A druggable addiction to de novo pyrimidine biosynthesis in diffuse midline glioma

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I N M EMORY OF K EITH N EELY,P H D,MPA, EMT-P

Abstract

Objective. We compared the use of two active cooling devices with passive cooling in a moderate-temperature (≈22°C) environment on heart rate (HR) and core temperature (T_c) recovery when applied to firefighters following 20 minutes of fire suppression. Methods. Firefighters (23 men, two women) performed 20 minutes of fire suppression at a live-fire evolution. Immediately following the evolution, the subjects removed their thermal protective clothing and were randomized to receive forearm immersion (FI), ice water perfused cooling vest (CV), or passive (P) cooling in an air-conditioned medical trailer for 30 minutes. Heart rate and deep gastric temperature were monitored every 5 minutes during recovery. Results. A single 20-minute bout of fire suppression resulted in near-maximal mean ± standard deviation HR (175 ± 13 b·min^?1, P; 172 ± 20 b·min^?1, FI; 177 ± 12 b·min^?1, CV) when compared with baseline (p < 0.001), a rapid and substantial rise in T_c (38.2° ± 0.7°, P; 38.3° ± 0.4°, FI; 38.3° ± 0.3°, CV) compared with baseline (p < 0.001), and body mass lost from sweating of nearly 1 kilogram. Cooling rates (°C·min) differed (p = 0.036) by device, with FI (0.05 ± 0.04) providing higher rates than P (0.03 ± 0.02) or CV (0.03 ± 0.04), although differences over 30 minutes were small and recovery of body temperature was incomplete in all groups. Conclusions. During 30 minutes of recovery following a 20-minute bout of fire suppression in a training academy setting, there is a slightly higher cooling rate for FI and no apparent benefit to CV when compared with P cooling in a moderate temperature environment.     

Postnatal maternal deprivation and pubertal stress have additive effects on dopamine D2 receptor and CaMKII beta expression in the striatum

The goal of this study was to determine whether two stressors commonly used to model aspects of neuropsychiatric disease in rats have an additive effect on striatal dopamine type 2 receptor (D2R) expression, a key player in the etiology of neuropsychiatric disease.     

Oxidative stress and DNA damage responses in rat and mouse lung to inhaled carbon nanoparticles

Abstract

We have investigated whether short-term nose-only inhalation exposure to electric spark discharge-generated carbon nanoparticles (～60 nm) causes oxidative stress and DNA damage responses in the lungs of rats (152 μg/m³; 4 h) and mice (142 μg/m³; 4 h, or three times 4 h). In both species, no pulmonary inflammation and toxicity were detected by bronchoalveolar lavage or mRNA expression analyses. Oxidative DNA damage (measured by fpg-comet assay), was also not increased in mouse whole lung tissue or isolated lung epithelial cells from rat. In addition, the mRNA expressions of the DNA base excision repair genes OGG1, DNA Polβ and XRCC1 were not altered. However, in the lung epithelial cells isolated from the nanoparticle-exposed rats a small but significant increase in APE-1 mRNA expression was measured. Thus, short-term inhalation of carbon nanoparticles under the applied exposure regimen, does not cause oxidative stress and DNA damage in the lungs of healthy mice and rats.     

Substance Use by Women Using Domestic Violence Shelters

This study investigated the connections between stressors, substance use, and experience of violence among women (N = 125) who accessed help from domestic violence shelters in British Columbia, Canada between October 2001 and June 2003. Changes in substance use and stressors following a shelter stay were explored, using both qualitative and quantitative methods. Women generally decreased their use of alcohol and stimulants, and this change was found to be integrally connected to social and structural supports made available to them. Future research that augments current stress models of addiction by considering social and structural factors that come into play in women's substance use and domestic violence is suggested. The study's limitations are noted.     

Yohimbine Depresses Excitatory Transmission in BNST and Impairs Extinction of Cocaine Place Preference Through Orexin-Dependent,Norepinephrine-Independent Processes

The alpha2 adrenergic receptor (α₂-AR) antagonist yohimbine is a widely used tool for the study of anxiogenesis and stress-induced drug-seeking behavior. We previously demonstrated that yohimbine paradoxically depresses excitatory transmission in the bed nucleus of the stria terminalis (BNST), a region critical to the integration of stress and reward pathways, and produces an impairment of extinction of cocaine-conditioned place preference (cocaine-CPP) independent of α₂-AR signaling. Recent studies show yohimbine-induced drug-seeking behavior is attenuated by orexin receptor 1 (OX₁R) antagonists. Moreover, yohimbine-induced cocaine-seeking behavior is BNST-dependent. Here, we investigated yohimbine-orexin interactions. Our results demonstrate yohimbine-induced depression of excitatory transmission in the BNST is unaffected by alpha1-AR and corticotropin-releasing factor receptor-1 (CRFR₁) antagonists, but is (1) blocked by OxR antagonists and (2) absent in brain slices from orexin knockout mice. Although the actions of yohimbine were not mimicked by the norepinephrine transporter blocker reboxetine, they were by exogenously applied orexin A. We find that, as with yohimbine, orexin A depression of excitatory transmission in BNST is OX₁R–dependent. Finally, we find these ex vivo effects are paralleled in vivo, as yohimbine-induced impairment of cocaine-CPP extinction is blocked by a systemically administered OX₁R antagonist. These data highlight a new mechanism for orexin on excitatory anxiety circuits and demonstrate that some of the actions of yohimbine may be directly dependent upon orexin signaling and independent of norepinephrine and CRF in the BNST.     

Written Emotional Expression During Recovery From Cocaine Dependence: Group and Individual Differences in Craving Intensity

We conducted a prospective, single-blind, parallel group, controlled trial to evaluate effects of written emotional expression in patients receiving intensive treatment for cocaine dependence in a residential-unit setting. Randomization to the emotional expression treatment produced changes in blood pressure and mood during writing sessions, possibly because of its ability to stimulate active coping behavior. At an initial follow-up visit, patients that had received written emotional expression reported lower values for craving intensity and were less likely to self-report use of cocaine. These results may indicate a therapeutic effect of written emotional expression during recovery from cocaine dependence.     

La peur de l’accouchement chez des nullipares : lien avec la douleur lors de l’accouchement,les symptômes de stress post-traumatique et les symptômes dépressifs post-partum

ObjectiveFear of childbirth is common in women who are pregnant with their first child and is associated with important consequences such as abortions and miscarriages. Twenty percent of nulliparous women seem to exhibit a mild or moderate fear, while 6% present an excessive and irrational fear known as tocophobia. Tocophobia is suggested to be associated with many negative consequences such as postpartum depression (PPD) and Post-traumatic stress (PTS). However, there is little empirical evidence to support these relationships. Recently, Fairbrother and Woody (2007) did not observe a link between the fear of childbirth and symptoms of PPD and PTS in nulliparous women. Some results, near the significance level, could be explained by a lack of statistical power. The present study focused on the link between the fear of childbirth and the process of delivery, the perception of pain, PPD and PTS. More specifically, it aimed to test three hypotheses: (i) fear of childbirth will be linked to the process of delivery, especially regarding the perception of pain, the use of anaesthesia and the use of Caesarean section; (ii) a high level of fear of childbirth will be associated with more negative postpartum consequences (namely PPD/PTS symptoms); (iii) the process of delivery and pain will also be related to post-delivery symptoms. Mediation effects were tested.MethodData from a longitudinal study were used to meet the hypotheses. A total of 176 nulliparous pregnant women responded to questionnaires at two time measurements (during pregnancy and at 5 weeks postpartum).ResultsFear of childbirth is related to the perception of pain at birth among women delivering vaginally, in the absence of anaesthesia. It is also linked to symptoms of PPD and PTS, regardless of whether or not anaesthesia was used. Fear of childbirth also appears to be strongly associated to symptoms of PTS in women who have experienced an unplanned caesarean section. Thus, symptoms of postpartum PTS could play a mediating role in the link between fear of childbirth and PPD.ConclusionsThese results support the relevance of taking into account the fear of childbirth and perception of pain in connection with symptoms of PTS and PPD in nulliparous women. The unplanned caesarean section (including emergency caesarean) also appears to be important in the study of the relationship between fear and symptoms of PTS. Fear of childbirth could render the experience of childbearing more negative and predispose to PTS and PPD. Enabling psychological vulnerabilities could also be an interesting avenue for understanding these links. Limitations are discussed.