Peripubertal Binge Ethanol, Age and Sex Modulate Microrna Expression in the Ventral and Dorsal Hippocampus of the Adolescent Rat

Adolescent binge ethanol (EtOH) abuse induces long-term changes in gene expression, resulting in an increased risk for the development of adult mood disorders. microRNAs (microRNAs) are small, noncoding RNAs that regulate gene expression by translational repression. microRNA altered in response to EtOH and puberty in the developing brain. The biogenesis of mature 22-24 nucleotide (nt), single-stranded microRNAs involves Drosha and Dicer enzymatic processing of microRNA precursors. A mature microRNA imperfectly base pairs with messenger RNA (mRNA) target genes,which leads to mRNA cleavage or translational repression. Our lab has found that repeated binge EtOH exposure alters gene expression in the hypothalamus and dysregulates the Hypothalamic-Pituitary-Adrenal (HPA) Axis in a sexually dimorphic, long-term and gonadal hormone-dependent manner in Wistar rats, and that a subset of microRNAs targeting brain-derived neurotrophic factor (BDNF) and sirtuin 1 (SIRT1) are differentially expressed in the ventral hippocampus dependent on age and 17β-estradiol (E2). We examine whether microRNA expression, microRNA biogenesis enzymes Drosha and Dicer, and microRNA target genes BDNF and SIRT1 are altered by peripubertal binge EtOH in the ventral and dorsal hippocampus. We also document sex differences in the expression of microRNAs sensitive to EtOH and E2 during pubertal development. Overall, we demonstrate : 1) peripubertal binge EtOH exposure induces long-term alterations in mature microRNA expression levels in the male rat hippocampus, and has the potential to modulate the expression of their downstream target genes, 2) expression profiles of EtOH-sensitive microRNAs (miR-10a-5p, miR-26a, miR-32, miR-103 and miR-495), E2-responsive microRNAs (miR-7a, miR-9, miR-125a and miR-181a), BDNF, SIRT1, Drosha and Dicer are differentially dependent on sex and age throughout pubertal development. This research increases our understanding of how pubertal binge EtOH exposure affects microRNA expression, provides evidence that microRNA are expressed in sexually dimorphic patterns throughout pubertal development, and suggest that microRNAs play a role in normal pubertal hippocampus development as well as hippocampus dysfunction following adolescent alcohol abuse

Silent brain infarcts and the risk of dementia and cognitive decline

BACKGROUND: Silent brain infarcts are frequently seen on magnetic resonance imaging (MRI) in healthy elderly people and may be associated with dementia and cognitive decline. METHODS: We studied the association between silent brain infarcts and the risk of dementia and cognitive decline in 1015 participants of the prospective, population-based Rotterdam Scan Study, who were 60 to 90 years of age and free of dementia and stroke at base line. Participants underwent neuropsychological testing and cerebral MRI at base line in 1995 to 1996 and again in 1999 to 2000 and were monitored for dementia throughout the study period. We performed Cox proportional-hazards and multiple linear-regression analyses, adjusted for age, sex, and level of education and for the presence or absence of subcortical atrophy and white-matter lesions. RESULTS: During 3697 person-years of follow-up (mean per person, 3.6 years), dementia developed in 30 of the 1015 participants. The presence of silent brain infarcts at base line more than doubled the risk of dementia (hazard ratio, 2.26; 95 percent confidence interval, 1.09 to 4.70). The presence of silent brain infarcts on the base-line MRI was associated with worse performance on neuropsychological tests and a steeper decline in global cognitive function. Silent thalamic infarcts were associated with a decline in memory performance, and nonthalamic infarcts with a decline in psychomotor speed. When participants with silent brain infarcts at base line were subdivided into those with and those without additional infarcts at follow-up, the decline in cognitive function was restricted to those with additional silent infarcts. CONCLUSIONS: Elderly people with silent brain infarcts have an increased risk of dementia and a steeper decline in cognitive function than those without such lesions

Alcohol intake in relation to brain magnetic resonance imaging findings in older persons without dementia

BACKGROUND: Consumers of light-to-moderate amounts of alcohol have a lower risk of dementia and, possibly, Alzheimer disease than do abstainers. Because vascular disease may contribute to symptoms of Alzheimer disease, reduction of cerebrovascular disease in consumers of light amounts of alcohol could account for that observation. However, a low concentration of alcohol may also have direct effects on the hippocampus, a brain structure highly affected by Alzheimer disease. OBJECTIVE: We investigated alcohol intake in relation to brain magnetic resonance imaging (MRI) findings of presumed vascular

Risk of postpartum depressive symptoms is influenced by psychological burden related to the COVID-19 pandemic and dependent of individual stress coping

PURPOSE: There are different studies worldwide, which have shown a higher risk of mental disorders due to the COVID-19 pandemic. One aim of this study was to identify influencing factors of the psychological burden related to the COVID-19 pandemic and the impact on the development of postpartum depression. Further, the role of individual stress and coping strategies was analyzed in this context. MATERIALS AND METHODS: Between March and October 2020, 131 women in obstetric care at the LMU Clinic Munich completed a questionnaire at consecutive stages during their perinatal period. The times set for the questionnaire were before birth, 1 month, 2 months, and 6 months after birth. The questionnaire was designed to evaluate the psychological burden related to the COVID-19 pandemic. For this a modified version of the Stress and coping inventory (SCI) and the Edinburgh Postnatal Depression Scale (EPDS) was used. RESULTS: We could show that the psychological burden related to the COVID-19 pandemic influenced the EPDS score 1, 2 and 6 months after birth. In addition, the prenatal stress and individual coping strategies affected the EPDS and the burden related to the COVID-19 pandemic before and after birth significantly. CONCLUSION: An association of the psychological burden related to the COVID-19 pandemic with the risk of developing postpartum depressive symptoms could be shown in this study. In this context, the separation of the partner and the family was recognized as an important factor. Furthermore, the SCI was identified as an effective screening instrument for identifying mothers with an increased risk of postpartum depression. Hereby allowing primary prevention by early intervention or secondary prevention by early diagnosis. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00404-022-06854-0

Neoadjuvant anti-PD-1 immunotherapy promotes a survival benefit with intratumoral and systemic immune responses in recurrent glioblastoma.

Glioblastoma is the most common primary malignant brain tumor in adults and is associated with poor survival. The Ivy Foundation Early Phase Clinical Trials Consortium conducted a randomized, multi-institution clinical trial to evaluate immune responses and survival following neoadjuvant and/or adjuvant therapy with pembrolizumab in 35 patients with recurrent, surgically resectable glioblastoma. Patients who were randomized to receive neoadjuvant pembrolizumab, with continued adjuvant therapy following surgery, had significantly extended overall survival compared to patients that were randomized to receive adjuvant, post-surgical programmed cell death protein 1 (PD-1) blockade alone. Neoadjuvant PD-1 blockade was associated with upregulation of T cell- and interferon-γ-related gene expression, but downregulation of cell-cycle-related gene expression within the tumor, which was not seen in patients that received adjuvant therapy alone. Focal induction of programmed death-ligand 1 in the tumor microenvironment, enhanced clonal expansion of T cells, decreased PD-1 expression on peripheral blood T cells and a decreasing monocytic population was observed more frequently in the neoadjuvant group than in patients treated only in the adjuvant setting. These findings suggest that the neoadjuvant administration of PD-1 blockade enhances both the local and systemic antitumor immune response and may represent a more efficacious approach to the treatment of this uniformly lethal brain tumor

The influence of the dietary exposome on oxidative stress in pregnancy complications

Pregnancy complications including fetal growth restriction, preeclampsia, and preterm birth, as well as gestational diabetes, affect one in every four to five pregnancies. Accumulating evidence indicates that increased production of reactive oxygen species accompanies these complications. Given that reactive oxygen species are cell stress-inducing agents, they may have a causal role in disease pathophysiology, although the exact mechanisms by which they contribute to pregnancy complications are not completely understood. Since many environmental and lifestyle factors and exposures are known to modulate reactive oxygen species production, the exposome of pregnant women could contribute to increased generation of reactive oxygen species. The objective of this review is to provide a comprehensive overview of the endogenous and exogenous exposome factors that regulate reactive species in healthy and complicated pregnancies. We also provide a description of dietary interventions aimed at the reduction of reactive species in order to attenuate adverse pregnancy outcome. Dietary interventions in general hold minimal risk in pregnancy and could therefore be considered a promising therapeutic approach

Defining care products to finance health care in the Netherlands

A case-mix project started in the Netherlands with the primary goal to define a complete set of health care products for hospitals. The definition of the product structure was completed 4 years later. The results are currently being used for billing purposes. This paper focuses on the methodology and techniques that were developed and applied in order to define the casemix product structure. The central research question was how to develop a manageable product structure, i.e., a limited set of hospital products, with acceptable cost homogeneity. For this purpose, a data warehouse with approximately 1.5 million patient records from 27 hospitals was build up over a period of 3 years. The data associated with each patient consist of a large number of a priori independent parameters describing the resource utilization in different stages of the treatment process, e.g., activities in the operating theatre, the lab and the radiology department. Because of the complexity of the database, it was necessary to apply advanced data analysis techniques. The full analyses process that starts from the database and ends up with a product definition consists of four basic analyses steps. Each of these steps has revealed interesting insights. This paper describes each step in some detail and presents the major results of each step. The result consists of 687 product groups for 24 medical specialties used for billing purposes