tbuckley/cabot-search huggingface dataset:
Increased secretory demand rather than a defect in the proinsulin conversion mechanism causes hyperproinsulinemia in a glucose-infusion rat model of non-insulin-dependent diabetes mellitus.
Authors: C Alarcón, J L Leahy, G T Schuppin, C J Rhodes
Journal: Journal of Clinical Investigation (1995)

Hyperproinsulinemia in non-insulin-dependent diabetes mellitus (NIDDM) is due to an increased release of proinsulin from pancreatic beta cells. This could reside in increased secretory demand placed on the beta cell by hyperglycemia or in the proinsulin conversion mechanism. In this study, biosynthesis of the proinsulin conversion enzymes (PC2, PC3, and carboxypeptidase-H [CP-H]) and proinsulin, were examined in islets isolated from 48-h infused rats with 50% (wt/vol) glucose (hyperglycemic, hyperinsulinemic, and increased pancreatic proinsulin to insulin ratio), 20% (wt/vol) glucose (normoglycemic but hyperinsulinemic), and 0.45% (wt/vol) saline (controls). A decrease in the islet content of PC2, PC3, and CP-H from hyperglycemic rats was observed. This reduction did not correlate with any deficiency in mRNA levels or biosynthesis of PC2, PC3, CP-H, or proinsulin. Furthermore, proinsulin conversion rate was comparable in islets from hyperglycemic and control rats. However, in islets from hyperglycemic rats an abnormal increased proportion of proinsulin was secreted, that was accompanied by an augmented release of PC2, PC3 and CP-H. Stimulation of the beta cell's secretory pathway by hyperglycemia, resulted in proinsulin being prematurely secreted from islets before its conversion could be completed. Thus, hyperproinsulinemia induced by chronic hyperglycemia likely results from increased beta cell secretory demand, rather than a defect in the proinsulin processing enzymes per se.
Quinidine‐induced agranulocytosis
Authors: Saramma J. Alexander, Robin I. Gilmore
Journal: American Journal of Hematology (1984)

Abstract A case of agranulocytosis in an 86‐year‐old man after 8 weeks treatment with quinidine sulfate is described. Acute phase serum from the patient demonstrated antineutrophil activity by the microgranulocytotoxicity assay. Review of the literature reveals that more than one mechanism could cause this idiosyncratic immune‐mediated agranulocytosis.
Purchasers, professionals, and public health Criticisms of Abrams report are misdirected..
Authors: B Jacobson, T Jewell, G Scally, G Morgan, Z Iqbal, P Monk, A Wheeler, S Jennings, M Gee, G Bickler
Journal: BMJ (1994)

EDITOR, - Andrew Harris and Jonathan Shapiro's strident criticisms of the tunnel vision of the Abrams report are misplaced.1,2 Their analysis shows naivety and a lack of understanding of the real imperatives in public health. The ire that they direct at the Abrams report - without any explanation to readers of what it recommends - is misdirected. Sadly, the narrow focus of the report is needed since the government has shown little legislative commitment to public health.

Moreover, local evidence suggests that mergers of district health authorities and family health services authorities, instead of strengthening public health, have in some cases resulted in a “rationalisation” and loss of public health resources in the name of economies of scale. But the authors' most glaring error is to have equated the public health function with the purchasing activity of district health authorities and family health services authorities. Have they forgotten that most health is gained or lost outside the NHS?

The authors should not let their personal views of public health physicians cloud the real issues about the importance of securing an independent public health voice for local populations. Our energies should be directed instead at developing local alliances to ensure that the real public health issues are still heard. When we have secured this let us argue about the qualifications for leadership in public health.

The Abrams report, while it missed an opportunity to recommend how local public health alliances might be strengthened, should not be held solely responsible for this omission. Its predecessor, the Acheson report, focused almost exclusively on the role of public health physicians.3 Neither report has helped health authorities to build strong, multidisciplinary links with either primary care or, more importantly, local authorities, whose services have a much greater impact on health than the NHS. …
TNF-like weak inducer of apoptosis (TWEAK) and TNF-α cooperate in the induction of keratinocyte apoptosis
Authors: Maya Zimmermann, Andrea Koreck, Norbert Meyer, Tomasz Basinski, Flurina Meiler, Burgler Simone, Stefan Woehrl, Katharina Moritz, Thomas Eiwegger, Peter Schmid-Grendelmeier, Lajos Kemeny, Cezmi A. Akdis
Journal: Journal of Allergy and Clinical Immunology (2011)
Relationship between serum amyloid A and coronary artery disease in women: The NHLBI-sponsored women's ischemia syndrome evaluation (WISE) study
Authors: B. Delia Johnson, Kevin Kip, Paul M. Ridker, Tjendimin Tjandrawan, C. Noel Bairey Merz, Barry L. Sharaf, Carl J. Pepine, William J. Rogers, Sunil Mankad, Mario P. Stylianou, Gerald M. Pohost, Steven E. Reis
Journal: Journal of the American College of Cardiology (2003)
Cubilin Maintains Blood Levels of HDL and Albumin
Authors: Obaidullah Aseem, Brian T. Smith, Marion A. Cooley, Brent A. Wilkerson, Kelley M. Argraves, Alan T. Remaley, W. Scott Argraves
Journal: Journal of the American Society of Nephrology (2013)

Cubilin is an endocytic receptor highly expressed in renal proximal tubules, where it mediates uptake of albumin and filtered forms of apoA-I/HDL. Cubilin deficiency leads to urinary loss of albumin and apoA-I; however, the consequences of cubilin loss on the homeostasis of blood albumin and apoA-I/HDL have not been studied. Using mice heterozygous for cubilin gene deletion (cubilin HT mice), we show that cubilin haploinsufficiency leads to reduced renal proximal tubular uptake of albumin and apoA-I and significantly increased urinary loss of albumin and apoA-I. Moreover, cubilin HT mice displayed significantly decreased blood levels of albumin, apoA-I, and HDL. The levels of albumin and apoA-I protein or mRNA expressed in the liver, kidney, or intestine of cubilin HT mice did not change significantly. The clearance rate of small HDL3 particles (density>1.13 g/ml) from the blood increased significantly in cubilin HT mice. In contrast, the rate of clearance of larger HDL2 particles from the blood did not change significantly, indicating a decreased half-life for HDL particles capable of filtering through the glomerulus. On the basis of these findings, we conclude that cubilin deficiency reduces renal salvage and delivery back to the blood of albumin and apoA-I, which decreases blood levels of albumin and apoA-I/HDL. These findings raise the possibility that therapeutic increase of renal cubilin expression might reduce proteinuria and increase blood levels of albumin and HDL.
Depletion of the oncoprotein Bcl-3 induces centrosome amplification and aneuploidy in cancer cells
Authors: Ruben Zamora, Magali Espinosa, Gisela Ceballos-Cancino, Blanca Segura, Vilma Maldonado, Jorge Melendez-Zajgla
Journal: Molecular Cancer (2010)

Bcl-3 is an atypical member of the inhibitor of NF-kappa B family of proteins since it can function as a coactivator of transcription. Although this oncogene was described in leukemia, it is overexpressed in a number of solid tumors as well. The oncogenic potential of Bcl-3 has been associated with its capacity to increase proliferation by means of activating the cyclin D1 promoter and to its antiapoptotic role mediated by the inhibiton of p53 activity. In the course of dissecting these properties, we found that depleting Bcl-3 protein using shRNAs induce a decrease of proliferation and clonogenic survival associated with the induction of multinucleation and increased ploidy. These effects were associated with a DNA damage response, a delay in G2/M checkpoint and the induction of centrosome amplification.
Association of Nephrin Gene Polymorphisms With Type 2 Diabetes in a Japanese Population: The Funagata Study 
Authors: M. Daimon
Journal: Diabetes Care (2006)

Nephrin is a major component of the glomerular filtration barrier, and its expression was at first thought to be specific to kidney glomerular podocytes (1). However, it was later found in nonrenal tissues, such as the pancreas (2–4), as well. Several studies (2,3,5) have shown the expression of nephrin in human pancreatic islet cells. Therefore, nephrin may play some roles in the pancreatic islet and, thus, may be involved in the pathophysiology leading to diabetes. We here examined the association of the nephrin gene polymorphisms with type 2 diabetes.

The associations of three single nucleotide polymorphisms (SNPs) (C294T, −61C/G, and C2289T) of the nephrin gene with diabetes were examined using two (first and second) sample sets (diabetes, n = 72 and 31, respectively; impaired glucose tolerance [IGT], n = 75 and 77, respectively; and normal glucose tolerance [NGT], n = 227 and 244, respectively) from the cohort population of the Funagata Study, a Japanese community-based study (6). The study conditions were the same as those in our previous report (7).

Three SNPs in the nephrin gene (C to T at nucleotide position 294 in exon 3 from the translation intitiation codon ATG (C294T) (JSNP database ID: IMS-JST 035656), C to G in intron 5 at nucleotide position 61 upstream from the intron 5/exon 6 splicing site …
Evaluation of Randomized Discontinuation Design
Authors: Boris Freidlin, Richard Simon
Journal: Journal of Clinical Oncology (2005)

Single-arm phase II trials may not be appropriate for testing cytostatic agents. We evaluate two kinds of randomized designs for the early development of target-based cytostatic agents.We compared power of the randomized discontinuation and upfront randomization designs under two models for the treatment effect of targeted cytostatic agents.The randomized discontinuation design is not as efficient as upfront randomization if treatment has a fixed effect on tumor growth rate or if treatment benefit is restricted to slower-growing tumors. On the other hand, the randomized discontinuation design can be advantageous under a model where only a subset of patients, those expressing the molecular target, is sensitive to the agent. To achieve efficiency, the design parameters must be carefully structured to provide adequate enrichment of the randomly assigned patients.With careful planning, the randomized discontinuation designs can be useful in some settings in the early development of targeted agents where a reliable assay to select patients expressing the target is not available.
TUBERCULOSIS VERRUCOSA CUTIS AMONG CHINESE IN HONG KONG.
Authors: P. C. MITCHELL
Journal: British Journal of Dermatology (1954)

Journal Article TUBERCULOSIS VERRUCOSA CUTIS AMONG CHINESE IN HONG KONG. Get access P. C. MITCHELL, M.C., T.B., M.B., Ch.B.(Aberdeen), M.R.C.P.(Edinburgh). P. C. MITCHELL, M.C., T.B., M.B., Ch.B.(Aberdeen), M.R.C.P.(Edinburgh). Major, R.A.M.C.; lately Lecturer in Dermatology in the University of Hong Kong Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 66, Issue 12, 1 December 1954, Pages 444–448, https://doi.org/10.1111/j.1365-2133.1954.tb12576.x Published: 01 December 1954
Enhanced Expression of RAD51 Associating Protein-1 Is Involved in the Growth of Intrahepatic Cholangiocarcinoma Cells
Authors: Kazutaka Obama, Seiji Satoh, Ryuji Hamamoto, Yoshiharu Sakai, Yusuke Nakamura, Yoichi Furukawa
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Intrahepatic cholangiocarcinoma (ICC) is the second most common primary cancer in the liver, and its incidence is increasing in developed countries. Experimental Design: To discover novel molecular targets for the diagnosis and treatment of ICCs, we earlier analyzed expression profiles of 25 ICCs using a cDNA microarray containing 27,648 genes. In this study, we focused on the RAD51 associating protein-1 (RAD51AP1) gene because its expression was frequently elevated in our microarray data. Results: Quantitative PCR confirmed that RAD51AP1 expression was elevated in the great majority of the ICCs examined. Immunohistochemical analysis with anti-RAD51AP1 antibody further corroborated its accumulation in 14 of 23 ICC tissues (61%). Notably, suppression of RAD51AP1 by short interfering RNA resulted in growth suppression of cholangiocarcinoma cells, suggesting its involvement in the development and/or progression of ICC. Because RAD51AP1 interacts with RAD51, a molecule involved in DNA repair, we investigated whether RAD51AP1 is implicated in DNA strand breaks using γ-irradiation. As a result, γ-irradiation augmented RAD51AP1 protein expression and brought a focus formation in the nuclei, where accumulated RAD51AP1 colocalized with phosphorylated histone 2AX (γ-H2AX) and RAD51. These data suggest that RAD51AP1 may play a role in cell proliferation as well as DNA repair. Conclusion: Our findings may contribute to the better understanding of cholangiocarcinogenesis and open a new avenue to the development of novel therapeutic and/or diagnostic approach to this type of tumor.
DNA copy number changes in tumors within the spectrum of cellular, atypical, and metastasizing fibrous histiocytoma
Authors: Yann Charli-Joseph, Andrea Saggini, Leona A. Doyle, Christopher D. Fletcher, Jingly Weier, Sonia Mirza, Swapna Vemula, Philip E. LeBoit
Journal: Journal of the American Academy of Dermatology (2014)
Vitamin-D deficiency is associated with chronic bacterial colonisation and disease severity in bronchiectasis
Authors: James D Chalmers, Brian J McHugh, Catherine Docherty, John R W Govan, Adam T Hill
Journal: Thorax (2012)

<h3>Introduction</h3> Vitamin-D deficiency has been linked to an increased risk of respiratory infections. The objective of this study was to determine the frequency and clinical importance of vitamin-D deficiency in patients with bronchiectasis. <h3>Methods</h3> 25-hydroxyvitamin-D was measured by immunoassay in 402 stable patients with bronchiectasis. Patients were classified as vitamin-D deficient (serum 25-hydroxyvitamin-D &lt;25 nmol/l), insufficient (25 nmol/l–74 nmol/l) or sufficient (≥75 nmol/l). Disease severity was assessed, including exacerbation frequency, measurement of airway inflammatory markers, sputum bacteriology and lung function over 3 years follow-up. <h3>Results</h3> 50% of bronchiectasis patients were vitamin-D deficient, 43% insufficient and only 7% sufficient. This compared to only 12% of age and sex matched controls with vitamin-D deficiency (p&lt;0.0001). Vitamin-D deficient patients were more frequently chronically colonised with bacteria (p&lt;0.0001), 21.4% of vitamin-D deficient subjects were colonised with <i>Pseudomonas aeruginosa</i> compared to 10.4% of insufficient patients and 3.6% of sufficient patients, p=0.003. Vitamin-D deficient patients had lower FEV<sub>1</sub>% predicted (p=0.002), and more frequent pulmonary exacerbations (p=0.04). Vitamin-D deficient patients had higher sputum levels of inflammatory markers and demonstrated a more rapid decline in lung function over 3 years follow-up. Defects in neutrophil function and assessment of airway LL-37 levels did not provide a mechanistic explanation for these findings. Vitamin-D deficient patients had, however, higher levels of Vitamin-D Binding Protein in sputum sol. <h3>Conclusions</h3> Vitamin-D deficiency is common in bronchiectasis and correlates with markers of disease severity. The mechanism of this association is unclear.
Comparison of Ipratropium Bromide and Albuterol Sulfate Chlorofluorocarbon Metered-Dose Inhaler and Albuterol Hydrofluoroalkane Metered-Dose Inhaler in a Crossover Trial in Patients with Moderate-to-Severe Asthma
Authors: E.R. Bleecker, W.W. Busse, J.F. Donohue, S. Garfinkel, T. Lystig, R.C. Manuel, R. Schlenker-Herceg, R.A. Wise
Journal: Journal of Allergy and Clinical Immunology (2011)
Immediate and delayed impact of oral glucocorticoid therapy on risk of serious infection in older patients with rheumatoid arthritis: a nested case–control analysis
Authors: William G Dixon, Michal Abrahamowicz, Marie-Eve Beauchamp, David W Ray, Sasha Bernatsky, Samy Suissa, Marie-Pierre Sylvestre
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Objectives</h3> To explore the relationship of serious infection risk with current and prior oral glucocorticoid (GC) therapy in elderly patients with rheumatoid arthritis (RA). <h3>Methods</h3> A case-control analysis matched 1947 serious infection cases to five controls, selected from 16207 RA patients aged ≥65 between 1985–2003 in Quebec, Canada. Adjusted odds ratios for infection associated with different GC patterns were estimated using conventional models and a weighted cumulative dose (WCD) model. <h3>Results</h3> The WCD model predicted risks better than conventional models. Current and recent GC doses had highest impact on current risk. Doses taken up to 2.5 years ago were also associated with increased risk, albeit to a lesser extent. A current user of 5mg prednisolone had a 30%, 46% or 100% increased risk of serious infection when used continuously for the last 3 months, 6 months or 3 years, respectively, compared to a non-user. The risk associated with 5mg prednisolone taken for the last 3 years was similar to that associated with 30mg taken for the last month. Discontinuing a two-year course of 10mg prednisolone six months ago halved the risk compared to ongoing use. <h3>Conclusions</h3> GC therapy is associated with infection risk in older patients with RA. The WCD model provided more accurate risk estimates than conventional models. Current and recent doses have greatest impact on infection risk, but the cumulative impact of doses taken in the last 2–3 years still affects risk. Knowing how risk depends on pattern of GC use will contribute to an improved benefit/harm assessment.
The Prognostic Implication of the Basal-Like (Cyclin Ehigh/p27low/p53+/Glomeruloid-Microvascular-Proliferation+) Phenotype of <b> <i>BRCA1</i> </b>-Related Breast Cancer
Authors: William D. Foulkes, Jean-Sébastien Brunet, Ingunn M. Stefansson, Oddbjørn Straume, Pierre O. Chappuis, Louis R. Bégin, Nancy Hamel, John R. Goffin, Nora Wong, Michel Trudel, Linda Kapusta, Peggy Porter, Lars A. Akslen
Journal: Cancer Research (2004)

Abstract Previous studies have shown that BRCA1-related breast cancers are often high-grade tumors that do not express estrogen receptors, HER2, p27Kip1, or cyclin D1, but do express p53 and cyclin E. In addition, the expression of cytokeratin 5/6 (CK5/6), indicating a basal epithelial phenotype, is frequent in BRCA1-related breast cancer. Here, in a series of 247 breast cancers, we demonstrate that CK5/6 expression was associated with nearly all of the features of BRCA1-related breast cancer and was also associated with a poor prognosis. In a parsimonious multivariable proportional hazards model, protein levels of cyclin E, p27Kip1, p53, and the presence of glomeruloid microvascular proliferation all independently predicted outcome after breast cancer. In this model, only cyclin E and p27Kip1 levels were independent predictors in lymph node-negative cancers, whereas glomeruloid microvascular proliferation and tumor size independently predicted outcome in node-positive disease. The molecular determinants of the basal epithelial phenotype encapsulate many of the key features of breast cancers occurring in germ-line BRCA1 mutation carriers and have independent prognostic value. Basal breast cancer deserves recognition as an important subtype of breast cancer.
The United Kingdom Infantile Spasms Study (UKISS) comparing hormone treatment with vigabatrin on developmental and epilepsy outcomes to age 14 months: a multicentre randomised trial
Authors: Andrew L Lux, Stuart W Edwards, Eleanor Hancock, Anthony L Johnson, Colin R Kennedy, Richard W Newton, Finbar JK O'Callaghan, Christopher M Verity, John P Osborne
Journal: The Lancet Neurology (2005)
Relevance of the International Prognostic Index in the Rituximab Era
Authors: Kevin Tay, David Tai, Miriam Tao, Richard Quek, Tam-Cam Ha, Soon-Thye Lim
Journal: Journal of Clinical Oncology (2010)

TO THEEDITOR:Wereadwithinterestthismeta-anaylsisbyZiepert etal 1 involving1,062patientswithdiffuselargeB-celllymphomaaccrued fromthreeprospectivephaseII/IIItrials:MinT(Mab-TheraInternational Trial), RICOVER-60 (cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab [R-CHOP] for patients older than age 60 years),andMegaCHOEP(dose-escalatedregimenofcyclophosphamide, doxorubicin,vincristine,etoposide,andprednisone)trials. 2-4 Theauthors affirms the prognostic relevance of the International Prognostic Index (IPI)scoreforallthreeendpointsofprogression-freesurvival,event-free survival,andoverallsurvival.Thus,theyconcludedthatIPIshouldremain the major tool for risk stratification for patients with diffuse large B-cell lymphoma in the era of rituximab. WhileweagreewithZiepertetal 1 thattheIPIwillremainanimpor
Guidelines for Antihypertensive Treatment
Authors: Antonio Salvetti, Lorenzo Ghiadoni
Journal: Journal of the American Society of Nephrology (2004)

ABSTRACT. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) Study, the largest double-blind, randomized trial in hypertensive patients, confirmed and strengthened the clinical relevance of thiazide diuretics in the treatment of hypertension but did not prove the superiority of these drugs. Its claim of the superiority of chlorthalidone was based on some secondary outcomes, principally represented by (1) an increased incidence of stroke in the doxazosin and lisinopril arms, an effect that might be explained by differences in systolic BP; (2) greater morbidity but not mortality for congestive heart failure (CHF) in the doxazosin, amlodipine, and lisinopril arms, a finding that might reflect poor accuracy in the diagnosis and/or especially the switching from diuretic treatment in 90% of patients. Moreover, the ALLHAT study has other limitations, and its conclusions are in contrast with data from overall controlled clinical trials indicating that given the same BP reduction, the benefit of different drug classes is similar. As to whether the ALLHAT study will influence ongoing guidelines concerning the choice of antihypertensive drugs, the answer is "yes" if interpretation of its data in favor of diuretics and cost of drugs become the preponderant considerations, as it was in recent JNC VII guidelines. However, the more liberal approach based on the choice of all available drug classes seems still to be valid, as is in the ESH-ESC guidelines, if the preponderant consideration is that the real benefit of antihypertensive therapy is due to efficient BP control and not to a particular benefit of a single drug class.