tbuckley/cabot-search huggingface dataset:
Circulating Retinol-Binding Protein-4, Insulin Sensitivity, Insulin Secretion, and Insulin Disposition Index in Obese and Nonobese Subjects
Authors: Montserrat Broch, Joan Vendrell, Wifredo Ricart, Cristóbal Richart, José-Manuel Fernández-Real
Journal: Diabetes Care (2007)

OBJECTIVE—Recent investigations disclosed an upregulation of retinol-binding protein-4 (RBP4) in the adipose tissue of several insulin-resistant mouse models and increased serum RBP4 concentration in subjects with obesity and type 2 diabetes in association with insulin resistance. There is some experimental evidence that RBP4 also could been linked to insulin secretion. RESEARCH DESIGN AND METHODS—We aimed to evaluate insulin secretion, insulin sensitivity, insulin disposition index (minimal model analysis), and circulating RBP4 (enzyme-linked immunosorbent assay) in nondiabetic men with a wide range of obesity (n = 107). RESULTS—Serum RBP4 concentration was nonsignificantly different among lean, overweight, and obese subjects. Circulating RBP4 was not associated with age, BMI, waist-to-hip ratio, or metabolic parameters, including insulin sensitivity (r = −0.03, P = 0.6). On the contrary, circulating RBP4 was negatively associated with insulin secretion, especially in obese subjects (r = −0.48, P = 0.007), in whom RBP4 also was linked to insulin disposition index (r = −0.44, P = 0.01). On multiple regression analyses to predict insulin secretion (acute insulin response [AIRg]), insulin sensitivity was the only factor that contributed to 17% of AIRg variance in nonobese subjects. In obese subjects, however, RBP4 emerged as an independent factor that contributed independently to AIRg variance (23%). CONCLUSIONS—Our results suggest that oversecretion of RBP4 may negatively affect β-cell function directly or by preventing the binding of transthyretin to its receptor. These mechanisms could be behind the association between increased circulating RBP4 and type 2 diabetes. RBP4 could be one signal from insulin-resistant tissues that impacts on β-cell secretion.
Increased risk of lymphoma among inflammatory bowel disease patients treated with azathioprine and 6-mercaptopurine
Authors: A Kandiel
Journal: Gut (2005)

<b>Background:</b> Inflammatory bowel disease (IBD) is commonly treated with immunomodulators such as azathioprine and 6-mercaptopurine (6-MP). Studies examining lymphoma risk in IBD patients treated with these medications have been underpowered and have yielded conflicting conclusions. <b>Aims:</b> The purpose of this meta-analysis was to provide a more precise estimate of the relative risk of lymphoma among IBD patients treated with azathioprine or 6-MP. <b>Methods:</b> Studies were included if they were English language, full article, cohort studies specifically designed to evaluate cancer as an adverse outcome of treatment with azathioprine or 6-MP. Pooled standardised incidence ratios were calculated to estimate the relative risk of lymphoma associated with therapy. Heterogeneity was assessed using Poisson regression. Sensitivity analyses examined the influence of individual studies on risk estimate and heterogeneity statistics. <b>Results:</b> Six studies were identified that met our inclusion criteria. When the data were combined across all studies, the pooled relative risk was 4.18 (95% confidence interval 2.07–7.51; 11 observed cases, 2.63 expected). Sensitivity analysis showed that exclusion of any one study had a relatively small effect on the pooled relative risk estimate (range 3.49–5.21) but excluding either the study with the highest or lowest estimated relative risk eliminated the statistically significant heterogeneity. <b>Conclusions:</b> Our data suggest an approximate fourfold increased risk of lymphoma in IBD patients treated with azathioprine/6-MP. The increased risk of lymphoma could be a result of the medications, the severity of the underlying disease, or a combination of the two.
Mutant HSP70 Reverses Autoimmune Depigmentation in Vitiligo
Authors: Jeffrey A. Mosenson, Andrew Zloza, John D. Nieland, Elizabeth Garrett-Mayer, Jonathan M. Eby, Erica J. Huelsmann, Previn Kumar, Cecele J. Denman, Andrew T. Lacek, Frederick J. Kohlhapp, Ahmad Alamiri, Tasha Hughes, Steven D. Bines, Howard L. Kaufman, Andreas Overbeck, Shikhar Mehrotra, Claudia Hernandez, Michael I. Nishimura, Jose A. Guevara-Patino, I. Caroline Le Poole
Journal: Science Translational Medicine (2013)

Vitiligo can be reversed through immune targeting with mutant heat shock protein 70.
Does the Prevailing Hypothesis That Small-Fiber Dysfunction Precedes Large-Fiber Dysfunction Apply to Type 1 Diabetic Patients?
Authors: Ari Breiner, Leif Erik Lovblom, Bruce A. Perkins, Vera Bril
Journal: Diabetes Care (2014)

The prevailing hypothesis that early subclinical small-fiber injury precedes large-fiber damage in diabetic sensorimotor polyneuropathy (DSP) is based on lower intraepithelial nerve fiber density in type 2 prediabetic patients despite normal nerve conduction studies (NCSs). We aimed to confirm the same hypothesis in type 1 diabetic patients by examining whether: (1) subjects without DSP include a spectrum with both normal and abnormal small-fiber measures and (2) subjects with DSP have concurrent evidence of abnormal small-fiber measures.A healthy control population (n = 53) was used to generate threshold values for four small-fiber tests: cooling detection thresholds (CDTs), laser Doppler imaging of heat-evoked flare (LDIflare), heart rate variability (HRV), and corneal confocal microscopy. Based on NCS results, type 1 diabetic patients (n = 131) were dichotomized according to the presence or absence of DSP.Threshold values derived from healthy control subjects were 26.5 °C, 1.4 cm2, 13%, and 12.9 mm/mm2 for CDT, LDIflare, HRV, and corneal nerve fiber length, respectively. Among type 1 diabetic patients, 57 of 131 had evidence of DSP, and 74 of 133 did not. Using abnormality of any small-fiber test to define small-fiber dysfunction, 55 of 57 (96.5%) DSP patients and 39 of 74 (52.7%) control subjects without DSP had concurrent small-fiber damage. The severity of small-fiber abnormalities worsened with an increasing number of NCS abnormalities (ANOVA, P < 0.01).Our findings in type 1 diabetes support the prevailing hypothesis that small-fiber dysfunction occurs early in DSP. However, further research is required to determine which combination of small-fiber tests is most suitable as a surrogate marker in clinical trials.
Pharmacokinetics of piperacillin and tazobactam in critically ill patients with renal failure, treated with continuous veno-venous hemofiltration (CVVH)
Authors: T. S. van der Werf, P. O. M. Mulder, J. G. Zijlstra, D. R. A. Uges, C. A. Stegeman
Journal: Intensive Care Medicine (1997)
Coordination of Centrosome Homeostasis and DNA Repair Is Intact in MCF-7 and Disrupted in MDA-MB 231 Breast Cancer Cells
Authors: Ilie D. Acu, Tieju Liu, Kelly Suino-Powell, Steven M. Mooney, Antonino B. D'Assoro, Nicholas Rowland, Alysson R. Muotri, Ricardo G. Correa, Yun Niu, Rajiv Kumar, Jeffrey L. Salisbury
Journal: Cancer Research (2010)

Abstract When cells encounter substantial DNA damage, critical cell cycle events are halted while DNA repair mechanisms are activated to restore genome integrity. Genomic integrity also depends on proper assembly and function of the bipolar mitotic spindle, which is required for equal chromosome segregation. Failure to execute either of these processes leads to genomic instability, aging, and cancer. Here, we show that following DNA damage in the breast cancer cell line MCF-7, the centrosome protein centrin2 moves from the cytoplasm and accumulates in the nucleus in a xeroderma pigmentosum complementation group C protein (XPC)–dependent manner, reducing the available cytoplasmic pool of this key centriole protein and preventing centrosome amplification. MDA-MB 231 cells do not express XPC and fail to move centrin into the nucleus following DNA damage. Reintroduction of XPC expression in MDA-MB 231 cells rescues nuclear centrin2 sequestration and reestablishes control against centrosome amplification, regardless of mutant p53 status. Importantly, the capacity to repair DNA damage was also dependent on the availability of centrin2 in the nucleus. These observations show that centrin and XPC cooperate in a reciprocal mechanism to coordinate centrosome homeostasis and DNA repair and suggest that this process may provide a tractable target to develop treatments to slow progression of cancer and aging. Cancer Res; 70(8); 3320–8. ©2010 AACR.
Suppression of human alpha-globin gene expression mediated by the recombinant adeno-associated virus 2-based antisense vectors.
Authors: S Ponnazhagan, M L Nallari, A Srivastava
Journal: The Journal of Experimental Medicine (1994)

We sought to investigate the usefulness of the adeno-associated virus 2 (AAV)-based vectors to suppress the excess production of the human alpha-globin gene product towards developing a treatment modality for beta-thalassemia since accumulation of free alpha-globin reduces the lifespan of red blood cells in these patients. We constructed recombinant AAV virions containing the human alpha-globin gene sequences in antisense orientation driven by the herpesvirus thymidine kinase (TK) promoter, the SV40 early gene promoter, and the human alpha-globin gene promoter, respectively, as well as a bacterial gene for resistance to neomycin (neoR) as a selectable marker. These recombinant virions were used to infect a human erythroleukemia cell line (K562) that express high levels of alpha-globin mRNA. Clonal populations of neoR cells were obtained after selection with the drug G418, a neomycin analogue. Total genomic DNA samples isolated from these cells were analyzed on Southern blots to document stable integration of the transduced neo and alpha-globin genes. Total cellular RNA samples isolated from mock-infected and recombinant virus-infected cultures were also analyzed by Northern blots. Whereas the TK promoter-driven antisense alpha-globin sequences showed no inhibition of expression of the endogenous alpha-globin gene, the SV40 promoter and the alpha-globin gene promoter-driven antisense alpha-globin sequences suppressed the expression of this constitutively over-expressed gene by approximately 29 and 91%, respectively, at the transcriptional level. These studies suggest the feasibility of utilizing the AAV-based antisense gene transfer approach in the potential treatment of beta-thalassemia.
Rabies superantigen as a Vbeta T-dependent adjuvant.
Authors: E Astoul, M Lafage, M Lafon
Journal: The Journal of Experimental Medicine (1996)

Recently we reported evidence that nucleocapsid (NC) of rabies virus is a Vbeta8-specific exogenous superantigen (SAg) in humans and a Vbeta6-specific SAg in BALB/c mice. NC was also found to stimulate rabies vaccination by enhancing the rabies neutralizing antibody response. In this study, we tested the hypothesis that the stimulating effect of NC and its SAg properties are linked. To do this, we studied the effect of rabies SAg on the immune response to an unrelated antigen, the influenza virus, and compared the response in two congenic strains of mice, BALB/c and BALB/D2. BALB/c mice are rabies SAg responsive, whereas BALB/D2 mice are not responsive to SAg activation by rabies NC because they lack the SAg recognition element, the Vbeta6 T cell receptor. In BALB/c mice, coinjection of rabies SAg with inactivated influenza virus resulted in a rapid and long-term increase in (a) the titres of influenza virus-specific antibodies (IgG and IgM), including protective hemagglutination-inhibiting antibodies, (b) antigen-specific proliferation and, (c) IL-2 and IL-4 secretion by lymph node lymphocytes, when compared to mice that received influenza virus only. In contrast, in BALB/D2 mice, neither antibody nor lymphocyte responses were stimulated. Moreover, during establishment of the primary response, the increase in influenza-primed T cells was mainly restricted to those bearing a Vbeta6 TCR. These data establish that rabies SAg can stimulate both T and B cell-specific responses to an unrelated antigen, depending on expression of the SAg target (Vbeta6 T lymphocytes). This is the first report linking NC adjuvant properties with its SAg mechanism.
Prognostic value of KIT/PDGFRA mutations in gastrointestinal stromal tumours (GIST): Polish Clinical GIST Registry experience
Authors: A. Wozniak, P. Rutkowski, A. Piskorz, M. Ciwoniuk, C. Osuch, E. Bylina, J. Sygut, M. Chosia, J. Rys, K. Urbanczyk, W. Kruszewski, P. Sowa, J. Siedlecki, M. Debiec-Rychter, J. Limon
Journal: Annals of Oncology (2011)
The Liver as a Lymphoid Organ
Authors: Ian Nicholas Crispe
Journal: Annual Review of Immunology (2009)

The liver receives blood from both the systemic circulation and the intestine, and in distinctive, thin-walled sinusoids this mixture passes over a large macrophage population, termed Kupffer cells. The exposure of liver cells to antigens, and to microbial products derived from the intestinal bacteria, has resulted in a distinctive local immune environment. Innate lymphocytes, including both natural killer cells and natural killer T cells, are unusually abundant in the liver. Multiple populations of nonhematopoietic liver cells, including sinusoidal endothelial cells, stellate cells located in the subendothelial space, and liver parenchymal cells, take on the roles of antigen-presenting cells. These cells present antigen in the context of immunosuppressive cytokines and inhibitory cell surface ligands, and immune responses to liver antigens often result in tolerance. Important human pathogens, including hepatitis C virus and the malaria parasite, exploit the liver's environment, subvert immunity, and establish persistent infection.
Genetic Impacts of a Butyrophilin-like 2 (BTNL2) Gene Variation On Specific Ige Responsiveness to Dermatophagoides Farinae (Der F) in Japanese
Authors: D. Takahashi, N. Hizawa, S. Konno, A. Isada, A. Takahashi, T. Hattori, Y. Maeda, M. Nishimura
Journal: Journal of Allergy and Clinical Immunology (2006)
Meeting the old man's friend
Authors: A. Torres, R. Menendez
Journal: Thorax (2009)

<h3>Abstract</h3> <h3>Introduction</h3> From June 2014-October 2015, the Michigan Department of Health and Human Services (MDHHS) reported a Legionnaires’ disease (LD) outbreak in Genesee County, Michigan, of which Flint is the county seat. MDHHS’ final case count for the outbreak was 90 cases, including 10 deaths among Genesee County residents. As LD is not routinely tested for as a cause of community-acquired pneumonia, the size of the outbreak may have been underestimated. Specifically, some LD cases may have been classified as pneumonias of other or unexplained etiologies. <h3>Objective</h3> To estimate excess pneumonia deaths in Genesee County during the 2014-15 LD outbreak and compare this with reported deaths due to LD. <h3>Methods</h3> We used data from the CDC WONDER database, which contains monthly county-level counts of death certificates, on all pneumonia deaths among residents of Genesee and a set of similar counties from 2011-2017. We calculated excess pneumonia deaths in Genesee during the period of the LD outbreak (May 2014-October 2015). We used data from the Genesee County Vital Records Division to map pneumonia deaths by census tract to assess geographic overlap with reported LD cases. <h3>Results</h3> We estimated 70.0 excess pneumonia deaths (90% uncertainty interval (UI): 36 to 103) in Genesee County during the LD outbreak. This is substantially higher than the 10 LD deaths among Genesee County residents reported by MDHHS. Areas of high pneumonia mortality overlapped with those with high LD incidence and were primarily located in western Flint and northwestern non-Flint Genesee County. <h3>Conclusions</h3> These findings are consistent with the hypothesis that the LD outbreak was larger than reported. Earlier detection and response to this outbreak may have facilitated identification of these additional cases.
Vitamin D <sub>3</sub> –Upregulated Protein-1 (VDUP-1) Regulates Redox-Dependent Vascular Smooth Muscle Cell Proliferation Through Interaction With Thioredoxin
Authors: P. Christian Schulze, Gilles W. De Keulenaer, Jun Yoshioka, Kimberly A. Kassik, Richard T. Lee
Journal: Circulation Research (2002)

Reactive oxygen species are important cellular signaling molecules, and thioredoxin (TRX) is a key regulator of cellular redox balance. We investigated the interaction of TRX with its endogenous inhibitor, vitamin D 3 –upregulated protein (VDUP)-1, in human aortic smooth muscle cells (SMCs). Adenoviral gene transfer of TRX enhanced TRX enzyme activity 2.7±0.4-fold ( P &lt;0.05 versus cells infected with adenoviral vector expressing green fluorescent protein [AdGFP]) and resulted in a 3.8±0.5-fold increase of cellular DNA synthesis as detected by methyl-[ 3 H]thymidine incorporation ( P &lt;0.001). Platelet-derived growth factor (PDGF) also increased TRX enzyme activity 2.5±3.3-fold ( P &lt;0.05 versus no stimulation) and DNA synthesis 6.5±0.3-fold ( P &lt;0.001 versus no stimulation) without significant changes in TRX expression. PDGF and H 2 O 2 time-dependently suppressed VDUP-1 expression (13-fold and 30-fold reduction after 1 hour, respectively; P &lt;0.001), and this was inhibited by the cell-permeable antioxidants N -acetylcysteine and 4,5-dihydroxy-1,3-benzene-disulfonic acid (Tiron). Overexpression of VDUP-1 (AdVDUP-1) reduced TRX activity at baseline (−61±23% versus control cells, P &lt;0.05) and abolished PDGF-induced TRX activity (−9±27% in AdVDUP-1–infected cells; P =NS versus control cells). In addition, overexpression of VDUP-1 blocked PDGF-induced DNA synthesis (1.3±0.4-fold increase in AdVDUP-1–infected cells versus 6.5±0.4-fold increase in AdGFP-infected cells, P &lt;0.001). In conclusion, VDUP-1 has marked antiproliferative effects in SMCs through the suppression of TRX activity, suggesting that the regulation of VDUP-1 is a critical molecular switch in the transduction of pro-oxidant mitogenic signals. These data also demonstrate that activation of the reductase TRX plays a pivotal role in the redox-dependent proliferation of SMCs.
Pulse Pressure and Prediction of Incident Foot Ulcers in Type 2 Diabetes
Authors: Matteo Monami, Maria Vivarelli, Carla Maria Desideri, Claudia Colombi, Niccolò Marchionni, Edoardo Mannucci
Journal: Diabetes Care (2009)

OBJECTIVE To assess the relevance of pulse pressure as a predictor of foot ulcers in type 2 diabetic subjects. RESEARCH DESIGN AND METHODS A cohort study was performed on a consecutive series of 1,945 type 2 diabetic outpatients without a foot ulcer at baseline. Incident foot ulcers were identified through the regional hospital discharge system, which contains ICD codes of current diagnoses. RESULTS During a follow-up of mean ± SD 4.2 ± 2.2 years, 86 ulcers were observed. After adjusting for confounders, the highest quartiles of pulse pressure had a 2.39-fold (95% CI 1.14–5.02) risk of foot ulcers. When ischemic ulcers were considered separately, the highest pulse pressure quartile was associated with an increased age- and sex-adjusted risk (2.08 [95% CI 1.02–4.24]), whereas no increase of risk was observed for neuropathic ulcers. CONCLUSIONS Elevated pulse pressure represents an independent predictor of foot ulcers in diabetic patients; this parameter should be considered for the stratification of risk of ischemic or neuroischemic ulcers.
Vaccination with synthetic analog peptides derived from WT1 oncoprotein induces T-cell responses in patients with complete remission from acute myeloid leukemia
Authors: Peter G. Maslak, Tao Dao, Lee M. Krug, Suzanne Chanel, Tatyana Korontsvit, Victoria Zakhaleva, Ronghua Zhang, Jedd D. Wolchok, Jianda Yuan, Javier Pinilla-Ibarz, Ellin Berman, Mark Weiss, Joseph Jurcic, Mark G. Frattini, David A. Scheinberg
Journal: Blood (2010)
Etanercept (Enbrel): update on therapeutic use
Authors: G. Spencer-Green
Journal: Annals of the Rheumatic Diseases (2000)

Tumour necrosis factor (TNF) is an important inflammatory disease mediator in a wide spectrum of articular diseases, including adult and juvenile rheumatoid arthritis (RA, JRA). Etanercept (Enbrel), approved in the United States and in Europe for use in patients with RA and JRA, is an effective inhibitor of TNF that has been shown to provide rapid and sustained improvement in both of these diseases. Long term studies continue to show that etanercept controls signs and symptoms of RA and JRA with no change in rate or type of adverse event over time. To demonstrate that etanercept is effective as first line treatment for patients with early active RA who have not been previously treated with methotrexate, and to examine the effect of etanercept on radiographic progression, a double blind, placebo controlled study was recently conducted, comparing etanercept with methotrexate (median dose 20 mg per week). Both etanercept 25 mg twice weekly and rapidly escalated methotrexate were effective in reducing the signs and symptoms of RA, and etanercept was significantly better than methotrexate in slowing the rate of radiographic erosions. In patients with severe psoriatic arthritis (PsA), a double blind, placebo controlled study demonstrated that etanercept was also effective in reducing disease activity in PsA. Etanercept has been well tolerated in all of these clinical trials and offers an important new treatment option to patients with inflammatory articular diseases.
Watchful Waiting vs Repair of Inguinal Hernia in Minimally Symptomatic Men
Authors: Robert J. Fitzgibbons, Anita Giobbie-Hurder, James O. Gibbs, Dorothy D. Dunlop, Domenic J. Reda, Martin McCarthy, Leigh A. Neumayer, Jeffrey S. T. Barkun, James L. Hoehn, Joseph T. Murphy, George A. Sarosi, William C. Syme, Jon S. Thompson, Jia Wang, Olga Jonasson
Journal: JAMA (2006)

Many men with inguinal hernia have minimal symptoms. Whether deferring surgical repair is a safe and acceptable option has not been assessed.To compare pain and the physical component score (PCS) of the Short Form-36 Version 2 survey at 2 years in men with minimally symptomatic inguinal hernias treated with watchful waiting or surgical repair.Randomized trial conducted January 1, 1999, through December 31, 2004, at 5 North American centers and enrolling 720 men (364 watchful waiting, 356 surgical repair) followed up for 2 to 4.5 years.Watchful-waiting patients were followed up at 6 months and annually and watched for hernia symptoms; repair patients received standard open tension-free repair and were followed up at 3 and 6 months and annually.Pain and discomfort interfering with usual activities at 2 years and change in PCS from baseline to 2 years. Secondary outcomes were complications, patient-reported pain, functional status, activity levels, and satisfaction with care.Primary intention-to-treat outcomes were similar at 2 years for watchful waiting vs surgical repair: pain limiting activities (5.1% vs 2.2%, respectively; P = .06 [corrected]); PCS (improvement over baseline, 0.29 points vs 0.13 points; P = .79). Twenty-three percent of patients assigned to watchful waiting crossed over to receive surgical repair (increase in hernia-related pain was the most common reason offered); 17% assigned to receive repair crossed over to watchful waiting. Self-reported pain in watchful-waiting patients crossing over improved after repair. Occurrence of postoperative hernia-related complications was similar in patients who received repair as assigned and in watchful-waiting patients who crossed over. One watchful-waiting patient (0.3%) experienced acute hernia incarceration without strangulation within 2 years; a second had acute incarceration with bowel obstruction at 4 years, with a frequency of 1.8/1000 patient-years inclusive of patients followed up for as long as 4.5 years.Watchful waiting is an acceptable option for men with minimally symptomatic inguinal hernias. Delaying surgical repair until symptoms increase is safe because acute hernia incarcerations occur rarely.Clinical Trials Registration ClinicalTrials.gov Identifier: NCT00263250.