tbuckley/cabot-search huggingface dataset:
Association between hemochromatosis genotype and lead exposure among elderly men: the normative aging study.
Authors: Robert O Wright, Edwin K Silverman, Joel Schwartz, Shring-Wern Tsaih, Jody Senter, David Sparrow, Scott T Weiss, Antonio Aro, Howard Hu
Journal: Environmental Health Perspectives (2004)

Because body iron burden is inversely associated with lead absorption, genes associated with hemochromatosis may modify body lead burden. Our objective was to determine whether the C282Y and/or H63D hemochromatosis gene (HFE) is associated with body lead burden. Patella and tibia lead levels were measured by K X-ray fluorescence in subjects from the Normative Aging Study. DNA samples were genotyped for C282Y and H63D using polymerase chain reaction/restriction fragment length polymorphism (PCR/RFLP). A series of multivariate linear regression models were constructed with bone or blood lead as dependent variables; age, smoking, and education as independent variables; and C282Y or H63D as independent risk factors and/or effect modifiers. Of 730 subjects, 94 (13%) carried the C282Y variant and 183 (25%) carried the H63D variant. In the crude analysis, mean tibia, patella, and blood lead levels were consistently lower in carriers of either HFE variant compared with levels in subjects with wild-type genotypes. In multivariate analyses that adjusted for age, smoking, and education, having an HFE variant allele was an independent predictor of significantly lower patella lead levels (p < 0.05). These data suggest that HFE variants have altered kinetics of lead accumulation after exposure. Among elderly men, subjects with HFE variants had lower patella lead levels. These effects may be mediated by alterations in lead toxicokinetics via iron metabolic pathways regulated by the HFE gene product and body iron stores.
USP18 is crucial for IFN-γ-mediated inhibition of B16 melanoma tumorigenesis and antitumor immunity
Authors: Bangxing Hong, Haiyan Li, Yong Lu, Mingjun Zhang, Yuhuan Zheng, Jianfei Qian, Qing Yi
Journal: Molecular Cancer (2014)

Interferon (IFN)-γ-mediated immune response plays an important role in tumor immunosurveillance. However, the regulation of IFN-γ-mediated tumorigenesis and immune response remains elusive. USP18, an interferon stimulating response element, regulates IFN-α-mediated signaling in anti-viral immune response, but its role in IFN-γ-mediated tumorigenesis and anti-tumor immune response is unknown.In this study, USP18 in tumorigenesis and anti-tumor immune response was comprehensively appraised in vivo by overexpression or downregulation its expression in murine B16 melanoma tumor model in immunocompetent and immunodeficient mice.Ectopic expression or downregulation of USP18 in B16 melanoma tumor cells inhibited or promoted tumorigenesis, respectively, in immunocompetent mice. USP18 expression in B16 melanoma tumor cells regulated IFN-γ-mediated immunoediting, including upregulating MHC class-I expression, reducing tumor cell-mediated inhibition of T cell proliferation and activation, and suppressing PD-1 expression in CD4+ and CD8+ T cells in tumor-bearing mice. USP18 expression in B16 melanoma tumor cells also enhanced CTL activity during adoptive immunotherapy by prolonging the persistence and enhancing the activity of adoptively transferred CTLs and by reducing CTL exhaustion in the tumor microenvironment. Mechanistic studies demonstrated that USP18 suppressed tumor cell-mediated immune inhibition by activating T cells, inhibiting T-cell exhaustion, and reducing dendritic cell tolerance, thus sensitizing tumor cells to immunosurveillance and immunotherapy.These findings suggest that stimulating USP18 is a feasible approach to induce B16 melanoma specific immune response.
Book: The Science of the Placebo: Toward an Interdisciplinary Research Agenda
Authors: A. J M de Craen
Journal: BMJ (2002)

Eds Harry A Guess, Arthur Kleinman, John W Kusek, Linda W Engel BMJ Books, £15.95, pp 343 ISBN 0 7279 1594 0 Rating: ![Graphic][1]</img>![Graphic][2]</img>![Graphic][3]</img> Most doctors are aware of placebos and the placebo effect, but probably few have given the subject any serious thought. Perhaps studying the use of placebos is incompatible with pursuing a “serious medical career.” Perhaps we think we already know why placebos are used in clinical research. Or perhaps we do not question the existence of placebo effects in medicine simply because we think we know that the placebo effect is there. So why should we … [1]: /embed/inline-graphic-1.gif [2]: /embed/inline-graphic-2.gif [3]: /embed/inline-graphic-3.gif
Digital necrosis from dandelion tea
Authors: B. Moriarty, J.H. Pinney, M.P. Owen-Casey, M.H.A. Rustin, F. Deroide, C. Laing, A. Davenport
Journal: British Journal of Dermatology (2013)

Journal Article Digital necrosis from dandelion tea Get access B. Moriarty, B. Moriarty Department of Dermatology Royal Free Hampstead NHS Trust Pond St, London NW3 2QG U.K Search for other works by this author on: Oxford Academic Google Scholar J.H. Pinney, J.H. Pinney Centre for Nephrology Royal Free Hampstead NHS Trust Pond St, London NW3 2QG U.K Search for other works by this author on: Oxford Academic Google Scholar M.P. Owen‐Casey, M.P. Owen‐Casey Department of Cellular Pathology Royal Free Hampstead NHS Trust Pond St, London NW3 2QG U.K Search for other works by this author on: Oxford Academic Google Scholar M.H.A. Rustin, M.H.A. Rustin Department of Dermatology Royal Free Hampstead NHS Trust Pond St, London NW3 2QG U.K Search for other works by this author on: Oxford Academic Google Scholar F. Deroide, F. Deroide Department of Cellular Pathology Royal Free Hampstead NHS Trust Pond St, London NW3 2QG U.K Search for other works by this author on: Oxford Academic Google Scholar C. Laing, C. Laing Centre for Nephrology Royal Free Hampstead NHS Trust Pond St, London NW3 2QG U.K Search for other works by this author on: Oxford Academic Google Scholar A. Davenport A. Davenport Centre for Nephrology Royal Free Hampstead NHS Trust Pond St, London NW3 2QG U.K Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 169, Issue 1, 1 July 2013, Pages 227–230, https://doi.org/10.1111/bjd.12288 Published: 01 July 2013
Successful 2-week treatment with terbinafine (LamisilR) for moccasin tinea pedis and tinea manuum
Authors: J.E. WHITE, P.J. PERKINS, E.G.V. EVANS
Journal: British Journal of Dermatology (1991)

A new orally active antifungal agent, terbinafine, was used in the treatment of tinea pedis (‘dry type’ or moccasin type) and tinea manuum. Fifty‐three adults over the age of 16 years with fungal infections of the feet and/or hands were treated with either oral terbinafine, 250 mg, or placebo, once daily for 2 weeks. The diagnosis of fungal infection was confirmed by examination of skin scrapings by microscopy and culture. Of these, 28 patients were evaluable for efficacy. At 8 weeks, 12 out of 14 (86%) patients who received terbinafine were mycologically negative (microscopy and culture) compared to one out of 14 (7%) patients on placebo (P<0.001, Fishers exact test, one‐sided). At the end of the study 71% of patients in the terbinafine group were judged to have received effective therapy compared to 0% in the placebo group (P<0.001), Terbinafine was well tolerated, and more side‐effects were seen in the placebo group.
Aldehyde dehydrogenase 1 positive glioblastoma cells show brain tumor stem cell capacity
Authors: M. Rasper, A. Schafer, G. Piontek, J. Teufel, G. Brockhoff, F. Ringel, S. Heindl, C. Zimmer, J. Schlegel
Journal: Neuro-Oncology (2010)

Glioblastoma (GBM) is the most aggressive primary brain tumor and is resistant to all therapeutic regimens. Relapse occurs regularly and might be caused by a poorly characterized tumor stem cell (TSC) subpopulation escaping therapy. We suggest aldehyde dehydrogenase 1 (ALDH1) as a novel stem cell marker in human GBM. Using the neurosphere formation assay as a functional method to identify brain TSCs, we show that high protein levels of ALDH1 facilitate neurosphere formation in established GBM cell lines. Even single ALDH1 positive cells give rise to colonies and neurospheres. Consequently, the inhibition of ALDH1 in vitro decreases both the number of neurospheres and their size. Cell lines without expression of ALDH1 do not form tumor spheroids under the same culturing conditions. High levels of ALDH1 seem to keep tumor cells in an undifferentiated, stem cell-like state indicated by the low expression of beta-III-tubulin. In contrast, ALDH1 inhibition induces premature cellular differentiation and reduces clonogenic capacity. Primary cell cultures obtained from fresh tumor samples approve the established GBM cell line results.
Cystatin C Identifies Chronic Kidney Disease Patients at Higher Risk for Complications
Authors: Carmen A. Peralta, Ronit Katz, Mark J. Sarnak, Joachim Ix, Linda F. Fried, Ian De Boer, Walter Palmas, David Siscovick, Andrew S. Levey, Michael G. Shlipak
Journal: Journal of the American Society of Nephrology (2010)

Although cystatin C is a stronger predictor of clinical outcomes associated with CKD than creatinine, the clinical role for cystatin C is unclear. We included 11,909 participants from the Multi-Ethnic Study of Atherosclerosis (MESA) and the Cardiovascular Health Study (CHS) and assessed risks for death, cardiovascular events, heart failure, and ESRD among persons categorized into mutually exclusive groups on the basis of the biomarkers that supported a diagnosis of CKD (eGFR <60 ml/min per 1.73 m(2)): creatinine only, cystatin C only, both, or neither. We used CKD-EPI equations to estimate GFR from these biomarkers. In MESA, 9% had CKD by the creatinine-based equation only, 2% had CKD by the cystatin C-based equation only, and 4% had CKD by both equations; in CHS, these percentages were 12, 4, and 13%, respectively. Compared with those without CKD, the adjusted hazard ratios (HR) for mortality in MESA were: 0.80 (95% CI 0.50 to 1.26) for CKD by creatinine only; 3.23 (95% CI 1.84 to 5.67) for CKD by cystatin C only; and 1.93 (95% CI 1.27 to 2.92) for CKD by both; in CHS, the adjusted HR were 1.09 (95% CI 0.98 to 1.21), 1.78 (95% CI 1.53 to 2.08), and 1.74 (95% CI 1.58 to 1.93), respectively. The pattern was similar for cardiovascular disease (CVD), heart failure, and kidney failure outcomes. In conclusion, among adults diagnosed with CKD using the creatinine-based CKD-EPI equation, the adverse prognosis is limited to the subset who also have CKD according to the cystatin C-based equation. Cystatin C may have a role in identifying persons with CKD who have the highest risk for complications.
Albuminuria and Risk of Cardiovascular Events, Death, and Heart Failure in Diabetic and Nondiabetic Individuals
Authors: Hertzel C. Gerstein
Journal: JAMA (2001)

ContextMicroalbuminuria is a risk factor for cardiovascular (CV) events. The relationship between the degree of albuminuria and CV risk is unclear.ObjectivesTo estimate the risk of CV events in high-risk individuals with diabetes mellitus (DM) and without DM who have microalbuminuria and to determine whether levels of albuminuria below the microalbuminuria threshold increase CV risk.DesignThe Heart Outcomes Prevention Evaluation study, a cohort study conducted between 1994 and 1999 with a median 4.5 years of follow-up.SettingCommunity and academic practices in North and South America and Europe.ParticipantsIndividuals aged 55 years or more with a history of CV disease (n = 5545) or DM and at least 1 CV risk factor (n = 3498) and a baseline urine albumin/creatinine ratio (ACR) measurement.Main Outcome MeasuresCardiovascular events (myocardial infarction, stroke, or CV death); all-cause death; and hospitalization for congestive heart failure.ResultsMicroalbuminuria was detected in 1140 (32.6%) of those with DM and 823 (14.8%) of those without DM at baseline. Microalbuminuria increased the adjusted relative risk (RR) of major CV events (RR, 1.83; 95% confidence interval [CI], 1.64-2.05), all-cause death (RR, 2.09; 95% CI, 1.84-2.38), and hospitalization for congestive heart failure (RR, 3.23; 95% CI, 2.54-4.10). Similar RRs were seen for participants with or without DM, even after adjusting for other CV risk factors (eg, the adjusted RR of the primary aggregate end point was 1.97 [95% CI, 1.68-2.31] in those with DM and 1.61 [95% CI, 1.36-1.90] in those without DM).Compared with the lowest quartile of ACR (&lt;0.22 mg/mmol), the RRs of the primary aggregate end point in the second quartile (ie, ACR range, 0.22-0.57 mg/mmol) was 1.11 (95% CI, 0.95-1.30); third quartile, 1.38 (95% CI, 1.19-1.60; ACR range, 0.58-1.62 mg/mmol); and fourth quartile, 1.97 (95% CI, 1.73-2.25; ACR range, &gt;1.62 mg/mmol) (P for trend &lt;.001, even after excluding those with microalbuminuria). For every 0.4-mg/mmol increase in ACR level, the adjusted hazard of major CV events increased by 5.9% (95% CI, 4.9%-7.0%).ConclusionsOur results indicate that any degree of albuminuria is a risk factor for CV events in individuals with or without DM; the risk increases with the ACR, starting well below the microalbuminuria cutoff. Screening for albuminuria identifies people at high risk for CV events.
Deficiency of Neuronal Nitric Oxide Synthase Increases Mortality and Cardiac Remodeling After Myocardial Infarction
Authors: Roberto M. Saraiva, Khalid M. Minhas, Shubha V.Y. Raju, Lili A. Barouch, Eleanor Pitz, Karl H. Schuleri, Koenraad Vandegaer, Dechun Li, Joshua M. Hare
Journal: Circulation (2005)

Background— Neuronal nitric oxide synthase (NOS1) plays key cardiac physiological roles, regulating excitation-contraction coupling and exerting an antioxidant effect that maintains tissue NO-redox equilibrium. After myocardial infarction (MI), NOS1 translocates from the sarcoplasmic reticulum to the cell membrane, where it inhibits β-adrenergic contractility, an effect previously predicted to have adverse consequences. Counter to this idea, we tested the hypothesis that NOS1 has a protective effect after MI. Methods and Results— We studied mortality, cardiac remodeling, and upregulation of oxidative stress pathways after MI in NOS1-deficient (NOS1 −/− ) and wild-type C57BL6 (WT) mice. Compared with WT, NOS1 −/− mice had greater mortality (hazard ratio, 2.06; P =0.036), worse left ventricular (LV) fractional shortening (19.7±1.5% versus 27.2±1.5%, P &lt;0.05), higher LV diastolic diameter (5.5±0.2 versus 4.9±0.1 mm, P &lt;0.05), greater residual cellular width (14.9±0.5 versus 12.8±0.5 μm, P &lt;0.01), and equivalent β-adrenergic hyporesponsiveness despite similar MI size. Superoxide production increased after MI in both NOS1 −/− and WT animals, although NO increased only in WT. NADPH oxidase ( P &lt;0.05) activity increased transiently in both groups after MI, but NOS1 −/− mice had persistent basal and post-MI elevations in xanthine oxidoreductase activity. Conclusions— Together these findings support a protective role for intact NOS1 activity in the heart after MI, despite a potential contribution to LV dysfunction through β-adrenergic hyporesponsiveness. NOS1 deficiency contributes to an imbalance between oxidative stress and tissue NO signaling, providing a plausible mechanism for adverse consequences of NOS1 deficiency in states of myocardial injury.
Effectiveness of Non-nucleoside Reverse-Transcriptase Inhibitor-Based Antiretroviral Therapy in Women Previously Exposed to a Single Intrapartum Dose of Nevirapine: A Multi-country, Prospective Cohort Study
Authors: Jeffrey S. A. Stringer, Michelle S. McConnell, James Kiarie, Omotayo Bolu, Thanomsak Anekthananon, Tavatchai Jariyasethpong, Dara Potter, Winnie Mutsotso, Craig B. Borkowf, Dorothy Mbori-Ngacha, Peter Muiruri, John Odero Ong'ech, Isaac Zulu, Lungowe Njobvu, Bongkoch Jetsawang, Sonal Pathak, Marc Bulterys, Nathan Shaffer, Paul J. Weidle
Journal: PLoS Medicine (2010)

Background Intrapartum and neonatal single-dose nevirapine (NVP) reduces the risk of mother-to-child HIV transmission but also induces viral resistance to non-nucleoside reverse transcriptase inhibitor (NNRTI) drugs. This drug resistance largely fades over time. We hypothesized that women with a prior single-dose NVP exposure would have no more than a 10% higher cumulative prevalence of failure of their NNRTI-containing antiretroviral therapy (ART) over the first 48 wk of therapy than would women without a prior exposure. Methods and Findings We enrolled 355 NVP-exposed and 523 NVP-unexposed women at two sites in Zambia, one site in Kenya, and two sites in Thailand into a prospective, non-inferiority cohort study and followed them for 48 wk on ART. Those who died, discontinued NNRTI-containing ART, or had a plasma viral load ≥400 copies/ml at either the 24 wk or 48 wk study visits and confirmed on repeat testing were characterized as having failed therapy. Overall, 114 of 355 NVP-exposed women (32.1%) and 132 of 523 NVP-unexposed women (25.2%) met criteria for treatment failure. The difference in failure rates between the exposure groups was 6.9% (95% confidence interval [CI] 0.8%–13.0%). The failure rates of women stratified by our predefined exposure interval categories were as follows: 47 of 116 women in whom less than 6 mo elapsed between exposure and starting ART failed therapy (40%; p<0.001 compared to unexposed women); 25 of 67 women in whom 7–12 mo elapsed between exposure and starting ART failed therapy (37%; p = 0.04 compared to unexposed women); and 42 of 172 women in whom more than 12 mo elapsed between exposure and starting ART failed therapy (24%; p = 0.82 compared to unexposed women). Locally weighted regression analysis also indicated a clear inverse relationship between virologic failure and the exposure interval. Conclusions Prior exposure to single-dose NVP was associated with an increased risk of treatment failure; however, this risk seems largely confined to women with a more recent exposure. Women requiring ART within 12 mo of NVP exposure should not be prescribed an NNRTI-containing regimen as first-line therapy. Please see later in the article for the Editors' Summary
Molecular Pathways: Targeting Death Receptors and Smac Mimetics
Authors: Simone Fulda
Journal: Clinical Cancer Research (2014)

Inhibitor of apoptosis (IAP) proteins are overexpressed in multiple human malignancies, an event that is associated with poor prognosis and treatment resistance. Therefore, IAP proteins represent relevant targets for therapeutic intervention. Second mitochondrial activator of caspases (Smac) is a mitochondrial protein that is released into the cytosol upon the induction of programmed cell death and promotes apoptosis by neutralizing IAP proteins. On the basis of this property, a variety of small-molecule inhibitors have been developed that mimic the binding domain of the native Smac protein to IAP proteins. Evaluation of these Smac mimetics in preclinical studies revealed that they particularly synergize together with agents that trigger the death receptor pathway of apoptosis. Such combinations might therefore be of special interest for being included in the ongoing evaluation of Smac mimetics in early clinical trials.
Health-related Quality of Life after Acute Lung Injury
Authors: CRAIG R. WEINERT, CYNTHIA R. GROSS, JAMES R. KANGAS, CARON L. BURY, WILLIAM A. MARINELLI
Journal: American Journal of Respiratory and Critical Care Medicine (1997)

Our study objective was to assess health-related quality of life in survivors of acute lung injury (ALI) and to supplement generic and disease-specific questionnaires with findings from a focus group of ALI survivors. Six patients participated in the focus group, which revealed patient concerns with amnesia, depressed mood, avoidance behaviors, and a prolonged recovery period. Using a cross-sectional study design, 24 patients completed a questionnaire 6 to 41 mo after their lung injury. A total of 43% of the patients with ALI met criteria for depression; 43% had self-reported significant functional limitations, although 39% had minimal or no limitations. Significant respiratory and psychologic symptoms were reported in a quarter to a third of patients. There were large decrements in all domains of the SF-36 (a generic health-related quality-of-life instrument) in our sample compared with norms previously established for the general population. In addition, our patients had similar physical difficulties compared with previously studied patients with chronic medical illnesses but had more deficits in the social functioning and mental health domains. We conclude that long after lung injury, survivors have significantly lower health-related quality of life than the general population and are likely to have pulmonary and psychologic symptoms.
A novel method for the diagnosis of lung transplant rejection
Authors: R Agarwal
Journal: Thorax (2004)

▴Aharinejad S, Taghavi S, Klepetko W, Abraham D. Prediction of lung-transplant rejection by hepatocyte growth factor. Lancet2004;363:1503–8

[OpenUrl][1][CrossRef][2][PubMed][3]



The most common causes of morbidity and mortality following lung transplantation are primary graft failure, infection, and acute and chronic rejection. Clinical criteria alone are inaccurate for the diagnosis of graft rejection. The diagnosis can be made by transbronchial biopsy but this procedure is invasive and cannot be performed repeatedly. …

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cAMP-Specific Phosphodiesterase-4 Enzymes in the Cardiovascular System
Authors: Miles D. Houslay, George S. Baillie, Donald H. Maurice
Journal: Circulation Research (2007)

Cyclic AMP regulates a vast number of distinct events in all cells. Early studies established that its hydrolysis by cyclic nucleotide phosphodiesterases (PDEs) controlled both the magnitude and the duration of its influence. Recent evidence shows that PDEs also act as coincident detectors linking cyclic-nucleotide– and non–cyclic-nucleotide–based cellular signaling processes and are tethered with great selectively to defined intracellular structures, thereby integrating and spatially restricting their cellular effects in time and space. Although 11 distinct families of PDEs have been defined, and cells invariably express numerous individual PDE enzymes, a large measure of our increased appreciation of the roles of these enzymes in regulating cyclic nucleotide signaling has come from studies on the PDE4 family. Four PDE4 genes encode more than 20 isoforms. Alternative mRNA splicing and the use of different promoters allows cells the possibility of expressing numerous PDE4 enzymes, each with unique amino-terminal-targeting and/or regulatory sequences. Dominant negative and small interfering RNA–mediated knockdown strategies have proven that particular isoforms can uniquely control specific cellular functions. Thus the protein kinase A phosphorylation status of the β 2 adrenoceptor and, thereby, its ability to switch its signaling to extracellular signal-regulated kinase activation, is uniquely regulated by PDE4D5 in cardiomyocytes. We describe how cardiomyocytes and vascular smooth muscle cells selectively vary both the expression and the catalytic activities of PDE4 isoforms to regulate their various functions and how altered regulation of these processes can influence the development, or resolution, of cardiovascular pathologies, such as heart failure, as well as various vasculopathies.