Lipid A is the lipid anchor of a lipopolysaccharide in the outer leaflet of the outer membrane of Gram-negative bacteria. In general, lipid A consists of two phosphorylated N-acetyl glucosamine and ...several acyl chains that are directly linked to the two sugars. Depending on the bacterial species and environments, the acyl chain number and length vary, and lipid A can be chemically modified with phosphoethanolamine, aminoarabinose, or glycine residues, which are key to bacterial pathogenesis. In this work, homogeneous lipid bilayers of 21 distinct lipid A types from 12 bacterial species are modeled and simulated to investigate the differences and similarities of their membrane properties. In addition, different neutralizing ion types (Ca2+, K+, and Na+) are considered to examine the ion’s influence on the membrane properties. The trajectory analysis shows that (1) the area per lipid is mostly correlated to the acyl chain number, and the area per lipid increases as a function of the acyl chain number; (2) the hydrophobic thickness is mainly determined by the average acyl chain length with slight dependence on the acyl chain number, and the hydrophobic thickness generally increases with the average acyl chain length; (3) a good correlation is observed among the area per lipid, hydrophobic thickness, and acyl chain order; and (4) although the influence of neutralizing ion types on the area per lipid and hydrophobic thickness is minimal, Ca2+ stays longer on the membrane surface than K+ or Na+, consequently leading to lower lateral diffusion and a higher compressibility modulus, which agrees well with available experiments.
Increased risk of cerebrovascular accident in diabetes cannot be fully explained by traditional risk factors. Epidemiological studies show that postprandial hyperglycemia is strongly associated with ...cerebrovascular events and cerebrovascular-associated mortality. Postprandial hyperglycemia contributes to vascular damage by several mechanisms such as endothelial dysfunction, arthrosclerosis, oxidative stress, inflammation, and hypercoagulability. Hyperglycemia has deleterious effects on the vascular endothelium and leads to the development of cerebrovascular disease. Thus, an important strategy to reduce cerebrovascular risk in patients with diabetes is to reduce postprandial hyperglycemia. Glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase-4 inhibitors, and α-glucosidase inhibitors predominantly reduce postprandial plasma glucose levels. Among all of these, α-glucosidase inhibitors reduces postprandial hyperglycemia by delaying carbohydrate absorption from the intestine and this mechanism provides glycemic control without exacerbating coexisting cerebrovascular risk factors. Good glycemic control is proven to reduce the risk of cardiovascular complications, but equivalent evidence for cerebrovascular risk reduction is lacking. This review examines the evidences that postprandial hyperglycemia plays a major role in vascular damage, along with the complex interplay between hyperglycemia and coexisting risk factors. Furthermore, the mechanism by which α-glucosidase inhibitors may prevent this vascular damage as well as risk of hypoglycemia with α-glucosidase inhibitors are examined. Thus, this review suggests that α-glucosidase inhibitors are useful in reducing the risk of cerebrovascular events in patients with diabetes.
This Position Statement represents the consensus of an expert committee convened by the European Society of Endodontology (ESE) on External Cervical Resorption (ECR). The statement is based on ...current clinical and scientific evidence as well as the expertise of the committee. The primary aim is to provide a current authoritative position on the aetiology, histopathology, clinical presentation and management of ECR, and also to highlight areas where there is minimal evidence. Previously published review articles provide more detailed background information and the basis for this position statement (International Endodontic Journal 51, 1205, 2018, International Endodontic Journal 51, 1224, 2018). It is intended that this position statement will be updated at appropriate intervals, as further evidence emerges.
India is predominantly a rural country, where more than two-thirds of the population live in rural areas. The majority of the rural population use crop residue, firewood, and dung cake as cooking ...fuel sources. Combustion of these fuels emits life-threatening pollutants that contaminate the household environment, which can have serious health consequences, especially for young children. This study examines the use of cooking fuel sources and their association with acute respiratory infections (ARIs) in children aged 0–59 months.
This study used data from the second update of the Annual Health Survey (2012–13). The prevalence rate was measured in terms of the number of children per 1000 children suffering from ARIs. Bivariate analysis was used to analyze the use of different cooking fuels (in percentage) and the prevalence of ARIs in Uttar Pradesh.
District-level variations in the cooking fuels used were assessed by simple bivariate analysis for all districts of Uttar Pradesh. A logistic regression was used to examine the association of household environment and pollutants with ARIs.
In total, 89 per 1000 children suffered from ARIs in Uttar Pradesh. Infants (0–11 months) were significantly more likely to suffer from ARIs than older children (12–59 months). Households using dung cake for cooking and kerosene and other oils for lighting were found to have significantly higher odds for ARIs (odds ratio OR: 1.21; 95% confidence interval CI: 1.17–1.25 and OR: 1.07; 95% CI: 1.05–1.10, respectively). A considerable interdistrict difference was observed in the cooking fuel used and the prevalence of ARIs among children aged 0–59 months.
The type of cooking fuel and lighting source used were found to be significant predictors of ARIs among children aged 0–59 months. These results highlight the need for targeted efforts for the provision of clean cooking fuels (liquid petroleum gas/biogas/electricity) and for the improvement in knowledge and awareness of ARIs and exposure to cooking and lighting pollution.
•37.6% of households use dung cake as a cooking fuel and only 13.5% use clean fuels.•Interdistrict differences in cooking fuel sources and prevalence of acute respiratory infections (ARIs) are significant.•Type of cooking fuel and lighting source were found to be significant predictors of ARI.•This study helps to understand the prevalence of ARI and their determinants.
SARS-CoV-2, the etiologic agent of COVID-19, is a global pandemic with substantial mortality dominated by acute respiratory distress syndrome. We systematically evaluated lungs of 68 autopsies from 3 ...institutions in heavily hit areas (2 USA, 1 Italy). Detailed evaluation of several compartments (airways, alveolar walls, airspaces, and vasculature) was performed to determine the range of histologic features. The cohort consisted of 47 males and 21 females with a median age of 73 years (range 30–96). Co-morbidities were present in most patients with 60% reporting at least three conditions. Tracheobronchitis was frequently present, independent from intubation or superimposed pneumonia. Diffuse alveolar damage (DAD) was seen in 87% of cases. Later phases of DAD were less frequent and correlated with longer duration of disease. Large vessel thrombi were seen in 42% of cases but platelet (CD61 positive) and/or fibrin microthrombi were present at least focally in 84%. Ultrastructurally, small vessels showed basal membrane reduplication and significant endothelial swelling with cytoplasmic vacuolization. In a subset of cases, virus was detected using different tools (immunohistochemistry for SARS-CoV-2 viral spike protein, RNA in situ hybridization, lung viral culture, and electron microscopy). Virus was seen in airway epithelium and type 2 pneumocytes. IHC or in situ detection, as well as viable form (lung culture positive) was associated with the presence of hyaline membranes, usually within 2 weeks but up to 4 weeks after initial diagnosis. COVID-19 pneumonia is a heterogeneous disease (tracheobronchitis, DAD, and vascular injury), but with consistent features in three centers. The pulmonary vasculature, with capillary microthrombi and inflammation, as well as macrothrombi, is commonly involved. Viral infection in areas of ongoing active injury contributes to persistent and temporally heterogeneous lung damage.
The 2019 novel coronavirus, declared a pandemic, has infected 2.6 million people as of April 27, 2020, and has resulted in the death of 181,938 people. D-dimer is an important prognostic tool, is ...often elevated in patients with severe coronavirus disease-19 (COVID-19) infection and in those who suffered death. In this systematic review, we aimed to investigate the prognostic role of D-dimer in COVID-19-infected patients. We searched PubMed, Medline, Embase, Ovid, and Cochrane for studies reporting admission D-dimer levels in COVID-19 patients and its effect on mortality. Eighteen studies (16 retrospective and 2 prospective) with a total of 3682 patients met the inclusion criteria. The pooled weighted mean difference (WMD) demonstrated significantly elevated D-dimer levels in patients who died versus those who survived (WMD, 6.13 mg/L; 95% confidence interval CI 4.16-8.11; P < 0.001). Similarly, the pooled mean D-dimer levels were significantly elevated in patients with severe COVID-19 infection (WMD, 0.54 mg/L; 95% CI 0.28-0.80; P < 0.001). The risk of mortality was fourfold higher in patients with positive D-dimer versus negative D-dimer (risk ratio, 4.11; 95% CI, 2.48-6.84; P < 0.001) and the risk of developing severe disease was twofold higher in patients with positive D-dimer levels versus negative D-dimer (risk ratio, 2.04; 95% CI, 1.34-3.11; P < 0.001). Our meta-analysis demonstrates that patients with COVID-19 infection presenting with elevated D-dimer levels have an increased risk of severe disease and mortality.
We have reviewed accidental spinal administration of tranexamic acid. We performed a MEDLINE search of cases of administration of tranexamic acid during epidural or spinal anaesthesia between 1960 ...and 2018. No reports of epidural administration were identified. We identified 21 cases of spinal tranexamic acid administration. Life-threatening neurological and/or cardiac complications, requiring resuscitation and/or intensive care, occurred in 20 patients; 10 patients died. We used a Human Factors Analysis Classification System model to analyse any contributing factors, and the reports were also assessed using four published recommendations for the reduction in neuraxial drug error. In 20 cases, ampoule error was the cause; in the last case a spinal catheter was mistaken for an intravenous catheter. All were classified as skill-based errors. Several human factors related to organisational policy; dispensing and storage of drugs and preparation for spinal anaesthesia tasks were present. All errors could have been prevented by implementing the four published recommendations.
We have used a translational convergent functional genomics (CFG) approach to identify and prioritize genes involved in schizophrenia, by gene-level integration of genome-wide association study data ...with other genetic and gene expression studies in humans and animal models. Using this polyevidence scoring and pathway analyses, we identify top genes (DISC1, TCF4, MBP, MOBP, NCAM1, NRCAM, NDUFV2, RAB18, as well as ADCYAP1, BDNF, CNR1, COMT, DRD2, DTNBP1, GAD1, GRIA1, GRIN2B, HTR2A, NRG1, RELN, SNAP-25, TNIK), brain development, myelination, cell adhesion, glutamate receptor signaling, G-protein-coupled receptor signaling and cAMP-mediated signaling as key to pathophysiology and as targets for therapeutic intervention. Overall, the data are consistent with a model of disrupted connectivity in schizophrenia, resulting from the effects of neurodevelopmental environmental stress on a background of genetic vulnerability. In addition, we show how the top candidate genes identified by CFG can be used to generate a genetic risk prediction score (GRPS) to aid schizophrenia diagnostics, with predictive ability in independent cohorts. The GRPS also differentiates classic age of onset schizophrenia from early onset and late-onset disease. We also show, in three independent cohorts, two European American and one African American, increasing overlap, reproducibility and consistency of findings from single-nucleotide polymorphisms to genes, then genes prioritized by CFG, and ultimately at the level of biological pathways and mechanisms. Finally, we compared our top candidate genes for schizophrenia from this analysis with top candidate genes for bipolar disorder and anxiety disorders from previous CFG analyses conducted by us, as well as findings from the fields of autism and Alzheimer. Overall, our work maps the genomic and biological landscape for schizophrenia, providing leads towards a better understanding of illness, diagnostics and therapeutics. It also reveals the significant genetic overlap with other major psychiatric disorder domains, suggesting the need for improved nosology.
Mutations in NOTCH1 Cause Adams-Oliver Syndrome Stittrich, Anna-Barbara; Lehman, Anna; Bodian, Dale L. ...
American journal of human genetics,
09/2014, Letnik:
95, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Notch signaling determines and reinforces cell fate in bilaterally symmetric multicellular eukaryotes. Despite the involvement of Notch in many key developmental systems, human mutations in Notch ...signaling components have mainly been described in disorders with vascular and bone effects. Here, we report five heterozygous NOTCH1 variants in unrelated individuals with Adams-Oliver syndrome (AOS), a rare disease with major features of aplasia cutis of the scalp and terminal transverse limb defects. Using whole-genome sequencing in a cohort of 11 families lacking mutations in the four genes with known roles in AOS pathology (ARHGAP31, RBPJ, DOCK6, and EOGT), we found a heterozygous de novo 85 kb deletion spanning the NOTCH1 5′ region and three coding variants (c.1285T>C p.Cys429Arg, c.4487G>A p.Cys1496Tyr, and c.5965G>A p.Asp1989Asn), two of which are de novo, in four unrelated probands. In a fifth family, we identified a heterozygous canonical splice-site variant (c.743−1 G>T) in an affected father and daughter. These variants were not present in 5,077 in-house control genomes or in public databases. In keeping with the prominent developmental role described for Notch1 in mouse vasculature, we observed cardiac and multiple vascular defects in four of the five families. We propose that the limb and scalp defects might also be due to a vasculopathy in NOTCH1-related AOS. Our results suggest that mutations in NOTCH1 are the most common cause of AOS and add to a growing list of human diseases that have a vascular and/or bony component and are caused by alterations in the Notch signaling pathway.
Development of potent antimicrobial agents is a relentless topic of interest in therapeutic field and the medicinal field is always on the lookout for more advanced and effective antimicrobial ...agents. This research investigates the antimicrobial potential of a series of 1,3,4-oxadiazole derivatives synthesized through a systematic approach. The compounds were characterized using various spectroscopic techniques, including NMR, IR, and mass spectrometry, to confirm their structures. We develop into its pharmacological activities, including antibacterial and antifungal activity.
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