Early Life Stress Enhancement of Limbic Epileptogenesis in Adult Rats: Mechanistic Insights

BACKGROUND: Exposure to early postnatal stress is known to hasten the progression of kindling epileptogenesis in adult rats. Despite the significance of this for understanding mesial temporal lobe epilepsy (MTLE) and its associated psychopathology, research findings regarding underlying mechanisms are sparse. Of several possibilities, one important candidate mechanism is early life 'programming' of the hypothalamic-pituitary-adrenal (HPA) axis by postnatal stress. Elevated corticosterone (CORT) in turn has consequences for neurogenesis and cell death relevant to epileptogenesis. Here we tested the hypotheses that MS would augment seizure-related corticosterone (CORT) release and enhance neuroplastic changes in the hippocampus. METHODOLOGY/PRINCIPAL FINDINGS: Eight-week old Wistar rats, previously exposed on postnatal days 2-14 to either maternal separation stress (MS) or control brief early handling (EH), underwent rapid amygdala kindling. We measured seizure-induced serum CORT levels and post-kindling neurogenesis (using BrdU). Three weeks post-kindling, rats were euthanized for histology of the hippocampal CA3c region (pyramidal cell counts) and dentate gyrus (DG) (to count BrdU-labelled cells and measure mossy fibre sprouting). As in our previous studies, rats exposed to MS had accelerated kindling rates in adulthood. Female MS rats had heightened CORT responses during and after kindling (p<0.05), with a similar trend in males. In both sexes total CA3c pyramidal cell numbers were reduced in MS vs. EH rats post-kindling (p = 0.002). Dentate granule cell neurogenesis in female rats was significantly increased post-kindling in MS vs. EH rats. CONCLUSIONS/SIGNIFICANCE: These data demonstrate that early life stress results in enduring enhancement of HPA axis responses to limbic seizures, with increased hippocampal CA3c cell loss and augmented neurogenesis, in a sex-dependent pattern. This implicates important candidate mechanisms through which early life stress may promote vulnerability to limbic epileptogenesis in rats as well as to human MTLE and its associated psychiatric disorders

Gut bacteria responding to dietary change encode sialidases that exhibit preference for red meat-associated carbohydrates.

Dietary habits have been associated with alterations of the human gut resident microorganisms contributing to obesity, diabetes and cancer1. In Western diets, red meat is a frequently eaten food2, but long-term consumption has been associated with increased risk of disease3,4. Red meat is enriched in N-glycolylneuraminic acid (Neu5Gc) that cannot be synthesized by humans5. However, consumption can cause Neu5Gc incorporation into cell surface glycans6, especially in carcinomas4,7. As a consequence, an inflammatory response is triggered when Neu5Gc-containing glycans encounter circulating anti-Neu5Gc antibodies8,9. Although bacteria can use free sialic acids as a nutrient source10-12, it is currently unknown if gut microorganisms contribute to releasing Neu5Gc from food. We found that a Neu5Gc-rich diet induces changes in the gut microbiota, with Bacteroidales and Clostridiales responding the most. Genome assembling of mouse and human shotgun metagenomic sequencing identified bacterial sialidases with previously unobserved substrate preference for Neu5Gc-containing glycans. X-ray crystallography revealed key amino acids potentially contributing to substrate preference. Additionally, we verified that mouse and human sialidases were able to release Neu5Gc from red meat. The release of Neu5Gc from red meat using bacterial sialidases could reduce the risk of inflammatory diseases associated with red meat consumption, including colorectal cancer4 and atherosclerosis13

The impact of culture on the management of subsidiary organizations: the case of Viettel in Peru

As south-south investments increase so do the issues experienced by investing companies. One of these is the impact of culture. This article analyzes the effects of the subsidiary country culture on an investing firm’s organizational culture and the managerial practices used to address them. Data is gathered from cultural databases, a company-wide survey and semi structured interviews. Descriptive statistics are used to reveal country and organizational culture differences, with content analysis to expose management responses. There is a clear difference between the firm’s Vietnamese and Peruvian workers, with the company’s practices more amenable to the Vietnamese employees. Recognition of this has resulted in a number of initiatives to reduce its impact. The study’s results offer suggestions that may be valued by other foreign companies interested in operating in Peru and may be especially relevant to Southeast Asia and Asian companies interested in investing in or looking to start operations in Latin America.A medida que aumentan las inversiones sur-sur, también incrementan los problemas experimentados por las empresas inversoras. Uno de ellos es el impacto de la cultura. Este artículo analiza los efectos de la cultura del país filial en la cultura organizativa de una empresa inversora y las prácticas de gestión utilizadas para abordarlos. Los datos se recopilan de bases de datos culturales (Hofstede), una encuesta para analizar cultura organizacional (Modelo de Denison) y entrevistas semi-estructuradas. Existen diferencias culturales entre los trabajadores vietnamitas y peruanos. Las prácticas de la empresa favorecen más a los empleados vietnamitas debido a su cultura organizacional. Los reconocimientos de estas diferencias han generado iniciativas para reducir el impacto de la cultura nacional peruana sobre la cultura organizacional de la empresa. Las empresas extranjeras que operan en Perú, especialmente las del sudeste asiático y de Asia interesadas en invertir en América Latina pueden usar esto como un ejemplo para abordar las diferencias culturales nacionales y su impacto sobre las culturas organizacionales

A comprehensive single-cell map of T cell exhaustion-associated immune environments in human breast cancer

Immune checkpoint therapy in breast cancer remains restricted to triple negative patients, and long-term clinical benefit is rare. The primary aim of immune checkpoint blockade is to prevent or reverse exhausted T cell states, but T cell exhaustion in breast tumors is not well understood. Here, we use single-cell transcriptomics combined with imaging mass cytometry to systematically study immune environments of human breast tumors that either do or do not contain exhausted T cells, with a focus on luminal subtypes. We find that the presence of a PD-1high exhaustion-like T cell phenotype is associated with an inflammatory immune environment with a characteristic cytotoxic profile, increased myeloid cell activation, evidence for elevated immunomodulatory, chemotactic, and cytokine signaling, and accumulation of natural killer T cells. Tumors harboring exhausted-like T cells show increased expression of MHC-I on tumor cells and of CXCL13 on T cells, as well as altered spatial organization with more immature rather than mature tertiary lymphoid structures. Our data reveal fundamental differences between immune environments with and without exhausted T cells within luminal breast cancer, and show that expression of PD-1 and CXCL13 on T cells, and MHC-I - but not PD-L1 - on tumor cells are strong distinguishing features between these environments

The impact of factors beyond Breslow depth on predicting sentinel lymph node positivity in melanoma

BACKGROUND. In addition to Breslow depth, the authors previously described how increasing mitotic rate and decreasing age predicted sentinel lymph node (SLN) metastases in patients with melanoma. The objectives of the current study were to verify those previous results and to create a prediction model for the better selection of which patients with melanoma should undergo SLN biopsy. METHODS. The authors reviewed 1130 consecutive patients with melanoma in a prospective database who underwent successful SLN biopsy. After eliminating patients aged <16 years and patients who had melanomas that measured <1 mm, 910 remaining patients were reviewed for clinical and pathologic features and positive SLN status. Univariate association of patient and tumor characteristics with positive SLN status was explored by using standard logistic regression techniques, and the best multivariate model that predicted lymph node metastases was constructed by using a backward stepwise-elimination technique. RESULTS. The characteristics that were associated significantly with lymph node metastasis were angiolymphatic invasion, the absence of regression, increasing mitotic rate, satellitosis, ulceration, increasing Breslow depth, decreasing age, and location (trunk or lower extremity compared with upper extremity or head/neck). Previously reported interactions between mitotic rate and age and between Breslow depth and age were confirmed. The best multivariate model included patient age (linear), angiolymphatic invasion, the number of mitoses (linear), the interaction between patient age and the number of mitoses, Breslow depth (linear), the interaction between patient age and Breslow depth, and primary tumor location. CONCLUSIONS. Younger age, increasing mitotic rate (especially in younger patients), increasing Breslow depth (especially in older patients), angiolymphatic invasion, and trunk or lower extremity location of the primary tumor were associated with a greater likelihood of positive SLN status. The current results support the use of factors beyond Breslow depth to determine the risk of positive SLN status in patients with cutaneous melanoma. Cancer 2007. © 2006 American Cancer SocietyPeer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/55870/1/22382_ftp.pd

Research priorities for shoulder surgery : results of the 2015 James Lind Alliance patient and clinician priority setting partnership

OBJECTIVE: To run a UK based James Lind Alliance Priority Setting Partnership for 'Surgery for Common Shoulder Problems'. SETTING: This was a nationally funded and conducted process. It was organised from a musculoskeletal research centre and Biomedical Research Unit in Oxford. PARTICIPANTS: UK shoulder patients, carers and clinicians, involved in treating patients with shoulder pain and shoulder problems that might require surgery. INTERVENTIONS: These were national electronic and paper surveys capturing treatment uncertainties that are important to shoulder patients, carers and clinicians. OUTCOME MEASURES: The outcomes relevant to this study were the survey results and rankings. RESULTS: The process took 18 months to complete, with 371 participants contributing 404 in scope questions. The James Lind process then produced a final 10 research priorities and uncertainties that relate to the scope of 'Surgery for Common Shoulder Problems'. CONCLUSIONS: The final top 10 UK research priorities have been produced and are now being disseminated to partner organisations and funders to guide funding of shoulder research for the next 5-10 years on topics that are important to patients, their carers and clinicians