Cholinergic Neurotransmission Controls Orexigenic Endocannabinoid Signaling in the Gut in Diet-Induced Obesity.

The brain bidirectionally communicates with the gut to control food intake and energy balance, which becomes dysregulated in obesity. For example, endocannabinoid (eCB) signaling in the small-intestinal (SI) epithelium is upregulated in diet-induced obese (DIO) mice and promotes overeating by a mechanism that includes inhibiting gut-brain satiation signaling. Upstream neural and molecular mechanism(s) involved in overproduction of orexigenic gut eCBs in DIO, however, are unknown. We tested the hypothesis that overactive parasympathetic signaling at the muscarinic acetylcholine receptors (mAChRs) in the SI increases biosynthesis of the eCB, 2-arachidonoyl-sn-glycerol (2-AG), which drives hyperphagia via local CB1Rs in DIO. Male mice were maintained on a high-fat/high-sucrose Western-style diet for 60 d, then administered several mAChR antagonists 30 min prior to tissue harvest or a food intake test. Levels of 2-AG and the activity of its metabolic enzymes in the SI were quantitated. DIO mice, when compared to those fed a low-fat/no-sucrose diet, displayed increased expression of cFos protein in the dorsal motor nucleus of the vagus, which suggests an increased activity of efferent cholinergic neurotransmission. These mice exhibited elevated levels of 2-AG biosynthesis in the SI, that was reduced to control levels by mAChR antagonists. Moreover, the peripherally restricted mAChR antagonist, methylhomatropine bromide, and the peripherally restricted CB1R antagonist, AM6545, reduced food intake in DIO mice for up to 24 h but had no effect in mice conditionally deficient in SI CB1Rs. These results suggest that hyperactivity at mAChRs in the periphery increases formation of 2-AG in the SI and activates local CB1Rs, which drives hyperphagia in DIO.

A Sexually Dimorphic Role for Intestinal Cannabinoid Receptor Subtype-1 in the Behavioral Expression of Anxiety.

Background: Increasing evidence suggests that the endocannabinoid system (ECS) in the brain controls anxiety and may be a therapeutic target for the treatment of anxiety disorders. For example, both pharmacological and genetic disruption of cannabinoid receptor subtype-1 (CB1R) signaling in the central nervous system is associated with increased anxiety-like behaviors in rodents, while activating the system is anxiolytic. Sex is also a critical factor that controls the behavioral expression of anxiety; however, roles for the ECS in the gut in these processes and possible differences between sexes are largely unknown. Objective: In this study, we aimed to determine if CB1Rs in the intestinal epithelium exert control over anxiety-like behaviors in a sex-dependent manner. Methods: We subjected male and female mice with conditional deletion of CB1Rs in the intestinal epithelium (intCB1-/-) and controls (intCB1+/+) to the elevated plus maze (EPM), light/dark box, and open field test. Corticosterone (CORT) levels in plasma were measured at baseline and immediately after EPM exposure. Results: When compared with intCB1+/+ male mice, intCB1-/- male mice exhibited reduced levels of anxiety-like behaviors in the EPM and light/dark box. In contrast to male mice, no differences were found between female intCB1+/+ and intCB1-/- mice. Circulating CORT was higher in female versus male mice for both genotype groups at baseline and after EPM exposure; however, there was no effect of genotype on CORT levels. Conclusions: Collectively, these results indicate that genetic deletion of CB1Rs in the intestinal epithelium is associated with an anxiolytic phenotype in a sex-dependent manner.

Structural Racism as an Environmental Justice Issue: A Multilevel Analysis of the State Racism Index and Environmental Health Risk from Air Toxics.

Communities of color and poor neighborhoods are disproportionately exposed to more air pollution-a pattern known as environmental injustices. Environmental injustices increase susceptibility to negative health outcomes among residents in affected communities. The structural mechanisms distributing environmental injustices in the USA are understudied. Bridging the literatures on the social determinants of health and environmental justice highlights the importance of the environmental conditions for health inequalities and sheds light on the institutional mechanisms driving environmental health inequalities. Employing a critical quantitative methods approach, we use data from an innovative state racism index to argue that systematic racialized inequalities in areas from housing to employment increase outdoor airborne environmental health risks in neighborhoods. Results of a multilevel analysis in over 65,000 census tracts demonstrate that tracts in states with higher levels of state-level Black-white gaps report greater environmental health risk exposure to outdoor air pollution. The state racism index explains four-to-ten percent of county- and state-level variation in carcinogenic risk and noncarcinogenic respiratory system risks from outdoor air toxics. The findings suggest that the disproportional exposure across communities is tied to systematic inequalities in environmental regulation and other structural elements such as housing and incarceration. Structural racism is an environmental justice issue.

Intersectional inequalities in industrial air toxics exposure in the United States.

Environmental justice and health research demonstrate unequal exposure to environmental hazards at the neighborhood-level. We use an innovative method-eco-intersectional multilevel (EIM) modeling-to assess intersectional inequalities in industrial air toxics exposure across US census tracts in 2014. Results reveal stark inequalities in exposure across analytic strata, with a 45-fold difference in average exposure between most and least exposed. Low SES, multiply marginalized (high % Black, high % female-headed households) urban communities experienced highest risk. These inequalities were not described by additive effects alone, necessitating the use of interaction terms. We advance a critical intersectional approach to evaluating environmental injustices.

A Recurrent FAM83H Mutation in an Extended Colombian Family and Variable Craniofacial Phenotypes.

Amelogenesis imperfecta (AI) is a collection of rare genetic disorders affecting the quantity and/or quality of the tooth enamel. AI can be classified into three major types according to the clinical phenotype: hypoplastic, hypocalcified, and hypomatured. Among them, the hypocalcified type shows the weakest physical properties, leaving rough and discolored enamel surfaces after tooth eruption. To date, mutations in the FAM83H gene are responsible for the autosomal-dominant hypocalcified AI. In this study, we recruited a four-generation Colombian family with hypocalcified AI and identified a recurrent nonsense mutation in the FAM83H gene (NM_198488.5:c.1289C>A, p.(Ser430 *)) by candidate gene sequencing. Cephalometric analyses revealed the anterior open bite that occurred in the proband is not correlated with the AI in this family.

Diferencias en el umbral de presión de los tejidos perilaríngeos entre pacientes con odinofonía e individuos asintomáticos / Differences in the perilaryngeal tissue pressure thresholds between patients with odynophonia and asymptomatic individuals

Introducción: La odinofonía se define como el dolor durante la fonación. Se trata de una molestia frecuente en los profesionales de la voz. Se ha estimado que quienes la sufren presentarían mayor sensibilidad perilaríngea; sin embargo, esta situación no ha sido del todo evidenciada. Objetivo: Comparar los umbrales de presión de los tejidos perilaríngeos entre pacientes con odinofonía e individuos asintomáticos. Material y método: Se incluyó a un total de 42 mujeres profesionales de la voz o estudiantes de carreras afines. De este total, se formaron 2grupos, el primero (G1) estuvo compuesto por 21 individuos asintomáticos (sin dolor durante la fonación), cuya edad era de 21.5±1.94 años. Mientras que el segundo (G2), con una edad promedio de 25.1±2.27 años, incluyó a 21 sujetos que presentaban dolor durante la fonación. A ambos grupos se los evaluó, mediante algometría, los umbrales de presión de los tejidos perilaríngeos. Resultado: Los umbrales de presión de las personas que sufren de odinofonía fluctuaron entre 300 a 2,000 g, mientras que en los individuos asintomáticos se encontraron entre 1,000 a 2,700 g. Conclusión: Los umbrales de presión perilaríngeos son significativamente más bajos en aquellos pacientes que sufren de odinofonía en comparación con quienes son asintomáticos.(AU)

Introduction: Odynophonia is defined as pain during phonation. Referring to frequent discomfort that professionals of the voice experience. It is estimated that those who suffer this symptom will present high perilaryngeal sensitivity; however, this situation has not been proved. Objective: The main objective of this investigation is to compare the perilaryngeal tissue pressure thresholds between patients with odynophonia and asymptomatic individuals. Material and method: A total of 42 female voice professionals and students with related careers were included. From this total, 2groups were extracted, the first (G1) was composed of 21 asymptomatic individuals (without pain during phonation), aged 21.5±1.94 years. Meanwhile, the second group (G2) comprised 21 subjects who presented pain during phonation with a mean age of 25.1±2.27 years. The perilaryngeal tissue pressure thresholds of both groups were evaluated through algometry. Results: The pressure threshold in those suffering from odynophonia fluctuated between 300 and 2,000 grams, while that of asymptomatic individuals were between 1,000 to 2,700 grams. Conclusion: Perilaryngeal tissue pressure thresholds were significantly lower in the patients suffering odynophonia in comparison with those who were asymptomatic.(AU)

Intersectional environmental justice and population health inequalities: A novel approach.

Drawing on the traditions of environmental justice, intersectionality, and social determinants of health, and using data from the EPA's NATA 2014 estimates of cancer risk from air toxics, we demonstrate a novel quantitative approach to evaluate intersectional environmental health risks to communities: Eco-Intersectional Multilevel (EIM) modeling. Results from previous case studies were found to generalize to national-level patterns, with multiply marginalized tracts with a high percent of Black and Latinx residents, high percent female-headed households, lower educational attainment, and metro location experiencing the highest risk. Overall, environmental health inequalities in cancer risk from air toxics are: (1) experienced intersectionally at the community-level, (2) significant in magnitude, and (3) socially patterned across numerous intersecting axes of marginalization, including axes rarely evaluated such as gendered family structure. EIM provides an innovative approach that will enable explicit consideration of structural/institutional social processes in the social production of intersectional and geospatial inequalities.

Técnica de terapia inhalatoria: evaluación de una intervención educativa realizada a estudiantes de Medicina, posgrados de Pediatría y cuidadores de niños y adolescentes internados en un hospital pediátrico de referencia. Período junio-agosto de 2019 / Inhalation therapy: Assessment of a training intervention delivered to Medical students, Postgraduate students of Pediatrics and to caregivers of children and adolescents admitted to a Reference Pediatric Hospital from June to August, 2019 / Terapia por inalação: avaliação de uma intervenção de treinamento com estudantes de medicina, estudantes de pós-graduação em pediatria e cuidadores de crianças e adolescentes internados em um hospital pediátrico de referência de junho a agosto de 2019

Resumen: Introducción: las patologías respiratorias con broncoobstrucción representan una causa frecuente de ingresos hospitalarios, siendo la vía inhalatoria de elección en su tratamiento. Objetivos: conocer la técnica de inhaloterapia realizada por estudiantes de Medicina, posgrados de Pediatría y cuidadores, y de los niños y adolescentes hospitalizados. Metodología: estudio prospectivo, descriptivo, de junio a agosto de 2019. Se elaboró un cuestionario con el procedimiento de la técnica inhalatoria con máscara facial, boquilla e higiene del dispositivo. Se solicitó al cuidador que describiera el procedimiento que realizaba al administrar fármacos inhalados. Se realizó una intervención explicando la correcta técnica y posteriormente se solicitó que describiera nuevamente el procedimiento. Estudiantes de Medicina y posgrados de Pediatría fueron evaluados según recomendaciones internacionales. Resultados: del total de 80 participantes, tres realizaron el procedimiento de forma adecuada. Luego de la intervención, 27 lograron una técnica correcta. En cuanto a la higiene del dispositivo, tres participantes lo realizaron correctamente previo a la intervención. Posteriormente, 44 lo refirieron adecuadamente. Participaron 25 profesionales de la salud, 15 describieron de forma correcta el procedimiento en menores de 5 años y siete en niños mayores. Posteriormente al taller informativo, 24 lograron describir adecuadamente la técnica en menores de 5 años y 15 en mayores. Conclusiones: la mayoría de los cuidadores desconocen la correcta técnica de inhaloterapia. Se debería implementar intervenciones destinadas a evaluar y entrenar a los pacientes de forma regular. Es fundamental capacitar al personal de salud para la mejora en la calidad de utilización del dispositivo.

Summary: Introduction: broncho-obstructive respiratory pathologies are a frequent cause of hospital admissions, and inhalation remains the main choice of treatment. Objectives: learn about the inhalation technique performed by medical students and postgraduate students of pediatrics and by caregivers of hospitalized children and adolescents. Methodology: prospective, descriptive study carried out from June to August 2019. A questionnaire was prepared about the inhalation technique requiring facial mask, and mouthpiece and about the hygiene of the device. Caregivers were asked to describe the procedure performed when administering inhaled drugs. An intervention was performed explaining the correct technique and the caregiver was asked to describe the procedure again. Medical and Pediatrics' students were assessed as per the international recommendations. Results: out of 80 participants, 3 performed the procedure appropriately. After the intervention, 27 they performed the technique correctly. 3 participants performed the device hygiene correctly before the intervention, and after the intervention, 44 did it properly. 25 health professionals participated, 15 correctly described the procedure on children under 5 years of age and 7 described it correctly on older children. After the information workshop, 24 managed to adequately describe the technique on children under 5 years of age and 15 for older patients. Conclusions: Most caregivers are unaware of correct inhalation therapy techniques. Regular interventions aimed at evaluating and training patients should be implemented. It is essential to train health staff to improve the quality of use of the device.

Resumo: Introdução: as patologias respiratórias bronco-obstrutivas são uma causa frequente de internações hospitalares e a inalação é ainda a principal opção de tratamento. Objetivos: aprender sobre a técnica de inalação realizada por estudantes de Medicina e Pediatria e por cuidadores de crianças e adolescentes hospitalizados. Metodologia: estudo prospectivo, descritivo, realizado de junho a agosto de 2019. Elaborou-se um questionário sobre a técnica de inalação que requer máscara facial e bocal e sobre a higiene do dispositivo. Pediu-se ao cuidador que descrevesse o procedimento realizado ao administrar drogas inaladas. Fizemos uma intervenção explicando a técnica correta e pedimos ao cuidador que descrevesse o procedimento novamente. Avaliamos aos estudantes de medicina e aos de pós-graduação em Pediatria de acordo com as recomendações internacionais. Resultados: dos 80 participantes, 3 realizaram o procedimento adequadamente. Após a intervenção, 27 deles realizaram a técnica corretamente. 3 participantes realizaram a higiene do dispositivo corretamente antes da intervenção e, após a intervenção, 44 a realizaram corretamente. Participaram 25 profissionais de saúde, 15 descreveram corretamente o procedimento para crianças menores de 5 anos e 7 descreveram corretamente para crianças maiores. Após o workshop informativo, 24 conseguiram descrever adequadamente a técnica para crianças menores de 5 anos e 15 para pacientes mais maiores. Conclusões: a maioria dos cuidadores desconhecem as técnicas corretas de terapia por inalação. Devem-se implementar intervenções regulares destinadas a avaliar e treinar pacientes. É essencial treinar a equipe de saúde para melhorar a qualidade de uso do dispositivo.

Astrocyte-Selective Volume Increase in Elevated Extracellular Potassium Conditions Is Mediated by the Na+/K+ ATPase and Occurs Independently of Aquaporin 4.

Astrocytes and neurons have been shown to swell across a variety of different conditions, including increases in extracellular potassium concentration (^[K+]o). The mechanisms involved in the coupling of K+ influx to water movement into cells leading to cell swelling are not well understood and remain controversial. Here, we set out to determine the effects of ^[K+]o on rapid volume responses of hippocampal CA1 pyramidal neurons and stratum radiatum astrocytes using real-time confocal volume imaging. First, we found that elevating [K+]o within a physiological range (to 6.5 mM and 10.5 mM from a baseline of 2.5 mM), and even up to pathological levels (26 mM), produced dose-dependent increases in astrocyte volume, with absolutely no effect on neuronal volume. In the absence of compensating for addition of KCl by removal of an equal amount of NaCl, neurons actually shrank in ^[K+]o, while astrocytes continued to exhibit rapid volume increases. Astrocyte swelling in ^[K+]o was not dependent on neuronal firing, aquaporin 4, the inwardly rectifying potassium channel Kir 4.1, the sodium bicarbonate cotransporter NBCe1, , or the electroneutral cotransporter, sodium-potassium-chloride cotransporter type 1 (NKCC1), but was significantly attenuated in 1 mM barium chloride (BaCl2) and by the Na+/K+ ATPase inhibitor ouabain. Effects of 1 mM BaCl2 and ouabain applied together were not additive and, together with reports that BaCl2 can inhibit the NKA at high concentrations, suggests a prominent role for the astrocyte NKA in rapid astrocyte volume increases occurring in ^[K+]o. These findings carry important implications for understanding mechanisms of cellular edema, regulation of the brain extracellular space, and brain tissue excitability.

Multisystem Involvement in a Patient with a PTCH1 Mutation: Clinical and Imaging Findings.

In this article, we report on a Brazilian female patient born to consanguineous parents and presenting with alobar holoprosencephaly, severe eye involvement, and unusual skin hyperpigmented lesions. She was found to have a mutation (c.2240T > C; p.Val751Gly) in exon 15 of the PTCH1 gene. Mutations in this gene are associated with the nevoid basal cell carcinoma syndrome (NBCCS, OMIM 109400) and, in other instances, with holoprosencephaly (holoprosencephaly-7, OMIM 610828). Severe eye involvement ranging from orbital coloboma to microphthalmia has been seldom reported in patients with NBCCS with PTCH1 mutations. To our knowledge, this is the first report of an individual with central nervous system, skin, and eye manifestations due to a PTCH1 mutation. Mechanisms involved in these multisystem manifestations are discussed.

Clinical and genetic study on 356 Brazilian patients with a distinct phenotype of cleft lip and palate without alveolar ridge involvement.

Oral clefts include cleft lip (CL), cleft lip with cleft palate (CLP) and cleft palate (CP), with wide variations in clinical presentation and degree of severity. We described a sample of individuals with CL and CP without alveolar arch involvement (CL + CP) to verify if the characteristics of this group are distinct from those with CL with or without CP (CL/P) described in literature. The sample was composed of 356 patients with CL + CP, registered at HRCA-USP, Bauru-SP-Brazil. The following characteristics were investigated: sex ratio, parental age at the time of conception, parental consanguinity, familial recurrence, laterality of the cleft and associated anomalies. A subgroup of 30 individuals with microforms of CL and CP were taken from the sample and compared with the remaining cases. Statistical differences were found between this CL + CP sample and the literature data for groups with CL/P regarding laterality, sex ratio, consanguinity, familial recurrence, and the presence of associated anomalies. The microform sample showed a statistical difference in paternal age. In most evaluated aspects, this sample presents similar characteristics to the consulted literature data for CL/P; as do the group of microform cleft cases when compared with the remaining CL + CP sample in this study. Microforms of cleft can represent a target group for investigation into the embryogenetic mechanisms of oral clefts and their phenotypic variability.

Richieri-Costa-Pereira syndrome: a unique acrofacial dysostosis type. An overview of the Brazilian cases.

We reported on 16 new Brazilian patients and review findings in 12 previously reported cases (25 apparently unrelated Brazilian families) from Hospital of Rehabilitation of Craniofacial Anomalies, presenting with Richieri-Costa-Pereira syndrome. All patients display a unique pattern of anomalies consisting of microstomia, micrognathia, abnormal fusion of mandible, cleft palate/Robin sequence, absence of central lower incisors, minor ears anomalies, hypoplastic first ray, abnormal tibiae, hypoplastic halluces, and clubfeet. Learning disability was also a common finding. The sex-ratio showed deviation toward to female (1.8F:1M). Recurrence in sibs was observed in nine instances and consanguinity in 11, supporting the hypothesis of autosomal recessive inheritance. Nineteen of the 25 families lived in São Paulo State, seven of them (10 affected individuals) from an isolated region named "Vale do Ribeira." The geographic barrier of this region associated with the high incidence of the consanguineous matting suggested that this condition is caused by a rare mutation with a founder effect. With the exception of one patient in France, all known cases are of Brazilian origin. The causative gene of this rare syndrome remains unknown.