Benefits and Burdens of Using a SNP Array in Pregnancies at Increased Risk for the Common Aneuploidies

We present the nature of pathogenic SNP array findings in pregnancies without ultrasound (US) abnormalities and show the additional diagnostic value of SNP array as compared with rapid aneuploidy detection and karyotyping. 1,330 prenatal samples were investigated with a 0.5‐Mb SNP array after the exclusion of the most common aneuploidies. In 2.7% (36/1,330) of the cases, pathogenic chromosome aberrations were found; a microscopically detectable abnormality in 0.7% and a submicroscopic aberration in 2%. Our results show that in addition to the age‐ or screening‐related aneuploidy risk, in pregnancies without US abnormalities, there is a risk of 1:148 (9/1,330) for a (sub)microscopic abnormality associated with an early‐onset often severe disease, 1:222 (6/1,330) for a submicroscopic aberration causing an early‐onset disease, 1:74 (18/1,330) for carrying a susceptibility locus for a neurodevelopmental disorder, and 1:443 (3/1,330) for a late‐onset disorder (hereditary neuropathy with liability to pressure palsies in all three cases). These risk figures are important for adequate pretest counseling so that prospective parents can make informed individualized choices between targeted prenatal testing and broad testing with SNP array. Based on our results, we believe if invasive testing is performed, SNP array should be the preferred cytogenetic technique irrespective of the indication.     

Incidental findings in multislice computed tomography prior to transcatheter aortic valve implantation: frequency,clinical relevance and outcome

Multislice computed tomography (MSCT) has emerged as the mainstay in patients planned for transcatheter aortic valve implantation (TAVI). Incidental findings (IF) in MSCT are common. However, the exact incidence, clinical relevance and further consequences of IF are unclear and it is controversial whether IF adversely affect patients’ outcome. We analyzed MSCT data of 1050 patients screened for TAVI between January 2011 and December 2014. Median follow-up of patients was 20 months. In total, 3194 IF were identified, which were classified into clinically non-relevant IF (2872, 90%) and clinically relevant IF (322, 10%). In 25% of patients (258/1050) at least one clinically relevant IF was present. Age (80?±?7 vs. 80?±?7 years; p?=?0.198) and EuroSCORE II (3.6% [2.1–5.7] vs. 3.6% [2.1–5.9]; p?=?0.874) was similar between patients with and without a clinically relevant IF. TAVI was performed less frequently in patients with a clinically relevant IF (76% vs. 85%; p?<?0.001), with more patients receiving surgical aortic valve replacement in that group (14% vs. 11%; p?=?0.042), possibly due to the high rate of incidental aneurysms of the ascending aorta (n?=?48). If TAVI was performed mortality did not differ (30-days: 4% vs. 3%; p?=?0.339, 1-year: 11% vs. 14%; p?=?0.226) between patients with and without a clinically relevant IF. Our study is the largest study to analyze prevalence, clinical relevance and therapeutic consequences of IF during screening for TAVI. IF in pre-procedural MSCT are common and clinically relevant in one-quarter of patients. However, these findings had no impact on overall mortality.     

Cathepsin L,transmembrane peptidase/serine subfamily member 2/4, and other host proteases in COVID-19 pathogenesis – with impact on gastrointestinal tract

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) seems to employ two routes of entrance to the host cell; via membrane fusion (with the cells expressing both angiotensin converting enzyme 2 (ACE2) and transmembrane peptidase/serine subfamily member 2/4 (TMPRSS2/4)) or via receptor-mediated endocytosis (to the target cells expressing only ACE2). The second mode is associated with cysteine cathepsins (probably cathepsin L) involvement in the virus spike protein (S protein) proteolytic activation. Also furin might activate the virus S protein enabling it to enter cells. Gastrointestinal tract (GIT) involvement in SARS-CoV-2 infection is evident in a subset of coronavirus disease 2019 (COVID-19) patients exhibiting GIT symptoms, such as diarrhea, and presenting viral-shedding in feces. Considering the abundance and co-localization of ACE2 and TMPRSS2 in the lower GIT (especially brush-border enterocytes), these two receptors seem to be mainly involved in SARS-CoV-2 invasion of the digestive tract. Additionally, in vitro studies have demonstrated the virions capability of infection and replication in the human epithelial cells lining GIT. However, also furin and cysteine cathepsins (cathepsin L) might participate in the activation of SARS-CoV-2 spike protein contributing to the virus invasiveness within GIT. Moreover, cathepsin L (due to its involvement in extracellular matrix components degradation and remodeling, the processes enhanced during SARS-CoV-2-induced inflammation) might be responsible for the dysregulation of absorption/ digestion functions of GIT, thus adding to the observed in some COVID-19 patients symptoms such as diarrhea.     

Distinct roles of CSF family cytokines in macrophage infiltration and activation in glioma progression and injury response

Gliomas attract brain‐resident (microglia) and peripheral macrophages and reprogram these cells into immunosuppressive, pro‐invasive cells. M‐CSF (macrophage colony‐stimulating factor, encoded by the CSF1 gene) has been implicated in the control of recruitment and polarization of macrophages in several cancers. We found that murine GL261 glioma cells overexpress GM‐CSF (granulocyte–macrophage colony‐stimulating factor encoded by the CSF2 gene) but not M‐CSF when compared to normal astrocytes. Knockdown of GM‐CSF in GL261 glioma cells strongly reduced microglia‐dependent invasion in organotypical brain slices and growth of intracranial gliomas and extended animal survival. The number of infiltrating microglia/macrophages (Iba1⁺ cells) and intratumoural angiogenesis were reduced in murine gliomas depleted of GM‐CSF. M1/M2 gene profiling in sorted microglia/macrophages suggests impairment of their pro‐invasive activation in GM‐CSF‐depleted gliomas. Deficiency of M‐CSF (op/op mice) did not affect glioma growth in vivo and the accumulation of Iba1⁺ cells, but impaired accumulation of Iba1⁺ cells in response to demyelination. These results suggest that distinct cytokines of the CSF family contribute to macrophage infiltration of tumours and in response to injury. The expression of CSF2 (but not CSF1) was highly up‐regulated in glioblastoma patients and we found an inverse correlation between CSF2 expression and patient survival. Therefore we propose that GM‐CSF triggers and drives the alternative activation of tumour‐infiltrating microglia/macrophages in which these cells support tumour growth and angiogenesis and shape the immune microenvironment of gliomas. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Association Between IL-6 Concentration and Diabetes-Related Variables in DM1 Patients with and without Microvascular Complications

Interleukin 6 (IL-6) plays an important role in the initiation and acceleration of chronic inflammation and could contribute to development of microvascular complications in patients with type 1 diabetes (DM1). Therefore, this study was aimed to investigate the association between concentration of IL-6 in relation to glucose control, lipid profile, and body mass index (BMI) in 69 DM1 patients subdivided according to the absence or presence of microvascular complications. BMI, level of fasting plasma glucose (FPG), and concentrations of total cholesterol (TCH), LDL cholesterol (LDL-C), and IL-6 were higher in DM1 patients compared to the control group. In DM1 patients, IL-6 concentration was positively correlated with level of FPG, LDL-C, TCH concentrations, and BMI. These correlations were stronger in the subgroup of patients with microvascular complications. In addition, BMI independently influences IL-6 concentration in DM1 patients. In conclusion, elevated IL-6 concentration is associated with diabetes-related variables which could accelerate progression of microvascular complications in DM1 patients.     

Early life malnutrition and fluctuating asymmetry in the rat bony labyrinth

Maternal malnutrition during gestation and lactation is known to have adverse effects on offspring. We evaluate the impact of maternal diet on offspring bony labyrinth morphology. The bony labyrinth develops early and is thought to be stable to protect vital sensory organs within. For these reasons, bony labyrinth morphology has been used extensively to assess locomotion, hearing function, and phylogeny in primates and numerous other taxa. While variation related to these parameters has been documented, there is still a component of intraspecific variation that is unexplained. Although the labyrinthine developmental window is small, it may provide the opportunity for developmental instability to produce corresponding shape differences, as measured by fluctuating asymmetry (FA). We hypothesized that (a) offspring with poor maternal diet would exhibit increased FA, but (b) no unilateral shape difference. To test these hypotheses, we used two groups of rats (Rattus norvegicus; Crl:WI[Han] strain), one control group and one group exposed to a isocaloric, protein-restricted maternal diet during gestation and suckling. Individuals were sampled at weaning, sexual maturity, and old age. A Procrustes analysis of variance identified statistically significant FA in all diet-age subgroups. No differences in level of FA were identified among the subgroups, rejecting our first hypothesis. A principal components analysis identified no unilateral shape differences, supporting our second hypothesis. These results indicate that bony labyrinth morphology is remarkably stable and likely protected from a poor maternal diet during development. In light of this result, other factors must be explored to explain intraspecific variation in labyrinthine shape.