Impaired expression of the COSMOC/MOCOS gene unit in ASD patient stem cells.

Autism spectrum disorders (ASD) are complex neurodevelopmental disorders with a very large number of risk loci detected in the genome. However, at best, each of them explains rare cases, the majority being idiopathic. Genomic data on ASD derive mostly from post-mortem brain analyses or cell lines derived from blood or patient-specific induced pluripotent stem cells (iPSCS). Therefore, the transcriptional and regulatory architecture of the nervous system, particularly during early developmental periods, remains highly incomplete. To access the critical disturbances that may have occurred during pregnancy or early childhood, we recently isolated stem cells from the nasal cavity of anesthetized patients diagnosed for ASD and compared them to stem cells from gender-matched control individuals without neuropsychiatric disorders. This allowed us to discover MOCOS, a non-mutated molybdenum cofactor sulfurase-coding gene that was under-expressed in the stem cells of most ASD patients of our cohort, disturbing redox homeostasis and synaptogenesis. We now report that a divergent transcription upstream of MOCOS generates an antisense long noncoding RNA, to which we coined the name COSMOC. Surprisingly, COSMOC is strongly under-expressed in all ASD patients of our cohort with the exception of a patient affected by Asperger syndrome. Knockdown studies indicate that loss of COSMOC reduces MOCOS expression, destabilizes lipid and energy metabolisms of stem cells, but also affects neuronal maturation and splicing of synaptic genes. Impaired expression of the COSMOC/MOCOS bidirectional unit might shed new lights on the origins of ASD that could be of importance for future translational studies.

Putative dendritic correlates of chronic traumatic encephalopathy: A preliminary quantitative Golgi exploration.

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disorder that is associated with repetitive head impacts. Neuropathologically, it is defined by the presence of perivascular hyperphosphorylated tau aggregates in cortical tissue (McKee et al., 2016, Acta Neuropathologica, 131, 75-86). Although many pathological and assumed clinical correlates of CTE have been well characterized, its effects on cortical dendritic arbors are still unknown. Here, we quantified dendrites and dendritic spines of supragranular pyramidal neurons in tissue from human frontal and occipital lobes, in 11 cases with (Mage = 79 ± 7 years) and 5 cases without (Mage = 76 ± 11 years) CTE. Tissue was stained with a modified rapid Golgi technique. Dendritic systems of 20 neurons per region in each brain (N = 640 neurons) were quantified using computer-assisted morphometry. One key finding was that CTE neurons exhibited increased variability and distributional changes across six of the eight dendritic system measures, presumably due to ongoing degeneration and compensatory reorganization of dendritic systems. However, despite heightened variation among CTE neurons, CTE cases exhibited lower mean values than Control cases in seven of the eight dendritic system measures. These dendritic alterations may represent a new pathological marker of CTE, and further examination of dendritic changes could contribute to both mechanistic and functional understandings of the disease.

Deletion of Mocos Induces Xanthinuria with Obstructive Nephropathy and Major Metabolic Disorders in Mice.

Background: Xanthinuria type II is a rare autosomal purine disorder. This recessive defect of purine metabolism remains an under-recognized disorder. Methods: Mice with targeted disruption of the molybdenum cofactor sulfurase (Mocos) gene were generated to enable an integrated understanding of purine disorders and evaluate pathophysiologic functions of this gene which is found in a large number of pathways and is known to be associated with autism. Results: Mocos-deficient mice die with 4 weeks of age due to renal failure of distinct obstructive nephropathy with xanthinuria, xanthine deposits, cystic tubular dilation, Tamm-Horsfall (uromodulin) protein (THP) deposits, tubular cell necrosis with neutrophils, and occasionally hydronephrosis with urolithiasis. Obstructive nephropathy is associated with moderate interstitial inflammatory and fibrotic responses, anemia, reduced detoxification systems, and important alterations of the metabolism of purines, amino acids, and phospholipids. Conversely, heterozygous mice expressing reduced MOCOS protein are healthy with no apparent pathology. Conclusions: Mocos-deficient mice develop a lethal obstructive nephropathy associated with profound metabolic changes. Studying MOCOS functions may provide important clues about the underlying pathogenesis of xanthinuria and other diseases requiring early diagnosis.

Effect of provider-selected order indications on appropriateness of antimicrobial orders in a pediatric hospital.

PURPOSE: The effect of mandatory provider-selected order indications (PSOIs) on appropriateness of antimicrobial ordering in a tertiary pediatric hospital was evaluated. METHODS: Mandatory PSOIs for 14 antimicrobials were implemented in September 2013. Data on initial and final orders in the first 24 hours after ordering were collected from the electronic medical record. Orders from pre-PSOI and post-PSOI implementation were randomly selected and compared with documentation at the time of order to elicit the documentation-determined clinical indication (DDCI). Appropriateness of the order for the DDCI was evaluated and compared between groups using 2-sample t tests, chi-square tests, and logistic regression. RESULTS: Among the total 1,304 orders included in the review, 275 (21.1%) were inappropriate based on DDCI. The indications associated with the greatest number of inappropriate orders in both groups were suspected sepsis/bacteremia, meningitis/central nervous system infection, and pneumonia. A total of 128 (18.3%) of 700 initial orders were inappropriate compared with the DDCI in the pre-PSOI period, and 82 (17.8%) of 461 initial orders were inappropriate in the post-PSOI period (p = 0.83). A total of 78 (11.1%) of 700 final orders were inappropriate in the pre-PSOI period, and 29 (6.3%) of 461 final orders were inappropriate in the post-intervention period (p = 0.01). Overall, 84 (12%) of 700 inappropriate orders reached the patient in the pre-PSOI period versus 43 (9.3%) of 461 inappropriate orders in the post-PSOI period (p = 0.15). CONCLUSION: PSOIs were effective in reducing inappropriate antimicrobial orders in the first 24 hours after ordering if the correct indication was selected.

Comparative morphology of gigantopyramidal neurons in primary motor cortex across mammals.

Gigantopyramidal neurons, referred to as Betz cells in primates, are characterized by large somata and extensive basilar dendrites. Although there have been morphological descriptions and drawings of gigantopyramidal neurons in a limited number of species, quantitative investigations have typically been limited to measures of soma size. The current study thus employed two separate analytical approaches: a morphological investigation using the Golgi technique to provide qualitative and quantitative somatodendritic measures of gigantopyramidal neurons across 19 mammalian species from 7 orders; and unbiased stereology to compare the soma volume of layer V pyramidal and gigantopyramidal neurons in primary motor cortex between 11 carnivore and 9 primate species. Of the 617 neurons traced in the morphological analysis, 181 were gigantopyramidal neurons, with deep (primarily layer V) pyramidal (n = 203) and superficial (primarily layer III) pyramidal (n = 233) neurons quantified for comparative purposes. Qualitatively, dendritic morphology varied considerably across species, with some (sub)orders (e.g., artiodactyls, perissodactyls, feliforms) exhibiting bifurcating, V-shaped apical dendrites. Basilar dendrites exhibited idiosyncratic geometry across and within taxonomic groups. Quantitatively, most dendritic measures were significantly greater in gigantopyramidal neurons than in superficial and deep pyramidal neurons. Cluster analyses revealed that most taxonomic groups could be discriminated based on somatodendritic morphology for both superficial and gigantopyramidal neurons. Finally, in agreement with Brodmann, gigantopyramidal neurons in both the morphological and stereological analyses were larger in feliforms (especially in the Panthera species) than in other (sub)orders, possibly due to specializations in muscle fiber composition and musculoskeletal systems.

Neocortical neuronal morphology in the Siberian Tiger (Panthera tigris altaica) and the clouded leopard (Neofelis nebulosa).

Despite extensive investigations of the neocortex in the domestic cat, little is known about neuronal morphology in larger felids. To this end, the present study characterized and quantified the somatodendritic morphology of neocortical neurons in prefrontal, motor, and visual cortices of the Siberian tiger (Panthera tigris altaica) and clouded leopard (Neofelis nebulosa). After neurons were stained with a modified Golgi technique (N = 194), dendritic branching and spine distributions were analyzed using computer-assisted morphometry. Qualitatively, aspiny and spiny neurons in both species appeared morphologically similar to those observed in the domestic cat. Although the morphology of spiny neurons was diverse, with the presence of extraverted, inverted, horizontal, and multiapical pyramidal neurons, the most common variant was the typical pyramidal neuron. Gigantopyramidal neurons in the motor cortex were extremely large, confirming the observation of Brodmann ([1909] Vergleichende Lokalisationlehre der Grosshirnrinde in ihren Prinzipien dargestellt auf Grund des Zellenbaues. Leipzig, Germany: J.A. Barth), who found large somata for these neurons in carnivores in general, and felids in particular. Quantitatively, a MARSplines analysis of dendritic measures differentiated typical pyramidal neurons between the Siberian tiger and the clouded leopard with 93% accuracy. In general, the dendrites of typical pyramidal neurons were more complex in the tiger than in the leopards. Moreover, dendritic measures in tiger pyramidal neurons were disproportionally large relative to body/brain size insofar as they were nearly as extensive as those observed in much larger mammals (e.g., African elephant). Comparison of neuronal morphology in a more diverse collection of larger felids may elucidate the comparative context for the relatively large size of the pyramidal neurons observed in the present study. J. Comp. Neurol. 524:3641-3665, 2016. © 2016 Wiley Periodicals, Inc.

Prevalencia de algunos factores de riesgo cardiovascular en dos poblaciones de altura del distrito de Huaraz (3100 msnm) / Prevalence of cardiovascular risk factors in two populations of Huaraz district level (3100 masl)

Objetivo: estudiar la prevalencia de algunos factores de riesgo cardiovascular (FRC9 en adultos nativos de altura del distrito de Huaraz-Ancash (3100 m.s.n.m.). Material y métodos: estudio comparativo y transversal de individuos mayores de 18 años que vivían en área urbana (Barrio Belén) y el área rural (Comunidad de Paquishca), del distrito de Huaraz. Luego de un muestreo por etapas, la muestra quedó conformada por 204 personas (102 del área urbana y 102 del área rural). Se utilizó una encuesta previamente validada, que se aplicó en agosto del 2004 y se evaluaron nueve parámetros. Resultados: se halló que los FRC se encontraron presentes en Huaraz y fueron más prevalentes en la población urbana (95%) que en la rural (66.7%). Al comparar el área urbana con la rural, se halló que la prevalencia de HTA fue 18.6% urbano y 3.9% rural; hipercolesterolemia (13.7% vs. 2%): LDL elevado (39.2% vs. 5.9%); HDL disminuido (51% vs. 48%); hiperglucemia (5.9% vs. 2%); obesidad (15.7% vs. 2%); tabaquismo (21.6% vs. 5%); alcoholismo (12.7% vs. 6.9%) y sedentarismo (73.5% vs. 26.5%); respectivamente. Seis de los nueve FRC estudiados fueron más prevalentes en la población urbana (HTA, hipercolesterolemia, LDL elevado, obesidad, tabaquismo y sedentarismo) por lo que se considera esta diferencia estadísticamente significativa. Asimismo, la prevalencia individual acumulada de los FRC también fue mayor en el área urbana. Conclusiones: los FRC se encuentran presentes en la población adulta de altura del distrito de Huaraz y son más prevalentes en la población urbana que en la rural.

Prevalencia de algunos factores de riesgo cardiovascular en dos poblaciones de Huaraz (3 100 m sobre el nivel del mar) / Prevalence of some cardiovascular risk factors in two populations in Huaraz (3.100 m above sea level)

Objetivo: estudiar la prevalencia de algunos factores de riesgo cardiovascular (FRC) en adultos nativos de altura del distrito de Huaraz-Ancash (3 100 m sobre el nivel del mar). Material y métodos: estudio comparativo y transversal en individuos mayores de 18 años que vivían en área urbana (barrio de Belén) y área rural (comunidad de Paquishca), del distrito de Huaraz. Luego de un muestreo por etapas, la muestra quedó conformada por 204 personas (102 del área urbana y 102 del área rural). Se utilizó una encuesta previamente validada, que se aplicó en agosto del 2004 y se evaluaron nueve parámetros. Resultados: se halló que los FRC se encontraban presentes en Huaraz y fueron más prevalentes en la población urbana 95% que en la rural 66,7%. Comparando el área urbana con la rural, se halló que la prevalencia de HTA fué 18,6% urbano y 3,9% rural; hipercolesterolemia 13,7% vs 2%; LDL elevado 39,2% vs 5,9%; HDL disminuido 51% vs 48%; hiperglucemia 5,9% vs 2%; obesidad 15,7% vs 2%; tabaquismo 21,6% vs 5%; alcoholismo 12,7% vs 6,9% y sedentarismo 73,5% vs 26,5%; respectivamente. Seis de los nueve FRC estudiados fueron más prevalentes en la población urbana (HTA, hipercolesterolemia, LDL elevado, obesidad, tabaquismo y sedentarismo); siendo la diferencia estadísticamente significativa. Asimismo, la prevalencia individual acumulada de los FRC también fué mayor en el área urbana. Conclusiones: los FRC se encuentran presentes en la población adulta de altura del distrito de Huaraz y son más prevalentes en la población urbana que en la rural.

Objective: to study the prevalence of some of cardiovascular risk factors (RCF) in high altitude born adults of the district of Huaraz-Ancash (3,100 m above sea level). Materials and methods: comparative study and cross sectional study in individuals over age 18 living in urban (neighborhood of Bethlehem) and the rural (community of Paquishca) areas of the district of Huaraz. After staged sampling, the sample consisted of 204 people (102 urban and 102 rural). A previously validated survey was applied in August, 2004, evaluating 9 parameters. Results: RCF were found in Huaraz, with a greater prevalence in the urban population (95%) that in the rural one (66,7%). Comparing urban vs. rural populations, the prevalence of arterial hypertension AHT was 18,6% vs. 3,9% rural; hypercolesterolemia 13,7% vs. 2%; high LDL 39,2% vs. 5,9%; low HDL 51% vs. 48%; hyperglycemia 5,9% vs. 2%; obesity 15,7% vs. 2%; smoking 21,6% vs. 5%; alcoholism 12.7% vs. 6.9% and sedentary lifestyle 73,5% vs. 26,5%. Six of the nine RCF studied were more prevalent in the urban population (AHT, hypercolesterolemia, high LDL, obesity, smoking and sedentary lifestyle), with statistically significant differences. The accumulated individual prevalence of the RCF was also greater in the urban area. Conclusions: RCF are present in the adult high altitude population of the district of Huaraz, and they are more prevalent in the urban population than in the rural one.

MAU-8 is a Phosducin-like Protein required for G protein signaling in C. elegans.

The mau-8(qm57) mutation inhibits the function of GPB-2, a heterotrimeric G protein beta subunit, and profoundly affects behavior through the Galphaq/Galphao signaling network in C. elegans. mau-8 encodes a nematode Phosducin-like Protein (PhLP), and the qm57 mutation leads to the loss of a predicted phosphorylation site in the C-terminal domain of PhLP that binds the Gbetagamma surface implicated in membrane interactions. In developing embryos, MAU-8/PhLP localizes to the cortical region, concentrates at the centrosomes of mitotic cells and remains associated with the germline blastomere. In adult animals, MAU-8/PhLP is ubiquitously expressed in somatic tissues and germline cells. MAU-8/PhLP interacts with the PAR-5/14.3.3 protein and with the Gbeta subunit GPB-1. In mau-8 mutants, the disruption of MAU-8/PhLP stabilizes the association of GPB-1 with the microtubules of centrosomes. Our results indicate that MAU-8/PhLP modulates G protein signaling, stability and subcellular location to regulate various physiological functions, and they suggest that MAU-8 might not be limited to the Galphaq/Galphao network.