tbuckley/cabot-search huggingface dataset:
Replacement by Homologous Recombination of the <i>minK</i> Gene With <i>lacZ</i> Reveals Restriction of <i>minK</i> Expression to the Mouse Cardiac Conduction System
Authors: Sabina Kupershmidt, Tao Yang, Mark E. Anderson, Andy Wessels, Kevin D. Niswender, Mark A. Magnuson, Dan M. Roden
Journal: Circulation Research (1999)

Abstract —The minK gene encodes a 129-amino acid peptide the expression of which modulates function of cardiac delayed rectifier currents ( I Kr and I Ks ), and mutations in minK are now recognized as one cause of the congenital long-QT syndrome. We have generated minK- deficient mice in which the bacterial lacZ gene has been substituted for the minK coding region such that β-galactosidase expression is controlled by endogenous minK regulatory elements. In cardiac myocytes isolated from wild-type neonatal mice, I Ks is rarely recorded, while I Kr is common. In minK (–/–) myocytes, I Ks is absent and I Kr is significantly reduced and its deactivation slowed; these results further support a role for minK in modulating both I Ks and I Kr . Despite these changes, ECGs in (+/+) and (–/–) animals are no different at adult and at neonatal stages. ECG responses to isoproterenol are also similar in the 2 groups. β-Galactosidase staining in postnatal minK (–/–) hearts is highly restricted, to the sinus-node region, caudal atrial septum, and proximal conducting system. Moreover, as early as embryonal day 11, segmentally restricted β-galactosidase expression is observed in the portions of the sinoatrial and atrioventricular junctions that are thought to give rise to the conducting system, thereby implicating minK expression as an early event in conduction system development. More generally, the restricted nature of minK expression in the mouse heart suggests species-specific roles of this gene product in mediating the electrophysiological properties of the heart.
Quality Improvement Initiatives
Authors: Rodney A. Hayward, Timothy P. Hofer, Eve A. Kerr, Sarah L. Krein
Journal: Diabetes Care (2004)

To outline the principles that direct the Veterans Affairs (VA) Quality Enhancement Research Initiative (QUERI) dedicated to diabetes quality improvement (QUERI-DM).We discuss the VA initiatives aimed at improving diabetes care for veterans as well as general issues that should be considered in quality improvement initiatives. We specifically describe some of the epidemiological, statistical, and organizational issues that have guided our quality improvement (QI) programs.The five principles that have guided the QUERI-DM process are: 1) treating clinical guidelines and goals distinct from quality standards and quality improvement priorities; 2) targeting high-risk patients and high-impact quality issues; 3) profiling processes over outcomes; 4) targeting processes that will improve patient outcomes; and 5) paying attention to the loci of practice variation.The authors recommend that all five principles be considered when moving from practice guidelines to performance measures and QI initiatives. Targeting high-priority problems and high-risk groups can greatly improve the effectiveness and efficiency of QI interventions.
Doppler Tissue Imaging Quantitates Regional Wall Motion During Myocardial Ischemia and Reperfusion
Authors: Geneviève Derumeaux, Michel Ovize, Joseph Loufoua, Xavier André-Fouet, Yves Minaire, Alain Cribier, Brice Letac
Journal: Circulation (1998)

Background —Quantification of regional myocardial function is a major unresolved issue in cardiology. We evaluated the accuracy of pulsed Doppler tissue imaging (DTI), a new echocardiographic technique, to quantify regional myocardial dysfunction induced by acute ischemia and reperfusion. Methods and Results —In nine open-chest anesthetized pigs, various degrees of regional wall motion abnormalities were induced by graded reduction of left anterior descending coronary artery (LAD) blood flow. Pulsed Doppler tissue imaging was performed from an epicardial apical four-chamber view with the sample placed within the middle part of the septal wall. Peak septal velocities were calculated during systole, isovolumic relaxation, and early and late diastole. Regional myocardial blood flow and systolic and diastolic dysfunctions were assessed by radioactive microspheres and ultrasonic crystals, respectively. Ischemia resulted in a significant rapid reduction of systolic velocities and an early decrease in the ratio of early to late diastolic velocities. Both changes were detected by pulsed DTI within 5 seconds of coronary artery occlusion. The decrease in systolic velocity significantly correlated with both systolic shortening ( r =.90, P &lt;.0001) and regional myocardial blood flow ( r =.96, P &lt;.0001) during reduction of LAD blood flow. Conclusions —These results suggest that DTI may be a promising new tool for the quantification of ischemia-induced regional myocardial dysfunction.
CpG-A and CpG-B oligonucleotides differentially enhance human peptide–specific primary and memory CD8+ T-cell responses in vitro
Authors: Simon Rothenfusser, Veit Hornung, Maha Ayyoub, Stefanie Britsch, Andreas Towarowski, Anne Krug, Anja Sarris, Norbert Lubenow, Daniel Speiser, Stefan Endres, Gunther Hartmann
Journal: Blood (2003)
Effect of Gene Therapy on Visual Function in Leber's Congenital Amaurosis
Authors: James W.B. Bainbridge, Alexander J. Smith, Susie S. Barker, Scott Robbie, Robert Henderson, Kamaljit Balaggan, Ananth Viswanathan, Graham E. Holder, Andrew Stockman, Nick Tyler, Simon Petersen-Jones, Shomi S. Bhattacharya, Adrian J. Thrasher, Fred W. Fitzke, Barrie J. Carter, Gary S. Rubin, Anthony T. Moore, Robin R. Ali
Journal: New England Journal of Medicine (2008)

Early-onset, severe retinal dystrophy caused by mutations in the gene encoding retinal pigment epithelium-specific 65-kD protein (RPE65) is associated with poor vision at birth and complete loss of vision in early adulthood. We administered to three young adult patients subretinal injections of recombinant adeno-associated virus vector 2/2 expressing RPE65 complementary DNA (cDNA) under the control of a human RPE65 promoter. There were no serious adverse events. There was no clinically significant change in visual acuity or in peripheral visual fields on Goldmann perimetry in any of the three patients. We detected no change in retinal responses on electroretinography. One patient had significant improvement in visual function on microperimetry and on dark-adapted perimetry. This patient also showed improvement in a subjective test of visual mobility. These findings provide support for further clinical studies of this experimental approach in other patients with mutant RPE65. (ClinicalTrials.gov number, NCT00643747 [ClinicalTrials.gov].).
Selective CD4+ T Cell Help for Antibody Responses to a Large Viral Pathogen: Deterministic Linkage of Specificities
Authors: Alessandro Sette, Magdalini Moutaftsi, Juan Moyron-Quiroz, Megan M. McCausland, D. Huw Davies, Robert J. Johnston, Bjoern Peters, Mohammed Rafii-El-Idrissi Benhnia, Julia Hoffmann, Hua-Poo Su, Kavita Singh, David N. Garboczi, Steven Head, Howard Grey, Philip L. Felgner, Shane Crotty
Journal: Immunity (2008)
Preoperative Therapy With Trastuzumab and Paclitaxel Followed by Sequential Adjuvant Doxorubicin/Cyclophosphamide for HER2 Overexpressing Stage II or III Breast Cancer: A Pilot Study
Authors: Harold J. Burstein, Lyndsay N. Harris, Rebecca Gelman, Susan C. Lester, Raquel A. Nunes, Carolyn M. Kaelin, Leroy M. Parker, Leif W. Ellisen, Irene Kuter, Michele A. Gadd, Roger L. Christian, Patricia Rae Kennedy, Virginia F. Borges, Craig A. Bunnell, Jerry Younger, Barbara L. Smith, Eric P. Winer
Journal: Journal of Clinical Oncology (2002)

Trastuzumab combined with chemotherapy improves outcomes for women with human epidermal growth factor receptor 2 (HER2) overexpressing advanced breast cancer. We conducted a pilot study of preoperative trastuzumab and paclitaxel, followed by surgery and adjuvant doxorubicin and cyclophosphamide chemotherapy in earlier stage breast cancer.Patients with HER2-positive (2+ or 3+ by immunohistochemistry) stage II or III breast cancer received preoperative trastuzumab (4 mg/kg x 1, then 2 mg/kg/wk x 11) in combination with paclitaxel (175 mg/m(2) every 3 weeks x 4). Patients received adjuvant doxorubicin and cyclophosphamide chemotherapy following definitive breast surgery. Clinical and pathologic response rates were determined after preoperative therapy. Left ventricular ejection fraction and circulating levels of HER2 extracellular domain were measured serially.Preoperative trastuzumab and paclitaxel achieved clinical response in 75% and complete pathologic response in 18% of the 40 women on study. HER2 3+ tumors were more likely to respond than 2+ tumors (84% v 38%). No unexpected treatment-related noncardiac toxicity was encountered. Four patients developed grade 2 cardiotoxicity (asymptomatic declines in left ventricular ejection fraction). Baseline HER2 extracellular domain was elevated in 24% of patients and declined with preoperative therapy. Immunohistochemical analyses of posttherapy tumor specimens indicated varying patterns of HER2 expression following trastuzumab-based treatment.Preoperative trastuzumab and paclitaxel is active against HER2 overexpressing early-stage breast cancer and may be feasible as part of a sequential treatment program including anthracyclines. The observed changes in cardiac function merit further investigation. Correlative analyses of HER2 status may facilitate understanding of tumor response and resistance to targeted therapy.
EULAR evidence based recommendations for gout. Part II: Management. Report of a task force of the EULAR Standing Committee For International Clinical Studies Including Therapeutics (ESCISIT)
Authors: W Zhang
Journal: Annals of the Rheumatic Diseases (2006)

<b>Objective:</b> To develop evidence based recommendations for the management of gout. <b>Methods:</b> The multidisciplinary guideline development group comprised 19 rheumatologists and one evidence based medicine expert representing 13 European countries. Key propositions on management were generated using a Delphi consensus approach. Research evidence was searched systematically for each proposition. Where possible, effect size (ES), number needed to treat, relative risk, odds ratio, and incremental cost-effectiveness ratio were calculated. The quality of evidence was categorised according to the level of evidence. The strength of recommendation (SOR) was assessed using the EULAR visual analogue and ordinal scales. <b>Results:</b> 12 key propositions were generated after three Delphi rounds. Propositions included both non-pharmacological and pharmacological treatments and addressed symptomatic control of acute gout, urate lowering therapy (ULT), and prophylaxis of acute attacks. The importance of patient education, modification of adverse lifestyle (weight loss if obese; reduced alcohol consumption; low animal purine diet) and treatment of associated comorbidity and risk factors were emphasised. Recommended drugs for acute attacks were oral non-steroidal anti-inflammatory drugs (NSAIDs), oral colchicine (ES = 0.87 (95% confidence interval, 0.25 to 1.50)), or joint aspiration and injection of corticosteroid. ULT is indicated in patients with recurrent acute attacks, arthropathy, tophi, or radiographic changes of gout. Allopurinol was confirmed as effective long term ULT (ES = 1.39 (0.78 to 2.01)). If allopurinol toxicity occurs, options include other xanthine oxidase inhibitors, allopurinol desensitisation, or a uricosuric. The uricosuric benzbromarone is more effective than allopurinol (ES = 1.50 (0.76 to 2.24)) and can be used in patients with mild to moderate renal insufficiency but may be hepatotoxic. When gout is associated with the use of diuretics, the diuretic should be stopped if possible. For prophylaxis against acute attacks, either colchicine 0.5–1 mg daily or an NSAID (with gastroprotection if indicated) are recommended. <b>Conclusions:</b> 12 key recommendations for management of gout were developed, using a combination of research based evidence and expert consensus. The evidence was evaluated and the SOR provided for each proposition.
PNUTS Functions as a Proto-Oncogene by Sequestering PTEN
Authors: Sridhar Kavela, Swapnil R. Shinde, Raman Ratheesh, Kotapalli Viswakalyan, Murali D. Bashyam, Swarnalata Gowrishankar, Mohana Vamsy, Sujit Pattnaik, Subramanyeshwar Rao, Regulagadda A. Sastry, Mukta Srinivasulu, Junjie Chen, Subbareddy Maddika
Journal: Cancer Research (2012)

PTEN is a well-defined tumor suppressor gene that antagonizes the PI3K/Akt pathway to regulate a multitude of cellular processes, such as survival, growth, motility, invasiveness, and angiogenesis. While the functions of PTEN have been studied extensively, the regulation of its activity during normal and disease conditions still remains incompletely understood. In this study, we identified the protein phosphatase-1 nuclear targeting subunit PNUTS (PPP1R10) as a PTEN-associated protein. PNUTS directly interacted with the lipid-binding domain (C2 domain) of PTEN and sequestered it in the nucleus. Depletion of PNUTS leads to increased apoptosis and reduced cellular proliferation in a PTEN-dependent manner. PNUTS expression was elevated in certain cancers compared with matched normal tissues. Collectively, our studies reveal PNUTS as a novel PTEN regulator and a likely oncogene.
Joint space width measures cartilage thickness in osteoarthritis of the knee: high resolution plain film and double contrast macroradiographic investigation.
Authors: J.C. Buckland-Wright, D.G. Macfarlane, J.A. Lynch, M.K. Jasani, C.R. Bradshaw
Journal: Annals of the Rheumatic Diseases (1995)

To test reliability of joint space width (JSW) measurements as a predictor of cartilage thickness in knees of patients with osteoarthritis (OA), using high definition microfocal radiography. JSW was measured from weight bearing plain film macroradiographs taken in the tunnel view and compared with the sum of femoral and tibial cartilage thicknesses measured from double contrast macroarthrograms of the same regions of the same knees obtained in the non-weight bearing lateral position. All knees had medial compartment OA. Comparison of the JSW with the sum of the tibial and femoral cartilage thicknesses revealed a highly significant correlation (p < 0.0001) between the two measurements in the medial but not the lateral compartment. In the middle region of both compartments, JSW was smaller than the cartilage thickness, indicating that, on standing, the curvature of the femoral condyles compressed the cartilage in this region. JSW reliably measured cartilage thickness in the medial but not the lateral compartment of knees with medial compartment OA. Depending upon the stage of OA disease, JSW reliably reflects cartilage thinning and compression.
Agent-assignment, tree-pruning, and Broca's aphasia
Authors: Frederick J. Newmeyer
Journal: Behavioral and Brain Sciences (2000)

I wholeheartedly endorse Grodzinsky's program of attempting to tie the particular deficits observed in Broca's aphasics' comprehension and production to changes in their mentally represented model of grammar. At the level of detail, however, I see problems with two specific changes that Grodzinsky posits. One is a default Agent-assignment strategy in comprehension. The other is the hypothesis that production involves pruning all functional projections above Agreement Phrase.
Evidence that nitric oxide mechanisms regulate small intestinal motility in humans
Authors: A Russo, R Fraser, K Adachi, M Horowitz, G Boeckxstaens
Journal: Gut (1999)

Background Non-cholinergic non-adrenergic neural mechanisms involving nerves containing NO have been shown to modulate smooth muscle in the gastrointestinal tract, and it has been suggested that release from tonic NO inhibition may be important in the regulation of cyclical fasting small intestinal motility. Aims To evaluate the role of NO mechanisms in the regulation of fasting small intestinal motor activity in humans using a specific NO synthase inhibitor, N G -monomethyl- l -arginine ( l -NMMA). Methods In seven healthy male volunteers, duodenal and jejunal pressures were measured for four hours with a nine lumen manometric catheter. Volunteers attended on four separate days on which they received an intravenous infusion of either saline or l -NMMA (0.5, 2, or 4 mg/kg/h) in random order. Intravenous infusions began 10 minutes after completion of phase III of the migrating motor complex (MMC). Results The first episode of phase III activity occurred earlier after infusion of 2 and 4 mg/kg/h l -NMMA than after infusion of 0.5 mg/kg/h l -NMMA or saline (mean (95% confidence interval) 52 (36–68) and 57 (18–97) v 116 (69–193) and 145 (64–226) minutes respectively) with a resultant MMC cycle length of 82 (59–105) and 86 (46–126) v 132 (49–198) and 169 (98–240) minutes respectively. The total number of phase III activities during the four hour recording was increased (p&lt;0.05) by l -NMMA at a dose of 4 mg/kg/h (2 (1–3)) but not at 2 mg/kg/h (1.5 (1–2)) or 0.5 mg/kg/h (1.3 (1–2)) compared with saline (1.3 (0.6–2)). l -NMMA had no effect on the duration, velocity, number of contractions per minute, length of migration, or site of origin of phase III of the MMC. The duration of phase I activity was shorter (p&lt;0.05) with 4 mg/kg/h l -NMMA than with saline (12 (1–23) v 31 (19–44) minutes). Conclusions These observations suggest that NO mechanisms play a role in the regulation of fasting small intestinal motor activity in humans.
THE EFFECT OF HETEROLOGOUS ANTI-LYMPHOCYTE SERUM ON LYMPHOCYTES OF THYMUS AND MARROW ORIGIN
Authors: H. F. Jeejeebhoy
Journal: The Journal of Experimental Medicine (1970)

When CY-treated mice were given sheep red blood cells the serum hemagglutinin titers produced were significantly lower than those found when mice received SRBC but not CY. Titers could be raised to the levels found in the latter group if, in addition to SRBC, the CY-treated mice received 2 x 10(7) normal syngeneic spleen cells or a mixture containing 1.2 x 10(8) normal thymus and 1.2 x 10(8) normal marrow cells. Inocula which contained fewer cells produced correspondingly smaller amounts of antibody. A synergistic interaction between normal thymus and marrow cells was always demonstrable in these experiments. Hemagglutinin titers produced by CY-treated mice given SRBC and 2 x 10(7) normal syngeneic spleen cells were always much higher than those found when the spleen cells were obtained from animals previously given ALS. Titers could be raised to normal levels if the animals in this latter group received additional injections containing mixtures of normal syngeneic thymus and marrow cells. Marrow cells alone were completely ineffective, while inocula which only contained thymus cells were much less effective than mixtures of thymus and marrow cells. These results suggest that immunosuppression by ALS is associated with the inactivation of both thymus and marrow-derived lymphocytes. In other experiments CY-treated mice received SRBC and mixtures of thymus and marrow cells from both untreated and ALS-treated donors. No decrease in the immunological competence of cells located within the thymus of ALS-treated donors was demonstrable in these experiments. Marrow cells were slightly affected but to a markedly lesser degree than were spleen cells of ALS-treated animals. In a final experiment, it was possible to show that the thymus and marrow cells of ALS-treated animals could repair the immunological defects which were present in their own spleen cell populations.
Favorable outcome of patients with relapsed or refractory Hodgkin’s disease treated with high-dose chemotherapy and stem cell rescue at the time of maximal response to conventional salvage therapy (Dexa-BEAM)
Authors: A Josting, I Kàtay, U Rueffer, S Winter, H Tesch, A Engert, V Diehl, P D Wickramanayake
Journal: Annals of Oncology (1998)
Effectiveness of Culture-Specific Diabetes Care for Surinam South Asian Patients in the Hague
Authors: Barend J.C. Middelkoop, Petronella H.L.M. Geelhoed-Duijvestijn, Gerrit van der Wal
Journal: Diabetes Care (2001)

An extremely high prevalence of diabetes has been found among South Asians, especially among immigrants living in a western society (1). In the Hague, we found a high prevalence of diabetes among South Asians from Surinam (2). Because usual diabetes care had insufficient affinity with the cultural and culinary traditions of this population, a new culture-specific type of care was developed. We investigated whether this intervention led to a decrease in HbA1c level, an improvement in lipid profile, or a decrease in BMI.

The intervention consisted of the referral of South Asian patients by their attending physician to a specialist diabetes nurse and a dietitian. These care providers received training to improve their knowledge of the South Asian cultural and culinary traditions. They made use of newly developed educational materials consisting of an audio-cassette containing general diabetes information recorded in the Surinam-Hindi language and two booklets, one containing general information on nutrition and another containing a carbohydrate variation list; both were based on South Asian cooking. It was expected that the advice from the dietitian would be more applicable, among other things, because of the information concerning calorie-equivalent dishes contained in the carbohydrate variation list. It was also expected that the interaction between patients and care providers would improve, resulting in improved compliance with …
Susceptibility of the Ovariectomized Hen to Cholesterol-Induced Coronary Atherogenesis
Authors: RUTH PICK, JEREMIAH STAMLER, LOUIS N. KATZ, Philip Johnson, Dolores Friedman
Journal: Circulation Research (1957)

A marked sex-difference in susceptibility to cholesterol-induced coronary atherosclerosis exists in mature, gonadally active birds--hens being protected against coronary involvement. This report concerns whether this protection is lost when hens are castrated.
A self paced treadmill walking test for breathless patients.
Authors: A Beaumont, A Cockcroft, A Guz
Journal: Thorax (1985)

A treadmill exercise test is described that retains the advantages of self paced walking but allows the measurement of cardiorespiratory variables. A horizontal treadmill was modified to allow patients to control their own speed. During exercise continuous measurements of speed, distance, heart rate, arterial oxygen saturation, and stride length were made and subjective assessments of breathlessness were recorded on a visual analogue scale. Ten men with severe chronic obstructive lung disease performed a 12 minute corridor walk and a self paced 12 minute treadmill walk on the same day and repeat treadmill walks on different days. Six of them performed three walks or more. Six patients had ventilatory measurements during treadmill exercise. There was no significant difference (p greater than 0.1) in the distance covered during corridor and treadmill walks, and distances on the treadmill were repeatable after the first walk. Use of a mouthpiece significantly reduced the distance covered on the treadmill. The self paced treadmill walk is a simple repeatable test and has advantages over both a corridor walking test and standard progressive tests for assessment of breathless patients.