Enhanced ER-associated degradation of HMG CoA reductase causes embryonic lethality associated with Ubiad1 deficiency.

UbiA prenyltransferase domain-containing protein-1 (UBIAD1) synthesizes the vitamin K subtype menaquinone-4 (MK-4). Previous studies in cultured cells (Schumacher et al., 2015) revealed that UBIAD1 also inhibits endoplasmic reticulum (ER)-associated degradation (ERAD) of ubiquitinated HMG CoA reductase (HMGCR), the rate-limiting enzyme of the mevalonate pathway that produces cholesterol and essential nonsterol isoprenoids. Gene knockout studies were previously attempted to explore the function of UBIAD1 in mice; however, homozygous germ-line elimination of the Ubiad1 gene caused embryonic lethality. We now report that homozygous deletion of Ubiad1 is produced in knockin mice expressing ubiquitination/ERAD-resistant HMGCR. Thus, embryonic lethality of Ubiad1 deficiency results from depletion of mevalonate-derived products owing to enhanced ERAD of HMGCR rather than from reduced synthesis of MK-4. These findings provide genetic evidence for the significance of UBIAD1 in regulation of cholesterol synthesis and offer the opportunity in future studies for the discovery of new physiological roles of MK-4.

Schnyder corneal dystrophy-associated UBIAD1 inhibits ER-associated degradation of HMG CoA reductase in mice.

Autosomal-dominant Schnyder corneal dystrophy (SCD) is characterized by corneal opacification owing to overaccumulation of cholesterol. SCD is caused by mutations in UBIAD1, which utilizes geranylgeranyl pyrophosphate (GGpp) to synthesize vitamin K2. Using cultured cells, we previously showed that sterols trigger binding of UBIAD1 to the cholesterol biosynthetic enzyme HMG CoA reductase (HMGCR), thereby inhibiting its endoplasmic reticulum (ER)-associated degradation (ERAD) (Schumacher et al. 2015). GGpp triggers release of UBIAD1 from HMGCR, allowing maximal ERAD and ER-to-Golgi transport of UBIAD1. SCD-associated UBIAD1 resists GGpp-induced release and is sequestered in ER to inhibit ERAD. We now report knockin mice expressing SCD-associated UBIAD1 accumulate HMGCR in several tissues resulting from ER sequestration of mutant UBIAD1 and inhibition of HMGCR ERAD. Corneas from aged knockin mice exhibit signs of opacification and sterol overaccumulation. These results establish the physiological significance of UBIAD1 in cholesterol homeostasis and indicate inhibition of HMGCR ERAD contributes to SCD pathogenesis.

Caracterización de los accidentes de tránsito en la región Callao-Perú, 1996-2004 / Characterization of traffic accidents in Callao-Perú, 1996-2004

Objetivo: Describir las características de los accidentes de tránsito en el Callao (de 1996 a 2004). Material y métodos: Estudio ecológico descriptivo de fuentes secundarias. Se tomó en cuenta la información registrada por las instituciones que participan en la cobertura de un accidente de tránsito en el Callao (policía, hospitales y morgue) y que forman parte del Comité Multisectorial para la Vigilancia y Prevención de los Accidentes de Tránsito. Los resultados se presentan en gráficos y tablas. Resultados: En el Callao se registraron 25 426 accidentes de tránsito entre 1996 y 2004. El tipo de accidente más común fue el choque. El exceso de velocidad fue la condición que más accidentes ha causado (29.9%). El 61% de los accidentes de tránsito se produjeron en fin de semana. La Av. Gambetta presentó la mayor cantidad de accidentes (4 414). De los 23 315 accidentes registrados entre 1996 y 2003, 48% concluyeron en daño material, la mayoría de éstos por choques (86.8%), mientras que 667 accidentes (3% del total) fueron fatales. Los atropellos tuvieron consecuencia fatal en 11.9%. Los años con mayor número de muertes fueron 1996 y 1998. Los atendidos son 66% hombres y 64.8% del total de atendidos correspondió al grupo etario de 20 a 64 años. La lesión medular fue el diagnóstico más frecuente (24%) en el Instituto Nacional de Rehabilitación con sede en el Callao. Los traumatismos múltiples y encéfalo-craneanos fueron la causa de muerte más común (70.7%). Conclusiones: Los accidentes de tránsito son un grave problema de salud pública en el Callao. Existe una leve disminución en frecuencia después del año 2000.

Objective: To describe the characteristics of traffic accidents in Callao from 1996 to 2004. Methods: Ecological, descriptive study of secondary sources. We took into account data collected by institutions involved in responding to traffic accidents in Callao (police, hospitals and morgue) and data from the ôMultisectorial Committee for the Surveillance and Prevention of Traffic Accidentsõ. The results are presented in graphs and tables. Results: Between 1996 and 2004 there were 25 426 registered traffic accidents in Callao. Collissions with other vehicles cars were the most common type of traffic accident. Speeding is the most common cause of accidents (29.9%). 61% of traffic accidents occur during the weekend. Gambetta Avenue had the highest number of accidents (4 414). Of the 23 315 accidents that occurred between 1996 and 2003, 48% resulted in vehicular damage, mostly from collissions with other vehicles (86.8%), and 667 accidents (3% of total) were fatal. 11.9% of run overs were fatal. 1996 and 1998 were the years with the highest number of fatalities. 66% of the persons treated for injuries due to traffic accidents were male and 64.8% were between teh ages of 20 to 64. Spinal cord injury was the most frequent diagnosis (24%) in the Callao center of the National Rehabilitation Institute. Multiple traumas and encephalo-cranial trauma were the most common cause of death (70.7%). Conclusions: Traffic accidents are a serious public health problem in Callao. There is a slight decrease in frequency after 2000.

Características del personal del Hospital de Emergencias José Casimiro Ulloa y nivel de conocimiento de medidas de acción durante sismo / Features staff at Hospital de Emergencias Jose Casimiro Ulloa and knowledge level action measures during earthquake

Objetivo: Determinar si existe asociación entre las características del personal que labora en el HEJCU y el nivel de conocimiento de las medidas de acción a tomar durante un sismo según el Plan de Respuesta Hospitalario del HEJCU. Materiales y Métodos: Se realizó un estudio de tipo Analítico Observacional de corte Transversal en el HEJCU. Para la recolección de datos se utilizó un cuestionario autodesarrollado de 13 preguntas dirigido a todo el personal que labora en el HEJCU. Se utilizó la prueba estadística de Chi-cuadrado para determinar las asociaciones. Resultados: Se analizaron 246 encuestas. El 50.81% de la población encuestada fueron varones, y 49.19% fueron mujeres. El 61.4% de la población tiene un nivel de conocimiento medio de las medidas de acción a tomar durante sismo. El 92.28% no pertenece a Brigadas operativas. El 13.01% de los entrevistados está totalmente capacitado (recibió el Plan de Respuesta Hospitalario del HEJCU y participó en talleres de capacitación para desastres). Se encontró asociación entre nivel de conocimientos y actividad laboral (p=0.02), OR= 5.56 [IC:1.74-17.80]. No se encontró asociación entre el nivel de conocimientos y las otras características del personal del HEJCU. Conclusión: El personal asistencial tiene mayor nivel de conocimientos que el personal administrativo en las medidas de acción a tomar durante un sismo. El haber recibido capacitación, el mayor tiempo de servicio y la participación en simulacros no muestra un mayor nivel de conocimientos en las medidas de acción a tomar durante sismo.

Objective: To determine whether there is an association between the characteristics of the workers from Hospital de Emergencias José Casimiro Ulloa (HEJCU) and their level of knowledge of how to perform during an earthquake according to the Hospital Response Plan from HEJCU. Material and Methods: This is a crosssectional study. It was performed at HEJCU, Lima-Peru. A 13 question self-administered survey was used to collect the data and all the employees were considered for the interview. In order to determine the association between variables, we used Chi-square statistic tests. Results: Two hundred forty-six questionnaires out of 259 were eligible to make the analysis. 50.81% of the population were male. 61.4% had a medium level of knowledge of how to perform during an seisms. 92.28% do not belong to earthquake brigades, 75.2% have participated in simulations, 13.01% have been well trained, in other words, have received the Hospital Disaster and Emergency Response Plan from HEJCU and have attended to the workshops on disaster management. An association between level of knowledge and labor activities was found (p=0.02), OR= 5.56 [IC:1.74-17.80]. There were not found an association between level of knowledge and other characteristics of the employees from HEJCU. Conclusion: Employees with medical activities had higher level of knowledge than employees with administrative activities. Time of service at the hospital, participation in simulations and having received training do not influence on the level of knowledge of the ways to perform during an earthquake.