The aim of this guideline is to present current and comprehensive recommendations for the diagnosis and treatment of acute spontaneous intracerebral hemorrhage.
A formal literature search of MEDLINE ...was performed. Data were synthesized with the use of evidence tables. Writing committee members met by teleconference to discuss data-derived recommendations. The American Heart Association Stroke Council's Levels of Evidence grading algorithm was used to grade each recommendation. Prerelease review of the draft guideline was performed by 6 expert peer reviewers and by the members of the Stroke Council Scientific Statements Oversight Committee and Stroke Council Leadership Committee. It is intended that this guideline be fully updated in 3 years' time.
Evidence-based guidelines are presented for the care of patients presenting with intracerebral hemorrhage. The focus was subdivided into diagnosis, hemostasis, blood pressure management, inpatient and nursing management, preventing medical comorbidities, surgical treatment, outcome prediction, rehabilitation, prevention of recurrence, and future considerations.
Intracerebral hemorrhage is a serious medical condition for which outcome can be impacted by early, aggressive care. The guidelines offer a framework for goal-directed treatment of the patient with intracerebral hemorrhage.
Idiopathic pulmonary fibrosis (IPF) is a devastating disease that probably involves several genetic loci. Several rare genetic variants and one common single nucleotide polymorphism (SNP) of MUC5B ...have been associated with the disease. Our aim was to identify additional common variants associated with susceptibility and ultimately mortality in IPF.
First, we did a three-stage genome-wide association study (GWAS): stage one was a discovery GWAS; and stages two and three were independent case-control studies. DNA samples from European-American patients with IPF meeting standard criteria were obtained from several US centres for each stage. Data for European-American control individuals for stage one were gathered from the database of genotypes and phenotypes; additional control individuals were recruited at the University of Pittsburgh to increase the number. For controls in stages two and three, we gathered data for additional sex-matched European-American control individuals who had been recruited in another study. DNA samples from patients and from control individuals were genotyped to identify SNPs associated with IPF. SNPs identified in stage one were carried forward to stage two, and those that achieved genome-wide significance (p<5 × 10(-8)) in a meta-analysis were carried forward to stage three. Three case series with follow-up data were selected from stages one and two of the GWAS using samples with follow-up data. Mortality analyses were done in these case series to assess the SNPs associated with IPF that had achieved genome-wide significance in the meta-analysis of stages one and two. Finally, we obtained gene-expression profiling data for lungs of patients with IPF from the Lung Genomics Research Consortium and analysed correlation with SNP genotypes.
In stage one of the GWAS (542 patients with IPF, 542 control individuals matched one-by-one to cases by genetic ancestry estimates), we identified 20 loci. Six SNPs reached genome-wide significance in stage two (544 patients, 687 control individuals): three TOLLIP SNPs (rs111521887, rs5743894, rs5743890) and one MUC5B SNP (rs35705950) at 11p15.5; one MDGA2 SNP (rs7144383) at 14q21.3; and one SPPL2C SNP (rs17690703) at 17q21.31. Stage three (324 patients, 702 control individuals) confirmed the associations for all these SNPs, except for rs7144383. Linkage disequilibrium between the MUC5B SNP (rs35705950) and TOLLIP SNPs (rs111521887 r(2)=0·07, rs5743894 r(2)=0·16, and rs5743890 r(2)=0·01) was low. 683 patients from the GWAS were included in the mortality analysis. Individuals who developed IPF despite having the protective TOLLIP minor allele of rs5743890 carried an increased mortality risk (meta-analysis with fixed-effect model: hazard ratio 1·72 95% CI 1·24-2·38; p=0·0012). TOLLIP expression was decreased by 20% in individuals carrying the minor allele of rs5743890 (p=0·097), 40% in those with the minor allele of rs111521887 (p=3·0 × 10(-4)), and 50% in those with the minor allele of rs5743894 (p=2·93 × 10(-5)) compared with homozygous carriers of common alleles for these SNPs.
Novel variants in TOLLIP and SPPL2C are associated with IPF susceptibility. One novel variant of TOLLIP, rs5743890, is also associated with mortality. These associations and the reduced expression of TOLLIP in patients with IPF who carry TOLLIP SNPs emphasise the importance of this gene in the disease.
National Institutes of Health; National Heart, Lung, and Blood Institute; Pulmonary Fibrosis Foundation; Coalition for Pulmonary Fibrosis; and Instituto de Salud Carlos III.
Bisphosphonium Benzene Diimides Gebresilassie, Feven Leake; Kim, Min Ji; Castellanos, Daniela ...
Chemistry : a European journal,
07/2024
Journal Article
Recenzirano
The incorporation of cationic groups onto electron‐poor compounds is a viable strategy for achieving potent electron acceptors, as evidenced by reports of air‐stable radical forms of large aromatic ...diimides such as naphthalene and perylene diimides. These ions have also been observed to exhibit anion‐π interaction tendencies of interest in molecular recognition applications. The benefits of phosphonium incorporation, however, have not yet been extended to the smallest benzene diimides. Here, we report that dibrominated pyromellitic diimide and mellophanic diimide both readily undergo substitution reactions with phosphine sources to yield bisphosphonium compounds. In the single crystalline form, these dications display anion‐π interactions and, in the case of mellophanic diimide, the stabilization of a bromide‐water H‐bonding ring pattern. The reaction of these dications with chemical reductants readily provides the singly and doubly reduced redox states, which were characterized by UV‐vis spectroscopy and found to exhibit intense absorptions extending into the near‐IR region. Taken together, this work demonstrates that phosphonium incorporation onto congested aromatic diimide scaffolds is synthetically viable and produces unusual electron‐poor compounds.
Objective
Prior studies investigating the association between APOE alleles ε2/ε4 and risk of intracerebral hemorrhage (ICH) have been inconsistent and limited to small sample sizes, and did not ...account for confounding by population stratification or determine which genetic risk model was best applied.
Methods
We performed a large‐scale genetic association study of 2189 ICH cases and 4041 controls from 7 cohorts, which were analyzed using additive models for ε2 and ε4. Results were subsequently meta‐analyzed using a random effects model. A proportion of the individuals (322 cases, 357 controls) had available genome‐wide data to adjust for population stratification.
Results
Alleles ε2 and ε4 were associated with lobar ICH at genome‐wide significance levels (odds ratio OR = 1.82, 95% confidence interval CI = 1.50–2.23, p = 6.6 × 10−10; and OR = 2.20, 95%CI = 1.85–2.63, p = 2.4 × 10−11, respectively). Restriction of analysis to definite/probable cerebral amyloid angiopathy ICH uncovered a stronger effect. Allele ε4 was also associated with increased risk for deep ICH (OR = 1.21, 95% CI = 1.08–1.36, p = 2.6 × 10−4). Risk prediction evaluation identified the additive model as best for describing the effect of APOE genotypes.
Interpretation
APOE ε2 and ε4 are independent risk factors for lobar ICH, consistent with their known associations with amyloid biology. In addition, we present preliminary findings on a novel association between APOE ε4 and deep ICH. Finally, we demonstrate that an additive model for these APOE variants is superior to other forms of genetic risk modeling previously applied. ANN NEUROL 2010
Apolipoprotein E (ApoE) genotypes have been associated with lobar intracerebral hemorrhage (ICH). Although statins have been associated with an increased risk of ICH, meta-analyses have not ...consistently shown a statin-induced risk of ICH. Here, we test whether hypercholesterolemia (HC) and ApoE polymorphisms affect the risk of ICH by statin use.
The Genetic and Environmental Risk Factors for Hemorrhagic Stroke (GERFHS) study is a prospective, demographically matched case-control study of ICH. A similar study of ICH, Genetic Risks for Medication-Related Hemorrhagic Stroke (GOCHA), was used as a replication cohort. Subjects were classified as normocholesterolemia, HC without statin use, and HC with statin use. Statistical comparisons were performed using Fisher exact test, χ2 tests, and the Breslow-Day test.
The discovery cohort consisted of 558 ICH cases and 1444 controls, and the replication cohort consisted of 1020 ICH cases and 382 controls. The association of lower risk for HC was not attenuated by statin use. Statin use was observed to confer a higher risk for lobar ICH in those carrying ApoE4/E4 and ApoE2/E4 genotypes in both discovery and replication cohorts, and a test for interaction showed a trend towards significance (P=0.11 for statin and ApoE4/E4).
Statin use does not seem to attenuate the association of HC with decreased risk for nonlobar ICH. Our data support a gene-by-drug effect for lobar ICH, but larger sample sizes are needed to confirm the association before any clinical change is warranted.
http://clinicaltrials.gov. Unique identifier: NCT00930280.
The course of disease for patients with idiopathic pulmonary fibrosis (IPF) is highly heterogeneous. Prognostic models rely on demographic and clinical characteristics and are not reproducible. ...Integrating data from genomic analyses may identify novel prognostic models and provide mechanistic insights into IPF.
Total RNA of peripheral blood mononuclear cells was subjected to microarray profiling in a training (45 IPF individuals) and two independent validation cohorts (21 IPF/10 controls, and 75 IPF individuals, respectively). To identify a gene set predictive of IPF prognosis, we incorporated genomic, clinical, and outcome data from the training cohort. Predictor genes were selected if all the following criteria were met: 1) Present in a gene co-expression module from Weighted Gene Co-expression Network Analysis (WGCNA) that correlated with pulmonary function (p < 0.05); 2) Differentially expressed between observed "good" vs. "poor" prognosis with fold change (FC) >1.5 and false discovery rate (FDR) < 2%; and 3) Predictive of mortality (p < 0.05) in univariate Cox regression analysis. "Survival risk group prediction" was adopted to construct a functional genomic model that used the IPF prognostic predictor gene set to derive a prognostic index (PI) for each patient into either high or low risk for survival outcomes. Prediction accuracy was assessed with a repeated 10-fold cross-validation algorithm and independently assessed in two validation cohorts through multivariate Cox regression survival analysis.
A set of 118 IPF prognostic predictor genes was used to derive the functional genomic model and PI. In the training cohort, high-risk IPF patients predicted by PI had significantly shorter survival compared to those labeled as low-risk patients (log rank p < 0.001). The prediction accuracy was further validated in two independent cohorts (log rank p < 0.001 and 0.002). Functional pathway analysis revealed that the canonical pathways enriched with the IPF prognostic predictor gene set were involved in T-cell biology, including iCOS, T-cell receptor, and CD28 signaling.
Using supervised and unsupervised analyses, we identified a set of IPF prognostic predictor genes and derived a functional genomic model that predicted high and low-risk IPF patients with high accuracy. This genomic model may complement current prognostic tools to deliver more personalized care for IPF patients.
Highlights • Polio (IPV) vaccination alone or simultaneously with one other vaccine was compared to vaccination with polio and four other vaccines. • IPV alone or with one other vaccine was ...associated with a lower proportion of polio seroconversions than IPV in combination with 4 other vaccines. • There was no difference between IPV alone or with one other vaccine than IPV in combination with 4 other vaccines with respect to healthcare encounters over one a one-year period.
Previous studies demonstrated association between mitochondrial DNA variants and ischemic stroke (IS). We investigated whether variants within a larger set of oxidative phosphorylation (OXPHOS) genes ...encoded by both autosomal and mitochondrial DNA were associated with risk of IS and, based on our results, extended our investigation to intracerebral hemorrhage (ICH).
This association study used a discovery cohort of 1643 individuals, a validation cohort of 2432 individuals for IS, and an extension cohort of 1476 individuals for ICH. Gene-set enrichment analysis was performed on all structural OXPHOS genes, as well as genes contributing to individual respiratory complexes. Gene-sets passing gene-set enrichment analysis were tested by constructing genetic scores using common variants residing within each gene. Associations between each variant and IS that emerged in the discovery cohort were examined in validation and extension cohorts.
IS was associated with genetic risk scores in OXPHOS as a whole (odds ratio OR, 1.17; P=0.008) and complex I (OR, 1.06; P=0.050). Among IS subtypes, small vessel stroke showed association with OXPHOS (OR, 1.16; P=0.007), complex I (OR, 1.13; P=0.027), and complex IV (OR, 1.14; P=0.018). To further explore this small vessel association, we extended our analysis to ICH, revealing association between deep hemispheric ICH and complex IV (OR, 1.08; P=0.008).
This pathway analysis demonstrates association between common genetic variants within OXPHOS genes and stroke. The associations for small vessel stroke and deep ICH suggest that genetic variation in OXPHOS influences small vessel pathobiology. Further studies are needed to identify culprit genetic variants and assess their functional consequences.
New method to prepare autologous fibrin glue on demand Alston, Steven M; Solen, Kenneth A; Broderick, Adam H ...
Translational research : the journal of laboratory and clinical medicine,
04/2007, Letnik:
149, Številka:
4
Journal Article
Recenzirano
Fibrin-based sealants are commonly employed to arrest bleeding after surgery. Usually, fibrinogen obtained from pooled human plasma is used to prepare sealants, with attendant risk of blood-borne ...infections. Availability of autologous fibrinogen would eliminate this risk. To prepare autologous fibrin sealant, fibrinogen was precipitated from human plasma using protamine. Under optimal conditions (10-mg/mL protamine and 22°C), 96 ± 4% of clottable fibrinogen was recovered by a simple and inexpensive technique. Nearly 50% of the plasma factor XIII was also recovered with the fibrinogen. Using bovine thrombin, the fibrinogen was clotted (1) in a specially designed mold to measure tensile strength and (2) in a lap joint between 2 aortic vessel strips to measure adhesion strength. Tensile and adhesion strengths increased with increasing fibrinogen concentration, and they were increased by the addition of calcium chloride. The addition of aprotinin and ϵ-aminocaproic acid to the fibrinogen concentrate before clotting had no effect on the mechanical properties of the clots. After adding thrombin to sealant containing 15-mg/mL fibrinogen, maximum tensile strength was achieved in 1–5 min, and maximum adhesion strength was reached in 5–15 min. For the sealant with 30–60-mg/mL fibrinogen and added calcium, the tensile strength was equivalent to that of the commercial fibrin sealant Tisseel. The adhesion strength of sealant with 30–60-mg/mL fibrinogen exceeded the adhesive strength of Tisseel under identical conditions. Autologous fibrin sealant is an attractive alternative to commercial sealants. It can be readily prepared from 5-mL plasma or more and exhibits mechanical properties equivalent to those of the leading commercial sealant.
Genetic variation influences risk of intracerebral hemorrhage (ICH). Hypertension (HTN) is a potent risk factor for ICH and several common genetic variants (single nucleotide polymorphisms SNPs) ...associated with blood pressure levels have been identified. We sought to determine whether the cumulative burden of blood pressure-related SNPs is associated with risk of ICH and pre-ICH diagnosis of HTN.
We conducted a prospective multicenter case-control study in 2272 subjects of European ancestry (1025 cases and 1247 control subjects). Thirty-nine SNPs reported to be associated with blood pressure levels were identified from the National Human Genome Research Institute genomewide association study catalog. Single-SNP association analyses were performed for the outcomes ICH and pre-ICH HTN. Subsequently, weighted and unweighted genetic risk scores were constructed using these SNPs and entered as the independent variable in logistic regression models with ICH and pre-ICH HTN as the dependent variables.
No single SNP was associated with either ICH or pre-ICH HTN. The blood pressure-based unweighted genetic risk score was associated with risk of ICH (OR, 1.11; 95% CI, 1.02-1.21; P=0.01) and the subset of ICH in deep regions (OR, 1.18; 95% CI, 1.07-1.30; P=0.001), but not with the subset of lobar ICH. The score was associated with a history of HTN among control subjects (OR, 1.17; 95% CI, 1.04-1.31; P=0.009) and ICH cases (OR, 1.15; 95% CI, 1.01-1.31; P=0.04). Similar results were obtained when using a weighted score.
Increasing numbers of high blood pressure-related alleles are associated with increased risk of deep ICH as well as with clinically identified HTN.
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