The risk stratification of adverse neonatal outcomes in women with gestational diabetes (STRONG) study

Aims: To assess the risk of adverse neonatal outcomes in women with gestational diabetes (GDM) by identifying subgroups of women at higher risk to recognize the characteristics most associated with an excess of risk. Methods: Observational, retrospective, multicenter study involving consecutive women with GDM. To identify distinct and homogeneous subgroups of women at a higher risk, the RECursive Partitioning and AMalgamation (RECPAM) method was used. Overall, 2736 pregnancies complicated by GDM were analyzed. The main outcome measure was the occurrence of adverse neonatal outcomes in pregnancies complicated by GDM. Results: Among study participants (median age 36.8 years, pre-gestational BMI 24.8 kg/m2), six miscarriages, one neonatal death, but no maternal death was recorded. The occurrence of the cumulative adverse outcome (OR 2.48, 95% CI 1.59–3.87), large for gestational age (OR 3.99, 95% CI 2.40–6.63), fetal malformation (OR 2.66, 95% CI 1.00–7.18), and respiratory distress (OR 4.33, 95% CI 1.33–14.12) was associated with previous macrosomia. Large for gestational age was also associated with obesity (OR 1.46, 95% CI 1.00–2.15). Small for gestational age was associated with first trimester glucose levels (OR 1.96, 95% CI 1.04–3.69). Neonatal hypoglycemia was associated with overweight (OR 1.52, 95% CI 1.02–2.27) and obesity (OR 1.62, 95% CI 1.04–2.51). The RECPAM analysis identified high-risk subgroups mainly characterized by high pre-pregnancy BMI (OR 1.68, 95% CI 1.21–2.33 for obese; OR 1.38 95% CI 1.03–1.87 for overweight). Conclusions: A deep investigation on the factors associated with adverse neonatal outcomes requires a risk stratification. In particular, great attention must be paid to the prevention and treatment of obesity

Selective screening for GDM in Italy: application and effectiveness of National Guidelines

In September 2011 the Italian Public Health Authority established selective screening for GDM to be performed based on the presence of risk factors. In a cohort of 2552 Caucasian pregnant women we evaluated to which extent the new national guidelines (NGL) are correctly applied; moreover we estimated the prevalence of GDM assessed by NGL. Our data show that the NGL are still properly implemented since the screening test was performed in nearly the totality of the women at 24th and 28th week of gestation. GDM prevalence is 10.9%, 25% greater as compared to the one determined with the old criteria 10 years ago

The dystrophin glycoprotein complex regulates the epigenetic activation of muscle stem cell commitment

Asymmetrically dividing muscle stem cells in skeletal muscle give rise to committed cells, where the myogenic determination factor Myf5 is transcriptionally activated by Pax7. This activation is dependent on Carm1, which methylates Pax7 on multiple arginine residues, to recruit the ASH2L:MLL1/2:WDR5:RBBP5 histone methyltransferase complex to the proximal promoter of Myf5. Here, we found that Carm1 is a specific substrate of p38γ/MAPK12 and that phosphorylation of Carm1 prevents its nuclear translocation. Basal localization of the p38γ/p-Carm1 complex in muscle stem cells occurs via binding to the dystrophin-glycoprotein complex (DGC) through β1-syntrophin. In dystrophin-deficient muscle stem cells undergoing asymmetric division, p38γ/β1-syntrophin interactions are abrogated, resulting in enhanced Carm1 phosphorylation. The resulting progenitors exhibit reduced Carm1 binding to Pax7, reduced H3K4-methylation of chromatin, and reduced transcription of Myf5 and other Pax7 target genes. Therefore, our experiments suggest that dysregulation of p38γ/Carm1 results in altered epigenetic gene regulation in Duchenne muscular dystrophy.We thank Drs. Jeffrey Dilworth and Lynn Megeney for careful reading of the manuscript. We also thank Jennifer Ritchie for animal husbandry, Dr. Lawrence Puente for mass spectrometry analysis, Dr. Chloë van Oostende for microscopy and imaging analysis, Paul Oleynik for FACS, and Fan Xiao, Natasha Mercier, and David Wilson for technical assistance. N.C.C. is a recipient of the Centre for Neuromuscular Disease Scholarship in Translational Research Award from the University of Ottawa Brain and Mind Research Institute and was supported by Postdoctoral fellowships from the Canadian Institutes of Health Research (CIHR) and the Ontario Institute for Regenerative Medicine (OIRM). F.P.C. was supported by a Postdoctoral fellowship from the French Muscular Dystrophy Association (AFM)-Téléthon (380782). C.E.B. is supported by a Postdoctoral fellowship from OIRM. M.L. was supported by a Postdoctoral fellowship from CIHR. P.M.-C. acknowledges support from ERC-2016-AdG-741966 (STEM-AGING) and SAF2015-67369-R. M.A.R. holds the Canada Research Chair in Molecular Genetics. These studies were carried out with support of grants to M.A.R. from the US NIH (R01AR044031), the Canadian Institutes of Health Research (FDN-148387), the Muscular Dystrophy Association (USA), E-Rare-2: Canadian Institutes of Health Research/Muscular Dystrophy Canada (ERA-132935), and the Stem Cell Network

Microinvasive breast carcinoma: An analysis from ten Senonetwork Italia breast centres

Background and objectives: We studied a large series of ductal carcinoma in situ with microinvasion (MIDC) an infrequent disease whose diagnosis and management are not well defined. Methods: 17,431 cases of breast carcinoma were treated between 2011 and 2016 by ten Italian Breast Units. Our analysis included diagnostic and clinic-pathological characteristics, surgical management, and the use of adjuvant therapies. Results: 15,091 cases (86.6%) were infiltrating carcinomas (IC), 2107 (12.1%) ductal carcinoma in situ (DCIS), and 233 (1.3%) MIDC. Age at diagnosis did not differ between DCIS and MIDC. MIDC were usually larger and expressed more frequently biologically aggressive features (higher Ki67 values, hormone receptor negativity and HER2/neu over-expression) (p < 0.01). Axillary lymph nodes were involved in 25 MIDC cases (12%), but >3 lymph nodes were involved in two cases only (1%). At multivariable analysis, only lymphovascular invasion (LVI) was associated with lymph node status (p < 0.01). Hormone therapy was prescribed in 388/1462 DCIS cases (26.5%), in 84/200 MIDC cases (42%), and in 11,086/14,188 IC cases (84.7%) (p < 0.01). Chemotherapy was administered in 28/190 MIDC cases (14.7%), and in 4080/11,548 IC cases (35.3%) (p < 0.001). Conclusions: This is one of the largest studies of MIDC reported in the literature. Approximately 10% of DCIS harbor one or more foci of MIDC, and the latter often expresses aggressive biological features. LVI is a predictor of axillary node involvement, but this is infrequent and usually limited. Conservative surgery is performed less often than in DCIS, and adjuvant chemotherapy is less frequently utilized compared to IC

Microinvasive breast carcinoma: An analysis from ten Senonetwork Italia breast centres

Background and objectives: We studied a large series of ductal carcinoma in situ with microinvasion (MIDC) an infrequent disease whose diagnosis and management are not well defined. Methods: 17,431 cases of breast carcinoma were treated between 2011 and 2016 by ten Italian Breast Units. Our analysis included diagnostic and clinic-pathological characteristics, surgical management, and the use of adjuvant therapies. Results: 15,091 cases (86.6%) were infiltrating carcinomas (IC), 2107 (12.1%) ductal carcinoma in situ (DCIS), and 233 (1.3%) MIDC. Age at diagnosis did not differ between DCIS and MIDC. MIDC were usually larger and expressed more frequently biologically aggressive features (higher Ki67 values, hormone receptor negativity and HER2/neu over-expression) (p < 0.01). Axillary lymph nodes were involved in 25 MIDC cases (12%), but >3 lymph nodes were involved in two cases only (1%). At multivariable analysis, only lymphovascular invasion (LVI) was associated with lymph node status (p < 0.01). Hormone therapy was prescribed in 388/1462 DCIS cases (26.5%), in 84/200 MIDC cases (42%), and in 11,086/14,188 IC cases (84.7%) (p < 0.01). Chemotherapy was administered in 28/190 MIDC cases (14.7%), and in 4080/11,548 IC cases (35.3%) (p < 0.001). Conclusions: This is one of the largest studies of MIDC reported in the literature. Approximately 10% of DCIS harbor one or more foci of MIDC, and the latter often expresses aggressive biological features. LVI is a predictor of axillary node involvement, but this is infrequent and usually limited. Conservative surgery is performed less often than in DCIS, and adjuvant chemotherapy is less frequently utilized compared to IC

Interplay between HGAL and Grb2 proteins regulates B-cell receptor signaling

International audienceKey Points• HGAL and Gb2 proteins directly interact upon BCR stimulation.• HGAL and Gb2 interaction plays a role in BCR clustering in sig-nalosomes and regulates BCR-induced biochemical signaling.Human germinal center (GC)-associated lymphoma (HGAL) is an adaptor protein expressed in GC B cells. HGAL regulates cell motility and B-cell receptor (BCR) signaling, processes that are central for the successful completion of the GC reaction. Herein, we demonstrate phosphorylation of HGAL by Syk and Lyn kinases at tyrosines Y80, Y86, Y106Y107, Y128, and Y148. The HGAL YEN motif (amino acids 107-109) is similar to the phosphopeptide motif pYXN used as a binding site to the growth factor receptor-bound protein 2 (Grb2). We demonstrate by biochemical and molecular methodologies that HGAL directly interacts with Grb2. Concordantly, microscopy studies demonstrate HGAL-Grb2 colocalization in the membrane central supramolecular activation clusters (cSMAC) following BCR activation. Mutation of the HGAL putative binding site to Grb2 abrogates the interaction between these proteins. Further, this HGAL mutant localizes exclusively in the peripheral SMAC and decreases the rate and intensity of BCR accumulation in the cSMAC. Furthermore, we demonstrate that Grb2, HGAL, and Syk interact in the same complex, but Grb2 does not modulate the effects of HGAL on Syk kinase activity. Overall, the interplay between the HGAL and Grb2 regulates the magnitude of BCR signaling and synapse formation

Arnold‐Chiari type 1 malformation in Potocki–Lupski syndrome

Potocki–Lupski syndrome (PTLS) is a genetic disorder that results from an interstitial duplication within chromosome 17p11.2. Children with PTLS typically present with infantile hypotonia, failure to thrive, and global developmental delay with or without major organ system involvement. Systematic clinical studies regarding growth, cardiovascular disease, and neurocognitive profiles have been published; however, systematic evaluation of central nervous system structure by magnetic resonance imaging (MRI) of the brain has not been reported. Herein, we describe three patients with PTLS who were found—in the course of routine clinical care—to have a type 1 Arnold‐Chiari malformation (CM‐1). This finding raises the question of whether the incidence of CM‐1 is increased in PTLS, and hence, if an MRI of the brain should be considered in the evaluation of all patients with this chromosomal duplication syndrome