Diagnosis of supra‐esophageal gastric reflux: correlation of oropharyngeal pH with esophageal impedance monitoring for gastro‐esophageal reflux

Background Oropharyngeal (OP) pH monitoring has been developed as a new way to diagnose supra‐esophageal gastric reflux (SEGR), but has not been well validated. Our aim was to determine the correlation between OP pH and gastro‐esophageal reflux (GER) events detected by multichannel intraluminal impedance‐pH (MII‐pH). Methods Fifteen patients (11 males, median age 10.8 years) with suspected GER were prospectively evaluated with ambulatory 24‐h OP pH monitoring (positioned at the level of the uvula) and concomitant esophageal MII‐pH monitoring. Potential OP events were identified by the conventional pH threshold of <4 and by the following alternative criteria: (i) relative pH drop >10% from 15‐min baseline and (ii) absolute pH drop below thresholds of <5.5, 5.0, and 4.5. The 2‐min window preceding each OP event was analyzed for correlation with an episode of GER detected by MII‐pH. Key Results A total of 926 GER events were detected by MII‐pH. Application of alternative pH criteria increased the identification of potential OP pH events; however, a higher proportion of OP events had no temporal correlation with GER (45–81%), compared with the conventional definition of pH < 4 (40%). A total of 306 full‐column acid reflux episodes were detected by MII‐pH, of which 10 (3.3%) were also identified by OP pH monitoring. Conclusions & Inferences Use of extended pH criteria increased the detection of potential SEGR events, but the majority of decreases in OP pH were not temporally correlated with GER. Oropharyngeal pH monitoring without concurrent esophageal measurements may overestimate the presence of SEGR in children.     

Risperidone long‐acting injection: a 6‐year mirror‐image study of healthcare resource use

Objective: To evaluate naturalistic use of risperidone long‐acting injection (RLAI) and its effect on healthcare resource use. Method: Mirror‐image comparison of healthcare resource use for 3 years before RLAI initiation and 3 years after. Results: In total, 211 of 277 patients consecutively prescribed RLAI were evaluable over the full 6‐year study period. Median days in hospital/patient increased significantly in the 3 years after RLAI initiation [87 days (inter‐quartile range 25–236) before vs. 192 days (47–426) after; P < 0.001]. Those 34 patients who continued RLAI for 3 years showed no change in median bed days [64 days (6.5–182) before vs. 64 days (12–180) after] and median number of admissions was decreased [1.5 (1–2.25) before vs. 1.00 (0–1.25) after; P = 0.001]. Healthcare costs more than doubled for the whole cohort (P < 0.001) and discontinuers (P < 0.001) and increased significantly for continuers (P = 0.010). Conclusion: RLAI did not decrease either time spent in hospital or overall healthcare costs in this patient cohort.     

Characteristics of gastro‐esophageal reflux episodes in Barrett’s esophagus,erosive esophagitis and healthy volunteers

Background Gastro‐esophageal reflux is considered a major culprit in the pathogenesis of Barrett’s esophagus (BE). Still, there is controversy on the role of weakly acidic and weakly alkaline reflux in BE. To compare characteristics of reflux episodes patients with BE, erosive esophagitis (EE), and healthy volunteers (HV). Methods One hundred consecutive patients with BE (75 short‐segment BE, 25 long‐segment BE), 50 with EE and 48 HV underwent multichannel intraluminal impedance‐pH off‐therapy. We quantified esophageal acid exposure, characteristics, and proximal extension of reflux episodes. Key Results Total and acid reflux episodes gradually increased from HV [28 (17.5–43) and 18 (8–31)] to EE [73.5 (54–96) and 52 (39–68)], short‐segment BE (SSBE) [83 (73.2–131) and 65 (43.3–95)] and long‐segment BE (LSBE) [105 (102–187) and 77 (75–107)]. Weakly acidic reflux episodes were significantly higher (P < 0.05) in LSBE [36 (27.5–50.5)] and SSBE [34 (18.5–41)] compared to EE [21.5 (15–37)] and HV [19 (14–25)]. No differences in terms of proportion of acid, weakly acidic and weakly alkaline reflux were found [HV (49%–49%–2%) vs EE (68%–32%–1%) vs SSBE (65%–34%–1%) vs LSBE (69%–30%–1%); P = ns]. In LSBE, a higher percentage of reflux episodes (P < 0.05) reached the proximal esophagus (59%) compared with SSBE (43%). Conclusions & Inferences Barrett esophagus patients have more severe reflux as shown by the number of acid and weakly acidic reflux episodes, re‐reflux episodes and proximal migration. Given that PPI change only the pH of the refluxate, the role of weakly acidic reflux in Barrett’s patients on acid suppressive therapy warrants further investigation.     

Gastroesophageal and laryngopharyngeal reflux profiles in patients with obstructive sleep apnea/hypopnea syndrome as determined by combined multichannel intraluminal impedance-pH monitoring

Background The profiles of gastroesophageal reflux (GER) and laryngopharyngeal reflux (LPR) in patients with obstructive sleep apnea/hypopnea syndrome (OSAHS) have never been explored. The aim of the study was to investigate the reflux profile in OSAHS patients. Methods Consecutive snoring out‐patients suspected with having OSAHS and 20 healthy volunteers were included. All subjects underwent simultaneous 24‐h combined multichannel intraluminal impedance–pH (MII–pH) monitoring and polysomnography. Obstructive sleep apnea/hypopnea syndrome was defined when the apnea/hypopnea index was over 5. Stepwise multiple logistic regression analysis was performed to determine the predictor for OSAHS. Key Results Fifty‐three patients were included, 37 with and 16 without OSAHS. The prevalence of reflux symptoms was similar between OSAHS (35.1%) and non‐OSHAS (37.5%) patients. More OSAHS patients, compared with non‐OSAHS patients and healthy volunteers, had pathologic acid GER, nocturnal acid GER, and prolonged acid clearance (P < 0.001). However, no difference in non‐acid reflux episodes was observed among the three groups. Laryngopharyngeal reflux was detected in 51.4%, 43.8%, and 35.0% of OSAHS, non‐OSAHS, and healthy volunteers, respectively (P = 0.034). In OSAHS patients, there was no difference in the sleep parameters between patients with and without LPR. Body mass index was the only predictor of OSAHS in the regression analysis. Conclusions & Inferences OSAHS patients have more pathologic acid GER and prolonged acid clearance than non‐OSAHS patients whereas non‐acid reflux was similar between the two groups. However, BMI, not GER, is the only independent predictor for OSAHS. Laryngopharyngeal reflux occurs in more than half of OSAHS patients despite no significant association with OSAHS.     

Clinical and genetic associations of autoantibodies to 3‐hydroxy‐3‐methyl‐glutaryl‐coenzyme a reductase in patients with immune‐mediated myositis and necrotizing myopathy

Introduction: Inhibition of 3‐hydroxy‐3‐methyl‐glutaryl‐coenzyme A reductase (HMGCR) with statins may trigger idiopathic inflammatory myositis (IIM) or immune‐mediated necrotizing myopathy (IMNM). Anti‐HMGCR antibodies have been detected in patients with IIM/IMNM. We aimed to determine the associations of anti‐HMGCR in IIM/IMNM. Methods: Anti‐HMGCR antibodies were detected by ELISA in sera from patients with IIM/IMNM. Results: Anti‐HMGCR antibodies were detected in 19 of 207 patients with IIM/IMNM, and there was a trend toward an association with male gender (P = 0.079). Anti‐HMGCR antibodies were associated strongly with statin exposure (OR = 39, P = 0.0001) and HLA‐DRB1*11 (OR = 50, P < 0.0001). The highest risk for development of anti‐HMGCR antibodies was among HLA‐DR11 carriers exposed to statins. Univariate analysis showed a strong association of anti‐HMGCR antibodies with diabetes mellitus (P = 0.008), which was not confirmed by multiple regression. Among anti‐HMGCR⁺ patients there was a trend toward increased malignancy (P = 0.15). Conclusions: Anti‐HMGCR antibodies are seen in all subtypes of IIM and IMNM and are associated strongly with statin use and HLA‐DR11. Muscle Nerve 52 : 196–203, 2015     

Alterations in 5‐HT2A receptor binding in various brain regions among 6‐hydroxydopamine‐induced Parkinsonian rats

The serotonergic system has close interactions with the dopaminergic system and is strongly implicated in the pathophysiological mechanisms and therapeutic paradigms of Parkinson's disease (PD). This study aims to investigate regional changes in 5‐hydroxytryptamine (5‐HT) 2A receptors in the rat brain 3 weeks after unilateral medial forebrain bundle lesion by 6‐hydroxydopamine (6‐OHDA). 5‐HT 2A receptor distributions and alterations in the postmortem rat brain were detected by [³H]ketanserin‐binding autoradiography. In the 6‐OHDA‐induced Parkinson's rat model, nigrostriatal dopaminergic neuron loss significantly mediated the decreased [³H]ketanserin binding, predominantly in the agranular insular cortex (17.3%, P = 0.03), cingulate cortex (18.2%, P < 0.001), prefrontal cortex (8%, P = 0.043), primary somatosensory cortex (17.7%, P = 0.002), and caudate putamen (14.5%, P = 0.02) compared to controls while a profound reduction of tyrosine hydroxylase (TH) immunostaining in the striatum was also observed. Alterations in [³H]ketanserin binding in the examined brain areas may represent the specific regions that mediate cognitive dysfunctions via the serotonin system. The downregulation of 5‐HT_2A receptor binding in this study also provides indirect evidence for plasticity in the serotonergic system in the rat brains. This study contributes to a better understanding of the critical roles of 5‐HT_2A receptors in treating neurodegenerative disorders and implicates 5‐HT_2A receptors as a novel therapeutic target in the treatment of PD. Synapse 64:224–230, 2010. © 2009 Wiley‐Liss, Inc.     

Specific T‐cell proliferation to myelin peptides in relapsing‐remitting multiple sclerosis

Background: The identification of major immunogenic peptides in multiple sclerosis (MS) is of great importance for the development of antigen‐specific therapies. Cellular reactivity against a selected mix of seven myelin peptides was evaluated in vitro. The evolution of this reactivity over time and its correlation with clinical variables was also analysed. Material and methods: Forty‐two patients with MS, 15 with other demyelinating diseases and 40 healthy donors (HD) were studied. Cell proliferation was measured by 3[H] thymidine incorporation into samples obtained at 0, 3, 6 and 12 months of MS patient follow‐up. Results: A positive reaction to the peptide mix was detected in 31 of the 42 patients (74%), 12 of the 40 HD (30%) and 6 of the 15 (40%) patients with other demyelinating diseases. Patients with positive proliferation had greater disability (EDSS score, 3 [1–5.5] vs. 1.0[1–2], P = 0.021), higher number of relapses (7 ± 4.1 vs. 3 ± 1.2, P < 0.001) and shorter time since the last relapse (9 ± 7.5 vs. 32 ± 12.3 months, P = 0.036). After 12 months of follow‐up, cell reactivity was maintained in 33 patients (78%). Conclusion: A high percentage of patients exhibit a significant and maintained reactivity to myelin peptides over time. Therefore, this mix may be useful as a source of antigen in the development of protocols aimed at inducing specific tolerance in MS.     

Increased cell‐free DNA concentrations in patients with obstructive sleep apnea

Aim: Blood concentrations of cell‐free DNA, which is considered to be released during apoptosis, are elevated under some pathological conditions such as cardiovascular disease and cancer. The association between obstructive sleep apnea (OSA) and cell‐free DNA concentrations has not been reported so far. The purpose of the present study was to examine the association between OSA and plasma DNA concentrations. Methods: A case–control study was conducted using a total of 164 men aged 39–67 years, who were free of coronary heart disease and cancer. Laboratory‐based overnight polysomnography was performed for all participants. Results: On the basis of polysomnography, patients with an apnea–hypopnea index (AHI) = 5–30 events/h were defined as having mild–moderate OSA (n = 33) and those with >30 events/h were defined as having severe OSA (n = 49). All 82 controls had AHI < 5 events/h. Plasma DNA concentrations from all participants were analyzed for the β‐globin gene using fluorescence‐based real‐time polymerase chain reaction. Patients with severe OSA had significantly higher plasma DNA concentrations than persons with mild–moderate OSA and those without OSA (P < 0.05). AHI was significantly associated with body mass index (P < 0.001), hypertension (P < 0.001), and plasma DNA concentration (P < 0.05). Conclusion: After taking into account hypertension and other potential risk factors, persons with high plasma DNA concentrations (>8 µg/L) had approximately fourfold higher odds of OSA than those with low DNA levels. Further data are warranted to confirm the association for men and to evaluate the association for women.     

Optimizing the risk estimation after a transient ischaemic attack – the ABCDE⊕ score

Background and purpose: The risk of stroke after a transient ischaemic attack (TIA) can be predicted by scores incorporating age, blood pressure, clinical features, duration (ABCD‐score), and diabetes (ABCD2‐score). However, some patients have strokes despite a low predicted risk according to these scores. We designed the ABCDE+ score by adding the variables ‘etiology’ and ischaemic lesion visible on diffusion‐weighted imaging (DWI) –‘DWI‐positivity’– to the ABCD‐score. We hypothesized that this refinement increases the predictability of recurrent ischaemic events. Methods: We performed a prospective cohort study amongst all consecutive TIA patients in a university hospital emergency department. Area under the computed receiver‐operating curves (AUCs) were used to compare the predictive values of the scores with regard to the outcome stroke or recurrent TIA within 90 days. Results: Amongst 248 patients, 33 (13.3%, 95%‐CI 9.3–18.2%) had a stroke (n = 13) or a recurrent TIA (n = 20). Patients with recurrent ischaemic events more often had large‐artery atherosclerosis as the cause for TIA (46% vs. 14%, P < 0.001) and positive DWI (61% vs. 35%; P = 0.01) compared with patients without recurrent events. Patients with and those without events did not differ with regard to age, clinical symptoms, duration, blood pressure, risk factors, and stroke preventive treatment. The comparison of AUCs [95%CI] showed superiority of the ABCDE+ score (0.67[0.55–0.75]) compared to the ABCD²‐score (0.48[0.37–0.58]; P = 0.04) and a trend toward superiority compared to the ABCD‐score (0.50[0.40–0.61]; P = 0.07). Conclusion: In TIA patients, the addition of the variables ‘etiology’ and ‘DWI‐positivity’ to the ABCD‐score seems to enhance the predictability of subsequent cerebral ischaemic events.     

Tract‐based spatial statistics analysis of diffusion‐tensor imaging data in pediatric‐ and adult‐onset multiple sclerosis

Background: White matter (WM) microstructure may vary significantly in pediatric‐onset (PO) and adult‐onset (AO) patients with multiple sclerosis (MS), a difference that could be explained by the effects of an inherent plasticity in the affected pediatric brains early in the disease, and a phenomenon that does not occur later in life. This hypothesis would support the observation that disease progression is much slower in POMS compared to AOMS patients. Objectives: To examine WM microstructure in the brain of adults with POMS and AOMS, using tract based spatial statistics (TBSS) analysis of diffusion‐tensor imaging (DTI). Methods: Adults with relapsing‐remitting (RR) POMS, who were diagnosed before age of 18 years (n = 16), were compared with age‐matched (AOA, n = 23) and disease duration‐matched (AOD, n = 22) RR patients who developed MS after the age of 18 years. Scans were analyzed using the FSL software package (Oxford, UK) and statistics were performed using TBSS to evaluate WM microstructure between groups based on the mean fractional anisotropy (FA) values obtained from the DTI. Results: Widespread cortical and deep WM area differences characterized by increased FA values were seen in the AOAMS compared with POMS group (P < 0.05, TFCE corrected). Significantly increased FA values of posterior WM areas were detected in the AODMS compared with POMS group (P < 0.05, TFCE corrected). Conclusion: Increased FA values in WM areas of the AOMS compared with the POMS patients suggest that diffuse WM microstructure changes are more attributable to age of onset than a simple function of disease duration and age. Hum Brain Mapp 35:53–60, 2014. © 2012 Wiley Periodicals, Inc.     

Different responses to interferon beta‐1b treatment in patients with neuromyelitis optica and multiple sclerosis

Background: Although the benefit of treatment for relapsing–remitting multiple sclerosis (MS) is firmly established, whether interferon beta‐1b (IFNB‐1b) therapy is efficacious for neuromyelitis optica (NMO) has been debated. Methods: We reviewed the responses to IFNB‐1b treatment in 18 patients with relapsing NMO and compared the results with those from 38 patients with relapsing–remitting MS. We compared clinical characteristics, the annualized relapse rate (ARR) and the probability of being relapse free before and after IFNB‐1b treatment in patients with NMO and MS. Results: The proportion of patients with more than 50% increase in the ARR after IFNB‐1b treatment was much higher in NMO than in MS (P = 0.046). ARR was significantly lower in patients with MS after IFNB‐1b administration than before (P = 0.015), but not in NMO. Kaplan–Meier and log‐rank statistical analyses revealed that relapse‐free rates were lower in NMO than MS after IFNB‐1b treatment (P = 0.032). The analyses also showed lower relapse‐free rates during the pre‐IFNB‐1b treatment period than the post‐IFNB‐1b treatment period in MS (P < 0.001), but not in NMO. Conclusion: IFNB‐1b treatment does not appear to be effective for preventing relapse in NMO likely because of differences between the immune‐pathogenesis of NMO and MS.     

High‐resolution esophageal pressure topography is superior to conventional sleeve manometry for the detection of transient lower esophageal sphincter relaxations associated with a reflux event

Background Transient lower esophageal sphincter relaxations (TLESRs) are the main mechanism underlying gastro‐esophageal reflux and are detected during manometric studies using well defined criteria. Recently, high‐resolution esophageal pressure topography (HREPT) has been introduced and is now considered as the new standard to study esophageal and lower esophageal sphincter (LES) function. In this study we performed a head‐to‐head comparison between HREPT and conventional sleeve manometry for the detection of TLESRs. Methods A setup with two synchronized MMS‐solar systems was used. A solid state HREPT catheter, a water‐perfused sleeve catheter, and a multi intraluminal impedance pH (MII‐pH) catheter were introduced in 10 healthy volunteers (M6F4, age 19–56). Subjects were studied 0.5 h before and 3 h after ingestion of a standardized meal. Tracings were blinded and analyzed by the three authors according to the TLESR criteria. Key Results In the HREPT mode 156 TLESRs were scored, vs 143 during sleeve manometry (P = 0.10). Hundred and twenty‐three TLESRs were scored by both techniques. Of all TLESRs (177), 138 were associated with reflux (78%). High‐resolution esophageal pressure topography detected significantly more TLESRs associated with a reflux event (132 vs 119, P = 0.015) resulting in a sensitivity for detection of TLESRs with reflux of 96% compared to 86% respectively. Analysis of the discordant TLESRs associated with reflux showed that TLESRs were missed by sleeve manometry due to low basal LES pressure (N = 5), unstable pharyngeal signal (N = 4), and residual sleeve pressure >2 mmHg (N = 10). Conclusions & Inferences The HREPT is superior to sleeve manometry for the detection of TLESRs associated with reflux. However, rigid HREPT criteria are awaited.     

Cross‐education after high‐frequency versus low‐frequency volume‐matched handgrip training

Introduction: Cross‐education training programs cause interlimb asymmetry of strength and hypertrophy. We examined the cross‐education effects from a high‐frequency (HF) versus a low‐frequency (LF) volume‐matched handgrip training program on interlimb asymmetry. Methods: Right‐handed participants completed either HF (n = 10; 2 × 6 repetitions 10 times per week) or LF (n = 9; 5 × 8 repetitions 3 times per week) training. Testing occurred twice before and once after 4 weeks of right‐handed isometric handgrip training totaling 120 weekly repetitions. Measures were maximal isometric handgrip and wrist flexion torque, muscle thickness, and muscle activation (electromyography; EMG). Results: Grip strength was greater in both limbs posttraining, pooled across groups (P < 0.001). Trained limb muscle thickness increased in both groups (P < 0.05; untrained, P = 0.897). EMG and wrist flexion torque did not change (all P > 0.103). Discussion: Both LF and HF induced cross‐education of grip strength to the untrained limb, but HF did not reduce asymmetry. These findings have implications for injury rehabilitation. Muscle Nerve 56 : 689–695, 2017     

Esophageal impedance baselines in infants before and after placebo and proton pump inhibitor therapy

Background Esophageal impedance monitoring records changes in conductivity. During esophageal rest, impedance baseline values may represent mucosal integrity. The aim of this study was to assess the influence of acid suppression on impedance baselines in a placebo‐controlled setting. Methods Impedance recordings from 40 infants (0–6 months) enrolled in randomized placebo‐controlled trials of proton pump inhibitor (PPI) were retrospectively analyzed. Infants underwent 24 h pH‐impedance monitoring prior to and after 2 weeks of double blind therapy with placebo or a PPI. Typical clinical signs of gastro‐esophageal reflux (GER) were recorded and I‐GERQ‐R questionnaire was completed. Key Results Median (IQR) impedance baseline increased on PPI treatment (from 1217 (826–1514) to 1903 (1560–2194) Ω, P < 0.001) but not with placebo (from 1445 (1033–1791) to 1650 (1292–1983) Ω, P = 0.13). Baselines before treatment inversely correlate with the number of GER, acid GER, weakly acid GER, acid exposure, and symptoms. The change in baseline on treatment inversely correlates with acid exposure and acid GER. Patients with initial low baselines have no improved symptomatic response to treatment. Conclusions & Inferences Impedance baselines are influenced by GER and increase significantly more with PPI therapy than with placebo. Clinical impact of this observation remains undefined as targeting therapy at infants with low baselines does not improve symptomatic response to treatment.     

3,4‐Diaminopyridine is more effective than placebo in a randomized,double‐blind,cross‐over drug study in LEMS

The purpose of this study was to investigate the clinical and electrophysiological efficacy of 3,4‐diaminopyridine (DAP) in patients with Lambert–Eaton myasthenic syndrome (LEMS) in a randomized, double‐blind, cross‐over drug trial. The diagnosis of LEMS was made based on the combination of fluctuating muscle weakness, diminished or absent reflexes, and more than 60% increment of the compound muscle action potential (CMAP) amplitude after brief exercise or 50‐HZ stimulation on a repetitive nerve stimulation (RNS) test. Evaluations were done at baseline, with placebo, and with 3,4‐DAP (up to 75–80 mg/day). Assignment of placebo or 3,4‐DAP was done in a double‐blinded manner. Measurements included subjective symptoms score, objective clinical measurements [LEMS classification, muscle strength score, quantitative myasthenia gravis (QMG) score] and RNS test and single‐fiber electromyography (SFEMG). The differences between placebo and baseline values (placebo change) were compared with the differences between 3,4‐DAP and baseline or placebo values (DAP change). Seven patients with LEMS (QMG score >9) participated in the study. One patient had major side‐effects with 3,4‐DAP and withdrew from the study. Statistically significant efficacy was noted with DAP change (N = 13) compared with placebo change (N = 7) according to the subjective symptoms score (P = 0.01), LEMS classification (P < 0.001), muscle strength score (P < 0.006), QMG score (P = 0.02), and CMAP (P = 0.03). For long‐term treatment, 2 patients preferred 3,4‐DAP, 1 chose guanidine hydrochloride, 1 preferred pyridostigmine, and 2 chose no treatment. A randomized, double‐blind, cross‐over drug trial of 3,4‐DAP showed significant efficacy over placebo in patients with LEMS. As a long‐term treatment, however, not all patients preferred this drug. Muscle Nerve, 2009     

Differential effects of selective and non‐selective muscarinic antagonists on gastrointestinal transit and bowel function in healthy women

Background The gastrointestinal effects of antimuscarinic drugs used to treat overactive bladder may be related to the selectivity of these agents for M₃‐muscarinic receptor subtypes. We compared the effects of non‐selective (fesoterodine) and M₃‐selective (solifenacin) antimuscarinics on gastrointestinal transit in healthy women. Methods Gastric emptying (GE), small‐intestinal transit (colonic filling at 6 h), colonic transit [geometric center at 24 h (GC24; primary endpoint) and 48 h (GC48)], and bowel habits were assessed by scintigraphy and bowel diaries before and after randomization to fesoterodine 8 mg, solifenacin 10 mg, or placebo (2 : 2 : 1) for 14 days. An interim analysis to finalize sample size was conducted. Key Results After 60 subjects [placebo (n = 12), fesoterodine (n = 25), solifenacin (n = 23)] completed the study, the study was terminated due to a prespecified criterion (sample size ≥452.5 needed to provide ≥80% power to demonstrate superiority of fesoterodine over solifenacin in GC24). Compared with baseline, (i) placebo delayed small‐intestinal, but not colonic, transit, (ii) fesoterodine significantly increased GE t_1/2vs placebo (17.0 min; P = 0.027), and (iii) fesoterodine and solifenacin delayed small‐intestinal (?36.8% and ?21.8%, respectively, P < 0.001 vs placebo) and colonic transit (GC24: ?0.44 and ?0.49, respectively, P < 0.05 vs placebo; GC48: ?0.25 and ?0.65, respectively, P > 0.05 vs placebo). Solifenacin increased stool hardness from baseline (P = 0.010 for difference vs fesoterodine); stool frequency was comparable. Conclusions & Inferences In healthy women, fesoterodine had greater effects on small‐intestinal transit and solifenacin had greater effects on colonic transit; the latter finding may explain why solifenacin, but not fesoterodine, increased stool hardness. (ClinicalTrials.gov ID: NCT00892034).     

Membrane permeability of trace amines: Evidence for a regulated,activity‐dependent,nonexocytotic, synaptic release

Both pre‐ and post‐synaptic effects of trace amines have been demonstrated. The putative intracellular location of Trace Amine‐Associated Receptors necessitate that membrane transport processes be present in order for post‐synaptic effects to occur. Here we examine the ability of trace amines to cross synthetic (Fluorosomes) and native (synaptosomes) lipid bilayer membranes. Trace amines readily crossed Fluorosome membranes by simple diffusion, p‐tyramine (P = 0.01) and tryptamine (P = 0.0004) showing significantly faster diffusion than dopamine and 5‐HT, respectively, with diffusion half‐lives of 13.5 ± 4.1 (p‐tyramine) and 6.8 ± 0.7 seconds (tryptamine). Similarly, release of [³H]p‐tyramine and [³H]2‐phenylethylamine from pre‐loaded synaptosomes occurred significantly quicker than did [³H]dopamine (P = 0.0001), with half lives of 38.9 (p‐tyramine), 7.8 (2‐phenylethylamine) and 133.6 seconds (dopamine). This was, however, significantly slower than the diffusion mediated passage across Fluorosome membranes (P = 0.0001), suggesting a role for transporters in mediating trace amine release. Further, a pronounced shoulder region was observed in the synaptosome [³H]p‐tyramine release curve, suggesting that multiple processes regulate release. No such shoulder region was present for [³H]dopamine release. Surprisingly, both [³H]p‐tyramine (P = 0.001) and [³H]2‐phenylethylamine (P = 0.0001) release from synaptosomes was significantly decreased under depolarizing conditions. As expected, depolarization significantly increased [³H]dopamine release. The data presented indicate that the release of p‐tyramine and 2‐phenylethylamine from neuronal terminals occurs by a different mechanism than dopamine, and does not involve classical exocytosis. The data are consistent with an initial release of trace amines by simple diffusion, followed by an activity‐dependent regulation of synaptic levels via one or more transporter proteins. Synapse 67:656–667, 2013 . © 2013 Wiley Periodicals, Inc.     

HLA‐B*15:02 association with carbamazepine‐induced Stevens‐Johnson syndrome and toxic epidermal necrolysis in an Indian population: a pooled‐data analysis and meta‐analysis

This study aimed to investigate the prevalence and association of HLA‐B*15:02 with carbamazepine‐induced Stevens‐Johnson syndrome and toxic epidermal necrolysis (CBZ‐SJS/TEN) in the Indian population in Malaysia, which mostly originated from Southern India. HLA‐B alleles in five Indian case patients with CBZ‐SJS/TEN and 52 CBZ‐tolerant controls, and followed by a pooled sample of seven cases from two centers in Malaysia were analyzed. Positive association for HLA‐B*15:02 with CBZ‐SJS/TEN was detected in Indians (40% [2/5] vs. 3.8% [2/52], odds ratio [OR] 16.7, p = 0.0349), of which 80% (4/5) of the Indian patients originated from Southern India. A pooled sample of seven cases showed stronger association between HLA‐B*15:02 and CBZ‐SJS/TEN (57.1% [4/7] vs. 3.8% [2/52], OR 33.3, 95% confidence interval [CI] 4.25–162.21, p = 1.05 × 10^?3). Subsequent meta‐analysis on Indians from Malaysia and India further demonstrated a significant and strong association between HLA‐B*15:02 and CBZ‐SJS/TEN (OR 38.54; 95% CI 6.83–217.34, p < 1.0 × 10^?4). Our study is the first on Indians predominantly from Southern India that demonstrated HLA‐B*15:02 as a strong risk factor for CBZ‐SJS/TEN despite a low population allele frequency. This stressed the importance of testing for HLA‐B*15:02, irrespective of the ancestral background, including populations with low allele frequency.     

Overlap of dyspepsia and gastroesophageal reflux in the general population: one disease or distinct entities?

Background The overlap of dyspepsia and gastroesophageal reflux (GER) is known to be frequent, but whether the overlap group is a distinct entity or not remains unclear. The aims of the study was to evaluate whether the overlap of dyspepsia and GER (dyspepsia‐GER overlap) occurs more than expected due to chance alone, and evaluate the risk factors for dyspepsia‐GER overlap. Methods In 2008 and 2009, a validated Bowel Disease Questionnaire was mailed to a total of 8006 community sample from Olmsted County, MN. Overall, 3831 of the 8006 subjects returned surveys (response rate 48%). Dyspepsia was defined by symptom criteria of Rome III; GER was defined by weekly or more frequent heartburn and/or acid regurgitation. Key Results Dyspepsia and GER occurred together more commonly than expected by chance. The somatic symptom checklist score was significantly associated with dyspepsia‐GER overlap vs GER alone or dyspepsia alone [OR = 1.9 (1.4, 2.5), and 1.6 (1.2, 2.1), respectively]. Insomnia was also significantly associated with dyspepsia‐GER overlap vs. GER alone or dyspepsia alone [OR = 1.4 (1.1, 1.7), OR = 1.3 (1.1, 1.6), respectively]. Moreover, proton pump inhibitor use was significantly associated with dyspepsia‐GER overlap vs dyspepsia alone [OR = 2.4 (1.5, 3.8)]. Conclusions & Inferences Dyspepsia‐GER overlap is common in the population and is greater than expected by chance.     

High‐dose statin therapy and risk of intracerebral hemorrhage: a meta‐analysis

Statin plays a major role in the primary and secondary prevention of cardiovascular disease (CVD). Inconsistent findings in the studies have been observed toward the risk of intracerebral hemorrhage (ICH) using higher dose of statin. To examine this issue, we performed a meta‐analysis of randomized controlled trials (RCTs) to assess the association between higher dose of various statins and risk of ICH among patients with CVD. Literature was searched for studies published before June 10, 2015, using electronic database ‘PubMed’, ‘EMBASE’, and ‘Google Scholar’ as well as from many trial databases. The following search terms were used: ‘Statin therapy’ AND ‘Cardiovascular Disease’, AND ‘Dose’ AND ‘Intracerebral hemorrhage’, AND ‘Randomized Controlled Trials’ AND ‘High Dose Statin’. High dose of statins was defined as atorvastatin 80 mg, simvastatin 80 mg, pravastatin 40 mg, rosuvastatin 20 mg per day. Fixed‐effect model was used to estimate the risk ratio (RR) and 95% confidence interval (CI) if heterogeneity was <50%; otherwise, random‐effect model was used. Begg's funnel plot was used to assess the publication bias. Seven RCTs involving 31,099 subjects receiving high‐dose statin and 31,105 subjects receiving placebo were analyzed in our meta‐analysis. A significant risk of ICH was observed in subjects with higher dose of statin (RR = 1.53; 95% CI: 1.16–2.01; P = 0.002). There was no difference in all‐cause mortality between the two groups (RR = 0.95; 95% CI: 0.86–1.06; P = 0.36). No publication bias was observed through Begg's funnel plot. Higher dose of statins was found to be associated with the risk of ICH. Future studies are needed to confirm these findings.