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Sickle cell disease (SCD) is the most common monogenetic condition in the United States (US) and one that has been subjected to a history of negative bias. Since SCD was first described approximately 120 years ago, the medical establishment has, directly and indirectly, harmed patients by reinforcing biases and assumptions about the disease. Furthermore, negative biases and stigmas have been levied upon patients with SCD by healthcare providers and society, researchers, and legislators. This article will explore the historical context of SCD in the US; discuss specific issues in care that lead to biases, social and self-stigma, inequities in access to care, and research funding; and highlight interventions over recent years that address racial biases and stigma.

Conociendo la importancia del componente morfosintáctico en el desarrollo del lenguaje, se decidió llevar a cabo el siguiente trabajo de investigación no experimental de tipo descriptivo, cuyo objetivo es comparar el nivel de desarrollo morfosintáctico en niños de 3, 4 y 5 años de dos instituciones educativas privadas de la ciudad de Arequipa y Lima. Para conocer el nivel de desarrollo morfosintáctico se empleó el instrumento Test Exploratorio de Gramática Española de A. Toronto-Chile, con el fin de medir el componente morfosintáctico del lenguaje oral. Este instrumento fue aplicado a 120 estudiantes del nivel inicial de 3, 4 y 5 años de dos colegios particulares de las ciudades de Lima y Arequipa seleccionado a través de muestreo intencional. Al finalizar el estudio se halló que no existen diferencias significativas entre los niños de Lima y Arequipa a nivel receptivo y expresivo; en cuanto a la edad se halló diferencias a nivel expresivo en los niños de 5 años. Por otro lado, también se encontró que existen diferencias significativas en su evolución según avanza su edad cronológica.

Oxytocin is a neuropeptide that can promote or inhibit affiliative social behaviors. Recent evidence suggests that these diverse effects are mediated by distinct oxytocin receptor-expressing neurons. An outstanding question is whether these behavioral effects are also driven by distinct or overlapping populations of oxytocin-producing neurons. The paraventricular nucleus (PVN) of the hypothalamus is a major source of oxytocin and sends projections to the mesolimbic dopamine system and extended amygdala. Previous work found that social defeat increased oxytocin neuron activity in the anterior PVN (aPVN) but not posterior PVN (pPVN). We reduced oxytocin synthesis with antisense morpholino oligonucleotides in either anterior or posterior PVN in California mice ( ), a strong model system for studying effects of social stress on brain function and behavior. Antisense morpholinos in aPVN had no effect on behavior in unstressed females but increased social approach and reduced social vigilance in females exposed to social defeat stress. In pPVN, antisense morpholinos reduced social approach in unstressed male and female California mice. We then used mice to compare electrophysiological profiles of oxytocin in aPVN and pPVN with a population of oxytocin neurons in the bed nucleus of the stria terminalis (BNST). Oxytocin neurons in aPVN and BNST had higher post-synaptic events and responded more strongly to current injections than oxytocin neurons in pPVN, though they had similar excitatory and inhibitory input balance at the observed resting membrane potential. These findings shed light onto functional and physiological heterogeneity of PVN oxytocin neurons. Our results suggest that context dependent effects of oxytocin are mediated by different populations of oxytocin neurons.

Social play behavior is a rewarding behavior predominantly displayed by juveniles of various mammalian species, including humans and rats. Although the mesolimbic reward system is involved in the regulation of social play, how brain regions in this system interact to regulate social play behavior is unknown. Here, we determined the involvement of the ventral pallidum (VP) as well as inputs from the nucleus accumbens (NAc) to the VP in the regulation of social play in male and female juvenile rats. We show that acute pharmacological inactivation of the VP, via microinfusion of the GABA-A receptor agonist muscimol, decreased social play behaviors in both sexes. Next, using Gad1-iCre rats, we show that chemogenetic stimulation of NAcGABA terminals in the VP decreased VP neuronal activation and decreased social play behaviors in both sexes. These findings together indicate that reduced inhibitory NAc input to the VP permits activation of the VP which facilitates the expression of social play behaviors. Lastly, we show that the equal expression of social play behavior in males and females is associated with a female-specific increase in NAc shell activation and a male-specific decrease in activation of the NAc shell neurons projecting to the VP. These sex-specific changes in NAc activity following social play exposure eliminated baseline sex differences in NAc activity. In conclusion, these findings support a model in which the sex-specific modulation of NAc inhibitory input to the VP facilitates activation of the VP that is necessary for the typical and equal expression of social play behavior in male and female juvenile rats.

Imbalance of reduction/oxidation (redox) in the brain is associated with numerous diseases including Alzheimer’s disease (AD), substance abuse disorders, and stroke. Moreover, cognitive decline can be caused by neuronal dysfunction that precedes cell death, and this dysfunction is in part produced by altered gene expression. However, the mechanisms by which redox state controls gene expression in neurons are not well understood. ΔFOSB is a neuronally enriched transcription factor critical for orchestrating gene expression underlying memory, mood, and motivated behaviors. It is dysregulated in many conditions including AD. We showed recently that ΔFOSB forms a redox-sensitive disulfide bond between cysteine 172 (C172) of ΔFOSB and C279 of its preferred binding partner JUND. This bond works as a redox switch to control DNA-binding, based on studies of recombinant proteins in vitro. Here, we show that this redox control of ΔFOSB function in vitro is conserved in vivo. We show that ΔFOSB C172 forms a redox-sensitive disulfide bond with JUND that regulates the stability of this AP1-transcription factor complex and its binding to DNA in cells. We also validate the formation of ΔFOSB-containing complexes held together via disulfide bonds in mouse brain in vivo. We show that exogenous oxidative stress reduces ΔFOSB binding to gene targets in mouse brain and that Fosb C172S knock-in mice, which lack a functional ΔFOSB redox switch, are insensitive to this oxidation-dependent reduction in target gene binding, demonstrating that ΔFOSB is regulated by a redox switch that modulates binding to target genes in the hippocampus. Finally, we demonstrate that FosB C172S knock-in mice are less sensitive to cognitive dysfunction induced by oxidative stress. This evidence supports ΔFOSB as an important mediator of oxidative stress-driven changes in gene expression and cognition and implicates ΔFOSB as a possible therapeutic target for diseases associated with oxidative stress in the brain, including AD.

This paper reviews the evidence for the effectiveness and cost-effectiveness of policies and programmes to reduce the harm caused by alcohol, in the areas of education and information, the health sector, community action, driving while under the influence of alcohol (drink-driving), availability, marketing, pricing, harm reduction, and illegally and informally produced alcohol. Systematic reviews and meta-analyses show that policies regulating the environment in which alcohol is marketed (particularly its price and availability) are effective in reducing alcohol-related harm. Enforced legislative measures to reduce drink-driving and individually directed interventions to already at-risk drinkers are also effective. However, school-based education does not reduce alcohol-related harm, although public information and education-type programmes have a role in providing information and in increasing attention and acceptance of alcohol on political and public agendas. Making alcohol more expensive and less available, and banning alcohol advertising, are highly cost-effective strategies to reduce harm. In settings with high amounts of unrecorded production and consumption, increasing the proportion of alcohol that is taxed could be a more effective pricing policy than a simple increase in tax. [PUBLICATION ABSTRACT]

Background: Epidemiologic studies show that high temperatures are related to mortality, but little is known about the exposure-response function and the lagged effect of heat. We report the associations between daily maximum apparent temperature and daily deaths during the warm season in 15 European cities. Methods: The city-specific analyses were based on generalized estimating equations and the city-specific results were combined in a Bayesian random effects meta-analysis. We specified distributed lag models in studying the delayed effect of exposure. Time-varying coefficient models were used to check the assumption of a constant heat effect over the warm season. Results: The city-specific exposure-response functions have a V shape, with a change-point that varied among cities. The meta-analytic estimate of the threshold was 29.4°C for Mediterranean cities and 23.3°C for north-continental cities. The estimated overall change in all natural mortality associated with a 1°C increase in maximum apparent temperature above the city-specific threshold was 3.12% (95% credibility interval = 0.60% to 5.72%) in the Mediterranean region and 1.84% (0.06% to 3.64%) in the north-continental region. Stronger associations were found between heat and mortality from respiratory diseases, and with mortality in the elderly. Conclusions: There is an important mortality effect of heat across Europe. The effect is evident from June through August; it is limited to the first week following temperature excess, with evidence of mortality displacement. There is some suggestion of a higher effect of early season exposures. Acclimatization and individual susceptibility need further investigation as possible explanations for the observed heterogeneity among cities.

This paper reviews the evidence for the effectiveness and cost-effectiveness of policies and programmes to reduce the harm caused by alcohol, in the areas of education and information, the health sector, community action, driving while under the influence of alcohol (drink-driving), availability, marketing, pricing, harm reduction, and illegally and informally produced alcohol. Systematic reviews and meta-analyses show that policies regulating the environment in which alcohol is marketed (particularly its price and availability) are effective in reducing alcohol-related harm. Enforced legislative measures to reduce drink-driving and individually directed interventions to already at-risk drinkers are also effective. However, school-based education does not reduce alcohol-related harm, although public information and education-type programmes have a role in providing information and in increasing attention and acceptance of alcohol on political and public agendas. Making alcohol more expensive and less available, and banning alcohol advertising, are highly cost-effective strategies to reduce harm. In settings with high amounts of unrecorded production and consumption, increasing the proportion of alcohol that is taxed could be a more effective pricing policy than a simple increase in tax.