Genotype, phenotype and disease severity reflected by serum LysoGb3 levels in patients with Fabry disease

Background: Fabry disease (FD) is a rare X-linked lysosomal storage disease caused by mutations in the α-galactosidase A (GLA) gene causing deficiency of α-galactosidase A which results in progressive glycosphingolipid accumulation, especially globotriaosylceramide (Gb3), in body liquids and lysosomes. In a large cohort of FD patients, we aimed to establish genotype/phenotype relations as indicated by serum LysoGb3 (deacylated Gb3). / Methods: In 69 consecutive adult FD patients (males: n = 28 (41%)) with a GLA-mutation confirmed diagnosis, we conducted a multidisciplinary clinical characterization during their routine annual examinations, and measured serum LysoGb3 levels by high-sensitive electrospray ionization liquid chromatography tandem mass spectrometry. / Results: Serum levels of LysoGb3 were significantly higher in Classic compared with Later-Onset phenotype and higher in the latter compared with controls, both in males (52 [40–83] vs 9.5 [4.5–20] vs 0.47 [0.41–0.61] ng/ml, P < 0.001) and in females (9.9 [7.9–14] vs 4.9 [1.6–4.9] vs 0.41 [0.33–0.48] ng/ml, P < 0.001), respectively. Multivariate linear regression analysis showed that LysoGb3 levels were independently associated with, serum creatinine (β = 0.09, 95%CI 0.04–0.13, P < 0.001) and the presence of cardiomyopathy (β = 25, 95%CI 9.8–41, P = 0.002). LysoGb3 levels were higher in males with frame-shift and nonsense mutations than in males with missense mutations (84 [72–109] vs 41 [37–52] ng/ml, P = 0.002). / Conclusion: LysoGb3 relates to disease severity, enzyme replacement response, and to the genotype severity in males. LysoGb3 supports identifying patients at risk who require intensive monitoring and treatment. LysoGb3 appears to be one marker of metabolic phenotyping of FD

Subtype-Specific Synaptic Proteome Alterations in Sporadic Creutzfeldt-Jakob Disease

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Counter-regulatory responses to postprandial hypoglycaemia in patients with post-bariatric hypoglycaemia vs surgical and non-surgical control individuals

Aims/hypothesis Post-bariatric hypoglycaemia is an increasingly recognised complication of bariatric surgery, manifesting particularly after Roux-en-Y gastric bypass. While hyperinsulinaemia is an established pathophysiological feature, the role of counter-regulation remains unclear. We aimed to assess counter-regulatory hormones and glucose fluxes during insulin-induced postprandial hypoglycaemia in patients with post-bariatric hypoglycaemia after Roux-en-Y gastric bypass vs surgical and non-surgical control individuals. Methods In this case–control study, 32 adults belonging to four groups with comparable age, sex and BMI (patients with post-bariatric hypoglycaemia, Roux-en-Y gastric bypass, sleeve gastrectomy and non-surgical control individuals) underwent a postprandial hypoglycaemic clamp in our clinical research unit to reach the glycaemic target of 2.5 mmol/l 150–170 min after ingesting 15 g of glucose. Glucose fluxes were assessed during the postprandial and hypoglycaemic period using a dual-tracer approach. The primary outcome was the incremental AUC of glucagon during hypoglycaemia. Catecholamines, cortisol, growth hormone, pancreatic polypeptide and endogenous glucose production were also analysed during hypoglycaemia. Results The rate of glucose appearance after oral administration, as well as the rates of total glucose appearance and glucose disappearance, were higher in both Roux-en-Y gastric bypass groups vs the non-surgical control group in the early postprandial period (all p<0.05). During hypoglycaemia, glucagon exposure was significantly lower in all surgical groups vs the non-surgical control group (all p<0.01). Pancreatic polypeptide levels were significantly lower in patients with post-bariatric hypoglycaemia vs the non-surgical control group (median [IQR]: 24.7 [10.9, 38.7] pmol/l vs 238.7 [186.3, 288.9] pmol/l) (p=0.005). Other hormonal responses to hypoglycaemia and endogenous glucose production did not significantly differ between the groups. Conclusions/interpretation The glucagon response to insulin-induced postprandial hypoglycaemia is lower in post-bariatric surgery individuals compared with non-surgical control individuals, irrespective of the surgical modality. No significant differences were found between patients with post-bariatric hypoglycaemia and surgical control individuals, suggesting that impaired counter-regulation is not a root cause of post-bariatric hypoglycaemia

Powstawanie fal silnych nieciągłości w nieliniowej hiperbolicznej termosprężystości

The most difficult type of waves to analyse in nonlinear thermo-elastic materials are the shock waves. We develop the theory of shock waves in heat conductive elastic materials. We consider the forming of the waves with strong discontinuity so called thermal shock waves in nonlinear thermoelasticity describing the propagation of the heat with nite speed. We proved the mathematical, physical, necessary and sucient conditions of the forming of the thermal shock wave and mechanical shock wave in the nonlinear thermoelasticity.W pracy przedstawiono teorię fal uderzeniowych w materiałach sprężystych przewodzących ciepło. Rozważano formowanie się fal silnych nieciągłości tzw. termicznych fal uderzeniowych w nieliniowej hiperbolicznej termosprężystości opisujących propagację ciepła ze skończoną prędkością. W pracy wyprowadzono i udowodniono matematyczne i fizyczne warunki konieczne i wystarczające do powstania termicznych fal uderzeniowych

Genotype, phenotype and disease severity reflected by serum LysoGb3 levels in patients with Fabry disease

Background: Fabry disease (FD) is a rare X-linked lysosomal storage disease caused by mutations in the α-galactosidase A (GLA) gene causing deficiency of α-galactosidase A which results in progressive glycosphingolipid accumulation, especially globotriaosylceramide (Gb3), in body liquids and lysosomes. In a large cohort of FD patients, we aimed to establish genotype/phenotype relations as indicated by serum LysoGb3 (deacylated Gb3). Methods: In 69 consecutive adult FD patients (males: n =28(41%)) with a GLA-mutation confirmed diagnosis, we conducted a multidisciplinary clinical characterization during their routine annual examinations, and measured serum LysoGb3 levels by high-sensitive electrospray ionization liquid chromatography tandem mass spectrometry. Results: Serum levels of LysoGb3 were significantly higher in Classic compared with Later-Onset phenotype and higher in the latter compared with controls, both in males (52 [40–83] vs 9.5 [4.5–20] vs 0.47 [0.41–0.61] ng/ml, P b 0.001) and in females (9.9 [7.9–14] vs 4.9 [1.6–4.9] vs 0.41 [0.33–0.48] ng/ml, P b 0.001), respectively. Multivariate linear regression analysis showed that LysoGb3 levels were independently associated with, serum creatinine (β = 0.09, 95%CI 0.04–0.13, P b 0.001) and the presence of cardiomyopathy (β = 25, 95%CI 9.8–41, P =0.002). LysoGb3 levels were higher in males with frame-shift and nonsense mutations than in males with missense mutations (84 [72–109] vs 41 [37–52] ng/ml, P = 0.002). Conclusion: LysoGb3 relates to disease severity, enzyme replacement response, and to the genotype severity in males. LysoGb3 supports identifying patients at risk who require intensive monitoring and treatment. LysoGb3 appears to be one marker of metabolic phenotyping of FD