Development of the lateral ventricular choroid plexus in a marsupial, Monodelphis domestica

<p>Abstract</p> <p>Background</p> <p>Choroid plexus epithelial cells are the site of blood/cerebrospinal fluid (CSF) barrier and regulate molecular transfer between the two compartments. Their mitotic activity in the adult is low. During development, the pattern of growth and timing of acquisition of functional properties of plexus epithelium are not known.</p> <p>Methods</p> <p>Numbers and size of choroid plexus epithelial cells and their nuclei were counted and measured in the lateral ventricular plexus from the first day of its appearance until adulthood. Newborn <it>Monodelphis </it>pups were injected with 5-bromo-2-deoxyuridine (BrdU) at postnatal day 3 (P3), P4 and P5. Additional animals were injected at P63, P64 and P65. BrdU-immunopositive nuclei were counted and their position mapped in the plexus structure at different ages after injections. Double-labelling immunocytochemistry with antibodies to plasma protein identified post-mitotic cells involved in protein transfer.</p> <p>Results</p> <p>Numbers of choroid plexus epithelial cells increased 10-fold between the time of birth and adulthood. In newborn pups each consecutive injection of BrdU labelled 20-40 of epithelial cells counted. After 3 injections, numbers of BrdU positive cells remained constant for at least 2 months. BrdU injections at an older age (P63, P64, P65) resulted in a smaller number of labelled plexus cells. Numbers of plexus cells immunopositive for both BrdU and plasma protein increased with age indicating that protein transferring properties are acquired post mitotically. Labelled nuclei were only detected on the dorsal arm of the plexus as it grows from the neuroependyma, moving along the structure in a 'conveyor belt' like fashion.</p> <p>Conclusions</p> <p>The present study established that lateral ventricular choroid plexus epithelial cells are born on the dorsal side of the structure only. Cells born in the first few days after choroid plexus differentiation from the neuroependyma remain present even two months later. Protein-transferring properties are acquired post-mitotically and relatively early in plexus development.</p

Influence of Birth Preparedness, Decision-Making on Location of Birth and Assistance by Skilled Birth Attendants among Women in South-Western Uganda

Introduction: Assistance by skilled birth attendants (SBAs) during childbirth is one of the strategies aimed at reducing maternal morbidity and mortality in low-income countries. However, the relationship between birth preparedness and decision-making on location of birth and assistance by skilled birth attendants in this context is not well studied. The aim of this study was to assess the influence of birth preparedness practices and decision-making and assistance by SBAs among women in south-western Uganda

Broad Spectrum Antiviral Activity of Favipiravir (T-705): Protection from Highly Lethal Inhalational Rift Valley Fever

Background:Development of antiviral drugs that have broad-spectrum activity against a number of viral infections would be of significant benefit. Due to the evolution of resistance to currently licensed antiviral drugs, development of novel anti-influenza drugs is in progress, including Favipiravir (T-705), which is currently in human clinical trials. T-705 displays broad-spectrum in vitro activity against a number of viruses, including Rift Valley Fever virus (RVFV). RVF is an important neglected tropical disease that causes human, agricultural, and economic losses in endemic regions. RVF has the capacity to emerge in new locations and also presents a potential bioterrorism threat. In the current study, the in vivo efficacy of T-705 was evaluated in Wistar-Furth rats infected with the virulent ZH501 strain of RVFV by the aerosol route.Methodology/Principal Findings:Wistar-Furth rats are highly susceptible to a rapidly lethal disease after parenteral or inhalational exposure to the pathogenic ZH501 strain of RVFV. In the current study, two experiments were performed: a dose-determination study and a delayed-treatment study. In both experiments, all untreated control rats succumbed to disease. Out of 72 total rats infected with RVFV and treated with T-705, only 6 succumbed to disease. The remaining 66 rats (92%) survived lethal infection with no significant weight loss or fever. The 6 treated rats that succumbed survived significantly longer before succumbing to encephalitic disease.Conclusions/Significance:Currently, there are no licensed antiviral drugs for treating RVF. Here, T-705 showed remarkable efficacy in a highly lethal rat model of Rift Valley Fever, even when given up to 48 hours post-infection. This is the first study to show protection of rats infected with the pathogenic ZH501 strain of RVFV. Our data suggest that T-705 has potential to be a broad-spectrum antiviral drug. © 2014 Caroline et al

Association of TGFβ1, TNFα, CCR2 and CCR5 gene polymorphisms in type-2 diabetes and renal insufficiency among Asian Indians

BACKGROUND: Cytokines play an important role in the development of diabetic chronic renal insufficiency (CRI). Transforming growth factor β1 (TGF β1) induces renal hypertrophy and fibrosis, and cytokines like tumor necrosis factor-alpha (TNFα), chemoattractant protein-1 (MCP-1), and regulated upon activation and normal T cell expressed and secreted (RANTES) mediate macrophage infiltration into kidney. Over expression of these chemokines leads to glomerulosclerosis and interstitial fibrosis. The effect of MCP-1 and RANTES on kidney is conferred by their receptors i.e., chemokine receptor (CCR)-2 and CCR-5 respectively. We tested association of nine single nucleotide polymorphisms (SNPs) from TGFβ1, TNFα, CCR2 and CCR5 genes among individuals with type-2 diabetes with and without renal insufficiency. METHODS: Type-2 diabetes subjects with chronic renal insufficiency (serum creatinine ≥ 3.0 mg/dl) constituted the cases, and matched individuals with diabetes of duration ≥ 10 years and normoalbuminuria were evaluated as controls from four centres in India. Allelic and genotypic contributions of nine SNPs from TGFβ1, TNFα, CCR2 and CCR5 genes to diabetic CRI were tested by computing odds ratio (OR) and 95% confidence intervals (CI). Sub-analysis of CRI cases diabetic retinopathy status as dependent variable and SNP genotypes as independent variable in a univariate logistic regression was also performed. RESULTS: SNPs Tyr81His and Thr263Ile in TGF β1 gene were monomorphic, and Arg25Pro in TGF β1 gene and Δ32 polymorphism in CCR5 gene were minor variants (minor allele frequency <0.05) and therefore were not considered for case-control analysis. A significant allelic association of 59029G>A SNP of CCR5 gene has been observed and the allele 59029A seems to confer predisposition to development of diabetic CRI (OR 1.39; CI 1.04–1.84). In CRI subjects a compound group of genotypes "GA and AA" of SNP G>A -800 was found to confer predisposition for proliferative retinopathy (OR 3.03; CI 1.08–8.50, p = 0.035). CONCLUSION: Of the various cytokine gene polymorphisms tested, allele 59029A of CCR5 gene is significantly associated with diabetic renal insufficiency among Asian Indians. Result obtained for 59029G>A SNP of CCR5 gene is in conformity with reports from a Japanese population but due to sub-optimal power of the sample, replication in larger sample set is warranted

Generation and Characterization of Conditional Heparin-Binding EGF-Like Growth Factor Knockout Mice

Recently, neurotrophic factors and cytokines have been shown to be associated in psychiatric disorders, such as schizophrenia, bipolar disorder, and depression. Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is a member of the EGF family, serves as a neurotrophic molecular and plays a significant role in the brain. We generated mice in which HB-EGF activity is disrupted specifically in the ventral forebrain. These knockout mice showed (a) behavioral abnormalities similar to those described in psychiatric disorders, which were ameliorated by typical or atypical antipsychotics, (b) altered dopamine and serotonin levels in the brain, (c) decreases in spine density in neurons of the prefrontal cortex, (d) reductions in the protein levels of the NR1 subunit of the N-methyl-D-aspartate (NMDA) receptor and post-synaptic protein-95 (PSD-95), (e) decreases in the EGF receptor, and in the calcium/calmodulin-dependent protein kinase II (CaMK II) signal cascade. These results suggest the alterations affecting HB-EGF signaling could comprise a contributing factor in psychiatric disorder

The Ciliogenic Transcription Factor RFX3 Regulates Early Midline Distribution of Guidepost Neurons Required for Corpus Callosum Development

The corpus callosum (CC) is the major commissure that bridges the cerebral hemispheres. Agenesis of the CC is associated with human ciliopathies, but the origin of this default is unclear. Regulatory Factor X3 (RFX3) is a transcription factor involved in the control of ciliogenesis, and Rfx3–deficient mice show several hallmarks of ciliopathies including left–right asymmetry defects and hydrocephalus. Here we show that Rfx3–deficient mice suffer from CC agenesis associated with a marked disorganisation of guidepost neurons required for axon pathfinding across the midline. Using transplantation assays, we demonstrate that abnormalities of the mutant midline region are primarily responsible for the CC malformation. Conditional genetic inactivation shows that RFX3 is not required in guidepost cells for proper CC formation, but is required before E12.5 for proper patterning of the cortical septal boundary and hence accurate distribution of guidepost neurons at later stages. We observe focused but consistent ectopic expression of Fibroblast growth factor 8 (Fgf8) at the rostro commissural plate associated with a reduced ratio of GLIoma-associated oncogene family zinc finger 3 (GLI3) repressor to activator forms. We demonstrate on brain explant cultures that ectopic FGF8 reproduces the guidepost neuronal defects observed in Rfx3 mutants. This study unravels a crucial role of RFX3 during early brain development by indirectly regulating GLI3 activity, which leads to FGF8 upregulation and ultimately to disturbed distribution of guidepost neurons required for CC morphogenesis. Hence, the RFX3 mutant mouse model brings novel understandings of the mechanisms that underlie CC agenesis in ciliopathies

Management of peripheral facial nerve palsy

Peripheral facial nerve palsy (FNP) may (secondary FNP) or may not have a detectable cause (Bell’s palsy). Three quarters of peripheral FNP are primary and one quarter secondary. The most prevalent causes of secondary FNP are systemic viral infections, trauma, surgery, diabetes, local infections, tumor, immunological disorders, or drugs. The diagnosis of FNP relies upon the presence of typical symptoms and signs, blood chemical investigations, cerebro-spinal-fluid-investigations, X-ray of the scull and mastoid, cerebral MRI, or nerve conduction studies. Bell’s palsy may be diagnosed after exclusion of all secondary causes, but causes of secondary FNP and Bell’s palsy may coexist. Treatment of secondary FNP is based on the therapy of the underlying disorder. Treatment of Bell’s palsy is controversial due to the lack of large, randomized, controlled, prospective studies. There are indications that steroids or antiviral agents are beneficial but also studies, which show no beneficial effect. Additional measures include eye protection, physiotherapy, acupuncture, botulinum toxin, or possibly surgery. Prognosis of Bell’s palsy is fair with complete recovery in about 80% of the cases, 15% experience some kind of permanent nerve damage and 5% remain with severe sequelae

Gene Expression Programs of Mouse Endothelial Cells in Kidney Development and Disease

Endothelial cells are remarkably heterogeneous in both morphology and function, and they play critical roles in the formation of multiple organ systems. In addition endothelial cell dysfunction can contribute to disease processes, including diabetic nephropathy, which is a leading cause of end stage renal disease. In this report we define the comprehensive gene expression programs of multiple types of kidney endothelial cells, and analyze the differences that distinguish them. Endothelial cells were purified from Tie2-GFP mice by cell dissociation and fluorescent activated cell sorting. Microarrays were then used to provide a global, quantitative and sensitive measure of gene expression levels. We examined renal endothelial cells from the embryo and from the adult glomerulus, cortex and medulla compartments, as well as the glomerular endothelial cells of the db/db mutant mouse, which represents a model for human diabetic nephropathy. The results identified the growth factors, receptors and transcription factors expressed by these multiple endothelial cell types. Biological processes and molecular pathways were characterized in exquisite detail. Cell type specific gene expression patterns were defined, finding novel molecular markers and providing a better understanding of compartmental distinctions. Further, analysis of enriched, evolutionarily conserved transcription factor binding sites in the promoters of co-activated genes begins to define the genetic regulatory network of renal endothelial cell formation. Finally, the gene expression differences associated with diabetic nephropathy were defined, providing a global view of both the pathogenic and protective pathways activated. These studies provide a rich resource to facilitate further investigations of endothelial cell functions in kidney development, adult compartments, and disease

Long-Term Relationships between Synaptic Tenacity, Synaptic Remodeling, and Network Activity

Long term time-lapse imaging reveals that individual synapses undergo significant structural remodeling not only when driven by activity, but also when network activity is absent, raising questions about how reliably individual synapses maintain connections