Wnt5a Regulates Ventral Midbrain Morphogenesis and the Development of A9–A10 Dopaminergic Cells In Vivo

Wnt5a is a morphogen that activates the Wnt/planar cell polarity (PCP) pathway and serves multiple functions during development. PCP signaling controls the orientation of cells within an epithelial plane as well as convergent extension (CE) movements. Wnt5a was previously reported to promote differentiation of A9–10 dopaminergic (DA) precursors in vitro. However, the signaling mechanism in DA cells and the function of Wnt5a during midbrain development in vivo remains unclear. We hereby report that Wnt5a activated the GTPase Rac1 in DA cells and that Rac1 inhibitors blocked the Wnt5a-induced DA neuron differentiation of ventral midbrain (VM) precursor cultures, linking Wnt5a-induced differentiation with a known effector of Wnt/PCP signaling. In vivo, Wnt5a was expressed throughout the VM at embryonic day (E)9.5, and was restricted to the VM floor and basal plate by E11.5–E13.5. Analysis of Wnt5a−/− mice revealed a transient increase in progenitor proliferation at E11.5, and a precociously induced NR4A2+ (Nurr1) precursor pool at E12.5. The excess NR4A2+ precursors remained undifferentiated until E14.5, when a transient 25% increase in DA neurons was detected. Wnt5a−/− mice also displayed a defect in (mid)brain morphogenesis, including an impairment in midbrain elongation and a rounded ventricular cavity. Interestingly, these alterations affected mostly cells in the DA lineage. The ventral Sonic hedgehog-expressing domain was broadened and flattened, a typical CE phenotype, and the domains occupied by Ngn2+ DA progenitors, NR4A2+ DA precursors and TH+ DA neurons were rostrocaudally reduced and laterally expanded. In summary, we hereby describe a Wnt5a regulation of Wnt/PCP signaling in the DA lineage and provide evidence for multiple functions of Wnt5a in the VM in vivo, including the regulation of VM morphogenesis, DA progenitor cell division, and differentiation of NR4A2+ DA precursors

Synaptic Wnt signaling—a contributor to major psychiatric disorders?

Wnt signaling is a key pathway that helps organize development of the nervous system. It influences cell proliferation, cell fate, and cell migration in the developing nervous system, as well as axon guidance, dendrite development, and synapse formation. Given this wide range of roles, dysregulation of Wnt signaling could have any number of deleterious effects on neural development and thereby contribute in many different ways to the pathogenesis of neurodevelopmental disorders. Some major psychiatric disorders, including schizophrenia, bipolar disorder, and autism spectrum disorders, are coming to be understood as subtle dysregulations of nervous system development, particularly of synapse formation and maintenance. This review will therefore touch on the importance of Wnt signaling to neurodevelopment generally, while focusing on accumulating evidence for a synaptic role of Wnt signaling. These observations will be discussed in the context of current understanding of the neurodevelopmental bases of major psychiatric diseases, spotlighting schizophrenia, bipolar disorder, and autism spectrum disorder. In short, this review will focus on the potential role of synapse formation and maintenance in major psychiatric disorders and summarize evidence that defective Wnt signaling could contribute to their pathogenesis via effects on these late neural differentiation processes

Bilateral renal agenesis/hypoplasia/dysplasia (BRAHD):postmortem analysis of 45 cases with breakpoint mapping of two de novo translocations

Bilateral renal agenesis/hypoplasia/dysplasia (BRAHD) is a relatively common, lethal malformation in humans. Established clinical risk factors include maternal insulin dependent diabetes mellitus and male sex of the fetus. In the majority of cases, no specific etiology can be established, although teratogenic, syndromal and single gene causes can be assigned to some cases.45 unrelated fetuses, stillbirths or infants with lethal BRAHD were ascertained through a single regional paediatric pathology service (male:female 34:11 or 3.1:1). The previously reported phenotypic overlaps with VACTERL, caudal dysgenesis, hemifacial microsomia and Müllerian defects were confirmed. A new finding is that 16/45 (35.6%; m:f 13:3 or 4.3:1) BRAHD cases had one or more extrarenal malformations indicative of a disoder of laterality determination including; incomplete lobulation of right lung (seven cases), malrotation of the gut (seven cases) and persistence of the left superior vena cava (five cases). One such case with multiple laterality defects and sirelomelia was found to have a de novo apparently balanced reciprocal translocation 46,XY,t(2;6)(p22.3;q12). Translocation breakpoint mapping was performed by interphase fluorescent in-situ hybridization (FISH) using nuclei extracted from archival tissue sections in both this case and an isolated bilateral renal agenesis case associated with a de novo 46,XY,t(1;2)(q41;p25.3). Both t(2;6) breakpoints mapped to gene-free regions with no strong evidence of cis-regulatory potential. Ten genes localized within 500 kb of the t(1;2) breakpoints. Wholemount in-situ expression analyses of the mouse orthologs of these genes in embryonic mouse kidneys showed strong expression of Esrrg, encoding a nuclear steroid hormone receptor. Immunohistochemical analysis showed that Esrrg was restricted to proximal ductal tissue within the embryonic kidney.The previously unreported association of BRAHD with laterality defects suggests that renal agenesis may share a common etiology with heterotaxy in some cases. Translocation breakpoint mapping identified ESRRG as a plausible candidate gene for BRAHD

The bacterial agents of nosocomial pneumonia in the reanimation unit patients and their antimicrobial susceptibilities [Reanimasyon ünitesi hastalarinda nozokomiyal pnömoninin bakteriyel etkenleri ve antimikrobik duyarliliklari]

Nosocomial pneumonia is seen with high frequency especially in the patients treated with endotracheal intubation and mechanical ventilation in the intensive care units, This study was planned to determine the bacterial agents that may be responsible for nosocomial pneumonia in the patients in the Reanimation Unit in our hospital and their antibiotic susceptibilities. From March 1993 until May 1998, all of the patients admitted to the Reanimation Unit because of severe respiratory failure and requiring mechanical ventilation for therapy were included into the study. The age range was 15-65 years old. Of the patients with nosocomial pneumonia, 1041 deep tracheal aspiration samples were obtained and examined by classical culture methods. The most frequently isolated bacteria were Pseudomonas aeruginosa (37.46%), Staphylococcus aureus (28.82%) and Enterobacteriaceae strains (18.51%). Antibiotic susceptibilities of the bacteria isolated were examined by the disk diffusion method and imipenem and sefoperazone/sulbactam were found to be the most effective antibiotics against P. aeruginosa and Enterobacteriaceae strains. Of S. aureus strains, 80% were resistant to methicillin and all of them were susceptible to vancomycin. However, it was found that most of the bacteria had high resistance rates for several antibiotics tested. As a result, it may be concluded that it is important to determine and follow up the incidence and antimicrobial susceptibilities of the bacteria causing nosocomial pneumonia in the reanimation units of hospitals in order to apply more effective therapeutic measures

Morphological changes in Candida albicans induced by a silver anode

Background: A silver anode, but not a cathode, has a broad spectrum antibacterial and antifungal effect at low electric current levels. In this study, the antifungal effect of the silver anode has been studied at a cellular level in order to establish a basis for treatment of mycoses. Methods: Candida albicans cells were exposed to 15 µA of anodic direct current with silver electrodes in a culture medium for 24 hours. Yeast cells near the anode and untreated controls were examined using a transmission electron microscope. Then, the plates were incubated at 37°C for 4 more weeks without electricity. Results: Vesicle formation in the cytoplasm which began at the center of the cell was observed in the silver anode treated cells. Cytoplasmic leakage out of the cell occurred which was probably due to osmotic imbalance caused by an alteration of the cell membrane permeability even though the original ultrastructure of the cell wall was intact. In the plates which had been incubated longer, there was no growth inside the inhibition zone around the silver anode. Conclusion: Silver anode treated C. albicans cells showed a clear damage which was irreversible

Comparison of moclobemide and placebo in young adolescents with major depressive disorder

Purpose: In a prospective, randomized double-blind 5-week study, it was aimed to compare the efficacy of moclobemide with placebo in the treatment of young adolescents with major depressive disorder. Methods: 9 girls and 11 boys, range 9-15 years, who fulfilled the criteria for major depressive disorder according to DSM-4 were evaluated at an outpatient child and adolescent psychiatry clinic, and included in a double-blind study, comparing moclobemide and placebo during 5 weeks of treatment. SPECT was used in evaluation. Children Depression Inventory (CDI), State and Trait Anxiety Inventory for Children (STAIC-S, STAIC-T) were given to the patients, and Children Depression Inventory for Parents (CDI-P) were given to the parents at the beginning and at the end of the study. Clinical Global Impression (CGI) (Global Recovery, Severity and Adverse Effects) were recorded by the same child psychiatrists weekly. Adverse Effects Forms were self-recorded by the children weekly. Results: At the end of the study the average score of Adverse Effects show statistically no difference. Global recovery scores showed a statistically significant difference in favour of moclobemide group. There were reductions in anxiety and depression scores in both groups at the end of study. In SPECT findings, regional cerebral blood flow increased significantly at anterofrontal and left prefrontal regions at end of the study in moclobemide group. There were significant increases in right temporo-occipital and right temporal regions in both study groups in favour of moclobemide group. Conclusion: Moclobemide was considered to be effective, tolerable and safe in young adolescents