Circulating myeloid-derived MMP8 in stress susceptibility and depression.

Psychosocial stress has profound effects on the body, including the immune system and the brain1,2. Although a large number of pre-clinical and clinical studies have linked peripheral immune system alterations to stress-related disorders such as major depressive disorder (MDD)3, the underlying mechanisms are not well understood. Here we show that expression of a circulating myeloid cell-specific proteinase, matrix metalloproteinase 8 (MMP8), is increased in the serum of humans with MDD as well as in stress-susceptible mice following chronic social defeat stress (CSDS). In mice, we show that this increase leads to alterations in extracellular space and neurophysiological changes in the nucleus accumbens (NAc), as well as altered social behaviour. Using a combination of mass cytometry and single-cell RNA sequencing, we performed high-dimensional phenotyping of immune cells in circulation and in the brain and demonstrate that peripheral monocytes are strongly affected by stress. In stress-susceptible mice, both circulating monocytes and monocytes that traffic to the brain showed increased Mmp8 expression following chronic social defeat stress. We further demonstrate that circulating MMP8 directly infiltrates the NAc parenchyma and controls the ultrastructure of the extracellular space. Depleting MMP8 prevented stress-induced social avoidance behaviour and alterations in NAc neurophysiology and extracellular space. Collectively, these data establish a mechanism by which peripheral immune factors can affect central nervous system function and behaviour in the context of stress. Targeting specific peripheral immune cell-derived matrix metalloproteinases could constitute novel therapeutic targets for stress-related neuropsychiatric disorders.

Frailty Worsens Antidepressant Treatment Outcomes in Late Life Depression.

OBJECTIVE: To investigate the relationship between frailty and treatment response to antidepressant medications in adults with late life depression (LLD). METHODS: Data were evaluated from 100 individuals over age 60 years (34 men, 66 women) with a depressive diagnosis, who were assessed for frailty at baseline (characteristics include gait speed, grip strength, activity levels, fatigue, and weight loss) and enrolled in an 8-week trial of antidepressant medication followed by 10 months of open-treatment. RESULTS: Frail individuals (n = 49 with ≥3 deficits in frailty characteristics) did not differ at baseline from the non/intermediate frail (n = 51 with 0-2 deficits) on demographic, medical comorbidity, cognitive, or depression variables. On average, frail individuals experienced 2.82 fewer Hamilton Rating Scale for Depression (HRSD) points of improvement (t = 2.12, df 89, p = 0.037) than the non/intermediate frail over acute treatment, with this difference persisting over 10 months of open-treatment. Weak grip strength and low physical activity levels were each associated with decreased HRSD improvement, and lower response and remission rates over the course of the study. Despite their poorer outcomes, frail individuals received more antidepressant medication trials than the non/intermediate frail. CONCLUSION: Adults with LLD and frailty have an attenuated response to antidepressant medication and a greater degree of disability compared to non/intermediate frail individuals. This disability and attenuated response remain even after receiving a greater number of antidepressant medication trials. Future research must focus on understanding the specific pathophysiology associated with the frail-depressed phenotype to permit the design and implementation of precision medicine interventions for this high-risk population.

Sex-specific role of high-fat diet and stress on behavior, energy metabolism, and the ventromedial hypothalamus.

BACKGROUND: Scientific evidence highlights the influence of biological sex on the relationship between stress and metabolic dysfunctions. However, there is limited understanding of how diet and stress concurrently contribute to metabolic dysregulation in both males and females. Our study aimed to investigate the combined effects of high-fat diet (HFD) induced obesity and repeated stress on fear-related behaviors, metabolic, immune, and hypothalamic outcomes in male and female mice. METHODS: To investigate this, we used a highly reliable rodent behavioral model that faithfully recapitulates key aspects of post-traumatic stress disorder (PTSD)-like fear. We subjected mice to footshock stressor followed by a weekly singular footshock stressor or no stressor for 14 weeks while on either an HFD or chow diet. At weeks 10 and 14 we conducted glucose tolerance and insulin sensitivity measurements. Additionally, we placed the mice in metabolic chambers to perform indirect calorimetric measurements. Finally, we collected brain and peripheral tissues for cellular analysis. RESULTS: We observed that HFD-induced obesity disrupted fear memory extinction, increased glucose intolerance, and affected energy expenditure specifically in male mice. Conversely, female mice on HFD exhibited reduced respiratory exchange ratio (RER), and a significant defect in glucose tolerance only when subjected to repeated stress. Furthermore, the combination of repeated stress and HFD led to sex-specific alterations in proinflammatory markers and hematopoietic stem cells across various peripheral metabolic tissues. Single-nuclei RNA sequencing (snRNAseq) analysis of the ventromedial hypothalamus (VMH) revealed microglial activation in female mice on HFD, while male mice on HFD exhibited astrocytic activation under repeated stress. CONCLUSIONS: Overall, our findings provide insights into complex interplay between repeated stress, high-fat diet regimen, and their cumulative effects on health, including their potential contribution to the development of PTSD-like stress and metabolic dysfunctions, emphasizing the need for further research to fully understand these interconnected pathways and their implications for health.

In our study, we attempted to investigate how the combination of diet, stress, and sex can affect various aspects of health in mice. Specifically, we aimed to elucidate the neurobiology of underlying stress and metabolic dysfunction with a focus on sex-specific differences. We recognize that stress and metabolic disorders often co-occur and exhibit distinct patterns between sexes. In the present study, we observed that male mice fed a high-fat diet exhibited an inability to extinguish fear memory, mirroring a hallmark symptom observed in PTSD patients. We also observed sex-specific differences in metabolic and immune function in response to the diet and stress challenge. We uncovered that both repeated stress and a HFD can induce alterations in the quantity and types of immune cells present in various peripheral tissues, suggesting potential pathways through which metabolic diseases may develop. Our investigation further revealed that the ventromedial hypothalamus, responsible for regulating metabolism and stress behavior, exhibited distinct transcriptomic activity patterns in males and females. These findings shed light on the complex connections between high fat diet, stress levels, and overall health, emphasizing the importance of continued research in this area.

Stress-activated brain-gut circuits disrupt intestinal barrier integrity and social behaviour.

Chronic stress underlies the etiology of both major depressive disorder (MDD) and irritable bowel syndrome (IBS), two highly prevalent and debilitating conditions with high rates of co-morbidity. However, it is not fully understood how the brain and gut bi-directionally communicate during stress to impact intestinal homeostasis and stress-relevant behaviours. Using the chronic social defeat stress (CSDS) model, we find that stressed mice display greater intestinal permeability and circulating levels of the endotoxin lipopolysaccharide (LPS) compared to unstressed control (CON) mice. Interestingly, the microbiota in the colon also exhibit elevated LPS biosynthesis gene expression following CSDS. Additionally, CSDS triggers an increase in pro-inflammatory colonic IFNγ+ Th1 cells and a decrease in IL4+ Th2 cells compared to CON mice, and this gut inflammation contributes to stress-induced intestinal barrier permeability and social avoidance behaviour. We next investigated the role of enteric neurons and identified that noradrenergic dopamine beta-hydroxylase (DBH)+ neurons in the colon are activated by CSDS, and that their ablation protects against gut pathophysiology and disturbances in social behaviour. Retrograde tracing from the colon identified a population of corticotropin-releasing hormone-expressing (CRH+) neurons in the paraventricular nucleus of the hypothalamus (PVH) that innervate the colon and are activated by stress. Chemogenetically activating these PVH CRH+ neurons is sufficient to induce gut inflammation, barrier permeability, and social avoidance behaviour, while inhibiting these cells prevents these effects following exposure to CSDS. Thus, we define a stress-activated brain-to-gut circuit that confers colonic inflammation, leading to impaired intestinal barrier function, and consequent behavioural deficits.

Infección por Sporothrix schenckii en agricultores del caserío "Peñón de Gabante": Municipio Tovar. Estado Aragua. Venezuela / Infection caused by Sporothrix schenckii in farmers from the village "Peñón de Gabante": Tovar municipality. Aragua state. Venezuela

In Aragua state (Venezuela) there are farming communities such as the Tovar municipality that meet geographical and climatic conditions favourable for the development of the fungus Sporothrix schenckii, in which farmer workers would be particularly exposed and at risk of infection and development of sporotrichosis. Accordingly, it was determined the prevalence of this infection in 148 farmers of both sexes from the village "Peñón de Gabante" through the intradermoreaction to esporotrichin. The overall prevalence was 24% and the frequency of infection increased with the age of the farmers, the time working as farmers and it was higher in men (27.6%) than in women (20.8%), reaching values of 39.1% in persons of 50 years and older and 28% in those with more than 10 years occupied in agriculture, although it was independent of these variables. Also, it was found a lower percentage of intradermal positivity (21.8%) in farmers that reported regular use of protective equipment in compare to those whom used it irregularly (27.9%) even though the differences weren't statistically significant. Statistically significant association (p< 0.005) was found between the clinical signs referred by farmers and the intradermopositivity to the esporotrichin, direct contact with plants with thorny branches and/or fruits of prickly shell (p< 0.001) and direct contact with the soil during the process of preparation, fertilization and sowing the crops (p<0.005). These findings suggest that the studied area is endemic to Sporothrix schenckii and farmers found in occupational risk of acquiring this infection.

En el estado Aragua, Venezuela, existen comunidades agrícolas como las del municipio Tovar, que reúnen condiciones geográficas y climáticas favorables para el desarrollo del hongo Sporothrix schenckii, en las que los agricultores estarían particularmente expuestos y a riesgo de adquirir la infección y desarrollar esporotricosis. En conse cuencia, se determinó la prevalencia de esta infección en 148 agricultores de ambos sexos del caserío "Peñón de Gabante", mediante la intradermorreacción a la esporotriquina. La prevalencia fue 24% y la frecuencia de infección incrementó con la edad de los agricultores, el tiempo desarrollando esta labor y fue mayor en hombres (27,6%) que en mujeres (20,8%), alcanzando valores de 39,1% en las personas con edades de 50 años o más y de 28% en aquellos con más de 10 años laborando en la agricultura, aunque resultó independiente de estas variables. Se halló un menor porcentaje de positividad (21,8%) en los agricultores que utilizan en forma regular equipos de protección en comparación con aquellos que lo hacen irregularmente (27,9%), aunque las diferencias no fueron estadísticamente significativas. Se encontró asociación estadísticamente significativa entre la intradermopositividad a la esporotriquina y los signos clínicos relacionados a la esporotricosis (p< 0,005), el contacto directo tanto con plantas de ramas espinosas y/o frutos de cáscara espinosa (p< 0,001) y con el contacto directo con la tierra durante el proceso de preparación, abono y/o siembra de sus cultivos (p< 0,005). Estos hallazgos sugieren que la zona estudiada es endémica para Sporothrix schenckii y los agricultores se encuentran en riesgo ocupacional de contraer esta infección.

Incidencia de rotura uterina en el Hospital Dr. Patrocinio Peñuela Ruíz 1982-2003 / Incidence of uterine rupture at the Hospital Dr. Patrocinio Peñuela Ruíz 1982-2003

El presente es un estudio retrospectivo y longitudinal realizado en el Hospital Patrocinio Peñuela Ruíz, San Cristóbal, Estado Táchira, basado en la revisión de las historias clínicas entre los años 1982-2003 con diagnóstico de Rotura Uterina. Encontrándose una Tasa de 0.22 por 1000 partos (1 de 4512 partos). El 50 por ciento pertenecia al grupo 1 a 4 paras. La edad gestacional predominante fue 37-41 semanas 83.33 por ciento. El 66.66 por ciento de los casos tenían útero indemne, el factor determinante más frecuente fue el uso de Oxitócico (66.66 por ciento), el 50 por ciento de las rupturas fueron espontáneas, la Histeretomía fue usada en un 50 por ciento, el diagnóstico intraoperatorio fue del 83.33 por ciento, la mortalidad fetal fue del 33.33 por ciento