The rat suprachiasmatic nucleus: the master clock ticks at 30?Hz

AbstractThe suprachiasmatic nucleus (SCN) of the hypothalamus has an essential role in orchestrating circadian rhythms of behaviour and physiology. In the present study, we recorded from single SCN neurons in urethane‐anaesthetized rats, categorized them by the statistical features of their electrical activity and by their responses to light, and examined how activity in the light phase differs from activity in the dark phase. We classified cells as light‐on cells or light‐off cells according to how their firing rate changed in acute response to light, or as non‐responsive cells. In both sets of light‐responsive neurons, responses to light were stronger at subjective night than in subjective day. Neuronal firing patterns were analysed by constructing hazard functions from interspike interval data. For most light‐responsive cells, the hazard functions showed a multimodal distribution, with a harmonic sequence of modes, indicating that spike activity was driven by an oscillatory input with a fundamental frequency of close to 30 Hz; this harmonic pattern was rarely seen in non‐responsive SCN cells. The frequency of the rhythm was the same in light‐on cells as in light‐off cells, was the same in subjective day as at subjective night, and was unaffected by exposure to light. Paired recordings indicated that the discharge of adjacent light‐responsive neurons was very tightly synchronized, consistent with electrical coupling.     

Parental smoking impairs vaccine responses in children with atopic genotypes

BACKGROUND: Gene-environment interactions play central roles in controlling postnatal maturation of immune function, but their effects on infant vaccine responses are unknown. Genetic variants associated with atopy and the environmental factor of exposure to parental smoking (PS) of tobacco independently alter immune responses. OBJECTIVE: We sought to investigate the hypothesis that genetic variants associated with atopy and their interaction with PS influence infant vaccine responsiveness. METHODS: In 200 infants with parental atopic history, relationships were sought between polymorphisms in the IL-4, IL-4 receptor alpha (IL-4Ralpha), and IL-13 genes; PS; and immune responses to diphtheria/tetanus vaccination. RESULTS: Analyses stratified by PS unmasked negative associations between atopic alleles of these genes and vaccine outcomes. The most consistent involved the IL-4Ralpha 551 QR/QQ genotypes, which were associated with reduced IgG levels (P = .02) and T-cell responses (IFN-gamma, P = .002; IL-10, P = .01; 1L-13, P = .01; IL-5, P = .06) to tetanus toxoid and parallel reductions in polyclonal T-cell responses and innate immune responses in PS-exposed infants. CONCLUSION: PS potentiates suppressive effects of variants in immune response genes in children. These effects are not observed in the absence of this exposure. Ultimately, this finding might have implications for infant vaccination in countries with high smoking rates. It might also have broader implications in relation to environmental toxicology because it demonstrates specific mechanisms through which the developing immune system might be differentially sensitive to low-level toxicant exposures. CLINICAL IMPLICATIONS: PS interacts with genes associated with atopy to impair vaccine responses. These interactions might have vaccine design and public health implications.     

A new risk prediction model for critical care: the Intensive Care National Audit & Research Centre (ICNARC) model

OBJECTIVE: To develop a new model to improve risk prediction for admissions to adult critical care units in the UK. DESIGN: Prospective cohort study. SETTING: The setting was 163 adult, general critical care units in England, Wales, and Northern Ireland, December 1995 to August 2003. PATIENTS: Patients were 216,626 critical care admissions. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The performance of different approaches to modeling physiologic measurements was evaluated, and the best methods were selected to produce a new physiology score. This physiology score was combined with other information relating to the critical care admission-age, diagnostic category, source of admission, and cardiopulmonary resuscitation before admission-to develop a risk prediction model. Modeling interactions between diagnostic category and physiology score enabled the inclusion of groups of admissions that are frequently excluded from risk prediction models. The new model showed good discrimination (mean c index 0.870) and fit (mean Shapiro's R 0.665, mean Brier's score 0.132) in 200 repeated validation samples and performed well when compared with recalibrated versions of existing published risk prediction models in the cohort of patients eligible for all models. The hypothesis of perfect fit was rejected for all models, including the Intensive Care National Audit & Research Centre (ICNARC) model, as is to be expected in such a large cohort. CONCLUSIONS: The ICNARC model demonstrated better discrimination and overall fit than existing risk prediction models, even following recalibration of these models. We recommend it be used to replace previously published models for risk adjustment in the UK.     

Dependence of antibody gene diversification on uracil excision

Activation-induced deaminase (AID) catalyses deamination of deoxycytidine to deoxyuridine within immunoglobulin loci, triggering pathways of antibody diversification that are largely dependent on uracil-DNA glycosylase (uracil-N-glycolase [UNG]). Surprisingly efficient class switch recombination is restored to ung(-/-) B cells through retroviral delivery of active-site mutants of UNG, stimulating discussion about the need for UNG's uracil-excision activity. In this study, however, we find that even with the overexpression achieved through retroviral delivery, switching is only mediated by UNG mutants that retain detectable excision activity, with this switching being especially dependent on MSH2. In contrast to their potentiation of switching, low-activity UNGs are relatively ineffective in restoring transversion mutations at C:G pairs during hypermutation, or in restoring gene conversion in stably transfected DT40 cells. The results indicate that UNG does, indeed, act through uracil excision, but suggest that, in the presence of MSH2, efficient switch recombination requires base excision at only a small proportion of the AID-generated uracils in the S region. Interestingly, enforced expression of thymine-DNA glycosylase (which can excise U from U:G mispairs) does not (unlike enforced UNG or SMUG1 expression) potentiate efficient switching, which is consistent with a need either for specific recruitment of the uracil-excision enzyme or for it to be active on single-stranded DNA.     

Cavernous sinus haemangioma: systematic review and pooled analysis relating to a rare skull base pathology

Neurosurgical Review - Cavernous sinus haemangiomas (CSHs) are rare malformations of the microcirculation arising from the cavernous sinus. A systematic review and pooled data analysis of the...     

Carbetocin at elective Cesarean delivery: a sequential allocation trial to determine the minimum effective dose

Purpose

The purpose of this study was to determine the intravenous dose of carbetocin required to produce effective uterine contraction in 90% of females (ED₉₀) undergoing elective Cesarean delivery (CD) under spinal anesthesia.

Methods

We conducted a double-blind dose-finding study of carbetocin. Forty females undergoing elective CD received carbetocin intravenously upon delivery of the fetus. The dose of carbetocin for each patient was determined according to a biased-coin up-and-down sequential allocation scheme designed to cluster doses close to ED₉₀. The initial dose was 10 μg, with increments/decrements of 5 μg. The anesthesiologist, obstetrician, and patient were blinded to the dose. The obstetrician assessed the uterine tone at one-minute intervals for five minutes after carbetocin administration. In case of unsatisfactory tone, additional uterotonics were administered. The primary outcome was requirement for additional intraoperative uterotonics. Secondary outcomes were postoperative requirement for additional uterotonics within 24 hr of delivery, estimated blood loss and side effects.

Results

The ED₉₀ of carbetocin was 14.8 μg (95% confidence interval 13.7 to 15.8). Thirty-seven patients (92.5%) had adequate uterine tone with no requirement of additional intraoperative uterotonics. Two patients (5%) required postoperative uterotonics within 24 hr. The overall mean (SD) estimated blood loss was 786 (403) mL and the overall incidence of hypotension (decrease in systolic blood pressure ≥ 20% baseline) was 37.5%.

Conclusion

Based on our study, the ED₉₀ of carbetocin at elective CD is less than one-fifth the currently recommended dose of 100 μg. This study was registered at clinicaltrials.gov (NCT-01651130).