Comparative genome sequence analysis of the Bpa/Str region in mouse and Man.

The progress of human and mouse genome sequencing programs presages the possibility of systematic cross-species comparison of the two genomes as a powerful tool for gene and regulatory element identification. As the opportunities to perform comparative sequence analysis emerge, it is important to develop parameters for such analyses and to examine the outcomes of cross-species comparison. Our analysis used gene prediction and a database search of 430 kb of genomic sequence covering the Bpa/Str region of the mouse X chromosome, and 745 kb of genomic sequence from the homologous human X chromosome region. We identified 11 genes in mouse and 13 genes and two pseudogenes in human. In addition, we compared the mouse and human sequences using pairwise alignment and searches for evolutionary conserved regions (ECRs) exceeding a defined threshold of sequence identity. This approach aided the identification of at least four further putative conserved genes in the region. Comparative sequencing revealed that this region is a mosaic in evolutionary terms, with considerably more rearrangement between the two species than realized previously from comparative mapping studies. Surprisingly, this region showed an extremely high LINE and low SINE content, low G+C content, and yet a relatively high gene density, in contrast to the low gene density usually associated with such regions.

Early identification of patients at risk for symptomatic vasospasm after aneurysmal subarachnoid hemorrhage.

OBJECTIVE: To develop a scheme for early identification of individuals at risk for symptomatic vasospasm after subarachnoid hemorrhage (SAH). DESIGN: Analysis of prospectively collected data from the placebo-treated group in a multicenter clinical trial. SETTINGS: Fifty-four neurosurgical centers in North America. MEASUREMENTS AND MAIN RESULTS: We identified independent predictors of symptomatic vasospasm using stepwise logistic regression analysis from demographic, clinical, laboratory, and neuroimaging characteristics of the participants. We developed a scoring system (symptomatic vasospasm risk index) based on a combination of these predictors. Out of 283 patients in the analysis (all treated with oral nimodipine), 93 (33%) developed symptomatic vasospasm within 14 days after SAH. There were four independent predictors of symptomatic vasospasm: thickness of subarachnoid clot on computed tomographic scan (odds ratio [OR], 4.1; 95% confidence interval [CI], 1.8-10.0); early rise in middle cerebral artery mean flow velocity (MCA-MFV), defined as a value > or =110 cm/sec recorded on or before post-SAH day 5 (OR, 1.9; 95% CI, 1.1-3.3), Glasgow Coma Scale score <14 (OR, 1.8; 95% CI, 1.1-3.1); and rupture of anterior cerebral or internal carotid artery aneurysm (OR, 1.9; 95% CI, 1.0-3.4). The probability of identifying patients who would develop symptomatic vasospasm (percentage of area under receiver operating characteristics curve +/- SEM) was higher with symptomatic vasospasm risk index (68%+/-8%) compared with thickness of clot (62%+/-8%; p = .08) or MCA-MFV (45%+/-7%, p < .05) criteria alone. CONCLUSIONS: Patients at high risk for symptomatic vasospasm can be identified early in the course of SAH using a risk index. A risk index based on a combination of variables may represent a predictive paradigm superior to conventionally used criteria based on clot thickness or MCA-MFV criteria.

Factors associated with aneurysm size in patients with subarachnoid hemorrhage: effect of smoking and aneurysm location.

OBJECTIVE: Intracranial aneurysm size is an important determinant of risk of rupture and outcome after rupture. Risk factors influencing aneurysm formation and growth are not well defined. In this study, we examined the association between known risk factors for cerebrovascular disease and size of intracranial aneurysms in patients with aneurysmal subarachnoid hemorrhage. METHODS: We analyzed prospectively collected data from the placebo-treated group in a multicenter clinical trial conducted at 54 neurosurgical centers in North America. The presence, location, and size of intracranial aneurysms were determined by review of the admission angiograms. Pertinent information regarding the presence of various cerebrovascular risk factors was collected for each patient. Using logistic regression analysis, we identified independent determinants of aneurysm size from demographic, clinical, and angiographic characteristics of the participants. The impact of aneurysm size on 3-month mortality was analyzed after adjusting for potential confounding factors. RESULTS: For 298 patients admitted with subarachnoid hemorrhage, the ruptured aneurysms were graded as small (<13 mm) in 235 patients (79%) and large (> or =13 mm) in 63 patients (21%). In the logistic regression model, both smoking at any time (odds ratio, 2.2; 95% confidence interval, 1.1-4.5) and middle cerebral artery origin (odds ratio, 2.5; 95% confidence interval, 1.3-4.9) were independently associated with large aneurysms. Neither hypertension, diabetes mellitus, nor alcohol and illicit drug use were associated with large-sized aneurysms. After adjusting for initial Glasgow Coma Scale score and age in the logistic regression model, the presence of large-sized aneurysms was independently associated with 3-month mortality (odds ratio, 2.3; 95% confidence interval, 1.1-4.8). CONCLUSION: Cigarette smoking and middle cerebral artery origin seem to increase the risk for developing large aneurysms in patients predisposed to intracranial aneurysm formation. Further studies are required to investigate the mechanism underlying the association between cigarette smoking and intracranial aneurysm formation.

Prognostic value and determinants of ultraearly angiographic vasospasm after aneurysmal subarachnoid hemorrhage.

OBJECTIVE: A small number of patients with aneurysmal subarachnoid hemorrhage have angiographic evidence of cerebral vasospasm within 48 hours of the onset of hemorrhage. The present study analyzes the prognostic value and determinants of this ultraearly angiographic finding. METHODS: We analyzed prospectively collected data from the placebo-treated group in a multicenter clinical trial conducted at 54 neurosurgical centers in North America. The presence and severity of ultraearly angiographic vasospasm (UEAV) was determined by a blinded review of the admission angiograms. Using logistic regression analysis, we identified independent determinants of UEAV from demographic, clinical, laboratory, and neuroimaging characteristics of the patients. The impact of UEAV on the risk of symptomatic vasospasm and 3-month outcome was analyzed after adjusting for potential confounding factors. RESULTS: Of 296 patients in the analysis, 37 (13%) had angiographic evidence of vasospasm at admission. An initial Glasgow Coma Scale score of less than 14 (odds ratio [OR], 2.5; 95% confidence interval [CI], 1.1-6.0), and serum sodium greater than 138 mmol/L (OR, 3.4; 95% CI, 1.5-8.3) were associated with UEAV. UEAV was associated with increased risk of symptomatic vasospasm (OR, 2.5; 95% CI, 1.2-5.4) and poor outcome at 3 months (OR, 2.8; 95% CI, 1.2-6.3), after adjusting for other variables. This risk of symptomatic vasospasm was not influenced by early surgery (within 48 h of hemorrhage onset). Poor outcome was more likely to occur in patients with UEAV who did not undergo early surgery (P = 0.03). CONCLUSION: Our analysis suggests that patients with angiographic evidence of vasospasm at admission are at high risk for both symptomatic vasospasm and poor outcome. We also found that early surgery did not aggravate this risk.

Pharmacokinetics of tirilazad and U-89678, an active, reduced metabolite, following acute head trauma in adults.

The pharmacokinetics of tirilazad and U-89678 (an active metabolite) were evaluated in 55 adults (48 males, 7 females) with moderate or severe head injury who received 10.0 mg/kg/day tirilazad mesylate for 5 days. Trough plasma samples were obtained daily; serial plasma samples were obtained over one dosing interval on day 5. Plasma tirilazad and U-89678 were quantified by HPLC. Sixty-two percent of the subjects received concomitant anticonvulsants, of which 91% received phenytoin. Plasma tirilazad and U-89678 concentrations in head-injured patients were similar to or lower than those observed in healthy volunteers. Sufficient data were available to calculate pharmacokinetic parameters for day 5 in 26 patients; 11 received no anticonvulsants. The AUC0-6 (are under the concentration-time curve at 0-6 h) for tirilazad mesylate on day 5 in patients receiving anticonvulsants (median = 4972 ng h/mL) differed significantly from that in patients not receiving anticonvulsants (median = 9704 ng h/mL) (p = 0.0051). Similarly, the AUC0-6 of U-89678 in patients receiving anticonvulsants (median = 561 ng h/mL) was significantly different from that in patients who were not (median = 2494 ng h/mL) (p = 0.0016). Comparison of pharmacokinetic data from patients not receiving anticonvulsants to historical data in healthy volunteers suggests that head injury has little effect on tirilazad pharmacokinetics within 5 days of injury. These results suggest that the major factor affecting tirilazad pharmacokinetics in head-injured patients is concomitant use of enzyme-inducing anticonvulsants.

Brief review of published alprazolam clinical studies.

The clinical efficacy of alprazolam has been evaluated in both anxiety states and depressive disorders. In anxiety neurosis, studies have been conducted vs placebo and/or other benzodiazepine tranquilizers. Reports, to date, with regard to panic/phobia disorders have been limited to open-label studies and a single report from a placebo-controlled study. In depression, both open-label and double-blind studies (vs tricyclic antidepressants) have been published.