tbuckley/cabot-search huggingface dataset:
Atrio-Esophageal Fistula as a Complication of Percutaneous Transcatheter Ablation of Atrial Fibrillation
Authors: Carlo Pappone, Hakan Oral, Vincenzo Santinelli, Gabriele Vicedomini, Christopher C. Lang, Francesco Manguso, Lucia Torracca, Stefano Benussi, Ottavio Alfieri, Robert Hong, William Lau, Kirk Hirata, Neil Shikuma, Burr Hall, Fred Morady
Journal: Circulation (2004)

Radiofrequency ablation for atrial fibrillation is becoming widely practiced.Two patients undergoing circumferential pulmonary vein ablation for atrial fibrillation in different centers developed symptoms compatible with endocarditis 3 to 5 days after the procedure. Their clinical condition deteriorated rapidly, and both suffered multiple gaseous and/or septic embolic events causing cerebral and myocardial damage. One patient survived after emergency cardiac and esophageal surgery; the other died of extensive systemic embolization. An atrio-esophageal fistula was identified in both patients.Atrio-esophageal fistulas can occur after catheter ablation in the posterior wall of the left atrium. This diagnosis should be excluded in any patient with symptoms or signs of endocarditis after left atrial ablation, and expeditious cardiac surgery is critical if the diagnosis is confirmed. Lower power and temperature settings for applications of radiofrequency energy along the posterior left atrial wall may prevent further cases of fistula formation.
Comparison of a Whole-Blood Interferon γ Assay With Tuberculin Skin Testing for Detecting Latent &lt;EMPH TYPE="ITAL"&gt;Mycobacterium tuberculosis&lt;/EMPH&gt; Infection
Authors: Gerald H. Mazurek
Journal: JAMA (2001)

ContextIdentifying persons with latent tuberculosis infection (LTBI) is crucial to the goal of TB elimination. A whole-blood interferon γ (IFN-γ) assay, the QuantiFERON-TB test, is a promising in vitro diagnostic test for LTBI that has potential advantages over the tuberculin skin test (TST).ObjectivesTo compare the IFN-γ assay with the TST and to identify factors associated with discordance between the tests.Design and SettingProspective comparison study conducted at 5 university-affiliated sites in the United States between March 1, 1998 and June 30, 1999.ParticipantsA total of 1226 adults (mean age, 39 years) with varying risks of Mycobacterium tuberculosis infection or documented or suspected active TB, all of whom underwent both the IFN-γ assay and the TST.Main Outcome MeasureLevel of agreement between the IFN-γ assay and the TST.ResultsThree hundred ninety participants (31.8%) had a positive TST result and 349 (28.5%) had a positive IFN-γ assay result. Overall agreement between the IFN-γ assay and the TST was 83.1% (κ = 0.60). Multivariate analysis revealed that the odds of having a positive TST result but negative IFN-γ assay result were 7 times higher for BCG-vaccinated persons compared with unvaccinated persons. The IFN-γ assay provided evidence that among unvaccinated persons with a positive TST result but negative IFN-γ assay result, 21.2% were responding to mycobacteria other than M tuberculosis.ConclusionsFor all study participants, as well as for those being screened for LTBI, the IFN-γ assay was comparable with the TST in its ability to detect LTBI, was less affected by BCG vaccination, discriminated responses due to nontuberculous mycobacteria, and avoided variability and subjectivity associated with placing and reading the TST.
Phase IIB Trial of Oral Midostaurin (PKC412), the FMS-Like Tyrosine Kinase 3 Receptor (FLT3) and Multi-Targeted Kinase Inhibitor, in Patients With Acute Myeloid Leukemia and High-Risk Myelodysplastic Syndrome With Either Wild-Type or Mutated FLT3
Authors: Thomas Fischer, Richard M. Stone, Daniel J. DeAngelo, Ilene Galinsky, Elihu Estey, Carlo Lanza, Edward Fox, Gerhard Ehninger, Eric J. Feldman, Gary J. Schiller, Virginia M. Klimek, Stephen D. Nimer, D. Gary Gilliland, Catherine Dutreix, Alice Huntsman-Labed, Jodi Virkus, Francis J. Giles
Journal: Journal of Clinical Oncology (2010)

Mutations leading to constitutive activation of the FMS-like tyrosine kinase 3 receptor (FLT3) occur in blasts of 30% of patients with acute myeloid leukemia (AML). Midostaurin (PKC412; N-benzoylstaurosporin) is a multitargeted tyrosine kinase inhibitor, with demonstrated activity in patients with AML/myelodysplastic syndrome (MDS) with FLT3 mutations.Ninety-five patients with AML or MDS with either wild-type (n = 60) or mutated (n = 35) FLT3 were randomly assigned to receive oral midostaurin at 50 or 100 mg twice daily. The drug was discontinued in the absence of response at 2 months, disease progression, or unacceptable toxicity. Response was defined as complete response, partial response (PR), hematologic improvement, or reduction in peripheral blood or bone marrow blasts by ≥ 50% (BR).The rate of BR for the population in whom efficacy could be assessed (n = 92) was 71% in patients with FLT3-mutant and 42% in patients with FLT3 wild-type. One PR occurred in a patient with FLT3-mutant receiving the 100-mg dose regimen. Both doses were well-tolerated; there were no differences in toxicity or response rate according to the dose of midostaurin.These results suggest that midostaurin has hematologic activity in both patients with FLT3-mutant and wild-type. The degree of clinical activity observed supports additional studies that combine midostaurin and other agents such as chemotherapy especially in FLT3-mutant AML.
RNAi-mediated knock-down of Dab and Numb attenuate Aβ levels via γ-secretase mediated APP processing
Authors: Zhongcong Xie, Yuanlin Dong, Uta Maeda, Weiming Xia, Rudolph E Tanzi
Journal: Translational Neurodegeneration (2012)

Amyloid-β-protein (Aβ), the key component of senile plaques in Alzheimer's disease (AD) brain, is produced from amyloid precursor protein (APP) by cleavage of β-secretase and then γ-secretase. APP adaptor proteins with phosphotyrosine-binding (PTB) domains, including Dab (gene: DAB) and Numb (gene: NUMB), can bind to and interact with the conserved YENPTY-motif in the APP C-terminus. Here we describe, for the first time, the effects of RNAi knock-down of Dab and Numb expression on APP processing and Aβ production. RNAi knock-down of Dab and Numb in H4 human neuroglioma cells stably transfected to express either FL-APP (H4-FL-APP cells) or APP-C99 (H4-APP-C99 cells) increased levels of APP-C-terminal fragments (APP-CTFs) and lowered Aβ levels in both cell lines by inhibiting γ-secretase cleavage of APP. Finally, RNAi knock-down of APP also reduced levels of Numb in H4-APP cells. These findings suggest that pharmacologically blocking interaction of APP with Dab and Numb may provide novel therapeutic strategies of AD. The notion of attenuating γ-secretase cleavage of APP via the APP adaptor proteins, Dab and Numb, is particularly attractive with regard to therapeutic potential, given that side effects of γ-secretase inhibition owing to impaired proteolysis of other γ-secretase substrates, e.g. Notch, might be avoided.
Heart Rate–Corrected QT Interval Is an Independent Predictor of All-Cause and Cardiovascular Mortality in Individuals With Type 2 Diabetes: The Diabetes Heart Study
Authors: Amanda J. Cox, Amir Azeem, Joseph Yeboah, Elsayed Z. Soliman, Shivani R. Aggarwal, Alain G. Bertoni, J. Jeffrey Carr, Barry I. Freedman, David M. Herrington, Donald W. Bowden
Journal: Diabetes Care (2014)

Heart rate-corrected QT (QTc) interval is associated with mortality in the general population, but this association is less clear in individuals with type 2 diabetes. We assessed the association of QTc interval with all-cause and cardiovascular disease (CVD) mortality in the Diabetes Heart Study.We studied 1,020 participants with type 2 diabetes (83% European Americans; 55% women; mean age 61.4 years) who were free of atrial fibrillation, major ventricular conduction defects, and antiarrhythmic therapy at baseline. QT duration was automatically calculated from a standard 12-lead electrocardiogram (ECG). Following American Heart Association/American College of Cardiology Foundation recommendations, a linear scale was used to correct the QT for heart rate. Using Cox regression, risk was estimated per 1-SD increase in QTc interval as well as prolonged QTc interval (>450 ms) vs. normal QTc interval for mortality.At baseline, the mean (SD) QTc duration was 414.9 ms (18.1), and 3.0% of participants had prolonged QTc. After a median follow-up time of 8.5 years (maximum follow-up time 13.9 years), 204 participants were deceased. In adjusted multivariate models, a 1-SD increase in QTc interval was associated with an 18% higher risk for all-cause mortality (hazard ratio 1.18 [95% CI 1.03-1.36]) and 29% increased risk for CVD mortality (1.29 [1.05-1.59]). Similar results were obtained when QTc interval was used as a categorical variable (prolonged vs. normal) (all-cause mortality 1.73 [0.95-3.15]; CVD mortality 2.86 [1.35-6.08]).Heart rate QTc interval is an independent predictor of all-cause and CVD mortality in this population with type 2 diabetes, suggesting that additional prognostic information may be available from this simple ECG measure.
A172: Metaphyseal Chondrodysplasia, Ectodermal Dysplasia, Short Stature, Hypergammaglobulinemia, and Spontaneous Inflammation Without Infections in an Extended Family Due to Mutation in NFKB1A
Authors: Edward J. Oberle, James W. Verbsky, John Routes, Mary Hintermeyer, Elizabeth Worthey, Trivikram Dasu, Christine Bengtson, Alyssa Buzzell
Journal: Arthritis & Rheumatology (2014)

Background/Purpose:

Autoinflammatory disorders are characterized by chronic inflammation and a variety of systemic complaints. Defects in the NF-kB essential modifier pathway, or NEMO, are associated with an immune deficiency characterized by ectodermal dysplasia. We investigated an extended family with features of both chronic inflammation and NEMO following an autosomal dominant inheritance.



Methods:

Eight individuals from one family were evaluated. The proband, a male patient age 12 with known hypohydrosis, presented to our rheumatology clinic for chronic articular pain with bony hypertrophy of wrists, knees, and ankles. Plain radiographs and standard labs were obtained including ESR, CRP, CBC, and immunoglobulins for all affected individuals. Films were reviewed by two musculoskeletal radiologists. The proband underwent a proximal tibial bone biopsy, as well as genetic testing for known autoinflammatory disorders and mutations in NF-kB pathway. The Tolllike Receptor (TLR) assay was used to evaluate NF-kB function.



Results:

The proband, his father age 30, two brothers age 7 and 9, and his 2-year-old sister were all found to have ectodermal dysplasia, short stature and failure to thrive, chronic inflammation, elevated WBC, and hypergammaglobulinemia (Figure 1). Radiographs of proband displayed sclerotic lesions of the metaphyses of distal radius/ulna, distal femora, and proximal and distal tibia/fibula (Figure 2). The patient's father was evaluated as a child for bone issues, and radiographs demonstrate widened metaphyses of distal ulna and tibia. Bone biopsy of the proband was consistent with metaphyseal chondrodysplasia. Genetic testing for known autoinflammatory disorders was negative while testing of the NFKB1A gene demonstrated a heterozygous mutation (W11X). TLR responses were normal in two affected individuals indicating intact NF-kB signaling. No infections were noted in the family. 




Figure 1. Family pedigree.

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Figure 2. Proband radiographs.

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Conclusion:

This series demonstrates the clinical variability that can occur due to mutations in NFKB1A. Infections were not prevalent in this family, but spontaneous inflammation was common. In addition, this is the first report of metaphyseal chondrodysplasia as a complication of NEMO or related disorders.
Development of Autoantibodies in the TrialNet Natural History Study
Authors: Kendra Vehik, Craig A. Beam, Jeffrey L. Mahon, Desmond A. Schatz, Michael J. Haller, Jay M. Sosenko, Jay S. Skyler, Jeffrey P. Krischer
Journal: Diabetes Care (2011)

OBJECTIVE Understanding the relationship between age and islet autoantibody (Ab) seroconversion can establish the optimal screening interval(s) to assess risk for type 1 diabetes, identify subjects who can participate in prevention trials, and determine associated costs. This study assessed the rates of seroconversion to glutamic acid decarboxylase positive (GAD65+), insulin positive (mIAA+), and insulinoma-associated protein 2 positive (ICA512+) in a large cohort of relatives of type 1 diabetes probands undergoing Ab rescreening in the TrialNet Natural History Study. RESEARCH DESIGN AND METHODS Of 32,845 children aged &amp;lt;18 years screened for Abs, 1,287 (3.9%) were GAD65+, 778 (2.4%) were mIAA+, 677 (2.1%) were ICA512+, and 31,038 were Ab-negative. Ab-negative children were offered annual rescreening up to 18 years of age. Cox regression was used to estimate the risk for GAD65, mIAA, and ICA512 seroconversion. RESULTS There were 205 children who seroconverted to GAD65+, 155 who seroconverted to mIAA+, and 53 who seroconverted to ICA512+ over 5.8 years of follow-up. The risk of mIAA (hazard ratio 0.89 [95% CI 0.85–0.92]) and GAD65 (0.96 [0.93–0.99]) seroconversion significantly decreased with increasing age (i.e., for each 1-year increase in age, the risk of seroconversion decreased by 11% [P &amp;lt; 0.0001] for mIAA and 4% [P = 0.04] for GAD65) across all ages. The cumulative Ab seroconversion was 2% for those &amp;lt;10 years of age versus 0.7% for those ≥10 years of age. CONCLUSIONS The risk of development of islet Abs declines with increasing age in type 1 diabetes relatives. These data support annual screening for children &amp;lt;10 years of age and one additional screening in adolescence.
Analysis of transforming growth factor beta1 gene polymorphisms in patients with systemic sclerosis
Authors: A Crilly
Journal: Annals of the Rheumatic Diseases (2002)

To determine the distribution of transforming growth factor beta1 (TGFbeta1) genotypes at codon 10 (+869 polymorphism) and codon 25 (+915 polymorphism) in patients with scleroderma (SSc). Differences between diffuse and limited SSc (dSSc and lSSc) were also investigated.Patients with lSSc (n=89) and dSSc (n=63) were compared with 147 controls. DNA was isolated from peripheral blood and polymorphisms at codons 10 (C/T) and 25 (G/C) of the TGFbeta1 gene analysed by polymerase chain reaction and sequence specific oligonucleotide probing.Significantly more patients with SSc than controls carried allele C at codon 10 (controls v SSc, 38% v 48%, chi(2)=8.2, 1df, p=0.004), OR=1.95 (95% CI 1.16 to 3.27). The difference remained when patients with SSc were split into those with limited or diffuse disease, (controls v dSSc, chi(2)=5, 1df, p=0.02 and controls v lSSc, chi(2)=6, 1df, p=0.013). The patients with SSc had significantly more subjects heterozygous at codon 10 (controls v SSc, chi(2)=45, 1df, p<0.0001). Possession of allele C at codon 10 gave an OR=4.8 (95% CI 2.8 to 8.4). No difference in allele frequency was seen between patients with SSc and controls at codon 25. More patients with SSc than controls carried the GG genotype (controls v SSc, 80% v 88%, chi(2)=7, 2df, p=0.027). Possession of allele G gave an OR=1.7 (95% CI 0.5 to 5.9). There was no difference between diffuse and limited disease at either codon.These results suggest that patients with SSc are genetically predisposed to high TGFbeta1 production. These polymorphisms do not, however, explain the difference in the clinical phenotypes of limited and diffuse SSc.
Genetic variants of hemophilia B: detection by means of a specific PTC inhibitor
Authors: Harold R. Roberts, James E. Grizzle, William D. McLester, George D. Penick
Journal: Journal of Clinical Investigation (1968)

Hemophilia B can be divided into at least two mutant forms different from the mild, moderate, and severe categories previously described. In about 90% of hemophilia B patients, PTC-inhibitor-neutralizing activity is reduced in proportion to PTC clotting activity. In about 10% of the patients, PTC-inhibitor-neutralizing activity is fully effective, whereas PTC clotting activity is reduced. Extensive pedigree studies indicate that the presence or absence of inhibitor-neutralizing activity is genetically determined. It is suggested that those hemophilia B mutants with decreased inhibitor-neutralizing material produce decreased amounts of PTC-protein. It is further suggested that those with normal levels of inhibitor-neutralizing material produce normal amounts of PTC-protein, which is structurally altered so as to lose procoagulant activity but which retains inhibitor-neutralizing activity. The latter group may be analogous to CRM+ mutants described in bacteria and Neurospora.
International Union of Basic and Clinical Pharmacology. XCVI. Pattern Recognition Receptors in Health and Disease
Authors: Clare E. Bryant, Selinda Orr, Brian Ferguson, Martyn F. Symmons, Joseph P. Boyle, Tom P. Monie
Journal: Pharmacological Reviews (2015)

Since the discovery of Toll, in the fruit fly <i>Drosophila melanogaster</i>, as the first described pattern recognition receptor (PRR) in 1996, many families of these receptors have been discovered and characterized. PRRs play critically important roles in pathogen recognition to initiate innate immune responses that ultimately link to the generation of adaptive immunity. Activation of PRRs leads to the induction of immune and inflammatory genes, including proinflammatory cytokines and chemokines. It is increasingly clear that many PRRs are linked to a range of inflammatory, infectious, immune, and chronic degenerative diseases. Several drugs to modulate PRR activity are already in clinical trials and many more are likely to appear in the near future. Here, we review the different families of mammalian PRRs, the ligands they recognize, the mechanisms of activation, their role in disease, and the potential of targeting these proteins to develop the anti-inflammatory therapeutics of the future.
Brain Stimulation for Torsion Dystonia
Authors: Michael D. Fox, Ron L. Alterman
Journal: JAMA Neurology (2015)

<h3>Importance</h3> Dystonia is a heterogeneous neurologic disorder characterized by abnormal muscle contractions for which standard medical therapy is often inadequate. For such patients, therapeutic brain stimulation is becoming increasingly used. <h3>Objectives</h3> To review the evidence and effect sizes for treating different types of dystonia with different types of brain stimulation and to discuss recent advances relevant to patient selection, surgical approach, programming, and mechanism of action. <h3>Evidence Review</h3> PubMed was searched for publications on the clinical effect of brain stimulation in dystonia up through December 31, 2014. Recent meta-analyses, consensus statements, and evidence-based guidelines were incorporated. Emphasis was placed on deep brain stimulation (DBS) and randomized clinical trials; however, other stimulation modalities and trial designs were included. For each intervention the mean change in dystonia severity, number of patients studied, and evidence of efficacy based on American Academy of Neurology criteria were determined. <h3>Findings</h3> Strong (level B) evidence supports the use of DBS for the treatment of primary generalized or segmental dystonia, especially when due to mutation in the<i>DYT1</i>gene, as well as for patients with cervical dystonia. Large effect sizes have also been reported for DBS treatment of tardive dystonia, writer's cramp, cranial dystonia, myoclonus dystonia, and off-state dystonia associated with Parkinson disease. Lesser benefit is generally seen in dystonia secondary to structural brain damage. Other brain stimulation techniques, including epidural cortical stimulation and noninvasive brain stimulation, have been investigated, but generally report smaller effect sizes in fewer patients. <h3>Conclusions and Relevance</h3> Patients with dystonia that is not adequately controlled with standard medical therapy should be referred for consideration of DBS, especially patients with generalized, segmental, or cervical dystonia. Other less-invasive stimulation modalities require further research before being considered a therapeutic alternative.
Genome-Wide Association Study of Clinical Dimensions of Schizophrenia: Polygenic Effect on Disorganized Symptoms
Authors: Ayman H. Fanous, Baiyu Zhou, Steven H. Aggen, Sarah E. Bergen, Richard L. Amdur, Jubao Duan, Alan R. Sanders, Jianxin Shi, Bryan J. Mowry, Ann Olincy, Farooq Amin, C. Robert Cloninger, Jeremy M. Silverman, Nancy G. Buccola, William F. Byerley, Donald W. Black, Robert Freedman, Frank Dudbridge, Peter A. Holmans, Stephan Ripke, Pablo V. Gejman, Kenneth S. Kendler, Douglas F. Levinson
Journal: American Journal of Psychiatry (2012)

Multiple sources of evidence suggest that genetic factors influence variation in clinical features of schizophrenia. The authors present the first genome-wide association study (GWAS) of dimensional symptom scores among individuals with schizophrenia. Based on the Lifetime Dimensions of Psychosis Scale ratings of 2,454 case subjects of European ancestry from the Molecular Genetics of Schizophrenia (MGS) sample, three symptom factors (positive, negative/disorganized, and mood) were identified with exploratory factor analysis. Quantitative scores for each factor from a confirmatory factor analysis were analyzed for association with 696,491 single-nucleotide polymorphisms (SNPs) using linear regression, with correction for age, sex, clinical site, and ancestry. Polygenic score analysis was carried out to determine whether case and comparison subjects in 16 Psychiatric GWAS Consortium (PGC) schizophrenia samples (excluding MGS samples) differed in scores computed by weighting their genotypes by MGS association test results for each symptom factor. No genome-wide significant associations were observed between SNPs and factor scores. Most of the SNPs producing the strongest evidence for association were in or near genes involved in neurodevelopment, neuroprotection, or neurotransmission, including genes playing a role in Mendelian CNS diseases, but no statistically significant effect was observed for any defined gene pathway. Finally, polygenic scores based on MGS GWAS results for the negative/disorganized factor were significantly different between case and comparison subjects in the PGC data set; for MGS subjects, negative/disorganized factor scores were correlated with polygenic scores generated using case-control GWAS results from the other PGC samples. The polygenic signal that has been observed in cross-sample analyses of schizophrenia GWAS data sets could be in part related to genetic effects on negative and disorganized symptoms (i.e., core features of chronic schizophrenia).