Loss-of-function mutations in acid beta-glucosidase 1 (GBA1) are among the strongest genetic risk factors for Lewy body disorders such as Parkinson’s disease (PD) and Lewy body dementia (DLB). Altered lipid metabolism in PD patient–derived neurons, carrying either GBA1 or PD αS mutations, can shift the physiological α-synuclein (αS) tetramer–monomer (T:M) equilibrium toward aggregation-prone monomers. A resultant increase in pSer129+ αS monomers provides a likely building block for αS aggregates. 3K αS mice, representing a neuropathological amplification of the E46K PD–causing mutation, have decreased αS T:M ratios and vesicle-rich αS+ aggregates in neurons, accompanied by a striking PD-like motor syndrome. We asked whether enhancing glucocerebrosidase (GCase) expression could benefit αS dyshomeostasis by delivering an adeno-associated virus (AAV)–human wild-type (wt) GBA1 vector into the brains of 3K neonates. Intracerebroventricular AAV-wtGBA1 at postnatal day 1 resulted in prominent forebrain neuronal GCase expression, sustained through 6 mo. GBA1 attenuated behavioral deficits both in working memory and fine motor performance tasks. Furthermore, wtGBA1 increased αS solubility and the T:M ratio in both 3K-GBA mice and control littermates and reduced pS129+ and lipid-rich aggregates in 3K-GBA. We observed GCase distribution in more finely dispersed lysosomes, in which there was increased GCase activity, lysosomal cathepsin D and B maturation, decreased perilipin-stabilized lipid droplets, and a normalized TFEB translocation to the nucleus, all indicative of improved lysosomal function and lipid turnover. Therefore, a prolonged increase of the αS T:M ratio by elevating GCase activity reduced the lipid- and vesicle-rich aggregates and ameliorated PD-like phenotypes in mice, further supporting lipid modulating therapies in PD.

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From a group of 130 youngsters with inflammatory bowel disease, 22 were severely growth retarded (below the third percentile in height). This had preceded gastrointestinal symptoms for 1 to 11.4 years in 8 patients and corticosteroid therapy in 14. Endocrine evaluation demonstrated abnormally low 24-hour urinary gonadotropins in five of six patients more than age 16, and depressed growth hormone response to insulininduced hypoglycemia in 11 of 13 tested. Growth retardation in this group was attributed to a secondary hypopituitarism.

The flexible fiberoptic endoscope has not been employed consistently in the removal of foreign bodies from the gastrointestinal tract due to size limitations of the forceps and biopsy channel. The following report describes a technique for extracting large irregular objects from the upper-gastrointestinal tract, employing the polypectomy snare. It is a safe and reproducible procedure for the careful extraction of impacted objects.