IGHMBP2 mutation associated with organ-specific autonomic dysfunction

Biallelic mutations in the IGHMBP2 have been associated with two distinct phenotypes: spinal muscular atrophy with respiratory distress type 1 (SMARD1) and CMT2S. We describe a patient who developed progressive muscle weakness and wasting in her upper and lower limbs from infancy. She developed respiratory involvement at age 9, eventually requiring 24-h non-invasive ventilation, and severe autonomic dysfunction restricted to the gastrointestinal tract. Neurophysiological studies at age 27 years revealed absent sensory and motor responses and severe chronic denervation changes in proximal muscles of the upper limbs. Targeted multigene panel sequencing detected a novel homozygous missense variant in the IGHMBP2 gene (c.1325A > G; p.Tyr442Cys). This variant was validated by Sanger sequencing and co-segregation analysis confirmed that both parents were asymptomatic heterozygous carriers. This case report confirms that IGHMBP2 related disorders can result in a severe peripheral neuropathy with gastrointestinal autonomic dysfunction requiring parenteral nutrition

Evaluación de la contaminación con agentes citotóxicos en hospitales en Colombia.

Introducción: Las revisiones del 2007 a la farmacopea americana vigente en todo el hemisferio occidental (USP capítulo 797) incluyen una sección sobre el manejo de fármacos peligrosos como preparaciones magistrales estériles, donde se recomienda el muestreo ambiental para detectar trazas de fármacos peligrosos no contenidos, afirmando que esta medida de calidad debe llevarse a cabo de forma rutinaria. Objetivo: Determinar la tasa de contaminación con agentes citotóxicos en las áreas de trabajo de tres instituciones hospitalarias de Colombia. Material y métodos: Estudio descriptivo, prospectivo, transversal. Se recolectaron muestras de 18 áreas evaluando simultáneamente la presencia de tres fármacos que han sido históricamente usados como trazadores de contaminación química: Ciclofosfamida, 5-Fluorouracilo y Carboplatino. Se evalúan superficies de áreas de preparación (cabina de seguridad biológica-CSB o aislador de barrera-AB), alistamiento y administración de medicamentos oncológicos incluyendo áreas comunes a la central de mezclas y la sala de administración de medicamentos oncológicos. Resultados: En el departamento de enfermería y farmacia existe contaminación química debido a los medicamentos citostáticos. En enfermería la contaminación se dio más debido a Carboplatino mientras que en el área de central de mezclas, el fármaco que más detectado fue 5-fluoruracilo. La comparación entre ambos departamentos permite evidenciar que la mayor tasa de contaminación se ha encontrado en farmacia. El principio activo más detectado fue 5-fluoruracilo. Conclusión: Se recomienda que las instituciones revisen los estándares para la preparación y administración de fármacos peligrosos a la luz de la normatividad mundial (USP, ASHP, ISOPP) en aspectos como la política y el procedimiento actual, controles de ingeniería, procedimientos de limpieza, manipulación de los viales del fabricante, evaluación de la CSB o AB, capacitación y educación del personal tanto en las áreas de preparación y administración, uso de EPP adecuados, la incidencia de derrames recientes en el área de la farmacia o de preparación que podrían elevar los niveles de detección y la implementación de CSTD

Evaluación de la contaminación con agentes citotóxicos en hospitales en Colombia.

Introducción: Las revisiones del 2007 a la farmacopea americana vigente en todo el hemisferio occidental (USP capítulo 797) incluyen una sección sobre el manejo de fármacos peligrosos como preparaciones magistrales estériles, donde se recomienda el muestreo ambiental para detectar trazas de fármacos peligrosos no contenidos, afirmando que esta medida de calidad debe llevarse a cabo de forma rutinaria. Objetivo: Determinar la tasa de contaminación con agentes citotóxicos en las áreas de trabajo de tres instituciones hospitalarias de Colombia. Material y métodos: Estudio descriptivo, prospectivo, transversal. Se recolectaron muestras de 18 áreas evaluando simultáneamente la presencia de tres fármacos que han sido históricamente usados como trazadores de contaminación química: Ciclofosfamida, 5-Fluorouracilo y Carboplatino. Se evalúan superficies de áreas de preparación (cabina de seguridad biológica-CSB o aislador de barrera-AB), alistamiento y administración de medicamentos oncológicos incluyendo áreas comunes a la central de mezclas y la sala de administración de medicamentos oncológicos. Resultados: En el departamento de enfermería y farmacia existe contaminación química debido a los medicamentos citostáticos. En enfermería la contaminación se dio más debido a Carboplatino mientras que en el área de central de mezclas, el fármaco que más detectado fue 5-fluoruracilo. La comparación entre ambos departamentos permite evidenciar que la mayor tasa de contaminación se ha encontrado en farmacia. El principio activo más detectado fue 5-fluoruracilo. Conclusión: Se recomienda que las instituciones revisen los estándares para la preparación y administración de fármacos peligrosos a la luz de la normatividad mundial (USP, ASHP, ISOPP) en aspectos como la política y el procedimiento actual, controles de ingeniería, procedimientos de limpieza, manipulación de los viales del fabricante, evaluación de la CSB o AB, capacitación y educación del personal tanto en las áreas de preparación y administración, uso de EPP adecuados, la incidencia de derrames recientes en el área de la farmacia o de preparación que podrían elevar los niveles de detección y la implementación de CSTD

The Functional DRD3 Ser9Gly Polymorphism (rs6280) Is Pleiotropic, Affecting Reward as Well as Movement

Abnormalities of motivation and behavior in the context of reward are a fundamental component of addiction and mood disorders. Here we test the effect of a functional missense mutation in the dopamine 3 receptor (DRD3) gene (ser9gly, rs6280) on reward-associated dopamine (DA) release in the striatum. Twenty-six healthy controls (HCs) and 10 unmedicated subjects with major depressive disorder (MDD) completed two positron emission tomography (PET) scans with [11C]raclopride using the bolus plus constant infusion method. On one occasion subjects completed a sensorimotor task (control condition) and on another occasion subjects completed a gambling task (reward condition). A linear regression analysis controlling for age, sex, diagnosis, and self-reported anhedonia indicated that during receipt of unpredictable monetary reward the glycine allele was associated with a greater reduction in D2/3 receptor binding (i.e., increased reward-related DA release) in the middle (anterior) caudate (p<0.01) and the ventral striatum (p<0.05). The possible functional effect of the ser9gly polymorphism on DA release is consistent with previous work demonstrating that the glycine allele yields D3 autoreceptors that have a higher affinity for DA and display more robust intracellular signaling. Preclinical evidence indicates that chronic stress and aversive stimulation induce activation of the DA system, raising the possibility that the glycine allele, by virtue of its facilitatory effect on striatal DA release, increases susceptibility to hyperdopaminergic responses that have previously been associated with stress, addiction, and psychosis

Tracing of temporo-entorhinal connections in the human brain: cognitively impaired argyrophilic grain disease cases show dendritic alterations but no axonal disconnection of temporo-entorhinal association neurons

Argyrophilic grain disease (AGD), a neurodegenerative disorder, is often associated with mild to moderate Alzheimer’s disease (AD)-related pathology. The development of dementia in AGD is associated with the extent of coexisting AD-related pathology. Therefore, the question arises whether the degenerative changes in the neuronal network of demented AGD-patients represent a distinct pattern or show similar changes of disconnection as considered for AD. We were able to apply DiI-tracing in two human autopsy cases with mild AD-related pathology (controls), in one AD-patient, in one non-demented patient with advanced AD-related pathology, and in three cognitively impaired AGD-patients. DiI-crystals were injected into the entorhinal cortex. Pyramidal neurons of layers III and V of the adjacent temporal neocortex (area 35) were retrogradely marked with the tracer and analyzed. The AD case did not exhibit any retrogradely labeled neurons in the temporal neocortex. In the non-demented case with advanced AD-related pathology, the number of traced neurons was reduced as compared to that in the two controls and in the three AGD cases. In contrast, all three cognitively impaired AGD cases exhibited labeled pyramidal neurons in area 35 in an almost similar number as in the controls. However, alterations in the dendritic tree were observed in the AGD cases. These results show the existence of temporo-entorhinal connections in the adult human brain similar to those reported in animal models. Furthermore, the present study based on seven cases is the first attempt to study changes in the neuronal network in a human tauopathy with targeted axonal tracing techniques. Our findings in three cognitively impaired AGD cases suggest that AGD-related dementia constitutes a distinct disorder with a characteristic pattern of degeneration in the neuronal network

Ketamine enhances structural plasticity in mouse mesencephalic and human iPSC-derived dopaminergic neurons via AMPAR-driven BDNF and mTOR signaling

Among neurobiological mechanisms underlying antidepressant properties of ketamine, structural remodeling of prefrontal and hippocampal neurons has been proposed as critical. The suggested mechanism involves downstream activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, which trigger mammalian target of rapamycin (mTOR)-dependent structural plasticity via brain-derived neurotrophic factor (BDNF) and protein neo-synthesis. We evaluated whether ketamine elicits similar molecular events in dopaminergic (DA) neurons, known to be affected in mood disorders, using a novel, translational strategy that involved mouse mesencephalic and human induced pluripotent stem cells-derived DA neurons. Sixty minutes exposure to ketamine elicited concentration-dependent increases of dendritic arborization and soma size in both mouse and human cultures as measured 72 hours after application. These structural effects were blocked by mTOR complex/signaling inhibitors like rapamycin. Direct evidence of mTOR activation by ketamine was revealed by its induction of p70S6 kinase. All effects of ketamine were abolished by AMPA receptor antagonists and mimicked by the AMPA-positive allosteric modulator CX614. Inhibition of BDNF signaling prevented induction of structural plasticity by ketamine or CX614. Furthermore, the actions of ketamine required functionally intact dopamine D3 receptors (D3R), as its effects were abolished by selective D3R antagonists and absent in D3R knockout preparations. Finally, the ketamine metabolite (2R,6R)-hydroxynorketamine mimicked ketamine effects at sub-micromolar concentrations. These data indicate that ketamine elicits structural plasticity by recruitment of AMPAR, mTOR and BDNF signaling in both mouse mesencephalic and human induced pluripotent stem cells-derived DA neurons. These observations are of likely relevance to the influence of ketamine upon mood and its other functional actions in vivo.Molecular Psychiatry advance online publication, 21 November 2017; doi:10.1038/mp.2017.241

Tomato Pathogenesis-related Protein Genes are Expressed in Response to Trialeurodes vaporariorum and Bemisia tabaci Biotype B Feeding

The temporal and spatial expression of tomato wound- and defense-response genes to Bemisia tabaci biotype B (the silverleaf whitefly) and Trialeurodes vaporariorum (the greenhouse whitefly) feeding were characterized. Both species of whiteflies evoked similar changes in tomato gene expression. The levels of RNAs for the methyl jasmonic acid (MeJA)- or ethylene-regulated genes that encode the basic β-1,3-glucanase (GluB), basic chitinase (Chi9), and Pathogenesis-related protein-1 (PR-1) were monitored. GluB and Chi9 RNAs were abundant in infested leaves from the time nymphs initiated feeding (day 5). In addition, GluB RNAs accumulated in apical non-infested leaves. PR-1 RNAs also accumulated after whitefly feeding. In contrast, the ethylene- and salicylic acid (SA)-regulated Chi3 and PR-4 genes had RNAs that accumulated at low levels and GluAC RNAs that were undetectable in whitefly-infested tomato leaves. The changes in Phenylalanine ammonia lyase5 (PAL5) were variable; in some, but not all infestations, PAL5 RNAs increased in response to whitefly feeding. PAL5 RNA levels increased in response to MeJA, ethylene, and abscisic acid, and declined in response to SA. Transcripts from the wound-response genes, leucine aminopeptidase (LapA1) and proteinase inhibitor 2 (pin2), were not detected following whitefly feeding. Furthermore, whitefly infestation of transgenic LapA1:GUS tomato plants showed that whitefly feeding did not activate the LapA1 promoter, although crushing of the leaf lamina increased GUS activity up to 40 fold. These studies indicate that tomato plants perceive B. tabaci and T. vaporariorum in a manner similar to baterical pathogens and distinct from tissue-damaging insects

Demographic, socio-economic, and cultural factors affecting fertility differentials in Nepal

<p>Abstract</p> <p>Background</p> <p>Traditionally Nepalese society favors high fertility. Children are a symbol of well-being both socially and economically. Although fertility has been decreasing in Nepal since 1981, it is still high compared to many other developing countries. This paper is an attempt to examine the demographic, socio-economic, and cultural factors for fertility differentials in Nepal.</p> <p>Methods</p> <p>This paper has used data from the Nepal Demographic and Health Survey (NDHS 2006). The analysis is confined to ever married women of reproductive age (8,644). Both bivariate and multivariate analyses have been performed to describe the fertility differentials. The bivariate analysis (one-way ANOVA) was applied to examine the association between children ever born and women's demographic, socio-economic, and cultural characteristics. Besides bivariate analysis, the net effect of each independent variable on the dependent variable after controlling for the effect of other predictors has also been measured through multivariate analysis (multiple linear regressions).</p> <p>Results</p> <p>The mean numbers of children ever born (CEB) among married Nepali women of reproductive age and among women aged 40-49 were three and five children, respectively. There are considerable differentials in the average number of children ever born according to women's demographic, socio-economic, and cultural settings. Regression analysis revealed that age at first marriage, perceived ideal number of children, place of residence, literacy status, religion, mass media exposure, use of family planning methods, household headship, and experience of child death were the most important variables that explained the variance in fertility. Women who considered a higher number of children as ideal (β = 0.03; p < 0.001), those who resided in rural areas (β = 0.02; p < 0.05), Muslim women (β = 0.07; p < 0.001), those who had ever used family planning methods (β = 0.08; p < 0.001), and those who had a child-death experience (β = 0.31; p < 0.001) were more likely to have a higher number of CEB compared to their counterparts. On the other hand, those who married at a later age (β = -0.15; p < 0.001), were literate (β = -0.05; p < 0.001), were exposed to both (radio/TV) mass media (β = -0.05; p < 0.001), were richest (β = -0.12; p < 0.001), and were from female-headed households (β = -0.02; p < 0.05) had a lower number of children ever born than their counterparts.</p> <p>Conclusion</p> <p>The average number of children ever born is high among women in Nepal. There are many contributing factors for the high fertility, among which are age at first marriage, perceived ideal number of children, literacy status, mass media exposure, wealth status, and child-death experience by mothers. All of these were strong predictors for CEB. It can be concluded that programs should aim to reduce fertility rates by focusing on these identified factors so that fertility as well as infant and maternal mortality and morbidity will be decreased and the overall well-being of the family maintained and enhanced.</p