260 research outputs found
The Asymmetric Thick Disk: A Star Count and Kinematic Analysis. II The Kinematics
We report a kinematic signature associated with the observed asymmetry in the
distribution of thick disk/inner halo stars interior to the Solar circle
described in Paper I. In that paper we found a statistically significant excess
(20% to 25 %) of stars in quadrant I (l ~ 20 deg to 55 deg) both above and
below the plane (b ~ +/- 25 deg to +/- 45 deg) compared to the complementary
region in quadrant IV. We have measured Doppler velocities for 741 stars,
selected according to the same magnitude and color criteria, in the direction
of the asymmetry and in the corresponding fields in quadrant IV. We have also
determined spectral types and metallicities measured from the same spectra. We
not only find an asymmetric distribution in the V_LSR velocities for the stars
in the two regions, but the angular rate of rotation, w, for the stars in
quadrant I reveals a slower effective rotation rate compared to the
corresponding quadrant IV stars. We use our [Fe/H] measurements to separate the
stars into the three primary population groups, halo, thick disk, and disk, and
conclude that it is primarily the thick disk stars that show the slower
rotation in quadrant I. A solution for the radial, tangential and vertical
components of the V_LSR velocities, reveals a significant lag of ~ 80 to 90
km/s in the direction of Galactic rotation for the thick disk stars in quadrant
I, while in quadrant IV, the same population has only a ~ 20 km/s lag. The
results reported here support a rotational lag among the thick disk stars due
to a gravitational interaction with the bar as the most likely explanation for
the asymmetry in both the star counts and the kinematics. The affected thick
disk stars, however, may be associated with the recently discovered Canis Major
debris stream or a similar merger event (abridged).Comment: Accepted for publication in the Astronomical Journa
Quality of Life in Chronic Pancreatitis is Determined by Constant Pain, Disability/Unemployment, Current Smoking, and Associated Co-Morbidities
OBJECTIVES: Chronic pancreatitis (CP) has a profound independent effect on quality of life (QOL). Our aim was to identify factors that impact the QOL in CP patients. METHODS: We used data on 1,024 CP patients enrolled in the three NAPS2 studies. Information on demographics, risk factors, co-morbidities, disease phenotype, and treatments was obtained from responses to structured questionnaires. Physical and mental component summary (PCS and MCS, respectively) scores generated using responses to the Short Form-12 (SF-12) survey were used to assess QOL at enrollment. Multivariable linear regression models determined independent predictors of QOL. RESULTS: Mean PCS and MCS scores were 36.7+/-11.7 and 42.4+/-12.2, respectively. Significant (P \u3c 0.05) negative impact on PCS scores in multivariable analyses was noted owing to constant mild-moderate pain with episodes of severe pain or constant severe pain (10 points), constant mild-moderate pain (5.2), pain-related disability/unemployment (5.1), current smoking (2.9 points), and medical co-morbidities. Significant (P \u3c 0.05) negative impact on MCS scores was related to constant pain irrespective of severity (6.8-6.9 points), current smoking (3.9 points), and pain-related disability/unemployment (2.4 points). In women, disability/unemployment resulted in an additional 3.7 point reduction in MCS score. Final multivariable models explained 27% and 18% of the variance in PCS and MCS scores, respectively. Etiology, disease duration, pancreatic morphology, diabetes, exocrine insufficiency, and prior endotherapy/pancreatic surgery had no significant independent effect on QOL. CONCLUSIONS: Constant pain, pain-related disability/unemployment, current smoking, and concurrent co-morbidities significantly affect the QOL in CP. Further research is needed to identify factors impacting QOL not explained by our analyses
Mechanisms of CFTR Functional Variants That Impair Regulated Bicarbonate Permeation and Increase Risk for Pancreatitis but Not for Cystic Fibrosis
CFTR is a dynamically regulated anion channel. Intracellular WNK1-SPAK activation causes CFTR to change permeability and conductance characteristics from a chloride-preferring to bicarbonate-preferring channel through unknown mechanisms. Two severe CFTR mutations (CFTRsev) cause complete loss of CFTR function and result in cystic fibrosis (CF), a severe genetic disorder affecting sweat glands, nasal sinuses, lungs, pancreas, liver, intestines, and male reproductive system. We hypothesize that those CFTR mutations that disrupt the WNK1-SPAK activation mechanisms cause a selective, bicarbonate defect in channel function (CFTRBD) affecting organs that utilize CFTR for bicarbonate secretion (e.g. the pancreas, nasal sinus, vas deferens) but do not cause typical CF. To understand the structural and functional requirements of the CFTR bicarbonate-preferring channel, we (a) screened 984 well-phenotyped pancreatitis cases for candidate CFTRBD mutations from among 81 previously described CFTR variants; (b) conducted electrophysiology studies on clones of variants found in pancreatitis but not CF; (c) computationally constructed a new, complete structural model of CFTR for molecular dynamics simulation of wild-type and mutant variants; and (d) tested the newly defined CFTRBD variants for disease in non-pancreas organs utilizing CFTR for bicarbonate secretion. Nine variants (CFTR R74Q, R75Q, R117H, R170H, L967S, L997F, D1152H, S1235R, and D1270N) not associated with typical CF were associated with pancreatitis (OR 1.5, p = 0.002). Clones expressed in HEK 293T cells had normal chloride but not bicarbonate permeability and conductance with WNK1-SPAK activation. Molecular dynamics simulations suggest physical restriction of the CFTR channel and altered dynamic channel regulation. Comparing pancreatitis patients and controls, CFTRBD increased risk for rhinosinusitis (OR 2.3, p<0.005) and male infertility (OR 395, p<<0.0001). WNK1-SPAK pathway-activated increases in CFTR bicarbonate permeability are altered by CFTRBD variants through multiple mechanisms. CFTRBD variants are associated with clinically significant disorders of the pancreas, sinuses, and male reproductive system.Fil: LaRusch, Jessica. Univeristy of Pittsburgh. School of Medicine; Estados UnidosFil: Jung, Jinsei. Yonsei University College of Medicine; Corea del SurFil: General, Ignacio. University of Pittsburgh; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Lewis, Michele D.. Mayo Clinic. Division of Gastroenterology and Hepatology; Estados UnidosFil: Park, Hyun Woo. Yonsei University College of Medicine; Corea del SurFil: Brand, Randall E.. Univeristy of Pittsburgh. School of Medicine; Estados UnidosFil: Gelrud, Andres. Univeristy of Pittsburgh. School of Medicine; Estados UnidosFil: Anderson, Michelle A.. University of Michigan; Estados UnidosFil: Banks, Peter A.. Brigham and Women’s Hospital. Division of Gastroenterology; Estados UnidosFil: Conwell, Darwin. Brigham and Women’s Hospital. Division of Gastroenterology; Estados UnidosFil: Lawrence, Christopher. Medical University of South Carolina; Estados UnidosFil: Romagnuolo, Joseph. Medical University of South Carolina; Estados UnidosFil: Baillie, John. University of Duke; Estados UnidosFil: Alkaade, Samer. St. Louis University. School of Medicine; Estados UnidosFil: Cote, Gregory. Indiana University; Estados UnidosFil: Gardner, Timothy B.. Dartmouth-Hitchcock Medical Center; Estados UnidosFil: Amann, Stephen T.. North Mississippi Medical Center; Estados UnidosFil: Slivka, Adam. Univeristy of Pittsburgh. School of Medicine; Estados UnidosFil: Sandhu, Bimaljit. Virginia Commonwealth University Medical Center; Estados UnidosFil: Aloe, Amy. Univeristy of Pittsburgh. School of Medicine; Estados UnidosFil: Kienholz, Michelle L.. Univeristy of Pittsburgh. School of Medicine; Estados UnidosFil: Yadav, Dhiraj. Univeristy of Pittsburgh. School of Medicine; Estados UnidosFil: Barmada, M. Michael. Univeristy of Pittsburgh. School of Medicine; Estados UnidosFil: Bahar, Ivet. Univeristy of Pittsburgh. School of Medicine; Estados UnidosFil: Lee, Min Goo. Yonsei University College of Medicine; Corea del SurFil: Whitcomb, David C.. Univeristy of Pittsburgh. School of Medicine; Estados UnidosFil: North American Pancreatitis Study Group. No especifica
Mapping the Asymmetric Thick Disk: III. The Kinematics and Interaction with the Galactic Bar
In the first two papers of this series, Larsen et al (2010a,b) describe our
faint CCD survey in the inner Galaxy and map the over-density of Thick Disk
stars in Quadrant I (Q1) to 5 kpc or more along the line of sight. The regions
showing the strongest excess are above the density contours of the bar in the
Galactic disk. In this third paper on the asymmetric Thick Disk, we report on
radial velocities and derived metallicity parameters for over 4000 stars in Q1,
above and below the plane and in Q4 above the plane. We confirm the
corresponding kinematic asymmetry first reported by Parker et al. (2004),
extended to greater distances and with more spatial coverage. The Thick Disk
stars in Q1 have a rotational lag of 60 -- 70 km/s relative to circular
rotation, and the Metal-Weak Thick Disk stars have an even greater lag of 100
km/s. Both lag their corresponding populations in Q4 by approximately 30 km/s.
Interestingly, the Disk stars in Q1 also appear to participate in the
rotational lag by about 30 km/s. The enhanced rotational lag for the Thick Disk
in Q1 extends to 4 kpc or more from the Sun. At 3 to 4 kpc, our sight lines
extend above the density contours on the near side of the bar, and as our lines
of sight pass directly over the bar the rotational lag appears to decrease.
This is consistent with a "gravitational wake" induced by the rotating bar in
the Disk which would trap and pile up stars behind it. We conclude that a
dynamical interaction with the stellar bar is the most probable explanation for
the observed kinematic and spatial asymmetries
Functional Studies on the IBD Susceptibility Gene IL23R Implicate Reduced Receptor Function in the Protective Genetic Variant R381Q
Genome-wide association studies (GWAS) in several populations have demonstrated significant association of the IL23R gene with IBD (Crohn's disease (CD) and ulcerative colitis (UC)) and psoriasis, suggesting that perturbation of the IL-23 signaling pathway is relevant to the pathophysiology of these diseases. One particular variant, R381Q (rs11209026), confers strong protection against development of CD. We investigated the effects of this variant in primary T cells from healthy donors carrying IL23RR381 and IL23RQ381 haplotypes. Using a proprietary anti-IL23R antibody, ELISA, flow cytometry, phosphoflow and real-time RT-PCR methods, we examined IL23R expression and STAT3 phosphorylation and activation in response to IL-23. IL23RQ381 was associated with reduced STAT3 phosphorylation upon stimulation with IL-23 and decreased number of IL-23 responsive T-cells. We also observed slightly reduced levels of proinflammatory cytokine secretion in IL23RQ381 positive donors. Our study shows conclusively that IL23RQ381 is a loss-of-function allele, further strengthening the implication from GWAS results that the IL-23 pathway is pathogenic in human disease. This data provides an explanation for the protective role of R381Q in CD and may lead to the development of improved therapeutics for autoimmune disorders like CD
Identification of GSK3186899/DDD853651 as a Preclinical Development Candidate for the Treatment of Visceral Leishmaniasis
The leishmaniases are diseases that
affect millions of people across
the world, in particular visceral leishmaniasis (VL) which is fatal
unless treated. Current standard of care for VL suffers from multiple
issues and there is a limited pipeline of new candidate drugs. As
such, there is a clear unmet medical need to identify new treatments.
This paper describes the optimization of a phenotypic hit against Leishmania donovani, the major causative organism
of VL. The key challenges were to balance solubility and metabolic
stability while maintaining potency. Herein, strategies to address
these shortcomings and enhance efficacy are discussed, culminating
in the discovery of preclinical development candidate GSK3186899/DDD853651
(<b>1</b>) for VL
Proving the Effectiveness of the Fundamentals of Robotic Surgery (FRS) Skills Curriculum: A Single-blinded, Multispecialty, Multi-institutional Randomized Control Trial
Objective:
To demonstrate the noninferiority of the fundamentals of robotic surgery (FRS) skills curriculum over current training paradigms and identify an ideal training platform.
Summary Background Data:
There is currently no validated, uniformly accepted curriculum for training in robotic surgery skills.
Methods:
Single-blinded parallel-group randomized trial at 12 international American College of Surgeons (ACS) Accredited Education Institutes (AEI). Thirty-three robotic surgery experts and 123 inexperienced surgical trainees were enrolled between April 2015 and November 2016. Benchmarks (proficiency levels) on the 7 FRS Dome tasks were established based on expert performance. Participants were then randomly assigned to 4 training groups: Dome (n = 29), dV-Trainer (n = 30), and DVSS (n = 32) that trained to benchmarks and control (n = 32) that trained using locally available robotic skills curricula. The primary outcome was participant performance after training based on task errors and duration on 5 basic robotic tasks (knot tying, continuous suturing, cutting, dissection, and vessel coagulation) using an avian tissue model (transfer-test). Secondary outcomes included cognitive test scores, GEARS ratings, and robot familiarity checklist scores.
Results:
All groups demonstrated significant performance improvement after skills training (P < 0.01). Participating residents and fellows performed tasks faster (DOME and DVSS groups) and with fewer errors than controls (DOME group; P < 0.01). Inter-rater reliability was high for the checklist scores (0.82–0.97) but moderate for GEARS ratings (0.40–0.67).
Conclusions:
We provide evidence of effectiveness for the FRS curriculum by demonstrating better performance of those trained following FRS compared with controls on a transfer test. We therefore argue for its implementation across training programs before surgeons apply these skills clinically
Chronic pancreatitis: Pediatric and adult cohorts show similarities in disease progress despite different risk factors
Objectives:
To investigate the natural history of chronic pancreatitis (CP), patients in the North American Pancreatitis Study2 (NAPS2, adults) and INternational Study group of Pediatric Pancreatitis: In search for a cuRE (INSPPIRE, pediatric) were compared.
Methods:
Demographics, risk factors, disease duration, management and outcomes of 224 children and 1,063 adults were compared using appropriate statistical tests for categorical and continuous variables.
Results:
Alcohol was a risk in 53% of adults and 1% of children (p<0.0001); tobacco in 50% of adults and 7% of children (p<0.0001). Obstructive factors were more common in children (29% vs 19% in adults, p=0.001). Genetic risk factors were found more often in children. Exocrine pancreatic insufficiency was similar (children 26% vs adult 33%, p=0.107). Diabetes was more common in adults than children (36% vs 4% respectively, p<0.0001). Median emergency room visits, hospitalizations, and missed days of work/school were similar across the cohorts. As a secondary analysis, NAPS2 subjects with childhood onset (NAPS2-CO) were compared to INSPPIRE subjects. These two cohorts were more similar than the total INSPPIRE and NAPS2 cohorts, including for genetic risk factors. The only risk factor significantly more common in the NAPS2-CO cohort compared with the INSPPIRE cohort was alcohol (9% NAPS2-CO vs 1% INSPPIRE cohorts, p=0.011).
Conclusions:
Despite disparity in age of onset, children and adults with CP exhibit similarity in demographics, CP treatment, and pain. Differences between groups in radiographic findings and diabetes prevalence may be related to differences in risk factors associated with disease and length of time of CP
Differences in Age at Onset of Symptoms, and Effects of Genetic Variants, in Patients With Early- vs Late-Onset Idiopathic Chronic Pancreatitis in a North American Cohort
Background & Aims
Idiopathic chronic pancreatitis (ICP) is the second most common subtype of CP. In 1994, researchers reported the bimodal age at onset of ICP symptoms: early-onset ICP (EO-ICP; median age, 19.2 years) and late-onset ICP (LO-ICP; median age, 56.2 years). Ages of onset and clinical features of ICP differed from those of alcohol-related CP (ACP). However, variants in PRSS1 had not yet been associated with ICP. We reexamined ages of onset of ICP in a large, North American cohort of patients, and investigated the effects of genetic factors and alcohol use in patients with EO-ICP, LO-ICP, or ACP.
Methods
We performed a cross-sectional analysis of patients with CP of European ancestry enrolled in the North American Pancreatitis Study 2 studies, a prospective study of 1195 patients with CP from 26 centers in the United States from August 2000 through December 2014. We compared age at onset of symptoms for 130 patients with CP who were lifetime abstainers from alcohol (61 patients with early onset and 69 patients with late onset), 308 light to moderate alcohol drinkers with CP, and 225 patients with ACP and heavy to very heavy alcohol use. DNA from available patients was analyzed for variants associated with CP in SPINK1, CFTR, and CTRC. The Kruskal-Wallis test was used to compare continuous variables across groups and based on genetic variants.
Results
Median ages at onset of symptoms were 20 years for patients with EO-ICP and no alcohol use, 58 years for patients with LO-ICP and no alcohol use, 47 years for light to moderate alcohol drinkers with CP, and 44 years for patients with ACP. A higher proportion of patients with EO-ICP had constant pain (65%) than patients with LO-ICP (31%) (P=.04). A higher proportion of patients with ACP had pseudocysts (43%) than patients with EO-ICP (11%) (P=.001). A higher proportion of patients with EO-ICP had pathogenic variants in SPINK1, CFTR, or CTRC (49%) than patients with LO-ICP (23%), light to moderate alcohol drinking with CP (26%), or ACP (23%) (P=.001). Among patients with variants in SPINK1, those with EO-ICP had onset of symptoms at a median age of 12 years, and light to moderate alcohol drinkers with CP had an age at onset of 24 years. Among patients with variants in CFTR, light to moderate alcohol drinkers had an age at onset of symptoms of 41 years, but this variant did not affect age at onset of EO-ICP or ACP.
Conclusions
We confirmed previously reported ages at onset of symptoms for EO-ICP and LO-ICP in a North American cohort. We found differences in clinical features among patients with EO-ICP, LO-ICP, and ACP. Almost half of patients with EO-ICP have genetic variants associated with CP, compared to about one-quarter of patients with LO-CP or ACP. Genetic variants affect ages at onset of symptoms in some groups
Epigenetic Regulation of Learning and Memory by Drosophila EHMT/G9a
Behavioral phenotyping and genome-wide profiling of the histone modifier EHMT in Drosophila reveals a mechanism through which an epigenetic writer may control cognition
- …