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Schizophrenia is a highly heritable mental disorder which can be occurred as a result of mutations or single nucleotide polymorphisms (SNPs) in various genes. Proline dehydrogenase (PRODH) gene is one of the most important genes which can be associated with increased risk of schizophrenia in several populations. Here, we considered the effect of PRODH gene polymorphisms on the incidence of schizophrenia in Iranian populations. This study was done using the analysis of 3 SNPs markers, including G1496A, G758A and C1482T. Molecular analysis was performed on 263 schizophrenic patients and 278 healthy individuals (control group). These examinations were executed by PCR-based restriction fragment length polymorphism (RFLP) technique. Statistical analysis was performed by SPSS software (16.0). Our findings showed that G1496A and C1482T polymorphisms in patients were significantly higher than controls and there were meaningful correlations between the occurrence of these polymorphisms and schizophrenia in the population (P < 0.001). However­, there was no significant relationship between G758A in the PRODH gene and schizophrenia. Haplotype analysis showed that AAT, AAC and GAT blocks (variation alleles are bold) had significant correlations with schizophrenia. PRODH gene can be considered as one of the important genes involved in schizophrenia development among the Iranian population.

Hyperprolinemia type I (HPI) is an autosomal recessive metabolic disorder caused by defects in proline oxidase. We herein describe a case of a patient with HPI and harboring the NM_016335.4 (PRODH_v001):c.1397 C > T (p.T466M) mutation and polymorphisms in the PRODH gene, as detected by plasma amino acid analysis and Sanger sequencing. The patient presented with short stature, carbohydrate-rich dietary preferences, and mild intellectual disability that was suggestive of a neurodevelopmental or learning disorder.

Patients with medulloblastoma, the most common malignant pediatric brain tumor. need improved treatment options. Conventional medulloblastoma treatment, with resection, chemotherapy, and radiation, leaves survivors at risk of neurocognitive injury, growth defects, and psychosocial impairment. Moreover, there is no effective therapy for recurrent medulloblastoma. We seek to identify novel treatments that will address systemic toxicity and tumor recurrence. We tested a nanoparticle formulation of the CDK4/6 inhibitor, palbociclib (POx-palbo) in mice genetically-engineered to develop medulloblastoma (G-Smo mice) and found a significant anti-tumor effect that was consistently limited by the recurrence of OLIG2+ medulloblastoma stem cells. We then tested the hypothesis that directly targeting OLIG2 function would improve the efficacy of palbociclib and forestall resistance. We therefore examined the potential efficacy of CT-179, a first-in-class OLIG2 inhibitor, in G-Smo mice engineered to express luciferase as an SHH reporter. These studies showed that CT-179 decreased SHH signaling and prolonged event-free survival. Pharmacodynamic studies of G-Smo mice during treatment showed that CT-179 alters cell-cycle progression and promotes a shift towards cell-cycle arrest. Mechanistically, CT-179 decreased the Olig2 phosphorylation. The combination of CT-179 and POx-palbo increased event-free survival of G-Smo mice compared to either agent administered alone. Our studies show both the potential of the palbociclib CT-179 combination, and the potential for CT-179 to improve the efficacy of therapies limited by OLIG2+ stem cell recurrence. As OLIG2+ stem cells have been shown to drive recurrence to conventional therapy and OLIG2 phosphorylation disables p53-driven apoptosis, CT-179 may be a versatile agent to enhance both targeted and cytotoxic treatments.

Lately, microdeletions of the 22q region, responsible for DiGeorge syndrome or velocardiofacial syndrome, have been increasingly related to neuropsychiatric disorders including schizophrenia and bipolar disorder. These manifestations seem to be related to certain genes located in the hemideleted region such as the proline dehydrogenase (PRODH) and the catechol-o-methyltransferase (COMT) genes. We describe a teenager who started his adolescent psychiatric care presenting cognitive impairment, irritable mood and aggressive behaviour with schizophrenia-like symptoms that scored 153 in the Positive and Negative Symptoms Scale (PANSS) assessment. Worsening of symptoms when the patient was treated with valproic acid, and plasma aminoacids showing an increase in alanine and proline, suggested a mitochondrial involvement of the proline metabolic pathway. Mild dysmorphic features also suggested a possible 22q11 deletion syndrome that was confirmed. A mutation for Hyperprolinemia type I was also detected. Knowledge of the correct diagnosis was crucial for an adequate treatment. info:eu-repo/semantics/publishedVersion

Mutations in proline dehydrogenase (PRODH) are linked to behavioral alterations in schizophrenia and as part of DiGeorge and velo-cardio-facial syndromes, but the role of PRODH in their etiology remains unclear. We here establish a Drosophila model to study the role of PRODH in behavioral disorders. We determine the distribution of the Drosophila PRODH homolog slgA in the brain and show that knock-down and overexpression of human PRODH and slgA in the lateral neurons ventral (LNv) lead to altered aggressive behavior. SlgA acts in an isoform-specific manner and is regulated by casein kinase II (CkII). Our data suggest that these effects are, at least partially, due to effects on mitochondrial function. We thus show that precise regulation of proline metabolism is essential to drive normal behavior and we identify Drosophila aggression as a model behavior relevant for the study of mechanisms impaired in neuropsychiatric disorders. ispartof: Disease Models and Mechanisms vol:10 issue:6 pages:705-716 ispartof: location:England status: published

OBJECTIVE. The purpose of this prospective study was to assess the feasibility and reliability of pulse oximetry screening to detect critical congenital heart defects in a newborn nursery.METHODS. The study was performed in a large urban hospital with an exclusively inborn population. Stable neonates who had a gestational age of ≥35 weeks and birth weight of ≥2100 g and in whom a critical congenital heart defect was not suspected were admitted to the newborn nursery. When the 4-hour pulse oximetry reading was RESULTS. Of 15299 admissions to newborn nursery during the 12-month study period, 15233 (99.6%) neonates were screened with 4-hour pulse oximetry. Pulse oximetry readings were ≥96% for 14374 (94.4%) neonates; 77 were subsequently evaluated before discharge for cardiac defects on the basis of clinical examination. Seventy-six were normal, and 1 had tetralogy of Fallot with discontinuous pulmonary arteries. Pulse oximetry readings at 4 hours were CONCLUSIONS. All neonates with a critical congenital heart defect were detected clinically, and no cases of critical congenital heart defect were detected by pulse oximetry screening. These results indicate that pulse oximetry screening does not improve detection of critical congenital heart defects above and beyond clinical observation and assessment. Our findings do not support a recommendation for routine pulse oximetry screening in seemingly healthy neonates.

Background We have previously shown that lipophilic components (LPC) of the brown seaweed Ascophyllum nodosum (ANE) improved freezing tolerance in Arabidopsis thaliana. However, the mechanism(s) of this induced freezing stress tolerance is largely unknown. Here, we investigated LPC induced changes in the transcriptome and metabolome of A. thaliana undergoing freezing stress. Results Gene expression studies revealed that the accumulation of proline was mediated by an increase in the expression of the proline synthesis genes P5CS1 and P5CS2 and a marginal reduction in the expression of the proline dehydrogenase (ProDH) gene. Moreover, LPC application significantly increased the concentration of total soluble sugars in the cytosol in response to freezing stress. Arabidopsis sfr4 mutant plants, defective in the accumulation of free sugars, treated with LPC, exhibited freezing sensitivity similar to that of untreated controls. The 1H NMR metabolite profile of LPC-treated Arabidopsis plants exposed to freezing stress revealed a spectrum dominated by chemical shifts (δ) representing soluble sugars, sugar alcohols, organic acids and lipophilic components like fatty acids, as compared to control plants. Additionally, 2D NMR spectra suggested an increase in the degree of unsaturation of fatty acids in LPC treated plants under freezing stress. These results were supported by global transcriptome analysis. Transcriptome analysis revealed that LPC treatment altered the expression of 1113 genes (5%) in comparison with untreated plants. A total of 463 genes (2%) were up regulated while 650 genes (3%) were down regulated. Conclusion Taken together, the results of the experiments presented in this paper provide evidence to support LPC mediated freezing tolerance enhancement through a combination of the priming of plants for the increased accumulation of osmoprotectants and alteration of cellular fatty acid composition.