Fabry disease and the heart: an overview of the natural history and the effect of enzyme replacement therapy

Fabry disease is a genetic disorder caused by the deficiency of α-galactosidase A, resulting in the lysosomal accumulation of glycosphingolipids. Fabry disease may result in cardiac, cerebral and renal complications. Cardiac abnormalities in patients with Fabry disease were first described in the 1960s. In the 1990s a form of Fabry disease confined to the heart was reported; however, this variant is extremely rare and a more appropriate concept is of cardiac predominance of the disease in some patients. Up to 60% of males with classic Fabry disease have cardiac abnormalities, including left ventricular hypertrophy, valvular dysfunction and conduction abnormalities. Recent data suggest that left ventricular mass and systolic function in patients with Fabry disease improve after 12 months of enzyme replacement therapy (ERT); however, many of the patients studied are relatively young and have mild cardiac abnormalities, suggesting that more research into the efficacy of ERT in older patients is necessary.
Conclusion: Cardiac manifestations are common in patients with Fabry disease and are not confined to a 'cardiac variant' of the disease.     

Hemoglobin switching during murine embryonic development: evidence for two populations of embryonic erythropoietic progenitor cells

Explants of normal mouse embryonic tissues and disaggregated embryonic single cells were cultured in vitro to study the erythropoietic progenitor cells present during embryonic development. The results indicate that there are two populations of erythropoietic progenitor cells committed to different hemoglobin synthetic programs. These progenitor cells are present at an early gestational stage prior to the formation of the fetal hepatic primordium. One population of progenitors can be stimulated by erythropoietin alone to form usually small erythroid colonies after culture for six days in vitro. These erythroblasts primarily synthesize embryonic hemoglobins, but produce some adult hemoglobins as well. The other population of progenitors requires stimulation by both erythropoietin and adult spleen cell- conditioned medium, and usually forms large erythroid colonies after culture for six days in vitro. These erythroblasts produce only adult hemoglobins.     

Cumulative effects of dibutyl phthalate and diethylhexyl phthalate on male rat reproductive tract development: altered fetal steroid hormones and genes.

Exposure to plasticizers di(n-butyl) phthalate (DBP) and diethylhexyl phthalate (DEHP) during sexual differentiation causes male reproductive tract malformations in rats and rabbits. In the fetal male rat, these two phthalate esters decrease testosterone (T) production and insulin-like peptide 3 (insl3) gene expression, a hormone critical for gubernacular ligament development. We hypothesized that coadministered DBP and DEHP would act in a cumulative dose-additive fashion to induce reproductive malformations, inhibit fetal steroid hormone production, and suppress the expression of insl3 and genes responsible for steroid production. Pregnant Sprague Dawley rats were gavaged on gestation days (GD) 14-18 with vehicle control, 500 mg/kg DBP, 500 mg/kg DEHP, or a combination of DBP and DEHP (500 mg/kg each chemical; DBP+DEHP); the dose of each individual phthalate was one-half of the effective dose predicted to cause a 50% incidence of epididymal agenesis. In experiment one, adult male offspring were necropsied, and reproductive malformations and androgen-dependent organ weights were recorded. In experiment two, GD18 testes were incubated for T production and processed for gene expression by quantitative real-time PCR. The DBP+DEHP dose increased the incidence of many reproductive malformations by >or=50%, including epididymal agenesis, and reduced androgen-dependent organ weights in cumulative, dose-additive manner. Fetal T and expression of insl3 and cyp11a were cumulatively decreased by the DBP+DEHP dose. These data indicate that individual phthalates with a similar mechanism of action, but with different active metabolites (monobutyl phthalate versus monoethylhexyl phthalate), can elicit dose-additive effects when administered as a mixture.     

Effect of inherited deficiency of the fifth component of complement on arthritis induced in mice by mycoplasma pulmonis

Mycoplasma pulmonis inoculated parenterally into mice deficient in the fifth component of complement (C5) caused a chronic arthritis of significantly greater magnitude than in immunologically normal mice. During the chronic phase of arthritis M pulmonis organisms were isolated from the joints and organs of C5 deficient mice more frequently and in larger numbers than from immunologically normal mice. The implications of the results are discussed in relation to the pathogenesis of M pulmonis induced arthritis and human connective tissue diseases.     

Trends and cyclic variation in the incidence of childhood type 1 diabetes in two Italian regions over 33 years and during the COVID-19 pandemic

Aim

There is conflicting evidence about the impact of the COVID-19 pandemic on the incidence of type 1 diabetes. Here, we analysed long-term trends in the incidence of type 1 diabetes in Italian children and adolescents from 1989 to 2019 and compared the incidence observed during the COVID-19 pandemic with that estimated from long-term data.

Materials and Methods

This was a population-based incidence study using longitudinal data from two diabetes registries in mainland Italy. Trends in the incidence of type 1 diabetes from 1 January 1989 to 31 December 2019 were estimated using Poisson and segmented regression models.

Results

There was a significant increasing trend in the incidence of type 1 diabetes of 3.6% per year [95% confidence interval (CI): 2.4-4.8] between 1989 and 2003, a breakpoint in 2003, and then a constant incidence until 2019 (0.5%, 95% CI: -1.3 to 2.4). There was a significant 4-year cycle in incidence over the entire study period. The rate observed in 2021 (26.7, 95% CI: 23.0-30.9) was significantly higher than expected (19.5, 95% CI: 17.6-21.4; p = .010).

Conclusion

Long-term incidence analysis showed an unexpected increase in new cases of type 1 diabetes in 2021. The incidence of type 1 diabetes now needs continuous monitoring using population registries to understand better the impact of COVID-19 on new-onset type 1 diabetes in children.