tbuckley/cabot-search huggingface dataset:
East Midlands Sports Medicine Potential
Authors: Frank Newton
Journal: British Journal of Sports Medicine (1982)

A recent spell on the Executive Committee of the BASM leaves me with the view that the Organisation should be far more involved in producing some form of National Care Scheme for sportsmen.The proposed Scheme outlined by Peter Sperryn is a step forward, but will it be too complicated to work?I am myself, far more interested in providing a sports injury service at "grass-roots" level, and with this in mind, I am writing to ask any members of BASM, who live in the East Midlands regional area of the Sports Council to write to me if they are interested in convening a Meeting in order to set up a Regional Organisation for the exchange of practical ideas and experience which is specifically aimed at maintaining existing services and expanding these where possible.
Serial Measurements of Cystatin C Are More Accurate Than Creatinine-Based Methods in Detecting Declining Renal Function in Type 1 Diabetes
Authors: Erosha Premaratne, Richard J. MacIsaac, Sue Finch, Sianna Panagiotopoulos, Elif Ekinci, George Jerums
Journal: Diabetes Care (2008)

Cystatin C-and creatinine-based methods were compared with (99m)-technetium-diethylene-triamine-penta-acetic acid ((99m)Tc-DTPA) plasma clearance (isotopic glomerular filtration rate [iGFR]) for detecting declining renal function.Glomerular filtration rate (GFR) was monitored over a mean of 10.1 years in 85 subjects with type 1 diabetes (with an average of 5.6 measurements per individual). Baseline mean +/- SD iGFR of the cohort was 106.1 +/- 2.6 ml/min per 1.73 m(2). The rates of decline in GFR (DeltaGFR) were derived using linear regression.In 19 of 85 subjects with declining renal function (i.e., DeltaiGFR >3.3 ml/min per 1.73 m(2) per year), DeltaGFR (ml/min per 1.73 m(2) per year) was 6.5 by iGFR, 4.2 by 10(4)/creatinine, 3.6 by Cockcroft-Gault formula, 3.4 by the Modification of Diet in Renal Disease (MDRD)-6 equation, and 3.5 by the MDRD-4 variable equation (P < 0.01 vs. iGFR). In comparison, DeltaGFR was 6.1 using the formula Cys-GFR = (86.7/cystatin C concentration) - 4.2 (not significant).Cystatin C was more accurate in detecting decline in renal function than creatinine-based methods in this population of subjects with type 1 diabetes and a normal mean baseline GFR.
Nonclinical Antiangiogenesis and Antitumor Activities of Axitinib (AG-013736), an Oral, Potent, and Selective Inhibitor of Vascular Endothelial Growth Factor Receptor Tyrosine Kinases 1, 2, 3
Authors: Dana D. Hu-Lowe, Helen Y. Zou, Maren L. Grazzini, Max E. Hallin, Grant R. Wickman, Karin Amundson, Jeffrey H. Chen, David A. Rewolinski, Shinji Yamazaki, Ellen Y. Wu, Michele A. McTigue, Brion W. Murray, Robert S. Kania, Patrick O'Connor, David R. Shalinsky, Steve L. Bender
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Axitinib (AG-013736) is a potent and selective inhibitor of vascular endothelial growth factor (VEGF) receptor tyrosine kinases 1 to 3 that is in clinical development for the treatment of solid tumors. We provide a comprehensive description of its in vitro characteristics and activities, in vivo antiangiogenesis, and antitumor efficacy and translational pharmacology data. Experimental Design: The potency, kinase selectivity, pharmacologic activity, and antitumor efficacy of axitinib were assessed in various nonclinical models. Results: Axitinib inhibits cellular autophosphorylation of VEGF receptors (VEGFR) with picomolar IC50 values. Counterscreening across multiple kinase and protein panels shows it is selective for VEGFRs. Axitinib blocks VEGF-mediated endothelial cell survival, tube formation, and downstream signaling through endothelial nitric oxide synthase, Akt and extracellular signal-regulated kinase. Following twice daily oral administration, axitinib produces consistent and dose-dependent antitumor efficacy that is associated with blocking VEGFR-2 phosphorylation, vascular permeability, angiogenesis, and concomitant induction of tumor cell apoptosis. Axitinib in combination with chemotherapeutic or targeted agents enhances antitumor efficacy in many tumor models compared with single agent alone. Dose scheduling studies in a human pancreatic tumor xenograft model show that simultaneous administration of axitinib and gemcitabine without prolonged dose interruption or truncation of axitinib produces the greatest antitumor efficacy. The efficacious drug concentrations predicted in nonclinical studies are consistent with the range achieved in the clinic. Although axitinib inhibits platelet-derived growth factor receptors and KIT with nanomolar in vitro potencies, based on pharmacokinetic/pharmacodynamic analysis, axitinib acts primarily as a VEGFR tyrosine kinase inhibitor at the current clinical exposure. Conclusions: The selectivity, potency for VEGFRs, and robust nonclinical activity may afford broad opportunities for axitinib to improve cancer therapy.
Dissecting and Targeting the Growth Factor–Dependent and Growth Factor–Independent Extracellular Signal-Regulated Kinase Pathway in Human Schwannoma
Authors: Sylwia Ammoun, Christine Flaiz, Natalia Ristic, Jennifer Schuldt, C. Oliver Hanemann
Journal: Cancer Research (2008)

Abstract Schwannomas are tumors of the nervous system that occur sporadically and in patients with the cancer predisposition syndrome neurofibromatosis type 2 (NF2). Schwannomas and all NF2-related tumors are caused by loss of the tumor suppressor merlin. Using our human in vitro model for schwannoma, we analyzed extracellular signal-regulated kinase 1/2 (ERK1/2) and AKT signaling pathways, their upstream growth factor receptors, and their role in schwannoma cell proliferation and adhesion to find new systemic therapies for these tumors that, to date, are very difficult to treat. We show here that human primary schwannoma cells show an enhanced basal Raf/mitogen-activated protein/ERK kinase/ERK1/2 pathway activity compared with healthy Schwann cells. Due to a strong and prolonged activation of platelet-derived growth factor receptor β (PDGFRβ), which is highly overexpressed, ERK1/2 and AKT activation was further increased in schwannoma, leading to increased proliferation. Using specific inhibitors, we discovered that ERK1/2 activation involves the integrin/focal adhesion kinase/Src/Ras signaling cascades and PDGFRβ-mediated ERK1/2 activation is triggered through the phosphatidylinositol 3-kinase/protein kinase C/Src/c-Raf pathway. Due to the complexity of signals leading to schwannoma cell proliferation, potential new therapeutic agents should target several signaling pathways. The PDGFR and c-Raf inhibitor sorafenib (BAY 43-9006; Bayer Pharmaceuticals), currently approved for treatment of advanced renal cell cancer, inhibits both basal and PDGFRβ-mediated ERK1/2 and AKT activity and decreases cell proliferation in human schwannoma cells, suggesting that this drug constitutes a promising tool to treat schwannomas. We conclude that our schwannoma in vitro model can be used to screen for new therapeutic targets in general and that sorafenib is possible candidate for future clinical trials. [Cancer Res 2008;68(13):5236–45]
Expression of a Mutant (Arg <sup>92</sup> Gln) Human Cardiac Troponin T, Known to Cause Hypertrophic Cardiomyopathy, Impairs Adult Cardiac Myocyte Contractility
Authors: Ali J. Marian, Guiling Zhao, Yukihiro Seta, Robert Roberts, Qun-tao Yu
Journal: Circulation Research (1997)

Abstract The mechanism(s) by which mutations in sarcomeric proteins cause hypertrophic cardiomyopathy (HCM) remains unknown. A leading hypothesis proposes that mutant sarcomeric proteins impair cardiac myocyte contractility, providing an impetus for compensatory hypertrophy. To test this hypothesis, we determined the impact of expression of a mutant (Arg 92 Gln) human cardiac troponin T (cTnT), known to cause HCM in humans, on adult cardiac myocyte contractility. A full-length human cTnT cDNA was cloned, and the Arg 92 Gln mutation was induced. Recombinant adenoviruses Ad5/CMV/cTnT-N and Ad5/CMV/cTnT-Arg 92 Gln were generated through homologous recombination. Adult feline cardiac myocytes were infected with recombinant adenoviruses or a control viral vector (Ad5ΔE1) at a multiplicity of infection of 100. Expression levels of the full-length normal and mutant cTnT proteins were equal on Western blots. Expression of the exogenous cTnT proteins in cardiac myocytes was also shown by immunocytochemistry and immunofluorescence, and their incorporation into myofibrils was confirmed by Western blotting on myofibrillar extracts. Electron microscopy showed intact sarcomere structure in rod-shaped cardiac myocytes in all groups. Cell fractional shortening and the peak velocity of shortening were not significantly different among the groups 24 hours after transduction. However, 48 hours after transduction, both fractional shortening and the peak velocity of shortening were significantly reduced (24% [ P &lt;.001] and 26% [ P &lt;.001], respectively) in cardiac myocytes in the Ad5/CMV/cTnT-Arg 92 Gln compared with the Ad5/CMV/cTnT-N groups. The magnitude of the reductions was greater at 72 hours after transduction (45% and 39%, respectively; P &lt;.001). Our results indicated that expression of the mutant (Arg 92 Gln) cTnT, known to cause HCM in humans, impaired intact adult cardiac myocyte contractility. Our data also show that both normal and mutant cTnT were incorporated into myofibrils. These results provide a potential mechanism by which mutations in sarcomeric proteins cause HCM.
Department of Health is fair to patients with osteoporosis
Authors: D. Barlow, C. Cooper, J. Reeve, D. Reid
Journal: BMJ (1996)

described as "not screening" is nothing more than a ploy for circumventing the need to consider the overall potential benefits and costs of widespread testing.By accepting the report's recommendations, the Depart- ment of Health is undermining the firm national lead on the evaluation of potential new screening pro- grammes promised by the chiefmedical officer.
Bone marrow-generated dendritic cells pulsed with a class I-restricted peptide are potent inducers of cytotoxic T lymphocytes.
Authors: A Porgador, E Gilboa
Journal: The Journal of Experimental Medicine (1995)

It has previously been shown that bone marrow-generated dendritic cells (DC) are potent stimulators in allogeneic mixed leukocyte reactions and are capable of activating naive CD4+ T cells in situ in an antigen-specific manner. In this study we have investigated whether bone marrow-generated DC are capable of inducing antigen-specific CD8+ T cell responses in vivo. Initial attempts to induce specific cytotoxic T lymphocyte (CTL) responses in mice injected with bone marrow-generated DC pulsed with ovalbumin (OVA) peptide were frustrated by the presence of high levels of nonspecific lytic activity, which obscured, though not completely, the presence of Ag-specific CTL. Using conditions that effectively differentiate between antigen-specific and nonspecific lytic activity, we have shown that bone marrow-generated DC pulsed with OVA peptide are potent inducers of OVA-specific CTL responses in vivo, compared with splenocytes or RMA-S cells pulsed with OVA peptide, or compared with immunization with free OVA peptide mixed with adjuvant. Antibody-mediated depletion experiments have shown that the cytotoxic effector cells consist primarily of CD8+ cells, and that induction of CTL in vivo is dependent on CD4+ as well as on CD8+ T cells. These results provide the basis for exploring the role of bone marrow-generated DC in major histocompatibility class I-restricted immune responses, and they provide the rationale for using bone marrow-generated DC in CTL-mediated immunotherapy of cancer and infectious diseases.
The relationship between proton nuclear magnetic resonance relaxation parameters and myocardial perfusion with acute coronary arterial occlusion and reperfusion.
Authors: A V Ratner, R D Okada, J B Newell, G M Pohost
Journal: Circulation (1985)

Previous investigators have demonstrated that acute myocardial ischemia, whether followed by reperfusion or not, is associated with prolongation of the proton nuclear magnetic resonance (NMR) relaxation times T1 and T2. Heretofore, the relationship between the severity of ischemia and alterations of these relaxation times has not been assessed. In our studies, changes in T1 and T2 were compared with myocardial perfusion in dogs both before and during 30 and 60 min of coronary arterial occlusion. In addition, studies were performed to assess the impact of reperfusion on relaxation times after 30 and 60 min of coronary occlusion. In the reperfusion studies the relationship between myocardial relaxation times and flow during the preocclusion, occlusion, and the 15 min reperfusion periods were studied. In the occlusion-only preparations, there was a significant inverse relationship between the relaxation times and flow during occlusion. In the reperfusion preparations there was a significant direct relationship between T1 and T2 and flow during the period of reperfusion. There was no significant relationship between the relaxation times and flow during occlusion in groups that subsequently underwent reperfusion, and no relationship between T1 and T2 and preocclusion flow in either the occlusion-only or reperfusion groups. These data suggest that the proton relaxation times provide an indication of the severity of an ischemic insult. Since NMR images can be generated that are sensitive to differences in these relaxation parameters, NMR imaging may provide a means to assess noninvasively the severity of the myocardial ischemic insult.
1343 COMBINATION OF IL28 RS12979860 GENOTYPE WITH PRETREATMENT SERUM IP-10 LEVELS IS THE BEST PREDICTOR OF SVR TO PEGINTERFERON/RIBAVIRIN THERAPY IN CHRONIC HEPATITIS C, GT1 PATIENTS
Authors: K. Rutter, J. Aberle, A. Stättermayer, S. Bernhardt, T.M. Scherzer, H. Holzmann, H. Hofer, P. Steindl-Munda, P. Ferenci
Journal: Journal of Hepatology (2011)
ERRATUM: TREATMENT OF GRAM-POSITIVE NOSOCOMIAL PNEUMONIA: PROSPECTIVE RANDOMIZED COMPARISON OF QUINUPRISTIN/ DALFOPRISTIN VERSUS VANCOMYCIN
Authors: Jean-Yves Fagon
Journal: American Journal of Respiratory and Critical Care Medicine (2001)

Nosocomial pneumonia is a frequent complication in hospitalized patients. Gram-positive pathogens, particularly Staphylococcus aureus, are responsible for the increasing frequency of nosocomial pneumonia. To evaluate the efficacy and safety of intravenous quinupristin/dalfopristin (Synercid) in the treatment of nosocomial pneumonia caused by gram-positive pathogens we conducted a prospective, randomized, open-label, international, multicenter, comparative clinical trial. Two hundred ninety-eight patients with nosocomial pneumonia were enrolled in 74 active centers in five countries: a subgroup of 171 (87 quinupristin/dalfopristin-treated and 84 vancomycin-treated patients) were evaluable for the major efficacy end points. One hundred fifty received 7.5 mg/kg of quinupristin/dalfopristin every 8 h; 148 patients received 1 g of vancomycin every 12 h. Aztreonam at a dose of 2 g every 8 h could be administered in both groups for coverage of gram-negative organisms, and tobramycin was added for coverage against Pseudomonas aeruginosa. The primary efficacy end point was the clinical response between the seventh and the thirteenth day after the end of treatment in clinically evaluable patients with documented causative pathogen(s) at baseline (bacteriologically evaluable population). Therapy was clinically successful (cure or improvement) in 49 (56.3%) of patients receiving quinupristin/dalfopristin and 49 (58.3%) patients receiving vancomycin (difference, -2.0% [95% Cl, -16.8% to 12.8%]) in the bacteriologically evaluable population. Equivalent clinical success rates were also observed in the all-treated population (n = 298), and in the bacteriologically evaluable patients intubated in baseline (39/72 [54%] compared with 36/67 [54%]). The by-pathogen bacteriologic response was similar in both treatment groups, with equivalent clinical success rates for Streptococcus pneumoniae, Staphylococcus aureus, and methicillin-resistant Staphylococcus aureus. Adverse events (venous and nonvenous) were equally distributed between groups; 15.3% of quinupristin/dalfopristin patients and 9.5% of vancomycin patients discontinued therapy because of an adverse clinical event. In this study quinupristin/dalfopristin was shown to be equivalent to vancomycin in the treatment of nosocomial pneumonia caused by gram-positive pathogens. Quinupristin/dalfopristin merits further evaluation for the treatment of nosocomial pneumonia caused by methicillin-resistant S. aureus.
UK alcohol guidance has little relevance to people’s lives, study finds:
Authors: Bryan Christie
Journal: BMJ (2015)

Guidelines on the amount of alcohol people should drink are largely ignored in the United Kingdom because they are not seen as relevant to people’s lives, a report has found. A study carried out by the Sheffield Alcohol Research Group, in collaboration with the University of Stirling, found that the government’s “lower risk” guidance lacked credibility among drinkers.1 In their analysis of drinkers’ responses to the lower risk guidance, the researchers found three key reasons for the advice being ignored:
Subcutaneous fat necrosis of the newborn complicating hypothermic cardiac surgery
Authors: S-D. CHUANG, H-C. CHIU, C-C. CHANG
Journal: British Journal of Dermatology (2006)

A newborn male infant developed subcutaneous fat necrosis (SCFN) with extensive calcification, 1 week after hypothermic cardiac surgery. The lesions resolved spontaneously, without sequelae, within 10 weeks. Five cases of SCFN occurring after induced hypothermia, used as an adjuvant in cardiac surgery, have been reported to date in the English literature. Our description of a sixth case re‐emphasizes hypothermia as one possible cause of SCFN of the newborn.
Exome Sequencing,<i>ANGPTL3</i>Mutations, and Familial Combined Hypolipidemia
Authors: Kiran Musunuru, James P. Pirruccello, Ron Do, Gina M. Peloso, Candace Guiducci, Carrie Sougnez, Kiran V. Garimella, Sheila Fisher, Justin Abreu, Andrew J. Barry, Tim Fennell, Eric Banks, Lauren Ambrogio, Kristian Cibulskis, Andrew Kernytsky, Elena Gonzalez, Nicholas Rudzicz, James C. Engert, Mark A. DePristo, Mark J. Daly, Jonathan C. Cohen, Helen H. Hobbs, David Altshuler, Gustav Schonfeld, Stacey B. Gabriel, Pin Yue, Sekar Kathiresan
Journal: New England Journal of Medicine (2010)

We sequenced all protein-coding regions of the genome (the "exome") in two family members with combined hypolipidemia, marked by extremely low plasma levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides. These two participants were compound heterozygotes for two distinct nonsense mutations in ANGPTL3 (encoding the angiopoietin-like 3 protein). ANGPTL3 has been reported to inhibit lipoprotein lipase and endothelial lipase, thereby increasing plasma triglyceride and HDL cholesterol levels in rodents. Our finding of ANGPTL3 mutations highlights a role for the gene in LDL cholesterol metabolism in humans and shows the usefulness of exome sequencing for identification of novel genetic causes of inherited disorders. (Funded by the National Human Genome Research Institute and others.).
Vaccine induced protection against hepatitis B
Authors: P. Van Damme
Journal: BMJ (2003)

EDITOR—Whittle et al report one of the few long term follow up studies of children vaccinated against hepatitis B.1 The reported reduction in the rate of carriers of hepatitis B surface antigen in two villages in the Gambia, from 13% to 1% and from 35% to 2% respectively, represents a major achievement in public health.

We are concerned, however, that those who are influential in deciding policy of hepatitis B vaccination may not appreciate that relevant information is missing in …
Re: Risk/Benefit Assessment of Tamoxifen to Prevent Breast Cancer--Still a Work in Progress?
Authors: M. H. Gail
Journal: JNCI Journal of the National Cancer Institute (2000)

The selective estrogen receptor modulators (SERMs), e.g., tamoxifen and raloxifene, represent an exciting new class of therapeutic agents, which may prove to be effective against a wide variety of conditions, including breast cancer, osteoporosis, and potentially other conditions. There are two principal limitations to the use of the currently available SERMs. First, the specificity of the mix of agonist and antagonist actions is limited. Newer agents with greater specificity hold the promise for highly targeted therapeutic actions with fewer undesirable side effects. Second, clinical trial data showing which populations benefit or suffer excessive risk from treatment with SERMs are very limited. It is with respect to this second limitation that Gail et al. (1), reporting in this issue of the Journal, have proposed estimates of benefits and risk for the use of tamoxifen for the prevention of breast cancer. The authors use data, based primarily on the Breast Cancer Prevention Trial (BCPT) (2), to construct guidelines to assess the benefits and risks of tamoxifen therapy for use in counseling women at risk for breast cancer. In this trial, 13 388 women at increased risk for breast cancer (projected absolute risk of at least 1.66% over 5 years) were randomly assigned to treatment with either tamoxifen or placebo and followed for an average period of 4.1 years. Tamoxifen was associated with an overall 49% reduction in risk of invasive breast cancer. However, increased risks of endometrial cancer, stroke, pulmonary embolism, and deep venous thrombosis were noted with tamoxifen, with relative risks of 2.53, 1.59, 3.01, and 1.60, respectively, compared with placebo. The authors estimated the reduction in risk of invasive breast cancer as well as the increases in risk of endometrial cancers, stroke, venous thromboembolic events, and fractures associated with tamoxifen treatment. The relative risk versus benefit of tamoxifen treatment for a woman of a given age and ethnicity was derived from the BCPT data in combination with background incidences of each condition derived from population-based surveys, hospital discharge databases, and death certificate databases. Risk/benefit assessment of any therapeutic tool is an extremely important process, particularly when a preventive care strategy is to be recommended, because most therapies have beneficial effects coupled with potentially harmful side effects. Risks and benefits to a population from any therapy may differ substantially, depending on age, concomitant illnesses and treatments, ethnicity, socioeconomic status, educational level, living environment, and health behaviors of the population. Therefore, the efforts of Gail et al. are commendable. Furthermore, the BCPT is a formidable database upon which to draw in formulating guidelines.
Therapy of chronic relapsing thrombotic thrombocytopenic purpura with prednisone and azathioprine
Authors: Joel L. Moake, Christine K. Rudy, Joseph H. Troll, Andrew I. Schafer, Mark J. Weinstein, Noreen M. Colannino, Suchen L. Hong
Journal: American Journal of Hematology (1985)

Abstract As a 51‐year‐old woman recovered from an initial acute episode of thrombotic thrombocytopenic purpura (TTP), her plasma was found to contain unusually large von Willebrand factor (vWF) multimers. Clinical, hematological, and vWF studies of her siblings and children were normal. The unusually large vWF forms were presumably derived from endothelial cells, persisted in her plasma after recovery, and were associated with recurrent episodes of TTP during the subsequent 6 months. After the last episode of relapse they disappeared from her plasma following 3 ½ weeks of therapy with prednisone and did not return during 17 months of treatment with prednisone and/or azathioprine. She is now receiving no drugs, has normal plasma vWF forms, and has not had any more episodes of TTP. We conclude that our patient had an acquired defect in the conversion of unusually large vWF multimers derived from endothelial cells to the somewhat smaller vWF forms usually present in circulation. The defect may have been immune‐mediated, because it was eliminated during therapy with immunosuppressive drugs.