The Hedgehog proteins play a crucial role in metazoan embryo development. Constitutive activation of the pathway is associated with multiple types of cancer. Recent experimental data suggest involvement of Hedgehog signaling in vascular remodeling, germ cell migration, and axon guidance. The molecular mechanisms underlying these effects remain elusive. Here we show that yolk sac-derived endothelial cells and embryonic fibroblasts can directly respond to the Hedgehog signal by increased migration in an in vitro scratch (wound) assay. We also identify Hedgehog transcriptional target genes in these cells, many of which participate in cell migration, axon guidance, and angiogenesis processes. Inhibition of one such molecular pathway, neuropilin-flavomonooxygenase, blocks Hedgehog-induced cell migration. These findings suggest that Hedgehog signaling directly affects embryonic endothelial and fibroblast cell migration via molecules and pathways known to regulate cell migration in response to a variety of environmental cues.
Background
Currently, postpartum depression (PPD) screening is mainly based on self‐report symptom‐based assessment, with lack of an objective, integrative tool which identifies women at increased risk, before the emergent of PPD. We developed and validated a machine learning‐based PPD prediction model utilizing electronic health record (EHR) data, and identified novel PPD predictors.
Methods
A nationwide longitudinal cohort that included 214,359 births between January 2008 and December 2015, divided into model training and validation sets, was constructed utilizing Israel largest health maintenance organization's EHR‐database. PPD was defined as new diagnosis of a depressive episode or antidepressant prescription within the first year postpartum. A gradient‐boosted decision tree algorithm was applied to EHR‐derived sociodemographic, clinical, and obstetric features.
Results
Among the birth cohort, 1.9% (n = 4104) met the case definition of new‐onset PPD. In the validation set, the prediction model achieved an area under the curve (AUC) of 0.712 (95% confidence interval, 0.690–0.733), with a sensitivity of 0.349 and a specificity of 0.905 at the 90th percentile risk threshold, identifying PPDs at a rate more than three times higher than the overall set (positive and negative predictive values were 0.074 and 0.985, respectively). The model's strongest predictors included both well‐recognized (e.g., past depression) and less‐recognized (differing patterns of blood tests) PPD risk factors.
Conclusions
Machine learning‐based models incorporating EHR‐derived predictors, could augment symptom‐based screening practice by identifying the high‐risk population at greatest need for preventive intervention, before development of PPD.
BackgroundWhile accumulating evidence suggests that vitamin D deficiency may be involved in the risk to develop schizophrenia and its outcome, there are no studies on vitamin D supplementation in this context. We sought to assess the effect of vitamin D supplementation on psychiatric, cognitive and metabolic parameters in chronic clozapine-treated schizophrenia patients.MethodsThis eight-week, randomized, double-blind, placebo-controlled clinical trial, recruited schizophrenia patients who had been maintained on clozapine treatment for at least 18 weeks and had low levels of vitamin D (< 75 nmol/l) and total PANSS scores > 70 (to ascertain the presence of residual symptoms). Patients were randomly allocated to either weekly oral drops of vitamin D (14,000 IU) or placebo and subsequently assessed at two-week intervals for psychosis severity, mood, cognition and metabolic profile.ResultsTwenty four patients were randomly assigned to vitamin D (aged 39.4 ± 9.6 years, 75% males) and the other 23 patients to the placebo arm (aged 42.5 ± 11.2 years, 60.9% males). After eight weeks, the vitamin D group exhibited a significant increase in vitamin D levels (31.4 vs − 0.4 nmol/l, p < 0.0001). There was no significant effect of vitamin D on psychotic, depressive or metabolic parameters. However, in the vitamin D group, there was a trend towards improved cognition (effect size = 0.17, significance lost following Bonferroni correction).ConclusionsVitamin D supplementation was associated with a trend towards improved cognition, but did not affect psychosis, mood or metabolic status. It is possible that the robust decrease in the PANSS scores in both groups may have obscured an effect of vitamin D supplementation.
These observations suggest a possible role for SCL in renal vasculogenesis. Undifferentiated mesenchymal cells expressing SCL during early nephrogenesis might represent putative progenitors that can simultaneously give rise to kidney, blood, and endothelium.
Objectives
Recent evidence has associated mood disorders with blood‐brain barrier (BBB)/ neurovascular unit (NVU) dysfunction, and reduction in blood vessels coverage by the water channel aquaporin‐4 (AQP4) immunoreactive astrocytes. Lithium is an established treatment for mood disorders, yet, its mechanism of action is partially understood. We investigated the effects of lithium on BBB integrity and NVU‐related protein expression in chronic mild stress (CMS) rat model of depressive‐like behavior.
Methods
Male Wistar rats were exposed for 5 weeks to unpredictable mild stressors with daily co‐administration of lithium chloride to half of the stressed and unstressed groups. Sucrose preference and open field tests were conducted to validate the depressive‐like phenotype, and dynamic contrast‐enhanced MRI analysis was utilized to assess BBB integrity in brain regions relevant to the pathophysiology of depression. Hippocampal AQP4 and claudin‐5 expression were studied using immunofluorescence, western blot, and enzyme‐linked immunosorbent assays.
Results
Lithium administration to the stressed rats prevented the reductions in sucrose preference and distance traveled in the open field, and normalized the stress‐induced hippocampal BBB hyperpermeability, whereas lithium administration to the unstressed rats increased hippocampal BBB permeability. Additionally, lithium treatment attenuated the decrease in hippocampal AQP4 to glial fibrillary acidic protein immunoreactivity ratio in the stressed rats and upregulated hippocampal claudin‐5 and BDNF proteins expression.
Conclusions
Our findings suggest that lithium administration in a rat CMS model of depressive‐like behavior is associated with attenuation of stressed‐induced hippocampal BBB/NVU disruption. These protective effects may be relevant to the mode of action of lithium in depression.
Our findings suggest that poor adherence to AD is associated with increased all-cause mortality in people with PD. Given the high prevalence of depression and AD effectiveness, efforts to promote adherence should be prioritized in clinical practice.
Our results support the notion of an imbalance of fluid and electrolyte homeostasis among bipolar episodes, which is suggestive for relative hemoconcentration during depressive episodes and relative hemodilution during manic episodes. These findings may eventually lead to novel therapeutic targets.
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