Citations

Autologous mesenchymal stem/stromal cells (MSCs) have demonstrated important therapeutic effects in several diseases. Cardiovascular risk factors may impair MSC mitochondrial structure and function, but the underlying mechanisms remain unknown. We hypothesized that metabolic syndrome (MetS) induces epigenetic alterations in mitochondria-related genes in swine MSCs. Pigs were fed a Lean or MetS diet (n = 6 each) for 16 weeks. MSCs were collected from subcutaneous abdominal fat, and DNA hydroxymethylation (5 hmC) profiles of mitochondria-related genes (MitoCarta-2.0) were analyzed by hydroxymethylated DNA immunoprecipitation and next-generation sequencing (hMeDIP-seq) in Lean- and MetS-MSCs untreated or treated with the epigenetic modulator vitamin (Vit)-C (n = 3 each). Functional analysis of genes with differential 5 hmC regions was performed using DAVID6.8. Mitochondrial structure (electron microscopy), oxidative stress, and membrane potential were assessed. hMeDIP-seq identified 172 peaks (associated with 103 mitochondrial genes) with higher and 416 peaks (associated with 165 mitochondrial genes) with lower 5 hmC levels in MetS-MSCs versus Lean-MSCs (≥2-fold, p < 0.05). Genes with higher 5 hmC levels in MetS + MSCs were primarily implicated in fatty acid metabolism, whereas those with lower 5 hmC levels were associated with electron transport chain activity. Vit-C increased 5 hmC levels in mitochondrial antioxidant genes, improved mitochondrial structure and membrane potential, and decreased oxidative stress. MetS alters 5 hmC levels of mitochondria-related genes in swine MSCs. Vit-C modulated 5 hmC levels in these genes and preserved mitochondrial structure and function in MetS-MSCs. These observations may contribute to development of strategies to overcome the deleterious effects of MetS on MSCs.

Purpose: Treatment sequelae compromising reproductive health are highly prevalent in childhood cancer survivors, and a main determinant of health and quality of life. Follicular reserve determines ovarian function life span; thus, its preservation is important in the care of female survivors. Anti-Müllerian hormone (AMH) is a biomarker to measure functional ovarian reserve. We aimed to evaluate the effect of leuprolide during gonadotoxic therapy on pubertal females' post-treatment functional ovarian reserve using AMH levels. Methods: We conducted a single-center retrospective study including all pubertal females who had undergone gonadotoxic treatments between January 2010 and April 2020, and had an AMH level after completion of therapy. We used multivariable linear regressions to compare AMH-level beta coefficients in patients stratified by gonadotoxic risk, adjusting for leuprolide use. Results: Fifty-two females meeting study eligibility were included, of which 35 received leuprolide. The use of leuprolide was associated with higher post-treatment AMH levels in the lower gonadotoxic risk group (beta 2.74, 95% CI 0.97–4.51; p = 0.004). This association was lost in the higher gonadotoxic risk groups. Conclusions: Leuprolide may have a protective effect on the functional ovarian reserve. However, this is limited by increasing treatment gonadotoxicity. Larger, prospective studies are needed to elucidate the potential benefits of gonadotropin-releasing hormone agonist on preservation of ovarian reserve among children receiving gonadotoxic therapies, as cancer survivors.

Abstract Lithium is regarded as the first-line treatment for bipolar disorder (BD), a severe and disabling mental disorder that affects about 1% of the population worldwide. Nevertheless, lithium is not consistently effective, with only 30% of patients showing a favorable response to treatment. To provide personalized treatment options for bipolar patients, it is essential to identify prediction biomarkers such as polygenic scores. In this study, we developed a polygenic score for lithium treatment response (Li+PGS) in patients with BD. To gain further insights into lithium's possible molecular mechanism of action, we performed a genome-wide gene-based analysis. Using polygenic score modeling, via methods incorporating Bayesian regression and continuous shrinkage priors, Li+PGS was developed in the International Consortium of Lithium Genetics cohort (ConLi+Gen: N=2,367) and replicated in the combined PsyCourse (N=89) and BipoLife (N=102) studies. The associations of Li+PGS and lithium treatment response — defined in a continuous ALDA scale and a categorical outcome (good response vs. poor response) were tested using regression models, each adjusted for the covariates: age, sex, and the first four genetic principal components. Statistical significance was determined at P<����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������

Abstract There are few causes of treatable neurodevelopmental diseases described to date. Branched-chain ketoacid dehydrogenase kinase (BCKDK) deficiency causes branched-chain amino acid (BCAA) depletion and is linked to a neurodevelopmental disorder characterized by autism, intellectual disability and microcephaly. We report the largest cohort of patients studied, broadening the phenotypic and genotypic spectrum. Moreover, this is the first study to present newborn screening findings and mid-term clinical outcome. In this cross-sectional study, patients with a diagnosis of BCKDK deficiency were recruited via investigators’ practices through a MetabERN initiative. Clinical, biochemical and genetic data were collected. Dried blood spot (DBS) newborn screening (NBS) amino acid profiles were retrieved from collaborating centres and compared to a healthy newborn reference population. Twenty-one patients with BCKDK mutations were included from 13 families. Patients were diagnosed between 8 months and 16 years (mean: 5.8 years, 43% female). At diagnosis, BCAA levels (leucine, valine and isoleucine) were below reference values in plasma and in CSF. All patients had global neurodevelopmental delay; 18/21 had gross motor function (GMF) impairment with GMF III or worse in 5/18, 16/16 intellectual disability, 17/17 language impairment, 12/17 autism spectrum disorder, 9/21 epilepsy, 12/15 clumsiness, 3/21 had sensorineural hearing loss and 4/20 feeding difficulties. No microcephaly was observed at birth, but 17/20 developed microcephaly during follow-up. Regression was reported in six patients. Movement disorder was observed in 3/21 patients: hyperkinetic movements (1), truncal ataxia (1) and dystonia (2). After treatment with a high-protein diet (≥ 2 g/kg/day) and BCAA supplementation (100–250 mg/kg/day), plasma BCAA increased significantly (P &lt; 0.001), motor functions and head circumference stabilized/improved in 13/13 and in 11/15 patients, respectively. Among cases with follow-up data, none of the three patients starting treatment before 2 years of age developed autism at follow-up. The patient with the earliest age of treatment initiation (8 months) showed normal development at 3 years of age. NBS in DBS identified BCAA levels significantly lower than those of the normal population. This work highlights the potential benefits of dietetic treatment, in particular early introduction of BCAA. Therefore, it is of utmost importance to increase awareness about this treatable disease and consider it as a candidate for early detection by NBS programmes.

Background: Estimation of insulin sensitivity (S I ) and its daily variation are key for optimizing insulin therapy in patients with type 1 diabetes (T1D). We recently developed a method for S I estimation from continuous glucose monitoring (CGM) and continuous subcutaneous insulin infusion (CSII) data in adults with T1D (S I SP ) and validated it under restrained experimental conditions. Herein, we validate in vivo a new version of S I SP performing well in daily life unrestrained conditions. Methods: The new S I SP was tested in both simulated and real data. The simulated dataset consists of 100 virtual adults of the UVa/Padova T1D Simulator monitored during an open-loop experiment, whereas the real dataset consists of 10 youths with T1D monitored during a hybrid closed-loop meal study. In both datasets, participants underwent two consecutive meals (breakfast and lunch, at 7 and 11 am) with the same carbohydrate content (70 g). Plasma glucose and insulin were measured during each meal to estimate the oral glucose minimal model S I (S I MM ). CGM and CSII data were used for S I SP calculation, which was then validated against the gold standard S I MM . Results: S I SP was estimated with good precision (median coefficient of variation <20%) in 100% of the real and 91% of the simulated meals. S I SP and S I MM were highly correlated, both in the simulated and real datasets ( R = 0.82 and R = 0.83, P < 0.001), and exhibited a similar intraday pattern. Conclusions: S I SP is suitable for estimating S I in both closed- and open-loop settings, provided that the subject wears a CGM sensor and a subcutaneous insulin pump.

Background: Heart disease is linked to worse acute outcomes after coronavirus disease 2019 (COVID-19), although long-term outcomes and prognostic factor data are lacking. We aim to characterize the outcomes and the impact of underlying heart diseases after surviving COVID-19 hospitalization. Methods: We conducted an analysis of the prospective registry HOPE-2 (Health Outcome Predictive Evaluation for COVID-19-2, NCT04778020). We selected patients discharged alive and considered the primary end-point all-cause mortality during follow-up. As secondary main end-points, we included any readmission or any post-COVID-19 symptom. Clinical features and follow-up events are compared between those with and without cardiovascular disease. Factors with p < 0.05 in the univariate analysis were entered into the multivariate analysis to determine independent prognostic factors. Results: HOPE-2 closed on 31 December 2021, with 9299 patients hospitalized with COVID-19, and 1805 died during this acute phase. Finally, 7014 patients with heart disease data were included in the present analysis, from 56 centers in 8 countries. Heart disease (+) patients were older (73 vs. 58 years old), more frequently male (63 vs. 56%), had more comorbidities than their counterparts, and suffered more frequently from post-COVID-19 complications and higher mortality (OR heart disease: 2.63, 95% CI: 1.81–3.84). Vaccination was found to be an independent protector factor (HR all-cause death: 0.09; 95% CI: 0.04–0.19). Conclusions: After surviving the acute phase, patients with underlying heart disease continue to present a more complex clinical profile and worse outcomes including increased mortality. The COVID-19 vaccine could benefit survival in patients with heart disease during follow-up.