Focus on the management of thunderclap headache: from nosography to treatment

Thunderclap headache (TCH) is an excruciating headache characterized by a very sudden onset. Recognition and accurate diagnosis of TCH are important in order to rule out the various, serious underlying brain disorders that, in a high percentage of cases, are the real cause of the headache. Primary TCH, which may recur intermittently and generally has a spontaneous, benign evolution, can thus be diagnosed only when all other potential underlying causes have been excluded through accurate diagnostic work up. In this review, we focus on the management of TCH, paying particular attention to the diagnostic work up and treatment of the condition

Molecular Design, Functional Characterization and Structural Basis of a Protein Inhibitor Against the HIV-1 Pathogenicity Factor Nef

Increased spread of HIV-1 and rapid emergence of drug resistance warrants development of novel antiviral strategies. Nef, a critical viral pathogenicity factor that interacts with host cell factors but lacks enzymatic activity, is not targeted by current antiviral measures. Here we inhibit Nef function by simultaneously blocking several highly conserved protein interaction surfaces. This strategy, referred to as “wrapping Nef”, is based on structure-function analyses that led to the identification of four target sites: (i) SH3 domain interaction, (ii) interference with protein transport processes, (iii) CD4 binding and (iv) targeting to lipid membranes. Screening combinations of Nef-interacting domains, we developed a series of small Nef interacting proteins (NIs) composed of an SH3 domain optimized for binding to Nef, fused to a sequence motif of the CD4 cytoplasmic tail and combined with a prenylation signal for membrane association. NIs bind to Nef in the low nM affinity range, associate with Nef in human cells and specifically interfere with key biological activities of Nef. Structure determination of the Nef-inhibitor complex reveals the molecular basis for binding specificity. These results establish Nef-NI interfaces as promising leads for the development of potent Nef inhibitors

Brain Protection for Cerebral Aneurysm Surgery

Knowledge about the cellular physiology of cerebral ischemia is expanding rapidly, and we stand at the edge of a new age in which clinicians are able to directly intervene in these processes. Experience from the recent clinical trials using recominant tissue plasminogen activator emphasizes that urgent intervention is necessary. Furthermore, recent studies in animal models of middle cerebral artery occlusion demonstrate that between 40% and 50% of ischemic tissue can potentially be salvaged up to 2 hours after ischemia. Ongoing studies with NMDA receptor antagonists, free radical scavengers, calcium channel blockers, and other innovative therapies should identify which agents are effective in limiting the deleterious effects of the ischemic cascade and rescuing the ischemic penumbra. The neurosurgeon is in the enviable position of being able to benefit from advances in ischemic research, in part, because the neurovascular surgeon can institute protective measures prophylactically before the onset of ischemic insult. Until new and effective therapies become available, the risks of ischemia in the operating room can be reduced by careful attention to normal physiological processes, including blood pressure, oxygenation, and glucose levels as well as the judicious use of barbiturates and hypothermia

Circumstances surrounding aneurysmal subarachnoid hemorrhage

The circumstances surrounding aneurysmal subarachnoid hemorrhage were investigated in a group of 500 consecutive patients admitted to a neurosurgical center. Subarachnoid hemorrhage occurred during stressful events in 42.8% of the patients, during nonstrenuous activities in 34.4%, and during rest or sleep in 11.8%. The activities or events preceding subarachnoid hemorrhage were not known in the remaining 11.0%. Men were more likely to have suffered their hemorrhage during stressful events than women (54.1% versus 36.6%; p less than 0.00025). Only 30.1% of aneurysms arising from the internal carotid artery ruptured during stressful events compared with 48.1% of aneurysms at other locations (p less than 0.005). Physiological responses to the various activities and events are discussed as they may relate to mechanisms underlying aneurysmal subarachnoid hemorrhage. Two important factors in the precipitation of aneurysmal rupture are increased arterial blood pressure and decreased cerebrospinal fluid pressure around the aneurysm. These factors result in a high transmural pressure and concomitant wall stress. Physical exertion, activities involving the Valsalva maneuver, and emotional strain are associated with an increase in blood pressure and frequently preceded subarachnoid hemorrhage. Fluctuations in cerebrospinal fluid pressure around the aneurysm mainly occur during Valsalva's maneuver and postural change