Oligodendrocyte gene expression is downregulated in stress‐related neuropsychiatric disorders, including depression. In mice, chronic social stress (CSS) leads to depression‐relevant changes in brain ...and emotional behavior, and the present study shows the involvement of oligodendrocytes in this model. In C57BL/6 (BL/6) mice, RNA‐sequencing (RNA‐Seq) was conducted with prefrontal cortex, amygdala and hippocampus from CSS and controls; a gene enrichment database for neurons, astrocytes and oligodendrocytes was used to identify cell origin of deregulated genes, and cell deconvolution was applied. To assess the potential causal contribution of reduced oligodendrocyte gene expression to CSS effects, mice heterozygous for the oligodendrocyte gene cyclic nucleotide phosphodiesterase (Cnp1) on a BL/6 background were studied; a 2 genotype (wildtype, Cnp1+/−) × 2 environment (control, CSS) design was used to investigate effects on emotional behavior and amygdala microglia. In BL/6 mice, in prefrontal cortex and amygdala tissue comprising gray and white matter, CSS downregulated expression of multiple oligodendroycte genes encoding myelin and myelin‐axon‐integrity proteins, and cell deconvolution identified a lower proportion of oligodendrocytes in amygdala. Quantification of oligodendrocyte proteins in amygdala gray matter did not yield evidence for reduced translation, suggesting that CSS impacts primarily on white matter oligodendrocytes or the myelin transcriptome. In Cnp1 mice, social interaction was reduced by CSS in Cnp1+/− mice specifically; using ionized calcium‐binding adaptor molecule 1 (IBA1) expression, microglia activity was increased additively by Cnp1+/− and CSS in amygdala gray and white matter. This study provides back‐translational evidence that oligodendrocyte changes are relevant to the pathophysiology and potentially the treatment of stress‐related neuropsychiatric disorders.
Reduced cyclic nucleotide phosphodiesterase (Cnp1) expression is induced by chronic social stress (CSS) and increases CSS impact on social interest.
Automated treatment planning and/or optimization systems (ATPS) are in the process of broad clinical implementation aiming at reducing inter-planner variability, reducing the planning time allocated ...for the optimization process and improving plan quality. Five different ATPS used clinically were evaluated for advanced head and neck cancer (HNC).
Three radiation oncology departments compared 5 different ATPS: 1) Automatic Interactive Optimizer (AIO) in combination with RapidArc (in-house developed and Varian Medical Systems); 2) Auto-Planning (AP) (Philips Radiation Oncology Systems); 3) RapidPlan version 13.6 (RP1) with HNC model from University Hospital A (Varian Medical Systems, Palo Alto, USA); 4) RapidPlan version 13.7 (RP2) combined with scripting for automated setup of fields with HNC model from University Hospital B; 5) Raystation multicriteria optimization algorithm version 5 (RS) (Laboratories AB, Stockholm, Sweden). Eight randomly selected HNC cases from institution A and 8 from institution B were used. PTV coverage, mean and maximum dose to the organs at risk and effective planning time were compared. Ranking was done based on 3 Gy increments for the parallel organs.
All planning systems achieved the hard dose constraints for the PTVs and serial organs for all patients. Overall, AP achieved the best ranking for the parallel organs followed by RS, AIO, RP2 and RP1. The oral cavity mean dose was the lowest for RS (31.3 ± 17.6 Gy), followed by AP (33.8 ± 17.8 Gy), RP1 (34.1 ± 16.7 Gy), AIO (36.1 ± 16.8 Gy) and RP2 (36.3 ± 16.2 Gy). The submandibular glands mean dose was 33.6 ± 10.8 Gy (AP), 35.2 ± 8.4 Gy (AIO), 35.5 ± 9.3 Gy (RP2), 36.9 ± 7.6 Gy (RS) and 38.2 ± 7.0 Gy (RP1). The average effective planning working time was substantially different between the five ATPS (in minutes): < 2 ± 1 for AIO and RP2, 5 ± 1 for AP, 15 ± 2 for RP1 and 340 ± 48 for RS, respectively.
All ATPS were able to achieve all planning DVH constraints and the effective working time was kept bellow 20 min for each ATPS except for RS. For the parallel organs, AP performed the best, although the differences were small.
Summary
In the Middle East and North Africa (MENA), a vitamin D dose ≥2000 IU/day may be needed to allow to the majority of the population to reach the target 25-hydroxyvitamin D (25(OH)D) level ...≥20 ng/ml. Data in the region on the effect of vitamin D supplementation on various skeletal and extra-skeletal effects are scarce.
Introduction
Hypovitaminosis D is prevalent worldwide, more so in the Middle East and North Africa (MENA). This study aims to determine the effects of vitamin D replacement on the mean difference in 25-hydroxyvitamin D 25(OH)D level reached and other outcomes, in the MENA.
Methods
This is a meta-analysis of randomized trials from the MENA, administering vitamin D supplementation for at least 3 months, without language or time restriction. We conducted a comprehensive search in seven databases until July 2015. We abstracted data from published reports, independently and in duplicate. We calculated the mean difference (MD) and 95 % CI of 25(OH)D level reached for eligible comparisons, and pooled data using RevMan version 5.3.
Results
We identified 2 studies in elderly and 17 in adults; for the latter, 11 were included in the meta-analysis. Comparing a high vitamin D dose (>2000 IU/day) to placebo (nine studies), the MD in 25(OH)D level achieved was 18.3 (CI 14.1; 22.5) ng/ml;
p
value < 0.001;
I
2
= 92 %. Comparing an intermediate dose (800–2000 IU/day) to placebo (two studies), the MD in 25(OH)D level achieved was 14.7 (CI 4.6; 24.9) ng/ml;
p
value 0.004;
I
2
= 91 %. Accordingly, 89 and 71 % of participants, in the high and intermediate dose groups, respectively, reached the desirable level of 20 ng/ml. The risk of bias in the included studies was unclear to high, except for three studies.
Conclusion
In the MENA region, vitamin D doses ≥2000 IU/day may be needed to reach the target 25(OH)D level ≥20 ng/ml. The long-term safety and the efficacy of such doses on various outcomes are unknown.
Bardet-Biedl syndrome protein 4 (BBS4) localization has been studied in human embryos/fetuses from Carnegie stage 15 to 37 gestational weeks in neurosensory organs and brain, underlying the major ...clinical signs of BBS. We observed a correlation between the differentiation of the neurosensory cells (hair cells, photoreceptors, olfactory neurons) and the presence of a punctate BBS4 immunostaining in their apical cytoplasm. In the brain, BBS4 was localized in oligodendrocytes and myelinated tracts. In individual myelinated fibers, BBS4 immunolabelling was discontinuous, predominantly at the periphery of the myelin sheath. BBS4 immunolabelling was confirmed in postnatal developing white matter tracts in mouse as well as in mouse oligodendrocytes cultures. In neuroblasts/neurons, BBS4 was only present in reelin-expressing Cajal-Retzius cells. Our results show that BBS4, a protein of the BBSome, has both basal body/ciliary localization in neurosensory organs but extra-ciliary localization in oligodendrocytes. The presence of BBS4 in developing oligodendrocytes and myelin described in the present paper might attribute a new role to this protein, requiring further investigation in the field of myelin formation.
Although hypercalcemia and hypercalciuria are known to occur in breast-fed pre-term infants, to the best of our knowledge, it has never been reported in a term baby previously. We report a term male ...baby who was followed-up during pregnancy for having bright kidneys, but a follow-up renal ultrasound (US) after birth had revealed normal scan. Laboratory investigations revealed normal serum calcium (Ca), phosphorous (PO₄) and alkaline phosphatase (ALP). The baby was being fed by breast milk. Follow-up US two months later showed early nephrocalcinosis along with hypercalcemia and hypercalciuria; by the age of three months, nephrocalcinosis was more extensive and the serum Ca level was more than 12 mg/L with hypercalciuria. Parathyroid hormone (PTH), phosphorous (PO₄), ALP and thyroid function tests were all normal. Antenatal history revealed a hypothyroid mother who was maintained on L-thyroxin, calcium and vitamin D supplement during pregnancy. Her blood tests showed normal serum Ca, low PO₄ and elevated PTH. The baby was diagnosed to have hypercalciuria and hypercalcemia secondary to maternal hypophosphatemia (maternal vitamin D deficiency). Breast feeding was stopped and the baby was started on formula, whereby he showed remarkable improvement both for his blood chemistry as well as his hypercalciuria.
► Periventricular area is involved in the Brown Norway MOG-induced opticospinal model of demyelination. ► Markers of astrocyte expression (AQP4 and GFAP) are significantly modified in opticospinal ...region and periventricular area. ► Disability scores were correlated with demyelination and inflammation but not with AQP4/GFAP expression. ► A neuromyelitis optica-phenotype was observed in this model but without any antibodies against AQP4. ► This model has characteristics of both opticospinal multiple sclerosis and neuromyelitis optica.
Opticospinal demyelinating diseases in humans are mostly characterized by the opticospinal form of multiple sclerosis (MS) and neuromyelitis optica (NMO). Increasing attention has recently focused on astrocyte markers, aquaporin-4 (AQP4) and glial fibrillary acidic protein (GFAP) in these diseases. We induced opticospinal demyelination in Brown Norway rats with soluble recombinant rat myelin oligodendrocyte glycoprotein (1–116) and incomplete Freund's adjuvant. Clinical, MRI, neuropathological and immunological evaluations were performed, with a focus on AQP4 and GFAP. We confirmed the opticospinal phenotype, including extensive myelitis, but also showed the MRI-characterized involvement of the periventricular area. Expression levels of myelin, AQP4 and GFAP showed the early involvement of astrocytes before demyelination in the optic nerve. The overexpression of AQP4 was particularly pronounced in the spinal cord and was concomitant with demyelination and astrocyte apoptosis. The disability scores were correlated with demyelination and inflammation but not with AQP4/GFAP expression. No antibodies against the linear and conformational epitopes of AQP4 were detected. Whereas a NMO-like phenotype was observed in this model, the AQP4/GFAP expression during the disease process was more closely related to opticospinal MS than NMO. However, this model raises the question of a continuum between opticospinal MS and the seronegative NMO subtype.
Carbonic anhydrase (CA) V is a mitochondrial enzyme that has been reported in several tissues of the gastrointestinal tract. In liver, it participates in ureagenesis and gluconeogenesis by providing ...bicarbonate ions for two other mitochondrial enzymes: carbamyl phosphate synthetase I and pyruvate carboxylase. This study presents evidence of immunohistochemical localization of CA V in the rodent nervous tissue. Polyclonal rabbit antisera against a polypeptide of 17 C-terminal amino acids of rat CA V and against purified recombinant mouse isozyme were used in western blotting and immunoperoxidase stainings. Immunohistochemistry showed that CA V is expressed in astrocytes and neurons but not in oligodendrocytes, which are rich in CA II, or capillary endothelial cells, which express CA IV on their plasma face. The specificity of the immunohistochemical results was confirmed by western blotting, which identified a major 30-kDa polypeptide band of CA V in mouse cerebral cortex, hippocampus, cerebellum, spinal cord, and sciatic nerve. The expression of CA V in astrocytes and neurons suggests that this isozyme has a cell-specific, physiological role in the nervous system. In astrocytes, CA V may play an important role in gluconeogenesis by providing bicarbonate ions for the pyruvate carboxylase. The neuronal CA V could be involved in the regulation of the intramitochondrial calcium level, thus contributing to the stability of the intracellular calcium concentration. CA V may also participate in bicarbonate ion-induced GABA responses by regulating the bicarbonate homeostasis in neurons, and its inhibition could be the basis of some neurotropic effects of carbonic anhydrase inhibitors.
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