tbuckley/cabot-search huggingface dataset:
Mapping of a Functional Recombination Motif that Defines Isotype Specificity for μ→γ3 Switch Recombination Implicates NF-κB p50 as the Isotype-specific Switching Factor
Authors: Amy L. Kenter, Robert Wuerffel, Carmen Dominguez, Ananth Shanmugam, Hongmei Zhang
Journal: The Journal of Experimental Medicine (2004)

Ig class switch recombination (CSR) requires expression of activation-induced deaminase (AID) and production of germline transcripts to target S regions for recombination. However, the mechanism of CSR remains unclear. Here we show that an extrachromosomal S plasmid assay is AID dependent and that a single consensus repeat is both necessary and sufficient for isotype-specific CSR. Transfected switch substrates specific for μ→γ3 and μ→γ1 are stimulated to switch with lipopolysaccharide (LPS) alone or LPS and interleukin-4, respectively. An Sγ3/Sγ1 substrate containing only three Sγ3-associated nucleotides reconstituted LPS responsiveness and permitted mapping of a functional recombination motif specific for μ→γ3 CSR. This functional recombination motif colocalized with a binding site for NF-κB p50, and p50 binding to this site was previously established. We show a p50 requirement for plasmid-based μ→γ3 CSR using p50-deficient B cells. Switch junctions from p50-deficient B cells showed decreased lengths of microhomology between Sμ and Sγ3 relative to wild-type cells, indicating a function for p50 in the mechanics of CSR. We note a striking parallel between the affects of p50 and Msh2 deficiency on Sμ/Sγ3 junctions. The data suggest that p50 may be the isotype-specific factor in μ→γ3 CSR and epistatic with Msh2.
Evaluation of Exposure to Arsenic in Residential Soil
Authors: Joyce S. Tsuji, Maria D. Van Kerkhove, Rhonda S. Kaetzel, Carolyn G. Scrafford, Pamela J. Mink, Leila M. Barraj, Eric A. Crecelius, Michael Goodman
Journal: Environmental Health Perspectives (2005)

In response to concerns regarding arsenic in soil from a pesticide manufacturing plant, we conducted a biomonitoring study on children younger than 7 years of age, the age category of children most exposed to soil. Urine samples from 77 children (47% participation rate) were analyzed for total arsenic and arsenic species related to ingestion of inorganic arsenic. Older individuals also provided urine (n = 362) and toenail (n = 67) samples. Speciated urinary arsenic levels were similar between children (geometric mean, geometric SD, and range: 4.0, 2.2, and 0.89-17.7 microg/L, respectively) and older participants (3.8, 1.9, 0.91-19.9 microg/L) and consistent with unexposed populations. Toenail samples were < 1 mg/kg. Correlations between speciated urinary arsenic and arsenic in soil (r = 0.137, p = 0.39; n = 41) or house dust (r = 0.049, p = 0.73; n = 52) were not significant for children. Similarly, questionnaire responses indicating soil exposure were not associated with increased urinary arsenic levels. Relatively low soil arsenic exposure likely precluded quantification of arsenic exposure above background.
Pulsatile Stress in Middle-Aged Patients With Type 1 or Type 2 Diabetes Compared With Nondiabetic Control Subjects
Authors: Jean-Christophe Philips, Monique Marchand, André J. Scheen
Journal: Diabetes Care (2010)

OBJECTIVE Arterial pulse pressure is considered to be an independent cardiovascular risk factor. We compared pulse pressure during an active orthostatic test in middle-aged patients with type 1 diabetes and with type 2 diabetes and corresponding nondiabetic control subjects. RESEARCH DESIGN AND METHODS Forty patients with type 1 diabetes (mean age 50 years, diabetes duration 23 years, and BMI 23.0 kg/m2) were compared with 40 nonhypertensive patients with type 2 diabetes (respectively, 50 years, 8 years, and 29.7 kg/m2). Patients taking antihypertensive agents or with renal insufficiency were excluded. All patients were evaluated with a continuous noninvasive arterial blood pressure monitoring (Finapres) in standing (1 min), squatting (1 min), and again standing position (1 min). Patients with type 1 or type 2 diabetes were compared with two groups of 40 age-, sex- and BMI-matched healthy subjects. RESULTS Patients with type 1 diabetes and patients with type 2 diabetes showed significantly higher pulse pressure, heart rate, and double product of pulse pressure and heart rate (PP×HR) (type 1: 5,263 vs. 4,121 mmHg/min, P = 0.0004; type 2: 5,359 vs. 4,321 mmHg, P = 0.0023) levels than corresponding control subjects. There were no significant differences between patients with type 1 diabetes and type 2 diabetes regarding pulse pressure (59 vs. 58 mmHg), heart rate (89 vs. 88/min), and PP×HR (5,263 vs. 5,359 mmHg/min). CONCLUSIONS Patients with type 1 diabetes have increased levels of peripheral PP, an indirect marker of arterial stiffness, and PP×HR, an index of pulsatile stress, comparable to those of nonhypertensive patients with type 2 diabetes at similar mean age of 50 years.
Diagnosing malaria in UK migrants from sub-Saharan Africa
Authors: A. T Abegunde
Journal: Journal of the Royal Society of Medicine (2006)

The editorial 'Too little quality; too many doctors' (June 2006 JRSM 1 ) is incorrect to suggest that the General Medical Council (GMC) had a 'sudden demand for overseas graduates to have a work permit'.The GMC does not have any visa requirements for international medical graduates (IMGs).The Home Office is responsible for setting visa requirements.International medical graduates are responsible for ensuring that they have the appropriate visa when they enter the UK.
Pivalate-Generating Prodrugs and Carnitine Homeostasis in Man
Authors: E. P. Brass
Journal: Pharmacological Reviews (2002)

Prodrugs that liberate pivalate (trimethylacetic acid) after hydrolysis have been developed to improve the bioavailability of therapeutic candidates. Catabolism of pivalate released by activation of a prodrug is limited in mammalian tissues. Pivalate can be activated to a coenzyme A thioester in cells. In humans, formation and urinary excretion of pivaloylcarnitine generated from pivaloyl-CoA is the major route of pivalate elimination. Because the total body carnitine pool is limited and can only slowly be replenished through normal diet or biosynthesis, treatment with large doses of pivalate prodrugs may deplete tissue carnitine content. Animal models and long-term treatment of patients with pivalate prodrugs have resulted in toxicity consistent with carnitine depletion. However, low plasma carnitine concentrations after pivalate prodrug exposure may not reflect tissue carnitine content and, thus, cannot be used as a surrogate for potential toxicity. The extent of tissue carnitine depletion will be dependent on the dose of pivalate, because carnitine losses may approximate the pivalate exposure on a stoichiometric basis. These concepts, combined with estimates of carnitine dietary intake and biosynthetic rates, can be used to estimate the impact of pivalate exposure on carnitine homeostasis. Thus, even in populations with altered carnitine homeostasis due to underlying conditions, the use of pivalate prodrugs for short periods of time is unlikely to result in clinically significant carnitine depletion. In contrast, long-term treatment with substantial doses of pivalate prodrugs may require administration of carnitine supplementation to avoid carnitine depletion.
Expression of CX3CL1 and CX3CR1 in human asthmatic lung in relation to cell survival
Authors: Danen Cunoosamy, Xiao-Hong Zhou, Maria Rehnberg, Karin Svensson, Kristian Sandberg
Journal: European Respiratory Journal (2014)

Expression of fractalkine (CX3CL1) is elevated in asthma and may be involved in controlling the inflammatory response in lungs by regulating influx of leukocytes, cell survival and function of fractalkine receptor (CX3CR1) expressing cells. In this study, the cellular distribution of CX3CR1 and CX3CL1 in lungs from asthmatics was determined by immunohistochemistry using validated antibodies. CX3CR1 is expressed in bronchial epithelial cells, endothelial cells, CD3 +  cells, CD4 +  cells, CD207 +  cells, CD68 +  cells, and mast cells. Interestingly, very few of the CD8 +  cells that were located to lamina propria and submucosa expressed CX3CR1 whereas within the bronchial epithelium in asthmatics, numerous CD8 +  cells were co-expressing CX3CR1. Overall, no difference in expression intensity was observed comparing lung biopsies from healthy volunteers and asthmatics, independent of disease severity (GINA). CX3CL1 was expressed in airway epithelia with highest intensity at the apical side facing the airway lumen, inflammatory cells in lamina propria and smooth muscle cells. Steroid treatment did not affect the expression pattern, nor the intensity in staining.  The changed expression pattern of CX3CR1 expressing cells in asthmatics suggest that CX3CR1 signaling could be of importance for cellular redistribution in inflamed airways. A potent and highly selective small molecule CX3CR1 antagonist was therefore used to study the role of CX3CL1 to mediate cell survival in CX3CR1 expressing leukocytes. The data suggest that CX3CR1 signaling does enhance cell survival and that pharmacological inhibition of CX3CR1 signaling may be efficacious in reducing chronic airway inflammation and hyper responsiveness.
E-Cadherin Gene Promoter Hypermethylation in Primary Human Gastric Carcinomas
Authors: G. Tamura
Journal: JNCI Journal of the National Cancer Institute (2000)

Background: E (epithelial)-cadherin, the cell adhesion molecule also considered a potential invasion/metastasis suppressor, is mutationally inactivated in nearly half of all undifferentiated-scattered (diffuse-type) gastric carcinomas. In addition, silencing of E-cadherin by CpG methylation within its promoter region has been reported in several gastric carcinoma cell lines. We investigated the methylation status of the E-cadherin promoter region in 53 primary human gastric carcinomas. Methods: Hypermethylation of the E-cadherin promoter was determined by utilizing methylation-specific polymerase chain reaction (PCR)–single-strand conformation polymorphism (MSP–SSCP) analysis followed by direct sequencing of PCR products. Expression of E-cadherin was studied by western blot analysis. All statistical tests were two-sided. Results: Hypermethylation of the E-cadherin promoter was evident in 27 (51%) of 53 primary gastric carcinomas examined by MSP–SSCP. It occurred more frequently in carcinomas of the undifferentiated-scattered type (in 15 [83%] of 18) than in other histologic subtypes (in 12 [34%] of 35) (P = .0011, Fisher's exact test), and it was present at similar rates in early (in six [60%] of 10) versus advanced (in 21 [49%] of 43) carcinomas (P = .73, Fisher's exact test). Methylation occurring at all cytosine–guanosine sequences (CpGs) near the transcriptional start site was confirmed in six of six tumors examined by bisulfite–DNA sequencing, including two early gastric carcinomas. In addition, loss or diminished expression of E-cadherin was confirmed by western blotting in four of the six tumor tissues demonstrating hypermethylation. Conclusions: The E-cadherin promoter frequently undergoes hypermethylation in human gastric cancers, particularly those of the undifferentiated-scattered histologic subtype. E-cadherin promoter hypermethylation is associated with decreased expression and may occur early in gastric carcinogenesis.
Activity and safety of a prolonged daily schedule of zoledronic acid in a patient with bone metastases from urothelial carcinoma
Authors: M.P. Brizzi, C.M. Sculli, F. Ragni, F. Porpiglia, M. Tampellini, G. Gorzegno, A.M. Priola, L. Dogliotti, A. Berruti
Journal: Annals of Oncology (2009)
Cross-reactive IgE antibody responses to tropomyosins from Ascaris lumbricoides and cockroach
Authors: Ana Beatriz R. Santos, Gutemberg M. Rocha, Constance Oliver, Virgínia P.L. Ferriani, Rodrigo C. Lima, Mário S. Palma, Valéria S.F. Sales, Rob C. Aalberse, Martin D. Chapman, L. Karla Arruda
Journal: Journal of Allergy and Clinical Immunology (2008)
Drug retention rates and relevant risk factors for drug discontinuation due to adverse events in rheumatoid arthritis patients receiving anticytokine therapy with different target molecules
Authors: Ryoko Sakai, Michi Tanaka, Toshihiro Nanki, Kaori Watanabe, Hayato Yamazaki, Ryuji Koike, Hayato Nagasawa, Koichi Amano, Kazuyoshi Saito, Yoshiya Tanaka, Satoshi Ito, Takayuki Sumida, Atsushi Ihata, Yoshiaki Ishigatsubo, Tatsuya Atsumi, Takao Koike, Atsuo Nakajima, Naoto Tamura, Takao Fujii, Hiroaki Dobashi, Shigeto Tohma, Takahiko Sugihara, Yukitaka Ueki, Akira Hashiramoto, Atsushi Kawakami, Noboru Hagino, Nobuyuki Miyasaka, Masayoshi Harigai
Journal: Annals of the Rheumatic Diseases (2012)

Objective To compare reasons for discontinuation and drug retention rates per reason among anticytokine therapies, infliximab, etanercept and tocilizumab, and the risk of discontinuation of biological agents due to adverse events (AE) in patients with rheumatoid arthritis (RA). Method This prospective cohort study included Japanese RA patients who started infliximab (n=412, 636.0 patient-years (PY)), etanercept (n=442, 765.3 PY), or tocilizumab (n=168, 206.5 PY) as the first biological therapy after their enrolment in the Registry of Japanese Rheumatoid Arthritis Patients for Long-term Safety (REAL) database. Drug retention rates were calculated using the Kaplan–Meier method. To compare risks of drug discontinuation due to AE for patients treated with these biological agents, the Cox proportional hazard model was applied. Results The authors found significant differences among the three therapeutic groups in demography, clinical status, comorbidities and usage of concomitant drugs. Development of AE was the most frequent reason for discontinuation of biological agents in the etanercept and tocilizumab groups, and the second most frequent reason in the infliximab group. Discontinuation due to good control was observed most frequently in the infliximab group. Compared with etanercept, the use of infliximab (HR 1.69; 95% CI 1.14 to 2.51) and tocilizumab (HR 1.98; 95% CI 1.04 to 3.76) was significantly associated with a higher risk of discontinuation of biological agents due to AE. Conclusions Reasons for discontinuation are significantly different among biological agents. The use of infliximab and tocilizumab was significantly associated with treatment discontinuation due to AE compared with etanercept.
Evidence that Clearance of Hepatitis C Virus RNA after α-Interferon Therapy in Dialysis Patients Is Sustained after Renal Transplantation
Authors: Nassim Kamar, Olivier Toupance, Matthias Buchler, Karine Sandres-Saune, Jacques Izopet, Dominique Durand, Lionel Rostaing
Journal: Journal of the American Society of Nephrology (2003)

To date, there is no available treatment of hepatitis C virus (HCV) infection after renal transplantation (RT). Among 55 anti-HCV-positive/HCV RNA-positive hemodialysis patients who were treated with IFN-alpha (9 MU/wk during 6 or 12 mo), 21 of them (38%) had a sustained virologic response. Of these, 16 (76%) underwent RT 38 mo (range, 2 to 57 mo) after alpha-IFN therapy. There were 13 men and 3 women aged 46 yr (range, 27 to 68 yr). At RT, HCV serology was still positive in 15 patients, and HCV viremia was negative in all patients. Immunosuppression relied on anticalcineurin agents with or without steroids and/or antimetabolites; in addition, 12 of them received induction therapy with antithymocyte globulins. At the last follow-up after RT, at 22.5 mo (range, 2 to 88 mo), HCV viremia remained negative in all patients. Moreover, HCV RNA was not present in peripheral blood mononuclear cells when assessed in eight patients. HCV serology was found to be still positive in 13 patients. Three patients presented with acute rejection, one presented with a suppurative lymphocele, one died from a sepsis, and four presented with a cytomegalovirus infection. None of them developed posttransplant diabetes mellitus. In conclusion, hemodialysis patients waiting for a RT need to be treated with alpha-IFN because when HCV RNA clearance occurred, they experienced no relapse after transplantation despite chronic immunosuppressive treatment.
Preventing Cigarette Smoking Among School Children
Authors: J A Best, S J Thomson, S M Santi, E A Smith, K S Brown
Journal: Annual Review of Public Health (1988)

Research to develop and ensure diffusion of smoking prevention programs must (a) be based on an appreciation of the social, psychological, and biological determinants at each stage in the onset process, (b) disentangle major interactions between program content, participant, provider, and setting factors as they determine impact, and (c) ensure both that diffusion is based on empirically grounded principles and that the process is monitored and its effectiveness evaluated. Sufficient evidence supports the tentative conclusion that social influence curricula can be efficacious--at least with some youth. However, we lack key information for diffusion, in particular concerning provider and setting factors. Thus, a cautious advance to diffusion research is recommended, noting that there is much we do not know, and that the public health need for applications must be balanced with continuing research to clarify for whom and under what circumstances current curricula work. At the same time, there should be strong continuing research to improve current interventions, especially for high risk populations.
Treatment Patterns of Adjuvant Interferon Alfa-2B (Ifn-&amp;Agr;2B) for High-Risk Melanoma. a Retrospective Study of the Grupo Español Multidisciplinar De Melanoma (Gem)
Authors: S. Martin-Algarra, V. Soriano, J. Malvehy, A. Berrocal, M. Quindos, P. Martinez Del Prado, A. Soria, I. Márquez-Rodas, I. Palacio, P. Cerezuela, L. Alonso, G. López-Vivanco, G. Nocea, K. Stevinson, P. Del Barrio, M.V. Tornamira, V. Guillem Porta, E. Espinosa
Journal: Annals of Oncology (2014)
Cyclooxygenase-2: A Therapeutic Target
Authors: Marco E. Turini, Raymond N. DuBois
Journal: Annual Review of Medicine (2002)

▪ Abstract Cyclooxygenase (COX), also known as prostaglandin endoperoxide synthase, is the key enzyme required for the conversion of arachidonic acid to prostaglandins. Two COX isoforms have been identified, COX-1 and COX-2. In many situations, the COX-1 enzyme is produced constitutively (e.g., in gastric mucosa), whereas COX-2 is highly inducible (e.g., at sites of inflammation and cancer). Traditional nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit both enzymes, and a new class of COX-2 selective inhibitors (COXIBs) preferentially inhibit the COX-2 enzyme. This review summarizes our current understanding of the role of COX-1 and COX-2 in normal physiology and disease.
Chronic Reduction in Renal Mass in the Rat Attenuates Ischemia/Reperfusion Injury and Does Not Impair Tubular Regeneration
Authors: SVEN R. VERCAUTEREN, DIRK K. YSEBAERT, KATHLEEN E. DE GREEF, ERIK J. EYSKENS, MARC E. DE BROE
Journal: Journal of the American Society of Nephrology (1999)

Abstract. It is not known whether a kidney with chronic structural and functional changes is more vulnerable to an acute renal insult, and whether its regeneration capacity after injury is altered. To study this question, Lewis rats were submitted 10 wk after 5/6 nephrectomy to an ischemic insult of 60 min (remnant kidney [RK] group). Functional and morphologic data of the RK group were compared with data obtained in 10-wk uninephrectomized (1K) and normal (2K) Lewis rats with unilateral and bilateral renal ischemia, respectively. The acute postischemic decrease in creatinine clearance was smallest in the RK group, followed by the 2K and 1K groups, respectively. At days 1 and 3, fewer proximal tubules in the outer stripe of the outer medulla of the RK and 2K groups had undergone acute tubular necrosis compared with the 1K group. The mean percentage of tubules with signs of regeneration was maximal at day 3 in the three experimental groups. At day 10, regeneration was almost complete in the three groups. The number of leukocytes (OX1 + cells) present in the RK before ischemia did not increase after ischemia/reperfusion injury (377 ± 146 cells/mm 2 at day 0) in contrast to the 1K and 2K groups. In the latter groups, the number of leukocytes had increased gradually, reaching a maximum at day 15 (1K: 960 ± 308 cells/mm 2 ) and day 10 (2K: 668 ± 164 cells/mm 2 ), respectively. In conclusion, this study has shown that an RK exhibiting chronic morphologic changes of interstitial fibrosis and tubular atrophy is protected against ischemia/reperfusion injury, and that its regeneration capacity is preserved. The reperfusion injury is not followed by further accumulation of leukocytes, which were already present in the RK before ischemia.
Effect of a Peroxisome Proliferator–Activated Receptor-γ Agonist on Myocardial Blood Flow in Type 2 Diabetes
Authors: Graham T. McMahon, Jorge Plutzky, Edouard Daher, Tammy Bhattacharyya, George Grunberger, Marcelo F. DiCarli
Journal: Diabetes Care (2005)

OBJECTIVE—The relationship between coronary endothelial function and insulin resistance remains speculative. We sought to determine whether pioglitazone, an insulin-sensitizing peroxisome proliferator–activated receptor (PPAR)-γ agonist, improves cardiac endothelial function in individuals with type 2 diabetes. RESEARCH DESIGN AND METHODS—Sixteen subjects with insulin-treated type 2 diabetes and without overt cardiovascular disease were randomly assigned to receive either 45 mg of pioglitazone or matching placebo for 3 months. Rest and adenosine-stimulated myocardial blood flow (MBF) were quantified with [13N]ammonia and positron emission tomography at baseline and study conclusion. RESULTS—After 3 months, HbA1c levels dropped by 0.68% in the pioglitazone group and increased by 0.17% in the placebo group (P = 0.009 for difference between groups). Triglyceride (−93 vs. −39 mg/dl, P = 0.026) and HDL concentrations (+4.8 vs. −6.0 mg/dl, P = 0.014) improved significantly in the pioglitazone group compared with placebo. Despite these favorable changes, there was no demonstrable change in baseline MBF (−0.05 ± 0.24 vs. −0.09 ± 0.24 ml · min−1 · g−1, P = 0.45), adenosine-stimulated MBF (0.10 ± 0.75 vs. 0.14 ± 0.31 ml · min−1 · g−1, P = 0.25), or coronary flow reserve (0.45 ± 1.22 vs. 0.35 ± 0.72 ml · min−1 · g−1, P = 0.64) after 12 weeks of exposure to pioglitazone or placebo, respectively. Regression analysis revealed that lower glucose concentration at the time of the study was associated with higher coronary flow reserve (P = 0.012). CONCLUSIONS—Pioglitazone treatment for 12 weeks in subjects with insulin-requiring type 2 diabetes had no demonstrable effect on coronary flow reserve despite metabolic improvements. Higher ambient glucose levels contribute to impaired vascular reactivity in individuals with diabetes.
Cerebrospinal fluid diffusion of Zevalin® after high-activity treatment and stem cell support in a patient affected by diffuse large B-cell non-Hodgkin's lymphoma with central nervous system involvement
Authors: P.F. Ferrucci, A. Vanazzi, G. Tesoriere, M. Ferrari, M. Bartolomei, P. Rocca, M. Cremonesi, G. Paganelli, G. Martinelli
Journal: Annals of Oncology (2005)