Nkx2-5 and Sarcospan genetically interact in the development of the muscular ventricular septum of the heart

The muscular ventricular septum separates the flow of oxygenated and de-oxygenated blood in air-breathing vertebrates. Defects within it, termed muscular ventricular septal defects (VSDs), are common, yet less is known about how they arise than rarer heart defects. Mutations of the cardiac transcription factor NKX2-5 cause cardiac malformations, including muscular VSDs. We describe here a genetic interaction between Nkx2-5 and Sarcospan (Sspn) that affects the risk of muscular VSD in mice. Sspn encodes a protein in the dystrophin-glycoprotein complex. Sspn knockout (Sspn(KO)) mice do not have heart defects, but Nkx2-5(+/−)/Sspn(KO) mutants have a higher incidence of muscular VSD than Nkx2-5(+/−) mice. Myofibers in the ventricular septum follow a stereotypical pattern that is disrupted around a muscular VSD. Subendocardial myofibers normally run in parallel along the left ventricular outflow tract, but in the Nkx2-5(+/−)/Sspn(KO) mutant they commonly deviate into the septum even in the absence of a muscular VSD. Thus, Nkx2-5 and Sspn act in a pathway that affects the alignment of myofibers during the development of the ventricular septum. The malalignment may be a consequence of a defect in the coalescence of trabeculae into the developing ventricular septum, which has been hypothesized to be the mechanistic basis of muscular VSDs

MRI Digital Artery Volume Index (DAVIX) as a surrogate outcome measure of digital ulcer disease in patients with systemic sclerosis: a prospective cohort study

Background Vascular fibrosis is a key manifestation of systemic sclerosis that leads to the narrowing of small and medium arteries, causing vascular clinical manifestations including digital ulcers and pulmonary arterial hypertension. We investigated the potential of the MRI-based Digital Artery Volume Index (DAVIX) as a surrogate outcome measure of vascular fibrosis by using it to quantify and predict the burden of digital ulcer disease in patients with systemic sclerosis. Methods Two independent cohorts of patients participating in the prospective observational study STRIKE were consecutively enrolled from the Scleroderma Clinic of the Leeds Teaching Hospitals Trust, Leeds, UK. Eligible patients were aged 18 years or older and fulfilled the very early diagnosis of systemic sclerosis (VEDOSS) or the 2013 American College of Rheumatology (ACR)–European Alliance of Associations for Rheumatology (EULAR) systemic sclerosis classification criteria. DAVIX was calculated as the percentage mean of the ratio of digital artery volume to finger volume in the four fingers of the dominant hand. Data were collected at baseline and 12-month follow-up, and the primary outcome was the presence of digital ulcers at 12-month follow-up. Findings Between Feb 7, 2018, and April 11, 2022, we included 85 patients in the exploratory cohort and 150 in the validation cohort. In the exploratory cohort, the mean age was 54·5 years (SD 11·6), 75 (88%) of 85 patients were women, ten (12%) were men, and 69 (82%) were White. In the validation cohort, the mean age was 53·5 years (SD 13·8), 136 (91%) of 150 patients were women, 14 (9%) were men, and 127 (85%) were White. In the exploratory cohort, DAVIX was significantly lower in patients with previous or active digital ulcers (0·34% [IQR 0·16–0·69]) than in those without digital ulcer disease (0·65% [0·42–0·88]; p=0·015); this finding was substantiated in the validation cohort (0·43% [0·20–0·73] vs 0·73% [0·53–0·97]; p<0·0001). Patients who developed new digital ulcers during 12-month follow-up had a lower DAVIX (0·23% [0·10–0·66]) than those who did not (0·65% [0·45–0·91]; p=0·0039). DAVIX was negatively correlated with disease duration (r=−0·415; p<0·0001), the ratio of forced vital capacity to the diffusing capacity of the lungs for carbon monoxide (r=−0·334; p=0·0091), nailfold capillaroscopy pattern (r=−0·447; p<0·0001), and baseline modified Rodnan skin score (r=−0·305; p=0·014) and was positively correlated with the diffusing capacity of carbon monoxide (r=0·368; p=0·0041). DAVIX was negatively correlated with change in score on the Scleroderma Health Assessment Questionnaire-Disability Index (r=−0·308; p=0·024), Visual Analogue Scale (VAS) Raynaud's (r=−0·271; p=0·044), and VAS digital ulcers (r=−0·291; p=0·044). Interpretation DAVIX is a promising surrogate outcome measure of digital ulcer disease in patients with systemic sclerosis. The ability of DAVIX to non-invasively predict future digital ulcers and worsening of patient-reported outcomes could aid patient enrichment and stratification in clinical trials. Clinically, DAVIX could offer insights into the assessment of vascular activity. The sensitivity of DAVIX to change over time and with treatment will establish its value as an imaging outcome measure of vascular disease. Funding National Institute for Health Research Biomedical Research Centre and University of Leeds Industry Engagement Accelerator Fund

Inter-population variations in concentrations, determinants of and correlations between 2,2',4,4',5,5'-hexachlorobiphenyl (CB-153) and 1,1-dichloro-2,2-bis (p-chlorophenyl)-ethylene (p,p'-DDE): a cross-sectional study of 3161 men and women from Inuit and European populations

BACKGROUND: The study is part of a collaborative project (Inuendo), aiming to assess the impact of dietary persistent organochlorine pollutants (POPs) on human fertility. The aims with the present study are to analyze inter-population variations in serum concentrations of 2,2',4,4',5,5'-hexachlorobiphenyl (CB-153) and 1,1-dichloro-2,2-bis (p-chlorophenyl)-ethylene (p,p'-DDE), to assess inter-population variations in biomarker correlations, and to evaluate the relative impact of different determinants for the inter-individual variations in POP-biomarkers. METHOD: In study populations of 3161 adults, comprising Greenlandic Inuits, Swedish fishermen and their wives, and inhabitants from Warsaw, Poland and Kharkiv, Ukraine, serum concentrations of CB-153 and p,p'-DDE, were analysed by gas chromatography-mass spectrometry. RESULTS: The median serum concentrations of CB-153 were for male and female Inuits 200 and 110, for Swedish fishermen 190 and their wives 84, for Kharkiv men and women 44 and 27, and for Warsaw men and women 17 and 11 ng/g lipids, respectively. The median serum concentrations of p,p'-DDE were for Kharkiv men and women 930 and 650, for male and female Inuits 560 and 300, for Warsaw men and women 530 and 380, and for Swedish fishermen 240 and their wives 140 ng/g lipids, respectively. The correlation coefficients between CB-153 and p,p'-DDE varied between 0.19 and 0.92, with the highest correlation among Inuits and the lowest among men from Warsaw. Men had averagely higher serum concentrations of CB-153 and p,p'-DDE, and there were positive associations between age and the POP-biomarkers, whereas the associations with BMI and smoking were inconsistent. Dietary seafood was of importance only in the Inuit and Swedish populations. CONCLUSION: CB-153 concentrations were much higher in Inuits and Swedish fishermen's populations than in the populations from Eastern Europe, whereas the pattern was different for p,p'-DDE showing highest concentrations in the Kharkiv population. The correlations between the POP-biomarkers varied considerably between the populations, underlining that exposure sources differ and that the choice of representative biomarkers of overall POP exposure has to be based on an analysis of the specific exposure situation for each population. Age and gender were consistent determinants of serum POPs; seafood was of importance only in the Inuit and Swedish populations

Bioelectrical impedance analysisfor the assessment of body composition in patients with systemic sclerosis

Objectives The aim of the present study was to evaluate the body composition by bioelectrical impedance analysis (BIA) and to assess the nutritional status by BMI and possible correlations with epidemiological and clinical characteristics in patients with SSc Methods Malnutrition was defined as BMI &lt;18.5 kg/m 2 or unintentional weight loss &gt;10% in combination with a fat-free mass index (FFMI) &lt;15 kg/m 2 for women or &lt;17 kg/m 2 for men or BMI &lt;20.0 kg/m 2 (age &lt;70 years) or &lt;22 kg/m 2 (age &gt;70 years). Body composition was assessed in 40 patients (female) (age mean ±sd: 45.2±12.2) and 20 healthy controls (age mean ±sd 41.5±5.3) with BIA (Akern, Italy) and BMI. The manufacturer’s equation and the Geneva equation were used to estimate fat mass (FFM). In addition, correlations with disease activity, gastrointestinal severity, disease subset, autoantibody profile, skin score were evaluated. Results Malnutrition was found in 10% of patients vs 8% of healty controls; and low FFMI in 30% of patients vs 10 5 of HC. Bioimpedentiometry showed a Fat Free Mass (FFM) (metabolically active component of fat free mass) reduced in patients compared to controls (46.8±7.6 vs 53.6±6.3 respectively; p=0.01). Furthermore, with the same instrument a lower basal metabolic rate was found in patients compared to controls: 1462±145 vs 1720±169 calories (p=0.001). The correlations between FFM and basal metabolism with the clinical features of the patients were not statistically significant Conclusions This study confrim the study of Spanjer MJ et al1 and shows a relatively low prevalence of malnutrition in comparison with other studies, but a high prevalence of low FFMI, underlining the necessity of measuring body composition in SSc patients with a standardised and validated method. Furthermore, Caporali et al,2 have shown an alteration of the nutritional status of patients of SSc probably related to a gastro-intestinal commitment. In our patients despite the presence of an apparent good nutritional status the use of bioimpedanceometry revealed a different body composition, a lower share of muscle mass, in patients compared to controls, related, in part, to musculoskeletal involvement by systemic sclerosis (increase in muscle catabolism and/or poor nutrient supply due to malabsorption phenomena). The early detection of such alterations could be useful to insert subjects at risk in physical rehabilitation programs. References [1] Spanjer MJet al, Rheumatology2017 [2] Caporaliet al; Clin Nutr2012 Disclosure of Interest None declare