9 research outputs found
Controlled dual drug release from adhesive electrospun patches for prevention and treatment of alveolar osteitis
Approximately one in five individuals experience alveolar osteitis (AO) following wisdom tooth extraction. AO is characterised by loss of the blood clot from the tooth extraction socket leading to infection and pain, resulting in repeated hospital visits that impose a substantial burden on healthcare systems. Current treatments are sub-optimal; to address this we developed a novel drug-loaded mucoadhesive patch composed of dual electrospun polyvinyl pyrrolidone/Eudragit RS100 (PVP/RS100) and poly(N-isopropylacrylamide) (PNIPAM) fibres protected by a poly(ε-caprolactone) (PCL) backing layer. These patches demonstrated controlled release of the long-acting analgesic bupivacaine HCl and the anti-inflammatory drug prednisolone. Topical application of patches to tissue-engineered gingival mucosa showed that patch-released bupivacaine and prednisolone achieved sustained tissue permeation with 54.8 ± 3.3 % bupivacaine HCl and 65.8 ± 5.1 % prednisolone permeating the epithelium after 24 h. The drugs retained their functionality after release; bupivacaine HCl significantly (p < 0.05) inhibited veratridine-induced intracellular calcium flux in SH-SY5Y neuronal cells, while prednisolone significantly reduced gene expression of IL-6 (2-fold; p < 0.001), CXCL8 (5.1-fold; p < 0.01) and TNF-α (1.5-fold; p < 0.001) in stimulated THP-1 monocytes. Taken together, these data show that dual electrospun patches have the potential to provide a mucoadhesive covering to prevent blood clot loss while delivering pain relief and anti-inflammatory therapeutics at tooth extraction sites to prevent and treat AO. This study not only offers a future therapeutic pathway for AO but also contributes valuable insights into future advancements in drug delivery devices for periodontal or oral mucosal tissue
Serum magnesium and calcium levels in relation to ischemic stroke : Mendelian randomization study
ObjectiveTo determine whether serum magnesium and calcium concentrations are causally associated with ischemic stroke or any of its subtypes using the mendelian randomization approach.MethodsAnalyses were conducted using summary statistics data for 13 single-nucleotide polymorphisms robustly associated with serum magnesium (n = 6) or serum calcium (n = 7) concentrations. The corresponding data for ischemic stroke were obtained from the MEGASTROKE consortium (34,217 cases and 404,630 noncases).ResultsIn standard mendelian randomization analysis, the odds ratios for each 0.1 mmol/L (about 1 SD) increase in genetically predicted serum magnesium concentrations were 0.78 (95% confidence interval [CI] 0.69-0.89; p = 1.3
7 10-4) for all ischemic stroke, 0.63 (95% CI 0.50-0.80; p = 1.6
7 10-4) for cardioembolic stroke, and 0.60 (95% CI 0.44-0.82; p = 0.001) for large artery stroke; there was no association with small vessel stroke (odds ratio 0.90, 95% CI 0.67-1.20; p = 0.46). Only the association with cardioembolic stroke was robust in sensitivity analyses. There was no association of genetically predicted serum calcium concentrations with all ischemic stroke (per 0.5 mg/dL [about 1 SD] increase in serum calcium: odds ratio 1.03, 95% CI 0.88-1.21) or with any subtype.ConclusionsThis study found that genetically higher serum magnesium concentrations are associated with a reduced risk of cardioembolic stroke but found no significant association of genetically higher serum calcium concentrations with any ischemic stroke subtype
Applying lactic acids bacteria starter cultures to produce bread with high content of oat flour
Celem pracy badawczej było otrzymanie pieczywa owsianego o dużej zawartości mąki owsianej razowej i odpowiedniej jakości sensorycznej, poprzez zastosowanie wyselekcjonowanych kultur starterowych. Wyizolowano jedenaście szczepów bakterii fermentacji mlekowej (LAB) naturalnie występujących w ekologicznej mące owsianej. Sześć z wyizolowanych szczepów należało do gatunku Lactobacillus plantarum, po dwa do Pediococcus acidilactici i Pediococcus pentosaceus i jeden do Leuconostoc mesenteroides. Przydatność wyizolowanych LAB do komponowania piekarskich kultur starterowych określono na podstawie oceny: zdolności do wzrostu w różnej temperaturze, ilości syntetyzowanego kwasu mlekowego i octowego oraz indywidualnej zdolności każdego ze szczepów LAB do modyfikowania przebiegu fermentacji i pozytywnego wpływania na cechy sensoryczne zakwasu. Z wyselekcjonowanych szczepów LAB sporządzono trzy mieszane kultury starterowe, różniące się liczbą szczepów i składem gatunkowym. W próbnych wypiekach stosowano mieszaną kulturę starterową, charakteryzującą się zdolnością hamowania rozwoju pleśni w zakwasie owsianym, w skład której wchodziły: L. plantarum KKP 1797, L. plantarum KKP 1803, P. pentosaceus KKP 1804, P. acidilactici KKP 1805, L. mesenteroides KKP 1807. Przygotowano
cztery warianty doświadczalne chlebów pszenno-owsianych na zakwasie wyprowadzonym z otrzymaną kulturą starterową, różniące się udziałem razowej mąki owsianej. Pieczywo z 30-
procentowym udziałem mąki owsianej w zakwasie piekarskim charakteryzowało się objętością i jakością sensoryczną pozwalającą na zakwalifikowanie go do I klasy jakościowej zgodnie z polską normą (PN-A-74108:1996).The objective of the research study was to produce oat breads, containing a high amount of wholemeal oat flour and showing a proper sensory quality, by means of applying some selected starter cultures. Eleven strains of lactic acid bacteria (LAB), occurring naturally in organic wholemeal oat flour, were isolated. Among the isolated strains, six strains belonged to Lactobacillus plantarum species, two strains to Pediococcus acidilactici, two strains to Pediococcus pentosaceus, and one strain belonged to Leuconostoc mesenteroides species. The suitability of the isolated LAB for making baker’s starter cultures was determined based on the results of assessing the following: capability of growing at various temperatures, quantity of synthesized lactic acid and acetic acid, and individual ability of each LAB strain to modify the fermentation process and to positively impact sensory qualities of sourdough. From among the LAB strains selected, three mixed starter cultures were prepared; they varied in the number of strains and in the strain composition. A mixed starter culture, characterized by the capability of inhibiting mould growth in oat sourdough, was added to the baked experimental products; this started culture consisted of: L. plantarum KKP 1797, L. plantarum KKP 1803, P. pentosaceus KKP 1804, P. acidilactici KKP 1805, and L. mesenteroides
KKP 1807. Four experimental variants of wheat-oats bread were prepared using the sourdough
produced with the application of the starter culture made; the sourdoughs used to make the four bread variants differed in the content of wholemeal oat flour. The bread containing 30 % of wholemeal oat flour in the sourdough was characterized by such a volume and sensory quality that it was possible to classify it into the first quality class according to PN-A-74108:1996
Genetic variants in CETP increase risk of intracerebral hemorrhage
OBJECTIVE: In observational epidemiologic studies, higher plasma high-density lipoprotein cholesterol (HDL-C) has been associated with increased risk of intracerebral hemorrhage (ICH). DNA sequence variants that decrease cholesteryl ester transfer protein (CETP) gene activity increase plasma HDL-C; as such, medicines that inhibit CETP and raise HDL-C are in clinical development. Here, we test the hypothesis that CETP DNA sequence variants associated with higher HDL-C also increase risk for ICH. METHODS: We performed 2 candidate-gene analyses of CETP. First, we tested individual CETP variants in a discovery cohort of 1,149 ICH cases and 1,238 controls from 3 studies, followed by replication in 1,625 cases and 1,845 controls from 5 studies. Second, we constructed a genetic risk score comprised of 7 independent variants at the CETP locus and tested this score for association with HDL-C as well as ICH risk. RESULTS: Twelve variants within CETP demonstrated nominal association with ICH, with the strongest association at the rs173539 locus (odds ratio [OR] = 1.25, standard error [SE] = 0.06, p = 6.0 x 10-4 ) with no heterogeneity across studies (I2 = 0%). This association was replicated in patients of European ancestry (p = 0.03). A genetic score of CETP variants found to increase HDL-C by approximately 2.85mg/dl in the Global Lipids Genetics Consortium was strongly associated with ICH risk (OR = 1.86, SE = 0.13, p = 1.39 x 10-6 ). INTERPRETATION: Genetic variants in CETP associated with increased HDL-C raise the risk of ICH. Given ongoing therapeutic development in CETP inhibition and other HDL-raising strategies, further exploration of potential adverse cerebrovascular outcomes may be warranted. Ann Neurol 2016;80:730-740
Association of Apolipoprotein e with Intracerebral Hemorrhage Risk by Race/Ethnicity : A Meta-analysis
Importance: Genetic studies of intracerebral hemorrhage (ICH) have focused mainly on white participants, but genetic risk may vary or could be concealed by differing nongenetic coexposures in nonwhite populations. Transethnic analysis of risk may clarify the role of genetics in ICH risk across populations. Objective: To evaluate associations between established differences in ICH risk by race/ethnicity and the variability in the risks of apolipoprotein E (APOE) ϵ4 alleles, the most potent genetic risk factor for ICH. Design, Setting, and Participants: This case-control study of primary ICH meta-analyzed the association of APOE allele status on ICH risk, applying a 2-stage clustering approach based on race/ethnicity and stratified by a contributing study. A propensity score analysis was used to model the association of APOE with the burden of hypertension across race/ethnic groups. Primary ICH cases and controls were collected from 3 hospital- and population-based studies in the United States and 8 in European sites in the International Stroke Genetic Consortium. Participants were enrolled from January 1, 1999, to December 31, 2017. Participants with secondary causes of ICH were excluded from enrollment. Controls were regionally matched within each participating study. Main Outcomes and Measures: Clinical variables were systematically obtained from structured interviews within each site. APOE genotype was centrally determined for all studies. Results: In total, 13124 participants (7153 [54.5%] male with a median [interquartile range] age of 66 [56-76] years) were included. In white participants, APOE ϵ2 (odds ratio [OR], 1.49; 95% CI, 1.24-1.80; P <.001) and APOE ϵ4 (OR, 1.51; 95% CI, 1.23-1.85; P <.001) were associated with lobar ICH risk; however, within self-identified Hispanic and black participants, no associations were found. After propensity score matching for hypertension burden, APOE ϵ4 was associated with lobar ICH risk among Hispanic (OR, 1.14; 95% CI, 1.03-1.28; P =.01) but not in black (OR, 1.02; 95% CI, 0.98-1.07; P =.25) participants. APOE ϵ2 and ϵ4 did not show an association with nonlobar ICH risk in any race/ethnicity. Conclusions and Relevance: APOE ϵ4 and ϵ2 alleles appear to affect lobar ICH risk variably by race/ethnicity, associations that are confirmed in white individuals but can be shown in Hispanic individuals only when the excess burden of hypertension is propensity score-matched; further studies are needed to explore the interactions between APOE alleles and environmental exposures that vary by race/ethnicity in representative populations at risk for ICH
Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes (vol 50, pg 524, 2018)
The Author(s), under exclusive licence to Springer Nature America, Inc. An amendment to this paper has been published and can be accessed via a link at the top of the paper
Stroke genetics informs drug discovery and risk prediction across ancestries
Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry(1,2). Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis(3), and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach(4), we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry(5). Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.Paroxysmal Cerebral Disorder
GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes.
Carotid artery intima media thickness (cIMT) and carotid plaque are measures of subclinical atherosclerosis associated with ischemic stroke and coronary heart disease (CHD). Here, we undertake meta-analyses of genome-wide association studies (GWAS) in 71,128 individuals for cIMT, and 48,434 individuals for carotid plaque traits. We identify eight novel susceptibility loci for cIMT, one independent association at the previously-identified PINX1 locus, and one novel locus for carotid plaque. Colocalization analysis with nearby vascular expression quantitative loci (cis-eQTLs) derived from arterial wall and metabolic tissues obtained from patients with CHD identifies candidate genes at two potentially additional loci, ADAMTS9 and LOXL4. LD score regression reveals significant genetic correlations between cIMT and plaque traits, and both cIMT and plaque with CHD, any stroke subtype and ischemic stroke. Our study provides insights into genes and tissue-specific regulatory mechanisms linking atherosclerosis both to its functional genomic origins and its clinical consequences in humans