GABA A receptors and inhibitory neurotransmission in the amygdalar complex

The amygdalar complex (AC) located in the mid-temporal lobe plays a key role in processing emotionally salient information to generate appropriate behavioural output. Inhibitory signalling mediated by GABAergic neurons, and acting through GABARs within the AC, potently modulates local processing and output of the AC. Disorders of emotional processing such as anxiety and stress, engage the AC, and some of the treatments for these disorders are thought to act via GABARs receptors in AC. Here we review GABAergic circuits in the AC, the distribution of GABARs and their putative functional roles through subunit specific GABARs signalling

Pre-pregnancy predictors of hypertension in pregnancy among Aboriginal and Torres Strait Islander women in north Queensland, Australia; a prospective cohort study

BACKGROUND Compared to other Australian women, Indigenous women are frequently at greater risk for hypertensive disorders of pregnancy. We examined pre-pregnancy factors that may predict hypertension in pregnancy in a cohort of Aboriginal and Torres Strait Islander women in north Queensland. METHODS Data on a cohort of 1009 Indigenous women of childbearing age (15–44 years) who participated in a 1998–2000 health screening program in north Queensland were combined with 1998–2008 Queensland hospitalisations data using probabilistic data linkage. Data on the women in the cohort who were hospitalised for birth (n = 220) were further combined with Queensland perinatal data which identified those diagnosed with hypertension in pregnancy. RESULTS Of 220 women who gave birth, 22 had hypertension in the pregnancy after their health check. The mean age of women with and without hypertension was similar (23.7 years and 23.9 years respectively) however Aboriginal women were more affected compared to Torres Strait Islanders. Pre-pregnancy adiposity and elevated blood pressure at the health screening program were predictors of a pregnancy affected by hypertension. After adjusting for age and ethnicity, each 1 cm increase in waist circumference showed a 4% increased risk for hypertension in pregnancy (PR 1.04; 95% CI; 1.02-1.06); each 1 point increase in BMI showed a 9% adjusted increase in risk (1.09; 1.04-1.14). For each 1 mmHg increase in baseline systolic blood pressure there was an age and ethnicity adjusted 6% increase in risk and each 1 mmHg increase in diastolic blood pressure showed a 7% increase in risk (1.06; 1.03-1.09 and 1.07; 1.03-1.11 respectively). Among those free of diabetes at baseline, the presence of the metabolic syndrome (International Diabetes Federation criteria) predicted over a three-fold increase in age-ethnicity-adjusted risk (3.5; 1.50-8.17). CONCLUSIONS Pre-pregnancy adiposity and features of the metabolic syndrome among these young Aboriginal and Torres Strait Islander women track strongly to increased risk of hypertension in pregnancy with associated risks to the health of babies.Sandra K Campbell, John Lynch, Adrian Esterman and Robyn McDermot

MK-0448, a Specific Kv1.5 Inhibitor: Safety, Pharmacokinetics and Pharmacodynamic Electrophysiology in Experimental Animal Models and in Humans.

BACKGROUND: -We evaluated the viability of I(Kur) as a target for maintenance of sinus rhythm in patients with a history of atrial fibrillation through the testing of MK-0448, a novel I(Kur) inhibitor. METHODS AND RESULTS: -In vitro MK-0448 studies demonstrated strong inhibition of I(Kur) with minimal off-target activity. In vivo MK-0448 studies in normal anesthetized dogs demonstrated significant prolongation of the atrial refractory period compared with vehicle controls without affecting the ventricular refractory period. In studies of a conscious dog heart failure model, sustained AF was terminated with bolus intravenous MK-0448 doses of 0.03 and 0.1 mg/kg. These data led to a two-part first-in-human study: Part I evaluated safety and pharmacokinetics, and Part II was an invasive electrophysiologic (EP) study in healthy subjects. MK-0448 was well-tolerated with mild adverse experiences, most commonly irritation at the injection site. During the EP study, ascending doses of MK-0448 were administered, but no increases in atrial or ventricular refractoriness were detected despite achieving plasma concentrations in excess of 2 μM. Follow-up studies in normal anesthetized dogs designed to assess the influence of autonomic tone demonstrated that prolongation of atrial refractoriness with MK-0448 was markedly attenuated in the presence of vagal nerve simulation, suggesting that the effects of I(Kur) blockade on atrial repolarization may be negated by enhanced parasympathetic neural tone. CONCLUSIONS: -The contribution of I(Kur) to human atrial electrophysiology is less prominent than in preclinical models and therefore is likely to be of limited therapeutic value for the prevention of atrial fibrillation

Gridded and direct Epoch of Reionisation bispectrum estimates using the Murchison Widefield Array

We apply two methods to estimate the 21~cm bispectrum from data taken within the Epoch of Reionisation (EoR) project of the Murchison Widefield Array (MWA). Using data acquired with the Phase II compact array allows a direct bispectrum estimate to be undertaken on the multiple redundantly-spaced triangles of antenna tiles, as well as an estimate based on data gridded to the $uv$-plane. The direct and gridded bispectrum estimators are applied to 21 hours of high-band (167--197~MHz; $z$=6.2--7.5) data from the 2016 and 2017 observing seasons. Analytic predictions for the bispectrum bias and variance for point source foregrounds are derived. We compare the output of these approaches, the foreground contribution to the signal, and future prospects for measuring the bispectra with redundant and non-redundant arrays. We find that some triangle configurations yield bispectrum estimates that are consistent with the expected noise level after 10 hours, while equilateral configurations are strongly foreground-dominated. Careful choice of triangle configurations may be made to reduce foreground bias that hinders power spectrum estimators, and the 21~cm bispectrum may be accessible in less time than the 21~cm power spectrum for some wave modes, with detections in hundreds of hours.Comment: 19 pages, 10 figures, accepted for publication in PAS

Effect of Covered Metallic Stents Compared With Plastic Stents on Benign Biliary Stricture Resolution A Randomized Clinical Trial

Importance Endoscopic placement of multiple plastic stents in parallel is the first-line treatment for most benign biliary strictures; it is possible that fully covered, self-expandable metallic stents (cSEMS) may require fewer endoscopic retrograde cholangiopancreatography procedures (ERCPs) to achieve resolution. Objective To assess whether use of cSEMS is noninferior to plastic stents with respect to stricture resolution. Design, Setting, and Participants Multicenter (8 endoscopic referral centers), open-label, parallel, randomized clinical trial involving patients with treatment-naive, benign biliary strictures (N = 112) due to orthotopic liver transplant (n = 73), chronic pancreatitis (n = 35), or postoperative injury (n = 4), who were enrolled between April 2011 and September 2014 (with follow-up ending October 2015). Patients with a bile duct diameter less than 6 mm and those with an intact gallbladder in whom the cystic duct would be overlapped by a cSEMS were excluded. Interventions Patients (N = 112) were randomized to receive multiple plastic stents or a single cSEMS, stratified by stricture etiology and with endoscopic reassessment for resolution every 3 months (plastic stents) or every 6 months (cSEMS). Patients were followed up for 12 months after stricture resolution to assess for recurrence. Main Outcomes and Measures Primary outcome was stricture resolution after no more than 12 months of endoscopic therapy. The sample size was estimated based on the noninferiority of cSEMS to plastic stents, with a noninferiority margin of −15%. Results There were 55 patients in the plastic stent group (mean [SD] age, 57 [11] years; 17 women [31%]) and 57 patients in the cSEMS group (mean [SD] age, 55 [10] years; 19 women [33%]). Compared with plastic stents (41/48, 85.4%), the cSEMS resolution rate was 50 of 54 patients (92.6%), with a rate difference of 7.2% (1-sided 95% CI, −3.0% to ∞; P < .001). Given the prespecified noninferiority margin of −15%, the null hypothesis that cSEMS is less effective than plastic stents was rejected. The mean number of ERCPs to achieve resolution was lower for cSEMS (2.14) vs plastic (3.24; mean difference, 1.10; 95% CI, 0.74 to 1.46; P < .001). Conclusions and Relevance Among patients with benign biliary strictures and a bile duct diameter 6 mm or more in whom the covered metallic stent would not overlap the cystic duct, cSEMS were not inferior to multiple plastic stents after 12 months in achieving stricture resolution. Metallic stents should be considered an appropriate option in patients such as these

Prognostic implications of physiologic and radiographic changes in idiopathic interstitial pneumonia

Idiopathic interstitial pneumonias are a diverse group of lung diseases with varied prognoses. We hypothesized that changes in physiologic and radiographic parameters would predict survival. We retrospectively examined 80 patients with usual interstitial pneumonia and 29 patients with nonspecific interstitial pneumonia. Baseline characteristics were examined together with 6-month change in forced vital capacity, diffusing capacity for carbon monoxide, and ground glass infiltrate and fibrosis on high resolution computed tomography. Patients with usual interstitial pneumonia were more likely to have a statistically significant or marginally significant decline in lung volume, diffusing capacity for carbon monoxide, and an increase in ground glass infiltrates (p <= 0.08) compared with patients with nonspecific interstitial pneumonia. For patients with usual interstitial pneumonia, change in forced vital capacity was the best physiologic predictor of mortality (p = 0.05). In a multivariate Cox proportional hazards model controlling for histopathologic diagnosis, gender, smoking history, baseline forced vital capacity, and 6-month change in forced vital capacity, a decrease in forced vital capacity remained an independent risk factor for mortality (decrease > 10%; hazard ratio 2.47; 95% confidence interval 1.29, 4.73; p = 0.006). We conclude that a 6-month change in forced vital capacity gives additional prognostic information to baseline features for patients with idiopathic interstitial pneumonia.Supported by National Institutes of Health NHLBI grants P50HL46487, NIH/NCRR 3 MO1 RR00042-33S3, NIH/NIA P60 AG08808-06, NHLBI, 1 K24 HL04212, and 1 K23 HL68713.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/91973/1/2003 AJRCCM - Prognostic Implications of Physiologic and Radiographic Changes in Idiopathic Interstitial Pneumonia.pd

Prognostic value of desaturation during a six minute walk test in Idiopathic Interstitial Pneumonia

Exercise-induced hypoxia is an index of the severity of interstitial lung disease. We hypothesized that desaturation during a 6-minute walk test would predict mortality for patients with usual interstitial pneumonia (n = 83) and nonspecific interstitial pneumonia (n = 22). Consecutive patients with biopsy-proven disease performed a 6-minute walk test between January 1996 and December 2001. Desaturation was defined as a fall in oxygen saturation to 88% or less during the 6-minute walk test. Desaturation was common (44 of 83 usual interstitial pneumonia and 8 of 22 nonspecific interstitial pneumonia; chi square, p = 0.39). Patients with usual interstitial pneumonia or nonspecific interstitial pneumonia who desaturated had a significantly higher mortality than patients who did not desaturate (respective log-rank tests, p = 0.0018, p = 0.0089). In patients with usual interstitial pneumonia, the presence of desaturation was associated with an increased hazard of death (hazard ratio, 4.2; 95% confidence interval, 1.40, 12.56; p = 0.01) after adjusting for age, sex, smoking, baseline diffusion capacity for carbon monoxide, FVC, and resting saturation.Weconclude that knowledge of desaturation during a 6-minute walk test adds prognostic information for patients with usual interstitial pneumonia and nonspecific interstitial pneumonia.Supported in part by National Institutes of Health NHLBI Grant #P50HL46487, NHLBI, 1 K24 HL04212, and 1 K23 HL68713.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/91972/1/2003 AJRCCM - Prognostic value of desaturation during a six minute walk test in Idiopathic Interstitial Pneumonia.pd

Fibroblastic Foci in Usual Interstitial Pneumonia: Idiopathic versus Collagen Vascular Disease

A histologic feature of usual interstitial pneumonia is the presence of fibroblastic foci. As some patients with usual interstitial pneumonia and an underlying collagen vascular disease have a better prognosis, we hypothesized that they would have fewer fibroblastic foci. Pathologists reviewed surgical lung biopsies from 108 patients with usual interstitial pneumonia (nine with collagen vascular disease) and assigned a score (absent 0, mild 1, moderate 2, and marked 3) for fibroblastic foci. Patients with idiopathic usual interstitial pneumonia had a higher median profusion of fibroblastic foci (1.75 vs. 1.0, p = 0.003). Baseline characteristics were similar, although patients with a collagen vascular disease were younger, had a shorter duration of symptoms, and had a higher percentage of predicted total lung capacity. Profusion of fibroblastic foci was the most discriminative feature for separating idiopathic from collagen vascular disease–associated usual interstitial pneumonia (odds ratio 8.31; 95% confidence interval, 1.98, 59.42; p = 0.002 for a one-unit increase in fibroblastic foci score). No deaths were noted in the collagen vascular disease–associated usual interstitial pneumonia group; 52 deaths occurred in the idiopathic usual interstitial pneumonia group (log rank; p = 0.005). We conclude that patients with collagen vascular disease–associated usual interstitial pneumonia have fewer fibroblastic foci and improved survival.Supported in part by National Institutes of Health National Heart, Lung, and Blood Institute grant #P50HL46487, NIH/NCRR 3 MO1 RR00042–33S3, NIH/NIA P60 AG08808–06, NHLBI 1 K24 HL04212, and 1 K23 HL68713.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/91974/1/2003 AJRCCM - Fibroblastic Foci in Usual Interstitial Pneumonia -Idiopathic versus Collagen Vascular Disease.pd