Periodic Estrogen Receptor-Beta Activation: A Novel Approach to Prevent Ischemic Brain Damage.

In women, the risk for cerebral ischemia climbs rapidly after menopause. At menopause, production of ovarian hormones; i.e., progesterone and estrogen, slowly diminishes. Estrogen has been suggested to confer natural protection to premenopausal women from ischemic stroke and some of its debilitating consequences. This notion is also strongly supported by laboratory studies showing that a continuous chronic 17ß-estradiol (E2; a potent estrogen) regimen protects brain from ischemic injury. However, concerns regarding the safety of the continuous intake of E2 were raised by the failed translation to the clinic. Recent studies demonstrated that repetitive periodic E2 pretreatments, in contrast to continuous E2 treatment, provided neuroprotection against cerebral ischemia in ovariectomized rats. Periodic E2 pretreatment protects hippocampal neurons through activation of estrogen receptor subtype beta (ER-ß). Apart from neuroprotection, periodic activation of ER-ß in ovariectomized rats significantly improves hippocampus-dependent learning and memory. Difficulties in learning and memory loss are the major consequence of ischemic brain damage. Periodic ER-ß agonist pretreatment may provide pharmacological access to a protective state against ischemic stroke and its debilitating consequences. The use of ER-ß-selective agonists constitutes a safer target for future research than ER-α agonist or E2, inasmuch as it lacks the ability to stimulate the proliferation of breast or endometrial tissue. In this review, we highlight ER-ß signaling as a guide for future translational research to reduce cognitive decline and cerebral ischemia incidents/impact in post-menopausal women, while avoiding the side effects produced by chronic E2 treatment.

'Lead us not into temptation': adolescence and alcohol policy in Europe.

Although the World Health Organization and the European Community recognize harm to children and young people due to alcohol-whether their own or someone else's drinking-effective policies to reduce harm are not widely followed. The alcohol beverage industry's drive to use social networking systems blurs the line between user-generated and industry marketing materials, such that young people are more frequently and at a younger age, potentially exposed to the promotion of alcoholic drinks. This contravenes recommendations arising out of the emerging scientific literature that delaying the onset of drinking and reducing the prevalence of heavy session drinking are likely to promote a healthier next generation.

Hypertension, brain damage and cognitive decline.

Loss of cognitive function is one the most devastating manifestations of ageing and vascular disease. Cognitive decline is rapidly becoming an important cause of disability worldwide and contributes significantly to increased mortality. There is growing evidence that hypertension is the most important modifiable vascular risk factor for development and progression of both cognitive decline and dementia. High blood pressure contributes to cerebral small and large vessel disease resulting in brain damage and dementia. A decline in cerebrovascular reserve capacity and emerging degenerative vascular wall changes underlie complete and incomplete brain infarcts, haemorrhages and white matter hyperintensities. This review discusses the complexity of factors linking hypertension to brain functional and structural changes, and to cognitive decline and dementia. The evidence for possible clinical markers useful for prevention of decreased cognitive ability, as well as recent data on vascular mechanism in the pathogenesis of cognitive decline, and the role of antihypertensive therapies in long-term prevention of late-life cognitive decline will be reviewed.

Questioning the 'neuroprotective' hypothesis: does drug treatment prevent brain damage in early psychosis or schizophrenia?

The idea that psychotic disorders are characterised by progressive neurodegeneration that can be reversed by drug treatment is used to justify early treatment of increasing numbers of mostly young people. I argue that there is little evidence to support the view that old- or new-generation antipsychotics are 'neuroprotective', and some evidence that the drugs themselves may be responsible for the decline in brain matter observed in some studies.

Extracranial-intracranial bypass to reduce the risk of ischemic stroke in intracranial aneurysms of the anterior cerebral circulation: a systematic review.

BACKGROUND AND PURPOSE: If clip application or coil placement for treatment of intracranial (IC) aneurysms is not feasible, the parent vessel can be occluded to induce thrombosis of the aneurysm. In the case that such an occlusion cannot be tolerated without subsequent sequel, the additional construction of an extracranial (EC)-IC bypass is needed for sufficient ipsilateral revascularization. Hitherto, the effectiveness of this combined treatment option was not investigated in a controlled randomized trial or in a review. The aim of the current report was to analyze clinical effectiveness of EC-IC bypass for cerebral revascularization in patients with Hunterian ligation in case of otherwise untreatable aneurysm of the anterior cerebral circulation. Special reference was given to different hemodynamic subgroups. METHODS: A computerized database search was conducted from November 1985 to November 2002 using MEDLINE, relevant Internet sources, and full-text journal articles using appropriate indexed terms. Journal of Neurosurgery, Neurosurgery, Acta Neurochirurgica, and Stroke were manually searched for the period November 1985 to November 2002 and checked reference lists of all relevant articles for additional eligible studies. Language restriction was done for English, French, and German. Reports dealing with EC-IC bypass surgery for cerebral revascularization in case of aneurysm of the anterior cerebral circulation were reviewed when appropriate. Studies were included that contained evaluable data on clinical state, preoperative and postoperative hemodynamic state, surgical outcome, and follow-up. A statistical analysis was performed for different outcome parameters and clinical effectiveness in the included studies. RESULTS: Overall, 20 studies were included, each with a study quality of 0-1. The postoperative outcome related to death or stroke depended mainly on preoperative hemodynamic subgroups (cerebral blood flow [CBF]/cerebral blood volume [CBV]; oxygen extraction fraction [OEF]). The final functional status was worse the more CBF/CBV ratio and OEF increased. Perioperative risk for death (0.8%) or stroke (1.5%) during the first month after operation was similar to the death or stroke rate during the following 2 to 12 months after operation. Neurologic function was improved over the preoperative state in 74% of the patients and was unchanged in 9%. The modified Rankin scale score was postoperatively 0 to 1 in 81% and 2 in 6% of the patients. Long-term patency was excellent, with 2.3% failure rate per year after the first year after surgery. There was no de novo aneurysm formation in the follow-up. CONCLUSION: Neurologic function and subsequent stroke attributable to hemodynamic insufficiency in patients with otherwise untreatable IC aneurysm improves significantly by EC-IC bypass surgery if the brain area corresponding to the impaired neurologic function remains viable. The hemodynamic parameters observed for patients who experience improved neurologic function or diminished stroke risk profile after EC-IC bypass surgery contain both significantly elevated OEF and CBF/CBV. Therefore, hemodynamic state represents an important indicator for EC-IC bypass surgery. The large amount of data leads to narrow stroke with no significant heterogeneity, and the overall results are, therefore, likely to be statistically robust.

[Is it possible to protect the preterm infant brain and to decrease later neurodevelopmental disabilities?]. / Est-il possible de protéger le cerveau de l'enfant né prématuré et de diminuer le taux de séquelles neuro-développementales ?

With improving neonatal survival for very premature babies, the challenge for neonatalogists is to ameliorate outcome of surviving babies. Several pharmacological molecules have been shown to have protective effects in different types of in vitro or in vivo animal models of acquired cerebral brain damages. However translational research and conduction of therapeutic trials in human remain difficult due to failure to recognize start of deleterious cascade leading to cerebral damage and additional toxic effect of potential protective molecules. This review concentrates on best evidence emerging in recent years on prevention on brain damage by early drug administration. It has been shown in two randomised trials that prenatal low-dose of magnesium sulphate does not increase paediatric mortality in very-preterm infants and has non significant neuroprotective effects on occurrence of motor dysfunction (with a 0.62 odds ratio in the French trial Premag and 0.71 relative risk in the Australian trial ACTOMgSO4), justifying that magnesium sulphate should be discussed as a stand-alone treatment or as part of a combination treatment, at least in the context of clinical trials. Antenatal corticosteroid therapy increases the survival of very-preterm infants, including the most immature. Moreover in an observational recent study of the Epipage cohort, it has been observed a significant decrease in white matter injury in the 28-32 weeks' gestation group but no effect on long term outcome and behaviour. Conversely in the most immature of the 24-27 weeks' gestation group, no effect has been detected either in white matter injury incidence or in long term outcome rates. Caffeine has a protective effect since a decrease in cerebral palsy has been noted in the caffeine group in a randomised trial studying caffeine versus placebo. For what concern other widely used potential protective molecules during the perinatal period, there is no evidence of cerebral protection with indometacine, nitric oxide, eythropoietin, phenobarbital, and etamsylate. Due to their specific properties, a careful evaluation of aspirin, anaesthetic drugs and tocolytics should be done in the next months.

Uric acid reduces brain damage and improves the benefits of rt-PA in a rat model of thromboembolic stroke.

Uric acid is a natural antioxidant that protects the brain in a model of transient focal ischemia in rats. Here we sought to investigate whether uric acid was protective in a model of thromboembolic brain ischemia in rats, and whether the global benefit of recombinant tissue plasminogen activator (rt-PA) was improved by the combined treatment. Adult male Sprague-Dawley rats underwent either ischemia by thromboembolic middle cerebral artery occlusion (MCAO) or sham operation. Uric acid (16 mg/kg) was injected intravenously (i.v.). 20 mins after MCAO, whereas rt-PA (10 mg/kg) was administered i.v. at 3 h. A group of rats received the combined treatment. Rats underwent two neurologic examinations (30 mins and 24 h after MCAO). At 24 h, infarct volume was measured and brain neutrophil infiltration and protein tyrosine nitration were assessed. Treatment with either uric acid or rt-PA reduced infarct volume versus controls (P<0.05). The protective effect against brain ischemia was greater after cotreatment of uric acid with rt-PA (P<0.001), which added further benefit to rt-PA alone (P<0.05). The neurologic score worsened during the first 24 h in treatment controls, whereas it improved in rats receiving uric acid and/or rt-PA. Uric acid strongly reduced ischemia-induced tyrosine nitration, but it was more effective alone than combined with rt-PA, suggesting that reperfusion enhances nitrotyrosine formation. All treatments reduced postischemic brain neutrophil infiltration. These results show that uric acid administered early after thromboembolic stroke is neuroprotective in the rat brain, as it reduces infarct volume, ameliorates the neurologic function, attenuates the inflammatory response, and extends the benefits of rt-PA.

The ischemic stroke patient who worsens: new assessment and management approaches.

The stroke patient who deteriorates presents a common and rewarding diagnostic challenge. Up to one third of ischemic stroke patients worsen after admission, though the frequency of deterioration is declining with modern supportive care. The causes of clinical worsening are diverse; common etiologies include collateral failure, brain edema, seizures, reocclusion after successful initial therapeutic recanalization, and systemic medical complications. Clot propagation and recurrent embolization are only infrequent mechanisms of worsening. The advent of multimodal computed tomography and magnetic resonance imaging has transformed the evaluation of the deteriorating stroke patient. History, physical examination, screening blood work, and emergent reassessment of the cervical and cerebral vasculatures, regional hypoperfusion, and infarct core will yield a firm diagnosis of the cause of clinical worsening in the majority of patients. The therapeutic armamentarium for the worsening stroke patient has expanded greatly. Treatment options now include rescue late endovascular recanalization therapy, pressor collateral enhancement therapy, hemicraniectomy, and additional novel interventions in addition to enhanced supportive care. Because most causes of worsening can be treated effectively, the deteriorating stroke patient merits a swift and incisive diagnostic and therapeutic response.

The neurotoxicity of alcohol.

Patterns of drinking are changing throughout the world and in many countries this will be detrimental to the health and welfare of the local population. Even uncomplicated alcoholics who have no specific neurological or hepatic problems show signs of regional brain damage and cognitive dysfunction. Many of these changes are exaggerated and other brain regions damaged in patients who have additional vitamin B1 (thiamine) deficiency (Wernicke-Korsakoff syndrome). Quantitative neuropathology techniques and improvements in neuroimaging have contributed significantly to the documentation of these changes but mechanisms underlying the damage are not understood. A human brain bank targeting alcohol cases has been established in Sydney, Australia and provides fresh and frozen tissue for alcohol researchers. The tissues can be used to test hypotheses developed from structural neuropathological studies or from animal models and in vitro studies. Identification of reversible pathological changes and preventative medical approaches in alcoholism should enhance rehabilitation and treatment efforts, thereby mitigating debilitating morbidities and reducing mortality associated with this universal public health problem.

Management of adult infectious encephalitis in metropolitan France.

Infectious encephalitis is a severe disease leading to a high mortality and morbidity. The most frequent causes include Herpes simplex virus, Varicella Zoster virus, Listeria monocytogenes, and Mycobacterium tuberculosis. Urgent treatment is required (anti-infective therapy and nonspecific supportive care). The aim of this study was to define treatment strategy, empirical and after microbiological documentation at 48hours, through a systematic literature review.

[Update on congenital and neonatal herpes infections: infection due to cytomegalovirus and herpes simplex]. / Actualizacion en infecciones herpeticas congenitas y neonatales: infeccion por citomegalovirus y herpes simple.

Newborn infants are a population which is especially susceptible to viral infections that frequently affect the central nervous system. Herpes infections can be transmitted to the foetus and to the newborn infant, and give rise to severe clinical conditions with long-term sensory and cognitive deficits. Two thirds of newborn infants with encephalitis due to herpes simplex virus and half of the children with symptomatic congenital infection by cytomegalovirus develop sequelae, which results in high community health costs in the long term. Fortunately, the better knowledge about these infections gained in recent years together with the development of effective antiviral treatments have improved the patients' prognosis. Valganciclovir (32 mg/kg/day in two doses for six months) prevents the development of hypoacusis and improves the neurological prognosis in symptomatic congenital infection due to cytomegalovirus. Acyclovir (60 mg/kg/day in three doses for 2-3 weeks) prevents the development of severe forms in skin-eyes-mouth herpes disease, and lowers the rate of mortality and sequelae when the disease has disseminated and is located in the central nervous system.

TITLE: Actualizacion en infecciones herpeticas congenitas y neonatales: infeccion por citomegalovirus y herpes simple.Los neonatos son una poblacion especialmente susceptible a las infecciones viricas que frecuentemente afectan al sistema nervioso central. Las infecciones herpeticas pueden transmitirse al feto y al recien nacido, y ocasionar cuadros clinicos graves con deficits sensoriales y cognitivos a largo plazo. Dos terceras partes de los neonatos con encefalitis por virus herpes simple y la mitad de los niños con infeccion congenita sintomatica por citomegalovirus desarrollan secuelas, lo cual supone un alto coste sociosanitario a largo plazo. Afortunadamente, el mejor conocimiento de estas infecciones en los ultimos años y el desarrollo de tratamientos antivirales efectivos han mejorado el pronostico de los pacientes. El valganciclovir (32 mg/kg/dia en dos dosis durante seis meses) previene el desarrollo de hipoacusia y mejora el pronostico neurologico en la infeccion congenita sintomatica por citomegalovirus. El aciclovir (60 mg/kg/dia en tres dosis durante 2-3 semanas) previene el desarrollo de formas graves en la enfermedad herpetica cutanea-ocular-oral, y disminuye la mortalidad y las secuelas en la enfermedad diseminada y localizada en el sistema nervioso central.

Thiamine (vitamin B1) deficiency and associated brain damage is still common throughout the world and prevention is simple and safe!

Many different population groups throughout the world have thiamine deficiency and are at risk of developing severe neurological and cardiac disorders. Alcoholics are most at risk but other important clinical groups should be monitored carefully. The most severe, potentially fatal disease caused by thiamine deficiency is the neurological disorder Wernicke-Korsakoff syndrome. This can be difficult to diagnose and many cases remain undiagnosed. Treatment with thiamine generally results in a dramatic clinical improvement. Thiamine supplementation of stable food products like flour is an effective, simple and safe public health measure that can improve the thiamine status of all population groups.

"Time is Brain:" A concept anaiysis.

Time is brain has been heard echoing in the world of acute stroke since the early nineties. At that time, the use of intravenous recombinant tissue plasminogen activator (rt-PA) revolutionized the approach to treating acute ischemic stroke. However, the use of rt-PA is strongly time dependant, with a narrow window of opportunity of only 4.5 hours. There is also convincing scientific evidence of a significant relationship between time to rt-PA treatment and patient outcomes. Similar to rt-PA in the '90s, time sensitive endovascular therapy has transformed the treatment of acute stroke. Hence, time is brain has been referred to as a battle cry, with these three words significantly influencing the multidisciplinary stroke teams who provide care to stroke victims. Despite agreement in the scientific literature that time is brain represents the essence of hyperacute stroke care, this concept has not been studied through the methodological approach of a concept analysisframework. Therefore, the purpose of this concept analysis was to explore the concept of time is brain within the context of acute stroke. Walker and Avants (2011) approach to concept analyses was used to gain insight into the provision of optimal acute stroke care in clinical nursing practice.