tbuckley/cabot-search huggingface dataset:
A urate gene-by-diuretic interaction and gout risk in participants with hypertension: results from the ARIC study
Authors: Mara A McAdams-DeMarco, Janet W Maynard, Alan N Baer, Linda W Kao, Anna Kottgen, Josef Coresh
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Objective</h3> To test for a urate gene-by-diuretic interaction on incident gout. <h3>Methods</h3> The Atherosclerosis Risk in Communities Study is a prospective population-based cohort of 15 792 participants recruited from four US communities (1987–1989). Participants with hypertension and available single nucleotide polymorphism (SNP) genotype data were included. A genetic urate score (GUS) was created from common urate-associated SNPs for eight genes. Gout incidence was self-reported. Using logistic regression, the authors estimated the adjusted OR of incident gout by diuretic use, stratified by GUS median. <h3>Results</h3> Of 3524 participants with hypertension, 33% used a diuretic and 3.1% developed gout. The highest 9-year cumulative incidence of gout was in those with GUS above the median and taking a thiazide or loop diuretic (6.3%). Compared with no thiazide or loop diuretic use, their use was associated with an OR of 0.40 (95% CI 0.14 to 1.15) among those with a GUS below the median and 2.13 (95% CI 1.23 to 3.67) for those with GUS above the median; interaction p=0.006. When investigating the genes separately, SLC22A11 and SLC2A9 showed a significant interaction, consistent with the former encoding an organic anion/dicarboxylate exchanger, which mediates diuretic transport in the kidney. <h3>Conclusions</h3> Participants who were genetically predisposed to hyperuricaemia were susceptible to developing gout when taking thiazide or loop diuretics, an effect not evident among those without a genetic predisposition. These findings argue for a potential benefit of genotyping individuals with hypertension to assess gout risk, relative in part to diuretic use.
Phase I Trial of the Cyclin-Dependent Kinase Inhibitor and Protein Kinase C Inhibitor 7-Hydroxystaurosporine in Combination With Fluorouracil in Patients With Advanced Solid Tumors
Authors: Jeremy Kortmansky, Manish A. Shah, Andreas Kaubisch, Amanda Weyerbacher, Sandy Yi, William Tong, Rebecca Sowers, Mithat Gonen, Eileen O'Reilly, Nancy Kemeny, David I. Ilson, Leonard B. Saltz, Robert G. Maki, David P. Kelsen, Gary K. Schwartz
Journal: Journal of Clinical Oncology (2005)

Purpose Preclinical studies indicate that the cyclin-dependent kinase and protein kinase C inhibitor 7-hydroxystaurosporine (UCN-01) potentiates the cytotoxic effects of fluorouracil (FU). We designed a phase I clinical trial of FU in combination with UCN-01. Patients and Methods FU was administered as a weekly 24-hour infusion. Doses were escalated in successive cohorts according to a modified Fibonacci design. UCN-01 was administered once every 4 weeks, immediately after disconnection from FU, at a dose of 135 mg/m 2 over 72 hours in cycle 1 and 67.5 mg/m 2 over 36 hours in subsequent cycles. FU and UCN-01 pharmacokinetics were obtained on all patients, and thymidylate synthetase (TS) activity was measured in peripheral-blood mononuclear cells by reverse-transcriptase polymerase chain reaction. Results We escalated the weekly FU dose to 2,600 mg/m 2 in combination with once a month infusions of UCN-01. Dose-limiting toxicity included arrhythmia and syncope. Other toxicities included hyperglycemia, headache, and nausea and vomiting. The mean maximal plasma concentration of UCN-01 was 33.5 μmol/L. There was significant interpatient variability, which correlated with plasma concentrations of alpha-1 acid glycoprotein. FU was rapidly cleared and the dose had no effect on the area under the curve of UCN-01. Changes in TS expression were detectable in peripheral-blood mononuclear cells after administration of UCN-01 but did not correlate with toxicity or activity. We observed no objective response, although seven patients had stable disease, six of whom had received prior fluoropyrimidines. Conclusion The combination of weekly infusions of FU and monthly UCN-01 can be administered safely and warrants further study in phase II trials. The recommended phase II dose of FU in combination with monthly UCN-01 is 2,600 mg/m 2 .
Human invariant natural killer T cells acquire transient innate responsiveness via histone H4 acetylation induced by weak TCR stimulation
Authors: Xiaohua Wang, Kathleen A. Bishop, Subramanya Hegde, Lance A. Rodenkirch, J. Wesley Pike, Jenny E. Gumperz
Journal: The Journal of Experimental Medicine (2012)

Invariant NKT cells (iNKT cells) are innate T lymphocytes that are thought to play an important role in producing an early burst of IFN-γ that promotes successful tumor immunosurveillance and antimicrobial immunity. The cellular activation processes underlying innate IFN-γ production remain poorly understood. We show here that weak T cell receptor (TCR) stimulation that does not directly activate iNKT cell IFN-γ messenger RNA transcription nevertheless induces histone H4 acetylation at specific regions near the IFNG gene locus. This renders the iNKT cells able to produce IFN-γ in an innate manner (i.e., not requiring concurrent TCR stimulation) upon exposure to IL-12 and IL-18. The iNKT cells retain the capacity for innate activation for hours to days after the initial weak TCR stimulation, although their innate responsiveness gradually declines as a function of histone deacetylation. These results explain how iNKT cells are able to mediate rapid innate IFN-γ secretion in a manner that does not require them to undergo permanent TH1 differentiation. Moreover, our results also indicate that iNKT cell motility is maintained during activation by IL-12 and IL-18. Therefore, iNKT cells activated through this pathway can continue to migrate and may thus disseminate the IFN-γ that they produce, which may amplify its impact.
Pemphigus vulgaris induced by D-penicillamine therapy in a patient with systemic sclerosis
Authors: Michael Shapiro, Sergio Jimenez, Victoria P. Werth
Journal: Journal of the American Academy of Dermatology (2000)

D: -Penicillamine-induced pemphigus occurs infrequently, typically in patients with rheumatoid arthritis. We describe a patient with systemic sclerosis who experienced this complication 3 months after starting D -penicillamine therapy. Nikolsky's sign, histopathologic findings, and direct immunofluorescence all confirmed the diagnosis. Termination of disease progression required intravenous pulse glucocorticoids, azathioprine, and 3 courses of plasmapheresis. The presentation, treatment, and etiology of D -penicillamine-induced pemphigus are reviewed, and the incidence of this complication in scleroderma patients is examined.
Preparation of 125-I-labeled human thyroxine-binding alpha globulin and its turnover in normal and hypothyroid subjects.
Authors: R R Cavalieri, F A McMahon, J N Castle
Journal: Journal of Clinical Investigation (1975)

A protein with the electrophoretic, immunologic, and hormone-binding properties of thyroxine-binding globulin (TBG) has been prepared from human plasma and labeled with radioiodine (125-I) by an enzymatic method of iodination. The [125-I]TBG retained the electrophoretic and immunologic characteristics of unlabeled TBG but exhibited a partial loss of thyroxine-binding activity, as assessed by affinity chromatography. The in vivo behavior of [125I]TBG was studied in six euthyroid subjects (controls) with normal serum levels of TBG as measured both by radioimmunoassay and by determination of maximal T4-binding capacity and in four male patients with untreated primary hyperthyroidism, three of whom had elevated serum TBG. The half-time of the final slope of the plasma disappearance curve averaged 5.0 days plus or minus 1.2 (SD) in the controls and ranged from 3.9 to 109 days in the hypothyroid patients. The distribution volume was similar in the two groups, 6.7 plus or minus 1.3 vs. 7.1 plus or minus 2.1 liters. The catabolic clearance rate averaged 0.99 plus or minus 0.33 liters plasma/24 h in the controls and 0.92 plus or minus 0.46 in the hypothyroids. The absolute turnover rate of TBG, calculated from the catabolic clearance rate multiplied by the serum concentration of radioimmunoassayable TBG, averaged 17.8 plus or minus 2.1 mg/day in the controls and ranged from 14.8 to 33.2 mg/day in the hypothyroids. Among the entire group of subjects there was no correlation between the serum TBG concentration and the absolute turnover rate of TBG.
Mouse Model of X-Linked Alport Syndrome
Authors: Michelle N. Rheault, Stefan M. Kren, Beth K. Thielen, Hector A. Mesa, John T. Crosson, William Thomas, Yoshikazu Sado, Clifford E. Kashtan, Yoav Segal
Journal: Journal of the American Society of Nephrology (2004)

ABSTRACT. X-linked Alport syndrome (XLAS) is a progressive disorder of basement membranes caused by mutations in the <i>COL4A5</i> gene, encoding the α5 chain of type IV collagen. A mouse model of this disorder was generated by targeting a human nonsense mutation, G5X, to the mouse <i>Col4a5</i> gene. As predicted for a nonsense mutation, hemizygous mutant male mice are null and heterozygous carrier female mice are mosaic for α5(IV) chain expression. Mutant male mice and carrier female mice are viable through reproductive age and fertile. Mutant male mice died spontaneously at 6 to 34 wk of age, and carrier female mice died at 8 to 45 wk of age, manifesting proteinuria, azotemia, and progressive and manifold histologic abnormalities of the kidney glomerulus and tubulointerstitium. Ultrastructural abnormalities of the glomerular basement membrane, including lamellation and splitting, were characteristic of human XLAS. The mouse model described here recapitulates essential clinical and pathologic findings of human XLAS. With α5(IV) expression reflecting X-inactivation patterns, it will be especially useful in studying determinants of disease variability in the carrier state.
A role for elevated H-2 antigen expression in resistance to neoplasia caused by radiation-induced leukemia virus. Enhancement of effective tumor surveillance by killer lymphocytes.
Authors: D Meruelo
Journal: The Journal of Experimental Medicine (1979)

Resistance to neoplasia caused by radiation-induced leukemia virus (RadLV) is mediated by gene(s) in the H-2D region of the major histocompatibility complex. The previous observation that rapid increases in cellular synthesis and cell-surface expression of H-2 antigens are detectable immediately after virus inoculation has suggested that altered expression of H-2 antigens may play a significant role in the mechanism(s) of host defense to virus infection. This concept is supported by the following observations. First, cell-mediated immunity against RadLV transformed or infected cells can be detected with ease when H-2-positive target cells are used in the cell-mediated lympholysis (CML) assay. (Although RadLV transformed cells obtained from overtly leukemic animals and maintained in tissue culture are H-2 negative, these cells can regain their H-2 phenotype by in vivo passage in normal animals. The H-2-negative cells are poor targets in a CML assay.) Second, resistant mice develop greater numbers of effectors when infected with RadLV than do susceptible mice. Third, injection of normal (uninfected) thymocytes into syngeneic recipients of resistant or susceptible H-2 type does not stimulate a CML response. However, injection of RadLV infected thymocytes from resistant mice produces a vigorous CMI response, and such thymocytes elicit the strongest response at a time when both H-2 and viral antigen expression is elevated. By contrast, injection of infected thymocytes from susceptible mice, which express viral antigens, but low levels of H-2 antigens, does not stimulate a CML reaction. These findings may explain the easier induction of leukemia found by many investigators when virus is inoculated into neonatal mice and the preferential thymus tropism of some oncogenic type-C RNA virus. Cells expressing very low levels of H-2, such as thymocytes, may serve as permissive targets for virus infection because they lack an important component (H-2 antigens) of the dual or altered recognition signal required to trigger a defensive host immune response.
Presence of lymphocyte aggregates in the synovium of patients with early arthritis in relationship to diagnosis and outcome: is it a constant feature over time?
Authors: Marleen G H van de Sande, Rogier M Thurlings, Maria J H Boumans, Carla A Wijbrandts, Maria Grazia Modesti, Daniëlle M Gerlag, Paul P Tak
Journal: Annals of the Rheumatic Diseases (2010)

Objectives To evaluate the presence of lymphocyte aggregates in synovial tissue of patients with early arthritis in relationship to clinical outcome and to determine whether this is a stable feature over time. Methods Arthroscopic synovial biopsy samples were collected in a prospective cohort of disease-modifying antirheumatic drug-naïve patients with early arthritis (&lt;1 year's disease duration) at baseline (n=93) and, if rheumatoid arthritis was suspected, after 6 months of follow-up (n=17). After 2 years of follow-up, definitive diagnosis and clinical outcome were assessed. Size of synovial lymphocyte aggregates was graded (score 1–3). Lymphoid neogenesis (LN) was defined by the presence of grade ≥2 aggregates and subclassified based on the presence of follicular dendritic cells (FDCs). Results LN was present in 36% of all patients and FDCs in 15% of patients with LN. Presence of lymphocyte aggregates differed over time. LN was associated with the degree of synovial inflammation. There was no relationship between the presence of lymphocyte aggregates at baseline and definitive diagnosis or clinical outcome after follow-up. Conclusions Presence of lymphocyte aggregates is a dynamic phenomenon related to the degree of synovitis and can be detected in different forms of early arthritis. This feature does not appear to be related to clinical outcome.
High Levels of Aberrant DNA Methylation in <i>Helicobacter pylori</i>–Infected Gastric Mucosae and its Possible Association with Gastric Cancer Risk
Authors: Takao Maekita, Kazuyuki Nakazawa, Mami Mihara, Takeshi Nakajima, Kimihiko Yanaoka, Mikitaka Iguchi, Kenji Arii, Atsushi Kaneda, Tetsuya Tsukamoto, Masae Tatematsu, Gen Tamura, Daizo Saito, Takashi Sugimura, Masao Ichinose, Toshikazu Ushijima
Journal: Clinical Cancer Research (2006)

Risk prediction of gastric cancers is important to implement appropriate screening procedures. Although aberrant DNA methylation is deeply involved in gastric carcinogenesis, its induction by Helicobacter pylori, a strong gastric carcinogen, is unclear. Here, we analyzed the effect of H. pylori infection on the quantity of methylated DNA molecules in noncancerous gastric mucosae and examined its association with gastric cancer risk.Gastric mucosae were collected from 154 healthy volunteers (56 H. pylori negative and 98 H. pylori positive) and 72 cases with differentiated-type gastric cancers (29 H. pylori negative and 43 H. pylori positive) by endoscopy. The numbers of DNA molecules methylated and unmethylated for eight regions of seven CpG islands (CGI) were quantified by quantitative PCR after bisulfite modification, and fractions of methylated molecules (methylation levels) were calculated.Among healthy volunteers, methylation levels of all the eight regions were 5.4- to 303-fold higher in H. pylori positives than in H. pylori negatives (P < 0.0001). Methylation levels of the LOX, HAND1, and THBD promoter CGIs and p41ARC exonic CGI were as high as 7.4% or more in H. pylori-positive individuals. Among H. pylori-negative individuals, methylation levels of all the eight regions were 2.2- to 32-fold higher in gastric cancer cases than in age-matched healthy volunteers (P < or = 0.01). Among H. pylori-positive individuals, methylation levels were highly variable, and that of only HAND1 was significantly increased in gastric cancer cases (1.4-fold, P = 0.02).It was indicated that H. pylori infection potently induces methylation of CGIs to various degrees. Methylation levels of specific CGIs seemed to reflect gastric cancer risk in H. pylori-negative individuals.
Postextrasystolic T wave changes in normal canine hearts
Authors: M. S YOON, D. P O'CONNELL, J. HAN
Journal: Cardiovascular Research (1984)

Journal Article Postextrasystolic T wave changes in normal canine hearts Get access MYUNG S YOON, MYUNG S YOON From the Department of Medicine (Cardiology), Albany Medical College of Union University, and the Electrocardiography Laboratory, Albany Medical Center Hospital, Albany, New York. Search for other works by this author on: Oxford Academic PubMed Google Scholar DANIEL P O'CONNELL, DANIEL P O'CONNELL From the Department of Medicine (Cardiology), Albany Medical College of Union University, and the Electrocardiography Laboratory, Albany Medical Center Hospital, Albany, New York. Search for other works by this author on: Oxford Academic PubMed Google Scholar JAOK HAN JAOK HAN * From the Department of Medicine (Cardiology), Albany Medical College of Union University, and the Electrocardiography Laboratory, Albany Medical Center Hospital, Albany, New York. *Address for reprints: Jaok Han, Department of Medicine, Albany Medical College, Albany, New York, 12208 USA. Search for other works by this author on: Oxford Academic PubMed Google Scholar Cardiovascular Research, Volume 18, Issue 11, November 1984, Pages 711–713, https://doi.org/10.1093/cvr/18.11.711 Published: 01 November 1984
A comprehensive target selectivity survey of the BCR-ABL kinase inhibitor INNO-406 by kinase profiling and chemical proteomics in chronic myeloid leukemia cells
Authors: U Rix, L L Remsing Rix, A S Terker, N V Fernbach, O Hantschel, M Planyavsky, F P Breitwieser, H Herrmann, J Colinge, K L Bennett, M Augustin, J H Till, M C Heinrich, P Valent, G Superti-Furga
Journal: Leukemia (2009)
Frontiers of Mutagenesis and DNA Repair
Authors: Mark R. Kelley, Alan E. Tompkinson, Kandace J. Williams, Norman R. Drinkwater, Victor A. Fung
Journal: Cancer Research (2004)

Abstract The Chemical Pathology Study Section, Center for Scientific Review, NIH hosted a 1-day workshop in Ventura, California, in the winter of 2003. There were 32 invited participants including invited speakers. The workshop consisted of three sessions and focused on recent developments in our understanding of the molecular mechanisms of mutagenesis and DNA repair, namely, error-prone DNA polymerases, DNA repair models and DNA repair networks.
Local anaesthesia for venepuncture
Authors: C J Bowley
Journal: Journal of the Royal Society of Medicine (2005)

Examining the potential impact of the proposed two-year cut in otology training, Jaydip Ray and colleagues conclude that intensification of training would be necessary to eradicate the significant difference in specialist surgical experience between current year-four and year-six otology trainees (June 2005 JRSM 1 ).In our opinion their article misses the point regarding the changes.The proposed model of four years' general training followed by two years of specialist training will not require future year-four trainees to have comparable operative experience to today's year-six trainees, as implied.The Specialist Advisory Committee for Otolaryngology has set stage-specific criteria of required operative competencies for higher surgical trainees. 2Georgalas et al., 3 in a recent survey of otolaryngology trainees, concluded that all stage-specific criteria were currently being met, and that training standards were satisfactory across the UK.They concluded that current training is adequate and that a system of twotier trainees, with four years of general training and two years devoted to the subspecialties, would be an adequate option for the vast majority of specialist registrars, provided that current standards are maintained. 2 Training in specialist otological surgery will not be offered or assessed in the new four-year 'generalist' higher surgical rotations, since specialist experience will be gained in accredited otology fellowships for prospective otologists.
Clinical diagnosis of ventilator associated pneumonia revisited: comparative validation using immediate post-mortem lung biopsies
Authors: N. Fabregas, S. Ewig, A. Torres, M. El-Ebiary, J. Ramirez, J. P. de la Bellacasa, T. Bauer, H. Cabello
Journal: Thorax (1999)

<h3>BACKGROUND</h3> A study was undertaken to assess the diagnostic value of different clinical criteria and the impact of microbiological testing on the accuracy of clinical diagnosis of suspected ventilator associated pneumonia (VAP). <h3>METHODS</h3> Twenty five deceased mechanically ventilated patients were studied prospectively. Immediately after death, multiple bilateral lung biopsy specimens (16 specimens/patient) were obtained for histological examination and quantitative lung cultures. The presence of both histological pneumonia and positive lung cultures was used as a reference test. <h3>RESULTS</h3> The presence of infiltrates on the chest radiograph and two of three clinical criteria (leucocytosis, purulent secretions, fever) had a sensitivity of 69% and a specificity of 75%; the corresponding numbers for the clinical pulmonary infection score (CPIS) were 77% and 42%. Non-invasive as well as invasive sampling techniques had comparable values. The combination of all techniques achieved a sensitivity of 85% and a specificity of 50%, and these values remained virtually unchanged despite the presence of previous treatment with antibiotics. When microbiological results were added to clinical criteria, adequate diagnoses originating from microbiological results which might have corrected false positive and false negative clinical judgements (n = 5) were countered by a similar proportion of inadequate diagnoses (n = 6). <h3>CONCLUSIONS</h3> Clinical criteria had reasonable diagnostic values. CPIS was not superior to conventional clinical criteria. Non-invasive and invasive sampling techniques had diagnostic values comparable to clinical criteria. An algorithm guiding antibiotic treatment exclusively by microbiological results does not increase the overall diagnostic accuracy and carries the risk of undertreatment.
Plasma cell infiltration of the small bowel: lack of evidence for a non-secretory form of alpha-heavy chain disease.
Authors: N H Gilinsky, A S Mee, D W Beatty, B H Novis, G Young, S Price, L R Purves, I N Marks
Journal: Gut (1985)

Eight patients with diffuse plasma cell infiltration of the small bowel who had the clinical features of immunoproliferative small intestinal disease (IPSID), but whose serum was negative for free alpha-heavy chains, were investigated for evidence of a non-secretory form of alpha-chain disease (alpha-CD). Molecular sieving and immunoblotting of serum, immunoperoxidase staining of biopsy specimens, and in vitro protein synthesis studies utilising an immunoprecipitation technique and polyacrylamide gel electrophoresis, failed to detect any new cases of alpha-CD. Four of the eight cases were found to have diffuse intestinal lymphoma. The remaining four patients, who were unsuccessfully investigated for evidence of a significant abnormality in cellular immunity, have not developed detectable alpha-CD protein or lymphoma over a mean of 143 months. Despite continuing exposure to possible environmental stimuli, it is concluded that not all cases of IPSID elaborate detectable alpha-CD protein or evolve to lymphoma.