tbuckley/cabot-search huggingface dataset:
Abstract 192: Scleraxis is a Required Component of the Cardiac Extracellular Matrix Gene Expression Program
Authors: Michael P Czubryt, Rushita A Bagchi, Patricia L Roche, Ryan Wang, Shreyas Devalapurkar, Ronen Schweitzer
Journal: Circulation Research (2014)

The collagenous cardiac extracellular matrix (ECM) reinforces the myocardium and facilitates intercellular communication, but excessive ECM production in fibrosis results in dysfunction and heart failure. The transcription factor scleraxis directly governs expression of type I fibrillar collagen in ECM-rich tissues including tendons and the heart. We have also shown that scleraxis is required for collagen 1α2 gene expression induced by the potent pro-fibrotic TGFβ-Smad signaling pathway. We therefore examined the broader role of scleraxis in myocardial ECM production, including mechanisms regulating the expression of scleraxis itself. Scleraxis knockout in mice resulted in a dramatic ~50% loss of cardiac ECM components including fibrillar collagens, proteoglycans and matrix metalloproteinases, concomitant with a significant decrease in fibroblast number. Scleraxis knockdown in primary cardiac proto-myofibroblasts recapitulated these changes without increasing cell death, suggesting a reduction in fibroblast precursors in knockout mice in vivo. Conversely, over-expression of scleraxis had the opposite effect, up-regulating expression of ECM genes and numerous markers indicative of increased commitment to a myofibroblast cell fate. Scleraxis increased proto-myofibroblast contractility via direct transactivation of the α-smooth muscle actin promoter. Similar to TGFβ, pro-fibrotic angiotensin II and Connective Tissue Growth Factor induced scleraxis expression, suggesting that scleraxis behaves as a common transcriptional effector for multiple fibrotic pathways. Fibrillar collagen gene expression induced by these factors was significantly attenuated by scleraxis knockdown, further implicating scleraxis in fibrotic ECM synthesis. Intriguingly, the histone deacetylase inhibitor trichostatin A, which has been reported to exert anti-fibrotic effects in the heart, significantly reduced scleraxis expression in cardiac myofibroblasts. These data collectively identify scleraxis as a central and requisite transcriptional regulator of fibroblast phenotype and the ECM gene expression program in the heart, and provide rationale for the investigation of anti-scleraxis strategies to attenuate fibrosis in patients.
Rapid Emergence of a Focal Epidemic of Lyme Disease in Coastal Massachusetts
Authors: Catherine C. Lastavica, Mark L. Wilson, Victor P. Berardi, Andrew Spielman, Robert D. Deblinger
Journal: New England Journal of Medicine (1989)

We describe a focal epidemic of Lyme disease, which spread from a nature preserve and affected an adjacent community of permanent residents in coastal Massachusetts. The attack rate from 1980 through 1987 was 35 percent among 190 residents living within 5 km of the nature preserve and was greatest (66 percent) among those living closest to the preserve. The risk of infection bore little relation to sex or age. Late Lyme disease, which clustered near the preserve, occurred mainly in residents infected early in the epidemic who did not have a history of erythema migrans and did not receive antibiotic therapy. All the residents with serologic evidence of infection had early or late clinical manifestations of Lyme disease, or both, during the period of study. The seasonal risk of infection was bimodal — greatest in June, with a secondary peak in October — and corresponded to periods of increased transmission. In the nature preserve, the density of the vector tick, Ixodes dammini, exceeded that in other New England sites. The zoonosis rapidly became endemic, and the severity of its impact correlated with the abundance of deer. This epidemic of Lyme disease demonstrated that outbreaks can be focal and can spread rapidly within a community of permanent residents. (N Engl J Med 1989; 320:133–7.)
Case 26-1993
Authors: Richard C. Cabot, Robert E. Scully, Eugene J. Mark, William F. McNeely, Betty U. McNeely, Thomas J. O'Donnell, John X. O'Connell
Journal: New England Journal of Medicine (1993)

Presentation of CaseA 73-year-old man was admitted to the hospital with a diagnosis of a contained, ruptured aneurysm of the left femoral artery.The patient was a retired shipyard pipe fitter, with known exposure to asbestos. He had smoked one pack of cigarettes daily for 30 years and then switched to pipe-smoking 32 years before admission. He also had “chronic bronchitis,” which was managed with theophylline, and hypertension, which was treated with enalapril. Ten years before entry a stage B1 carcinoma of the prostate gland was found and was treated at another hospital by radiation therapy with a . . .
PTU-104 Non-invasive detection, stratification and treatment of chronic hepatic c related liver disease amongst substance users in the community: a prospective study
Authors: S Verma, M O’Sullivan, H Williams, A-M Jones
Journal: Gut (2015)

<h3>Introduction</h3> Despite discovery of direct acting antiviral agents (DAA), a two- three fold increase in hepatitis C virus (HCV) detection/treatment is necessary to reduce the national HCV disease burden. Ninety percent of HCV positive individuals in England are people who inject drugs (PWID) with poor engagement with health services. Our aim was to assess feasibility of non-invasive detection, stratification and treatment of HCV related chronic liver disease (CLD) in the community. <h3>Method</h3> Two-year prospective study (Dec 2013–Nov 2015) conducted at a large substance misuse service in SE England. Individuals offered dry blood spot testing (DBST), mobile transient elastography (TE), and HCV treatment (pegylated interferon/ribavirin/telaprevir). Clinically significant hepatic fibrosis: liver stiffness measurement (LSM) ≥7.5 kPa. <h3>Results</h3> To date, 165 individuals recruited, mean age 39.8 ± 8.9 yrs, 84.8% male. One hundred and forty-one (85.5%) had history of injecting drug use (IDU) and 143 (86.7%) reported alcohol use. Eighty-three (50.3%) had had a psychiatric diagnosis. Uptake of DBST was 75 (45.5%), main reason for declining being recent prior testing. Overall prevalence of positive serological markers were: HBcAb 28.8% (n = 42), HCV antibody 62.2% (n = 97) and HCV PCR 75.2% (73/97) (genotype 3a 42.8%, 1a 34.3%). Of those with a positive HCV PCR (n = 73), 62 (84.9%) underwent TE, mean LSM being 7.7 ± 6.6. kPa. Twenty-one (33.9%) had LSM ≥7.5 kPa including 13 (21%) with cirrhosis (LSM ≥12 kPa), one of whom had decompensated disease. Of the 73 with a positive HCV PCR none had had prior treatment: fifteen (20.5%) were not treatment candidates (chaotic life style), interferon was inappropriate in 35 (47.9%) with 23 (31.5%) being eligible for interferon based treatment. Thirteen have commenced therapy (nine genotype 3a, three 1a and one 2b), of whom 4 have successfully completed with 8 achieving rapid virological response. <h3>Conclusion</h3> This novel community based liver service at a substance service has shown excellent uptake of both DBST and mobile TE amongst PWID, though prevalence of a positive HCV antibody (62.2%) remains high. Additionally, despite a mean age of &lt;40 yrs about a third of PWID have clinically significant HCV related hepatic fibrosis with 1:5 having established cirrhosis. Though community based interferon therapy is feasible in PWID, it is contraindicated in approximately 50% emphasising the urgent need for interferon-free regimens in this vulnerable population. <h3>Disclosure of interest</h3> S. Verma Grant/Research Support from: Gilead, Conflict with: Travel grants from Gilead, Abbvie, Roche, BMS and Janssen, M. O’Sullivan Conflict with: salary funded by Gilead, H. Williams: None Declared, A.-M. Jones: None Declared.
Closed-Chest Cardiac Massage in the Treatment of Ventricular Fibrillation Complicating Acute Myocardial Infarction
Authors: Arthur J. Moss, Robert K. Osborne, Arthur E. Baue, Robert S. Lees, Rex L. Jamison, James Spann
Journal: New England Journal of Medicine (1962)

SUCCESSFUL resuscitation in ventricular fibrillation complicating myocardial infarction has been reported with open thoracotomy and internal cardiac massage.1 The development of an effective external cardiac defibrillator by Zoll and his associates2 obviated the necessity for thoracotomy for defibrillation. It remained for the development of the technic of closed-chest cardiac massage by Kouwenhoven et al.3 to allow for the satisfactory treatment of ventricular fibrillation without resort to thoracotomy. Until recently, effective treatment of ventricular fibrillation or asystole has occurred most often in an operative or recovery room during anesthesia and surgery. We are aware of only a few cases in the . . .
Chest Thump for Reverting Ventricular Tachycardia
Authors: James E. Pennington, Jack Taylor, Bernard Lown
Journal: New England Journal of Medicine (1970)

A sharp precordial thump was employed to terminate 12 episodes of ventricular tachycardia (VT) in five patients with coronary heart disease. A precordial thump, through electromechanical transduction, provides a low energy current that depolarizes a re-entry pathway, the probable basis for most cases of clinical VT. Indeed, analysis of cardioversion energies for VT has demonstrated that 93 per cent of episodes are reversed with energies of 10 w sec or less. Chest thump is an important maneuver for treating cardiac arrest initiated by VT.
231TiP KEYNOTE-059: Phase 2 study of pembrolizumab (MK-3475) for recurrent or metastatic gastric or gastroesophageal junction adenocarcinoma
Authors: E. Van Cutsem, C.S. Fuchs, A.E. Denker, J. Tabernero, A. Ohtsu, B. Lam, M. Koshiji, Y.-J. Bang
Journal: Annals of Oncology (2015)
Carbimazole and the Autoimmune Response in Graves' Disease
Authors: Alan M. McGregor, Meryl M. Petersen, Sandra M. McLachlan, Patricia Rooke, Bernard Rees Smith, Reginald Hall
Journal: New England Journal of Medicine (1980)

Microsomal antibodies and antibodies directed toward the receptor for thyroid-stimulating hormone (TSH) decreased in parallel while patients with Graves' disease were taking carbimazole, whereas no significant changes were observed during treatment with placebo or propranolol. The changes in autoantibody levels during carbimazole treatment were independent of changes in serum thyroxine and could have been due to a direct effect of the drug on autoantibody synthesis. Evidence for this suggestion was provided when low doses of methimazole (the active metabolite of carbimazole) were found to inhibit thyroid-autoantibody production in cultured lymphocytes. Since thyroid lymphocytes are probably a major site of thyroid-antibody synthesis in Graves' disease and methimazole is concentrated in the thyroid during treatment, a local action of the drug on antibody production seems likely. This possibility could be important in the use of carbimazole to control hyperthyroidism.
Phenotyping of Lesions of Melanocyte Origin With Monoclonal Antibodies to Melanoma-Associated Antigens and to HLA Antigens&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: Natali, P. G., Bigotti, A., Cavaliere, R., Nicotra, M. R., Ferrone, S.
Journal: JNCI Journal of the National Cancer Institute (1984)

The antigenic profiles of a large number of surgically removed human benign and malignant lesions of melanocyte origin have been analyzed with the use of monoclonal antibodies (MoAb) against la antigens, against the HLA-A,B,C-beta 2-microglobulin molecular complex, against a cytoplasmic melanoma-associated antigen (MAA), and against membrane-bound MAA. Membrane-bound MAA include a high-molecular-weight MAA (HMW-MAA), a 115K MAA, and a 100K MAA. Appearance of the HMW-MAA and of the cytoplasmic MAA, as well as cytoplasmic distribution or loss of HLA-A,B,C antigens, occurs in benign lesions. Additional appearance of Ia antigens is associated with malignant transformation of melanocytes. The antigenic profile defined by the battery of MoAb used displays differences among benign lesions of different histogenesis, between benign and malignant lesions, and among malignant lesions with different histopathologic properties. These results suggest that phenotyping of surgically removed lesions with anti-MAA and anti-HLA MoAb may contribute to the understanding of the steps involved in tumor progression of melanocytes and may aid in the diagnosis of lesions with unusual histopathologic features.
Genetic mapping of a modifier locus affecting blood pressure in soluble guanylate cyclase alpha 1-deficient mice
Authors: Emmanuel S. Buys, Michael J. Raher, Andrew Kirby, Sarah R. Hayton, David M. Baron, Patrick Sips, Shahid Mohd, Kristen M. Rauwerdink, Qingshang Yan, Laurel T. Tainsh, Hannah Shakartzi, Christine Stevens, Kelly Decaluwe, Johan Van de Voorde, Tong Wang, Peter Brouckaert, Mark J. Daly, Kenneth D. Bloch
Journal: Circulation (2011)
Hospital Discharge One Week after Acute Myocardial Infarction
Authors: J. Frederick McNeer, Galen S. Wagner, Paul B. Ginsburg, Andrew G. Wallace, Charles B. McCants, Martin J. Conley, Robert A. Rosati
Journal: New England Journal of Medicine (1978)

Sixty-seven consecutive patients who had suffered an acute myocardial infarction but no serious complications during the first to fourth hospital days were considered for a trial of hospital discharge at one week. Thirty-three of the 67 patients were discharged at one week, the remainder having a mean hospital stay of 11 ±2 days. The incidence of late complications and recurrent infarctions, as well as mortality and functional status, were determined in all patients six months after discharge. No serious complications occurred in either subgroup within three weeks after discharge. There were no deaths in either subgroup and no difference in functional status at six months. Patients without serious complications during the four days after an acute myocardial infarction can be spared the economic costs and psychologic stress of prolonged hospitalization. (N Engl J Med 298:229–232, 1978)
Efficacy of Adjuvant Chemotherapy in High-Risk Node-Negative Breast Cancer
Authors: Edward G. Mansour, Robert Gray, Ahmad H. Shatila, C.K. Osborne, Douglass C. Tormey, Kennedy W. Gilchrist, M. Robert Cooper, Geoffrey Falkson
Journal: New England Journal of Medicine (1989)

We randomly assigned 536 women who had undergone either a modified radical mastectomy or a total mastectomy with low axillary-node dissection for potentially curable breast carcinoma to receive adjuvant chemotherapy or no-treatment observation. The patients were considered at high risk for recurrence because they had either an estrogen-receptor–negative tumor of any size or an estrogen-receptor–positive tumor at least 3 cm in diameter with no histopathological evidence of axillary-node involvement. The chemotherapy consisted of six four-week cycles of cyclophosphamide (100 mg per square meter of body-surface area orally on days 1 through 14), methotrexate (40 mg per square meter intravenously on days 1 and 8), fluorouracil (600 mg per square meter intravenously on days 1 and 8), and prednisone (40 mg per square meter orally on days 1 through 14). Treatments were balanced with respect to patients' characteristics. The analysis included 406 eligible patients who were entered in the study before October 1, 1987. The overall disease-free survival among patients treated with the four-drug regimen was 84 percent, as compared with 69 percent for the control group, at a median follow-up of three years (P = 0.0001). A treatment benefit was also observed in premenopausal and postmenopausal patients as well as in patients with estrogen-receptor–positive or with estrogen-receptor–negative tumors. Severe or life-threatening hematologic toxicity was encountered in 33 percent of the treated patients, with one death. Our results indicate that adjuvant chemotherapy with six cycles of cyclophosphamide, methotrexate, fluorouracil, and prednisone is effective in improving three-year disease-free survival among high-risk patients with axillary-node–negative, operable breast cancer. An analysis of the effect of treatment on survival awaits a longer follow-up. (N Engl J Med 1989; 320:485–90.)
Abbreviated Regimens of Zidovudine Prophylaxis and Perinatal Transmission of the Human Immunodeficiency Virus
Authors: Nancy A. Wade, Guthrie S. Birkhead, Barbara L. Warren, Tina T. Charbonneau, P. Tyler French, Ling Wang, Jeanne B. Baum, James M. Tesoriero, Robert Savicki
Journal: New England Journal of Medicine (1998)

The Pediatric AIDS Clinical Trials Group Protocol 076 reported a reduction in the rate of perinatal transmission of the human immunodeficiency virus (HIV) from 25.5 percent to 8.3 percent with a three-part regimen of zidovudine given ante partum, intra partum, and to the newborn. We examined the effects of abbreviated zidovudine regimens on perinatal HIV transmission using data from the HIV polymerase-chain-reaction (PCR) testing service of the New York State Department of Health. Pregnant women who received abbreviated regimens rather than the recommended regimens did so because of limited prenatal care or by choice.
Why screening tests to predict injury do not work—and probably never will…: a critical review
Authors: Roald Bahr
Journal: British Journal of Sports Medicine (2016)

This paper addresses if and how a periodic health examination to screen for risk factors for injury can be used to mitigate injury risk. The key question asked is whether it is possible to use screening tests to identify who is at risk for a sports injury-in order to address the deficit through a targeted intervention programme. The paper demonstrates that to validate a screening test to predict and prevent sports injuries, at least 3 steps are needed. First, a strong relationship needs to be demonstrated in prospective studies between a marker from a screening test and injury risk (step 1). Second, the test properties need to be examined in relevant populations, using appropriate statistical tools (step 2). Unfortunately, there is currently no example of a screening test for sports injuries with adequate test properties. Given the nature of potential screening tests (where test performance is usually measured on a continuous scale from low to high), substantial overlap is to be expected between players with high and low risk of injury. Therefore, although there are a number of tests demonstrating a statistically significant association with injury risk, and therefore help the understanding of causative factors, such tests are unlikely to be able to predict injury with sufficient accuracy. The final step needed is to document that an intervention programme targeting athletes identified as being at high risk through a screening programme is more beneficial than the same intervention programme given to all athletes (step 3). To date, there is no intervention study providing support for screening for injury risk.
Effects of Caffeine on Plasma Renin Activity, Catecholamines and Blood Pressure
Authors: David Robertson, Jürgen C. Frölich, R. Keith Carr, J. Throck Watson, John W. Hollifield, David G. Shand, John A. Oates
Journal: New England Journal of Medicine (1978)

Using a double-blind, randomized, cross-over protocol, we studied the effect of a single dose of oral caffeine on plasma renin activity, catecholamines and cardiovascular control in nine healthy, young, non-coffee drinkers maintained in sodium balance throughout the study period. Caffeine (250 mg) or placebo was administered in a methylxanthine-free beverage to overnight-fasted supine subjects who had had no coffee, tea or cola in the previous three weeks. Caffeine increased plasma renin activity by 57 per cent, plasma norepinephrine by 75 per cent and plasma epinephrine by 207 per cent. Urinary normetanephrine and metanephrine were increased 52 per cent and 100 per cent respectively. Mean blood pressure rose 14/10 mm Hg one hour after caffeine ingestion. There was a slight fall and then a rise in heart rate. Plasma caffeine levels were usually maximal one hour after ingestion but there was considerable individual variation. A 20 per cent increase in respiratory rate correlated well with plasma caffeine levels. Under the conditions of study caffeine was a potent stimulator of plasma renin activity and adrenomedullary secretion. Whether habitual ingestion has similar effects remains to be determined.
Phase II study of everolimus plus erlotinib in previously treated patients with advanced non-small cell lung cancer (NSCLC).
Authors: N. B. Leighl, J. Soria, J. Bennouna, N. Blais, A. M. Traynor, V. Papadimitrakopoulou, J. Klimovsky, A. Jappe, V. Jehl, B. E. Johnson
Journal: Journal of Clinical Oncology (2010)

7524 Background: Everolimus (RAD001) is an oral mTOR inhibitor that has been evaluated as monotherapy in a phase II study of NSCLC patients (pts) previously treated with platinum-based chemotherapy, with modest evidence of antitumor activity. Erlotinib (E) is an oral epidermal growth factor receptor-tyrosine kinase inhibitor approved as second- and third-line therapy for advanced/metastatic NSCLC. This phase I/II study is evaluating the combination of RAD001 and E (R+E) in pts with advanced NSCLC who progressed after ≤2 prior chemotherapy regimens (NCT00456833). Phase I results established the recommended dose for the R+E combination. Methods: The eligibility criteria included progressive NSCLC, WHO performance status ≤ 1 and adequate liver and bone marrow function. Pts were randomized to receive E 150 mg/day or RAD001 5 mg/day plus E 150 mg/day orally until disease progression or unacceptable toxicity. Survival data are being collected every 2 months (mo) following the end of treatment until all pts discontinue from the study. The primary study endpoint is disease control rate (DCR) (ie, the percentage of pts with stable disease or better response at 3 months). Other endpoints included overall response (OS), progression-free survival (PFS), safety, pharmacokinetics, and molecular markers. Results: 133 pts were randomized: 66 pts in the R+E group and 67 pts in the E group. DCR at 3 months was 39.4% (95% CI 27.6, 52.2) for R+E and 28.4% (95% CI 18.0, 40.7) for E. Median PFS was 2.9 mo vs 2.0 mo for R+E vs E. The most common grade 3/4 AEs reported in ≥ 4 pts were stomatitis in 21 (32%), asthenia in 7 (11%), diarrhea in 5 (8%), and rash, dermatitis and fatigue each in 4 (6%) pts in the R+E group and dyspnea in 4 (6%) pts in the E group. Safety data suggest no new safety concerns with the combination of everolimus plus erlotinib. Conclusions: The combination arm of everolimus plus erlotinib performed better with an 11% difference in DCR at 3 months favoring the combination but did not meet the prespecified threshold to support a phase III study. Studies in more selected subpopulations (by biomarkers) will likely contribute to an understanding of the further role of everolimus in NSCLC. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis AstraZeneca, Boehringer Ingelheim, Genentech, KW Group Diagnostics, Millennium, Pfizer Celgene Novartis Genzyme
Effect of Intravenous Phosphate on Serum Strontium and Calcium
Authors: Eugene Eisenberg
Journal: New England Journal of Medicine (1970)

Administration of phosphate intravenously to four hypercalcemic patients caused serum calcium and serum strontium to fall. Strontium was given intravenously 72 hours before phosphate infusion. The pattern of fall and the interval before the subsequent rise in serum calcium and strontium are not compatible with previously postulated effects of phosphate on bone resorption or formation. Acute administration of phosphate causes temporary deposition or sequestration of the alkaline earth metals in a form from which they are released in a relatively short time. The anatomic site of this action remains to be determined.