tbuckley/cabot-search huggingface dataset:
Low Testosterone and High C-Reactive Protein Concentrations Predict Low Hematocrit in Type 2 Diabetes
Authors: Vishal Bhatia, Ajay Chaudhuri, Rashmi Tomar, Sandeep Dhindsa, Husam Ghanim, Paresh Dandona
Journal: Diabetes Care (2006)

After the demonstration that one-third of male patients with type 2 diabetes have hypogonadotrophic hypogonadism, we have shown that patients with hypogonadotrophic hypogonadism also have markedly elevated C-reactive protein (CRP) concentrations. We have now hypothesized that type 2 diabetic subjects with hypogonadotrophic hypogonadism may have a lower hematocrit because testosterone stimulates, whereas chronic inflammation suppresses, erythropoiesis.Seventy patients with type 2 diabetes at a tertiary referral center were included in this study.The mean hematocrit in patients with hypogonadotrophic hypogonadism (n = 37), defined as calculated free testosterone (cFT) of <6.5 ng/dl, was 40.6 +/- 1.1%, whereas that in eugonadal patients (n = 33) was 43.3 +/- 0.7% (P = 0.011). The hematocrit was related to cFT concentration (r = 0.46; P < 0.0001); it was inversely related to plasma CRP concentration (r = 0.41; P < 0.0004). Patients with CRP <3 mg/l had a higher hematocrit (42.7 +/- 0.7%) than those with CRP >3 mg/l (39.9 +/- 1.1%; P < 0.05). The prevalence of normocytic normochromic anemia (hemoglobin <13 g/dl) was 23% in the entire group, whereas it was 37.8% in the men with hypogonadotrophic hypogonadism and 3% in the eugonadal men (P < 0.01). Erythropoietin concentration was elevated or high normal in all 11 patients with anemia in whom it was tested.We conclude that hypogonadotrophic hypogonadism in male type 2 diabetic subjects is associated with a lower hematocrit and a frequent occurrence of mild normocytic normochromic anemia with normal or high erythropoietin concentrations. In these patients, hematocrit is also inversely related to CRP concentration. Thus, low testosterone and chronic inflammatory mechanisms may contribute to mild anemia. Such patients may also have a high risk of atherosclerotic cardiovascular events in view of their markedly elevated CRP concentrations.
Relationship of Paraoxonase 1 (PON1) Gene Polymorphisms and Functional Activity With Systemic Oxidative Stress and Cardiovascular Risk
Authors: Tamali Bhattacharyya
Journal: JAMA (2008)

Paraoxonase 1 (PON1) is reported to have antioxidant and cardioprotective properties. The relationship between PON1 genotypes and functional activity with systemic measures of oxidative stress and cardiovascular disease (CVD) risk in humans has not been systematically investigated.To investigate the relationship of genetic and biochemical determinants of PON1 activity with systemic measures of oxidative stress and CVD risk in humans.The association between systemic PON1 activity measures and a functional polymorphism (Q192R) resulting in high PON1 activity with prevalent CVD and future major adverse cardiac events (myocardial infarction, stroke, or death) was evaluated in 1399 sequential consenting patients undergoing diagnostic coronary angiography between September 2002 and November 2003 at the Cleveland Clinic. Patients were followed up until December 2006. Systemic levels of multiple structurally defined fatty acid oxidation products were also measured by mass spectrometry in 150 age-, sex-, and race-matched patients and compared with regard to PON1 genotype and activity.Relationship between a functional PON1 polymorphism and PON1 activity with global indices of systemic oxidative stress and risk of CVD.The PON1 genotype demonstrated significant dose-dependent associations (QQ192 > QR192 > RR192) with decreased levels of serum PON1 activity and with increased levels of systemic indices of oxidative stress. Compared with participants with either the PON1 RR192 or QR192 genotype, participants with the QQ192 genotype demonstrated an increased risk of all-cause mortality (43/681 deaths [6.75%] in RR192 and QR192 and 62/584 deaths [11.1%] in QQ192; adjusted hazard ratio, 2.05; 95% confidence interval [CI], 1.32-3.18) and of major adverse cardiac events (88/681 events [13.6%] in RR192 and QR192 and 102/584 events [18.0%] in QQ192; adjusted hazard ratio, 1.48; 95% CI, 1.09-2.03; P = .01). The incidence of major adverse cardiac events was significantly lower in participants in the highest PON1 activity quartile (23/315 [7.3%]) and 235/324 [7.7%] for paraoxonase and arylesterase, respectively) compared with those in the lowest activity quartile (78/311 [25.1%] and 75/319 [23.5%]; P < .001 for paraoxonase and arylesterase, respectively). The adjusted hazard ratios for major adverse cardiac events between the highest and lowest PON1 activity quartiles were, for paraoxonase, 3.4 (95% CI, 2.1-5.5; P < .001) and for arylesterase, 2.9 (95% CI, 1.8-4.7; P < .001) and remained independent in multivariate analysis.This study provides direct evidence for a mechanistic link between genetic determinants and activity of PON1 with systemic oxidative stress and prospective cardiovascular risk, indicating a potential mechanism for the atheroprotective function of PON1.
Adenoviral-Directed Expression of the Type 1A Angiotensin Receptor Promotes Cardiomyocyte Hypertrophy via Transactivation of the Epidermal Growth Factor Receptor
Authors: Walter G. Thomas, Yves Brandenburger, Dominic J. Autelitano, Thao Pham, Hongwei Qian, Ross D. Hannan
Journal: Circulation Research (2002)

Angiotensin II (Ang II) may cause cardiac hypertrophy via type 1 Ang II receptors (AT(1)) on cardiomyocytes and through growth factors released from cardiac fibroblasts. Whereas cardiomyocyte-specific AT(1) receptor expression produces cardiac hypertrophy and remodeling in vivo, delineation of the signals that mediate growth to Ang II is challenging because the prevailing in vitro model (cultured neonatal cardiomyocytes) expresses low levels of AT(1) receptor and responds inconsistently to Ang II. In this study, when AT(1A) receptors were expressed using adenovirus in cultured neonatal cardiomyocytes, Ang II stimulated a robust hypertrophy that was not secondary to the release of cardiac fibroblast-derived factors, specifically endothelin-1. Hypertrophy was accompanied by the induction of the immediate-early response genes, c-fos and c-jun, and reexpression of atrial natriuretic peptide (ANP). Ang II-induced activation of an ANP promoter-reporter was inhibited by the dominant/negative mutants, GalphaqI and N17Ras, indicating that hypertrophic signaling by the AT(1A) receptor is via heterotrimeric G protein coupling and downstream Ras pathways. AT(1A)-mediated cardiomyocyte hypertrophy and mitogen-activated protein kinase (MAPK) activation were inhibited by the MAPK kinase inhibitor, PD98059, and the epidermal growth factor (EGF) receptor kinase antagonist, AG1478, but not by PKC inhibitor, bisindolylmaleimide-1. Moreover, Ang II-induced MAPK activation was prevented by treatment with a matrix metalloproteinase inhibitor, consistent with the tyrosine phosphorylation of the EGF receptor in response to AT(1A) receptor activation. These data unequivocally demonstrate that Ang II can directly promote cardiac myocyte growth via AT(1A) receptors expressed on these cells and reveal for the first time the important contribution of EGF receptor-transactivated MAPK signaling to this process.
Respiratory Syncytial Virus and Recurrent Wheeze in Healthy Preterm Infants
Authors: Maarten O. Blanken, Maroeska M. Rovers, Jorine M. Molenaar, Pauline L. Winkler-Seinstra, Adam Meijer, Jan L.L. Kimpen, Louis Bont
Journal: New England Journal of Medicine (2013)

Respiratory syncytial virus (RSV) infection is associated with subsequent recurrent wheeze. Observational studies cannot determine whether RSV infection is the cause of recurrent wheeze or the first indication of preexistent pulmonary vulnerability in preterm infants. The monoclonal antibody palivizumab has shown efficacy in preventing severe RSV infection in high-risk infants.In the double-blind, placebo-controlled MAKI trial, we randomly assigned 429 otherwise healthy preterm infants born at a gestational age of 33 to 35 weeks to receive either monthly palivizumab injections (214 infants) or placebo (215 infants) during the RSV season. The prespecified primary outcome was the total number of parent-reported wheezing days in the first year of life. Nasopharyngeal swabs were taken during respiratory episodes for viral analysis.Palivizumab treatment resulted in a relative reduction of 61% (95% confidence interval, 56 to 65) in the total number of wheezing days during the first year of life (930 of 53,075 days in the RSV-prevention group [1.8%] vs. 2309 of 51,726 days [4.5%] in the placebo group). During this time, the proportion of infants with recurrent wheeze was 10 percentage points lower in patients treated with palivizumab (11% vs. 21%, P=0.01).In otherwise healthy preterm infants, palivizumab treatment resulted in a significant reduction in wheezing days during the first year of life, even after the end of treatment. These findings implicate RSV infection as an important mechanism of recurrent wheeze during the first year of life in such infants. (Funded by Abbott Laboratories and by the Netherlands Organization for Health Research and Development; MAKI Controlled Clinical Trials number, ISRCTN73641710.).
MANAGEMENT OF LIVER ABSCESSES
Authors: C.T. Thomas, S.L. Berk, E. Thomas, D. Bertoli, P. Del Poggio, M. Mazzolari, G. Randone, K.M. De Cock, K.M. Bhatt, S.M. Bhatt, J-K.M. Eeftinck Schattenkerk, P.A. Kager, M.V. Shah, T.O. Ogada, P.H. Rees
Journal: The Lancet (1982)
Digoxin Associates with Mortality in ESRD
Authors: Kevin E. Chan, J. Michael Lazarus, Raymond M. Hakim
Journal: Journal of the American Society of Nephrology (2010)

The safety of prescribing digoxin in ESRD is unknown. Hypokalemia, which frequently occurs among dialysis patients, may enhance the toxicity of digoxin. Here, we analyzed the association between digoxin prescription and survival in a retrospective cohort using covariate- and propensity score-adjusted Cox models to minimize the potential for confounding by indication. Among 120,864 incident hemodialysis patients, digoxin use associated with a 28% increased risk for death (hazard ratio [HR] 1.28; 95% confidence interval 1.25 to 1.31). Increasing serum digoxin level was also significantly associated with mortality (HR 1.19 per ng/ml increase; 95% confidence interval 1.05 to 1.35). This increased mortality risk with level was most pronounced in patients with lower predialysis serum potassium (K) levels (HR 2.53 [P = 0.01] for K <4.3 mEq/L versus HR 0.86 [P = 0.35] for K >4.6 mEq/L). In conclusion, digoxin use among patients who are on hemodialysis associates with increased mortality, especially among those with low predialysis K concentrations.
Effect of Three Decades of Screening Mammography on Breast-Cancer Incidence
Authors: Archie Bleyer, H. Gilbert Welch
Journal: New England Journal of Medicine (2012)

To reduce mortality, screening must detect life-threatening disease at an earlier, more curable stage. Effective cancer-screening programs therefore both increase the incidence of cancer detected at an early stage and decrease the incidence of cancer presenting at a late stage.We used Surveillance, Epidemiology, and End Results data to examine trends from 1976 through 2008 in the incidence of early-stage breast cancer (ductal carcinoma in situ and localized disease) and late-stage breast cancer (regional and distant disease) among women 40 years of age or older.The introduction of screening mammography in the United States has been associated with a doubling in the number of cases of early-stage breast cancer that are detected each year, from 112 to 234 cases per 100,000 women--an absolute increase of 122 cases per 100,000 women. Concomitantly, the rate at which women present with late-stage cancer has decreased by 8%, from 102 to 94 cases per 100,000 women--an absolute decrease of 8 cases per 100,000 women. With the assumption of a constant underlying disease burden, only 8 of the 122 additional early-stage cancers diagnosed were expected to progress to advanced disease. After excluding the transient excess incidence associated with hormone-replacement therapy and adjusting for trends in the incidence of breast cancer among women younger than 40 years of age, we estimated that breast cancer was overdiagnosed (i.e., tumors were detected on screening that would never have led to clinical symptoms) in 1.3 million U.S. women in the past 30 years. We estimated that in 2008, breast cancer was overdiagnosed in more than 70,000 women; this accounted for 31% of all breast cancers diagnosed.Despite substantial increases in the number of cases of early-stage breast cancer detected, screening mammography has only marginally reduced the rate at which women present with advanced cancer. Although it is not certain which women have been affected, the imbalance suggests that there is substantial overdiagnosis, accounting for nearly a third of all newly diagnosed breast cancers, and that screening is having, at best, only a small effect on the rate of death from breast cancer.
Cardioprotection by Intermittent Fasting in Rats
Authors: Ismayil Ahmet, Ruiqian Wan, Mark P. Mattson, Edward G. Lakatta, Mark Talan
Journal: Circulation (2005)

Background— Intermittent fasting (IF), a dietary regimen in which food is available only every other day, increases the life span and reduces the incidence of age-associated diseases in rodents. We have reported neuroprotective effects of IF against ischemic injury of the brain. In this study, we examined the effects of IF on ischemic injury of the heart in rats. Methods and Results— After 3 months of IF or regular every-day feeding (control) diets started in 2-month-old rats, myocardial infarction (MI) was induced by coronary artery ligation. Twenty-four hours after MI, its size in the IF group was 2-fold smaller, the number of apoptotic myocytes in the area at risk was 4-fold less, and the inflammatory response was significantly reduced compared with the control diet group. Serial echocardiography revealed that during 10 weeks after MI (with continuation of the IF regimen), the left ventricular (LV) remodeling and MI expansion that were observed in the control diet group were absent in the IF group. In a subgroup of animals with similar MI size at 1 week after MI, further observation revealed less remodeling, better LV function, and no MI expansion in the IF group compared with the control group. Conclusions— IF protects the heart from ischemic injury and attenuates post-MI cardiac remodeling, likely via antiapoptotic and antiinflammatory mechanisms.
Differential Association and Localization of Myosin Phosphatase Subunits During Agonist-Induced Signal Transduction in Smooth Muscle
Authors: Heung-Mook Shin, Hyun-Dong Je, Cynthia Gallant, Terence C. Tao, David J. Hartshorne, Masaaki Ito, Kathleen G. Morgan
Journal: Circulation Research (2002)

It has been known for some time that agonist-induced contractions of vascular smooth muscle are often associated with a sensitization of the contractile apparatus to intracellular Ca 2+ . One mechanism that has been suggested to explain Ca 2+ sensitization is inhibition of myosin phosphatase activity. In the present study, we tested the hypothesis that differential localization of the phosphatase might be associated with its inhibition. Quantitative confocal microscopy of freshly dissociated, fully contractile smooth muscle cells was used in parallel with measurements of myosin light chain and myosin phosphatase phosphorylation. The results indicate that, in the smooth muscle cells, the catalytic and targeting subunits of the phosphatase are dissociated from each other in an agonist-specific manner and that the dissociation is accompanied by a slower rate of myosin phosphorylation. Targeting of myosin phosphatase to the cell membrane precedes the dissociation of subunits and is associated with phosphorylation of the targeting subunit at a Rho-associated kinase (ROK) phosphorylation site. The phosphorylation and membrane translocation of the targeting subunit are inhibited by a ROK inhibitor. This dissociation of subunits may provide a mechanism for the decreased phosphatase activity of phosphorylated myosin phosphatase.
Rheumatoid arthritis, treatment with corticosteroids and risk of malignant lymphomas: results from a case-control study
Authors: K. Hellgren, A. Iliadou, R. Rosenquist, N. Feltelius, C. Backlin, G. Enblad, J. Askling, E. Baecklund
Journal: Annals of the Rheumatic Diseases (2009)

<h3>Background</h3> Benefits and risks of corticosteroid treatment in rheumatoid arthritis (RA) are debated. Patients with RA are at increased risk of malignant lymphomas. In a large case–control study of risk factors for lymphoma in RA, it was recently reported that steroid treatment was associated with decreased lymphoma risk. <h3>Objective</h3> To further assess the nature of the association between steroid treatment in RA and the risk of lymphoma. <h3>Methods</h3> In a cohort of 74 651 patients with RA, 378 patients with lymphoma and 378 matched RA controls were identified, and information on inflammatory activity and different aspects of steroid treatment (duration, therapeutic strategy and mode of administration) abstracted from their medical records. Lymphomas were reclassified (WHO classification) and examined for Epstein–Barr virus. Relative risks were assessed as adjusted odds ratios (ORs) through conditional logistic regression. <h3>Results</h3> A total duration of oral steroid treatment of &lt;2 years was not associated with lymphoma risk (OR=0.87; 95% CI 0.51 to 1.5), whereas total treatment &gt;2 years was associated with a lower lymphoma risk (OR=0.43; 95% CI 0.26 to 0.72). RA duration at the initiation of oral steroids did not affect lymphoma risk. Intra-articular steroids were associated with a reduced lymphoma risk, but only when used as swift flare treatment (OR=0.22; 95% CI 0.13 to 0.37). Analyses by lymphoma subtype showed a reduced risk of diffuse large B-cell lymphoma (crude OR=0.59; 95% CI 0.37 to 0.94). <h3>Conclusion</h3> In this RA population, use of steroids was associated with reduced lymphoma risk. Whether this association is a generic effect of steroids or specific to the studied population remains unknown.
Spoken Language Development in Children Following Cochlear Implantation
Authors: John K. Niparko
Journal: JAMA (2010)

ContextCochlear implantation is a surgical alternative to traditional amplification (hearing aids) that can facilitate spoken language development in young children with severe to profound sensorineural hearing loss (SNHL).Objective To prospectively assess spoken language acquisition following cochlear implantation in young children.Design, Setting, and Participants Prospective, longitudinal, and multidimensional assessment of spoken language development over a 3-year period in children who underwent cochlear implantation before 5 years of age (n=188) from 6 US centers and hearing children of similar ages (n=97) from 2 preschools recruited between November 2002 and December 2004.Follow-up completed between November 2005 and May 2008.Main Outcome Measures Performance on measures of spoken language comprehension and expression (Reynell Developmental Language Scales). ResultsChildren undergoing cochlear implantation showed greater improvement in spoken language performance (10.4; 95% confidence interval [CI], 9.6-11.2points per year in comprehension; 8.4; 95% CI, 7.8-9.0 in expression) than would be predicted by their preimplantation baseline scores (5.4; 95% CI, 4.1-6.7,comprehension; 5.8; 95% CI, 4.6-7.0,expression), although mean scores were not restored to age-appropriate levels after 3 years.Younger age at cochlear implantation was associated with significantly steeper rate increases in comprehension (1.1; 95% CI, 0.5-1.7 points per year younger) and expression (1.0; 95% CI, 0.6-1.5 points per year younger).Similarly, each 1-year shorter history of hearing deficit was associated with steeper rate increases in comprehension (0.8; 95% CI, 0.2-1.2 points per year shorter) and expression (0.6; 95% CI, 0.2-1.0 points per year shorter).In multivariable analyses, greater residual hearing prior to cochlear implantation, higher ratings of parentchild interactions, and higher socioeconomic status were associated with greater rates of improvement in comprehension and expression. ConclusionThe use of cochlear implants in young children was associated with better spoken language learning than would be predicted from their preimplantation scores.
Phase II study of S-1 plus leucovorin in patients with metastatic colorectal cancer
Authors: W. Koizumi, N. Boku, K. Yamaguchi, Y. Miyata, A. Sawaki, T. Kato, Y. Toh, I. Hyodo, T. Nishina, T. Furuhata, K. Miyashita, Y. Okada
Journal: Annals of Oncology (2009)

S-1, a novel oral fluoropyrimidine, is well tolerated in patients with metastatic colorectal cancer (mCRC). The response rate of S-1 for colorectal cancer is high, ranging from 35% to 40%. This study aimed to evaluate the safety and efficacy of S-1 combined with oral leucovorin (LV) to enhance antitumor activity in chemotherapy-naive patients with mCRC.
Molecular Risk Assessment for Breast Cancer Development in Patients with Ductal Hyperplasias
Authors: Indira Poola, Jessy Abraham, Josephine J. Marshalleck, Qingqi Yue, Vinatha B. Lokeshwar, George Bonney, Robert L. DeWitty
Journal: Clinical Cancer Research (2008)

Abstract Purpose: It has been reported that approximately a million women are diagnosed with benign breast lesions that include ductal hyperplasias per year in the United States. Recent studies that followed women with benign lesions have established that about 8% to 9% of them will subsequently develop invasive breast cancer (IBC). However, currently, there are no means of identifying a subclass of “true precancerous tissues” in women with ductal hyperplasias who will subsequently develop cancer. The purpose of this study is to investigate whether expression of hyaluronoglucosaminidase 1 (HYAL1), a known tumor promoter, in hyperplastic tissues identifies a “true precancerous stage” and predicts subsequent IBC development. Experimental Design: A retrospective study was conducted with archival benign tissues of various histologic types and clinical information on development/nondevelopment of IBC. The control group was hyperplastic tissues from women who had no prior history of IBC and did not develop cancer in 5 to 7 years after diagnosis (n = 81). The test group was hyperplastic tissues from patients who developed cancer (n = 82). HYAL1 expression was studied by immunohistochemistry, and the results were statistically analyzed for significant association to develop cancer (P value), specificity, sensitivity, positive predictive value, and negative predictive value. Results: Statistical analysis of HYAL1 expression data showed very highly significant association between its expression and subsequent cancer development (P = 0) and very high sensitivity (0.83), specificity (0.84), positive predictive value (0.84), and negative predictive value (0.83). Conclusions: The expression of HYAL1 in ductal hyperplastic tissues is a strong predictor of subsequent development of IBC; therefore, it can be applied as a diagnostic marker either singly or in combination with other marker(s) to screen benign tissues to predict subsequent development of IBC. Detection at the precancerous stage and treatment could drastically cut down breast cancer incidence and deaths from it.