Severity scoring of manganese health effects for categorical regression

Characterizing the U-shaped exposure response relationship for manganese (Mn) is necessary for estimating the risk of adverse health from Mn toxicity due to excess or deficiency. Categorical regression has emerged as a powerful tool for exposure-response analysis because of its ability to synthesize relevant information across multiple studies and species into a single integrated analysis of all relevant data. This paper documents the development of a database on Mn toxicity designed to support the application of categorical regression techniques. Specifically, we describe (i) the conduct of a systematic search of the literature on Mn toxicity to gather data appropriate for dose-response assessment; (ii) the establishment of inclusion/exclusion criteria for data to be included in the categorical regression modeling database; (iii) the development of a categorical severity scoring matrix for Mn health effects to permit the inclusion of diverse health outcomes in a single categorical regression analysis using the severity score as the outcome variable; and (iv) the convening of an international expert panel to both review the severity scoring matrix and assign severity scores to health outcomes observed in studies (including case reports, epidemiological investigations, and in vivo experimental studies) selected for inclusion in the categorical regression database. Exposure information including route, concentration, duration, health endpoint(s), and characteristics of the exposed population was abstracted from included studies and stored in a computerized manganese database (MnDB), providing a comprehensive repository of exposure-response information with the ability to support categorical regression modeling of oral exposure data

Clinical and pathophysiologic spectrum of acquired distal renal tubular acidosis

Clinical and pathophysiologic spectrum of acquired distal renal tubular acidosis. Urinary acidification was studied in nine patients with hyper-chloremic metabolic acidosis. The aim of this study was to investigate the mechanism(s) of impaired distal acidification by the systematic administration of sodium sulfate and neutral phosphate. No impairment of proximal acidification was apparent because all patients had a fractional bicarbonate excretion below 5% at plasma bicarbonate concentrations above 22 mEq/liter. All patients except two were unable to lower urine pH below 5.5 despite systemic metabolic acidosis. The two patients who lowered urine pH normally were hyperkalemic and had selective aldosterone deficiency. Six patients failed to lower the urine pH below 5.5 with sodium sulfate (6.04 ± 0.16) and were unable to achieve a normal urine minus blood (U-B) Pco2 gradient with neutral phosphate (2.8 ± 3.5mm Hg). Control subjects, the two patients with selective aldosterone deficiency, and the remaining patient lowered the urine pH below 5.5 and increased the U-B Pco2 gradient above 25mm Hg in response to sodium sulfate and neutral phosphate infusion, respectively. The abnormal response to these agents exhibited by six patients strongly suggests that the mechanism of impaired distal acidification was that of secretory failure of the proton pump. The normal response of the remaining three patients indicates that the proton pump was able to secrete hydrogen ions normally under maximal stimulation. This pattern is totally predictable in patients with isolated selective aldosterone deficiency who are also capable of lowering the urine pH normally in the presence of systemic metabolic acidosis. The distinctive acidification pattern of the remaining patient who was also hyperkalemic can be explained on the basis of a voltage-dependent type of distal renal tubular acidosis. This type may be disclosed by the findings of impairment of both hydrogen ion and potassium secretion.Aspects clinique et physiopathologique de l'acidose tubulaire distale acquise. L'acidification urinaire a été étudiée chez neuf malades ayant une acidose métabolique hyperchlorémique. Le but de ce travail était d'étudier le mécanisme de l'altération de l'acidification distale par l'administration de sulfate de sodium et de phosphate neutre. Il n'est pas apparu d'altération de l'acidication proximale puisque tous les malades avaient une excrétion fractionnelle de bicarbonate inférieure à 5% à des concentrations de bicarbonate plasmatique supérieures à 22 mEq/litre. Tous les malades sauf deux étaient incapables d'abaisser leur pH urinaire au dessous de 5,5 malgré l'acidose métabolique. Les deux malades qui abaissaient le pH de l'urine à des valeurs normales étaient hyperkaliémiques et avaient un déficit sélectif d'aldostérone. Six malades n'ont pu abaisser leur pH urinaire en dessous de 5,5 avec le sulfate de sodium (6,04 ± 0,16) et ont été incapables de réaliser un gradient de Pco2 normal urine-sang sous phosphate neutre (2,8 ± 3,5mm Hg). Les sujets contrôles, les deux malades ayant un déficit d'aldostérone et le dernier malade ont abaissé le pH de l'urine au dessous de 5,5 et augmenté le gradient de Pco2 à plus de 25mm Hg en réponse aux administrations de sulfate de sodium et de phosphate neutre, respectivement. La résponse anormale des six malades suggère fortement que le mécanisme de l'altération de l'acidification distale est un défaut de fonctionnement de la pompe à protons. La réponse normale des trois derniers malades indique que la pompe était capable de sécréter des ions hydrogène dans des conditions de stimulation maximales. Cette modalité est prévisible chez les malades qui ont un déficit sélectif et isolé d'aldostérone et qui sont aussi capables d'abaisser le pH de leur urine en présence d'une acidose métabolique systémique. La modalité d'acidification particulière du dernier malade qui était en même temps hyperkaliémique peut être expliquée par un mécanisme dépendant de la différence de potentiel. Cette situation peut être reconnue par la constatation d'un désordre portant à la fois sur la sécrétion de ions hydrogène et celle de potassium

Esophageal sphincter device for gastroesophageal reflux disease

BACKGROUND Patients with gastroesophageal reflux disease who have a partial response to proton-pump inhibitors often seek alternative therapy. We evaluated the safety and effectiveness of a new magnetic device to augment the lower esophageal sphincter. METHODS We prospectively assessed 100 patients with gastroesophageal reflux disease before and after sphincter augmentation. The study did not include a concurrent control group. The primary outcome measure was normalization of esophageal acid exposure or a 50% or greater reduction in exposure at 1 year. Secondary outcomes were 50% or greater improvement in quality of life related to gastroesophageal reflux disease and a 50% or greater reduction in the use of proton-pump inhibitors at 1 year. For each outcome, the prespecified definition of successful treatment was achievement of the outcome in at least 60% of the patients. The 3-year results of a 5-year study are reported. RESULTS The primary outcome was achieved in 64% of patients (95% confidence interval [CI], 54 to 73). For the secondary outcomes, a reduction of 50% or more in the use of proton-pump inhibitors occurred in 93% of patients, and there was improvement of 50% or more in quality-of-life scores in 92%, as compared with scores for patients assessed at baseline while they were not taking proton-pump inhibitors. The most frequent adverse event was dysphagia (in 68% of patients postoperatively, in 11% at 1 year, and in 4% at 3 years). Serious adverse events occurred in six patients, and in six patients the device was removed. CONCLUSIONS In this single-group evaluation of 100 patients before and after sphincter augmentation with a magnetic device, exposure to esophageal acid decreased, reflux symptoms improved, and use of proton-pump inhibitors decreased. Follow-up studies are needed to assess long-term safety. (Funded by Torax Medical; ClinicalTrials.gov number, NCT00776997.

Telemedicine for the Spine Surgeon in the Age of COVID-19: Multicenter Experiences of Feasibility and Implementation Strategies.

STUDY DESIGN: Multicenter study. OBJECTIVES: The COVID-19 pandemic has obligated physicians to recur to additional resources and make drastic changes regarding the standard physician-patient encounter. In the last century, there has been a substantial improvement in technology, which over the years has opened the door to a new form of medical practicing known as telemedicine. METHODS: Healthcare workers from three hospitals involved in the care for COVID-19 patients in the united states were invited to share their experience using telemedicine to deliver clinical care to their patients. RESULTS: Since the appearance of this worldwide outbreak, social distancing has been a key factor in preventing the spread of the virus, for which measures have been taken to limit physical contact. Because of the ongoing situation, telemedicine has been progressively incorporated into the physician-patient encounters and quickly has become an essential component in the day-today medical practice. CONCLUSIONS: It is feasible to deliver viable spine practice with the use of telemedicine. A proper patient selection of patients requiring virtual treatment versus those requiring in-person visits should be considered

Demonstrating test‐retest reliability of electrophysiological measures for healthy adults in a multisite study of biomarkers of antidepressant treatment response

Growing evidence suggests that loudness dependency of auditory evoked potentials (LDAEP) and resting EEG alpha and theta may be biological markers for predicting response to antidepressants. In spite of this promise, little is known about the joint reliability of these markers, and thus their clinical applicability. New standardized procedures were developed to improve the compatibility of data acquired with different EEG platforms, and used to examine test‐retest reliability for the three electrophysiological measures selected for a multisite project—Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care (EMBARC). Thirty‐nine healthy controls across four clinical research sites were tested in two sessions separated by about 1 week. Resting EEG (eyes‐open and eyes‐closed conditions) was recorded and LDAEP measured using binaural tones (1000 Hz, 40 ms) at five intensities (60–100 dB SPL). Principal components analysis of current source density waveforms reduced volume conduction and provided reference‐free measures of resting EEG alpha and N1 dipole activity to tones from auditory cortex. Low‐resolution electromagnetic tomography (LORETA) extracted resting theta current density measures corresponding to rostral anterior cingulate (rACC), which has been implicated in treatment response. There were no significant differences in posterior alpha, N1 dipole, or rACC theta across sessions. Test‐retest reliability was .84 for alpha, .87 for N1 dipole, and .70 for theta rACC current density. The demonstration of good‐to‐excellent reliability for these measures provides a template for future EEG/ERP studies from multiple testing sites, and an important step for evaluating them as biomarkers for predicting treatment response.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/135271/1/psyp12758_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/135271/2/psyp12758.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/135271/3/psyp12758-sup-0001-suppinfo1.pd

Mineralocorticoid Receptor Blockade Attenuates Chronic Overexpression of the Renin-Angiotensin- Aldosterone System Stimulation of Reduced Nicotinamide Adenine Dinucleotide Phosphate Oxidase and Cardiac Remodeling

doi: 10.1210/en.2006-1691The renin-angiotensin-aldosterone system contributes to cardiac remodeling, hypertrophy, and left ventricular dysfunction. Angiotensin II and aldosterone (corticosterone in rodents) together generate reactive oxygen species (ROS) via reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, which likely facilitate this hypertrophy and remodeling. This investigation sought to determine whether cardiac oxidative stress and cellular remodeling could be attenuated by in vivo mineralocorticoid receptor (MR) blockade in a rodent model of the chronically elevated tissue renin-angiotensin-aldosterone system, the transgenic TG (mRen2) 27 rat (Ren2). The Ren2 overexpresses the mouse renin transgene with resultant hypertension, insulin resistance, proteinuria, and cardiovascular damage. Young (6- to 7-wk-old) male Ren2 and age-matched Sprague-Dawley rats were treated with spironolactone or placebo for 3 wk. Heart tissue ROS, immunohistochemical analysis of 3-nitrotyrosine,and NADPH oxidase (NOX) subunits (gp91phox recently renamed NOX2, p22phox, Rac1, NOX1, and NOX4) were measured. Structural changes were assessed with cine-magnetic resonance imaging, transmission electron microscopy, and light microscopy. Significant increases in Ren2 septal wall thickness (cine-magnetic resonance imaging) were accompanied by perivascular fibrosis, increased mitochondria, and other ultrastructural changes visible by light microscopy and transmission electron microscopy. Although there was no significant reduction in systolic blood pressure, significant improvements were seen with MR blockade on ROS formation and NOX subunits (each P < 0.05). Collectively, these data suggest that MR blockade, independent of systolic blood pressure reduction, improves cardiac oxidative stress-induced structural and functional changes, which are driven, in part, by angiotensin type 1 receptor-mediated increases in NOX.This research was supported by National Institutes of Health (NIH) Grants R01 HL73101-01A1 (to J.R.S.) and P01 HL-51952 (to C.F.), the Veterans Affairs Merit System (0018) (to J.R.S.), and Advanced Research Career Development (to C.S.). Male transgenic Ren2 rats and male Sprague-Dawley controls were kindly provided by C.F. through the Transgenic Core Facility supported in part by NIH Grant HL-51952

iPSCORE: A Resource of 222 iPSC Lines Enabling Functional Characterization of Genetic Variation across a Variety of Cell Types.

Large-scale collections of induced pluripotent stem cells (iPSCs) could serve as powerful model systems for examining how genetic variation affects biology and disease. Here we describe the iPSCORE resource: a collection of systematically derived and characterized iPSC lines from 222 ethnically diverse individuals that allows for both familial and association-based genetic studies. iPSCORE lines are pluripotent with high genomic integrity (no or low numbers of somatic copy-number variants) as determined using high-throughput RNA-sequencing and genotyping arrays, respectively. Using iPSCs from a family of individuals, we show that iPSC-derived cardiomyocytes demonstrate gene expression patterns that cluster by genetic background, and can be used to examine variants associated with physiological and disease phenotypes. The iPSCORE collection contains representative individuals for risk and non-risk alleles for&nbsp;95% of SNPs associated with human phenotypes through genome-wide association studies. Our study demonstrates the utility of iPSCORE for examining how genetic variants influence molecular and physiological traits in iPSCs and derived cell lines

Efficacy of transoral fundoplication vs omeprazole for treatment of regurgitation in a randomized controlled trial.

Background The aim of this randomized, crossover study was to determine if transoral fundoplication (TF) could further improve clinical outcomes in partial responders to high-dose (HD) proton-pump inhibitor (PPI) therapy and to evaluate durability of TF. Methods In seven United States centers, patients with hiatal hernia ≤2 cm and abnormal esophageal acid exposure (EAE) were randomized to TF (n = 40) or HD PPIs (n = 23) group. At 6-month follow-up, PPI patients underwent crossover. We assessed clinical outcomes 6-month post TF in crossover patients (COP), as compared to 6-month of HD PPI therapy, and 12-month outcomes in patients initially randomized to TF. The primary outcome was symptom control evaluated by Reflux Disease Questionnaire and Reflux Symptom Index. Secondary outcomes included healing of esophagitis, normalization of EAE and PPI use after TF. We analyzed 21 COP and 39 TF patients. McNemar’s test or Fisher exact test was used to compare proportions. Results Of 63 randomized patients, 3 were lost to follow-up, leaving 39 TF and 21 COP for analyses. In the COP, TF further improved control of regurgitation and of atypical symptoms achieved after six months of HD PPIs. Of 20 patients with GERD symptoms after six months of high-dose PPI therapy, 65% (13/20) reported global elimination of troublesome regurgitation and atypical symptoms post TF off PPIs; 67% (6/9) reported no troublesome regurgitation. Esophagitis further healed in 75% (6/8) of patients. Seventy-one percent of COP patients were off PPIs six months following TF. Normalization of EAE decreased from 52% after HD PPIs (on PPIs) to 33% after TF (off PPIs), p =0.388. In the original TF group, 12-month post TF, 77% of patients achieved complete symptom control, 82% ceased PPI therapy, 100% healed esophagitis and 45% normalized EAE. Conclusions The results of this study indicate that in patients with incomplete symptom control on high-dose PPI therapy TF may provide further elimination of symptoms and esophagitis healing. In the original TF group, the clinical outcomes of TF remained stable between 6- and 12-month follow-up. Trial registration Clinicaltrials.gov: NCT01647958

Galaxy Zoo: CANDELS barred discs and bar fractions

The formation of bars in disc galaxies is a tracer of the dynamical maturity of the population. Previous studies have found that the incidence of bars in discs decreases from the local Universe to z ~ 1, and by z > 1 simulations predict that bar features in dynamically mature discs should be extremely rare. Here, we report the discovery of strong barred structures in massive disc galaxies at z ~ 1.5 in deep rest-frame optical images from the Cosmic Assembly Near-Infrared Deep Extragalactic Legacy Survey. From within a sample of 876 disc galaxies identified by visual classification in Galaxy Zoo, we identify 123 barred galaxies. Selecting a subsample within the same region of the evolving galaxy luminosity function (brighter than L*), we find that the bar fraction across the redshift range 0.5 ≤ z ≤ 2 (fbar = 10.7+6.3 -3.5 per cent after correcting for incompleteness) does not significantly evolve.We discuss the implications of this discovery in the context of existing simulations and our current understanding of the way disc galaxies have evolved over the last 11 billion yearsPeer reviewedFinal Accepted Versio

Structure-Activity Studies Of 7-Heteroaryl-3-Azabicyclo[3.3.1]Non-6-Enes: A Novel Class Of Highly Potent Nicotinic Receptor Ligands

The potential for nicotinic ligands with affinity for the α4β2 or α7 subtypes to treat such diverse diseases as nicotine addiction, neuropathic pain, and neurodegenerative and cognitive disorders has been exhibited clinically for several compounds while preclinical activity in relevant in vivo models has been demonstrated for many more. For several therapeutic programs, we sought nicotinic ligands with various combinations of affinity and function across both subtypes, with an emphasis on dual α4β2-α7 ligands, to explore the possibility of synergistic effects. We report here the structure-activity relationships (SAR) for a novel series of 7-heteroaryl-3-azabicyclo[3.3.1]non-6-enes and characterize many of the analogues for activity at multiple nicotinic subtypes. © 2012 American Chemical Society