Plasma hyaluronidase activity in mucolipidoses II and III: Marked differences from other lysosomal enzymes

A nearly pathognomonic finding of the lysosomal storage disorders mucolipidoses II and III is the marked increase of plasma lysosomal enzyme activities. The genetic lesion in ML II and III causes defective function of the enzyme UDP-GlcNAc:lysosomal enzyme N-acetylglucosamine-l-phosphotransferase. Defective function of this enzyme results in deficient phosphorylation of lysosomal enzyme asparagine-linked oligosaccharides and a consequent misrouting of many newly synthesized lysosomal enzymes. These enzymes are secreted from cells instead of being targeted to lysosomes, with resultant marked elevations of multiple lysosomal enzyme activities in plasma. We report here that plasma hyaluronidase activity, an endoglycosidase of presumably lysosomal origin, is not increased in the plasma from individuals with mucolipidoses II and III, unlike most lysosomal enzymes. Our data suggest the possibility that hyaluronidase is not targeted to lysosomes by a lysosomal enzyme phosphosmannosyl recognition mechanism. Alternatively, hyaluronidase activity may not be present in the cell type(s) responsible for the lysosomal enzyme hypersecretion in mucolipidoses II and III which, along with its deficiency in fibroblasts and leukocytes, would constitute an unusual tissue distribution of activity for a soluble lysosomal enzyme. © 1996 Wiley-Liss, Inc.     

Comparison of Clinical and Echocardiographic Outcomes After Surgical Redo Mitral Valve Replacement and Transcatheter Mitral Valve-in-Valve Therapy

Objectives

There are minimal data regarding clinical outcomes and echocardiographic findings after transcatheter mitral valve-in-valve replacement (TMVR) compared with redo surgical mitral valve replacement (SMVR).

Nationwide Analysis of the Heat- and Cold-Related Mortality Trends in Switzerland between 1969 and 2017: The Role of Population Aging

Background: Because older adults are particularly vulnerable to nonoptimal temperatures, it is expected that the progressive population aging will amplify the health burden attributable to heat and cold due to climate change in future decades. However, limited evidence exists on the contribution of population aging on historical temperature–mortality trends.Objectives: We aimed to a) assess trends in heat- and cold-related mortality in Switzerland between 1969 and 2017 and b) to quantify the contribution of population aging to the observed patterns.Methods: We collected daily time series of all-cause mortality by age group (<65, 65–79, and 80 y and older) and mean temperature for each Swiss municipality (1969–2017). We performed a two-stage time-series analysis with distributed lag nonlinear models and multivariate longitudinal meta-regression to obtain temperature–mortality associations by canton, decade, and age group. We then calculated the corresponding excess mortality attributable to nonoptimal temperatures and compared it to the estimates obtained in a hypothetical scenario of no population aging.Results: Between 1969 and 2017, heat- and cold-related mortality represented 0.28% [95% confidence interval (CI): 0.18, 0.37] and 8.91% (95% CI: 7.46, 10.21) of total mortality, which corresponded to 2.4 and 77 deaths per 100,000 people annually, respectively. Although mortality rates for heat slightly increased over time, annual number of deaths substantially raised up from 74 (12;125) to 181 (39;307) between 1969–78 and 2009–17, mostly driven by the ≥80-y-old age group. Cold-related mortality rates decreased across all ages, but annual cold-related deaths still increased among the ≥80, due to the increase in the population at risk. We estimated that heat- and cold-related deaths would have been 52.7% and 44.6% lower, respectively, in the most recent decade in the absence of population aging.Discussion: Our findings suggest that a substantial proportion of historical temperature-related impacts can be attributed to population aging. We found that population aging has attenuated the decrease in cold-related mortality and amplified heat-related mortality. https://doi.org/10.1289/EHP9835     

Monoclonal antibodies to a rat nestin fusion protein recognize a 220-kDa polypeptide in subsets of fetal and adult human central nervous system neurons and in primitive neuroectodermal tumor cells.

Nestin is the major intermediate filament protein of embryonic central nervous system (CNS) progenitor cells. To identify proteins involved in early stages of lineage commitment in the developing human CNS we generated monoclonal antibodies to a TrpE-rat nestin fusion protein. This resulted in a monoclonal antibody (designated NST11) that did not recognize authentic human nestin, but did recognize a novel neuron-specific human polypeptide expressed in a subset of embryonic and adult CNS neurons as well as in medulloblastomas. NST11 immunoreactivity was abundant in developing spinal cord motor neurons, but was extinguished in these neurons by 17 weeks gestation. NST11 also labeled Purkinje cells at 17 weeks gestation, but Purkinje cells continued to express the NST11 antigen throughout gestation as well as in the adult cerebellum, and NST11 immunoreactivity was more abundant in Purkinje cells than in any other human CNS neurons. No NST11 immunoreactivity was detected in cells of the adult human peripheral nervous system or in a variety of adult non-neural human tissues. Further, NST11 almost exclusively stained cerebellar medulloblastomas. In Western blots of immature and mature human cerebral and cerebellar extracts, NST11 did not bind human nestin, but did detect an immunoband with a molecular weight of 220 kd. A similar immunoband was detected in medulloblastoma-derived cell lines with a neuron-like phenotype. These findings suggest that the NST11 monoclonal antibody recognizes a novel protein expressed by a subpopulation of immature and mature human CNS neurons, medulloblastomas, and medulloblastoma-derived cell lines.     

Aquaporin 1 regulates GTP-induced rapid gating of water in secretory vesicles

The swelling of secretory vesicles has been implicated in exocytosis, but the underlying mechanism of vesicle swelling remains largely unknown. Zymogen granules (ZGs), the membrane-bound secretory vesicles in exocrine pancreas, swell in response to GTP mediated by a G(alpha)i3 protein. Evidence is presented here that the water channel aquaporin-1 (AQP1) is present in the ZG membrane and participates in rapid GTP-induced vesicular water gating and swelling. Isolated ZGs exhibit low basal water permeability. However, exposure of granules to GTP results in a marked potentiation of water entry. Treatment of ZGs with the known water channel inhibitor Hg2+ is accompanied by a reversible loss in both the basal and GTP-stimulatable water entry and vesicle swelling. Introduction of AQP1-specific antibody raised against the carboxyl-terminal domain of AQP1 blocks GTP-stimulable swelling of vesicles. Our results demonstrate that AQP1 associated at the ZG membrane is involved in basal as well as GTP-induced rapid gating of water in ZGs of the exocrine pancreas.