tbuckley/cabot-search huggingface dataset:
Coordinated down-regulation of KCNQ1 and KCNE1 expression contributes to reduction of IKs in canine hypertrophied hearts
Authors: C Ramakers
Journal: Cardiovascular Research (2003)

Objective: In animal models of hypertrophy, electrical remodeling giving rise to QT prolongation occurs rapidly and is associated with the development of torsade de pointes (TdP) arrhythmias and sudden death. Chronic AV block (CAVB)-induced hypertrophy in dogs has been associated with a reduction in the slow component (IKs) of the delayed rectifier potassium current (IK), which contributes to a prolongation of ventricular repolarization, the development of an acquired form of long QT, and the substrate for triggered activity and TdP. The present study was designed to probe the molecular basis for the decrease in IKs by studying the characteristics of KCNE1 and KCNQ1, the putative genes responsible for formation of the channel. Methods and Results: Using a combination of Northern blot, competitive multiplex PCR and immunoblot assays, we found that CAVB reduces KCNE1 and KCNQ1 RNA in the canine ventricles by 70 and 80%, respectively. Protein levels of KCNE1 and KCNQ1 were reduced by 60 and 50%, respectively. We also demonstrate at the molecular level the basis for inter-ventricular difference in IKs density previously reported in hearts of normal dogs and show the basis for reduction of this difference in the CAVB dog. Conclusions: Our results indicate that the CAVB-induced reduction in IKs is due to a down-regulation of KCNE1 and KCNQ1 transcription. The data suggest that electrical remodeling of the cardiac ventricle during hypertrophy involves regulation of the gene expression through modulation of transcriptional and translational regulatory pathways. The reduction in KCNE1 and KCNQ1 expression increases the dependence of ventricular repolarization on the rapid component of IK and may potentiate the action of Class III antiarrhythmic agents.
Phase I Trial of AEG35156 Administered as a 7-Day and 3-Day Continuous Intravenous Infusion in Patients With Advanced Refractory Cancer
Authors: Emma Dean, Duncan Jodrell, Kate Connolly, Sarah Danson, Jacques Jolivet, Jon Durkin, Stephen Morris, Debra Jowle, Tim Ward, Jeff Cummings, Gemma Dickinson, Leon Aarons, Eric LaCasse, Lesley Robson, Caroline Dive, Malcolm Ranson
Journal: Journal of Clinical Oncology (2009)

To establish the maximum-tolerated dose and evaluate tolerability, pharmacokinetics, pharmacodynamic effects, and antitumor activity of AEG35156, a second-generation antisense to X-linked inhibitor of apoptosis (XIAP) protein, in patients with advanced refractory malignant tumors.This was a first-in-man, open-label, phase I dose-escalation study. AEG35156 was administered by continuous intravenous infusion over 7 days (7DI) or 3 days (3DI) of a 21-day treatment cycle. Dose escalation started at 48 mg/m(2)/d and continued until consistent dose-limiting toxicity (DLT) was observed.Thirty-eight patients were entered in seven cohorts. Grade 3 to 4 adverse events were uncommon and were predominantly abnormal laboratory values: elevated ALT, thrombocytopenia, and lymphopenia. DLTs comprised elevated hepatic enzymes, hypophosphatemia, and thrombocytopenia. The maximum-tolerated doses were defined as 125 mg/m(2)/d for the 7DI regimen and < or = 213 mg/m(2)/d for the 3DI schedule. AEG35156 area under the plasma concentration curve and peak plasma concentration increased proportionally with dose. Suppression of XIAP mRNA levels was maximal at 72 hours (mean suppression, 21%), and this coincided with a dramatic decrease in circulating tumor cells in a patient with non-Hodgkin's lymphoma. Two further patients had unconfirmed partial responses. Circulating biomarkers of cell death and apoptosis altered in association with drug infusion and toxicity.In this first-in-man study, AEG35156 was well tolerated, with predictable toxicities, pharmacokinetic properties, and clinical evidence of antitumor activity in patients with refractory lymphoma, melanoma, and breast cancer. Phase I/II trials of AEG35156 chemotherapy combinations are ongoing in patients with pancreatic, breast, non-small-cell lung cancer, acute myeloid leukemia, lymphoma, and solid tumors for which docetaxel is indicated.
Let's Get SEERious: More Accurate Staging With Consequent High Management Impact Is Not Just Stage Migration
Authors: Michael S. Hofman, David L. Ball, Michael P. Mac Manus, Robert Ware, Rodney J. Hicks
Journal: Journal of Clinical Oncology (2013)

issue in heath care resourcing. Although individuals with non–smallcell lung carcinoma (NSCLC), their physicians, and third-party health care payers deserve reassurance that the increasing use of positron emission tomography (PET) is beneficial, we have significant concerns regarding the methodology applied and, consequently, the validity of the resulting conclusions. Most importantly, we feel that all-cause survival is an inappropriate primary end point for judging the benefits of a diagnostic test. This parameter ignores the potential of a superior investigation to guide more efficient and appropriate use of therapeutic interventions and to induce changes in management that may influence quality of life or progressionfree survival in particular patient subgroups without necessarily affecting long-term survival. This is particularly relevant in a disease like NSCLC in which current therapeutic interventions have suboptimal efficacy and are associated with substantial cost and toxicity. Nevertheless, because it has been previously established that the dominant effect of applying PET to NSCLC staging is the detection of unrecognized metastases, 2,3 a logical assumption must be that palliative therapies would be more frequently applied with increasing use of PET. If PET inappropriately upstages patients and results in patients’ denial of potentially curative therapies, overall survival should logically deteriorate. The authors’ finding that all-cause survival did not change significantly with the increasing use of PET supports a conclusion that PET may reduce morbidity associated with futile therapies without negatively affecting overall patient outcomes. We believe that if any conclusion can be reached, their data thus support rather than repudiate the utility of PET in NSCLC. As there is currently no curative therapy available for stage 4 NSCLC, it is unreasonable to expect a large change in overall survival with the application of PET. The earliest study end point of 2-year overall survival used by the authors is, we contend, too long to reliably detect improvements in survival associated with better selection and delivery of palliative treatments in such patients. In our own recently published prospective trial of PET/computed tomography in NSCLC, the median survival of patients with stage 4 disease on PET was less than a year and almost all patients in this stage group died within 2 years. 4 Moreover, patients who died as an immediate complication of futile therapy would also not be detected because the study excluded patients who died within 2 months.
Corrigendum to “Polydopamine-mediated surface modification of scaffold materials for human neural stem cell engineering” [Biomaterials 33 (2012) 6952–6964]
Authors: Kisuk Yang, Jung Seung Lee, Jin Kim, Yu Bin Lee, Heungsoo Shin, Soong Ho Um, Jeong Beom Kim, Kook In Park, Haeshin Lee, Seung-Woo Cho
Journal: Biomaterials (2012)
The Infusion Center
Journal: JAMA (1999)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Outpatient follow-up ratio targets make no sense
Authors: A. Bamji
Journal: BMJ (2011)

My interest in the issue of outpatient follow-up began when my hospital trust asked me to reduce my ratio of new to follow-up consultations to 1:2.1 in 2006. Attempts to discover why led me to a new performance indicator from the NHS Institute for Innovation and Improvement; it appeared on the website as an “NHS better care, better value indicator.”

I am a rheumatologist. I deal with inflammatory joint disease, which according to specialty guidelines (endorsed by the National Institute for Health and Clinical Excellence) requires short term follow-up to stability, with appointments a month apart, and then specialist follow-up at least once a year. From my follow-up database I calculated that to achieve the trust’s target I would have to discharge half my patients. My trust managers said they were happy for me to do this because their GPs would have to re-refer them—and, by the by, said that I had no clinical responsibility for them. Re-referral would not only improve the ratio but also bring in extra money. (The Payment by Results tariff for a new patient consultation is £230 (€270; $360), that for a follow-up …
Glucose Control and Vascular Complications in Veterans with Type 2 Diabetes
Authors: William Duckworth, Carlos Abraira, Thomas Moritz, Domenic Reda, Nicholas Emanuele, Peter D. Reaven, Franklin J. Zieve, Jennifer Marks, Stephen N. Davis, Rodney Hayward, Stuart R. Warren, Steven Goldman, Madeline McCarren, Mary Ellen Vitek, William G. Henderson, Grant D. Huang
Journal: New England Journal of Medicine (2008)

The effects of intensive glucose control on cardiovascular events in patients with long-standing type 2 diabetes mellitus remain uncertain.We randomly assigned 1791 military veterans (mean age, 60.4 years) who had a suboptimal response to therapy for type 2 diabetes to receive either intensive or standard glucose control. Other cardiovascular risk factors were treated uniformly. The mean number of years since the diagnosis of diabetes was 11.5, and 40% of the patients had already had a cardiovascular event. The goal in the intensive-therapy group was an absolute reduction of 1.5 percentage points in the glycated hemoglobin level, as compared with the standard-therapy group. The primary outcome was the time from randomization to the first occurrence of a major cardiovascular event, a composite of myocardial infarction, stroke, death from cardiovascular causes, congestive heart failure, surgery for vascular disease, inoperable coronary disease, and amputation for ischemic gangrene.The median follow-up was 5.6 years. Median glycated hemoglobin levels were 8.4% in the standard-therapy group and 6.9% in the intensive-therapy group. The primary outcome occurred in 264 patients in the standard-therapy group and 235 patients in the intensive-therapy group (hazard ratio in the intensive-therapy group, 0.88; 95% confidence interval [CI], 0.74 to 1.05; P=0.14). There was no significant difference between the two groups in any component of the primary outcome or in the rate of death from any cause (hazard ratio, 1.07; 95% CI, 0.81 to 1.42; P=0.62). No differences between the two groups were observed for microvascular complications. The rates of adverse events, predominantly hypoglycemia, were 17.6% in the standard-therapy group and 24.1% in the intensive-therapy group.Intensive glucose control in patients with poorly controlled type 2 diabetes had no significant effect on the rates of major cardiovascular events, death, or microvascular complications with the exception of progression of albuminuria (P = 0.01) [added]. (ClinicalTrials.gov number, NCT00032487.)
Tumor-Suppressive Activity of the Cell Death Activator GRIM-19 on a Constitutively Active Signal Transducer and Activator of Transcription 3
Authors: Sudhakar Kalakonda, Shreeram C. Nallar, Daniel J. Lindner, Jiadi Hu, Sekhar P. Reddy, Dhananjaya V. Kalvakolanu
Journal: Cancer Research (2007)

Abstract Signal transducers and activators of transcription 3 (STAT3) was originally identified as a transcription factor that mediates cytokine-induced responses. In these pathways, Janus-activated kinase (JAK)–induced transient tyrosine phosphorylation of STAT3 promotes gene expression in response to a number of cytokines, which is inhibited by feedback mechanisms. A number of studies have shown that STAT3 is constitutively activated in human cancer cells, leading to cell proliferation. It is unclear, apart from a chronic tyrosyl phosphorylation of STAT3, what mechanisms contribute to the STAT3 deregulation in tumors. Earlier, we have isolated a novel growth inhibitory gene product, gene associated with retinoid-IFN–induced mortality 19 (GRIM-19), using a genetic approach. GRIM-19 is an IFN/retinoic acid–regulated growth suppressor. Subsequent analyses have shown that GRIM-19 binds to STAT3 and prevents interleukin-6–induced transcription of cellular genes. However, its effects on a constitutively active STAT3 and cellular transformation are unknown. In this study, we show that GRIM-19 suppresses constitutive STAT3-induced cellular transformation in vitro and in vivo by down-regulating the expression of a number of cellular genes involved in cell proliferation and apoptosis. [Cancer Res 2007;67(13):6212–20]
A Combined Array-Based Comparative Genomic Hybridization and Functional Library Screening Approach Identifies mir-30d As an Oncomir in Cancer
Authors: Ning Li, Sippy Kaur, Joel Greshock, Heini Lassus, Xiaomin Zhong, Yanling Wang, Arto Leminen, Zhongjun Shao, Xiaowen Hu, Shun Liang, Dionyssios Katsaros, Qihong Huang, Ralf Bützow, Barbara L. Weber, George Coukos, Lin Zhang
Journal: Cancer Research (2011)

Oncomirs are microRNAs (miRNA) that acts as oncogenes or tumor suppressor genes. Efficient identification of oncomirs remains a challenge. Here we report a novel, clinically guided genetic screening approach for the identification of oncomirs, identifying mir-30d through this strategy. mir-30d regulates tumor cell proliferation, apoptosis, senescence, and migration. The chromosomal locus harboring mir-30d was amplified in more than 30% of multiple types of human solid tumors (n = 1,283). Importantly, higher levels of mir-30d expression were associated significantly with poor clinical outcomes in ovarian cancer patients (n = 330, P = 0.0016). Mechanistic investigations suggested that mir-30d regulates a large number of cancer-associated genes, including the apoptotic caspase CASP3. The guided genetic screening approach validated by this study offers a powerful tool to identify oncomirs that may have utility as biomarkers or targets for drug development.
Is fetal <i>RHD</i> typing in all RhD negative women cost effective?
Authors: Ala Szczepura, Gouke Bonsel, Christian Krauth, Leeza Osipenko, Alexander Haverkamp
Journal: BMJ (2008)

<h3>Abstract</h3> Ward rounds are integral to maintaining patient safety in everyday clinical care. Junior doctors are often expected to conduct independent rounds on graduation, but many feel ill-equipped to do so. We developed a safety checklist and simulation sessions to improve junior-led ward round practice at one district general hospital. We found that embedding a checklist within simulation is an effective way to teach ward round skills and increase confidence among undergraduate and postgraduate medical trainees.
Aspirin- and Coumadin®-Related Bleeding After Coronary-Artery Bypass Graft Surgery
Authors: MICHAEL TOROSIAN
Journal: Annals of Internal Medicine (1978)

We studied 100 consecutive patients to evaluate the potential effect of platelet active and antithrombotic agents prescribed preoperatively on bleeding complications after coronary-artery bypass graft surgery. Preoperative hemostatic values were normal in all patients. Mean mediastinal blood loss was significantly greater in 13 patients taking aspirin (892 ± 91 ml) and six patients taking Coumadin® (warfarin sodium) (858 ± 168 ml) within 7 days of surgery than in 64 control subjects (439 ± 28, P < 0.001). Less marked but similar differences (P < 0.05) were noted with other agents inhibiting platelet function. However, in nine patients given heparin, mean mediastinal blood loss (436 ± 61 ml) was no different from that of control subjects. The degree of mediastinal blood loss did not correlate with age, sex, mean total operative time, bypass time, or number of vessels diseased or bypassed. In addition, patients taking aspirin or Coumadin required prolonged chest tube drainage compared to those in heparin or control groups (34 ± 4 versus 20 ± 1 h) (P < 0.001).
Y-Chromosomal Variation in Sub-Saharan Africa: Insights Into the History of Niger-Congo Groups
Authors: C. de Filippo, C. Barbieri, M. Whitten, S. W. Mpoloka, E. D. Gunnarsdottir, K. Bostoen, T. Nyambe, K. Beyer, H. Schreiber, P. de Knijff, D. Luiselli, M. Stoneking, B. Pakendorf
Journal: Molecular Biology and Evolution (2010)

Technological and cultural innovations as well as climate changes are thought to have influenced the diffusion of major language phyla in sub-Saharan Africa. The most widespread and the richest in diversity is the Niger-Congo phylum, thought to have originated in West Africa ∼10,000 years ago (ya). The expansion of Bantu languages (a family within the Niger-Congo phylum) ∼5,000 ya represents a major event in the past demography of the continent. Many previous studies on Y chromosomal variation in Africa associated the Bantu expansion with haplogroup E1b1a (and sometimes its sublineage E1b1a7). However, the distribution of these two lineages extends far beyond the area occupied nowadays by Bantu-speaking people, raising questions on the actual genetic structure behind this expansion. To address these issues, we directly genotyped 31 biallelic markers and 12 microsatellites on the Y chromosome in 1,195 individuals of African ancestry focusing on areas that were previously poorly characterized (Botswana, Burkina Faso, Democratic Republic of Congo, and Zambia). With the inclusion of published data, we analyzed 2,736 individuals from 26 groups representing all linguistic phyla and covering a large portion of sub-Saharan Africa. Within the Niger-Congo phylum, we ascertain for the first time differences in haplogroup composition between Bantu and non-Bantu groups via two markers (U174 and U175) on the background of haplogroup E1b1a (and E1b1a7), which were directly genotyped in our samples and for which genotypes were inferred from published data using linear discriminant analysis on short tandem repeat (STR) haplotypes. No reduction in STR diversity levels was found across the Bantu groups, suggesting the absence of serial founder effects. In addition, the homogeneity of haplogroup composition and pattern of haplotype sharing between Western and Eastern Bantu groups suggests that their expansion throughout sub-Saharan Africa reflects a rapid spread followed by backward and forward migrations. Overall, we found that linguistic affiliations played a notable role in shaping sub-Saharan African Y chromosomal diversity, although the impact of geography is clearly discernible.
Neuropsychology of First-Episode Schizophrenia: Initial Characterization and Clinical Correlates
Authors: R M Bilder, R S Goldman, D Robinson, G Reiter, L Bell, J A Bates, E Pappadopulos, D F Willson, J M Alvir, M G Woerner, S Geisler, J M Kane, J A Lieberman
Journal: American Journal of Psychiatry (2000)

OBJECTIVE: Neuropsychological impairments are well documented in schizophrenia and are important targets of treatment. Information about the severity and pattern of deficits after treatment for the first psychotic episode and about relationships between these deficits and syndromal characteristics remains limited. METHOD: Comprehensive neuropsychological assessments including 41 individual tests were given to 94 patients with first-episode schizophrenia after initial stabilization of psychosis and to a comparison group of 36 healthy volunteers. Profiles of neuropsychological deficits and the relationship of deficits to sex and handedness were examined. Correlations of neuropsychological deficit with a broad range of historical and clinical characteristics, including outcome, were explored. RESULTS: Patients had a large generalized neuropsychological deficit (1.5 standard deviations compared to healthy volunteers). Patients also had, superimposed on the generalized deficit, subtle relative deficits (less than 0.5 standard deviation compared to their own average profile) in memory and executive functions. Learning/memory dysfunction best distinguished patients from healthy individuals; after accounting for this difference, only motor deficits further distinguished the groups. Patients with higher neuropsychological ability had only memory deficits, and patients with lower ability had both memory and executive deficits. No sex differences were observed beyond the normal advantage for men in motor speed. Dextral patients had less severe generalized deficit. Severity of residual symptoms was associated with greater generalized deficit. Executive and attentional deficits were most linked to global functional impairment and poor outcome. CONCLUSIONS: The results document a large generalized deficit, and more subtle differential deficits, in clinically stabilized first-episode patients. Learning/memory deficits were observed even in patients with less severe generalized deficit, but the pattern was unlike the amnestic syndrome and probably reflects different mechanisms. Executive and attentional deficits marked the more severely disabled patients, and may portend relatively poor outcome. Failure to develop typical patterns of cerebral dominance may increase the risk for greater generalized deficit.
Water Ingestion as Prophylaxis Against Syncope
Authors: Chih-Cherng Lu, André Diedrich, Che-Se Tung, Sachin Y. Paranjape, Paul A. Harris, Daniel W. Byrne, Jens Jordan, David Robertson
Journal: Circulation (2003)

Background— Water ingestion raises blood pressure substantially in patients with perturbed autonomic control and more modestly in older subjects. It is unclear whether prophylactic water drinking improves orthostatic tolerance in normal healthy adults. Methods and Results— Twenty-two healthy subjects, 18 to 42 years of age, with no history of syncope underwent head-up tilt-table testing at 60° for 45 minutes or until presyncope or syncope occurred. In their initial test, participants were randomized to either 16 oz (473 mL) of water drinking 5 minutes before tilt-table testing or tilt-table testing alone, with the alternative in a second test on a different day. During the first 30 minutes of tilt, 8 of 22 subjects without water experienced presyncope but only 1 of 22 who had ingested water ( P =0.016). Water drinking attenuated the heart rate increase associated with tilt ( P &lt;0.001) while accentuating the increase in total peripheral resistance ( P =0.012). The average time study participants tolerated head-up tilt was 26% longer after water (41.1±8.1 versus 32.6±14.3 minutes, mean±SD), with a pairwise mean difference of 8.5±14.0 minutes (95% CI, 2.3 to 14.7 minutes; P =0.011). Conclusions— Water enhances tolerance of upright posture. The effect of water is mediated by increased peripheral vascular resistance. Water ingestion may constitute a simple and effective prophylaxis against vasovagal reactions in healthy subjects, such as those associated with blood donation.