tbuckley/cabot-search huggingface dataset:
New contract for general practitioners
Authors: P. Shekelle
Journal: BMJ (2003)

News p 465 

This week a proposed new contract between the NHS and general practitioners contains an initiative to improve the quality of primary care that is the boldest such proposal on this scale ever attempted anywhere in the world.1 The proposal spells out 76 quality indicators in 10 clinical domains of care, 56 in organisational areas, four assessing patients' experience, and a number of indicators for additional services. The proposal furthermore sets targets for performance that will be accompanied by increased payments to providers. Like any bold proposal this one offers the promise of a quantum change in performance rather than an incremental one. To get there, however, will require a great deal of work by all involved and may come at the price of other aspects of primary care being left out of this quality framework. The net effect on primary care will therefore depend on how this initiative is implemented and the follow on work of the NHS and general practitioners at building on what works and a willingness to discard or change …
Influence of prostaglandin E2, indomethacin, and reserpine on renal vascular responses to nerve stimulation, pressor and depressor hormones.
Authors: G D Fink, B M Chapnick, M R Goldberg, P W Paustian, P J Kadowitz
Journal: Circulation Research (1977)

The effects of prostaglandin E2 (PGE2) indomethacin, and reserpine were evaluated in the rabbit renal vascular bed in situ under conditions of controlled blood flow. Intrarenal infusion of PGE2, 0.03 and 0.3 microgram/min, decreased responses to renal nerve stimulation, intra-arterial norepinephrine, and angiotensin. Responses to nerve stimulation were decreased to a greater extent than responses to norepinephrine. At lower concentrations the effects of PGE2 on pressor responses and on vascular resistance could be separated. Reserpine decreased the histochemical evidence of adrenergic innervation and reduced the response to renal nerve stimulation, enhanced the response to norepinephrine, and was without effect on the response to angiotensin. Indomethacin decreased depressor responses to arachidonic acid, produced a small increase in renal vascular resistance but did not enhance renal pressor responses. The increase in renal vascular resistance after indomethacin was not modified by reserpine pretreatment. Indomethacin enhanced the renal response to bradykinin. These data show that PGE2 possesses the ability to modulate pressor responses in the kidney. However, experiments with indomethacin suggest that endogenous prostaglandins neither modulate pressor responses nor mediate the response of the renal vascular bed to bradykinin. In addition, these data suggest that the increase in renal resistance after indomethacin is not dependent on the adrenergic nervous system.
Does Reasonable Incomplete Surgical Revascularization Affect Early or Long-Term Survival in Patients With Multivessel Coronary Artery Disease Receiving Left Internal Mammary Artery Bypass to Left Anterior Descending Artery?
Authors: Ardawan Julian Rastan, Thomas Walther, Volkmar Falk, Joerg Kempfert, Denis Merk, Sven Lehmann, David Holzhey, Friedrich Wilhelm Mohr
Journal: Circulation (2009)

Background— The objective was to evaluate the impact of complete revascularization (CR) versus reasonable incomplete surgical revascularization (IR) in others than left anterior descending artery territory on early and late survival in patients with multivessel coronary artery disease (CAD). Methods and Results— During a 7-year period, 8.806 consecutive patients with multivessel CAD affecting the proximal left anterior descending artery or left main stem underwent sternotomy for isolated coronary artery bypass grafting including left internal mammary artery-left anterior descending artery bypass. A total of 936 patients (10.6%) had IR of the circumflex or right coronary artery territory. IR was based on the traditional classification. Follow-up was 3.5±2.2 years. Patient groups were comparable regarding age (CR 67.1 versus IR 67.6 years), ejection fraction (57.2% versus 57.5%), and logEuroscore (4.5% versus 4.5%). Patients receiving IR presented with more complex CAD. Mean number of distal anastomoses was 3.0±0.8 CR versus 2.4±0.6 IR. Operation time (176 versus 187 minutes) and cross-clamp time (52 versus 56 minutes) were longer in the IR group ( P &lt;0.001). Hospital mortality was 3.3% CR versus 3.2% IR ( P =0.520). Independent risk factors for hospital mortality were age, pulmonary hypertension, chronic obstructive pulmonary disease, peripheral vascular disease, and emergency indication, but not IR ( P =0.922). Arterial revascularization was protective. Cumulative survival at 1-year was 93.1% CR versus 93.6% IR and at 5 years 82.2 CR versus 80.9% IR ( P =0.457). Conclusions— In presence of left internal mammary artery-to-left anterior descending artery bypass, reasonable IR of the circumflex or right coronary artery territory did not adversely affect early or long-term survival in patients with multivessel CAD. In patients presenting with 1 poor target vessel; however, IR is a good therapeutic option and the benefit of CR should be balanced against the risks.
Evaluating eHealth: How to Make Evaluation More Methodologically Robust
Authors: Richard James Lilford, Jo Foster, Mike Pringle
Journal: PLoS Medicine (2009)

RL and JF are responsible for commissioning the NPFIT Evaluation Programme, and MP is Chairman at the Steering Committee for this programme. The views expressed here do not necessarily reflect those of the NHS or the Department of Health.



No specific funding was received for this work.



Provenance: Commissioned, externally peer reviewed
A Quantitative Assessment of Baroreceptor Reflex Sensitivity in Man, Awake and Asleep.
Authors: Peter Sleight
Journal: Annals of Internal Medicine (1968)

s1 May 1968A Quantitative Assessment of Baroreceptor Reflex Sensitivity in Man, Awake and Asleep.Peter Sleight, M.D., J. David Bristow, M.D., A. J. Honour, D.Phil., George W. Pickering, M.D., F.A.C.P., Harley S. Smyth, M.D.Peter Sleight, M.D.Search for more papers by this author, J. David Bristow, M.D.Search for more papers by this author, A. J. Honour, D.Phil.Search for more papers by this author, George W. Pickering, M.D., F.A.C.P.Search for more papers by this author, Harley S. Smyth, M.D.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-68-5-1162_1 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptAn investigation was made of the fall in blood pressure that occurs during a night's sleep. The stage of sleep was identified from the electroencephalogram (five channels), the electrooculogram, and the submental electromyogram. On the last of three successive nights intra-arterial pressure was recorded continuously. Transient reflex bradycardia was produced by the rise in pressure after repeated intravenous injections of 0.25 to 2.0 µg of angiotensin, when subjects were awake and in each successive stage of sleep. The results of each pressor test could be expressed as a straight line in 10 of 13 subjects when the systolic pressures of... This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAffiliations: Oxford, PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 1 May 1968Volume 68, Issue 5Page: 1162-1162KeywordsBlood pressureBradycardiaElectro oculogramElectroencephalographyElectromyographyFallsIntravenous injectionsReflexesSleepSystolic pressure Issue Published: 1 May 1968 PDF downloadLoading ...
Transcriptome classification of HCC is related to gene alterations and to new therapeutic targets
Authors: Sandrine Boyault, David S. Rickman, Aurélien de Reyniès, Charles Balabaud, Sandra Rebouissou, Emmanuelle Jeannot, Aurélie Hérault, Jean Saric, Jacques Belghiti, Dominique Franco, Paulette Bioulac-Sage, Pierre Laurent-Puig, Jessica Zucman-Rossi
Journal: Hepatology (2006)

Hepatocellular carcinomas (HCCs) are a heterogeneous group of tumors that differ in risk factors and genetic alterations. We further investigated transcriptome-genotype-phenotype correlations in HCC. Global transcriptome analyses were performed on 57 HCCs and 3 hepatocellular adenomas and validated by quantitative RT-PCR using 63 additional HCCs. We determined loss of heterozygosity, gene mutations, promoter methylation of CDH1 and CDKN2A , and HBV DNA copy number for each tumor. Unsupervised transcriptome analysis identified 6 robust subgroups of HCC (G1-G6) associated with clinical and genetic characteristics. G1 tumors were associated with low copy number of HBV and overexpression of genes expressed in fetal liver and controlled by parental imprinting. G2 included HCCs infected with a high copy number of HBV and mutations in PIK3CA and TP53 . In these first groups, we detected specific activation of the AKT pathway. G3 tumors were typified by mutation of TP53 and overexpression of genes controlling the cell cycle. G4 was a heterogeneous subgroup of tumors including TCF1 -mutated hepatocellular adenomas and carcinomas. G5 and G6 were strongly related to β-catenin mutations that lead to Wnt pathway activation; in particular, G6 tumors were characterized by satellite nodules, higher activation of the Wnt pathway, and E-cadherin underexpression. Conclusion: These results have furthered our understanding of the genetic diversity of human HCC and have provided specific identifiers for classifying tumors. In addition, our classification has potential therapeutic implications because 50% of the tumors were related to WNT or AKT pathway activation, which potentially could be targeted by specific inhibiting therapies. (Hepatology 2007;45:42–52.rpar;
A System for Small-Molecule Control of Conditionally Replication-Competent Adenoviral Vectors
Authors: Heung Chong, Anja Ruchatz, Tim Clackson, Victor M. Rivera, Richard G. Vile
Journal: Molecular Therapy (2002)

Replication-competent adenoviral vectors are potentially far more efficient than replication-defective vectors. However, for reasons of safety, there is a need to restrict viral replication both spatially, by limiting replication to certain cell types, and temporally. To control replication temporally, we have developed a system, based on the small-molecule dimerizer rapamycin, for regulating the replication of adenoviral vectors. In this system, one adenoviral vector, AdC4, expresses transcription factors whose activity is regulated by the non-immunosuppressive rapamycin analog AP21967. A second vector, Ad(Z12-I-E1aE1b19k), contains E1 genes placed downstream of binding sites for the regulated transcription factor. Co-infection of several cell lines by the vector pair leads to dimerizer-dependent E1 expression and an increase in viral replication, as shown by Southern blots and replication assays. Furthermore, expression of a reporter gene from a replication-defective vector, Ad-GM-CSF, can be augmented by up to 18-fold by co-infection with the pair of conditionally replicating vectors in the presence of dimerizer. Similar results are obtained when the vectors are directly injected into subcutaneous HT1080 xenograft tumors in nude mice. We believe that vectors based on this principle will be a useful additional tool to enhance efficiency and safety of gene delivery for anti-cancer therapy.
The Effect of Aprotinin on Outcome after Coronary-Artery Bypass Grafting
Authors: Andrew D. Shaw, Mark Stafford-Smith, William D. White, Barbara Phillips-Bute, Madhav Swaminathan, Carmelo Milano, Ian J. Welsby, Solomon Aronson, Joseph P. Mathew, Eric D. Peterson, Mark F. Newman
Journal: New England Journal of Medicine (2008)

Aprotinin has recently been associated with adverse outcomes in patients undergoing cardiac surgery. We reviewed our experience with this agent in patients undergoing cardiac surgery at Duke University Medical Center.We retrieved data on 10,275 consecutive patients undergoing surgical coronary revascularization at Duke between January 1, 1996, and December 31, 2005. We fit data to a logistic-regression model predicting each patient's likelihood of receiving aprotinin on the basis of preoperative characteristics and to models predicting long-term survival (up to 10 years) and decline in renal function, as measured by increases in serum creatinine levels.A total of 1343 patients (13.2%) received aprotinin, 6776 patients (66.8%) received aminocaproic acid, and 2029 patients (20.0%) received no antifibrinolytic therapy. All patients underwent coronary-artery bypass grafting, and 1181 patients (11.5%) underwent combined coronary-artery bypass grafting and valve surgery. In the risk-adjusted model, survival was worse among patients treated with aprotinin, with a main-effects hazard ratio for death of 1.32 (95% confidence interval [CI], 1.12 to 1.55) for the comparison with patients receiving no antifibrinolytic therapy (P=0.003) and 1.27 (95% CI, 1.10 to 1.46) for the comparison with patients receiving aminocaproic acid (P=0.004). As compared with the use of aminocaproic acid or no antifibrinolytic agent, aprotinin use was also associated with a larger risk-adjusted increase in the serum creatinine level (P<0.001) but not with a greater risk-adjusted incidence of dialysis (P=0.56).Patients who received aprotinin had a higher mortality rate and larger increases in serum creatinine levels than those who received aminocaproic acid or no antifibrinolytic agent.
Dysregulation of p38 and MKP-1 in Response to NOD1/TLR4 Stimulation in Sarcoid Bronchoalveolar Cells
Authors: Ruchi Rastogi, Wenjin Du, Donhong Ju, Gaila Pirockinaite, Yusen Liu, Gabriel Nunez, Lobelia Samavati
Journal: American Journal of Respiratory and Critical Care Medicine (2010)

Rationale: Sarcoidosis is a systemic inflammatory disorder characterized by distinct up-regulation of Th1 cytokines, such as tumor necrosis factor (TNF)-α and IL-12. The mechanism underlying this up-regulation remains unclear. Recognition of microbial moieties through Toll-like or Nod-like receptors evokes sequential activation of mitogen-activated protein kinases (MAPKs), which plays a role in Th1-immune response. Objectives: To test the hypothesis that dysregulation in MAPK signaling in response to microbial stimulation is important in mediating Th1 response in sarcoidosis.Methods: Ex vivo cultured bronchoalveolar lavage (BAL) cells isolated from patients with sarcoidosis and control subjects were stimulated with low-dose Toll-like receptor 4 (TLR4) and nucleotide-binding oligomerization domain 1 (NOD1) ligands as a model of microbial stimulation, and MAPK signaling and inflammatory response were analyzed.Measurements and Main Results: BAL cells from patients with sarcoidosis exhibited higher basal p38 activity, greater p38 phosphorylation, and more robust production of TNF-α and IL-12/IL-23p40 on stimulation with NOD1 and TLR4 agonists than cells isolated from control subjects. In contrast, control BAL cells had greater basal extracellular signal–regulated kinase (ERK) activity and NOD1 and TLR4 agonists preferentially activated the ERK pathway. Inhibition of p38, but not ERK, attenuated production of both IL12/IL23p40 and TNF-α. Interestingly, stimulation of cells from patients with sarcoidosis with either NOD1 or TLR4 ligand failed to induce MAPK phosphatase 1 (MKP-1). Adenovirus-mediated overexpression of MKP-1 attenuated p38 activation and decreased the production of IL12/IL23p40 and TNF-α in sarcoid BAL cells.Conclusions: Our results suggest that enhanced p38 signaling in response to microbial products is caused by abnormal regulation of MKP-1 and contributes to heightened inflammation in sarcoidosis.
Evidence for MPL W515L/K mutations in hematopoietic stem cells in primitive myelofibrosis
Authors: Ronan Chaligné, Chloé James, Carole Tonetti, Rodolphe Besancenot, Jean Pierre Le Couédic, Fanny Fava, Fréderic Mazurier, Isabelle Godin, Karim Maloum, Frédéric Larbret, Yann Lécluse, William Vainchenker, Stéphane Giraudier
Journal: Blood (2007)
1020. Noninvasive Optical Monitoring of Conditionally Replivative Adenovirus Replication
Authors: Julia Davydova, Hidetaka A. Ono, Long P. Le, Tatyana Gavrikova, Seiji Yamamoto, Amy R. Nelson, David T. Curiel, Masato Yamamoto
Journal: Molecular Therapy (2005)

The employment of conditionally replicative adenoviruses (CRAds) offers a promising alternative for cancer treatment. To maintain safety in clinical trials, a noninvasive detection system of viral replication is required. Our previous studies revealed the effective and transcriptionally-restricted cytocidal effect of infectivity-enhanced cyclooxygenase-2 (Cox-2) promoter-driven CRAds. However, there are no currently available methods to noninvasively monitor dynamic adenovirus replication, spreading ability, and extent of persistence in vivo. In this study, we have developed a system which allows monitoring of CRAds replication via the detection of fluorescence or luminescence reporters expressed from the E3 region. We deleted or mutated most E3 genes except adenovirus death protein (ADP), and incorporated the enhanced green fluorescent protein (EGFP) or the firefly luciferase (Luc) into the E3 region under the control of the adenovirus major late promoter (MLP). Since MLP turns on only when the virus is replicating, we hypothesized that the transgene expression would closely represent the viral replication in this configuration. Finally, we combined E1 shuttle vector with E1 expression cassette under control of Cox-2 promoter with E3ADPLuc cassette and generated imaging capable Cox-2 CRAds with different fiber modifications in order to overcome coxsackie-adenovirus receptor deficiency of cancer cells. In addition, we considered the structure of the E3 region with and without ADP since a strong cytocidal effect of ADP may not be optimal for imaging. To assess the replication dependent expression of the reporter gene from the E3 region, a replication permissive human lung adenocarcinoma A549 cells and mouse hepatoma BNL-1NG-A.2 cells, in which human adenoviruses do not productively replicate, were applied in our experiments. In vitro, all replication-competent reporter viruses showed transgene expression augmentation over time and in a dose-dependent manner during infection of A549 cells. The detected signal closely correlated with the viral DNA quantity resulting from viral replication. On the other hand, no EGFP/Luc expression was observed in BNL-1NG-A.2 cells, thus indicating the dependence of fluorescence/luminescent signal on productive replication. In vivo optical studies performed with a custom made in vivo imaging system revealed that after intratumoral administration of adenoviruses with the E3 imaging cassette the EGFP expression could be detected two days post-injection. Cox-2 CRAds with the luciferase expression showed the signal on day one and maintained it over four weeks. Importantly, in vivo reporter detection strongly correlated with the underlying level of replication. These data validate the applicability of our E3 reporter system for noninvasive in vivo monitoring of CRAd replication.
False-positive mediastinal lymph node cytology due to translesional endoscopic ultrasound-guided fine-needle aspiration in a patient with Barrett’s early cancer
Authors: L. Harbaum, N. Pomjanski, T. Hinterleitner, A. Böcking, C. Langner
Journal: Endoscopy (2009)

Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) is an established technique for diagnosis and staging of gastrointestinal malignancies. In a recent meta-analysis, the specificity and sensitivity of the procedure in assessing mediastinal lymph nodes have been calculated to be 96 % and 88 %, respectively [1].
TRANSCATHETER AORTIC VALVE IMPLANTATION IS NOT ASSOCIATED WITH A DETRIMENTAL EFFECT ON RIGHT VENTRICULAR FUNCTION AS OBSERVED AFTER SURGICAL AORTIC VALVE REPLACEMENT
Authors: Aleksander Kempny, Gerhard-Paul Diller, Stefan Orwat, Gerrit Kaleschke, Gregor Kerckhoff, Renate Schmidt, Julia Mascherbauer, Holger Reinecke, Helmut Baumgartner
Journal: Journal of the American College of Cardiology (2011)
Advances in Corneal Transplantation
Authors: Richard L. Lindstrom
Journal: New England Journal of Medicine (1986)

Disease of the cornea is the most common cause of blindness in the world.1 The cornea is the normally transparent anterior structure of the eye that functions similarly to the lens of a camera and has the appearance of a watch crystal. The normal cornea is a layered, avascular structure in which an outer epithelium and an inner endothelium surround the central stroma. The stroma imparts its optical properties to the cornea and is composed of a compact geometric arrangement of collagen fibers. Several million visually handicapped people worldwide might be expected to benefit from surgical replacement of their diseased . . .
Rheumatoid arthritis in a tribal Xhosa population in the Transkei, Southern Africa.
Authors: O L Meyers, G Daynes, P Beighton
Journal: Annals of the Rheumatic Diseases (1977)

An epidemiological survey of rheumatoid arthritis (RA) was undertaken in a tribal Xhosa community in the Transkei of Southern Africa. 577 respondents aged 18 and over were examined clinically and of these, 549 were investigated radiologically and 482 serologically. The presence of RA was then assessed by means of a modification of the Rome criteria, as used in previous comparable surveys. The prevalence of 9definite9 RA in the adults aged 18 and over in this population was 0-68% and of 9probable9 RA, 1-6%. The combined 9definite9 and 9probable9 prevalence was 2-2%. The relatively low prevalence of RA in this population is consistent with the results of other surveys in unsophisticated African Negro populations in West Africa and South Africa, and contrasts with the higher prevalence encountered in an urbanized South African Negro community and in populations in Europe and the USA.
The First Placebo-Controlled Trial in Cryopyrin-Associated Periodic Syndromes (CAPS): IL-1 Trap (rilonacept) Markedly Reduces Clinical and Laboratory Abnormalities in Patients with Familial Cold Autoinflammatory Syndrome (FCAS) and Muckle-Wells Syndrome (MWS)
Authors: H.M. Hoffman, S.P. Weinstein, N.J. Amar, M.L. Throne, E.P. Boling, I.M. Grimes, P. Belomestnov, D.R. Stein, C. Vicary, S.J. Mellis
Journal: Journal of Allergy and Clinical Immunology (2007)
Vagal afferent pathway mediates physiological action of cholecystokinin on pancreatic enzyme secretion.
Authors: Y Li, C Owyang
Journal: Journal of Clinical Investigation (1993)

To establish the mechanism(s) and site(s) of action of cholecystokinin (CCK) on pancreatic secretion under physiological conditions, we used an in vivo model using anesthetized rats with pancreaticobiliary cannulas. Infusion of CCK-8 (10-160 pmol/kg per h) produced a dose-dependent increase in plasma CCK levels. CCK-8 infusion at 40 pmol/kg per h produced a plasma CCK level of 7.9 +/- 1.5 pM and an 80% increase in pancreatic protein output over basal. This level was closely approximated by a postprandial peak plasma CCK level by 6.2 +/- 1.1 pM. Pretreatment with atropine or hexamethonium completely abolished pancreatic protein response to low doses of CCK-8 (10-40 pmol/kg per h) but had only partial effect on doses > 40 pmol/kg per h. Bilateral vagotomy also abolished the pancreatic responses to low doses of CCK-8. Similarly perivagal treatment with a sensory neurotoxin, capsaicin, caused a complete inhibition of pancreatic protein secretion in response to CCK-8 infusion. In contrast, pancreatic protein responses to bethanechol were similar in control and capsaicin-treated rats. In separate studies we demonstrated that gastroduodenal but not jejunal application of capsaicin for 30 min abolished pancreatic protein secretion in response to physiological doses of CCK-8. In conclusion, CCK at physiological levels stimulates pancreatic enzyme secretion via a capsaicin-sensitive afferent vagal pathway originating from the gastroduodenal mucosa.