Triarylmethanes, a New Class of Cx50 Inhibitors

The paucity of specific pharmacological agents has been a major impediment for delineating the roles of gap junction (GJ) channels formed by connexin proteins in physiology and pathophysiology. Here, we used the selective optimization of side activities (SOSA) approach, which has led to the design of high affinity inhibitors of other ion channels, to identify a specific inhibitor for channels formed by Cx50, a connexin subtype that is primarily expressed in the lens. We initially screened a library of common ion channel modulating pharmacophores for their inhibitory effects on Cx50 GJ channels, and identified four new classes of compounds. The triarlymethane (TRAM) clotrimazole was the most potent Cx50 inhibitor and we therefore used it as a template to explore the structure activity relationship (SAR) of the TRAMs for Cx50 inhibition. We describe the design of T122 (N-[(2-methoxyphenyl)diphenylmethyl]-1,3-thiazol-2-amine) and T136 (N-[(2-iodophenyl)diphenylmethyl]-1,3-thiazol-2-amine), which inhibit Cx50 with IC50s of 1.2 and 2.4 μM. Both compounds exhibit at least 10-fold selectivity over other connexins as well as major neuronal and cardiac voltage-gated K+ and Na+ channels. The SAR studies also indicated that the TRAM pharmacophore required for connexin inhibition is significantly different from the pharmacophore required for blocking the calcium-activated KCa3.1 channel. Both T122 and T136 selectively inhibited Cx50 GJ channels in lens epithelial cells, suggesting that they could be used to further explore the role of Cx50 in the lens. In addition, our results indicate that a similar approach may be used to find specific inhibitors of other connexin subtypes

Intranasal oxytocin in children and adolescents with autism spectrum disorder

BACKGROUND Experimental studies and small clinical trials have suggested that treatment with intranasal oxytocin may reduce social impairment in persons with autism spectrum disorder. Oxytocin has been administered in clinical practice to many children with autism spectrum disorder. METHODS We conducted a 24-week, placebo-controlled phase 2 trial of intranasal oxytocin therapy in children and adolescents 3 to 17 years of age with autism spectrum disorder. Participants were randomly assigned in a 1:1 ratio, with stratification according to age and verbal fluency, to receive oxytocin or placebo, administered intranasally, with a total target dose of 48 international units daily. The primary outcome was the least-squares mean change from baseline on the Aberrant Behavior Checklist modified Social Withdrawal subscale (ABC-mSW), which includes 13 items (scores range from 0 to 39, with higher scores indicating less social interaction). Secondary outcomes included two additional measures of social function and an abbreviated measure of IQ. RESULTS Of the 355 children and adolescents who underwent screening, 290 were enrolled. A total of 146 participants were assigned to the oxytocin group and 144 to the placebo group; 139 and 138 participants, respectively, completed both the baseline and at least one postbaseline ABC-mSW assessments and were included in the modified intention-to-treat analyses. The least-squares mean change from baseline in the ABC-mSW score (primary outcome) was −3.7 in the oxytocin group and −3.5 in the placebo group (least-squares mean difference, −0.2; 95% confidence interval, −1.5 to 1.0; P=0.61). Secondary outcomes generally did not differ between the trial groups. The incidence and severity of adverse events were similar in the two groups. CONCLUSIONS This placebo-controlled trial of intranasal oxytocin therapy in children and adolescents with autism spectrum disorder showed no significant between-group differences in the least-squares mean change from baseline on measures of social or cognitive functioning over a period of 24 weeks

‘Costa da Morte’ ataxia is spinocerebellar ataxia 36: clinical and genetic characterization

Spinocerebellar ataxia 36 has been recently described in Japanese families as a new type of spinocerebellar ataxia with motor neuron signs. It is caused by a GGCCTG repeat expansion in intron 1 of NOP56. Family interview and document research allowed us to reconstruct two extensive, multigenerational kindreds stemming from the same village (Costa da Morte in Galicia, Spain), in the 17th century. We found the presence of the spinocerebellar ataxia 36 mutation co-segregating with disease in these families in whom we had previously identified an ∼0.8 Mb linkage region to chromosome 20 p. Subsequent screening revealed the NOP56 expansion in eight additional Galician ataxia kindreds. While normal alleles contain 5–14 hexanucleotide repeats, expanded alleles range from ∼650 to 2500 repeats, within a shared haplotype. Further expansion of repeat size was frequent, especially upon paternal transmission, while instances of allele contraction were observed in maternal transmissions. We found a total of 63 individuals carrying the mutation, 44 of whom were confirmed to be clinically affected; over 400 people are at risk. We describe here the detailed clinical picture, consisting of a late-onset, slowly progressive cerebellar syndrome with variable eye movement abnormalities and sensorineural hearing loss. There were signs of denervation in the tongue, as well as mild pyramidal signs, but otherwise no signs of classical amyotrophic lateral sclerosis. Magnetic resonance imaging findings were consistent with the clinical course, showing atrophy of the cerebellar vermis in initial stages, later evolving to a pattern of olivo-ponto-cerebellar atrophy. We estimated the origin of the founder mutation in Galicia to have occurred ∼1275 years ago. Out of 160 Galician families with spinocerebellar ataxia, 10 (6.3%) were found to have spinocerebellar ataxia 36, while 15 (9.4%) showed other of the routinely tested dominant spinocerebellar ataxia types. Spinocerebellar ataxia 36 is thus, so far, the most frequent dominant spinocerebellar ataxia in this region, which may have implications for American countries associated with traditional Spanish emigration

Sensory reactivity symptoms are a core feature of ADNP syndrome irrespective of autism diagnosis

Background: Activity dependent neuroprotective protein (ADNP) syndrome is one of the most common single-gene causes of autism spectrum disorder (ASD) and intellectual disability, however, the phenotypes remain poorly described. Here we examine the sensory reactivity phenotype in children and adolescents with ADNP syndrome. Methods: Twenty-two individuals with ADNP syndrome received comprehensive clinical evaluations including standardized observations, caregiver interviews, and questionnaires to assess sensory reactivity symptoms. Relationships between sensory symptoms and age, sex, ASD, IQ, and adaptive behavior were examined. Genotype-phenotype correlations with the recurrent p.Tyr719* variant were also explored. Results: Sensory reactivity symptoms were observed and reported in all participants. A syndrome-specific phenotype was identified, characterized by high levels of sensory seeking across tactile, auditory, and visual domains. Tactile hyporeactivity, characterized by pain insensitivity, was reported in the majority of participants. Sensory symptoms were identified across individuals regardless of age, sex, IQ, adaptive ability, genetic variant, and most importantly, ASD status. No significant differences were identified between participants with and without the recurrent p.Tyr719* variant on any sensory measure. Conclusions: Sensory reactivity symptoms are a common clinical feature of ADNP syndrome. Quantifying sensory reactivity using existing standardized measures will enhance understanding of sensory reactivity in individuals with ADNP syndrome and will aid in clinical care. The sensory domain may also represent a promising target for treatment in clinical trials

Vivencias de las madres frente a la hospitalización de su hijo Preescolar en un Servicio de Pediatría - Hospital Referencial de Ferreñafe-2016

Cuando un niño es hospitalizado, los padres se ven afectados ya que significa la separación con su hijo a quien le brindan cuidado día a día, las madres son las que se involucran activamente en el cuidado del niño, ya que tiene que estar pendientes de su evolución de la enfermedad, ocasionándole diversos sentimientos emociones y reacciones durante la estancia hospitalaria. Esta investigación motivó a ¿Cómo son las vivencias de las madres frente a la hospitalización de su hijo preescolar en el servicio de pediatría de un hospital local MINSA. Ferreñafe-2016? y tuvo como objetivo comprender las vivencias de las madres frente a la hospitalización de su hijo preescolar, la presente investigación fue del tipo cualitativa con abordaje de Estudio de Caso. La muestra lo conformaron 10 madres de los niños preescolares hospitalizados obtenidos por la técnica de saturación y redundancia, para el recojo de información se utilizó la entrevista semiestructurada a profundidad. Para el análisis de los resultados se utilizó el análisis temático que generaron cuatro categorías: “Sentimientos negativos de las madres durante la estancia hospitalaria de mi hijo”, “Emociones negativas de las madres frente a la hospitalización de mi hijo”, “Reaccionando con angustia y ansiedad ante la hospitalización de mi hijo” y “Cambiando la rutina de la madre”. Llegando a la consideración que las madres pasan por vivencias intencionadas, causadas por la hospitalización como: sentimientos, emociones y reacciones negativas, que van desde la tristeza, culpa, miedo, preocupación, impotencia, hasta reaccionando con ansiedad y angustia