Lower IQ And Impaired Neural Development Due To Poor Nutrition

Poor nutrition early in life can impair neural development, leading to lower IQ in humans and flawed song learning in birds. Recent evidence indicates that many organisms can offset some of the changes associated with early poor nutrition by modifying their physical development. For example, poorly nourished children can undergo a period of accelerated growth once their diet improves, ultimately appearing normal as an adult. But such compensatory measures may come at a price, with cognitive or other developmental disabilities emerging later in life.

In a New study published in the open-access Journal PLoS Biology, Michael Fisher, Rudolph Nager, and Pat Monaghan explored the connection between early poor nutrition, compensatory growth, and learning ability in adulthood. To circumvent the confounding variables inherent in human studies and to control for genetic effects, the researchers compared the learning performance of zebra finch siblings reared on different quality diets after hatching. Only food quality, not quantity, was changed. The rate at which adult birds could learn a simple task, they found, depended on the rate of compensatory growth the birds showed following a period on lower-quality food early in life--not on the diet itself or on the degree of stunted growth.

After hatching, zebra finch siblings were raised on either a normal or low-quality diet for 20 days, and then switched to the higher-quality standard diet. While on the low-quality diet, birds grew slower and were lighter than their control siblings by the end of the 20 days. Once they were switched to the standard diet, birds reared on the poor diet then grew significantly more than their normally fed siblings and reached the same adult size.

The extent to which birds' growth was depressed during the poor nutrition phase of the experiment varied considerably, as did the degree of accelerated growth after the switch to a normal diet. As it happened, birds with the most stunted growth (relative to their control siblings) and those with the most accelerated growth (after switching diets) fell into different groups, allowing the researchers to distinguish cognitive effects associated with stunted growth from those associated with compensatory growth.

To test the adult birds' learning performance, the researchers tested them on an associative learning task. Though all the birds eventually learned the task, their learning rate depended on the rate of compensatory growth they had undergone as chicks. Undernourished birds that had grown fastest after switching to the normal diet performed poorest on the learning task compared to their control siblings. Since the undernourished birds were the only group that showed this relationship between growth rate and learning speed, the researchers concluded that it is the compensatory growth following reduced nutrition that accounts for poor learning performance in adulthood.

These results suggest that poor early nutrition can have long-lasting negative consequences for cognitive ability--for finches as well as humans, given similar findings in human infants. While it's unclear whether the learning defects stem from behavioral, hormonal, or neural changes, it's likely that resources normally dedicated to these pathways are diverted to support accelerated growth, shortchanging the co-opted pathway. Future study is needed to identify the underlying causes of impaired learning speed, an essential step in determining how to manage growth and nutrition for low birth weight babies and avoid the costs associated with compensatory growth.

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PLEASE MENTION THE OPEN-ACCESS JOURNAL PLoS BIOLOGY (http://www.plosbiology.org/) AS THE SOURCE FOR THESE ARTICLES AND PROVIDE A LINK TO THE FREELY-AVAILABLE TEXT. THANK YOU.

All works published in PLoS Biology are open access. Everything is immediately available--to read, download, redistribute, include in databases, and otherwise use--without cost to anyone, anywhere, subject only to the condition that the original authorship and source are properly attributed. Copyright is retained by the authors. The Public Library of Science uses the Creative Commons Attribution License.

Citation: Fisher MO, Nager RG, Monaghan P (2006) Compensatory growth impairs adult cognitive performance. PLoS Biol 4(8): e251. DOI: 10.1371/Journal.pbio.0040251

CONTACT:
Pat Monaghan, PhD
University of Glasgow
Graham Kerr Building
Glasgow, G12 8QQ
United Kingdom
p.monaghan@bio.gla.ac.uk

Contact: Natalie Bouaravong
Public Library of Science


Saludos Cordiales
Dr. José Manuel Ferrer Guerra

Autism: Carnegie Mellon Researchers Discover Key Deficiencies In Brains Of Autistics

In a pair of groundbreaking studies, brain scientists at Carnegie Mellon University and the University of Pittsburgh have discovered that the anatomical differences that characterize the brains of people with autism are related to the way those brains process information.

Previous studies have demonstrated a lower degree of synchronization among activated brain areas in people with autism, as well as smaller size of the corpus callosum, the white matter that acts as cables to wire the parts of the brain together. This latest research shows for the first time that the abnormality in synchronization is related to the abnormality in the cabling. The results suggest that the connectivity among brain areas is among the central problems in autism. The researchers have also found that people with autism rely heavily on the parts of the brain that deal with imagery, even when completing tasks that would not normally call for visualization.

"Human thought is a network property. You think not with one brain area at a time, but with a network of collaborating brain areas, with emphasis on collaborating. In autism, the network connectivity (the bandwidth) through which the areas communicate with each other may be limited, particularly in the connections to the frontal cortex, limiting what types of networks can be used," said Marcel Just, co-author of the studies and director of Carnegie Mellon's Center for Cognitive Brain Imaging.

Both studies focused on people with autism who have normal IQs. In one study, the researchers used functional magnetic resonance imaging (fMRI) to view which parts of the brain were activated in people with autism compared to a control group of normal participants while completing the Tower of London task. In a Tower of London task, participants must -- in a set number of moves -- rearrange the positions of three distinctive balls in three suspended pool pockets to match a specified pattern. This requires a person to strategize and plan several moves ahead.

The experiment confirmed the authors' previous findings that people with autism suffer from a lack of synchronization among brain regions, which helps to explain why some people with autism have normal or even superior skills in some areas, while many other types of thinking are disordered. In addition, their findings particularly implicate the lower synchronization between the frontal cortex and other portions of the brain. They have discovered that key portions of the corpus callosum seem to play a role in the limitation on synchronization. In people with autism, anatomical connectivity -- based on the size of the white matter -- was found to be positively correlated with functional connectivity, which is the synchronization of the active brain regions. They also found that the functional connectivity was lower in those participants in whom the autism was more severe. The study will be published in the Journal Cerebral Cortex.

The second study, to be published in the Journal Brain, examined a long-standing belief, supported through scientific research as well as anecdotal accounts, that people with autism rely heavily on visualization to process information. Temple Grandin, a professor at Colorado State University who has autism, says in her autobiography "Thinking in Pictures" that "Words are like a second language to me. … When someone speaks to me, his words are instantly translated into pictures."

To test this relationship between the language and visuospatial systems of the brain, the team used fMRI scans to view the patterns of activation in the brains of autistic and normal participants while they read a series of sentences to determine whether each one was true or false. The sentences either had high imagery content ("The number eight when rotated 90 degrees looks like a pair of eyeglasses") or low imagery content ("Addition, subtraction and multiplication are all math skills.")

The findings confirmed that the regions of the brain associated with visualization were activated when participants with autism read both kinds of sentences, while those regions of the brain were only activated when the control group read the high-imagery sentences. The results also replicated the researchers' findings in the Cerebral Cortex study, in that functional connectivity was lower among participants with autism, and that structural connectivity was positively correlated with functional connectivity. The authors believe that the heavy reliance on visualization by people with autism may be an adaptation to compensate for their lower ability to call on frontal regions of the brain.

"Thinking in autism is an adaption to the brain that Mother Nature provided. We now have evidence of a systematic relation between the properties of the brain and the properties of the thinking in autism," said Just, the D.O. Hebb Professor of Psychology at Carnegie Mellon.

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The papers were co-authored by Rajesh K. Kana, Timothy A. Keller and Vladimir L. Cherkassky of the Center for the Cognitive Brain Imaging; and Nancy Minshew of the departments of Psychiatry and Neurology at the University of Pittsburgh. The research was supported by the National Institute of Child Health and Human Development.

Contact: Jonathan Potts
Carnegie Mellon University



Saludos Cordiales
Dr. José Manuel Ferrer Guerra

Neurologists With Expertise In Movement Disorders And Brain Stimulation Therapy May Help

Neurologists With Expertise In Movement Disorders And Brain Stimulation Therapy May Help Improve Outcomes For Some Parkinson's Patients


Patients with Parkinson's disease who are undergoing a treatment known as deep brain stimulation may benefit from the direct involvement of a neurologist with expertise both in movement disorders and in deep brain stimulation, according to an article posted online today that will appear in the September 2006 print issue of Archives of Neurology, one of the JAMA/Archives journals.

Deep brain stimulation is a surgical procedure that involves implanting electrodes into the brain to electronically stimulate areas that control movement, treating Parkinson's disease symptoms such as tremor, stiffness and problems walking. It is the most effective surgical treatment for advanced cases of Parkinson's disease. Deep brain stimulation involves intensive patient management, including adjustments of electrical currents and medication dosages as a patient's condition changes. Many Medical centers in North America delegate these responsibilities to personnel who do not have extensive experience in Parkinson's disease care, such as surgical nurses, fellows or neurophysiologists, according to information in the article.

Elena Moro, M.D., Ph.D., and colleagues at University Health Network, University of Toronto, Ontario, studied whether the outcomes resulting from deep brain stimulation could be improved with the direct involvement of a neurologist with specific expertise both in the treatment of movement disorders in general and in deep brain stimulation in particular. Forty-four consecutive patients at the hospital who had already been receiving regular deep brain stimulation treatments for an average of 3.5 years underwent evaluation by such a neurologist-in other words, the neurologist changed the electric stimulation settings during the procedure and also adjusted the medications that patients received afterward. The patients underwent assessments for Parkinson's disease symptoms before and after their reprogrammed treatment, with following assessments at an average of 5 months (range 1 hour to 14 months) after the reprogramming.

Of the 44 patients, 24 (54.6 percent) showed additional improvement in their Parkinson's disease symptoms; 16 (36.4 percent) were unchanged; and four (9.1 percent) worsened. The patients who did improve experienced fewer tremors and less rigidity and bradykinesia (slowness of movement) and also had reductions in their medication dosages. The four patients who worsened had more speech and gait problems and were returned to their original settings.

"Further improvement of parkinsonian signs can be achieved in the majority of patients even after long-term stable stimulation," the authors conclude. "Improved patient outcomes from subthalamic nucleus deep brain stimulation are obtained when postoperative care is personally managed by a neurologist expert in movement disorders and deep brain stimulation who is directly responsible for stimulation programming and simultaneous drug adjustments based on observed clinical responses to changing stimulation parameters."
(Arch Neurol. 2006;63:(doi:10.1001/archneur.63.9.noc60069).

This study was partially funded through a Center of Excellence grant from the National Parkinson Foundation and a grant from Medtronic in support of fellow and nurse salaries. Please see full article for complete financial disclosure information.

Subthalamic Nucleus Stimulation
Improvements in Outcome With Reprogramming
Elena Moro, MD, PhD; Yu-Yan W. Poon, RN; Andres M. Lozano, MD, PhD; Jean A. Saint-Cyr, PhD; Anthony E. Lang, MD
Arch Neurol. 2006;63:(doi:10.1001/archneur.63.9.noc60069).
Link To Abstract


Saludos Cordiales
Dr. José Manuel Ferrer Guerra

Stroke Prediction: Which Inflammatory Markers Predict The Appearance Of A Stroke?

Patients that have suffered from a stroke have a higher risk of a similar event happening and, in consequence, greater possibilities of dying. For the first time, 52 hospitals in Spain, three of which (Basurto; Cruces and Bidasoa) in the Basque country, are participating in a study to determine if certain concrete inflammation markers can be linked to the appearance of a New stroke or other vascular events such as myocardiac arrest. The MÍTICO study was presented at the IV International Meeting on Isquemic Ictus.

The study included patients from different Autonomous Communities and that had suffered a stroke one to three months previously. By means of periodical controls, a number of inflammation markers found in the plasma (interleucines, metalloproteases, fibronectines) were studied over a period of a year. "We know that that there are certain inflammation markers that can contribute to patients suffering from New strokes or other vascular events such as heart attack. In fact, those who have chronic mouth infections or inflammatory processes have a greater risk of repeating these illnesses", explains doctor José Castillo, coordinator of the MÍTICO project.

A second objective of this work is to determine if the use of habitual pharmaceutical drugs in these patients (plaque antiagregants, antihypertensives, estatines) is also associated with a decrease in the inflammation markers analysed, I..e. What effect these treatments have on the inflammation markers. Doctor Castillo says that the conclusions of the study will be known in less than three months.

Another objective of the MÍTICO study is to find out the influence of the inflammation markers on the cognitive evolution of the patients. "The results will tell us up to what point the recurrence of New ictus events and inflammation markers condition the tendency to cognitive deterioration. Nevertheless, this will involve studies on many more patients in order to reach definitive conclusions", doctor Castillo pointed out.

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Ictus, general information

The studies undertaken in Spain show an incidence of ictus between 4.012 and 7.100 for every 100,000 inhabitants over 64 years. One in ten deaths in Spain is caused by an ictus or stroke - a term to describe brain diseases caused by a blood circulation problem. This neurological crisis is the third cause of death in Spain and the first amongst women. It causes more disabilities and premature deaths than do Alzheimer's disease and traffic accidents put together. Currently, almost a million persons have overcome, with or without after effects, this disease which causes one death every fourteen minutes in Spain. Every year some 120,000-130,000 Spanish people are affected by the infirmity.

Contact: Garazi Andonegi
Elhuyar Fundazioa


Saludos Cordiales
Dr. José Manuel Ferrer Guerra

Child Abuse: Warning Signs For Potential Re-abuse Identified

Doctors have identified a set of warning signs that could increase an abused child's risk of further abuse.

The findings are based on evidence drawn from a trawl of electronic databases, relevant print journals, and bibliography supplied by experts in the field, and published ahead of print in the Archives of Disease in Childhood.

Of 89 potentially eligible studies, 16 met the criteria for descriptions of substantiated maltreatment and recurring problems in children under the age of 18. Maltreatment included neglect and emotional, sexual, and physical abuse.

An analysis of these studies revealed that previous episodes of maltreatment; neglect rather than other forms of abuse; parental conflicts, including domestic violence; and parental mental health problems all strongly predicted further maltreatment.

Children who had endured a previous episode of maltreatment were six times more likely to be abused again, particularly within the next month. The risk appeared to level out after two years.

Other factors also seemed to have a role in the risk of further maltreatment, although less consistently so. They included drugs and alcohol misuse, "family stress," inadequate social support, families with younger children, and already being known to child protection services.

The authors conclude that their findings underscore the different factors at play in child abuse and neglect, which suggests that the matter can only effectively be dealt with if different professionals in health and social care cooperate closely with one another.

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Contact: Emma Dickinson
BMJ Specialty Journals




Saludos Cordiales
Dr. José Manuel Ferrer Guerra

Proton Therapy Center Opens To Patients

Launching a New era in radiation treatment, The University of Texas M. D. Anderson Cancer Center has started treating patients at its Proton Therapy Center.

The first National Cancer Institute-designated Comprehensive Cancer Center to offer the treatment, and just the fourth facility in the country, the $125 million, 94,000-square-foot Proton Therapy Center at M. D. Anderson will provide eligible patients with the most advanced innovation in radiation therapy.

Proton therapy is the most precise form of radiation treatment available for some tumors, according to James D. Cox, M.D., head of the Division of Radiation Oncology at M. D. Anderson. Because of proton therapy's precision, it minimizes harm to surrounding tissues and optimizes treatment of the tumor.

"The arrival of proton therapy marks a milestone for radiation treatment at M. D. Anderson, with the precision, safety and effectiveness it brings to patients," says Cox.

"When I started in this discipline three decades ago, we had to give radiation to large fields of the body because we couldn't determine exactly where the tumor was. Now, with the evolution of imaging techniques, we can pinpoint where the tumor is and plan the depth of the radiation to the tumor. With proton therapy, we will be able to increase doses of radiation, preserve healthy tissue and treat more patients much more successfully," he continues.

Protons differ from traditional x-ray treatment because they deposit the highest dose of energy when they come to a stop in the body, and have a very low dose of energy when they enter and have no dose as it exits the body.

"This differentiation gives radiation oncologists greater control and effectiveness in directing and depositing high levels of destructive energies at the tumor," says Cox. "Because a radiation oncologist has the advantage of more precise targeting, the patient receives the most potent radiation treatment possible without damaging surrounding organs or tissue."

Conventional radiation therapy, however, remains a proven and vital cancer treatment, and most often will still be the preferred radiation treatment, says Cox.

To date, more than 40,000 patients at 25 centers around the world have received proton therapy treatment. When M. D. Anderson's facility is operating at full capacity, it can accommodate 3,500 patients a year, making it the largest in the world.

Proton therapy has proved most effective for cancers of the prostate, eye, lung, brain, head and neck and cancers in children.

"There's a broad range of patients who will be treated with proton therapy, and they'll be selected very carefully based on the criteria that their tumor needs a high dose and it's close to sensitive normal organs," says Cox. "Our decisions about who will receive proton therapy largely will be made in the multidisciplinary care team, which also includes Medical and surgical expertise. The team is key to our recommendation for standard radiation therapy now, so we will extend proton as yet another option."

Cox says that patients do not feel anything during proton therapy treatment, and because of the minimal effect on healthy tissues, they experience few, if any, side effects.

He added that a major component to the Proton Therapy Center, like all clinical activities at M. D. Anderson, will be to explore New ways to best utilize and advance the field. One of many areas of research will be to investigate New disease sites that may benefit from the therapy. Exploring the interaction of chemotherapy and other molecular agents with proton therapy will be another area of research. All patients treated at the Proton Therapy Center at M. D. Anderson will be enrolled in clinical protocols that will document the results of therapy.

The two-story Proton Therapy Center features three gantry treatment rooms, one fixed-beam treatment room, an experimental treatment area, a full range of patient and research support areas, a synchrotron and beam transport system.

Gantry patient treatment rooms will have a patient treatment bed framed by a large wheel known as a gantry. The gantries, which are 35 feet in diameter and weigh approximately 200 tons -- equivalent to the weight of a Boeing 757 - - rotate around the patient to direct the proton beam precisely at the tumor target.

A compact particle accelerator, known as a synchrotron, accelerates protons to variable energies into the beam transport line. The synchrotron contains a ring of magnets that constrains the protons so that they travel in a set path inside the high vacuum chamber. During each revolution of travel through the chamber, the protons gain an increment of energy from radiofrequency power. After many cycles, the protons reach the energy required by a specific treatment plan and are extracted from the ring into the beam transport line, which then directs the proton beam to the patient in a treatment room.

A unique private-public partnership, the Proton Therapy Center was built through a collaboration to develop and operate the investor-owned freestanding $125 million facility. M. D. Anderson provided the facility site, valued at $2.5 million and has full clinical, research and staffing responsibilities. Other investors and partners in the project include: Hitachi, Ltd. and Hitachi America, Ltd., supplying the proton therapy technology; Sanders Morris Harris, Inc. the largest investment bank and securities firm based in the Southwest; The Styles Co., a Houston-based project development and management firm specializing in health-care facilities; the Houston Firefighters' Relief and Retirement Fund and Houston Police Officers' Pension System, lead financial investors in the project; General Electric Company; Varian Medical Systems; and IMPAC Medical Systems.

Located at 1840 Old Spanish Trail near Fannin in the University of Texas Research Park, the Proton Therapy Center is part of M. D. Anderson's Red and Charline McCombs Institute for the Early Detection and Treatment of Cancer. Comprised of six centers focused on the study of genomics, metastasis, proteomics, immunology, diagnostic imaging and drug development, the Institute houses all research facilities except the Proton Therapy Center, which will be the sole patient care facility.

University of Texas M. D. Anderson Cancer Center
http://www.mdanderson.org



Saludos Cordiales
Dr. José Manuel Ferrer Guerra

New Guidelines Address Prevention of Second Stroke

News Author: Laurie Barclay, MD
CME Author: Désirée Lie, MD, MSEd

The American Heart Association (AHA)/American Stroke Association (ASA) and others have created New guidelines to prevent second stroke in patients who have had an ischemic stroke or transient ischemic attack (TIA). The New guidelines are published in the February issue of Stroke.
"Due to the aging U.S. Population and other changing sociodemographics, the number of New and recurrent strokes is projected to increase to nearly 1 million annually by the year 2050," lead author Ralph L. Sacco, MD, MS, from Columbia University Medical Center in New York, NY, said in a news release. "The most frequent event that threatens a stroke survivor's quality of life is another stroke, which can cause further disability or death."

Nearly one third of the estimated 700,000 strokes occurring each year in the United States are recurrent strokes, and the risk for secondary stroke in survivors of stroke and TIA approaches 40% within 5 years. An important departure from earlier guidelines is that stroke and TIA are treated interchangeably.

"Both conditions increase the risk of a subsequent stroke and both require similar diagnostic workups and treatment," says Dr. Sacco, who is chair of the ASA Stroke Advisory Board and of the ASA Secondary Stroke Prevention Guidelines Committee. "Other documents have split the two conditions out, but we are treating TIA just as seriously as a stroke. For the last few years, we've been trying to get both the public and healthcare professionals to treat TIA as aggressively as stroke."

After reviewing Medical literature on recurrent stroke, including analysis of the results of several recently completed large clinical trials, the writing committee addressed modifiable risk factors and interventional recommendations. The former include smoking cessation, limiting alcohol, reducing obesity, and increasing physical activity. Therapeutic interventions include Medical treatment with anticoagulants and antiplatelet agents or surgical treatment with carotid artery surgery or angioplasty.

The guidelines also address special populations, including pregnant women, menopausal women, and ethnic minorities. The elderly, Mexican Americans, African Americans, and those with lower socioeconomic status are at high risk for recurrent stroke and may also face barriers to receiving optimal care.

Since publication of the previous secondary stroke prevention guidelines, the Women's Health Initiative was terminated early because of an increase in vascular events associated with hormonal replacement therapy.

"We recognize that stroke is on the rise and that as our population ages and becomes more diverse the predicted number of strokes is expected to increase," Dr. Sacco says. "There is a strong recommendation against the use of HRT [hormonal replacement therapy] based on all the New evidence."

The guidelines also provide further recommendations to prevent recurrent stroke in other specific circumstances, such as arterial dissections; patent foramen ovale; hyperhomocysteinemia; hypercoagulable states; sickle cell disease; cerebral venous sinus thrombosis; stroke among women, particularly during pregnancy or associated with the use of postmenopausal hormones; anticoagulation after cerebral hemorrhage; and special approaches for the implementation of guidelines and their use in high-risk populations.

Antihypertensive treatment is recommended to prevent recurrent stroke and other vascular events in those persons who have had an ischemic stroke or TIA and are beyond the hyperacute period. Absolute target blood pressure (BP) level and reduction are uncertain and should be individualized, but the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC-7) has defined normal BP levels as less than 120/80 mm Hg.

Several lifestyle modifications that have been linked to BP reductions should be included in a comprehensive regimen of antihypertensive therapy. The optimal drug regimen is still unclear and should be individualized, but available data support the use of diuretics and the combination of diuretics and an angiotensin-converting enzyme inhibitors.

More rigorous control of BP and lipids should be considered in diabetic patients; most patients will require combination therapy. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are recommended as first-line treatment. Reducing glucose to near-normoglycemic levels reduces microvascular and possibly macrovascular complications. The goal for hemoglobin A1c levels should be less than 7%.

Patients with hypercholesterolemia, comorbid coronary artery disease, or evidence of atherosclerotic stroke origin should be treated according to National Cholesterol Education Program III (NCEP III) guidelines, including lifestyle modification, diet, and medications, such as statins. The target low-density lipoprotein cholesterol level should be less than 100 mg/dL for those with coronary heart disease or symptomatic atherosclerotic disease and less than 70 mg/dL for very-high-risk persons with multiple risk factors.

Patients with ischemic stroke or TIA presumed to be atherosclerotic in origin, but with no preexisting indications for statins, are reasonable candidates for statin treatment. Niacin or gemfibrozil may be considered for those with low high-density lipoprotein cholesterol.

All healthcare providers should strongly recommend patients to quit smoking, avoid environmental tobacco smoke, reduce alcohol to no more than 2 drinks per day for men and 1 drink per day for nonpregnant women, reduce weight (target body mass index [BMI], 18.5 - 24.9 kg/m2 and waist circumference <35 inches for women and <40 inches for men), and participate in at least 30 minutes of moderate-intensity physical exercise on most days if not otherwise contraindicated.

Carotid endarterectomy (CEA) by a surgeon with a perioperative morbidity and mortality of less than 6% is recommended for patients with recent TIA or ischemic stroke within the last 6 months and ipsilateral severe (70% - 99%) carotid artery stenosis. When stenosis is less than 50%, there is no indication for CEA. The decision for CEA should be individualized for patients with intermediate levels of stenosis. When CEA is indicated, surgery is suggested within 2 weeks.

Patients with extracranial vertebral stenosis who are symptomatic despite medical therapies may respond to endovascular treatment.

"For patients with noncardioembolic ischemic stroke or TIA, antiplatelet agents rather than oral anticoagulation are recommended to reduce the risk of recurrent stroke and other cardiovascular events," the authors write. "Aspirin (50 to 325 mg/d), the combination of aspirin and extended-release dipyridamole, and clopidogrel are all acceptable options for initial therapy."

Some of the authors and/or reviewers have disclosed no relevant financial relationships with Boehringer Ingelheim, Sanofi, BMS, Wyeth, Novartis, Acuson, ATL, Nicolet, Aventis, AstraZeneca, GSK, Bayer, CuraGen Corp, Johnson & Johnson, Merck, Pfizer, Parke-Davis, Actelion, Boston Scientific, Cordis Neuro-vascular Inc, Cypress Bioscience, Galileo Laboratories, Guidant Corp, Maxygen, Merck, Neuron Therapeutics, and/or Renovis.

Stroke. 2006;37:577-617

Learning Objectives for This Educational Activity

Upon completion of this activity, participants will be able to:

• List options for preventing secondary stroke.
  
• Describe updated guidelines for secondary prevention after stroke or TIA.
  

Clinical Context

According to the authors, an estimated 200,000 of 700,000 people with stroke in the United States are persons with recurrent stroke, and survivors of stroke and TIA both have an increased risk for recurrent stroke as high as 40% within 5 years. The number of new and recurrent strokes is expected to increase to nearly 1 million annually by the year 2050, according to the authors. Recommendations from the AHA have dealt with ischemic stroke, subarachnoid hemorrhage, and intracerebral hemorrhage, and these current guidelines focus primarily on the use of evidence-based recommendations to prevent recurrent stroke in patients with a first stroke or TIA. In these guidelines, a new definition of TIA is proposed, as "a brief episode of neurological dysfunction caused by a focal disturbance of brain or retinal ischemia, with clinical symptoms typically lasting less than 1 hour and without evidence of infarction." TIA is considered as having the same basis for secondary prevention as stroke. Ischemic stroke is classified as large artery atherosclerotic (extracranial or intracranial), small vessel disease, embolism, dissection, hypercoagulable states, sickle cell disease, and infarcts of unknown cause.

Study Highlights

• Modifiable risk factors for stroke include eliminating smoking, limiting alcohol to no more than 2 drinks for men and 1 for women daily, reducing obesity, and encouraging physical activity.
  
• Comorbid diseases, such as hypertension and diabetes, should be aggressively managed according to known practice guidelines.
  
• Medical options include anticoagulants and antiplatelet agents.
  
• Interventional measures include CEA or carotid balloon angioplasty or stent (CAS) or extracranial-intracranial bypass surgery.
  
• BP lowering should follow recommendations of JNC-7 and benefit has been demonstrated with a reduction of 10/5 mm Hg. More than 1 antihypertensive agent may be required to prevent stroke.
  
• For patients with elevated cholesterol or comorbid cardiovascular disease, the recommendations of the NCEP III guidelines should be followed for target lipid levels, and treatment with statins to reduce the overall risk for vascular events is recommended.
  
• Weight reduction to maintain goal BMI between 18.5 and 24.9 kg/m2 and a waist circumference of less than 35 inches for women and less than 40 inches for men are recommended.
  
• At least 30 minutes of moderate intensity physical exercise on most days for those capable of engaging in physical activity is recommended.
  

Medical recommendations

• For patients with stroke or TIA with persistent or paroxysmal atrial fibrillation anticoagulation with adjusted-dose warfarin with target international normalized rate (INR) of 2.5 (range, 2.0 - 3.0) is recommended, and aspirin may be used for those who cannot tolerate warfarin.
  
• In those in whom stroke or TIA is caused by myocardial infarction with left ventricular intramural thrombus anticoagulation with INR of 2.0 to 3.0 for at least 3 months is reasonable, and aspirin up to 162 mg daily should be used concurrently for ischemic coronary disease.
  
• For those with dilated cardiomyopathy, either warfarin with INR of 2.0 to 3.0 or antiplatelet therapy may be considered.
  
• For those with rheumatic mitral valve disease, either warfarin with target INR of 2.5 and aspirin at 81 mg daily are suggested.
  
• For those with mechanical prosthetic valves, an INR target of 3.0 is recommended, and 75 to 100 mg/day of aspirin may be added.
  
• Compared with aspirin alone, both the combination of aspirin and extended-release dipyridamole and clopidogrel are safe. Aspirin with extended-release dipyridamole is recommended over aspirin alone.
  
• However, the addition of aspirin to clopidogrel increases the risk for hemorrhage and is not routinely recommended for ischemic stroke or TIA patients.
  

Surgical recommendations

• Patients with recent TIA or ischemic stroke within 6 months and ipsilateral severe (70% - 99%) carotid artery stenosis should receive CEA by a surgeon with a morbidity and mortality of less than 6%.
  
• Patients with recent TIA or stroke with moderate carotid stenosis (50% - 69%) may have CEA depending on comorbid factors, whereas CEA is not recommended for those with less than 50% stenosis.
  
• When CEA is recommended, surgery should be performed within 2 weeks.
  
• In those with symptomatic severe stenosis greater than 70% in whom stenosis is difficult to assess, CAS is not inferior to CEA and may be considered.
  
• Among patients with symptomatic carotid occlusion, extracranial-intracranial bypass is not routinely recommended.
  
• Endovascular treatment of patients with symptomatic extracranial vertebral stenosis may be considered when patients are having symptoms despite medical treatment.
  
• For those with hemodynamicaly significant intracranial stenosis who have symptoms despite medical therapy, the usefulness of endovascular therapy is uncertain.
  

Pearls for Practice

• Options for secondary prevention after stroke or TIA include lifestyle modification, treatment of comorbid cardiovascular disease, and medical and surgical therapies.
  
• New recommendations for secondary prevention of stroke include a new definition of TIA, aggressive anticoagulation, and specific surgical recommendations for carotid stenosis.

Saludos Cordiales
Dr. José Manuel Ferrer Guerra

Brain Pathway Signals Rats When To Eat

Brain Pathway Signals Rats When To Eat

By Michael Smith, MedPage Today Staff Writer
Reviewed by Zalman S. Agus, MD; Emeritus Professor at the University of Pennsylvania School of Medicine.

CINCINNATI, May 11 — A brain signaling pathway often intertwined with the development of cancer, obesity, and diabetes is actually a cellular food sensor playing a central role in regulating how much we eat, according to researchers here.

The pathway — mammalian Target Of Rapamycin or mTOR — is known to regulate cell-cycle progression and growth by sensing changes in energy availability, according to Randy Seeley, Ph.D., a psychiatry professor at the University of Cincinnati.


Increased or aberrant mTOR activity in peripheral tissue has been linked to cancer, diabetes and obesity. But Dr. Seeley and colleagues reported in the May 12 issue of the Journal Science that in the brains of experimental rats mTOR signals the animals when to eat and when not to.


The findings may have some implications for human obesity, Dr. Seeley said, although he cautioned that a great deal more needs to be learned before the research has practical applications.


The pathway is everywhere in the central nervous system, the researchers found, but is most active in the two regions of the hypothalamus — the paraventricular (PVN) and arcuate (ARC) nuclei. Also, two of mTOR's downstream targets — S6 kinase 1 and S6 ribosomal protein — were most active in those regions.


Because the ARC contains populations of neurons linked to the regulation of energy balance and regulated by the hormone leptin, Dr. Seeley and colleagues thought that changes in the body's energy status might have an impact on mTOR signaling. Using rats that had been starved for two days, the researchers found that mTOR activity was markedly reduced in the arcuate, but not in the paraventricular.


"Thus, mTOR activity in the arcuate is low when available fuels are low and the organism is predisposed to consume more calories," the researchers argued.


One implication of that finding is that increased mTOR signaling would lead to a suppression of appetite. The pathway is known to respond to the amino acid L-leucine with increased activity; when rats that had been without food for 24 hours were injected with the amino acid, their appetite was decreased (compared with controls) within four hours — an effect that lasted for a day, the researchers found.


On average, the treated rats lost 16 grams of body weight over that time, compared with less than four for the control animals. Both differences were statistically significant, at P<0.05 for food intake and P<0.005 for weight loss.


The opposite effect was also found: When satiated rats were given a well-known inhibitor of mTOR, the immune suppressant Rapamune (rapamycin), their intake of food over the next 30 minutes to an hour increased sharply compared to control rats. The difference was significant at P<0.05.


In the long run, research like this could alter the way we think about the human diet, Dr. Seeley said. "Rather than basing our diets only on macronutrients like fat or carbohydrates, we might one day be designing diets based on micronutrients like amino acids," he said.


But "we still have a lot to learn about how these nutrients would act if simply ingested with other nutrients, in what form they could be most effective, and even if they are effective at all when not administered directly to the brain," he added.


In other words, he said, it's too early for people to "run out and add more leucine to their diets."

Primary source: Science
Source reference:
Daniela Cota et al. "Hypothalamic mTOR Signaling Regulates Food Intake." Science 2006; 312:927-30.


Saludos Cordiales
Dr. José Manuel Ferrer Guerra

Anaesthetists Need Urgent Guidance On Patients Who Don't Want To Be Resuscitated

UK anaesthetists could face accusations of euthanasia or assisted suicide if they follow Do Not Attempt Resuscitation (DNAR) Orders during surgery, according to an editorial in the July issue of Anaesthesia.

Patients who have surgery often need routine interventions during anaesthesia that could be classed as resuscitation, points out Consultant Anaesthetist Dr Michael McBrien from the Royal Victoria Hospital in Belfast, Northern Ireland.

But automatically suspending DNAR Orders during surgery is no longer an acceptable option, according to Dr McBrien and his editorial co-author, Dr Gary Heyburn, Associate Specialist Orthogeriatrician at the Hospital.

"If the anaesthetist were to proceed and strictly obey the general understanding of a DNAR order under such circumstances, it could possibly be construed as an act of euthanasia or assisted suicide" they stress.

McBrien and Heyburn say that UK clinicians urgently need national guidance on how to manage the growing number of DNAR orders, pointing out that American guidelines have been in place since 1993.

"It is surprising that no guidelines or serious discussions on this matter have appeared in the UK to parallel the developments in North America" adds Dr McBrien.

The need for guidelines has been given added impetus by the fact that the Mental Capacity Act is due to come into force next year and that the European Convention on Human Rights is now enshrined in UK Law.

From 1 April 2007, the Act will give formal legal recognition to the patient's right to make advance decisions about the care they receive and reinforce the common law position about DNAR Orders that already exists.

"The paternalistic primary ethical principal of the past, namely immediate Medical benefit to the patient, has been overtaken" says Dr McBrien.

"If we are not to face litigation in the future we must read, understand and implement what the law requires from us in this area."

Clinicians also need clear guidance about how to handle requests made by parents of sick children or relatives of patients not deemed legally competent.

"Usually agreement will be reached about whether cardiopulmonary resuscitation should be attempted if the patient suffers respiratory or cardiac arrest" says Dr McBrien.

"If disagreement persists despite attempts to reach agreement, legal advice should be sought.

"Parents cannot require doctors to provide treatment contrary to their professional judgement, but doctors will try to accommodate parents' wishes as far as is compatible with protecting the child's interest."

With individual clinicians facing increasing dilemmas on numerous fronts the need for clear local and national guidelines has never been greater.

"A review of the basic ethical principles involved is needed to decide how individual anaesthetists and anaesthetic departments in the UK should manage this situation" conclude the authors.

"Dr McBrien and Dr Heyburn have done patients a service in stimulating discussion about the relationship between modern - and often quite complex - DNAR orders and the interventions required during anaesthesia" says the Journal's Editor-in-Chief Dr David Bogod, Consultant Anaesthetist at Nottingham City Hospital, UK.

"The issue actually extends to wider aspects of Medical practice by anaesthetists, including intensive and palliative care. While individual autonomy in these cases is often best served by a sensitive and detailed exploration of the patient's wishes by the doctors caring for them, it might be that some national guidance is needed.

"The Council of the Association of Anaesthetists of Great Britain and Ireland have advised us that they are actively considering setting up a working party for this purpose."

###

Notes to editors

Editorial. 'Do not attempt resuscitation' orders in the per-operative period. Michael McBrien and Gary Heyburn, Royal Victoria Hospital, Belfast. Anaesthesia. Volume 61, pages 625-627. (July 2006).

Anaesthesia, which was established in 1945, is the official Journal of the Association of Anaesthetists of Great Britain and Ireland. It publishes original, peer-reviewed articles to an international audience on all aspects of general and regional anaesthesia, intensive care and pain therapy, including research on equipment. Consultant Anaesthetist Dr David Bogod of Nottingham City Hospital, UK, is Editor in Chief of the Journal, which is published by Blackwell Publishing Ltd. http://www.blackwellpublishing.com/ana

In June 2006 Anaesthesia was named the highest ranked anaesthetic Journal in Europe and the fifth highest worldwide (out of 22) by the prestigious ISI Journal Citation Reports ®. These reports evaluate the world's leading journals and their impact and influence on the global research community. They cover 7,000 highly cited, peer reviewed journals in approximately 200 disciplines.

Contact: Annette Whibley
Blackwell Publishing Ltd


Saludos Cordiales
Dr. José Manuel Ferrer Guerra