Differential Impact of Smoking on Methylome and Transcriptome in Crohn's Disease and Ulcerative Colitis.

BACKGROUND: Smoking is an environmental factor that differentially impacts Crohn's disease (CD) and ulcerative colitis (UC). The mechanism of impact of smoking on disease risk and clinical outcomes remains to be established. METHODS: This study used a prospective cohort of patients with CD or UC. Self-reported smoking status was validated using serum cotinine measurement. We profiled methylation changes in peripheral blood using the Illumina Methylation BeadChip. Transcriptomic profiling was performed on ileal and colonic tissue using an Illumina TruSeq platform. We compared the methylation and transcriptional changes in current, former, and never smokers stratified by disease type. RESULTS: Our cohort included 200 patients with CD or UC with methylation profiles and 160 with transcriptomic data. The mean serum cotinine level was higher in current compared with former or never smokers. Epigenetic changes common to both CD and UC included hypomethylation at AHRR. Smoking-associated MGAT3 hypomethylation was associated with severe disease course only in UC, while IER3 hypomethylation was associated with worse course only in CD. Smoking downregulated several inflammatory pathways in UC. Current smoking in CD but not in UC was associated with upregulation of several genes mediating Paneth cell function. Genes with opposite direction of effects in CD and UC include HSD3B2 and GSTA1. CONCLUSIONS: Our findings suggest both common and differential effects of cigarette smoking on CD and UC. Paneth cell dysfunction may mediate adverse impact of smoking on CD. Bile acid and oxidative stress pathways may be relevant for the differential effect of smoking on CD and UC.

Smoking is a key environmental risk factor for the development of inflammatory bowel disease. Smoking induces changes differential epigenetic changes in the peripheral blood in Crohn's disease and ulcerative colitis. Smoking also induces down regulation of expression of various proinflammatory genes in the colon in ulcerative colitis.

Multi-modal skin atlas identifies a multicellular immune-stromal community associated with altered cornification and specific T cell expansion in atopic dermatitis.

In healthy skin, a cutaneous immune system maintains the balance between tolerance towards innocuous environmental antigens and immune responses against pathological agents. In atopic dermatitis (AD), barrier and immune dysfunction result in chronic tissue inflammation. Our understanding of the skin tissue ecosystem in AD remains incomplete with regard to the hallmarks of pathological barrier formation, and cellular state and clonal composition of disease-promoting cells. Here, we generated a multi-modal cell census of 310,691 cells spanning 86 cell subsets from whole skin tissue of 19 adult individuals, including non-lesional and lesional skin from 11 AD patients, and integrated it with 396,321 cells from four studies into a comprehensive human skin cell atlas in health and disease. Reconstruction of human keratinocyte differentiation from basal to cornified layers revealed a disrupted cornification trajectory in AD. This disrupted epithelial differentiation was associated with signals from a unique immune and stromal multicellular community comprised of MMP12 + dendritic cells (DCs), mature migratory DCs, cycling ILCs, NK cells, inflammatory CCL19 + IL4I1 + fibroblasts, and clonally expanded IL13 + IL22 + IL26 + T cells with overlapping type 2 and type 17 characteristics. Cell subsets within this immune and stromal multicellular community were connected by multiple inter-cellular positive feedback loops predicted to impact community assembly and maintenance. AD GWAS gene expression was enriched both in disrupted cornified keratinocytes and in cell subsets from the lesional immune and stromal multicellular community including IL13 + IL22 + IL26 + T cells and ILCs, suggesting that epithelial or immune dysfunction in the context of the observed cellular communication network can initiate and then converge towards AD. Our work highlights specific, disease-associated cell subsets and interactions as potential targets in progression and resolution of chronic inflammation.

The landscape of immune dysregulation in Crohn's disease revealed through single-cell transcriptomic profiling in the ileum and colon.

Crohn's disease (CD) is a chronic gastrointestinal disease that is increasing in prevalence worldwide. CD is multifactorial, involving the complex interplay of genetic, immune, and environmental factors, necessitating a system-level understanding of its etiology. To characterize cell-type-specific transcriptional heterogeneity in active CD, we profiled 720,633 cells from the terminal ileum and colon of 71 donors with varying inflammation status. Our integrated datasets revealed organ- and compartment-specific responses to acute and chronic inflammation; most immune changes were in cell composition, whereas transcriptional changes dominated among epithelial and stromal cells. These changes correlated with endoscopic inflammation, but small and large intestines exhibited distinct responses, which were particularly apparent when focusing on IBD risk genes. Finally, we mapped markers of disease-associated myofibroblast activation and identified CHMP1A, TBX3, and RNF168 as regulators of fibrotic complications. Altogether, our results provide a roadmap for understanding cell-type- and organ-specific differences in CD and potential directions for therapeutic development.

The CD4+ T cell response to a commensal-derived epitope transitions from a tolerant to an inflammatory state in Crohn's disease.

Reciprocal interactions between host T helper cells and gut microbiota enforce local immunological tolerance and modulate extra-intestinal immunity. However, our understanding of antigen-specific tolerance to the microbiome is limited. Here, we developed a systematic approach to predict HLA class-II-specific epitopes using the humanized bacteria-originated T cell antigen (hBOTA) algorithm. We identified a diverse set of microbiome epitopes spanning all major taxa that are compatible with presentation by multiple HLA-II alleles. In particular, we uncovered an immunodominant epitope from the TonB-dependent receptor SusC that was universally recognized and ubiquitous among Bacteroidales. In healthy human subjects, SusC-reactive T cell responses were characterized by IL-10-dominant cytokine profiles, whereas in patients with active Crohn's disease, responses were associated with elevated IL-17A. Our results highlight the potential of targeted antigen discovery within the microbiome to reveal principles of tolerance and functional transitions during inflammation.

Cloxacillin-induced acute vanishing bile duct syndrome: A case study and literature review.

Ductopenia is often regarded as a chronic process where ≥50% of portal tracts lack bile ducts, which is also known as vanishing bile duct syndrome (VBDS). One aetiology is drug-induced liver injury. Cloxacillin, an antistaphylococcal penicillin, typically causes "bland" cholestasis. We present the first case of cloxacillin-induced acute ductopenia or VBDS and a review of published cloxacillin-induced liver injuries. A 66-year-old woman with no prior liver disease, but known penicillin allergy, was treated for postcarotid angioplasty staphylococcal infection with 6 weeks of cloxacillin. She presented with a 2-week history of weakness and jaundice. Laboratory work-up showed elevated liver enzymes with a cholestatic pattern, hyperbilirubinemia and eosinophilia. She required ICU transfer for hypotension and was started empirically on prednisone. Liver biopsy revealed severe centrilobular cholestasis, mild necroinflammation and ductopenia with epithelial injury, but no ductular reaction. Two months later she was discharged on hydrocortisone and ursodiol with persistently elevated alkaline phosphatase and bilirubin. She was considered for liver transplantation but died of liver failure 4 months later. Four additional articles were found with histopathologic descriptions of cloxacillin-related liver injury. These included portal inflammation, cholestasis and mild necroinflammation. Clinical features were reported in two cases; both had mild symptoms with cholestatic liver enzymes and hyperbilirubinemia. Both patients recovered completely within 10-60 days. Cloxacillin-induced cholestasis can be secondary to acute ductopenia, which can result in worse clinical outcomes than previously described "bland" cholestasis. Liver biopsy is recommended to identify cases with acute VBDS.

Questionnaire and Portable Sleep Test Screening of Sleep Disordered Breathing in Acute Stroke and TIA.

Sleep disordered breathing (SDB) is highly prevalent, but frequently unrecognized among stroke patients. Polysomnography (PSG) is difficult to perform soon after a stroke. We evaluated the use of screening questionnaires and portable sleep testing (PST) for patients with acute stroke, subarachnoid hemorrhage, or transient ischemic attack to expedite SDB diagnosis and management. We performed a single-center retrospective analysis of a quality improvement study on SDB screening of consecutive daytime, weekday, adult admissions to a stroke unit. We excluded patients who were unable to communicate and lacked available family members. Patients were screened with the Epworth Sleepiness Scale, Berlin Questionnaire, and STOP-BANG Questionnaire and underwent overnight PST and/or outpatient PSG. The 4-item STOP Questionnaire was derived from STOP-BANG for a secondary analysis. We compared the sensitivity and specificity of the questionnaires for the diagnosis of at least mild SDB (apnea hypopnea index (AHI) ≥5) on PST and correlated AHI measurements between PST and PSG using the Spearman correlation. Out of sixty-eight patients included in the study, 54 (80%) were diagnosed with SDB. Only one (1.5%) had a previous SDB diagnosis. Thirty-three patients completed all questionnaires and a PST. The STOP-BANG questionnaire had the highest sensitivity for at least mild SDB (0.81, 95% CI (confidence interval): 0.65-0.92) but a low specificity (0.33, 95% CI 0.10, 0.65). The discrimination of all questionnaires was overall poor (C statistic range 0.502-0.640). There was a strong correlation (r = 0.71) between the AHI results estimated using PST and outpatient PSG among 28 patients. The 4-item STOP Questionnaire was the easiest to administer and had a comparable or better sensitivity than the other questionnaires. Inpatient PSTs were useful for screening in the acute setting to facilitate an early diagnosis of SDB and to establish further outpatient evaluations with sleep medicine.

Multi-omics reveal microbial determinants impacting responses to biologic therapies in inflammatory bowel disease.

The intestinal microbiome is a key determinant of responses to biologic therapy in inflammatory bowel disease (IBD). However, diverse therapeutics and variable responses among IBD patients have posed challenges in predicting clinical therapeutic success. In this prospective study, we profiled baseline stool and blood in patients with moderate-to-severe Crohn's disease or ulcerative colitis initiating anti-cytokine therapy (anti-TNF or -IL12/23) or anti-integrin therapy. Patients were assessed at 14 weeks for clinical remission and 52 weeks for clinical and endoscopic remission. Baseline microbial richness indicated preferential responses to anti-cytokine therapy and correlated with the abundance of microbial species capable of 7α/ß-dehydroxylation of primary to secondary bile acids. Serum signatures of immune proteins reflecting microbial diversity identified patients more likely to achieve remission with anti-cytokine therapy. Remission-associated multi-omic profiles were unique to each therapeutic class. These profiles may facilitate a priori determination of optimal therapeutics for patients and serve as targets for newer therapies.

Chronic Kidney Disease as Risk Factor for Enlarged Perivascular Spaces in Patients With Stroke and Relation to Racial Group.

BACKGROUND AND PURPOSE: Enlarged perivascular spaces (EPVS) are considered subclinical markers of small vessel disease, associated with increased risk of stroke and dementia. Increasing evidence links chronic kidney disease (CKD) to small vessel disease. We explored the relationship between CKD and EPVS burden and the influence of racial group in this relation. METHODS: Consecutive patients with stroke who underwent brain magnetic resonance imaging were included (n=894). Racial group was categorized as White, Black, or other (other racial groups). CKD was defined by glomerular filtration rate <60 mL/minute per 1.73 m2 for >3 months. EPVS were rated following a standardized method, dichotomized for analyses (mild [<20] versus severe [≥20]), and stratified by brain region (basal ganglia and centrum semiovale). RESULTS: In multivariable-adjusted analysis, the association of CKD with severe EPVS varied across racial groups. Comparing patients with and without CKD within racial groups, we found that Whites with CKD had higher odds of severe centrum semiovale EPVS (odds ratio [OR], 2.41 [95% CI, 0.98-5.88]). Among patients with CKD, Black patients had higher odds of severe EPVS in the basal ganglia and centrum semiovale compared with Whites (OR, 1.93 [95% CI, 1.18-3.16] and OR, 1.90 [95% CI, 1.16-3.11], respectively) and other racial groups (OR, 2.03 [95% CI, 1.23-3.36] and OR, 2.02 [95% CI, 1.22-3.34], respectively). CONCLUSIONS: CKD was more prevalent in our sample of patients with stroke with severe EPVS in the centrum semiovale. The relation differed when stratified by racial group and brain topography. Further studies are needed to confirm that CKD may relate differently to subclinical measures of small vessel disease according to race.

Perihematomal edema surrounding spontaneous intracerebral hemorrhage by CT: Ellipsoidal versus morphometric volumetry.

Perihematomal edema (PHE) surrounding intracerebral hemorrhage (ICH) may contribute to disease-associated morbidity. Before quantifying PHE's effects on morbidity, a fast, accurate, and reproducible method for measuring PHE volume is needed. The aim of this study is to demonstrate the use of a semiautomated dual clustering segmentation algorithm to generate PHE volumetrics on noncontrast computed tomography (CT) of the head and compare this technique to physicians' manual calculations.This is a single-center, retrospective imaging study that included head CTs performed from January 2008 to December 2014 on 154 patients with ICH. Subjects ≥ 18 years old who were admitted to the hospital with spontaneous ICH were included. Included subjects had head CTs performed upon admission and within 6 to 24 hours. Two neurologists, 2 neuroradiologists, and a computer program all calculated hemorrhage and PHE volumes. Inter-rater correlation was evaluated using 2 statistical methods: intraclass correlations (ICCs) and limits of agreement (LOA). Additionally, correlation between volumes was separately evaluated using Pearson correlation coefficient.There was an excellent correlation between measurements performed by neurologists and neuroradiologists using ABC/2 for ICH (0.93) and PHE (0.78). There was a good correlation between measurements performed by neurologists using ABC/2 and the volume measurements generated by the algorithm for ICH (0.69) and PHE (0.70). There was a fair correlation between measurements performed by neuroradiologists using ABC/2 and volume measurements generated by the algorithm for ICH (0.47) and good correlation for PHE (0.73).Although the ABC/2 method for measuring PHE is quick and practical, algorithms that do not assume ellipsoidal shape may be more accurate.

High Prevalence of Cerebral Microbleeds in Inner City Young Stroke Patients.

BACKGROUND: Data on cerebral microbleeds (CMBs) in younger populations are lacking, particularly in young stroke patients. We sought to characterize CMBs in an inner city cohort of young adults with stroke. METHODS: CMB presence, count, and topography were assessed on magnetic resonance imaging (MRI) scans of 104 young stroke patients (≤49 years) presenting to Boston Medical Center between January 2006 and February 2010. Subsequent MRIs were assessed for the occurrence of new microbleeds in 29 patients. We performed cross-sectional analysis comparing baseline characteristics between patients with and without microbleeds, and between predefined microbleed burden and topography categories. We performed additional analysis to assess the determinants of new microbleeds on repeat MRI. RESULTS: Microbleeds were present in 17% of the sample. Male sex (odds ratio [OR] 5.7, 95% confidence interval [CI] 1.0-32.6, P = .049), hypertension (OR 6.2, 95% CI 1.2-32, P = .03), moderate-severe white matter hyperintensities on MRI (OR 5.8, 95% CI 1.6-29.0, P = .01), and intracerebral hemorrhage (ICH; OR 5.0, 95% CI 1.2-20, P = .03) were over-represented in patients with microbleeds. Patients who developed new microbleeds on repeat MRI (14%) had higher microbleed counts on baseline MRI (50% versus 0% ≥ 3 CMBs, P = .02), history of illicit drug use (75% versus 24%, P = .08), positive serum toxicology for cocaine (67% versus 13%, P = .11), ICH as their presenting stroke subtype (50% versus 8%, P = .08), and over-representation of moderate-severe white matter hyperintensities (75% versus 20%, P = .05). CONCLUSIONS: Results from this inner city cohort suggest that microbleeds are prevalent in young stroke patients and are largely associated with modifiable risk factors.

Delay in Diagnosis of Basilar Artery Stroke.

BACKGROUND: Basilar artery stroke causes substantial morbidity and mortality. Although its unusual clinical presentation potentially contributes to a delay in diagnosis, this problem has not been systematically studied. We compared intervals between symptom onset, initial presentation, and diagnosis in stroke due to basilar artery (BA) versus left middle cerebral artery (LMCA) occlusion to determine the presence of and potential reasons for diagnostic delay in BA stroke. METHODS: We retrospectively identified 21 consecutive adult patients diagnosed with BA stroke between 2009 and 2011 from our hospital's prospective stroke registry. Patients were age-, sex-, and race-matched with 21 LMCA stroke patients from the same period. All subjects had confirmed clinical and radiographic diagnosis of stroke due to occlusion or stenosis of the BA, LMCA, or left internal carotid artery. Time to diagnosis was determined independently by two investigators through medical record review. The pre-specified primary outcome was latency from emergency department (ED) arrival to stroke diagnosis. RESULTS: Median time from ED arrival to diagnosis was 8 h 24 min (IQR: 2:43-26:32) for BA and 1 h 23 min (IQR: 0:41-1:45; p < 0.001) for LMCA. Median time from symptom onset to ED arrival was 7 h 44 min (IQR 1:23-21:30) for BA and 1 h 2 min (IQR 0:36-9:41; p = 0.06) for LMCA. Four of 21 (19 %) BA patients were diagnosed within a 4-h time frame to make intravenous thrombolysis possible compared to 13 of 21 (62 %) LMCA patients (p = 0.01). CONCLUSIONS: Our results suggest that both pre-hospital and in-hospital processes cause substantial, clinically significant delays in the diagnosis of BA stroke.

Recurrent vascular events in lacunar stroke patients with metabolic syndrome and/or diabetes.

OBJECTIVES: We used a prospective clinical trial to examine the risks conferred by metabolic syndrome (METS) and diabetes mellitus (DM) to recurrent strokes in the Secondary Prevention of Small Subcortical Strokes (SPS3) study cohort. METHODS: The SPS3 trial enrolled 3,020 patients with lacunar strokes. Participants were stratified into groups of METS only, DM only, both, or neither using American Heart Association/National Heart, Lung, and Blood Institute and World Health Organization guidelines. Annualized event rates of strokes, myocardial infarction (MI), and all-cause mortality were calculated, and hazard ratios (HRs) referencing the "neither" group were computed, controlling for significantly associated baseline characteristics. RESULTS: Among 2,999 participants, 25% had METS only, 6% had DM only, 32% had both conditions, and 37%had neither. Over a median of 3.8 years of follow-up, there were 274 recurrent strokes (240 ischemic, 34 hemorrhagic) and 74 MIs; among the 240 ischemic strokes, 134 (56%) were lacunar. The rates of any recurrent stroke (HR 1.7, 95% confidence interval [CI] 1.3­2.3) or lacunar stroke (HR 2.4, 95% CI 1.5­3.7) were significantly higher for those with concurrent METS and DM compared with those who had neither. Risk of incident MI was higher in participants with DM (HR 2.8, 95% CI 1.1­7.0) or concurrent DM and METS (HR 2.6, 95% CI 1.4­4.9). CONCLUSION: METS and DM were significant comorbid conditions in lacunar stroke patients and they were associated with stroke recurrence. In patients with lacunar infarcts, a vigilant approach to prevent development of DM in those with METS may be a potential strategy to reduce recurrent strokes.

Can blood pressure be lowered safely in older adults with lacunar stroke? The Secondary Prevention of Small Subcortical Strokes study experience.

OBJECTIVES: To determine safety and tolerability of lowering blood pressure in older adults with lacunar stroke. DESIGN: Cohort study. SETTING: The Secondary Prevention of Small Subcortical Strokes (SPS3) Trial, which compared the efficacy of two systolic blood pressure (SBP) targets (<130 mmHg and 130-149 mmHg) for secondary stroke prevention. PARTICIPANTS: Of 3,020 SPS3 participants, 494 aged 75 and older at baseline were used in these analyses. MEASUREMENTS: Rates of side effects related to lowering SBP and clinical outcomes, including stroke recurrence and vascular death, were examined. RESULTS: Older participants achieved SBP levels similar to those of younger participants (mean SBP of 125 mmHg and 137 mmHg in lower and higher SBP target groups, respectively). At least once during the approximately 3.5 years of follow-up, 21% reported dizziness, and 15% reported lightheadedness when standing; the only significant difference between the younger and older groups was unsteadiness when standing (23% vs 32% respectively, P < .001). There was no difference according to treatment group. In younger adults, recurrent stroke was less likely in the lower than the higher SBP group (hazard ratio (HR) = 0.77, 95% confidence interval (CI) = 0.59-1.01) but not in older participants (HR = 1.01, 95% CI = 0.59-1.73), although the interaction was not significant (P = .39). The lower SBP target was associated with a significant reduction in vascular death in older participants (HR = 0.42, 95% CI = 0.18-0.98), with a significant interaction between age and SBP group (P = .049). CONCLUSION: Except for unsteadiness when standing, there was no difference according to age in individuals with lacunar stroke with respect to side effects potentially related to lowering blood pressure. Although the lower SBP target was not associated with lower likelihood of recurrent stroke, these exploratory analyses suggested a possible benefit related to vascular death.

Larger A1/M1 diameter ratio predicts embolic anterior cerebral artery territorial stroke.

BACKGROUND AND PURPOSE: In contrast to middle cerebral artery territory strokes, anterior cerebral artery strokes (ACAS) occur rarely. The low frequency of ACAS, in relation to middle cerebral artery territory strokes, may be explained by differences in ACA and middle cerebral artery anatomy influencing their respective flow-directed embolism rates. We aimed to determine whether variability in ACA anatomy, and in particular A1 segment diameter, is associated with embolic ACAS. METHODS: Consecutive patients admitted to Boston Medical Center with embolic ACAS were reviewed. Ipsilateral and contralateral A1 diameters, M1 diameters, and terminal internal carotid artery bifurcation angles were measured from computed tomographic angiography and MRI angiography images. We compared these measurements between cases of ACAS and consecutive cases of embolic middle cerebral artery territory strokes. RESULTS: The study comprised 55 individuals (27 ACAS, 28 middle cerebral artery territory strokes) with mean age of 69 years. In multivariate regression analysis, larger ipsilateral A1 diameters (odds ratio per 1 mm increment: 8.5; 95% confidence interval, 1.4-53.3) and ipsilateral A1/M1 diameter ratio (odds ratio per 10% increment: 1.8; 95% confidence interval, 1.2-2.9) were associated with ACAS, whereas larger ipsilateral M1 diameters was protective for ACAS (odds ratio per 1 mm increment: 0.8; 95% confidence interval, 0.0-0.9). CONCLUSIONS: Larger ipsilateral A1 diameters and A1/M1 diameter ratio are associated with embolic ACAS. These findings suggest that A1 diameters and M1 diameters are important in determining the path of emboli that reach the terminal internal carotid artery.

Quality of life after lacunar stroke: the Secondary Prevention of Small Subcortical Strokes study.

BACKGROUND: We sought to describe the course and predictors of quality of life (QOL) after lacunar stroke. We hypothesized that there is a decline in QOL after recovery from lacunar stroke. METHODS: The Secondary Prevention of Small Subcortical Strokes is a clinical trial in lacunar stroke patients with annual assessments of QOL with the stroke-specific QOL score. The overall score was used and analyzed as a continuous variable (range 0-5). We fit linear mixed models to assess the trend in QOL over time, assuming linearity of time, and adjusted for demographics, medical risk factors, cognitive factors, and functional status in univariable and multivariable models. RESULTS: Among 2870 participants, mean age was 63.4 years (SD 10.7), 63% were men, 51% White, 32% Hispanic, 36% had college education, 36% had diabetes, 89% had hypertension, and 10% had prior stroke. Mean poststroke Barthel Index (BI) score was 95.4 (assessed on average 6 months after stroke). In the final multivariable model, there was an average increase in QOL of .6% per year, and factors associated with decline in QOL over time included age (-.0003 per year, P < .0001), any college education (-.0013 per year, .01), prior stroke (-.004 per year, P < .0001), and BI (-.0002 per year, P < .0001). CONCLUSIONS: In this clinical trial of lacunar stroke patients, there was a slight annual increase in QOL overall, and age, level of education, and prior stroke were associated with changes in QOL over time. Multiple strokes may cause decline in QOL over time in the absence of recurrent events.

The effect of a neurocritical care service without a dedicated neuro-ICU on quality of care in intracerebral hemorrhage.

BACKGROUND: Introduction of neurocritical care services to dedicated neuro-ICUs is associated with improved quality of care. The impact of a neurocritical care service without a dedicated neuro-ICU has not been studied. METHODS: We retrospectively identified all patients admitted to our institution with intracerebral hemorrhage (ICH) in two 12-month periods: immediately before the arrival of the first neurointensivist ("before") and after the neurocritical care service was established ("after"). There was no nursing team, ICU housestaff/physician extender team, or physical unit dedicated to the care of patients with critical neurologic illness during either period. Using an uncontrolled before-after design, we compared clinical outcomes and performance on quality metrics between groups. RESULTS: We included 74 patients with primary supratentorial ICH. Mortality, length of stay (LOS), proportion of patients with modified Rankin Score 0-3, and destination on discharge did not differ between groups when adjusted for confounders. Time to first two consecutive systolic blood pressure (SBP) measurements <180 mmHg was shorter in the "after" cohort (mean 4.5 vs. 3.2 h, p = 0.001). Area under the curve measurement for change in SBP from baseline over the first 24 h after ED arrival demonstrated greater, sustained SBP reduction in the "after" cohort (mean -187.9 vs. -720.9, p = 0.04). A higher proportion of patients were fed without passing a dysphagia screen in the "before" group (45 vs. 0%, p < 0.001). CONCLUSIONS: Introduction of a neurocritical service without a neuro-ICU at our institution was associated with a trend toward longer ICU LOS and improvement in some key metrics of quality of care for patients with ICH.

SNAP-25, a SNARE protein, inhibits two types of K channels in esophageal smooth muscle.

BACKGROUND & AIMS: The plasma membrane-associated soluble N-ethylmaleimide-sensitive factors attachment protein receptors (SNAREs), synaptosome-associated protein of 25 kilodaltons (SNAP-25), and syntaxin 1A, have been found to physically interact with and functionally modify membrane-spanning ion channels. Studies were performed in cat esophageal body and lower esophageal sphincter (LES) smooth muscle to (1) show the presence of SNAP-25, and (2) determine whether SNAP-25 affects K+ channel activity. METHODS: Single circular muscle cells from the esophageal body and sphincter were studied. Cellular localization of SNAP-25 and K+ channel activity were assessed. RESULTS: SNAP-25 was found in the plasma membrane of all regions examined. Outward K+ currents in body circular muscle were mainly composed of large conductance Ca2+-activated channel currents (K(Ca), 40.1%) and delayed rectifier K+ channel currents (K(V), 54.2%). Microinjection of SNAP-25 into muscle cells caused a dose-dependent inhibition of both outward K+ currents, maximal 44% at 10(-8) mol/L. Cleavage of endogenous SNAP-25 by dialyzing botulinum neurotoxin A into the cell interior resulted in a 35% increase in outward currents. CONCLUSIONS: SNAP-25 protein is present in esophageal smooth muscle cells, and inhibits both K(V) and K(Ca) currents in circular muscle cells. The findings suggest a role for SNAP-25 in regulation of esophageal muscle cell excitability and contractility, and point to potential new targets for treatment of esophageal motor disorders.