tbuckley/cabot-search huggingface dataset:
Complement Factor 3 Is Associated With Insulin Resistance and With Incident Type 2 Diabetes Over a 7-Year Follow-up Period: The CODAM Study
Authors: Nick Wlazlo, Marleen M.J. van Greevenbroek, Isabel Ferreira, Edith J.M. Feskens, Carla J.H. van der Kallen, Casper G. Schalkwijk, Bert Bravenboer, Coen D.A. Stehouwer
Journal: Diabetes Care (2014)

OBJECTIVE Immune dysregulation can affect insulin resistance (IR) and β-cell function and hence contribute to development of type 2 diabetes mellitus (T2DM). The complement system, as a regulator of immune and inflammatory homeostasis, may be a relevant contributor therein. However, longitudinal studies focusing on complement as a determinant of T2DM and IR are scarce. Therefore, we prospectively investigated the association of plasma complement factor 3 (C3) with (estimates of) IR in muscle, liver, and adipocytes, as well as with glucose tolerance, including incident T2DM. RESEARCH DESIGN AND METHODS Fasting C3, nonesterified fatty acids, glucose, and insulin (the latter two during oral glucose tolerance tests) were measured at baseline (n = 545) and after 7 years of follow-up (n = 394) in a prospective cohort study. RESULTS Over the 7-year period, C3 levels (per 0.1 g/L) were longitudinally associated with higher homeostasis model assessment of IR (HOMA2-IR; β = 15.2% [95% CI 12.9–17.6]), hepatic IR (β = 6.1% [95% CI 4.7–7.4]), adipocyte IR (β = 16.0% [95% CI 13.0–19.1]), fasting glucose (β = 1.8% [95% CI 1.2–2.4]), 2-h glucose (β = 5.2% [95% CI 3.7–6.7]), and area under the curve for glucose (β = 3.6% [95% CI 2.7–4.6]). In addition, greater changes in C3 (per 0.1 g/L) were associated with greater changes in HOMA2-IR (β = 0.08 [95% CI 0.02–0.15]) and greater changes in hepatic IR (β = 0.87 [95% CI 0.12–1.61]) over 7 years, but not glucose tolerance. Moreover, baseline C3 was associated with the 7-year incidence of T2DM (odds ratio 1.5 [95% CI 1.1–2.0]). CONCLUSIONS Changes in C3 were associated with changes in several measures of IR and may reflect progression of metabolic dysregulation, which eventually leads to abnormalities in glucose tolerance and T2DM.
Effect of Expansions in State Medicaid Eligibility on Access to Care and the Use of Emergency Department Services for Adult Medicaid Enrollees
Authors: Chima D. Ndumele, Vincent Mor, Susan Allen, James F. Burgess, Amal N. Trivedi
Journal: JAMA Internal Medicine (2014)

<h3>Importance</h3> Medicaid enrollees typically report worse access to care than other insured populations. Expansions in Medicaid through less restrictive income eligibility requirements and the resulting influx of new enrollees may further erode access to care for those already enrolled in Medicaid. <h3>Objective</h3> To assess the effect of previous Medicaid expansions on self-reported access to care and the use of emergency department services by Medicaid enrollees. <h3>Design, Setting, and Participants</h3> Quasi-experimental difference-in-differences design among 1714 adult Medicaid enrollees in 10 states that expanded Medicaid between June 1, 2000, and October 1, 2009, and 5097 Medicaid enrollees in 14 bordering control states that did not expand Medicaid. <h3>Main Outcomes and Measures</h3> Self-reported access to care and annualized emergency department use. <h3>Results</h3> Among states expanding their Medicaid program for adults, the mean income eligibility level increased from 82.6% to 144.2% of the federal poverty level. Income eligibility in matched control states remained constant at 77.1% of the federal poverty level. The proportion of adults reporting being enrolled in Medicaid increased from 7.2% to 8.8% in expansion states and from 6.1% to 6.4% in matched control states. In Medicaid program expansion states, the proportion of Medicaid enrollees reporting poor access to care declined from 8.5% before the expansion to 7.3% after the expansion. In matched control states, the proportion of Medicaid enrollees reporting poor access to care remained constant at 5.3%. The proportion of enrollees reporting any emergency department use decreased from 41.2% to 40.1% in expansion states and from 37.3% to 36.1% in matched control states. In the period following expansions, newly eligible enrollees reported poorer access to care than previously enrolled beneficiaries, although the overall difference between groups did not reach statistical significance. <h3>Conclusions and Relevance</h3> We found no evidence that expanding the number of individuals eligible for Medicaid coverage eroded perceived access to care or increased the use of emergency services among adult Medicaid enrollees.
APEX1 Regulation of Aldosterone Synthase Gene Transcription Is Disrupted by a Common Polymorphism in Humans
Authors: Frances McManus, William Sands, Louise Diver, Scott M. MacKenzie, Robert Fraser, Eleanor Davies, John M. Connell
Journal: Circulation Research (2012)

Rationale: The genetic mechanisms underlying hypertension are unclear, but relative aldosterone excess, present in ≈10% of hypertensive patients, is known to be a heritable trait. This phenotype associates with a T/C single nucleotide polymorphism (SNP) at position -344 of the aldosterone synthase gene ( CYP11B2 ). However, deletion of this SNP has no effect on gene transcription. We have identified another T/C SNP at -1651, in tight linkage disequilibrium with the -344 SNP and here investigate its functional effect on CYP11B2 transcription. Objective: We assessed the effect on transcriptional activity of the -1651 T/C SNP in vivo and in vitro and propose the mechanism by which transcriptional activity is altered. Methods and Results: We demonstrated that the SNP at -1651 exerts significant allele-dependent effects on CYP11B2 transcription. We confirm binding of the transcriptional repressor APEX1 to -1651T, which is associated with reduced transcriptional activity in relation to the less strongly bound -1651C. We show that inhibiting APEX1 by small molecule inhibition or small interfering RNA (SiRNA) leads to increased CYP11B2 transcription. In addition, overexpression of APEX1 is associated with reduced transcriptional activity. Finally, we also show that -1651T associates with lower excretion rates of aldosterone metabolites in human subjects. Conclusions: We conclude that APEX1 is a novel transcriptional repressor of CYP11B2 and that differential APEX1 binding at -1651 of CYP11B2 results in altered gene expression. This mechanism may contribute to the observed relationship between CYP11B2 genotype and aldosterone phenotype in a subgroup of hypertensive patients.
Cardiac disease in systemic lupus erythematosus: prospective study of 70 patients.
Authors: R Cervera, J Font, C Pare, M Azqueta, F Perez-Villa, A Lopez-Soto, M Ingelmo
Journal: Annals of the Rheumatic Diseases (1992)

A prospective two dimensional and Doppler echocardiographic study of 70 consecutive patients with systemic lupus erythematosus (SLE) and 40 controls was carried out. Forty patients (57%) were found to have echocardiographic disturbance. Valvular abnormalities were detected in 31 patients (44%) and in only two controls (5%). Mitral valve abnormalities were the most common findings (23/70 (33%)) with mild or moderate regurgitation the most frequent lesion (16% and 9% respectively). Three patients (4%) had a morphological echocardiographic pattern suggestive of non-infective verrucous vegetations affecting the mitral valve. No patient had haemodynamically significant clinical valve disease. Pericardial effusion was identified in 19 patients (27%), of whom 14 had mild and clinically silent disease. Myocardial abnormalities were found in 14 patients (20%), but clinical features of myocardial dysfunction were present in only one. Patients with antiphospholipid antibodies were found to have an increased prevalence of endocardial lesions, mainly valvular regurgitation. It is concluded that the inclusion of echocardiography in a study protocol of patients with SLE can identify an important subset of patients with cardiac abnormalities, many of which are clinically silent. In addition, the association of antiphospholipid antibodies with endocardial lesions suggests that these antibodies may have a prominent role in the pathogenetic mechanisms of heart valve disease in SLE.
Inhaled corticosteroids versus anti‐leukotrienes: a literature review on the clinical effects
Authors: P.W. Ind
Journal: Allergy (1999)

To cite this article: Dr. Ind Philip W . Inhaled corticosteroids versus anti‐leukotrienes: a literature review on the clinical effects. Allergy 1999, 54 , 43–46. Copyright © Munksgaard 1999 ISSN 0108–1675
Phylogenomic evidence supports past endosymbiosis, intracellular and horizontal gene transfer in Cryptosporidium parvum
Authors: Jinling Huang, Nandita Mullapudi, Cheryl A Lancto, Marla Scott, Mitchell S Abrahamsen, Jessica C Kissinger
Journal: Genome biology (2004)

Abstract Background The apicomplexan parasite Cryptosporidium parvum is an emerging pathogen capable of causing illness in humans and other animals and death in immunocompromised individuals. No effective treatment is available and the genome sequence has recently been completed. This parasite differs from other apicomplexans in its lack of a plastid organelle, the apicoplast. Gene transfer, either intracellular from an endosymbiont/donor organelle or horizontal from another organism, can provide evidence of a previous endosymbiotic relationship and/or alter the genetic repertoire of the host organism. Given the importance of gene transfers in eukaryotic evolution and the potential implications for chemotherapy, it is important to identify the complement of transferred genes in Cryptosporidium . Results We have identified 31 genes of likely plastid/endosymbiont (n = 7) or prokaryotic (n = 24) origin using a phylogenomic approach. The findings support the hypothesis that Cryptosporidium evolved from a plastid-containing lineage and subsequently lost its apicoplast during evolution. Expression analyses of candidate genes of algal and eubacterial origin show that these genes are expressed and developmentally regulated during the life cycle of C. parvum . Conclusions Cryptosporidium is the recipient of a large number of transferred genes, many of which are not shared by other apicomplexan parasites. Genes transferred from distant phylogenetic sources, such as eubacteria, may be potential targets for therapeutic drugs owing to their phylogenetic distance or the lack of homologs in the host. The successful integration and expression of the transferred genes in this genome has changed the genetic and metabolic repertoire of the parasite.
Dose-Additive Carcinogenicity of a Defined Mixture of “Dioxin-like Compounds”
Authors: Nigel J. Walker, Patrick W. Crockett, Abraham Nyska, Amy E. Brix, Michael P. Jokinen, Donald M. Sells, James R. Hailey, Micheal Easterling, Joseph K. Haseman, Ming Yin, Michael E. Wyde, John R. Bucher, Christopher J. Portier
Journal: Environmental Health Perspectives (2004)

Use of the dioxin toxic equivalency factor (TEF) approach in human risk assessments assumes that the combined effects of dioxin-like compounds in a mixture can be predicted based on a potency-adjusted dose-additive combination of constituents of the mixture. In this study, we evaluated the TEF approach in experimental 2-year rodent cancer bioassays with female Harlan Sprague-Dawley rats receiving 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 3,3 ,4,4 ,5-pentachlorobiphenyl (PCB-126), 2,3,4,7,8-pentachlorodibenzofuran (PeCDF), or a mixture of the three compounds. Statistically based dose-response modeling indicated that the shape of the dose-response curves for hepatic, lung, and oral mucosal neoplasms was the same in studies of the three individual chemicals and the mixture. In addition, the dose response for the mixture could be predicted from a combination of the potency-adjusted doses of the individual compounds. Finally, we showed that use of the current World Health Organization dioxin TEF values adequately predicted the increased incidence of liver tumors (hepatocellular adenoma and cholangiocarcinoma) induced by exposure to the mixture. These data support the use of the TEF approach for dioxin cancer risk assessments.
Aspirin Therapy in Primary Cardiovascular Disease Prevention
Authors: Sigrun Halvorsen, Felicita Andreotti, Jurriën M. ten Berg, Marco Cattaneo, Sergio Coccheri, Roberto Marchioli, João Morais, Freek W.A. Verheugt, Raffaele De Caterina
Journal: Journal of the American College of Cardiology (2014)

Although the use of oral anticoagulants (vitamin K antagonists) has been abandoned in primary cardiovascular prevention due to lack of a favorable benefit-to-risk ratio, the indications for aspirin use in this setting continue to be a source of major debate, with major international guidelines providing conflicting recommendations. Here, we review the evidence in favor and against aspirin therapy in primary prevention based on the evidence accumulated so far, including recent data linking aspirin with cancer protection. While awaiting the results of several ongoing studies, we argue for a pragmatic approach to using low-dose aspirin in primary cardiovascular prevention and suggest its use in patients at high cardiovascular risk, defined as ≥2 major cardiovascular events (death, myocardial infarction, or stroke) projected per 100 person-years, who are not at increased risk of bleeding.
Increased Incidence of Visceral Metastases in Scottish Patients With BRCA1/2-Defective Ovarian Cancer: An Extension of the Ovarian BRCAness Phenotype
Authors: Charlie Gourley, Caroline O. Michie, Patricia Roxburgh, Timothy A. Yap, Sharon Harden, Jim Paul, Kalpana Ragupathy, Radha Todd, Russell Petty, Nick Reed, Richard L. Hayward, Paul Mitchell, Tzyvia Rye, Jan H.M. Schellens, Jan Lubinski, James Carmichael, Stan B. Kaye, Melanie Mackean, Michelle Ferguson
Journal: Journal of Clinical Oncology (2010)

To compare the frequency of visceral relapse of BRCA1/2-deficient ovarian cancer to that of nonhereditary controls.All patients diagnosed in Scotland with epithelial ovarian cancer (EOC) or primary peritoneal cancer (PPC) and a germline BRCA1/2 mutation were identified. Those with previous malignancy were excluded. Each remaining patient who experienced relapse was matched with two nonhereditary controls.Seventy-nine patients with EOC/PPC and germline BRCA1/2 mutations were identified. Fifteen had inadequate clinical data, two had carcinosarcoma, 27 had previous breast cancer, and 16 were in remission. Of the remaining 19 patients who were BRCA1/2 deficient, 14 patients (74%) developed visceral metastases compared with six (16%) of 38 patients in the control group. The percentages of liver, lung, and splenic metastases were 53%, 32%, and 32%, respectively, in the patients compared with 5%, 3%, and 5%, respectively, in the controls. When events occurring outside the matched follow-up period were omitted, the percentages of visceral, liver, lung, and splenic metastases were 58%, 42%, 16%, and 32% in the patients compared with 5%, 0%, 0%, and 3% in controls (P < .001, P < .001, P = .066, and P = .011, respectively). In an independent validation set, the corresponding percentages of visceral, liver, lung, and splenic metastases were 63%, 46%, 13%, and 17% in the patients compared with 11%, 4%, 2%, and 2% in controls (P < .001, P < .001, P = .153, and P = .052, respectively).Although sporadic EOC commonly remains confined to the peritoneum, BRCA1/2-deficient ovarian cancer frequently metastasizes to viscera. These data extend the ovarian BRCAness phenotype, imply BRCA1/2-deficient ovarian cancer is biologically distinct, and suggest that patients with visceral metastases should be considered for BRCA1/2 sequencing.
Alterations in candidate genes PHF2, FANCC, PTCH1 and XPA at chromosomal 9q22.3 region: Pathological significance in early- and late-onset breast carcinoma
Authors: Satyabrata Sinha, Ratnesh K Singh, Neyaz Alam, Anup Roy, Susanta Roychoudhury, Chinmay Kumar Panda
Journal: Molecular Cancer (2008)

Abstract Introduction Younger women with breast carcinoma (BC) exhibits more aggressive pathologic features compared to older women; young age could be an independent predictor of adverse prognosis. To find any existing differences in the molecular pathogenesis of BC in both younger and older women, alterations at chromosomal (chr.) 9q22.32-22.33 region were studied owing to its association in wide variety of tumors. Present work focuses on comparative analysis of alterations of four candidate genes; PHF2, FANCC, PTCH1 and XPA located within 4.4 Mb region of the afore-said locus in two age groups of BC, as well as the interrelation and prognostic significance of alterations of these genes. Methods Deletion analysis of PHF2, FANCC, PTCH1 and XPA were examined in a subset of 47 early-onset (group-A: ≤ 40 years) and 59 late-onset (group-B: &gt; 40 years) breast carcinomas using both microsatellite and exonic markers. Methylation Sensitive Restriction analysis (MSRA) was done to check for promoter methylation. Quantitative real-time polymerase chain reaction (Q-PCR) and immunohistochemisty (IHC) was done in some genes to see their relative mRNA and protein expressions respectively. Clinico-pathological correlation of different parameters as well as patient survival was calculated using different statistical softwares like EpiInfo 6.04b, SPSS 10.0 etc. Results Either age group exhibited high frequency of overall alterations in PHF2, FANCC and PTCH1 compared to XPA. Samples with alteration (deletion/methylation) in these genes showed reduced level of mRNA expression as seen by Q-PCR. Immunohistochemical analysis of FANCC and PTCH1 also supported this observation. Poor patient survival was noted in both age groups having alterations in FANCC. Similar result was also seen with PTCH1 and XPA alterations in group-A and PHF2 alterations in group-B. This reflected their roles as prognostic tools in the respective groups in which they were altered. Conclusion Overall alterations of PHF2, FANCC and PTCH1 were comparatively higher than XPA. Differential association of alterations in FANCC and PTCH1 with that of PHF2, XPA and two breast cancer susceptibility genes (BRCA1/BRCA2) in the two age groups suggests differences in their molecular pathogenesis and dysregulation of multiple DNA repair pathways as well as hedgehog dependent stem cell renewal pathway.
Jacques-Louis David’s tumour: an opportunity to study the natural history of a pleomorphic adenoma of the parotid gland
Authors: Humphrey Wine, Michael Baum
Journal: Journal of the Royal Society of Medicine (2008)

The great artist and one-time revolutionary, Jacques-Louis David died in 1825. The cause of his death has been open to speculation. An extraordinary sequence of portraits of the artist describes his transition from handsome middle age to a deformed old man. During this phase a swelling appears at the angle of his left jaw and over a period of 20 years a facial palsy can be diagnosed. We submit that this evidence suggests that malignant transformation of a pleomorphic adenoma of the parotid gland was the proximal cause of his death.
Effects of the Endocrine-Disrupting Chemical DDT on Self-Renewal and Differentiation of Human Mesenchymal Stem Cells
Authors: Amy L. Strong, Zhenzhen Shi, Michael J. Strong, David F.B. Miller, Douglas B. Rusch, Aaron M. Buechlein, Erik K. Flemington, John A. McLachlan, Kenneth P. Nephew, Matthew E. Burow, Bruce A. Bunnell
Journal: Environmental Health Perspectives (2014)

Although the global use of the endocrine-disrupting chemical DDT has decreased, its persistence in the environment has resulted in continued human exposure. Accumulating evidence suggests that DDT exposure has long-term adverse effects on development, yet the impact on growth and differentiation of adult stem cells remains unclear.
Proinsulin/Insulin Autoantibodies Measured With Electrochemiluminescent Assay Are the Earliest Indicator of Prediabetic Islet Autoimmunity
Authors: Liping Yu, Fran Dong, Dongmei Miao, Alexandra R. Fouts, Janet M. Wenzlau, Andrea K. Steck
Journal: Diabetes Care (2013)

OBJECTIVE We evaluated a novel electrochemiluminescent assay for insulin/proinsulin autoantibodies (ECL-IAA) as a new marker of the onset of islet autoimmunity and as a predictor of type 1 diabetes. RESEARCH DESIGN AND METHODS The Diabetes Autoimmunity Study in the Young (DAISY) prospectively follows children at increased genetic risk for development of islet autoimmunity (defined as presence of autoantibodies to insulin, GAD65, IA-2, or zinc transporter 8 [ZnT8]) and type 1 diabetes (general population of children and first-degree relatives). Serial serum samples from subjects who progressed to type 1 diabetes and who had their first islet autoantibodies measured by age 18 months (N = 47) were tested using ECL-IAA. RESULTS Almost all prediabetic children tested positive for ECL-IAA (46 of 47, 98%) during follow-up. ECL-IAA was almost always the first autoantibody to appear (94% total; 21% very first [by itself]; 23% with only mIAA; 19% with another islet autoantibody [GAD or ZnT8]; and 30% with ≥2 other antibodies [mIAA, GAD, IA-2, or ZnT8]). Among the 46 subjects who were ECL-IAA positive, ECL-IAA antedated the onset of other islet autoantibodies by a mean of 2.3 years (range, 0.3–7.2 years). Both the age of appearance of autoantibody and IAA levels (but not GAD65, IA2, or ZnT8 levels) are major determinants of the age of diabetes onset. CONCLUSIONS This new ECL-IAA assay defines more precisely the onset of prediabetic autoimmunity and may help identify events triggering islet autoimmunity, as well as allow earlier intervention for type 1 diabetes. Nearly all young children progressing to diabetes are insulin autoantibody positive.
ALLOANTISERUM-INDUCED INHIBITION OF IMMUNE RESPONSE GENE PRODUCT FUNCTION
Authors: Ethan M. Shevach, William E. Paul, Ira Green
Journal: The Journal of Experimental Medicine (1974)

It has been previously shown that alloantisera prepared by reciprocal immunization of strain 2 and strain 13 guinea pigs specifically block the activation of T lymphocytes from immune guinea pigs by antigens, the response to which is controlled by Ir genes. In this report we have examined the effect of absorption of the 13 anti-2 serum with different populations of lymphoid cells. It is unlikely that the inhibitory activity of the anti-2 serum on the proliferation of (2 x 13)F1 lymphocytes to a DNP derivative of a copolymer of L-glutamic and L-lysine (DNP-GL) is due to the presence of antibodies specific for the unique antigenic determinants (idiotypes) of clonally distributed T-lymphocyte receptors. Thus, cells obtained from a normal animal and a DNP-GL immune animal were equivalent in their absorptive capacity. Populations of T lymphocytes were ineffective in absorbing either the cytotoxic or inhibitory activity of the anti-2 serum, while L2C leukemia cells, a malignant B-cell population, were most efficient in absorbing both activities. Thus, the antigen(s) against which the cytotoxic and inhibitory activities are directed are present to a greater extent on B lymphocytes than on T lymphocytes. However, these results do not allow us to definitively determine whether the inhibitory activity of the alloantisera is due to antibodies specific for Ir gene products or antibodies specific for linked antigens in the MHC. We also examined the effect of a number of anti-immunoglobulin reagents which had specificity for the heavy and/or light chains of guinea pig immunoglobulin on the in vitro lymphocyte proliferative response to antigen. Under conditions in which we were able to completely and specifically suppress the response of (2 x 13)F1 lymphocytes to DNP-GL with anti-2 serum, the anti-immunoglobulin reagents were devoid of inhibitory effect on the response of these same F1 cells to DNP-GL, a copolymer of L-glutamic and L-tyrosine (GT), or purified protein derivative of tuberculin (PPD). These results strongly suggest that conventional serum-type immunoglobulin is not important in antigen recognition by the T cells involved in the DNA synthetic response.