tbuckley/cabot-search huggingface dataset:
Altered Metabolite Exchange Between Subcellular Compartments in Intact Postischemic Rabbit Hearts
Authors: E. Douglas Lewandowski, Xin Yu, Kathryn F. LaNoue, Lawrence T. White, Chris Doumen, J. Michael O’Donnell
Journal: Circulation Research (1997)

Abstract To examine metabolic regulation in postischemic hearts, we examined oxidative recycling of 13 C within the glutamate pool (GLU) of intact rabbit hearts. Isolated hearts oxidized 2.5 mmol/L [2- 13 C]acetate during normal conditions (n=6) or during reperfusion after 10 minutes of ischemia (n=5). 13 C-Nuclear magnetic resonance spectra were acquired every 1 minute. Kinetic analysis of 13 C incorporation into GLU provided both tricarboxylic acid (TCA) cycle flux and the interconversion rate (F 1 ) between the TCA cycle intermediate, α-ketoglutarate (α-KG), and the largely cytosolic GLU. The rate-pressure product in postischemic hearts was 46% of normal ( P &lt;.05). No difference in substrate utilization occurred between groups, with acetate accounting for 92% of the carbon units entering the TCA cycle at the citrate synthase step. TCA cycle flux in postischemic hearts was normal (normal hearts, 10.7 μmol·min −1 ·g −1 ; postischemic hearts, 9.4 μmol·min −1 ·g −1 ), whereas F 1 was 72% lower at 2.9±0.4 versus 10.2±2.5 μmol·min −1 ·g −1 (mean±SE) in normal hearts ( P &lt;.05). From additional hearts perfused with 2.5 mmol/L [2- 13 C]acetate plus supplemental 5 mmol/L glucose, any potential differences in endogenous carbohydrate availability were proved not to account for the reduced rate α-KG and GLU exchange, which remained depressed in postischemic hearts. However, specific activities of the transaminase enzyme, catalyzing chemical exchange of α-KG and GLU, were the same, and transaminase flux was 100 μmol·min −1 ·g −1 in postischemic hearts versus 68 μmol·min −1 ·g −1 in normal hearts. Normal transaminase activity and the increased flux in postischemic hearts are contrary to the reduced F 1 . The findings indicate reduced metabolite transport rates across the mitochondrial membranes of stunned myocardium, particularly through the reversible α-KG–malate carrier.
Reconstructing Tuberculosis Services after Major Conflict: Experiences and Lessons Learned in East Timor
Authors: Nelson Martins, Paul M Kelly, Jocelyn A Grace, Anthony B Zwi
Journal: PLoS Medicine (2006)

Background Tuberculosis (TB) is a major public health problem in developing countries. Following the disruption to health services in East Timor due to violent political conflict in 1999, the National Tuberculosis Control Program was established, with a local non-government organisation as the lead agency. Within a few months, the TB program was operational in all districts. Methods and Findings Using the East Timor TB program as a case study, we have examined the enabling factors for the implementation of this type of communicable disease control program in a post-conflict setting. Stakeholder analysis was undertaken, and semi-structured interviews were conducted in 2003 with 24 key local and international stakeholders. Coordination, cooperation, and collaboration were identified as major contributors to the success of the TB program. The existing local structure and experience of the local non-government organisation, the commitment among local personnel and international advisors to establishing an effective program, and the willingness of international advisers and local counterparts to be flexible in their approach were also important factors. This success was achieved despite major impediments, including mass population displacement, lack of infrastructure, and the competing interests of organisations working in the health sector. Conclusions Five years after the conflict, the TB program continues to operate in all districts with high notification rates, although the lack of a feeling of ownership by government health workers remains a challenge. Lessons learned in East Timor may be applicable to other post-conflict settings where TB is highly prevalent, and may have relevance to other disease control programs.
Shifts in Pacemaker Dominance within the Sinoatrial Region of Cat and Rabbit Hearts Resulting from Increase of Extracellular Potassium
Authors: HSIN HSIANG LU
Journal: Circulation Research (1970)

Simultaneous recording of action potentials from cells in different parts of sinoatrial preparations from cat and rabbit hearts confirms the suggestion by Meek and Eyster that the dominant pacemaker site shifts during treatment with high [K + ]. The direction of the shift can be either upward or downward depending upon the location of the original dominant pacemaker site. In the majority of cases, the original dominant site is located in the upper part of the preparation, consequently the shift is from above downward. In environments with high [K + ], both true and latent pacemaker cell action potentials show a decrease in both maximal diastolic potential and the slope of the prepotential but these changes seem to be more marked in the true pacemaker cell. It is suggested that the shift of dominant pacemaker site in response to high [K + ] is due to the difference in sensitivity to K + between these two types of pacemaker cells.
Development of a highly sensitive method for detection of JAK2V617F
Authors: Anna H Zhao, Rufei Gao, Zhizhuang J Zhao
Journal: Journal of Hematology & Oncology (2011)

Abstract Background Ph- myeloproliferative neoplasms (MPNs) represent a heterogeneous group of chronic diseases characterized by increased expansion of hematopoietic cells of the myeloid lineage. JAK2V617F, an activation mutation form of tyrosine kinase JAK2, is found in the majority of patients with MPNs. Studies have demonstrated that JAK2V617F can cause MPNs, and various methods have been developed to detect JAK2V617F for diagnostic purposes. However, a highly sensitive method is still needed for the earliest possible detection and for disease prevention and treatment. Methods In the present study, we developed a method dubbed restriction fragment nested allele-specific PCR (RFN-AS-PCR). The method consists of three steps: 1) initial amplification of DNA samples with PCR primers surrounding the JAK2V617F mutation site, 2) digestion of the PCR products with restriction enzyme BsaXI which only cleaves the wild type allele, and 3) detection of JAK2V617F by allele-specific PCR with nested primers. Results We tested the sensitivity of the method by using purified plasmid DNAs and blood cell DNAs containing known proportions of JAK2V617F. We were able to detect JAK2V617F with a sensitivity of 0.001%. We further analyzed blood cell DNA samples from 105 healthy donors with normal blood cell counts and found three JAK2V617F-positive cases, which would have remained undetected using a less sensitive method. Conclusions We have developed a highly sensitive method that will allow for detection of JAK2V617F at a very early stage. This method may have major implications in diagnosis and prevention of MPNs and related diseases.
Cost-Effectiveness of Allopurinol and Febuxostat for the Management of Gout
Authors: Eric Jutkowitz, Hyon K. Choi, Laura T. Pizzi, Karen M. Kuntz
Journal: Annals of Internal Medicine (2014)

Gout is the most common inflammatory arthritis in the United States.To evaluate the cost-effectiveness of urate-lowering treatment strategies for the management of gout.Markov model.Published literature and expert opinion.Patients for whom allopurinol or febuxostat is a suitable initial urate-lowering treatment.Lifetime.Health care payer.5 urate-lowering treatment strategies were evaluated: no treatment; allopurinol- or febuxostat-only therapy; allopurinol-febuxostat sequential therapy; and febuxostat-allopurinol sequential therapy. Two dosing scenarios were investigated: fixed dose (80 mg of febuxostat daily, 0.80 success rate; 300 mg of allopurinol daily, 0.39 success rate) and dose escalation (≤120 mg of febuxostat daily, 0.82 success rate; ≤800 mg of allopurinol daily, 0.78 success rate).Discounted costs, discounted quality-adjusted life-years, and incremental cost-effectiveness ratios.In both dosing scenarios, allopurinol-only therapy was cost-saving. Dose-escalation allopurinol-febuxostat sequential therapy was more costly but more effective than dose-escalation allopurinol therapy, with an incremental cost-effectiveness ratio of $39 400 per quality-adjusted life-year.The relative rankings of treatments did not change. Our results were relatively sensitive to several potential variations of model assumptions; however, the cost-effectiveness ratios of dose escalation with allopurinol-febuxostat sequential therapy remained lower than the willingness-to-pay threshold of $109 000 per quality-adjusted life-year.Long-term outcome data for patients with gout, including medication adherence, are limited.Allopurinol single therapy is cost-saving compared with no treatment. Dose-escalation allopurinol-febuxostat sequential therapy is cost-effective compared with accepted willingness-to-pay thresholds.Agency for Healthcare Research and Quality.
Carvedilol (Carv) vs propranolol (Prop) in the long-term treatment ofportal hypertension (PH)
Authors: R. Bañares, A. Moitinho, A. Matilla, J.C. García-Pagán, M. Escudero, A. Escorsell, A. Diego, J.L. Lampreave, C. Piera, J. Bosch
Journal: Journal of Hepatology (2000)
Decreased membrane-bound ATP-hydrolytic activity in psoriatic epidermis*
Authors: G. MAHRLE, C. E. ORFANOS
Journal: British Journal of Dermatology (1974)

Journal Article Decreased membrane‐bound ATP‐hydrolytic activity in psoriatic epidermis Get access G. MAHRLE, G. MAHRLE Department of Dermatology, University of Cologne, Germany †Reprint requests to: Dr G. Mahrle, University Skin Clinic, 5 Köln‐Lindenthal, West Germany. Search for other works by this author on: Oxford Academic Google Scholar C. E. ORFANOS C. E. ORFANOS Department of Dermatology, University of Cologne, Germany Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 91, Issue 5, 1 November 1974, Pages 529–540, https://doi.org/10.1111/j.1365-2133.1974.tb12941.x Published: 01 November 1974 Article history Accepted: 21 March 1974 Published: 01 November 1974
Antitumor and antimetastatic activity of interleukin 12 against murine tumors.
Authors: M J Brunda, L Luistro, R R Warrier, R B Wright, B R Hubbard, M Murphy, S F Wolf, M K Gately
Journal: The Journal of Experimental Medicine (1993)

It has recently been demonstrated that in vivo administration of murine interleukin 12 (IL-12) to mice results in augmentation of cytotoxic natural killer (NK)/lymphocyte-activated killer cell activity, enhancement of cytolytic T cell generation, and induction of interferon gamma secretion. In this study, the in vivo activity of murine IL-12 against a number of murine tumors has been evaluated. Experimental pulmonary metastases or subcutaneous growth of the B16F10 melanoma were markedly reduced in mice treated intraperitoneally with IL-12, resulting in an increase in survival time. The therapeutic effectiveness of IL-12 was dose dependent and treatment of subcutaneous tumors could be initiated up to 14 d after injection of tumor cells. Likewise, established experimental hepatic metastases and established subcutaneous M5076 reticulum cell sarcoma and Renca renal cell adenocarcinoma tumors were effectively treated by IL-12 at doses which resulted in no gross toxicity. Local peritumoral injection of IL-12 into established subcutaneous Renca tumors resulted in regression and complete disappearance of these tumors. IL-12 was as effective in NK cell-deficient beige mice or in mice depleted of NK cell activity by treatment with antiasialo GM1, suggesting that NK cells are not the primary cell type mediating the antitumor effects of this cytokine. However, the efficacy of IL-12 was greatly reduced in nude mice suggesting the involvement of T cells. Furthermore, depletion of CD8+ but not CD4+ T cells significantly reduced the efficacy of IL-12. These results demonstrate that IL-12 has potent in vivo antitumor and antimetastatic effects against murine tumors and demonstrate as well the critical role of CD8+ T cells in mediating the antitumor effects against subcutaneous tumors.
Explaining variation in referral from primary to secondary care: cohort study
Authors: D. McBride, S. Hardoon, K. Walters, S. Gilmour, R. Raine
Journal: BMJ (2010)

To determine the extent to which referral for defined symptoms from primary care varies by age, sex, and social deprivation and whether any sociodemographic variations in referral differ according to the presence of national referral guidance and the potential of the symptoms to be life threatening.Cohort study using individual patient data from the health improvement network database in primary care.United Kingdom.5492 patients with postmenopausal bleeding, 23 121 with hip pain, and 101 212 with dyspepsia from 326 general practices, 2001-7.Multivariable associations between odds of immediate referral for postmenopausal bleeding and age and social deprivation; hazard rates of referral for hip pain or dyspepsia and age, sex, and social deprivation. Analyses for dyspepsia were stratified for people aged less than and more than 55 years because referral guidance differs by age.61.4% (3374/5492) of patients with postmenopausal bleeding, 17.4% (4019/23 121) with hip pain, and 13.8% (13 944/101 212) with dyspepsia were referred. The likelihood of referral for postmenopausal bleeding declined with increasing age: the adjusted odds ratio for patients aged 85 or more compared with those aged 55-64 was 0.39 (95% confidence interval 0.31 to 0.49). Patients aged 85 or more with hip pain were also less likely to be referred than those aged 55-64 (0.68, 0.57 to 0.81). Women were less likely than men to be referred for hip pain (hazard ratio 0.90, 95% confidence interval 0.84 to 0.96). More deprived patients with hip pain or dyspepsia (if aged <55) were less likely to be referred. Adjusted hazard ratios for those in the most deprived Townsend fifth compared with the least deprived were 0.72 (95% confidence interval 0.62 to 0.82) and 0.76 (0.68 to 0.85), respectively. No socioeconomic gradient was evident in referral for postmenopausal bleeding.Inequalities in referral associated with socioeconomic circumstances were more likely to occur in the absence of both explicit guidance and potentially life threatening conditions, whereas inequalities with age were evident for all conditions.
A Comprehensive Evaluation of Rhythm Monitoring Strategies for the Detection of Atrial Fibrillation Recurrence
Authors: Efstratios I. Charitos, Ulrich Stierle, Paul D. Ziegler, Malte Baldewig, Derek R. Robinson, Hans-Hinrich Sievers, Thorsten Hanke
Journal: Circulation (2012)

Intermittent rhythm monitoring (IRM) to detect atrial fibrillation (AF) recurrence is employed to evaluate the success of therapeutic interventions. In a large population of patients with continuous monitoring (CM), we investigated the sensitivity of various frequencies and durations of IRM strategies on the detection of AF recurrence, the dynamics behind AF recurrence detection, and we describe measures to evaluate temporal AF recurrence.Rhythm histories of 647 patients (mean AF burden, 0.12±0.22; median, 0.014; 687 patient-years) with implantable CM devices were reconstructed and analyzed. With the use of computationally intensive simulation, the sensitivity of IRM of various frequencies and durations on the identification of AF recurrence was evaluated. Prolonged-duration IRM was superior to shorter IRM (P<0.0001). However, even with aggressive IRM strategies, AF recurrence was not detected in a great proportion of patients. The temporal AF burden aggregation (AF density) was directly related to IRM sensitivity (P<0.0001). Even at similar AF burdens, patients with high-density AF required higher-frequency or prolonged-duration IRM to achieve the same sensitivity as in low-density AF (P<0.0001). Patients with high-density, low-burden AF benefit the most from CM for detection of AF recurrence.IRM follow-up is significantly inferior to CM. IRM strategies will not identify AF recurrence in a great proportion of patients at risk. Temporal AF characteristics play a significant role in AF recurrence detection with the use of IRM. For the scientific, evidence-based evaluation of AF treatments, CM should be strongly recommended. Prospective studies are required to evaluate whether CM to guide clinical management can also improve patient outcomes.URL: http://www.clinicaltrials.gov. Unique identifier: NCT00806689.
Psychological Reactions, Quality of Life, and Body Image After Bilateral Prophylactic Mastectomy in Women At High Risk for Breast Cancer: A Prospective 1-Year Follow-Up Study
Authors: Yvonne Brandberg, Kerstin Sandelin, Staffan Erikson, Göran Jurell, Annelie Liljegren, Annika Lindblom, Ann Lindén, Anna von Wachenfeldt, Marie Wickman, Brita Arver
Journal: Journal of Clinical Oncology (2008)

To prospectively evaluate body image, sexuality, emotional reactions (anxiety, depression), and quality of life in a sample of women having increased risk for breast cancer before and 6 months and 1 year after bilateral prophylactic mastectomy (BPM), and to compare preoperative expectations of the operation with postoperative reactions concerning the impact on six areas of the women's lives.A total of 90 of 98 consecutive women who underwent BPM during October 1997 to December 2005 were included. Data were collected by self-administered questionnaires (eg, Hospital Anxiety and Depression scale, Swedish Short Term-36 Health Survey, Body Image Scale, Sexual Activity Questionnaire) before the operation (n = 81), and 6 (n = 71) and 12 months (n = 65) after BPM.Anxiety decreased over time (P = .0004). No corresponding difference was found for depression. No differences in health-related quality of life over time were found, with one exception. A substantial proportion of the women reported problems with body image 1 year after BPM (eg, self consciousness, 48%; feeling less sexually attractive, 48%; and dissatisfaction with the scars, 44%). Sexual pleasure was rated lower 1-year post-BPM as compared with before operation (P = .005), but no differences over time in habit, discomfort, or activity were found.No negative effects on anxiety, depression, and quality of life were found. Anxiety and social activities improved. Negative impact on sexuality and body image was reported.
Does oral contraceptive use affect maximum force production in women?
Authors: K J Elliott, N T Cable, T Reilly
Journal: British Journal of Sports Medicine (2004)

To examine the effects of oral contraceptive use on maximum force production in young women.In the study, 21 female subjects (14 pill users and seven eumenorrheic controls) took part. All pill using subjects had been taking a combined, monophasic oral contraceptive pill for at least 6 months. Maximum dynamic and isometric leg strength, maximum isometric strength of the first dorsal interosseus (FDI) muscle, and plasma concentrations of oestradiol and progesterone were measured on days 7 and 14 of pill consumption and day 5 of pill withdrawal. The eumenorrheic group was tested (FDI strength and hormone concentrations) on days 2 and 21 of the menstrual cycle.There were no significant changes in the concentration of endogenous oestradiol or progesterone or any measure of muscle strength between pill phases (p<0.05). The pill group did not significantly differ from the eumenorrheic group (p<0.05), despite a significant increase in the concentration of progesterone and oestradiol on day 21 of the menstrual cycle compared with day 2 of the menstrual cycle and pill consumption and withdrawal (p<0.05).These data suggest that oral contraceptive use does not significantly affect muscle strength. Moreover, oral contraceptive users were not stronger or weaker than their eumenorrheic counterparts.
Phase I and pharmacokinetic study of CCI-779, a novel cytostatic cell-cycle inhibitor, in combination with 5-fluorouracil and leucovorin in patients with advanced solid tumors
Authors: C.J.A. Punt, J. Boni, U. Bruntsch, M. Peters, C. Thielert
Journal: Annals of Oncology (2003)

BackgroundCCI-779 is a novel ester of the immunosuppressive agent sirolimus that exerts cytostatic effects by the inhibition of the translation of cell-cycle regulatory proteins. We investigated the maximum tolerated dose (MTD) and pharmacokinetics (PK) of CCI-779 in combination with leucovorin (LV) and 5-fluorouracil (5-FU) in patients with advanced solid tumors.Patients and methodsPatients were treated with LV at 200 mg/m2 as a 1-h i.v. infusion directly followed by continuous 24-h i.v. infusion of 5-FU, in the first patient at 2000 mg/m2 and in subsequent patients at 2600 mg/m2. CCI-779 was administered directly prior to LV as a 30-min i.v. infusion at a starting dose of 15 mg/m2 beginning at day 8 and escalated in subsequent cohorts of patients. One cycle consisted of six weekly administrations followed by 1 week of rest. Blood samples were drawn to assess PK of CCI-779 as well as its effect on steady-state 5-FU exposures.ResultsTwenty-eight patients entered the study, the majority having tumor types for which 5-FU is used asa treatment. CCI-779 doses of 15, 25, 45 and 75 mg/m2 were investigated. Skin toxicity (rash) was prominent at all dose levels examined. Stomatitis was the dose-limiting toxicity (DLT) for 75 mg/m2 doses of CCI-779. Subsequently the cohort at 45 mg/m2 was expanded to a total of 15 patients, and at this dose level two treatment-related deaths occurred due to mucositis with bowel perforation. Based on the toxicities observed, it was decided to discontinue the study. Partial responses were observed in three patients with gastrointestinal tumors. No pharmacokinetic interaction between CCI-779 and 5-FU was observed.ConclusionsThe safety profiles of CCI-779 and 5-FU/LV suggest an overlap of drug-related toxicities, and the administration of these drugs at these doses and schedule resulted in unacceptable toxicity and therefore cannot be recommended. If CCI-779 is to be used in combination with 5-FU/LV, other doses or schedules of administration will need to be explored.
The Evolving Role of mTOR Inhibition in Transplantation Tolerance
Authors: Gearoid McMahon, Matthew R Weir, Xian C Li, Didier A Mandelbrot
Journal: Journal of the American Society of Nephrology (2011)

The mammalian target of rapamycin (mTOR) plays a key role in the immune response. mTOR inhibitors suppress T cell activation and proliferation and are effective immunosuppressants. Today there is growing interest in their potential role in inducing tolerance after transplantation. mTOR inhibitors induce anergy in naïve T cells, promote the expansion of regulatory T cells, and inhibit the maturation of dendritic cells, thus promoting immunologic tolerance. Here we review the mechanisms by which mTOR inhibitors promote tolerance. We discuss the clinical relevance of these mechanisms and suggest how they might be used in the design of future protocols to induce tolerance.