The paraventricular nucleus (PVN) in the hypothalamus is the main integration site that controls the hypothalamic-pituitary-adrenal (HPA) neuroendocrine stress system. Disruption of this system has been linked with alcoholism, but the specific role of the PVN has not been fully explored. Of particular interest is the ability of γ-aminobutyric acid type A receptors (GABA(A)Rs) in the PVN, to regulate ethanol self-administration behavior, as these receptors appear to play an essential role in mediating the effects of ethanol in the central nervous system and in the regulation of PVN activity. We observed that Long-Evans rats, in the intermittent access to 20% ethanol paradigm, consumed high amounts of ethanol and subsequently developed ethanol dependence. Microinjection of the GABA(A)R antagonist picrotoxin into the PVN, but not to the lateral ventricle of the brain, significantly reduced the intake of ethanol, but not the intake of sucrose. Picrotoxin-induced reduction was mimicked by another GABA(A)R antagonist bicuculline but was attenuated by the GABA(A)R agonist muscimol. Moreover, increased ethanol consumption was associated with lowered blood corticosterone levels, indicating a blunted HPA signaling, which was reversed by intra-PVN injection of picrotoxin, as indicated by the increased Fos immunostaining-positive cells in the PVN and the increased blood corticosterone levels. Taken together, our data provide evidence that in ethanol-dependent rats, the function of GABA(A)Rs in the PVN is upregulated, leading to a dampened HPA system. Moreover, it demonstrates that the GABA(A)R antagonists normalize HPA axis signaling and reduce excessive ethanol drinking. Therefore, drugs targeting GABA(A)Rs may be beneficial for alcoholics.

The mechanisms of ethanol addiction are not completely understood. The mesolimbic dopaminergic system is involved in many drug-related behaviors, including ethanol self-administration. The dopaminergic neurons in this system originate in the ventral tegmental area (VTA) and are under the control of GABAergic transmission. Our previous in vitro electrophysiological data indicate that glycine receptors (GlyRs) exist on the GABAergic terminals, which make synapses on VTA dopaminergic neurons, and activation of these GlyRs reduces GABAergic transmission and increases the activity of VTA dopaminergic neurons. In the current study, we tested the hypothesis that the activation of the presynaptic GlyRs in the VTA might interfere with ethanol self-administration. Glycine and strychnine, the selective antagonist of GlyRs, were injected, either alone or in combination, into the VTA of rats. Ethanol self-administration by rats was evaluated by using three different drinking models: intermittent access, continuous access, and operant self-administration. We found that the infusion of glycine into the VTA selectively reduced the intake of ethanol but not sucrose or water in rats chronically exposed to ethanol under the intermittent-access and continuous-access procedures and decreased lever-press responding for ethanol under an operant self-administration procedure. The effects of glycine probably were mediated by strychnine-sensitive GlyRs, because the coinjection of glycine and strychnine reduced neither ethanol intake in the home cages nor lever-press responding for ethanol in the operant chambers. Thus, GlyRs in the VTA may play a critical role in ethanol self-administration in animals chronically exposed to ethanol. Therefore, drugs targeting GlyRs may be beneficial for alcoholics.

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Background Pembrolizumab (PEMBRO) and ipilimumab + nivolumab (IPI + NIVO) are approved advanced melanoma (AM) immunotherapies. To address limited health-related quality of life (QoL) real-world evidence with immunotherapies in AM, we compared QoL in AM patients receiving either treatment in clinical practice. Methods A prospective US observational study enrolled adult AM patients initiating first-line PEMBRO or IPI + NIVO between June 2017 and March 2018. Endpoints included the QLQ-C30 global health score (GHS) and EuroQol visual analog scale (EQ-VAS) scores. Mean changes were compared using repeated measures mixed-effects models and are presented covariate adjusted. Results 225 PEMBRO and 187 IPI + NIVO patients were enrolled. From baseline through week 24, PEMBRO was associated with 3.2 mean GHS score increase (95% CI 0.5, 5.9; p = .02), while no change was observed with IPI + NIVO; 0.2 (95% CI − 2.6, 3.0; p = 0.87). Among objective treatment-responders, GHS scores associated with PEMBRO increased 6.0 (95% CI 3.1, 8.8; p < .0001); IPI + NIVO patients increased 3.8 (95% CI 0.8, 6.9; p = .01). In treatment non-responders, IPI + NIVO was associated with GHS/QoL deterioration of − 3.7 (95% CI − 6.8, − 0.6; p = .02), PEMBRO non-responders demonstrated no change; 0.7 (95% CI − 2.3, 3.7; p = 0.6). Between treatments, PEMBRO patients increased 2.6 greater in EQ-VAS (95% CI 0.6, 4.5; p = .01) vs IPI + NIVO at 24 weeks. Conclusions PEMBRO was associated with better 24-week QoL compared to IPI + NIVO in actual clinical practice settings. Real-world data has known limitations, but with further confirmation these results may have implications for treatment selection.

We describe an outbreak of Nocardia cyriacigeorgica soft-tissue infections attributable to unlicensed cosmetic injections and the first report using multilocus sequence typing sequence data for determining Nocardia strain relatedness in an outbreak. All 8 cases identified had a common source exposure and required hospitalization, surgical debridement, and prolonged antimicrobial therapy.