tbuckley/cabot-search huggingface dataset:
Vitiligo linked to stigmatization in British South Asian women: a qualitative study of the experiences of living with vitiligo
Authors: A.R. Thompson, S.A. Clarke, R.J. Newell, D.J. Gawkrodger
Journal: British Journal of Dermatology (2010)

Background Vitiligo is a visible condition that is more noticeable in darker‐skinned people. Beliefs about illness have been linked to psychosocial adjustment. There is some evidence that such beliefs may be influenced by cultural factors. Surprisingly little is known about beliefs in relation to vitiligo. Objectives The study sought to explore in depth the ways in which British Asian women manage and adjust psychosocially to vitiligo, and the potential role of ethnicity and culture in this process. Methods In‐depth semistructured interviews were conducted with seven British women of South Asian decent and analysed using the qualitative method of template analysis. Results Participants described feeling visibly different and all had experienced stigmatization to some extent. Avoidance and concealment were commonplace. Experiences of stigmatization were often perceived to be associated with cultural values related to appearance, status, and myths linked to the cause of the condition. Conclusions The findings of this study present a unique in‐depth analysis of British South Asians living with vitiligo and suggest there is a need for further research to explore cultural associations of disfigurement and of adjustment to chronic skin conditions. Furthermore, they suggest that in addition to individual therapeutic interventions there may be a need for community interventions aimed at dispelling myths and raising awareness of sources of support and treatment.
Asymmetric Dimethylarginine and the Risk of Cardiovascular Events and Death in Patients With Coronary Artery Disease
Authors: Renate Schnabel, Stefan Blankenberg, Edith Lubos, Karl J. Lackner, Hans J. Rupprecht, Christine Espinola-Klein, Nicole Jachmann, Felix Post, Dirk Peetz, Christoph Bickel, François Cambien, Laurence Tiret, Thomas Münzel
Journal: Circulation Research (2005)

As a competitive inhibitor of endothelial nitric oxide synthase, asymmetric dimethylarginine (ADMA) has been related to atherosclerotic disease. Little is known about the prognostic impact of baseline ADMA determination. In a prospective cohort of 1908 patients with coronary artery disease, we assessed baseline serum concentration of ADMA in 1874 consecutive patients with coronary artery disease. One hundred fourteen individuals developed the primary end point of death from cardiovascular causes or nonfatal myocardial infarction during a mean follow-up of 2.6+/-1.2 years. Median concentrations of ADMA levels were higher among individuals who subsequently developed the primary end point than among those who did not (0.70 versus 0.63 micromol/L; P<0.001). The risk of future cardiovascular event was associated with increasing thirds of baseline ADMA (P for trend, <0.001) such that individuals in the highest third at entry had a hazard ratio 2.48 times higher than those in the lowest third (95% confidence interval, 1.52 to 4.06; P<0.001). This relationship remained nearly unchanged after adjustment for most potential confounders. Prediction models that simultaneously incorporated ADMA, B-type natriuretic peptide, C-reactive protein, and creatinine in addition to traditional risk factors revealed B-type natriuretic peptide (hazard ratio, 1.96; 95% confidence interval, 1.3 to 3.0; P=0.002) and ADMA (hazard ratio, 1.90; 95% confidence interval, 1.3 to 2.8; P=0.001) as the strongest risk predictors. High levels of baseline ADMA independently predict future cardiovascular risk. ADMA has prognostic value beyond traditional risk factors and novel biomarkers and might guide therapeutic strategies.
Chemerin expression marks early psoriatic skin lesions and correlates with plasmacytoid dendritic cell recruitment
Authors: Cristina Albanesi, Claudia Scarponi, Sabatino Pallotta, Roberta Daniele, Daniela Bosisio, Stefania Madonna, Paola Fortugno, Safiyè Gonzalvo-Feo, Jean-Denis Franssen, Marc Parmentier, Ornella De Pità, Giampiero Girolomoni, Silvano Sozzani
Journal: The Journal of Experimental Medicine (2008)

Psoriasis is a type I interferon-driven T cell–mediated disease characterized by the recruitment of plasmacytoid dendritic cells (pDC) into the skin. The molecules involved in pDC accumulation in psoriasis lesions are unknown. Chemerin is the only inflammatory chemotactic factor that is directly active on human blood pDC in vitro. The aim of this study was to evaluate the role of the chemerin/ChemR23 axis in the recruitment of pDC in psoriasis skin. Prepsoriatic skin adjacent to active lesions and early lesions were characterized by a strong expression of chemerin in the dermis and by the presence of CD15+ neutrophils and CD123+/BDCA-2+/ChemR23+ pDC. Conversely, skin from chronic plaques showed low chemerin expression, segregation of neutrophils to epidermal microabscesses, and few pDC in the dermis. Chemerin expression was localized mainly in fibroblasts, mast cells, and endothelial cells. Fibroblasts cultured from skin of psoriatic lesions expressed higher levels of chemerin messenger RNA and protein than fibroblasts from uninvolved psoriatic skin or healthy donors and promoted pDC migration in vitro in a chemerin-dependent manner. Therefore, chemerin expression specifically marks the early phases of evolving skin psoriatic lesions and is temporally strictly associated with pDC. These results support a role for the chemerin/ChemR23 axis in the early phases of psoriasis development.
Expression of granzyme B sensitizes ALK+ ALCL tumour cells to apoptosis-inducing drugs
Authors: Joel D Pearson, Jingxi Zhang, Zuoqiao Wu, Kayla D Thew, Katelynn J Rowe, Julinor TC Bacani, Robert J Ingham
Journal: Molecular Cancer (2014)

The serine protease Granzyme B (GzB) is primarily expressed by cytotoxic T lymphocytes and natural killer cells, and functions in allowing these cells to induce apoptosis in virally-infected or transformed cells. Cancers of both lymphoid and non-lymphoid origin also express GzB, and in some cases this expression has been linked to pathogenesis or sensitizing tumour cells to cell death. For example, GzB expression in urothelial carcinoma was implicated in promoting tumour cell invasion, whereas its expression in nasal-type NK/T lymphomas was found to correlate with increased apoptosis. GzB expression is also a hallmark of the non-Hodgkin lymphoma, anaplastic lymphoma kinase-positive, anaplastic large cell lymphoma (ALK+ ALCL). Given the fact that ALK+ ALCL exhibits high levels of apoptosis and is typically responsive to conventional chemotherapy, we examined whether GzB expression might play a role in sensitizing ALK+ ALCL tumour cells to apoptosis.ALK+ ALCL cell lines stably expressing GzB or non-targeting (control) shRNA were generated and apoptosis was examined by anti-PARP western blotting and terminal deoxynucleotidyl transferase dUTP nick end labelling. Both spontaneous apoptosis and apoptosis in response to treatment with staurosporine or doxorubicin were investigated. In order to assess whether additional granzymes might be important in promoting cell death in ALK+ ALCL, we examined whether other human granzymes were expressed in ALK+ ALCL cell lines using reverse-transcriptase PCR and western blotting.Expression of several GzB shRNAs in multiple ALK+ ALCL cell lines resulted in a significant decrease in GzB levels and activity. While spontaneous apoptosis was similar in ALK+ ALCL cell lines expressing either GzB or control shRNA, GzB shRNA-expressing cells were less sensitive to staurosporine or doxorubicin-induced apoptosis as evidenced by reduced PARP cleavage and decreased DNA fragmentation. Furthermore, we found that GzB is the only granzyme that is expressed at significant levels in ALK+ ALCL cell lines.Our findings are the first to demonstrate that GzB expression sensitizes ALK+ ALCL cell lines to drug-induced apoptosis. This suggests that GzB expression may be a factor contributing to the favourable response of this lymphoma to treatment.
Evidence of a Cohort Effect for Age at Onset of Schizophrenia
Authors: C Di Maggio, M Martinez, J F Ménard, M Petit, F Thibaut
Journal: American Journal of Psychiatry (2001)

OBJECTIVE: The authors address whether a possible age-at-onset cohort effect may have introduced a bias into anticipation studies of schizophrenia. METHOD: A retrospective review of the medical records of all admissions for psychotic disorders (N=877) was conducted. All subjects with a confirmed DSM-IV diagnosis of schizophrenia and age-at-onset data were included (N=419). For analyses, subjects were placed into one of three successive birth cohorts: 1905–1944 (N=96), 1945–1964 (N=200), and 1965–1984 (N=123). RESULTS: The mean age at first appearance of psychotic symptoms and, similarly, the mean age at first hospitalization significantly decreased over time in successive birth cohorts (25.3, 23.3, and 20.4 years, respectively, for age at first appearance of psychotic symptoms). CONCLUSIONS: This potential birth cohort effect for age at onset of schizophrenia needs to be incorporated into genetic models.
Duration and Toxicity of Adjuvant Trastuzumab in Older Patients With Early-Stage Breast Cancer: A Population-Based Study
Authors: Ines Vaz-Luis, Nancy L. Keating, Nancy U. Lin, Huichuan Lii, Eric P. Winer, Rachel A. Freedman
Journal: Journal of Clinical Oncology (2014)

Few data are available regarding adjuvant trastuzumab use in older women with early-stage breast cancer. We examined rates and predictors of adjuvant trastuzumab completion and cardiac events in this population.We used Surveillance, Epidemiology, and End Results (SEER)-Medicare data to identify patients age ≥ 66 years with stage I to III breast cancer diagnosed between 2005 and 2009 who received trastuzumab. Completion of trastuzumab was defined as receipt of more than 270 days of therapy. We used multivariable logistic regression to examine patient, clinical, and geographic characteristics associated with trastuzumab completion. We also examined rates of hospital admissions for cardiac events.Among 2,028 women, most (71.2%) were younger than age 76 years and had a comorbidity score of 0 (66.8%); 85.2% received trastuzumab with chemotherapy. Overall, 1,656 women (81.7%) completed trastuzumab. Older patients and those with more comorbidity had lower odds of treatment completion (odds ratio [OR], 0.40 [95% CI, 0.30 to 0.55] for age ≥ 80 years v age 66 to 70 years; OR, 0.65 [95% CI, 0.49 to 0.88] for comorbidity score of 2 v 0). During treatment, 73 patients (3.6%) were hospitalized for cardiac events (2.6% of those who completed trastuzumab v 8.1% of those who did not; P < .001).Most older patients who initiated adjuvant trastuzumab completed therapy. Age and comorbidity were among factors that were associated with treatment completion, and rates of significant cardiac events were higher in those who did not complete therapy. Further exploration of toxicities and optimal treatments for older women with human epidermal growth factor receptor 2-positive breast cancer are warranted.
Angiotensin converting enzyme inhibition, AT1 receptor inhibition, and combination therapy with pacing induced heart failure: effects on left ventricular performance and regional blood flow patterns
Authors: R Krombach
Journal: Cardiovascular Research (1998)

Background: AT1 receptor activation has been demonstrated to cause increased vascular resistance properties which may be of particular importance in the setting of congestive heart failure (CHF). The overall goal of this study was to examine the effects of ACE inhibition (ACEI) alone, AT1 receptor blockade alone and combined ACEI and AT1 receptor blockade on LV pump function, systemic hemodynamics and regional blood flow patterns in the normal state and with the development of pacing induced CHF, both at rest and with treadmill induced exercise. Methods and results: Pigs (25 kg) were instrumented in order to measure cardiac output (CO), systemic (SVR) and pulmonary vascular (PVR) resistance, neurohormonal system activity, and myocardial blood flow distribution in the conscious state and assigned to one of 4 groups: (1) rapid atrial pacing (240 bpm) for 3 weeks (n=7); (2) ACEI (benazeprilat, 3.75 mg/day) and pacing (n=7); (3) AT1 receptor blockade (valsartan, 60 mg/day) and rapid pacing (n=7); and (4) ACEI and AT1 receptor blockade (benazeprilat/valsartan, 1/60 mg/day, respectively) and pacing (n=7). Measurements were obtained at rest and with treadmill exercise (15°, 3 miles/h; 10 min) in the normal control state and after the completion of the treatment protocols. With rapid pacing, CO was reduced at rest and with exercise compared to controls. ACEI or AT1 blockade normalized CO at rest, but remained lower than control values with exercise. Combination therapy normalized CO both at rest and with exercise. Resting SVR in the CHF group was higher than controls and SVR fell to a similar degree with exercise; all treatment groups reduced resting SVR. With exercise, SVR was reduced from rapid pacing values in the ACEI and combination therapy groups. PVR increased by over 4-fold in the rapid pacing group both at rest and with exercise, and was reduced in all treatment groups. In the combination therapy group, PVR was similar to control values with exercise. Plasma catecholamines and endothelin levels were increased by over 3-fold with chronic rapid pacing, and were reduced in all treatment groups. In the combination therapy group, the relative increase in catecholamines and endothelin with exercise were significantly blunted when compared to rapid pacing only values. LV myocardial blood flow at rest was reduced in the rapid pacing only and monotherapy groups, but was normalized with combination therapy. Conclusion: These findings suggest that with developing CHF, combined ACE inhibition and AT1 receptor blockade improved vascular resistive properties and regional blood flow distribution to a greater degree than that of either treatment alone. Thus, combined ACEI and AT1 receptor blockade may provide unique benefits in the setting of CHF.
Selective proteolysis of immunoglobulins by mouse macrophage elastase.
Authors: M J Banda, E J Clark, Z Werb
Journal: The Journal of Experimental Medicine (1983)

Mouse macrophage elastase, a metalloproteinase secreted by inflammatory macrophages, catalyzed the limited proteolysis of selected subclasses of mouse immunoglobulins, including monomeric IgG2a, IgG3, and some forms of IgG2b. Mouse IgG1 was resistant to elastase degradation; however, human IgG1 was degraded. IgG3 in immune complexes was cleaved in a manner similar to that of monomeric IgG3. Degradation by macrophage elastase was limited to the heavy chain, resulting in products that did not compete for binding to the macrophage Fc receptor. Macrophage elastase usually produced a pepsin-like rather than a papain-like pattern of proteolysis, resulting in the release of F(ab')2 and Fc' subfragments. This degradation of IgG differed from the papain-like cleavage of IgG by granulocyte elastase. Macrophage elastase degraded papain-generated Fc fragments of IgG2a into multiple fragments. Therefore, macrophage elastase at concentrations found in culture medium has the potential to regulate some aspects of cellular events associated with immunoglobulins.
Renal Cyst Formation in Fh1-Deficient Mice Is Independent of the Hif/Phd Pathway: Roles for Fumarate in KEAP1 Succination and Nrf2 Signaling
Authors: Julie Adam, Emine Hatipoglu, Linda O'Flaherty, Nicola Ternette, Natasha Sahgal, Helen Lockstone, Dilair Baban, Emma Nye, Gordon W. Stamp, Kathryn Wolhuter, Marcus Stevens, Roman Fischer, Peter Carmeliet, Patrick H. Maxwell, Chris W. Pugh, Norma Frizzell, Tomoyoshi Soga, Benedikt M. Kessler, Mona El-Bahrawy, Peter J. Ratcliffe, Patrick J. Pollard
Journal: Cancer Cell (2011)

The Krebs cycle enzyme fumarate hydratase (FH) is a human tumor suppressor whose inactivation is associated with the development of leiomyomata, renal cysts, and tumors. It has been proposed that activation of hypoxia inducible factor (HIF) by fumarate-mediated inhibition of HIF prolyl hydroxylases drives oncogenesis. Using a mouse model, we provide genetic evidence that Fh1-associated cyst formation is Hif independent, as is striking upregulation of antioxidant signaling pathways revealed by gene expression profiling. Mechanistic analysis revealed that fumarate modifies cysteine residues within the Kelch-like ECH-associated protein 1 (KEAP1), abrogating its ability to repress the Nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-mediated antioxidant response pathway, suggesting a role for Nrf2 dysregulation in FH-associated cysts and tumors.
High hepatotoxicity of pyrazinamide and ethambutol for treatment of latent tuberculosis: Table. 1—
Authors: A. B. Younossian, T. Rochat, J-P. Ketterer, J. Wacker, J-P. Janssens
Journal: European Respiratory Journal (2005)

Pyrazinamide (PZA) combined with either ethambutol (EMB) or a fluoroquinolone for 6–12 months is one of the treatments recommended for latent tuberculosis infection (LTBI) in contacts exposed to multidrug-resistant tuberculosis (MDR-TB). The aim of the present study was to describe the side effects related to combined PZA and EMB treatment given for LTBI, in contacts previously exposed to MDR-TB. In total, 12 consecutive contacts, all of African origin and aged 38±5 yrs, were treated with daily PZA (23±4 mg·kg −1 ) and EMB (17±4 mg·kg −1 ) at Geneva University Hospital outpatient clinic (Switzerland), as a result of contact-tracing procedures for two patients with contagious MDR-TB. Clinical status and liver function tests (aspartate aminotransferase (ALAT) and alanine aminotransferase (ASAT)) were monitored monthly. In seven cases (58%) treatment was discontinued after a median of 119 days, due to hepatic toxicity in six cases (ALAT or ASAT elevation more than four times the upper normal limit), and gastrointestinal symptoms in one case. In conclusion, combined pyrazinamide and ethambutol for latent tuberculosis infection may be associated with a high risk of hepatic toxicity, and warrants close monitoring. There is clearly a need for alternative preventive treatments for contacts exposed to multidrug-resistant tuberculosis.
A phase II study of dose-dense epirubicin plus cyclophosphamide followed by docetaxel plus capecitabine and pegfilgrastim support as preoperative therapy for patients with stage II, IIIA breast cancer
Authors: C. Natoli, E. Cianchetti, N. Tinari, D. Angelucci, A. Grassadonia, M. Zilli, C. Ficorella, E. Ricevuto, S. Grossi, M. De Tursi, C. Carella, A.I. Rispoli, S. Iacobelli
Journal: Annals of Oncology (2007)
Analysis of Mitosis and Antimitotic Drug Responses in Tumors by <i>In Vivo</i> Microscopy and Single-Cell Pharmacodynamics
Authors: James D. Orth, Rainer H. Kohler, Floris Foijer, Peter K. Sorger, Ralph Weissleder, Timothy J. Mitchison
Journal: Cancer Research (2011)

Cancer relies upon frequent or abnormal cell division, but how the tumor microenvironment affects mitotic processes in vivo remains unclear, largely due to the technical challenges of optical access, spatial resolution, and motion. We developed high-resolution in vivo microscopy methods to visualize mitosis in a murine xenograft model of human cancer. Using these methods, we determined whether the single-cell response to the antimitotic drug paclitaxel (Ptx) was the same in tumors as in cell culture, observed the impact of Ptx on the tumor response as a whole, and evaluated the single-cell pharmacodynamics (PD) of Ptx (by in vivo PD microscopy). Mitotic initiation was generally less frequent in tumors than in cell culture, but subsequently it proceeded normally. Ptx treatment caused spindle assembly defects and mitotic arrest, followed by slippage from mitotic arrest, multinucleation, and apoptosis. Compared with cell culture, the peak mitotic index in tumors exposed to Ptx was lower and the tumor cells survived longer after mitotic arrest, becoming multinucleated rather than dying directly from mitotic arrest. Thus, the tumor microenvironment was much less proapoptotic than cell culture. The morphologies associated with mitotic arrest were dose and time dependent, thereby providing a semiquantitative, single-cell measure of PD. Although many tumor cells did not progress through Ptx-induced mitotic arrest, tumor significantly regressed in the model. Our findings show that in vivo microscopy offers a useful tool to visualize mitosis during tumor progression, drug responses, and cell fate at the single-cell level.
Statin use and the risk of<i>Clostridium difficile</i>in academic medical centres
Authors: Christine Anne Motzkus-Feagans, Amy Pakyz, Ronald Polk, Giovanni Gambassi, Kate L Lapane
Journal: Gut (2012)

<h3>Objectives</h3> To estimate the possible relationship between statin use and the risk of healthcare facility onset <i>Clostridium difficile</i>. <h3>Methods</h3> Patients over 18 years of age admitted to hospitals contributing data to the University HealthSystem Consortium between 2002 and 2009 were eligible. Patients with the ICD-9-CM code 008.45 who received a minimum 3-day course of either metronidazole or oral vancomycin on/after day 5 of admission were considered incident cases of <i>C difficile</i> infection. 31 472 incident cases of <i>C difficile</i> infection were identified and matched to five controls, on hospital, year/quarter of admission date, and age ±10 years (N=78 096). Patients who were administered one drug in the statin class (atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin or simvastatin) before the index date were considered to be exposed. Conditional logistic regression modelling provided adjusted odds ratios and 95% CI. <h3>Results</h3> Compared with non-users, users of any drug within the statin class were 0.78 times less likely to develop <i>C difficile</i> infection in the hospital (95% CI 0.75 to 0.81) adjusting for potential confounders. Differences in estimates for specific statins were minimal. Niacin, fibrates and selective cholesterol absorption inhibitors showed no association with the risk of <i>C difficile</i> infection. <h3>Conclusions</h3> Our data were consistent with a growing body of literature demonstrating a reduced risk of infections with statin use. Statins9 pleiotropic properties may provide protection against <i>C difficile</i> infection.
A multicenter randomized phase II study of oral vs. intravenous vinorelbine in advanced non-small-cell lung cancer patients
Authors: J. Jassem, R. Ramlau, H. Karnicka-Młodkowska, K. Krawczyk, M. Krzakowski, P. Zatloukal, E. Lemarié, W. Hartmann, L. Novakova, M. O’Brien, A. Depierre
Journal: Annals of Oncology (2001)