c-Abl activates RIPK3 signaling in Gaucher disease.

Gaucher disease (GD) is caused by homozygous mutations in the GBA1 gene, which encodes the lysosomal ß-glucosidase (GBA) enzyme. GD affects several organs and tissues, including the brain in certain variants of the disease. Heterozygous GBA1 variants are a major genetic risk factor for developing Parkinson's disease. The RIPK3 kinase is relevant in GD and its deficiency improves the neurological and visceral symptoms in a murine GD model. RIPK3 mediates necroptotic-like cell death: it is unknown whether the role of RIPK3 in GD is the direct induction of necroptosis or if it has a more indirect function by mediating necrosis-independent. Also, the mechanisms that activate RIPK3 in GD are currently unknown. In this study, we show that c-Abl tyrosine kinase participates upstream of RIPK3 in GD. We found that the active, phosphorylated form of c-Abl is increased in several GD models, including patient's fibroblasts and GBA null mice. Furthermore, its pharmacological inhibition with the FDA-approved drug Imatinib decreased RIPK3 signaling. We found that c-Abl interacts with RIPK3, that RIPK3 is phosphorylated at a tyrosine site, and that this phosphorylation is reduced when c-Abl is inhibited. Genetic ablation of c-Abl in neuronal GD and GD mice models significantly reduced RIPK3 activation and MLKL downstream signaling. These results showed that c-Abl signaling is a new upstream pathway that activates RIPK3 and that its inhibition is an attractive therapeutic approach for the treatment of GD.

Finding pathogenic commonalities between Niemann-Pick type C and other lysosomal storage disorders: Opportunities for shared therapeutic interventions.

Lysosomal storage disorders (LSDs) are diseases characterized by the accumulation of macromolecules in the late endocytic system and are caused by inherited defects in genes that encode mainly lysosomal enzymes or transmembrane lysosomal proteins. Niemann-Pick type C disease (NPCD), a LSD characterized by liver damage and progressive neurodegeneration that leads to early death, is caused by mutations in the genes encoding the NPC1 or NPC2 proteins. Both proteins are involved in the transport of cholesterol from the late endosomal compartment to the rest of the cell. Loss of function of these proteins causes primary cholesterol accumulation, and secondary accumulation of other lipids, such as sphingolipids, in lysosomes. Despite years of studying the genetic and molecular bases of NPCD and related-lysosomal disorders, the pathogenic mechanisms involved in these diseases are not fully understood. In this review we will summarize the pathogenic mechanisms described for NPCD and we will discuss their relevance for other LSDs with neurological components such as Niemann- Pick type A and Gaucher diseases. We will particularly focus on the activation of signaling pathways that may be common to these three pathologies with emphasis on how the intra-lysosomal accumulation of lipids leads to pathology, specifically to neurological impairments. We will show that although the primary lipid storage defect is different in these three LSDs, there is a similar secondary accumulation of metabolites and activation of signaling pathways that can lead to common pathogenic mechanisms. This analysis might help to delineate common pathological mechanisms and therapeutic targets for lysosomal storage diseases.

Childhood bullous pemphigoid. Clinical and immunologic features, treatment, and prognosis.

A 2 1/2-month-old female infant presented with multiple tense bullae on the hands and feet. Analysis of biopsy specimens confirmed our clinical impression of childhood bullous pemphigoid. Confirmatory data included type IV collagen mapping of the basement membrane zone, a readily available technique that helps distinguish childhood bullous pemphigoid from childhood epidermolysis bullosa acquisita. To our knowledge, our patient is the youngest described with childhood bullous pemphigoid, and we use this opportunity to review the literature and examine the clinical and immunologic features, treatment, and prognosis of this rare childhood immunobullous disorder.

Aloe vera.

We review the scientific literature regarding the aloe vera plant and its products. Aloe vera is known to contain several pharmacologically active ingredients, including a carboxypeptidase that inactivates bradykinin in vitro, salicylates, and a substance(s) that inhibits thromboxane formation in vivo. Scientific studies exist that support an antibacterial and antifungal effect for substance(s) in aloe vera. Studies and case reports provide support for the use of aloe vera in the treatment of radiation ulcers and stasis ulcers in man and burn and frostbite injuries in animals. The evidence for a potential beneficial effect associated with the use of aloe vera is sufficient to warrant the design and implementation of well-controlled clinical trials.

Rehabilitation of partial laryngectomy patients.

Rehabilitation and function following three anatomically discrete forms of partial laryngectomy (hemilaryngectomy, subtotal supraglottic laryngectomy, and partial laryngopharyngectomy) were studied in 68 patients. Study parameters included posttreatment respiration, deglutition, taste, smell, and hearing function; articulation and voice analysis; and social, communicative, and vocational adjustment. The major portion of the study involved specific testing of posttreatment voice quality and articulation. Recorded word lists and sentences were evaluated by independent observers regarding breathiness, hoarseness, harshness, pitch, loudness, and intelligibility. These data were analyzed employing a Statistical Package for the Social Sciences (SPSS) through the Washington University computer facilities.