Upregulation of non-canonical and canonical inflammasome genes associates with pathological features in Krabbe disease and related disorders.

Infantile Krabbe disease is a rapidly progressive and fatal disorder of myelin, caused by inherited deficiency of the lysosomal enzyme ß-galactocerebrosidase. Affected children lose their motor skills and other faculties; uncontrolled seizures are a frequent terminal event. Overexpression of the sphingolipid metabolite psychosine is a pathogenic factor, but does not fully account for the pleiotropic manifestations and there is a clear need to investigate additional pathological mechanisms. We examined innate immunity, caspase-11 and associated inflammatory pathways in twitcher mice, an authentic model of Krabbe disease. Combined use of molecular tools, RNAscope in situ hybridization and immunohistochemical staining established that the expression of pro-inflammatory non-canonical caspase-11, canonical caspase-1, gasdermin D and cognate genes is induced in nervous tissue. Early onset and progressive upregulation of these genes accompany demyelination and gliosis and although the molecules are scant in healthy tissue, abundance of the respective translation products is greatly increased in diseased animals. Caspase-11 is found in reactive microglia/macrophages as well as astrocytes but caspase-1 and gasdermin D are restricted to reactive microglia/macrophages. The inflammasome signature is not unique to Krabbe disease; to varying degrees, this signature is also prominent in other lysosomal diseases, Sandhoff and Niemann-Pick Type-C1, and the lysolecithin toxin model of focal demyelination. Given the potent inflammatory response here identified in Krabbe disease and the other neurodegenerative disorders studied, a broad induction of inflammasomes is likely to be a dominant factor in the pathogenesis, and thus represents a platform for therapeutic exploration.

[Reversible severe cardiomyopathy caused by a slow permanent tachycardia]. / Reversible, schwere Kardiomyopathie als Folge einer langsamen, permanenten Schmalkomplextachykardie.

Incessant narrow QRS complex tachycardias may result in severe tachycardia-induced cardiomyopathy even if the heart rate during tachycardia is only moderately elevated. The risk of ventricular deterioration is particularly increased in patients with underlying congenital heart disease. In these patients, drug treatment is often insufficient. Thus, catheter ablation of the arrhythmogenic substrate is required in the majority of patients. After successful ablation, ventricular function may recover completely.

Expression of Ripk1 and DAM genes correlates with severity and progression of Krabbe disease.

Krabbe disease, an inherited leukodystrophy, is a sphingolipidosis caused by deficiency of ß-galactocerebrosidase: it is characterized by myelin loss, and pathological activation of macrophage/microglia and astrocytes. To define driving pathogenic factors, we explored the expression repertoire of candidate neuroinflammatory genes: upregulation of receptor interacting protein kinase 1 (Ripk1) and disease-associated microglia (DAM) genes, including Cst7 and Ch25h, correlated with severity of Krabbe disease genetically modelled in the twitcher mouse. Upregulation of Ripk1 in Iba1/Mac2-positive microglia/macrophage associated with the pathognomic hypertrophic/globoid phenotype of this disease. Widespread accumulation of ubiquitinin1 in white and grey matter co-localised with p62. In Sandhoff disease, another sphingolipid disorder, neuroinflammation, accumulation of p62 and increased Ripk1 expression was observed. The upregulated DAM genes and macrophage/microglia expression of Ripk1 in the authentic model of Krabbe disease strongly resemble those reported in Alzheimer disease associating with disturbed autophagosomal/lysosomal homeostasis. Activation of this shared molecular repertoire, suggests the potential for therapeutic interdiction at a common activation step, irrespective of proximal causation. To clarify the role of Ripk1 in the pathogenesis of Krabbe disease, we first explored the contribution of its kinase function, by intercrossing twitcher and the K45A kinase-dead Ripk1 mouse and breeding to homozygosity. Genetic ablation of Ripk1 kinase activity neither altered the neuropathological features nor the survival of twitcher mice. We conclude that Ripk1 kinase-dependent inflammatory and degenerative capabilities play no instrumental role in Krabbe disease; however, putative kinase-independent functions of Ripk1 remain formally to be explored in its molecular pathogenesis.

[Severe spotted fever by Rickettsia rickettsii, in tourist in the Argentine Northwest]. / Fiebre manchada grave por Rickettsia rickettsii en turista en el noroeste argentino.

On the fifth day after leaving the Parque Nacional El Rey, province of Salta, Argentina, where she made rural tourism, a woman of Italian origin, aged 47, developed an acute fever followed by a petechial and purpuric rash that progressed rapidly to multiorgan failure. She died on the sixth day after hospitalization. There were references to tick bites and a skin lesion similar to tache noire was found. The autopsy showed generalized vasculitis, ascites, pulmonary edema, acute tubular necrosis and portal centrilobular necrosis. Spleen and liver tissue were processed for PCR Rickettsia spp, based on the detection of the gltA gene. The result was positive. The amplicons obtained were sequenced and the results were compared with the preset sequences on the BLAST program, 99% coinciding with R. rickettsii. The low sensitivity of the health system to recognize this disease and the insufficient information generated from tourism-related media are factors that affect the delay to implement effective treatment and appropriate prevention standards.

Fiebre manchada grave por Rickettsia rickettsii en turista en el Noroeste Argentino / Severe spotted fever by Rickettsia rickettsii, in tourist in the Argentine Northwest

Al quinto día de retirarse del Parque Nacional El Rey, provincia de Salta, Argentina, donde realizó turismo rural, una mujer italiana de 47 años desarrolló un cuadro febril agudo seguido de un exantema petequial y purpúrico que progresó rápidamente a falla multiorgánica y falleció al sexto día de internación. Existieron referencias a mordeduras por garrapatas y se constató una lesión cutánea similar a la denominada tache noire. La autopsia mostró una vasculitis generalizada, ascitis, edema de pulmón, necrosis tubular aguda y necrosis portal centrolobulillar. Se procesó tejido esplénico y hepático con técnica de PCR para Rickettsia spp, basada en la detección del gen gltA. El resultado fue positivo. Los amplicones obtenidos fueron secuenciados y los resultados se compararon con las secuencias preestablecidas en el programa BLAST, coincidiendo en un 99% con R. rickettsii. La baja sensibilidad del sistema de salud en reconocer la enfermedad y la insuficiente información producida desde los medios relacionados con el turismo, son factores que inciden en el retardo de implementar un tratamiento eficaz y las normas de prevención adecuadas.

On the fifth day after leaving the Parque Nacional El Rey, province of Salta, Argentina, where she made rural tourism, a woman of Italian origin, aged 47, developed an acute fever followed by a petechial and purpuric rash that progressed rapidly to multiorgan failure. She died on the sixth day after hospitalization. There were references to tick bites and a skin lesion similar to tache noire was found. The autopsy showed generalized vasculitis, ascites, pulmonary edema, acute tubular necrosis and portal centrilobular necrosis. Spleen and liver tissue were processed for PCR Rickettsia spp, based on the detection of the gltA gene. The result was positive. The amplicons obtained were sequenced and the results were compared with the preset sequences on the BLAST program, 99% coinciding with R. rickettsii. The low sensitivity of the health system to recognize this disease and the insufficient information generated from tourism-related media are factors that affect the delay to implement effective treatment and appropriate prevention standards.

Cardiac resynchronization in a child with dilated cardiomyopathy and borderline QRS duration: speckle tracking guided lead placement.

Cardiac resynchronization therapy (CRT) is proved to prevent heart transplantation in some patients with dilated cardiomyopathy and mechanical dyssynchrony. We report of the benefit of CRT accomplished by atrial synchronized single-site left ventricular pacing in an 8-year-old boy with idiopathic dilated cardiomyopathy, normal atrioventricular conduction, borderline QRS complex duration (120 ms), and marked mechanical left ventricular dyssynchrony proved by echocardiographic speckle tracking.

Diagnosis of tachycardia mechanism with cryomapping in a toddler with complex congenital heart disease.

A 2.5-year-old patient with complex congenital heart disease involving dextrocardia, atrioventricular and ventriculoarterial discordance, pulmonary stenosis, ventricular septal defect (VSD), atrial septal defect (ASD), and paroxysmal supraventricular tachycardia (SVT) underwent electrophysiological study. The tachycardia mechanism was diagnosed with cryomapping. The ability of cryomapping to have transient and reversible effect on the tissue, unlike radiofrequency (RF) ablation, helped in the establishment of diagnosis in this toddler with typical atrioventricular nodal reentrant tachycardia. Cryomapping can be an additional safe diagnostic utility in young patients with complex congenital heart disease.

Estimación de proteínas séricas glicosiladas por reducción del nitro-blue tetrazolium en medio alcalino / The estimulation of serum glycosylated proteins for reduction of alkaline nitro-blue tetrazolium

En el presente trabajo se modifica el método cinético de Johnson y colaboradores para la determinación de proteínas séricas glicosiladas(PSG), mediante la técnica manual de punto final y se adapta en su forma original para el uso en un analizador automático. Se establece el intervalo de referencia de PSG en población no diabética y se aplica el método a muestras obtenidas de pacientes diabéticos tipo II para evaluar el uso de la determinación como indicador de control glucémico. La reacción se detiene al acidificar a pH 7.0-7.2; glucosa y bilirrubina no interfieren, al menos hasta 50 mmol/l y 4.5 mg%respectivamente; la hemólisis moderada interfiere. No hay diferencia en los resultados por edad y sexo en el grupo no diabético elegido(n=116), con edades comprendidas entre 15-35 años. Ambas técnicas son capaces de diferenciar individuos normales de diabéticos tipo II no compensados desde el punto de vista de su metabolismo hidrocarbonado. El método es rápido, sencillo y económico. Presenta repetibilidad y reproductividad aceptables; queda de manifiesto la mayor precisión de la técnica automatizada y la accesibilidad de la técnica manual a cualquier laboratorio clínico

Estimación de proteínas séricas glicosiladas por reducción del nitro-blue tetrazolium en medio alcalino / The estimulation of serum glycosylated proteins for reduction of alkaline nitro-blue tetrazolium

En el presente trabajo se modifica el método cinético de Johnson y colaboradores para la determinación de proteínas séricas glicosiladas(PSG), mediante la técnica manual de punto final y se adapta en su forma original para el uso en un analizador automático. Se establece el intervalo de referencia de PSG en población no diabética y se aplica el método a muestras obtenidas de pacientes diabéticos tipo II para evaluar el uso de la determinación como indicador de control glucémico. La reacción se detiene al acidificar a pH 7.0-7.2; glucosa y bilirrubina no interfieren, al menos hasta 50 mmol/l y 4.5 mg%respectivamente; la hemólisis moderada interfiere. No hay diferencia en los resultados por edad y sexo en el grupo no diabético elegido(n=116), con edades comprendidas entre 15-35 años. Ambas técnicas son capaces de diferenciar individuos normales de diabéticos tipo II no compensados desde el punto de vista de su metabolismo hidrocarbonado. El método es rápido, sencillo y económico. Presenta repetibilidad y reproductividad aceptables; queda de manifiesto la mayor precisión de la técnica automatizada y la accesibilidad de la técnica manual a cualquier laboratorio clínico