Inhalational anesthetics inhibit spreading depression: relevance to migraine

Cortical spreading depression (SD) has not been shown in the human neocortex by direct cortical recordings. However, animal studies suggest that cortical injury, such as that occurring during neurosurgical procedures, should result in the initiation of SD. It is possible that inhibition of SD by volatile anesthetic agents may partially explain the failure to observe SD in the human neocortex during surgery. This study examines the effect of the anesthetic agents α-chloralose, halothane, nitrous oxide and isoflurane on the initiation of cortical SD in the cat neocortex. SD was seen in 100% of cats anesthetized with α-chloralose ( n = 15), in 3 of 7 (42%) animals anesthetized with isoflurane ( p < 0.05, χ² with Yates correction) and none of the animals ( n = 4, 6 hemispheric preparations) anesthetized with halothane ( p < 0.005, χ² with Yates correction, halothane vs α-chloralose group). In all cases this inhibitory effect was reversible. In four animals the administration of nitrous oxide (66%) reduced the inspired concentration of isoflurane required to inhibit SD by 0.75%. This study suggests that halothane, and to a lesser extent isoflurane and nitrous oxide, protect against the initiation of cortical SD. This observation may partially explain why SD has not been demonstrated in human neocortex during surgery. Further studies are needed to determine if SD may occur under pathological conditions, such as during migraine with aura, where the cortex may be predisposed to SD.     

Pathogenesis of viral hemorrhagic fever

Single-stranded RNA viruses from four different families cause a syndrome of fever and malaise, 'capillary leak' with loss of plasma volume, and coagulation defects which can lead to bleeding. Although direct cytopathic effects can contribute to disease severity, most features of illness are caused by innate immune responses, as the systemic spread of virus to macrophages and dendritic cells leads to the release of mediators that modify vascular function and have procoagulant activity. The synthesis of tissue factor by infected cells can also trigger coagulation. Failure of adaptive immunity through impaired dendritic cell function and lymphocyte apoptosis can have a crucial role in fatal infection.     

Is fecundability associated with month of birth? An analysis of 19th and early 20th century family reconstitution data from The Netherlands

The relationship between fecundability and month of birth was investigated in a cohort of 1526 women who married between 1802 and 1929, using only women whose first marriage occurred before the age of 35 years. On the basis of their time to pregnancy (TTP, calculated as time between wedding and first birth minus gestational length), women were categorized into two groups: fecunds (TTP up to 12 months or prenuptial conceptions, n = 1348) and subfecunds (TTP >18 months, n = 118). By use of logistic regression, cosinor functions with a period of 1 year or 6 months and variable shift and amplitude were fitted through the monthly odds of subfecunds versus fecunds. The best fitting curve was unimodal, with a zenith in September (P = 0.13 for H0: no differences). Exclusion of childless women (n = 36, minimum follow-up 5 years) from the subfecunds led to a similar curve (P < 0.01), while childless women, as compared with fecunds, showed a birth distribution that was best represented with a bimodal curve with zeniths in January and July (P = 0.06). This study provides evidence for the existence of differences in fecundability by month of birth. The cause of this relationship is unclear, but may lie in a melatonin-dependent circannual variability of the quality of the oocyte.      

Blood withdrawal and infusion via umbilical catheters: effect on cerebral perfusion and influence of ibuprofen

Withdrawal and infusion of blood via umbilical catheters can affect cerebral blood flow in preterm infants. We compared the effects on cerebral perfusion of 3 ml/kg blood withdrawal and infusion via umbilical arterial (UAC) and venous (UVC) catheters in 16 infants < or =32 weeks gestation, age <24 h, on mechanical ventilation. Near infrared spectroscopy was used to monitor changes in cerebral oxy- and deoxyhemoglobin, total cerebral hemoglobin (an index of cerebral blood volume; CBV) and HbD (an index of cerebral intravascular oxygenation). In 10 infants the study was repeated 1 h after intravenous administration of 10 mg/kg ibuprofen as prophylaxis against PDA. Withdrawal and infusion via the UVC caused significant MABP and concordant HbD and CBV changes. Smaller modifications were seen following blood withdrawal and infusion via the UAC. Ibuprofen attenuated cerebral hemodynamic changes associated with withdrawal, but not infusion, from UAC and UVC.     

Allelic expression of APOE in human brain: effects of epsilon status and promoter haplotypes

The epsilon4 haplotype of APOE is the only undisputed genetic risk factor for late-onset Alzheimer's disease (LOAD). It has been proposed that at least two other polymorphisms in the promoter of the APOE gene (-219G>T and -491A>T) might also contribute to disease susceptibility, and modulate the impact of structural changes in the ApoE protein, by altering its expression. In order to assess the extent of cis-acting influences on APOE expression in human brain, highly quantitative measures of allele discrimination were applied to cortical RNA from individuals heterozygous for the epsilon alleles. A small, but significant, increase in the expression of epsilon4 allele was observed relative to that of the epsilon3 and epsilon2 alleles (P<0.0001). Similar differences were observed in brain tissue from confirmed LOAD subjects, and between cortical regions BA10 (frontopolar) and BA20 (inferior temporal). Stratification of epsilon4/epsilon3 allelic expression ratios according to heterozygosity for the -219G>T promoter polymorphism revealed significantly lower relative expression of haplotypes containing the -219T allele (P=0.02). Our data indicate that, in human brain, most of the cis-acting variance in APOE expression is accounted for by the epsilon4 haplotype, but there are additional, small, cis-acting influences associated with promoter genotype.     

Chromatin modification of Notch targets in olfactory receptor neuron diversification

Neuronal-class diversification is central during neurogenesis. This requirement is exemplified in the olfactory system, which utilizes a large array of olfactory receptor neuron (ORN) classes. We discovered an epigenetic mechanism in which neuron diversity is maximized via locus-specific chromatin modifications that generate context-dependent responses from a single, generally used intracellular signal. Each ORN in Drosophila acquires one of three basic identities defined by the compound outcome of three iterated Notch signaling events during neurogenesis. Hamlet, the Drosophila Evi1 and Prdm16 proto-oncogene homolog, modifies cellular responses to these iteratively used Notch signals in a context-dependent manner, and controls odorant receptor gene choice and ORN axon targeting specificity. In nascent ORNs, Hamlet erases the Notch state inherited from the parental cell, enabling a modified response in a subsequent round of Notch signaling. Hamlet directs locus-specific modifications of histone methylation and histone density and controls accessibility of the DNA-binding protein Suppressor of Hairless at the Notch target promoter.     

Evaluation of tick-borne encephalitis DNA vaccines in monkeys.

Tick-borne encephalitis is usually caused by infection with one of two flaviviruses: Russian spring summer encephalitis virus (RSSEV) or Central European encephalitis virus (CEEV). We previously demonstrated that gene gun inoculation of mice with naked DNA vaccines expressing the prM and E genes of these viruses resulted in long-lived homologous and heterologous protective immunity (Schmaljohn et al., 1997). To further evaluate these vaccines, we inoculated rhesus macaques by gene gun with the RSSEV or CEEV vaccines or with both DNA vaccines and compared resulting antibody titers with those obtained by vaccination with a commercial, formalin-inactivated vaccine administered at the human dose. Vaccinations were given at days 0, 30, and 70. All of the vaccines elicited antibodies detected by ELISA and by plaque-reduction neutralization tests. The neutralizing antibody responses persisted for at least 15 weeks after the final vaccination. Because monkeys are not uniformly susceptible to tick-borne encephalitis, the protective properties of the vaccines were assessed by passive transfer of monkey sera to mice and subsequent challenge of the mice with RSSEV or CEEV. One hour after transfer, mice that received 50 microl of sera from monkeys vaccinated with both DNA vaccines had circulating neutralizing antibody levels <20-80. All of these mice were protected from challenge with RSSEV or CEEV. Mice that received 10 microl of sera from monkeys vaccinated with the individual DNA vaccines, both DNA vaccines, or a commercial vaccine were partially to completely protected from RSSEV or CEEV challenge. These data suggest that DNA vaccines may offer protective immunity to primates similar to that obtained with a commercial inactivated-virus vaccine.     

No evidence for allelic association between schizophrenia and a functional variant of the human dopamine β-hydroxylase gene (DBH)

Dopamine β-hydroxylase (DBH), the enzyme that converts dopamine to norepinepherine, has been proposed as being involved in the aetiology of schizophrenia. Previous work identified a functional polymorphism at nucleotide 910 of the DBH gene that results in a codon change in the mature protein Ala304Ser, with the mutant allele being associated with a lower enzymatic activity. In this study we performed an RFLP analysis in an association study consisting of 178 unrelated schizophrenic patients and 178 unrelated control subjects, matched for age, sex, and ethnicity. The frequency of the Ser304 DBH allele was 0.10 in the patient group and 0.08 in the control group, with no significant allelic or genotypic association observed. Therefore, we were unable to obtain evidence that this polymorphism contributes directly to susceptibility to schizophrenia. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:557–559, 1999. © 1999 Wiley-Liss, Inc.     

PCT、CRP动力学评估脓毒血症预后及诊断意义的研究

目的 观察血清降钙素原(PCT)、C反应蛋白(CRP)及其动力学变化,评估其在严重脓毒症/感染性休克患者的诊断及预后价值.方法 本研究采用回顾性分析方法,2014年9月1日至2016年4月30日选择184例ICU中被诊断为严重脓毒症/感染性休克疾病患者,检测入院时血清PCT、CRP水平和治疗后第2,第3和第5天的PCT、CRP水平.结果 通过△PCT、△CRP评估PCT、CRP的动力学在存活者与死亡组中有显著性统计学意(△PCT2/0,P=0.0001;△PCT3/0,P=0.0001;△PCT5/0,P=0.0001;△CRP2/0,P=0.0069;△CRP3/0,P=0.0001;△CRP5/0,P=0.0001),在严重脓毒症和感染性休克组中也存在显著差异(PCT5,P=0.007;△PCT5/0,P=0.007).受试者工作特征曲线(ROC)模型显示,△PCT3/0(AUC=0.721)、△PCT5/0(AUC=0.77)、△CRP5/0(AUC=0.766)水平判断严重脓毒症/感染性休克患者预后有较好的临床意义.△PCT5/0 (0.619)对严重脓毒症或感染性休克有一定的辅助诊断效果,其在ROC曲线上灵敏度、特异性均较高的临界点为0.624,所以,以第5天的血清△PCT5/0水平＞0.624可作为预测感染性休克的临界点.结论 血清中PCT、CRP对严重脓毒症/感染性休克早期有较好的临床诊断及预后价值,其动力学研究可以提高对严重脓毒症/感染性休克诊断及预后评估的敏感性及准确性.