Online newspaper of professor Yasser Metwally

The author: Professor Yasser Metwally

http://yassermetwally.com

INTRODUCTION

April 30, 2008 — Cesarean delivery is an independent risk factor for stroke, according to the results of a nationwide, population-based study reported in the April issue of the American Journal of Obstetrics & Gynecology.

“CS [cesarean section] delivery has been associated with a significant increase in maternal death from cardiac arrest, complications from anesthesia, puerperal infection, and venous thromboembolism; indeed, stroke has been singled out as a crucial cause of maternal morbidity and death during pregnancy and puerperium,” write Shiyng-Yu Lin, MD, from the Taipei Medical University in Taipei, Taiwan, Republic of China, and colleagues. “Nevertheless, to the best of our knowledge, very few studies have used large-scale (nationwide population) datasets to explore the risks of postpartum stroke between the 2 different delivery modes (CS delivery vs vaginal delivery).”

The goal of this study was to assess the risk for postpartum stroke within 3, 6, or 12 months after delivery for cesarean vs vaginal delivery with use of a population-based dataset of records from the Taiwan National Health Insurance Research Database from 1998 through 2003. Cox proportional hazard regressions allowed calculations of stroke-free survival rates for cesarean vs vaginal delivery for 987,010 women with singleton deliveries from 1998 to 2002.

Compared with patients who had a vaginal delivery, the hazard ratio (HR) for postpartum stroke among mothers who underwent a cesarean delivery was 1.67 times greater within 3 months of delivery (95% confidence interval [CI], 1.29 – 2.16); 1.61 times greater within 6 months of delivery (95% CI, 1.31 – 1.98), and 1.49 times greater within 12 months of delivery (95% CI, 1.27 – 1.76).

“Our data [indicate] that cesarean section delivery is an independent risk factor for stroke,” the study authors write.

Limitations of this study include lack of certain clinical data such as cigarette smoking, alcohol consumption, and body mass index values; and stroke diagnoses totally reliant on claims data.

“Based on the results of this study, a reduction in the CS delivery rate should prove to be beneficial for stroke prevention, which suggests that, as far as possible, vaginal deliveries should be encouraged,” the study authors conclude. “Rather interestingly, a history of CS delivery is found to be a preventive factor against stroke in women who undergo subsequent CS deliveries. The mechanisms of precondition and the development of novel strategies for a reduction of CS deliveries among women who are at high risk clearly will require further studies.”

The Topnotch Stroke Research Center, Ministry of Education, Taiwan, sponsored this study.

• Clinical Context

Several studies have reported an association between pregnancy and delivery and increased risk for stroke, but more detailed analysis is needed. According to the World Health Organization, the risk for postpartum death for cesarean deliveries can be up to 3.6 times higher vs conventional vaginal deliveries.

Cesarean vs vaginal delivery has been associated with a higher risk for maternal death from cardiac arrest, complications from anesthesia, puerperal infection, and venous thromboembolism, and stroke is a significant cause of maternal morbidity and death during pregnancy and the puerperium. However, very few previous studies have used large-scale (nationwide population) datasets to compare the risks for postpartum stroke for cesarean vs vaginal delivery.

• Study Highlights

  1. The objective of this study was to evaluate the risk for postpartum stroke within 3, 6, or 12 months after cesarean vs vaginal delivery.

  2. The population-based dataset from the Taiwan National Health Insurance Research Database included 987,010 women with singleton deliveries from 1998 to 2002, from a population of 1,000,394 women who were admitted to hospitals or obstetric clinics for deliveries between January 1998 and December 2002.

  3. Stroke-free survival rates for cesarean vs vaginal delivery were calculated from Cox proportional hazard regressions.

  4. Cesarean deliveries accounted for 33.9% of all deliveries.

  5. Patients who had cesarean delivery were more likely to be older than those who had vaginal delivery (mean age, 27.5 vs 29.1 years).

  6. The postpartum stroke rate within the 3-month postdelivery period was 0.03%.

  7. Compared with patients who had a vaginal delivery, the HR for postpartum stroke within 3 months of delivery among mothers who underwent a cesarean delivery was 1.67 times greater (95% CI, 1.29 – 2.16), after adjustment for age and geographic location.

  8. Compared with patients who had a vaginal delivery, HR for postpartum stroke among mothers who underwent a cesarean delivery was 1.61 times greater within 6 months of delivery (95% CI, 1.31 – 1.98) and 1.49 times greater within 12 months of delivery (95% CI, 1.27 – 1.76), after adjustment for age and geographic location.

  9. After adjustment for potential risk factors for stroke, the risk for postpartum stroke for cesarean vs vaginal delivery was 44.7% higher during the 3-month postdelivery period (P < .001), 43.6% higher during the 6-month postdelivery period (P < .001), and 32.5% higher during the 12-month postdelivery period (P < .01).

  10. Among the cesarean delivery group, preeclampsia/eclampsia was found to increase the risk for the occurrence of stroke (odds ratio, 3.89 – 4.66).

  11. Based on these findings, the investigators concluded that cesarean delivery is an independent risk factor for stroke, and if possible, vaginal deliveries should be encouraged.

  12. In a paradoxical fashion, a history of cesarean delivery was shown to be a preventive factor against stroke in women who undergo subsequent cesarean deliveries.

  13. Limitations of this study include lack of certain clinical data such as cigarette smoking, alcohol consumption, and body mass index values; and stroke diagnoses totally reliant on claims data.

• Pearls for Practice

  1. Compared with patients who had a vaginal delivery, the HR for postpartum stroke among mothers who underwent a cesarean delivery was 1.67 times greater within 3 months of delivery, 1.61 times greater within 6 months of delivery, and 1.49 times greater within 12 months of delivery, after adjustment for age and geographic location. Cesarean delivery is an independent risk factor for stroke, and if possible, vaginal deliveries should be encouraged.

  2. Among the cesarean delivery group, preeclampsia/eclampsia was found to increase the risk for the occurrence of stroke. In a paradoxical fashion, a history of cesarean delivery was shown to be a preventive factor against stroke in women who undergo subsequent cesarean deliveries.

References

1. Am J Obstet Gynecol. 2008;198:391.e1-397.e7.

The author: Professor Yasser Metwally

http://yassermetwally.com

INTRODUCTION

April 30, 2008 — In children and teenagers with both headaches and sleep complaints, a new study using polysomnography showed an association between migraine and sleep-disordered breathing and between tension headache and bruxism.

Patients in this study were evaluated at St. Christopher Hospital for Children, Drexel University, in Philadelphia, Pennsylvania. Ninety patients with headache and sleep problems aged 5 to 19 years underwent polysomnography, an electroencephalography-based sleep test. Migraine was the most common type of headache, occurring in 60 of the 90 patients. Another 11 patients had chronic daily headache, 6 had tension headache, and 13 had nonspecific headache, such as morning headache. Sleep-disordered breathing, including obstructive sleep apnea, was about twice as common in the migraineurs as in patients with other types of headache (56% vs 30%, respectively), the authors found.

“Parents and doctors need to be aware of the strong likelihood of sleep disorders in children with migraine,” said lead author Martina Vendrame, MD, PhD, from the department of neurology at Temple University, also in Philadelphia.

Dr. Vendrame presented the results at the American Academy of Neurology (AAN) 60th Annual Meeting.

• Ask About Sleep

A neurologist who did not participate in the study called it “a good step in recognizing the broad reach of disordered sleep.” Bradley V. Vaughn, MD, professor of neurology at the University of North Carolina at Chapel Hill, moderated the highlights session on sleep disorders at the meeting.

“Children with headache should be questioned about symptoms of sleep disorders because there’s a high incidence of them in this group,” said Dr. Vaughn .

During a press briefing, Dr. Vendrame said physicians should ask parents of children with migraine about snoring, frequent awakening during sleep, and daytime sleepiness.

When asked whether the fact that all of their patients had reported sleep problems could have biased the study results, Dr. Vendrame agreed it was possible. She said, “We want to repeat the study in a general population of children or in children who have headache but do not report sleep complaints.”

However, polysomnograms showed disturbed sleep architecture in the study patients with severe migraine and with chronic daily headache (occurring more than 15 days a month). These children and teens took a longer time to fall asleep, had shorter rapid eye movement (REM) sleep, and slept less total time than did those with milder or less frequent migraine, she reported.

“Children with migraines take naps, and that can affect sleep architecture,” Dr. Vendrame said at the press conference. “But headache may contribute to sleep disorders in children. We think they share common mechanisms, which may be related to REM sleep.”

The authors observed other sleep disturbances. Three (50%) of the patients with tension headache had bruxism, whereas only 2.4% of the patients with other types of headache ground their teeth during sleep, according to the abstract.

• Referral

“Teeth grinding is related to dysfunction of the temporomandibular joint, and these children need to be referred to a dental specialist,” Dr. Vendrame said.

Most of the children with sleep apnea needed referral to an ear-nose-throat (ENT) specialist, and about 50% of those children underwent tonsillectomy, the author said. “After surgery, about 80% had less severe and less frequent migraine,” she said. “This needs more follow-up.”

American Academy of Pediatrics guidelines for children with symptoms of sleep disorders are to refer them for a sleep study, according to Dr. Vaughn. “However, there are not as many sleep centers that do sleep studies in children as there are for adults,” he said. “As a backup plan, have an ENT evaluate the child.”

Polysomnography is not part of the usual migraine workup in children. The sleep test monitors the brain, eye movements, breathing, cardiac rhythm, and muscle activity.

References

1. American Academy of Neurology 60th Annual Meeting: Abstract S49.008. Presented April 17, 2008.

The author: Professor Yasser Metwally

http://yassermetwally.com

INTRODUCTION

April 30, 2008 — Patients with migraine headaches are more likely to develop cutaneous allodynia (CA) than people who suffer other types of headache, according to a new study. The study also showed an association between CA and female sex, headache frequency, obesity, disability, and depression in patients who suffer migraines.

The study results, published in the April 22 issue of Neurology, suggest that CA, a neurological condition characterized by pain during normal activities, may even be a risk factor for migraine progression.

Identifying risk factors for progression of disease is a very important public health priority, said study author Marcelo E. Bigal, MD, PhD, from Albert Einstein College of Medicine, in the Bronx, New York, in a statement from the American Academy of Neurology. “For example, it may be that individuals with allodynia should be more aggressively treated to prevent migraine progression, as well as to decrease this sensitivity on the skin,” Dr. Bigal said.

• Headache Breakdown

Researchers surveyed a random sample of 24,000 people identified as having at least 1 severe headache in the previous year. Of these headache sufferers, 16,573 (69.0%) returned completed questionnaires. Headache types included: 11,094 with migraines; 1491 with probable migraine (PM); 1151 with severe episodic tension-type headaches (S-ETTH); 643 with transformed migraine (TM); 151 with other chronic daily headaches (O-CDH); and 2042 with unclassified headaches. Diagnoses of migraine and PM were based on criteria proposed by the second edition of the International Classification of Headache Disorders; diagnosis of CDH and TM followed the Silberstein and Lipton criteria.

As well as determining headache diagnosis, the detailed and validated 82-question survey also assessed headache-related impact, health-related quality of life, duration of headache, weight, height, comorbid disorders (arthritis, asthma, and chronic pain), and depression.

• Symptom Checklist

The questionnaire included the 12-item Allodynia Symptom Checklist (ASC-12) that collects information on the frequency of various allodynia symptoms in association with headache attacks. For people with more than 1 type of headache, questions were directed to the “most severe type of headache,” the authors note.

The researchers found that the prevalence of CA during headache attacks (defined as an ASC-12 score of 3 or more) was higher in those with TM than in episodic migraine and in both of these groups compared with PM, O-CDH, and S-ETTH.

Table 1. Prevalence of CA by Headache Type

References

1. Neurology 2008;70:1525-1533. Abstract

The author: Professor Yasser Metwally

http://yassermetwally.com

INTRODUCTION

April 29, 2008 — Spinal cord lesions produce a variety of types of voiding dysfunction depending on the level of the neuraxis involved. Acute herniation of a central disk at L5-S1 is a neurosurgical emergency when the patient comes in with sudden onset of painful urinary retention. The nerve roots of the cauda equina that supply the detrusor travel medially. The sensory inputs from the bladder are not affected. In central herniation patients usually experience no sciatic radiation of pain.

Spinal stenosis in the lumbosacral region, as it becomes symptomatic, usually results in intermittent episodes of urinary retention as a manifestation of intermittent claudication of the conus or cauda equina. Stenosis in the cervical region is more likely to produce long-tract involvement with bladder sphincter dyssynergia; that is, contraction of the bladder is accompanied by abnormal contraction of the sphincteric mechanism.

Spinal cord injury above the sacral segments but below the pontine micturition center results, in the acute phase, in a state of “spinal shock.” The detrusor is areflexic and insensate. Sphincteric activity continues. The patient may retain a large volume of urine. An indwelling catheter usually is placed to avoid overdistension, which in itself can render the bladder unresponsive.

As spinal shock resolves and reflexes are regained, tapping over the bladder often elicits a bladder contraction. The coordinated voiding regulated by the pontine micturition center is lost because of the disconnection of pathways traveling through the area of spinal cord damage. Dyssynergic voiding occurs and, if untreated, can result in very low bladder capacity with frequent contractions, poor emptying, high bladder pressures with trabecular formation, and eventually renal failure from hydroureter and hydronephrosis. Before treatment strategies were developed for managing the bladder in spinal cord injury, renal failure was the most common cause of death.

The spinal dysraphisms frequently produce abnormalities of voiding function. The nature of the dysfunction depends upon the spinal level of the abnormality. Meningomyelocele is now diagnosed in utero, and the infant, usually delivered by cesarean section, undergoes neurosurgery in the newborn period. Urodynamic studies and sphincter EMG done shortly after corrective surgery dictate the management. With very low lesions, function in the lower extremities may be normal while the sphincter is totally denervated. These children must wear diapers.

When the dysraphism affects supraspinal segments, the patient may experience inappropriate sphincter contraction with or without bladder contractions. In such patients, intermittent catheterization is instituted in the newborn nursery and continued at home. Repeat studies are done at ages 6 months and 1 year. Some children develop innervation of the sphincter and convert from voiding at low pressure to dyssynergic voiding. Management requires intermittent catheterization and usually anticholinergic drugs to reduce bladder contractions.

Late complications are seen during the adolescent growth spurt if tethering of the filum terminale occurs. Late deterioration of bladder function also may be seen in diastematomyelia. In both cases traction on the conus can compromise voiding function. Careful examination of the lower back may reveal a hair patch or a sacral dimple as evidence of underlying pathology. One of the author’s patients had no dysfunction until his spinal cord was compromised further by arthritic changes. He was 73 years old and had had no bowel or bladder dysfunction or lower extremity dysfunction until that time.

Syringomyelia or hydromyelia can occur as a late complication of spinal cord injury or may be seen as a congenital lesion. Intramedullary spinal cord tumors, gliomas or ependymomas, sometimes may be associated with development of a syrinx. Since most patients who develop a posttraumatic syrinx have spastic, dyssynergic bladders as a result of their injury, little change is seen. Syringes of other etiologies, in the author’s experience, seldom cause bowel or bladder dysfunction. Intramedullary cord tumors usually do not cause bladder dysfunction until they become large enough to cause compression of cord substance within the spinal canal.

References

1. Metwally, MYM: Textbook of neuroimaging, A CD-ROM publication, (Metwally, MYM editor) WEB-CD agency for electronic publication, version 9.2a April 2008 [Click to have a look at the home page]

The author: Professor Yasser Metwally

http://yassermetwally.com

INTRODUCTION

April 29, 2008 — Glioblastoma multiforme is by far the most common and most malignant of the glial tumors, and prognosis remains poor. Although the data are still preliminary, an investigational compound has shown promise in prolonging survival among patients with recurrent glioblastoma, researchers reported here at the American Association for Cancer Research 2008 Annual Meeting.

“Less than 5% of patients are still alive by 5 years,” said lead author Tracy Batchelor, MD, MPH, executive director of the Stephen E. and Catherine Pappas Center for Neuro-Oncology at the Massachusetts General Hospital Cancer Center in Boston. “There is a significant need for new therapeutics.”

Dr. Batchelor explained that the primary outcome of this study, which is a standard metric in this disease, is the proportion of patients who are alive without disease progression at 6 months. “Our percentage was 25.8%, and this compares favorably with historic controls, which are about 15%.

In this phase 2 trial, which was sponsored by the National Cancer Institute (NCI), Dr. Batchelor and colleagues evaluated the efficacy of AZD2171 (cediranib), an oral potent panvascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor. It is a selective VEGF-signaling inhibitor that targets all 3 VEGF receptors. The study cohort consisted of 31 patients with glioblastoma who had failed previous therapy with radiation, surgery, and chemotherapy.

AZD2171 has a half-life of 20 hours, which makes it compatible with once-daily dosing, and its primary target, VEGFR2, is expressed on glioblastoma endothelium. The researchers have observed the normalization of tumor vessels in patients with recurrent glioblastoma who received AZD2171 on a daily basis.

The median overall survival was 221 days, and progression-free survival was 117 days. Dr. Batchelor pointed out that the median survival in this study compared favorably with historic controls.

“Over half of our patients had reductions in tumor mass and edema, which is a much higher rate than that seen with other chemotherapeutic agents,” he said. “Cediranib normalized the blood and alleviated edema, which is a major cause of morbidity in this population and often requires patients to remain on steroids for long periods of time.”

Using magnetic resonance imaging, the researchers observed a reduction in edema. In 15 of the 16 patients who were on steroids at the start of the trial, steroid dosage was reduced after treatment with the experimental agent. Five of the patients were able to completely discontinue steroid use.

Toxicity was also manageable in this population, but 2 patients withdrew from the trial because of adverse events. The most common toxicities noted were fatigue, diarrhea, and hypertension, and 15 patients required a dose reduction.

There has been some concern about hemorrhage in this class of agents, Dr. Batchelor explained, but in this study there were no reported episodes of intracerebral hemorrhages and there were no treatment-related deaths. Currently, 30 patients have experienced disease progression, and 1 remains in follow-up without progression.

Blood biomarkers were serially assessed, and the authors observed that plasma VEGF, placental growth factor (PlGF), and stromal cell-derived factor (SDF)1-alpha increased after treatment was initiated. Plasma PlGF and VEGF decreased when treatment was discontinued, and basic fibroblast growth factor (FGF), SDF1-alpha, and viable circulating endothelial cells increased when tumors escaped treatment.

“Our plans are to move to a phase 3 trial, and we also have a grant from the NCI to study the drug in combination with radiation in newly diagnosed patients with glioblastoma,” said Dr. Batchelor.

References

1. American Association for Cancer Research (AACR) 2008 Annual Meeting: Abstract LB-247. Presented April 14, 2008.

The author: Professor Yasser Metwally

http://yassermetwally.com

INTRODUCTION

April 29, 2008 — Children with attention-deficit/hyperactivity disorder (ADHD) should receive careful cardiac evaluation—including an electrocardiogram (ECG)—before starting treatment with stimulant drugs, a new American Heart Association statement recommends [1].

The statement, published online April 21, 2008 in Circulation, notes that stimulant medications used to treat ADHD can increase heart rate and blood pressure, and although these side effects are insignificant for most children with ADHD, they are an important consideration for children who have certain forms of congenital heart disease or arrhythmias with a predisposition for sudden cardiac arrest. The statement says that these new recommendations “are not intended to limit the appropriate use of stimulants in children with ADHD, to label children with heart disease, or to limit their participation in athletic activities but to add clarity to who has or does not have heart disease and the extent of the risk.”

• Some conditions undetected by physical examination

It advises that after a diagnosis of ADHD has been made, but before therapy with a stimulant or other medication is initiated, a thorough evaluation should be performed, with special attention to symptoms that can indicate a cardiac condition, such as palpitations, near syncope, or syncope. All additional medications, including prescribed and over-the-counter medications, should be determined, and a complete family history should be obtained. Because “some of the cardiac conditions associated with sudden cardiac death might not be detected on a routine physical examination, we are suggesting that an ECG be added to increase the likelihood of identifying significant cardiac conditions that might place the child at risk,” the authors write.

Head of the statement-writing committee, Dr Victoria Vetter (University of Pennsylvania School of Medicine, Philadelphia), commented: “The FDA has issued medication guidelines for stimulant drugs used to treat ADHD that state that you should tell your doctor if you have any heart condition, but there are many children who have structural heart disease that could lead to sudden cardiac death who don’t know they have it until a significant event occurs. It is possible that using a stimulant medication could be a trigger for such an event. While there are patients who have had sudden cardiac arrest and strokes on these drugs, there are no large studies that have proven that the drugs have caused these events. However, it is thought that if adrenergic stimulation is increased, something these drugs do, this could trigger sudden cardiac arrest in susceptible patients.”

Vetter explained that the committee has therefore recommended that physicians consider ordering an ECG to aid them in deciding whether or not underlying heart disease is present before prescribing these drugs for ADHD and, if there is any indication of heart disease, the child should be referred to a pediatric cardiologist for a full examination, because ECGs can give false-positive results.

She added that children with underlying heart disease can still take drugs for ADHD if they are stable and under the care of a pediatric cardiologist. “Even if an underlying disorder is confirmed by the cardiologist, these children can still take stimulant drugs, but they should be monitored very carefully. We know that many children with structural heart disease have ADHD, and we still want them to take the drugs because ADHD has a huge emotional and social impact on children and affects the way they grow up and their ability to be successful. The drugs do work in helping this; we don’t want to limit people from getting these medications. We just want them to be used as safely as possible,” said Vetter.

• Class 2a recommendation

She stressed that if a child does not have access to an ECG or to a pediatric cardiologist who can evaluate an ECG or perform a cardiology consultation, this does not mean that they should not receive treatment for ADHD. “This is a class 2a recommendation—we feel it is useful, helpful, and reasonable, but it is has not been proven to be of benefit. We recommend that doctors use family history, a physical exam, and an ECG to make a decision about possible heart disease in children before prescribing stimulant drugs and, although we feel that an ECG is reasonable and helpful as a tool in identifying children with cardiac conditions that can lead to sudden cardiac death, if, in the view of the physician, a child requires immediate treatment with stimulant medications, this recommendation is not meant to keep them from getting that treatment,” she said.

The statement adds that once stimulant treatment begins, all children should have their heart health monitored periodically, with a blood-pressure check one to three months after starting medication and during routine follow-ups every six to 12 months thereafter. Because some heart conditions do not appear until adolescence, it is recommended that if the initial ECG was obtained when the child was younger than 12 years of age, a repeat ECG should be done when the child is older than 12 years.

In 2003, an estimated 2.5 million children in the US took medication for ADHD. Surveys indicate that ADHD affects an estimated 4% to 12% of all school-aged children in the US, and it appears more common in children with heart conditions. Studies report that, depending on the specific cardiac condition, 33% to 42% of pediatric cardiac patients have ADHD, Vetter said. The number of undiagnosed children with heart conditions is unknown because routine heart screening is not performed. However, Vetter said, in a recent pilot study, up to 2% of healthy school-aged children had potentially serious undiagnosed cardiac conditions identified by an ECG.

• Clinical Context

Concerns expressed by the US Food and Drug Administration regarding potential cardiovascular risks for stimulant medications used for ADHD, and requirements for specific heart-related labeling and medication guides, have posed several dilemmas for the clinician intending to prescribe stimulant medications to children with ADHD. These include how to know if the child has heart disease, a heart problem, or heart defect and what to do if these conditions are identified.

The goal of this statement from the American Heart Association Congenital Cardiac Defects Committee of the Council on Cardiovascular Disease in the Young and the Council on Cardiovascular Nursing was to provide the clinician with some tools to help identify these children, determine whether the use of stimulant medications is appropriate in a particular child, and monitor and follow up on children receiving these medications to lower the cardiovascular risks.

• Study Highlights

  1. Evaluation of children with ADHD being considered for treatment with stimulant medications should include patient history focusing on symptoms of fainting or dizziness, particularly with exercise; seizures; rheumatic fever; exercise-induced chest pain or shortness of breath; unexplained change in exercise tolerance; palpitations, increased heart rate, or extra or skipped beats; high blood pressure; significant heart murmur or heart problems; and intercurrent viral illness with chest pains or palpitations.

  2. Use of medications and health supplements should be elicited.

  3. Family history should ask about sudden or unexplained death at an early age; sudden cardiac death (SCD) or “heart attack” in relatives younger than 35 years; sudden death during exercise; cardiac arrhythmias; hypertrophic cardiomyopathy (HCM) or other cardiomyopathy (eg, dilated cardiomyopathy, right ventricular cardiomyopathy); long-QT syndrome (LQTS), short-QT syndrome, or Brugada’s syndrome; Wolff-Parkinson-White (WPW) or similar rhythm abnormalities; syncope or other event requiring resuscitation in those younger than 35 years; and Marfan’s syndrome.

  4. Physical examination should look for abnormal heart murmur, other cardiovascular abnormalities, and physical features of Marfan’s syndrome.

  5. Baseline ECG can often detect cardiovascular abnormalities (eg, HCM, LQTS, WPW anomaly) if read by a pediatric cardiologist or a cardiologist or clinician with expertise in reading pediatric ECGs.

  6. A second ECG may be useful after the child is older than 2 years if baseline ECG was done at younger than 12 years or if new symptoms or family history develops.

  7. Pediatric cardiology consult is recommended if the above evaluation shows any significant findings.

  8. Once stimulant drugs are started, the clinician should monitor cardiovascular status at each visit with physical examination and with questions concerning potential cardiac symptoms and new family history.

  9. Blood pressure and pulse should be monitored every 1 to 3 months during routine follow-up for all medications and more often during titration and weaning of alpha-agonists.

  10. Appropriate referral and testing are indicated for any cardiac symptoms.

  11. In patients with congenital heart disease that is not repaired or repaired but without current hemodynamic or arrhythmic concerns, or congenital heart disease that is considered to be stable, it is reasonable to consider the use of stimulant medication unless the patient’s pediatric cardiologist has specific concerns.

  12. After other methods of treatment of ADHD have been considered or used, it is reasonable to use stimulants with caution in patients with:

  13. Heart condition associated with SCD

  14. History of arrhythmia requiring resuscitation, direct-current cardioversion or defibrillation, or overdrive pacing

  15. History of arrhythmia associated with death or SCD

  16. Previous aborted SCD

  17. Other clinically significant, untreated, or uncontrolled arrhythmia

  18. Corrected QT interval on ECG of more than 0.46 second

  19. Heart rate or blood pressure more than 2 SD above means for age.

  20. After stimulant medications are started in such patients, these patients should be carefully monitored.

  21. If any of the listed conditions are diagnosed during treatment, discontinuation of the stimulant medication should be considered, at least until further testing and treatment are performed.

  22. Once arrhythmias are treated and controlled, the patient can be restarted on medication if the pediatric cardiologist approves.

• Pearls for Practice

  1. Evaluation of children with ADHD being considered for treatment with stimulant medications should include patient history focusing on cardiovascular symptoms, use of medications and health supplements, family cardiovascular history, physical examination focused on the cardiovascular system, and baseline ECG. Pediatric cardiology consultation is recommended if the evaluation shows any significant findings.

  2. Once stimulant drugs are started, the clinician should monitor cardiovascular status at each visit with a physical examination, vital signs, and questions concerning potential cardiac symptoms and new family history. Appropriate referral and testing are indicated for any cardiac symptoms.

References

1. Vetter VL, Elia J, Erickson C, et al. Cardiovascular monitoring of children and adolescents with heart disease receiving stimulant drugs. A scientific statement from the American Heart Association Congenital Cardiac Defects Committee of the Council on Cardiovascular Disease in the Young and the Council on Cardiovascular Nursing. Circulation. 2008; published online April 21. DOI:10.1161/CIRCULATIONAHA.107.189473.

The author: Professor Yasser Metwally

http://yassermetwally.com

INTRODUCTION

Apr 29, 2008 – Headache associated with acute stroke generally starts on the first day of the stroke and tends to be continuous, according to a study published in the April issue of Cephalalgia. In more than half of the study patients, it also appears to be a re-activation of a previous primary headache.

“Headache is frequent in the setting of acute stroke, but many of its characteristics remain to be reliably described,” Dr. A. Verdelho and colleagues from the University of Lisbon, Portugal, write. Previous studies have reported a wide variation in prevalence, a higher frequency associated with hemorrhagic stroke, and various areas of pain.

In the current study, the researchers describe the characteristics, duration, evolution, and type of headache associated with stroke in 124 patients, 61% with ischemic and 39% with hemorrhagic stroke. The patients’ median age was 58 years.

Patients consecutively admitted to a stroke unit were interviewed daily from stroke onset until day 8 using a validated headache questionnaire. Headaches were classified according to the International Headache Society classification.

Headache started on the first day of stroke in 107 patients (86%) and the mean headache duration was 3.8 days. Headaches were more often continuous and were more severe on the first day. The headache was more often bilateral and located in the anterior cranial region.

The most frequently described quality was pressure and the most frequent type of headache met the criteria for tension-type (61%). Eleven percent of headaches could not be classified using the IHS criteria.

Overall, 40% of patients who reported headache also experienced nausea and vomiting. Headache severity increased with cough and with movement.

Previous primary headache was documented in 71 patients. Reactivation of previous headache was documented in up to half of the patients.

“One of the most interesting findings of our study is that stroke can reactivate previous life-time headache,” Dr. Verdelho said in an interview with Reuters Health. “Half of our cohort (that had previous headache) had a similar headache with stroke,” she explained.

“So in these patients headache seems to be an entity that is reactivated by any brain insult and not specific for stroke,” the author noted. “By the contrary, continuous headache in patients without previous headache is probably a very useful symptom of brain lesion, and the IHS classification was difficult to use in these headaches.”

“I think we now have a better understanding of headache characteristics in the setting of acute stroke, and this fact is very useful in clinical practice. For instance, we have a prognosis of headache itself (in the setting of acute stroke),” Dr. Verdelho said.

References

1. Cephalalgia 2008;28:346-354.

The author: Professor Yasser Metwally

http://yassermetwally.com

INTRODUCTION

April 29, 2008 — Evidence supports a genetic predisposition to MS. There is excess occurrence in Northern Europeans relative to indigenous populations from the same geographic location, a familial aggregation (MS is 20 to 40 times more common in first-degree relatives with rapid drop-off with degree of relatedness), and lack of excess of MS despite the shared environment in adopted relatives of patients with MS Based on the monozygotic twin studies, the genetic risk of MS can be estimated to be 25 to 30%. This drops to 3 to 5% in dizygotic twins, thereby supporting the “complex” susceptibility to MS with a significant environmental-physiological contribution to susceptibility risk.

From a practical perspective, the risk of MS in a first-degree relative of a patient with established MS, corrected for the population risk, is on average 2 to 4%. This varies with incidence-prevalence figures for the population at large from which the individual is drawn. In families with MS, fathers with MS have almost twice the possibility of passing MS to their children than mothers with MS. This excess inheritance from fathers with MS ultimately balances the expected disease excess in children of mothers with MS because women have almost a twofold greater incidence of MS than men; therefore, the greater chance of inheritance from fathers does not change the way a physician should counsel MS patients. Other studies suggested a possible increase in maternal risk of inheritance of MS, or no parent-of-origin effect at all. This parent-of-origin effect is independent of a child’s sex and cannot be explained by classical gender-dependent inheritance patterns such as X-linked or mitochondrial inheritance.

Clinical phenotypic heterogeneity in MS appears to have a genetic basis. Relative pairs with MS in family studies have greater similarity of clinical course than expected by chance. A large international study found affected sibling pairs to be concordant for age and year of disease onset and disease course, but not for disease severity. Interestingly, in the same study, affected parent-affected child concordance was only present for age of onset. Besides sharing a similar genetic background, affected sibling pairs also likely share a relatively similar environment when compared with their parents. Therefore, the results of this study highlight the contribution of having both a similar genetic and similar environmental background to develop a similar MS clinical phenotype. However, especially with the concordance in year of disease onset in affected sibling pairs, this study also suggests that exposure to a possible environmental factor(s) at a similar critical period may also be necessary to develop a similar clinical phenotype.

• Genetic Epidemiology of Multiple Sclerosis

Genetic epidemiology studies are generally classified as hypothesis-independent whole genome studies (linkage or association) or hypothesis-driven candidate gene association studies. Each method has its drawbacks and strengths, but regardless of the method, a robust definition of the phenotype is necessary for the success of any genetic epidemiology study in complex disorders because different sets of genes and related pathways are potentially involved in different phenotypes. Some understanding of the concepts involved in each method is necessary to be able to interpret study results.

In disorders of complex etiology such as MS, where individual genetic contributions are expected to be common polymorphism effects, major limitations of hypothesis-independent whole genome studies relate to the sample size needed to study sufficient numbers of markers with adequate power to uncover small gene effects, especially when a correction for multiple comparisons is entertained.[1] Therefore, these studies are more likely to reveal false-negative results. However, a major advantage of these studies is the potential to discover novel pathways involved in disease etiopathogenesis that were not previously entertained.

Hypothesis-driven candidate gene association studies, on the other hand, require an intimate and scientifically well-supported understanding of the biology of the disease to identify reliable candidates to study. However, for most complex disorders, such candidates are not easily identified. The major advantage of these studies is the increased sensitivity and therefore the decreased sample size requirements, facilitating a dense study of the candidate region or the gene. These studies, however, are more prone to false-positive findings.

Ultimately, the study of genetic epidemiology of complex disorders requires a combined application of these methods, depending on the hypothesis under question.

• Genes of Multiple Sclerosis

A discussion of all the genetic studies in MS with controversial results is beyond the scope of this post. This review highlights some of the promising results from different regions and candidate genes of the human genome.

The HLA-DRB1*1501-DQB1*0602 haplotype on chromosome 6p21 is well accepted as a susceptibility locus for MS. This region was originally studied as a candidate for MS susceptibility in sporadic MS patient populations as part of the autoimmune hypothesis in MS, and later confirmed in hypothesis-independent genome-wide linkage studies in familial MS populations as part of large international efforts.[2,3] This association is further defined as being due to HLA-DRB1 rather than the DQ allele.[4,5] A study suggests that although the presence of HLA-DRB1*15 allele increases MS risk dominantly, HLA-DRB1*03 contributes to a smaller increased MS risk recessively. In addition, HLA-DRB1*14 decreases MS risk.[6] This study also confirms the previously defined lack of association between the HLA locus and disease course, disease severity, and age of onset in MS.[6]

There are other potential loci on chromosomes 5q33, 17q23, and 19p13 that show weak linkage with susceptibility to MS.[3] Another hypothesis-independent association study uniquely harnessing the greater haplotypic diversity and distinct patterns of linkage disequilibrium in patients of African descent identified an additional candidate locus on chromosome 1.[7] These loci await further confirmation of the likely candidate genes in these regions.

Cytotoxic T-lymphocyte antigen-4 (CTLA-4) is a costimulatory molecule involved in T-cell downregulation on engagement with B7. It is a key inhibitory molecule involved in the prevention of autoimmunity.[8] Polymorphisms of CTLA4 and the haplotypes formed between them have been associated with autoimmunity in general, although not driven by single polymorphism effects.[8] Several studies have shown an association with susceptibility to MS, although not always with the same markers, suggesting a haplotype effect rather than individual polymorphism effects.[9] Indeed, these effects in part may be driven via an interaction with the HLA-DRB1*15 allele.[10] Several other studies have failed to confirm these associations [10]. A recent study, however, suggests that CTLA4 polymorphisms are associated strongly in families with MS enriched for autoimmune diseases, but not in families without other autoimmune diseases.[11] This supports the notion that CTLA-4 acts as a common autoimmunity gateway and provokes further interest in this gene and chromosome region as a susceptibility marker for MS. Further work will be necessary to better understand the inherent contribution of CTLA4 polymorphisms to CTLA-4 function.

Interferon-gamma (IFNG) is a cytokine with key regulatory, immunomodulatory, and effector roles both in autoimmunity and MS. Polymorphisms of this regulator cytokine and the haplotypes formed between them are associated with MS susceptibility, likely in a gender-dependent fashion.[10,11] This association has not been confirmed in all studied populations.[12] Further confirmation and understanding of the inherent effects of the IFNG polymorphisms on expression will be necessary.

Apolipoprotein E (APOE) is associated with prevention of neurotoxicity and repair processes in a variety of neurological disorders.[13] APOE genotypes have been associated with disease severity in MS in some but not in all studies. APOE e3 and e4 alleles have been associated with neuronal loss measures on magnetic resonance spectroscopy.[14] The APOE e2 allele is associated with lesser disease severity in patients with familial MS,[15] and this association is present in women but not men with MS in population-based sporadic patients.[16] The APOE e4 allele has been associated with progressive disease in women and cognitive impairment in men with MS.[17] However, a meta-analysis failed to confirm these associations.[18] A study conducted in Greece suggests that APOE e4 allele may be associated with an unfavorable verbal learning score in MS patients.[19] Further studies are needed with more robust cognitive and imaging outcomes in MS before a conclusion regarding an association of APOE genotypes and MS can be reached.

Interleukin-7 receptor-a (IL7Ra/CD127) is a type I cytokine and is part of the cytokine receptor complex for the ligand IL7. IL7Ra-IL7 interaction is involved in proliferation of T and B lymphocytes with no redundancy. IL7Ra is located on chromosome 5p13, a region with some linkage of MS.[20] IL7Ra was associated with MS as a candidate gene,[21] followed by confirmation in two independent populations of patients with MS, one of which is a recent whole genomic study in MS.[21]

References

1-Weiss KM, Terwilliger JD. How many diseases does it take to map a gene with SNPs? Nat Genet 2000;26(2):151-157
2-GAMES; Transatlantic Multiple Sclerosis Genetics Cooperative. A meta-analysis of whole genome linkage screens in multiple sclerosis. J Neuroimmunol 2003;143(1-2):39-46
3-Sawcer S, Ban M, Maranian M, et al. A high-density screen for linkage in multiple sclerosis. Am J Hum Genet 2005;77:454-467
4-Oksenberg JR, Barcellos LF, Cree BA, et al. Mapping multiple sclerosis susceptibility to the HLA-DR locus in African Americans. Am J Hum Genet 2004;74(1):160-167
5- Lincoln MR, Montpetit A, Cader MZ, et al. A predominant role for the HLA class II region in the association of the MHC region with multiple sclerosis. Nat Genet 2005;37(10):1108-1112
6-Barcellos LF, Sawcer S, Ramsay PP, et al. Heterogeneity at the HLA-DRB1 locus and risk for multiple sclerosis. Hum Mol Genet 2006;15(18):2813-2824
7-Reich D, Patterson N, De Jager PL, et al. A whole-genome admixture scan finds a candidate locus for multiple sclerosis susceptibility. Nat Genet 2005;37(10):1113-1118
8-Gough SC, Walker LS, Sansom DM. CTLA4 gene polymorphism and autoimmunity. Immunol Rev 2005;204: 102-115
9-Harbo HF, Celius EG, Vartdal F, Spurkland A. CTLA4 promoter and exon 1 dimorphisms in multiple sclerosis. Tissue Antigens 1999;53(1):106-110
10-Alizadeh M, Babron MC, Birebent B, et al. Genetic interaction of CTLA-4 with HLA-DR15 in multiple sclerosis patients. Ann Neurol 2003;54(1):119-122
11-Roxburgh RH, Sawcer S, Maranian M, et al. No evidence of a significant role for CTLA-4 in multiple sclerosis. J Neuroimmunol 2006;171(1-2):193-197
12-Dai Y, Masterman T, Huang WX, et al. Analysis of an interferon-gamma gene dinucleotide-repeat polymorphism in Nordic multiple sclerosis patients. Mult Scler 2001; 7(3):157-163
13-Gee JR, Keller JN. Astrocytes: regulation of brain homeostasis via apolipoprotein E. Int J Biochem Cell Biol 2005; 37(6):1145-1150
14-Enzinger C, Ropele S, Strasser-Fuchs S, et al. Lower levels of N-acetylaspartate in multiple sclerosis patients with the apolipoprotein E epsilon4 allele [see comment]. Arch Neurol 2003;60(1):65-70
15-Schmidt S, Barcellos LF, DeSombre K, et al. Association of polymorphisms in the apolipoprotein E region with susceptibility to and progression of multiple sclerosis. Am J Hum Genet 2002;70(3):708-717
16-Kantarci OH, Hebrink DD, Achenbach SJ, et al. Association of APOE polymorphisms with disease severity in MS is limited to women [see comment]. Neurology 2004;62(5):811-814
17-Cocco E, Sotgiu A, Costa G, et al. HLA-DR, DQ and APOE genotypes and gender influence in Sardinian primary progressive MS. Neurology 2005;64(3):564-566
18-Burwick RM, Ramsay PP, Haines JL, et al. APOE epsilon variation in multiple sclerosis susceptibility and disease severity: some answers. Neurology 2006;66(9):1373-1383
19-Koutsis G, Panas M, Giogkaraki E, et al. APOE epsilon4 is associated with impaired verbal learning in patients with MS. Neurology 2007;68(8):546-549
20-Ebers GC, Kukay K, Bulman DE, et al. A full genome search in multiple sclerosis [see comment]. Nat Genet 1996;13(4):472-476
21-Zhang Z, Duvefelt K, Svensson F, et al. Two genes encoding immune-regulatory molecules (LAG3 and IL7R) confer susceptibility to multiple sclerosis. Genes Immun 2005;6(2):145-152

The author: Professor Yasser Metwally

http://yassermetwally.com

INTRODUCTION

April 28, 2008 — Researchers have concluded that urate, a naturally occurring metabolite and a major antioxidant in humans, may slow the progression of Parkinson’s disease (PD) and that urate could be an effective therapy for this disease.

Their study, published in the April 14 Online First issue of the Archives of Neurology, found that patients with early-stage PD who had the highest serum concentrations of urate progressed to the point of requiring dopaminergic therapy at about half the rate of those with the lowest concentrations. This association was much stronger in men.

• Considered an Unimportant Byproduct

For years, urate was considered an unimportant byproduct of metabolism that was simply excreted in the urine, said one of the study authors, Alberto Ascherio, MD, of the Departments of Nutrition and Epidemiology, Harvard School of Public Health in Boston, Massachusetts. However, these study results, coupled with those of an earlier study that linked the highest serum urate levels with lowered risk for the development of PD in men, have helped change that view. Now, there is growing acceptance that urate “plays an important role in keeping us healthy,” said Dr. Ascherio. “I think the two studies together are what makes this (latest result) a triumph.”

• Data From PRECEPT study

Dr. Ascherio and his colleagues used data from the Parkinson Research Examination of CEP-1347 Trial (PRECEPT), a large 2-year, double-blind, randomized trial of oral CEP-1347, a kinase inhibitor that has been found to be neuroprotective in animal models of PD. The PRECEPT study was designed to determine whether CEP-1347 could slow the progression of early-stage PD.

The 806 subjects who were at least 30 years old and had PD not requiring the use of dopaminergic therapy were enrolled in the PRECEPT study between April 2002 and April 2004 at 65 sites across the United States and Canada. Subjects were then regularly evaluated for disability requiring dopaminergic therapy.

• Urate Correlated With Male Sex, Body Mass Index, Diuretic Use

PRECEPT was chosen for this current investigation because it was the largest study to have measured serum urate at baseline, said Dr. Ascherio. Baseline results were available for 804 subjects (517 men and 287 women). These concentrations correlated positively with male sex, body mass index, use of thiazide diuretics, and history of gout and hypertension.

During follow-up, 493 participants (61%) deteriorated to the point of requiring dopaminergic therapy. The hazard ratio (HR) of reaching this endpoint declined with increasing concentrations of serum urate, with subjects in the top quintile reaching the endpoint at half the rate of subjects in the bottom quintile (HR, 0.51; 95% confidence interval (CI), 0.37 – 0.72; P < .001).

Men demonstrated a much stronger association (HR, 0.39; 95% CI, 0.26 – 0.60; P for trend < .001) vs women (HR, 0.77; 95% CI, 0.39 – 1.50; P for trend = .33).

• Other Protective Mechanisms in Women

It’s not clear why the link between urate and slowing of PD progression was so much stronger in men. Women have a lower level of urate to begin with, and very few have the high level of this metabolite that is associated with protection, said Dr. Ascherio. “The numbers are too small to make a strong statement about it. At the same time, women generally don’t have more PD than men, which suggests that there are other protective mechanisms in women, and these may include hormones or other factors,” he said.

Several dietary factors, including fructose and alcohol, tend to increase serum urate levels. On the other hand, dairy foods and vitamin C tend to decrease urate levels. To complicate matters, though, vitamin C is also a very strong antioxidant, said Dr. Ascherio. “Even if you take a lot of vitamin C, you may lower your urate but increase your ascorbates, so it could still be beneficial” in neuroprotection.

These dietary links are purely observational, Dr. Ascherio stressed. “This is not ready to make recommendations to the public to reduce the risk of PD,” he said. However, it is worth noting that although a high urate level may be neuroprotective, it also may raise the risks for kidney stones, gout, and cardiovascular disease.

As an antioxidant, urate shields other molecules from oxidation, a chemical process in which oxygen damages lipids, proteins, and other molecules that are important for cellular survival and reproduction. “Urate captures the oxygen and prevents the damage to other molecules; it’s a sort of scavenger of oxygen,” said Dr. Ascherio. However, he added that researchers do not yet fully understood the exact protective mechanism involving urate.

Dr. Ascherio and some of his colleagues have received a $5.6 million grant from the Michael J. Fox Foundation to carry out a phase 2 clinical trial to test the safety and tolerability of inosine, the precursor of urate. Their main goal is to see if inosine, which is available in supplement form, can safely raise serum urate levels. The trial will include 90 patients with early-stage PD and will continue for up to 2 years. “We are very excited,” said Dr. Ascherio.

This study was supported by the National Institutes of Health and the Beeson Scholars Program of the American Federation for Aging Research. The PRECEPT study was supported by Cephalon, Inc, and H. Lundbeck A/S. The analyses of the fully accessible PRECEPT database were carried out independently by the Parkinson Study Group Biostatistics Center in Rochester, New York. Three of the study authors have obtained funding. The other study authors have disclosed no relevant financial relationships.

• Clinical Context

Urate is the main product of purine metabolism and has antioxidant efficacy as a defense against oxidative damage. Because oxidative stress may contribute to the loss of dopaminergic neurons in the substantia nigra in patients with PD, the authors postulated that blood urate levels may be a determinant of progression of PD. Clinical features have been identified previously as predictors of progression in PD, but they rely on complex behavioral observations.

This is a longitudinal, prospective study of patients with early-stage PD who were enrolled in a randomized trial of a neuroprotectant vs placebo to slow the progression of PD. The intervention was determined to be futile in the interim analysis and was terminated early. This study was conducted in parallel with a randomized trial to examine the association between serum urate level and progression of PD in the same cohort.

• Study Highlights

  1. Included were 806 patients from 65 sites in the United States and Canada in the PRECEPT study who had early-stage PD (at least 2 cardinal signs), were at least 30 years old at the time of diagnosis, and did not require dopaminergic drugs.

  2. Excluded were those with atypical PD, a diagnosis of PD for 5 or more years, a tremor score of 3 or more, a Mini-Mental Status Examination score of 26 or less, a Beck Depression Inventory score of 15 or more, and use of symptomatic medication in the past 6 months.

  3. Patients were randomized to receive either placebo or the neuroprotector agent at different doses of 10, 25, or 50 mg twice daily.

  4. Serum urate level was measured at screening and at baseline (4 weeks apart), and participants were seen at month 1 and then every 3 months for a mean of 21.4 months.

  5. The primary endpoint was time to disability requiring dopaminergic therapy as determined by investigators blinded to the intervention.

  6. Secondary endpoints were changes in the Unified PD Rating Scale (UPDRS) and single-photon emission computed tomography (SPECT) imaging for striatal dopaminergic transporter indicative of dopamine depletion.

  7. SPECT was performed at baseline and at the end of the study for 399 participants, with a mean interval of 22 months between the 2 scans.

  8. The HR for reaching the endpoint by quintile of baseline urate concentration was calculated.

  9. Serum urate levels were available at baseline for 804 participants (517 men and 287 women).

  10. Serum urate levels correlated positively with male sex, BMI, use of thiazide diuretics, and history of gout and hypertension.

  11. 61% of participants reached the endpoint of requiring dopaminergic therapy.

  12. The HR for reaching the endpoint declined with increasing concentrations of baseline urate.

  13. There was a dose-dependent relationship with a 35% reduction in the rate of progression in the fourth quintile and 49% in the highest vs the lowest quintile.

  14. Those in the top quintile of urate level reached the endpoint at half the rate of those in the bottom quintile (HR, 0.51; P < .001).

  15. The association was markedly stronger in men vs women.

  16. The rate of change in the UPDRS score (points per year) in men and women combined was 16.9 for the lowest quintile of baseline urate level and 14.3 in the highest quintile of urate level.

  17. Among men, there was a modest but significant inverse association between baseline urate level and rate of change in the UPDRS score (P = .02).

  18. No significant association was found in women.

  19. The percentage change in striatal dopaminergic transporter declined with increasing urate concentration (P for trend = .002) for the 399 participants who had SPECT measurement at baseline and at 22 months.

  20. The authors suggested that serum urate level could be targeted as an endpoint for disease-modifying therapy in patients with PD.

• Pearls for Practice

  1. Serum urate level is inversely associated with risk for progression of PD to requiring dopaminergic medication, with a dose-dependent association, in patients with early-stage PD.

  2. The association between urate level and progression of PD as measured by the UPDRS is significant for men but not for women.

References

1. Arch Neurol. Published online April 14, 2008.

The author: Professor Yasser Metwally

http://yassermetwally.com

INTRODUCTION

April 26, 2008 — German researchers have created a membrane-anchored molecule that is highly effective in inhibiting beta-secretase, an enzyme that is critical for beta-amyloid formation in Alzheimer’s disease.

In designing molecules to block beta-secretase, scientists have typically focused on active-site binding and little attempt has been made to target the endosomes where the enzyme is active. As a result, many of these inhibitors are effective in inhibiting beta-secretase in the purified state, but have little impact in cellular assays.

In the present study, reported in the April 25th issue of Science, Dr. Kai Simons, from the Max Planck Institute of Molecule Cell Biology and Genetics in Dresden, and colleagues tested the efficacy of an otherwise soluble inhibitor that was anchored to a membrane instead and designed for uptake into endosomes via endocytosis.

The membrane-tethered version of this inhibitor was much more effective than the free version in reducing beta-secretase in cultured cells and in vivo, the report indicates.

“In addition to effectively targeting beta-secretase, this strategy could also be used in designing potent drugs against other membrane protein targets,” the authors conclude.

References

1. Science 2008;320:520-523.