tbuckley/cabot-search huggingface dataset:
17β-Estradiol inhibits matrix metalloproteinase-2 transcription via MAP kinase in fibroblasts
Authors: Shokoufeh Mahmoodzadeh, Elke Dworatzek, Stephan Fritschka, Thi Hang Pham, Vera Regitz-Zagrosek
Journal: Cardiovascular Research (2009)

Female sex and sex hormones contribute to cardiac remodelling. 17β-estradiol (E2) is involved in the modulation of extracellular matrix composition and function. Here, we analysed the effect of E2 on matrix metalloproteinase (MMP)-2 gene expression and studied the underlying molecular mechanisms in rat cardiac fibroblasts and in a human fibroblast cell line. In adult rat cardiac fibroblasts, E2 significantly decreased MMP-2 gene expression in an estrogen receptor (ER)-dependent manner. Transient transfection experiments of human MMP-2 (hMMP-2) promoter deletion constructs in a human fibroblast cell line revealed a regulatory region between −324 and −260 bp that is involved in E2/ERα-mediated repression of hMMP-2 gene transcription. Electrophoretic mobility shift assays (EMSA) and supershift analysis demonstrated the binding of transcription factor Elk-1 within this promoter region. Elk-1 was phosphorylated by E2 via the mitogen-activated protein kinase (MAPK) signalling pathway as shown by western blotting. Treatment of cells with the MAPK inhibitor PD98059 blocked the E2-dependent repression of hMMP-2 promoter activity as well as the endogenous MMP-2 mRNA levels in both human fibroblast cells and rat cardiac fibroblasts. E2 inhibits MMP-2 expression via the ER and the MAPK pathway in rat cardiac fibroblasts and in a human fibroblast cell line. These mechanisms may contribute to sex-specific differences in fibrotic processes that are observed in human heart and other diseases.
Percutaneous Coronary Intervention Versus Conservative Therapy in Nonacute Coronary Artery Disease
Authors: Demosthenes G. Katritsis, John P.A. Ioannidis
Journal: Circulation (2005)

Percutaneous coronary intervention (PCI) has been shown to improve symptoms compared with conservative medical treatment in patients with stable coronary artery disease (CAD); however, there is limited evidence on the effect of PCI on the risk of death, myocardial infarction, and subsequent revascularization. Therefore, we performed a meta-analysis of 11 randomized trials comparing PCI to conservative treatment in patients with stable CAD.A total of 2950 patients were included in the meta-analysis (1476 received PCI, and 1474 received conservative treatment). There was no significant difference between the 2 treatment strategies with regard to mortality, cardiac death or myocardial infarction, nonfatal myocardial infarction, CABG, or PCI during follow-up. By random effects, the risk ratios (95% CIs) for the PCI versus conservative treatment arms were 0.94 (0.72 to 1.24), 1.17 (0.88 to 1.57), 1.28 (0.94 to 1.75), 1.03 (0.80 to 1.33), and 1.23 (0.80 to 1.90) for these 5 outcomes, respectively. A possible survival benefit was seen for PCI only in trials of patients who had a relatively recent myocardial infarction (risk ratio 0.40, 95% CI 0.17 to 0.95). Except for PCI during follow-up, there was no significant between-study heterogeneity for any outcome.In patients with chronic stable CAD, in the absence of a recent myocardial infarction, PCI does not offer any benefit in terms of death, myocardial infarction, or the need for subsequent revascularization compared with conservative medical treatment.
Hepatitis B Virus Screening for Patients With Cancer Before Therapy: American Society of Clinical Oncology Provisional Clinical Opinion Update
Authors: Jessica P. Hwang, Mark R. Somerfield, Devena E. Alston-Johnson, Donna R. Cryer, Jordan J. Feld, Barnett S. Kramer, Anita L. Sabichi, Sandra L. Wong, Andrew S. Artz
Journal: Journal of Clinical Oncology (2015)

This updated provisional clinical opinion presents a revised opinion based on American Society of Clinical Oncology panel consensus in the context of an evolving database.Despite the 2010 provisional clinical opinion recommendation, there is still evidence of suboptimal hepatitis B virus (HBV) screening among patients at high risk for HBV infection or HBV reactivation after chemotherapy. This updated provisional clinical opinion introduces a risk-adaptive strategy to identify and treat patients with HBV infection to reduce their risk of HBV reactivation.Medical providers should screen by testing patients for HBV infection before starting anti-CD20 therapy or hematopoietic cell transplantation. Providers should also screen patients with risk factors for HBV infection. Screening should include both hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc), because reactivation can occur in patients who are HBsAg positive/anti-HBc positive or HBsAg negative/anti-HBc positive. Either total anti-HBc or anti-HBc immunoglobulin G (not immunoglobulin M) test should be used. Clinicians should start antiviral therapy for HBsAg-positive/anti-HBc-positive patients before or contemporaneously with cancer therapy and monitor HBsAg-negative/anti-HBc-positive patients for reactivation with HBV DNA and ALT levels, promptly starting antivirals if reactivation occurs. Clinicians can initiate antivirals for HBsAg-negative/anti-HBc-positive patients anticipating cancer therapies associated with a high risk of reactivation, or they can monitor HBV DNA and ALT levels and initiate on-demand antivirals. For patients who neither have HBV risk factors nor anticipate cancer therapy associated with a high risk of reactivation, current evidence does not support HBV screening before initiation of cancer therapy. Two panel members provided a minority viewpoint, involving a strategy of universal HBsAg and selective anti-HBc testing.
How doctors discuss major interventions with high risk patients: an observational study
Authors: C F Corke, P J Stow, D T Green, J W Agar, M J Henry
Journal: BMJ (2004)

<h3>Abstract</h3> <b>Objective</b> To investigate the difficulties doctors face in discussing treatment options with patients with acute, life threatening illness and major comorbidities. <b>Design</b> Observational study of doctor-patient interviews based on a standardised clinical scenario involving high risk surgery in a hypothetical patient (played by an actor) with serious comorbidities. <b>Participants</b> 30 trainee doctors 3-5 years after graduation. <b>Main outcome measures</b> Adequacy of coverage of various aspects was scored from 3 (good) to 0 (not discussed). <b>Results</b> The medical situation was considered to be well described (median score 2.7 (interquartile range 2.1-3.0)), whereas the patient9s functional status, values, and fears were poorly or minimally addressed (scores 0.5 (0.0-1.0), 0.5 (0.0-1.0), and 0.0 (0.0-1.5), respectively; all P &lt; 0.001 <i>v</i> score for describing the medical situation). Twenty nine of the doctors indicated that they wished to include the patient9s family in the discussion, but none identified a preferred surrogate decision maker. Six doctors suggested that the patient alone should speak with his family to reach a decision without the doctor being present. The doctors were reluctant to give advice, despite it being directly requested: two doctors stated that a doctor could not give advice, while 17 simply restated the medical risks, without advocating any particular course. Of the 11 who did offer advice, eight advocated intervention. <b>Conclusions</b> Doctors focused on technical medical issues and placed much less emphasis on patient issues such as functional status, values, wishes, and fears. This limits doctors9 ability to offer suitable advice about treatment options. Doctors need to improve their communication skills in this difficult but common clinical situation.
Gallbladder function, cholesterol stones, and bile composition.
Authors: G Antsaklis, M R Lewin, D J Sutor, A G Cowie, C G Clark
Journal: Gut (1975)

Gallbladder bile obtained at operation from five patients with no symptoms of biliary disease was undersaturated with cholesterol in every case. However, gallbladder bile from patients with stones composed of 97-100% crystalline cholesterol was on average just saturated with cholesterol when the gallbladder was functioning and undersaturated when it was not. Regardless of gallbladder function, the patients with stones had on average significantly more cholesterol in their bile than in the control group, but the differences between the mean composition of bile from functioning and non-functioning gallbladders were not significant. Common duct bile from patients with non-functioning and functioning gallbladders was on average supersaturated with cholesterol, but there was significantly more bile salt and significantly less cholesterol in the bile from patients with non-functioning gallbladders. Only in the case of patients with functioning gallbladders did the mean composition of the common duct and gallbladder biles differ significantly. The former contained significantly more cholesterol and less bile salt than the latter. It is suggested that patients with non-functioning gallbladders may be 9autocholecystectomised9 with the duct bile reverting to a more 9normal9 composition.
Selective Impairment in Sympathetic Vasomotor Control With Norepinephrine Transporter Inhibition
Authors: Jens Tank, Christoph Schroeder, Andre Diedrich, Elke Szczech, Sebastian Haertter, Arya M. Sharma, Friedrich C. Luft, Jens Jordan
Journal: Circulation (2003)

Norepinephrine transporter (NET) inhibition increases the responsiveness to vasoactive medications and attenuates the response to sympathetic stimuli. The phenomenon may be a result of impaired regulation of sympathetic vasomotor tone.We studied the effects of the selective NET blocker reboxetine and placebo on baroreflex control of heart rate (HR) and sympathetic traffic in a randomized, double-blind, crossover manner in healthy subjects. Subjects ingested 8 mg reboxetine or placebo 12 hours and 1 hour before testing. ECGs were measured for HR, brachial and finger blood pressure (BP), and muscle sympathetic nerve activity (MSNA). Sympathetic and parasympathetic baroreflex slopes were determined by use of incremental phenylephrine and nitroprusside infusions. The dose to reach BP changes of 12.5 mm Hg was significantly lower during NET inhibition (0.25 versus 0.64 microg x kg(-1) x min(-1) phenylephrine and 0.40 versus 1.10 microg x kg(-1) x min(-1) nitroprusside, P<0.01). Baroreflex control of HR was similar (16 ms/mm Hg with placebo versus 14 ms/mm Hg with reboxetine) but reset to higher BP values. MSNA and sympathetically mediated low-frequency BP oscillations were profoundly reduced at baseline and failed to increase sufficiently during nitroprusside infusion. Reboxetine attenuated BP and MSNA responses to cold pressor testing.NET inhibition profoundly and selectively reduces baroreflex control of sympathetic vasomotor tone and attenuates the responsiveness to sympathetic stimuli. The reduction in baroreflex buffering increases the sensitivity to vasoactive medications. Therefore, our findings represent a novel mechanism for drug interactions.
The Treatment of Minimal Change Disease in Adults
Authors: Jonathan Hogan, Jai Radhakrishnan
Journal: Journal of the American Society of Nephrology (2013)

Minimal change disease (MCD) is the etiology of 10%–25% of cases of nephrotic syndrome in adults. The mainstay of treatment for adult MCD, oral gucocorticoids, is based on two randomized controlled trials and extensive observational data in adults, and this treatment leads to remission in over 80% of cases. Relapses are common, and some patients become steroid-resistant (SR), steroid-dependent (SD), or frequently relapsing (FR). The data guiding the treatment of these patients are limited. Here, we review MCD in adults with particular focus on the evidence for immunosuppressive therapy in these patients.
Variation in the 3-Hydroxyl-3-Methylglutaryl Coenzyme A Reductase Gene Is Associated With Racial Differences in Low-Density Lipoprotein Cholesterol Response to Simvastatin Treatment
Authors: Ronald M. Krauss, Lara M. Mangravite, Joshua D. Smith, Marisa W. Medina, Dai Wang, Xiuqing Guo, Mark J. Rieder, Joel A. Simon, Steven B. Hulley, David Waters, Mohammed Saad, Paul T. Williams, Kent D. Taylor, Huiying Yang, Deborah A. Nickerson, Jerome I. Rotter
Journal: Circulation (2008)

Use of 3-hydroxyl-3-methylglutaryl-3 coenzyme A reductase (HMGCR) inhibitors, or statins, reduces cardiovascular disease risk by lowering plasma low-density lipoprotein cholesterol (LDL-C) concentrations. However, LDL-C response is variable and influenced by many factors, including racial ancestry, with attenuated response in blacks compared with whites. We hypothesized that single nucleotide polymorphisms in the gene encoding HMGCR, a rate-limiting enzyme in cholesterol synthesis and the direct enzymatic target of statins, contribute to variation in statin response.Genomic resequencing of HMGCR in 24 blacks and 23 whites identified 79 single nucleotide polymorphisms. Eleven single nucleotide polymorphisms were selected to tag common linkage disequilibrium clusters. These single nucleotide polymorphisms and the common haplotypes inferred from them were tested for association with plasma LDL-C and LDL-C response to simvastatin treatment (40 mg/d for 6 weeks) in 326 blacks and 596 whites. Black carriers of H7 and/or H2 had significantly lower baseline LDL-C (P=0.0006) and significantly attenuated LDL-C response compared with black participants who did not carry either haplotype as measured by absolute response (-1.23+/-0.04 mmol/L, n=209, versus -1.45+/-0.06 mmol/L, n=117; P=0.0008) and percent response (-36.9+/-1.0% versus -40.6+/-1.3%; P=0.02), but no haplotype effect was observed in whites. Percent LDL-C response was lowest in carriers of both H2 and H7, all but one of whom were black (-28.2+/-4.9%, n=12 H2+H7 carriers, versus -41.5+/-0.5%, n=650 H2/H7 noncarriers; P=0.001). LDL-C responses in H7 and/or H2 noncarriers were indistinguishable between blacks and whites.HMGCR gene polymorphisms are associated with reduced plasma LDL-C and LDL-C response to simvastatin, and these effects are most evident in blacks.
Results of treatment of 255 patients with metastatic renal cell carcinoma who received high-dose recombinant interleukin-2 therapy.
Authors: G Fyfe, R I Fisher, S A Rosenberg, M Sznol, D R Parkinson, A C Louie
Journal: Journal of Clinical Oncology (1995)

PURPOSE To determine the efficacy and toxicity of a high-dose interleukin-2 (IL-2) regimen in patients with metastatic renal cell carcinoma. PATIENTS AND METHODS Two hundred fifty-five assessable patients were entered onto seven phase II clinical trials. Proleukin (aldesleukin; Chiron Corp, Emeryville, CA) 600,000 or 720,000 IU/kg was administered by 15-minute intravenous (i.v.) infusion every 8 hours for up to 14 consecutive doses over 5 days as clinically tolerated with maximum support, including pressors. A second identical cycle of treatment was scheduled following 5 to 9 days of rest, and courses could be repeated every 6 to 12 weeks in stable or responding patients. RESULTS The overall objective response rate was 14% (90% confidence interval [CI], 10% to 19%), with 12 (5%) complete responses (CRs) and 24 (9%) partial responses (PRs). Responses occurred in all sites of disease, including bone, intact primary tumors, and visceral metastases, and in patients with large tumor burdens or bulky individual lesions. The median response duration for patients who achieved a CR has not been reached, but was 19.0 months for those who achieved a PR. Baseline Eastern Cooperative Oncology Group (ECOG) performance status (PS) was the only predictive prognostic factor for response to IL-2. While treatment was associated with severe acute toxicities, these generally reversed rapidly after therapy was completed. However, 4% of patients died of adverse events judged to be possibly or probably treatment-related. CONCLUSION High-dose IL-2 appears to benefit some patients with metastatic renal cell carcinoma by producing durable CRs or PRs. Despite severe acute treatment-associated toxicities, IL-2 should be considered for initial therapy of patients with appropriately selected metastatic renal cell carcinoma.
Survival Prediction in Patients With Glioblastoma Multiforme by Human Telomerase Genetic Variation
Authors: Luo Wang, Qingyi Wei, Li-E Wang, Kenneth D. Aldape, Yumei Cao, M. Fatih Okcu, Kenneth R. Hess, Randa El-Zein, Mark R. Gilbert, Shiao Y. Woo, Sujit S. Prabhu, Greg N. Fuller, Melissa L. Bondy
Journal: Journal of Clinical Oncology (2006)

Purpose Glioblastoma multiforme (GBM) is the most common and aggressive glioma with the poorest survival. Use of biomarkers for screening patients with GBM may be used to modify treatments and improve outcomes. The level of human telomerase (hTERT) expression is an independent predictor of outcome of many cancers, and a functional variant of hTERT MNS16A (shorter tandem repeats or short [S] allele) is associated with increased hTERT mRNA expression. We investigated whether hTERT MNS16A variant genotype predicted survival in GBM patients. Patients and Methods We genotyped hTERT MNS16A in 299 GBM patients using polymerase chain reaction and determined hTERT genotype by classifying the DNA band of 243 or 272 base pairs (bp) as S allele and 302 or 333 bp as long (L) allele. We compared overall survival using Kaplan-Meier estimates and equality of survival distributions using the log-rank test, and we computed univariate and multivariate Cox proportional hazards models to estimate the effects of selected variables. Results Overall survival differed significantly by hTERT MNS16A genotype, with median survivals of 25.1, 14.7, and 14.6 months for the SS, SL, and LL genotypes, respectively. Compared with the SS genotype, the hazard ratios for the SL and LL genotypes were 1.69 and 1.87, respectively, after adjustment for other factors. Multivariate Cox regression analysis showed an independent statistically significant association between the hTERT MNS16A variant genotype and outcome. Conclusion A functional hTERT MNS16A genotype is a potential biomarker for assessment of survival outcome of GBM. Larger studies are needed to verify these findings.
Long-Term Psychological Impact of Carrying a BRCA1/2 Mutation and Prophylactic Surgery: A 5-Year Follow-Up Study
Authors: Iris van Oostrom, Hanne Meijers-Heijboer, Litanja N. Lodder, Hugo J. Duivenvoorden, Arthur R. van Gool, Caroline Seynaeve, Conny A. van der Meer, Jan G.M. Klijn, Bert N. van Geel, Curt W. Burger, Juriy W. Wladimiroff, Aad Tibben
Journal: Journal of Clinical Oncology (2003)

To explore long-term psychosocial consequences of carrying a BRCA1/2 mutation and to identify possible risk factors for long-term psychological distress.Five years after genetic test disclosure, 65 female participants (23 carriers, 42 noncarriers) of our psychological follow-up study completed a questionnaire and 51 participants were interviewed. We assessed general and hereditary cancer-related distress, risk perception, openness to discuss the test result with relatives, body image and sexual functioning.Carriers did not differ from noncarriers on several distress measures and both groups showed a significant increase in anxiety and depression from 1 to 5 years follow-up. Carriers having undergone prophylactic surgery (21 of 23 carriers) had a less favorable body image than noncarriers and 70% reported changes in the sexual relationship. A major psychological benefit of prophylactic surgery was a reduction in the fear of developing cancer. Predictors of long-term distress were hereditary cancer-related distress at blood sampling, having young children, and having lost a relative to breast/ovarian cancer. Long-term distress was also associated with less open communication about the test result within the family, changes in relationships with relatives, doubting about the validity of the test result, and higher risk perception.Our findings support the emerging consensus that genetic predisposition testing for BRCA1/2 does not pose major mental health risks, but our findings also show that the impact of prophylactic surgery on aspects such as body image and sexuality should not be underestimated, and that some women are at risk for high distress, and as a result, need more attentive care.
Eccentric exercises; why do they work, what are the problems and how can we improve them?
Authors: J D Rees, R L Wolman, A Wilson
Journal: British Journal of Sports Medicine (2008)

Eccentric exercises (EE) have proved successful in the management of chronic tendinopathy, particularly of the Achilles and patellar tendons, where they have been shown to be effective in controlled trials. However, numerous questions regarding EE remain. The standard protocols are time-consuming and require very motivated patients. EE are effective in some tendinopathies but not others. Furthermore, the location of the lesion can have a profound effect on efficacy; for example, standard EE in insertional lesions of the Achilles are ineffective. Until recently little was known of the effect of EE on tendinopathic tendons, although a greater understanding of this process is emerging. Additionally, recent in vivo evidence directly comparing eccentric and concentric exercises provides a possible explanation for the therapeutic benefit of EE. The challenge now is to make EE more effective. Suggestions on areas of future research are made.
Informed Consent and the Capacity for Voluntarism
Authors: Laura Weiss Roberts
Journal: American Journal of Psychiatry (2002)

OBJECTIVE: Informed consent is built upon the elements of information, decisional capacity, and voluntarism. Of these elements, voluntarism in clinical and research consent is the least well understood. This has interfered with the ability to resolve key ethical problems faced by the field of psychiatry. METHOD: The author suggests that voluntarism encompasses an individual's ability to act in accordance with one's authentic sense of what is good, right, and best in light of one's situation, values, and prior history. Voluntarism further entails the capacity to make this choice freely and in the absence of coercion. Deliberateness, purposefulness of intent, clarity, genuineness, and coherence with prior life decisions are implicitly emphasized in this construction. RESULTS: The author offers and illustrates a framework for voluntarism in clinical and research consent decisions, focusing on four domains of potential influence: 1) developmental factors, 2) illness-related considerations, 3) psychological issues and cultural and religious values, and 4) external features and pressures. CONCLUSIONS: It is hoped that improved understanding of voluntarism will help in our efforts to fulfill the principle of respect for persons in clinical care and research.
Risk of therapy-related myelodysplastic syndrome/acute leukemia following high-dose therapy and autologous bone marrow transplantation for non-Hodgkin’s lymphoma
Authors: C. Hosing, M. Munsell, S. Yazji, B. Andersson, D. Couriel, M. de Lima, M. Donato, J. Gajewski, S. Giralt, M. Körbling, T. Martin, N.T. Ueno, R.E. Champlin, I.F. Khouri
Journal: Annals of Oncology (2002)