. Patient 1, whose starting weight was 155 kg, achieved a total weight loss of 51 kg over a period of 42 weeks; patient 2 (starting weight 152.8 kg) lost a total of 20.5 kg over the course of 12 weeks.

"Our study results confirm the crucial role of the MC4R signaling pathway in appetite regulation, and represent an important contribution to our understanding of the fundamental processes involved in the control of body weight" says Dr. Peter Kühnen. He goes on to add: "It currently remains unclear, however, whether this treatment will be of benefit to patients whose obesity has no clear genetic cause. Further studies will be needed to elucidate this."

Ref : http://www.nejm.org/doi/full/10.1056/NEJMoa1512693

Inosine treatment can help restore motor control after cortical injury

Brain tissue can die as the result of stroke, traumatic brain injury, or neurodegenerative disease. When the affected area includes the motor cortex, impairment of the fine motor control of the hand can result. In a new study published in Restorative Neurology and Neuroscience, researchers found that inosine, a naturally occurring purine nucleoside that is released by cells in response to metabolic stress, can help to restore motor control after brain injury.

Based on evidence from rodent studies, researchers used eight rhesus monkeys ranging in age from 5 to 10 years (approximately equivalent to humans from 15 to 30 years of age). All received medical examinations and motor skills were tested, including video recording of fine motor functions used to retrieve small food rewards. All monkeys were given initial MRI scans to ensure there were no hidden brain abnormalities.

Brain injuries were created in the area controlling each monkey's favored hand. Four monkeys received inosine treatment, while four received a placebo. Research staff were not informed regarding which monkeys were included in the treatment vs placebo groups. Recovery of motor function was then measured for a period of 14 weeks after surgery.

While both the treated and placebo groups recovered significant function, three out of four of the treated monkeys were able to return to their pre-operative grasping methods. The placebo group developed a compensatory grasping method for retrieving food rewards unlike the original thumb-and-finger method.

"In the clinical context, the enhanced recovery of grasp pattern suggests that inosine facilitates greater recovery from this type of cortical injury and motor impairment," explained lead investigator Tara L. Moore, PhD, of the Department of Anatomy & Neurobiology and the Department of Neurology, Boston University School of Medicine, Boston, MA, USA. "To our knowledge, this is the first study to demonstrate the positive effects of inosine for promoting recovery of function following cortical injury in a non-human primate."

Inosine has also been administered in human clinical trials for multiple sclerosis and Parkinson's disease and has been proven to be safe in doses up 3000 mg/day. Athletes have used inosine as a nutritional supplement for decades, and inosine supplements are widely available commercially. "Given the effectiveness of inosine in promoting cortical plasticity, axonal sprouting, and dendritic branching, the present evidence of efficacy after cortical injury in a non-human primate, combined with a long history of safe use, indicates a need for clinical trials with inosine after cortical injury and spinal cord injury," noted Dr. Moore.

The study points to neural plasticity, whereby the brain essentially "re-wires" connections between neurons to reestablish control pathways, as a therapeutic target for the recovery of fine motor control and grasping ability. Further study of cortical tissue from these monkeys is currently being completed and may provide further insights into the mechanisms underlying recovery.