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Background: Serum IgE is increased in heavy drinkers. Endotoxin mediates most of the immunological alterations associated with heavy drinking. The −159 C/T polymorphism in the promoter region of the gene encoding CD14 (an endotoxin receptor) is associated with serum IgE levels in different populations. Aim: To investigate the possible interaction between alcohol intake and the −159 C/T polymorphism in the promoter region of the CD14 gene for serum IgE levels. Methods: A total of 415 individuals (51.6% males, median age 50 years, range 18–92 years) were studied. A total of 140 individuals were alcohol abstainers, 112 were moderate drinkers (1–280 g/week), and 163 were heavy drinkers (>280 g/week). Main determinations included the CD14/−159 C/T genotype, a panel of skin prick tests, total serum IgE, and specific serum IgE against common aeroallergens (Phadiatop test). Results: Heavy drinking was associated with increased total serum IgE values and with positive specific serum IgE to common aeroallergens, but the association was stronger in carriers of the CD14/−159 C allele (either CC homozygotes or CT heterozygotes) than in CD14/−159 TT homozygotes. Both additive and multiplicative interactions between heavy drinking and the CD14/−159 C allele for total and specific serum IgE values was still present after adjusting for potential confounders. Neither alcohol consumption nor the CD14/−159 genotype was associated with skin prick test positivity. Conclusions: The CD14/−159 C/T polymorphism modifies the effect of alcohol consumption on serum IgE levels. [ABSTRACT FROM AUTHOR]

Two-step syntheses of triple-bridged triscationic bicyclophanes are presented. Molecular modeling has been undertaken by means of ab initio calculations (6-31G** level) on the triquinolina triscationic bicyclophane. This compound exists as two diastereomeric sets of enantiomers, one with C3 symmetry and the other with C1 symmetry. The C3-symmetrical derivative is 1.94 kcal mol-1 more stable than its C1-symmetrical one. This energy difference is sufficient to consider the former and its enantiomer the only two conformations existing in solution at room temperature. [ABSTRACT FROM AUTHOR]

Dystonia is a debilitating hyperkinetic movement disorder, which can be transmitted as a monogenic trait. Here, we describe homozygous frameshift, nonsense, and missense variants in TSPOAP1, which encodes the active-zone RIM-binding protein 1 (RIMBP1), as a genetic cause of autosomal recessive dystonia in 7 subjects from 3 unrelated families. Subjects carrying loss-of-function variants presented with juvenile-onset progressive generalized dystonia, associated with intellectual disability and cerebellar atrophy. Conversely, subjects carrying a pathogenic missense variant (p.Gly1808Ser) presented with isolated adult-onset focal dystonia. In mice, complete loss of RIMBP1, known to reduce neurotransmission, led to motor abnormalities reminiscent of dystonia, decreased Purkinje cell dendritic arborization, and reduced numbers of cerebellar synapses. In vitro analysis of the p.Gly1808Ser variant showed larger spike-evoked calcium transients and enhanced neurotransmission, suggesting that RIMBP1-linked dystonia can be caused by either reduced or enhanced rates of spike-evoked release in relevant neural networks. Our findings establish a direct link between dysfunction of the presynaptic active zone and dystonia and highlight the critical role played by well-balanced neurotransmission in motor control and disease pathogenesis. [ABSTRACT FROM AUTHOR]

Prophylactic mesh for prevention of parastomal hernia following end colostomy: an updated systematic review and meta-analysis of randomized controlled trials. Front Surg. 2016; 3: 49. 4 Ghinea R, White I, Benjamin B, Kidron D, Shpitz B, Avital S. Laparoscopic-assisted extralevator abdominoperineal excision using a parastomal prophylactic mesh and a biological mesh for pelvic floor reconstruction. The data that supports the findings of this study are available in the supplementary material of this article Extralevator abdominoperineal excision (ELAPE) has allowed for a substantial decrease in positive circumferential resection margins and intraoperative perforation. [Extracted from the article]

Abstract: There is a paucity of data about the epidemiology of alcohol withdrawal syndrome (AWS) and, particularly, with regard to temporal trends and sociodemographic factors. This study included 7,195 episodes of AWS in a defined community (Galicia, Spain) over a 11-year period. We looked for geographical correlations between AWS rate and sociodemographic factors (education and socioeconomic levels and rates of occupational activity and unemployment) within respective districts. We also investigated the inter- and intra-annual time trends for AWS. The median age of the participants was 49 years (interquartile range, 41–60 years), and 85% were men. The annual frequency of AWS episodes remained stable during the study period, with a consistent peak in episodes during the summer months and lowest frequency of episodes in winter months (P <.001). The age- and sex-adjusted geographical distribution of the AWS rate was uneven; districts with high rate tended to cluster. The mean education level was negatively correlated with AWS rate within a given district after adjusting for socioeconomic level, occupational activity rate, and unemployment rate (P <.001). In conclusion, we identified characteristic temporospatial patterns of AWS rate in this defined community. The rate of AWS tended to be higher in the summer months and lower in the winter months. The rate of AWS was higher in districts with low education levels. [Copyright &y& Elsevier]

Abstract: N-glycans from plant and invertebrate allergens can induce extensive immunoglobulin-E (IgE) cross-reactivity in vitro. IgE antibodies against these N-glycans, also termed cross-reactive carbohydrate determinants or CCDs, are prevalent in alcohol drinkers. This study investigated the prevalence and biological significance of IgE antibodies to N-glycans from wine glycoproteins in heavy drinkers. A structured questionnaire, skin prick tests, serum IgE levels, IgE-immunoblotting to wine extracts, and basophil activation tests were used to characterize 20 heavy drinkers and 10 control subjects. Eleven heavy drinkers (55%) showed IgE binding to proteins in wine extracts. The proteins were identified by mass spectrometry as grape-derived vacuolar invertase and thaumatin-like protein. Immunoblot reactivity was closely associated with the presence of IgE to CCDs and was inhibited by preincubation with a glycoconjugate containing bromelain-type N-glycans. The same conjugate, CCD-bearing allergens, and wine extracts activated basophils in patients with high-titer CCD-specific IgE but not in healthy controls. There was no relationship between immunoblot reactivity and consumption of any specific type of wine. No patient reported symptoms of hypersensitivity to Hymenoptera venom, food, or wine. In conclusion, heavy drinkers frequently show IgE reactivity to the N-glycans of wine glycoproteins. Glycans and wine glycoprotein extracts can induce basophil activation in sensitized alcoholics. The clinical significance of these findings remains to be elucidated. [Copyright &y& Elsevier]

Deep brain temperature detection by hypothalamic warm-sensitive neurons (WSNs) has been proposed to provide feedback information relevant for thermoregulation. WSNs increase their action potential firing rates upon warming, a property that has been presumed to rely on the composition of thermosensitive ion channels within WSNs. Here, we describe a synaptic mechanism that regulates temperature sensitivity of preoptic WSNs and body temperature. Experimentally induced warming of the mouse hypothalamic preoptic area in vivo triggers body cooling. TRPM2 ion channels facilitate this homeostatic response and, at the cellular level, enhance temperature responses of WSNs, thereby linking WSN function with thermoregulation for the first time. Rather than acting within WSNs, we—unexpectedly—find TRPM2 to temperature-dependently increase synaptic drive onto WSNs by disinhibition. Our data emphasize a network-based interoceptive paradigm that likely plays a key role in encoding body temperature and that may facilitate integration of diverse inputs into thermoregulatory pathways. [Display omitted] • Temperature in the hypothalamic preoptic area (POA) tracks body temperature in mice • TRPM2 participates in warmth detection in the POA in vivo • Presynaptic TRPM2 detects temperature increases to activate warm-sensitive neurons • Warming enhances inhibitory transmitter release via TRPM2 to mediate disinhibition Kamm, Boffi, et al. found that the ion channel TRPM2 mediates detection of warm temperatures in the mouse hypothalamus. Specifically, TRPM2 enhances the thermosensitivity of hypothalamic warm-sensitive neurons (WSNs) via a presynaptic mechanism. This study highlights the role of WSNs and TRPM2 in body temperature homeostasis under hot environments. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) is the most frequent and aggressive brain tumor in adults and the current treatments only have a modest effect on patient survival. Recent studies show that bozepinib (BZP), a purine derivative, has potential applications in cancer treatment. The aim of this study was to evaluate the effect of BZP against GBM cells, specially concerning the purinergic system. Thus, GBM cells (C6 and U138 cell lines) were treated with BZP and cell viability, cell cycle, and annexin/PI assays, and active caspase-3 measurements were carried out. Besides, the effect of BZP over the purinergic system was also evaluated in silico and in vitro. Finally, we evaluate the action of BZP against important markers related to cancer progression, such as Akt, NF-κB, and CD133. We demonstrate here that BZP reduces GBM cell viability (IC 50 = 5.7 ± 0.3 µM and 12.7 ± 1.5 µM, in C6 and U138 cells, respectively), inducing cell death through caspase-dependent apoptosis, autophagosome formation, activation of NF-κB, without any change in cell cycle progression or on the Akt pathway. Also, BZP modulates the purinergic system, inducing an increase in CD39 enzyme expression and activity, while inhibiting CD73 activity and adenosine formation, without altering CD73 enzyme expression. Curiously, one cycle of treatment resulted in enrichment of GBM cells expressing NF-κB and CD133+, suggesting resistant cells selection. However, after another treatment round, the resistant cells were eliminated. Altogether, BZP presented in vitro anti-glioma activity, encouraging further in vivo studies in order to better understand its mechanism of action. [Display omitted] [ABSTRACT FROM AUTHOR]

Toscana virus is a major cause of arboviral disease in humans in the Mediterranean basin during summer. However, early virus-host cell interactions and entry mechanisms remain poorly characterized. Investigating iPSC-derived human neurons and cell lines, we found that virus binding to the cell surface was specific, and 50% of bound virions were endocytosed within 10 min. Virions entered Rab5a+ early endosomes and, subsequently, Rab7a+ and LAMP-1+ late endosomal compartments. Penetration required intact late endosomes and occurred within 30 min following internalization. Virus entry relied on vacuolar acidification, with an optimal pH for viral membrane fusion at pH 5.5. The pH threshold increased to 5.8 with longer pre-exposure of virions to the slightly acidic pH in early endosomes. Strikingly, the particles remained infectious after entering late endosomes with a pH below the fusion threshold. Overall, our study establishes Toscana virus as a late-penetrating virus and reveals an atypical use of vacuolar acidity by this virus to enter host cells., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Koch et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)