tbuckley/cabot-search huggingface dataset:
Tone-dependent coronary arterial-venous pressure differences at the cessation of venous outflow during long diastoles.
Authors: S Satoh, F J Klocke, J M Canty
Journal: Circulation (1993)

BACKGROUND The origin and magnitude of the back pressure opposing diastolic coronary inflow remain controversial. The arterial pressure at which coronary inflow stops during a prolonged diastole, ie, "zero-flow pressure," is higher than coronary venous pressure. However, because of capacitive discharge as distending pressure falls, flow at the microcirculatory level exceeds inflow, and coronary outflow ceases later than inflow. If coronary arterial pressure continues to exceed venous pressure at the point of venous flow cessation, zero-flow pressure cannot be an artifact of capacitive discharge. METHODS AND RESULTS Coronary inflow and outflow, arterial pressure, and right atrial pressure have been measured during long diastoles in closed-chest dogs chronically instrumented with volumetric flow probes on the great cardiac vein or coronary sinus as well as the circumflex artery. Although venous outflow continued for 1 to 4 seconds after arterial inflow ceased, coronary artery pressure at the point of venous flow cessation (Pfv = 0) always exceeded right atrial pressure (13 +/- 1.3 mm Hg [SEM] vs 6 +/- 0.7 mm Hg, P &lt; .001). When vasomotor tone was augmented using vasopressin, the diastolic pressure-flow relation shifted to the right, with Pfv = 0 increasing to 21 +/- 2.4 mm Hg despite an unchanged right atrial pressure (6 +/- 0.5 mm Hg). CONCLUSIONS Transcoronary pressure differences persist when venous outflow stops and are larger when vasomotor tone is augmented. Measurements of zero-flow pressure that exceed venous pressure cannot be considered an artifact of continuing capacitive discharge after the cessation of arterial inflow. Diastolic coronary back pressure exceeds right atrial pressure and is tone dependent.
THE EVOLUTION OF THE IMMUNE RESPONSE
Authors: Joanne Finstad, Robert A. Good
Journal: The Journal of Experimental Medicine (1964)

1. Studies of the immune response have been carried out in more than 1700 lampreys representing three stages in the life cycle of these animals. 2. Lampreys used in this study were unable to clear certain soluble protein antigens and bacteriophage and were unable to make antibodies to these antigens. Hemocyanin was cleared from the circulation. 3. The immune responses demonstrated in lampreys include the production of specific antibody to killed Brucella cells, the rejection of skin homografts, and the development of a delayed allergic response to old tuberculin. 4. A responsive proliferation of lymphoid cells occurred in the protovertebral arch following antigen-adjuvant stimulation. 5. Electrophoretic and immunoelectrophoretic analysis of lamprey serum revealed gamma globulin. Ultracentrifugal analysis of serum revealed proteins with sedimentation coefficients of 17S, 8S, 7S, and 3S. 6. The antibodies thus far observed in the lamprey are of relatively high molecular weight and destroyed by 2-mercaptoethanol. 7. In the lamprey it would appear that there is reflected the coordinate evolution of a primitive thymus, primitive spleen containing lymphoid foci, a family of lymphocytes in the peripheral blood and capacity for gamma globulin synthesis and expression of adaptive immunity.
Utilization and Outcomes of Minimally Invasive Radical Prostatectomy
Authors: Jim C. Hu, Qin Wang, Chris L. Pashos, Stuart R. Lipsitz, Nancy L. Keating
Journal: Journal of Clinical Oncology (2008)

Demand for minimally invasive radical prostatectomy (MIRP) to treat prostate cancer is increasing; however, outcomes remain unclear. We assessed utilization, complications, lengths of stay, and salvage therapy rates for MIRP versus open radical prostatectomy assessed whether MIRP surgeon volume is associated with better outcomes.We identified 2,702 men undergoing MIRP and open radical prostatectomy during 2003 to 2005 from a national 5% sample of Medicare beneficiaries. We assessed the association between surgical approach and outcomes, adjusting for surgeon volume, age, race, comorbidity, and geographic region.MIRP utilization increased from 12.2% in 2003 to 31.4% in 2005. Men undergoing MIRP versus open radical prostatectomy had fewer perioperative complications (29.8% v 36.4%; P = .002) and shorter lengths of stay (1.4 v 4.4 days; P < .001); however, they were more likely to receive salvage therapy (27.8% v 9.1%, P < .001). In adjusted analyses, MIRP versus open radical prostatectomy was associated with fewer perioperative complications (odds ratio [OR], 0.73; 95% CI, 0.60 to 0.90), shorter lengths of stay (parameter estimate, -2.99; 95% CI, -3.45 to -2.53) but more anastomotic strictures (OR, 1.40; 95% CI, 1.04 to 1.87) and higher rates of salvage therapy (OR, 3.67; 95% CI, 2.81 to 4.81). Patients of high-volume MIRP experienced fewer anastomotic strictures (OR, 0.93; 95% CI, 0.87 to 0.99) and less salvage therapy (OR, 0.92; 95% CI, 0.88 to 0.98).Men undergoing MIRP versus open radical prostatectomy have lower risk for perioperative complications and shorter lengths of stay, but are at higher risk for salvage therapy and anastomotic strictures. However, risk for these unfavorable outcomes decreases with increasing MIRP surgical volume.
Effect on birth outcomes of a formalised approach to care in hospital labour assessment units: international, randomised controlled trial
Authors: E. D Hodnett, R. Stremler, A. R Willan, J. A Weston, N. K Lowe, K. R Simpson, W. D Fraser, A. Gafni
Journal: BMJ (2008)

To determine if a complex nursing and midwifery intervention in hospital labour assessment units would increase the likelihood of spontaneous vaginal birth and improve other maternal and neonatal outcomes.Multicentre, randomised controlled trial with prognostic stratification by hospital.20 North American and UK hospitals.5002 nulliparous women experiencing contractions but not in active labour; 2501 were allocated to structured care and 2501 to usual care.Usual nursing or midwifery care or a minimum of one hour of care by a nurse or midwife trained in structured care, consisting of a formalised approach to assessment of and interventions for maternal emotional state, pain, and fetal position.Primary outcome was spontaneous vaginal birth. Other outcomes included intrapartum interventions, women's views of their care, and indicators of maternal and fetal health during hospital stay and 6-8 weeks after discharge.Outcome data were obtained for 4996 women. The rate of spontaneous vaginal birth was 64.0% (n=1597) in the structured care group and 61.3% (n=1533) in the usual care group (odds ratio 1.12, 95% confidence interval 0.96 to 1.27). Fewer women allocated to structured care (n=403, 19.5%) rated staff helpfulness as less than very helpful than those allocated to usual care (n=544, 26.4%); odds ratio 0.67, 98.75% confidence interval 0.50 to 0.85. Fewer women allocated to structured care (n=233, 11.3%) were disappointed with the amount of attention received from staff than those allocated to usual care (n=407, 19.7%); odds ratio 0.51, 98.75% confidence interval 0.32 to 0.70. None of the other results met prespecified levels of statistical significance.A structured approach to care in hospital labour assessment units increased satisfaction with care and was suggestive of a modest increase in the likelihood of spontaneous vaginal birth. Further study to strengthen the intervention is warranted.Current Controlled Trials ISRCTN16315180.
Telomerase-selective virotherapy with fluorescently labelled adenovirus for cervical cancer treatment
Authors: Yosuke Kawakami, Angel A. Rivera, Long P. Le, Minghui Wang, Mariam A. Stoff-Khalili, Dirk M. Nettelbeck, Gene P. Siegal, Ronald D. Alvarez, Takashi Matsumoto, J. Michael Mathis, David T. Curiel
Journal: Cancer Research (2006)

2991   Conditionally replicative adenovirus (CRAd) is useful as a cervical cancer gene therapy strategy which seeks to achieve selective viral replication in tumor cells. Oncolysis of infected cells creates a “bystander effect”, leading to infection of neighboring cancer cells with progeny virus. However, one of the obstacles in CRAd clinical trials is the lack of a non-invasive monitoring procedure of CRAd replication and/or spread, thus hampering the understanding of CRAd biology in both an  in vitro  and  in vivo  setting. Current detection strategies, including reporter gene expression and viral component detection have been applied to analyze adenoviral vectors; however, these methods are inadequate for assessing transductional targeting. The objective of this proposal was to establish an efficient method for monitoring CRAd replication/spread while retaining CRAd-based therapeutic efficacy for cervical cancer. We have developed a specific genetic labeling system whereby an adenoviral vector incorporates a fusion between capsid protein IX and enhanced red fluorescence protein (RFP). The human telomerase reverse transcriptase (hTERT) promoter, which is active in many cancers but mostly inactive in normal organs including the liver, maintains this useful profile in our CRAd construct for cervical cancer. We employed an hTERT promoter-based CRAd with a pIX-RFP mutation (AdhTERT E1-IX-RFP) to evaluate the hTERT-selective oncolysis in  in vitro , which conventional hTERT-CRAd with wild type pIX can demonstrate. Then, we examined the correlation between red fluorescence and DNA replication and oncolysis, which are determined by viral E4 DNA copy number and MTS assay, respectively, in both hTERT-negative fibroblasts and WI-38 cells and hTERT-positive cervical cancer cell lines. RFP-labeled hTERT-CRAd showed effective oncolysis in cervical cancer cell lines but not in WI-38. Red fluorescence imaging paralleled both DNA replication and oncolysis in cervical cancer cells, whereas no fluorescence, DNA replication nor oncolysis was detected in WI-38 cells. Moreover, oncolysis and red fluorescence signal were observed in cervical cancer xenograft models. These results suggest that RFP-labeled hTERT-CRAd demonstrated selective and effective oncolysis, which can be monitored fluorescently. This fluorescently labeled hTERT-CRAd may thus contribute to the gene therapy of cervical cancer.
Prognosis of hepatocellular carcinoma: Assessment of eleven staging systems
Authors: Po-Hong Liu, Chia-Yang Hsu, Cheng-Yuan Hsia, Yun-Hsuan Lee, Chien-Wei Su, Yi-Hsiang Huang, Fa-Yauh Lee, Han-Chieh Lin, Teh-Ia Huo
Journal: Journal of Hepatology (2015)
The biology of vascular endothelial growth factors
Authors: T TAMMELA, B ENHOLM, K ALITALO, K PAAVONEN
Journal: Cardiovascular Research (2005)

The discovery of the vascular endothelial growth factor (VEGF) family members VEGF, VEGF-B, placental growth factor (PlGF), VEGF-C and VEGF-D and their receptors VEGFR-1, -2 and -3 has provided tools for studying the vascular system in development as well as in diseases ranging from ischemic heart disease to cancer. VEGF has been established as the prime angiogenic molecule during development, adult physiology and pathology. PlGF may primarily mediate arteriogenesis, the formation of collateral arteries from preexisting arterioles, with potential future therapeutic use in for example occlusive atherosclerotic disease. VEGF-C and VEGF-D are primarily lymphangiogenic factors, but they can also induce angiogenesis in some conditions. While many studies have addressed the role of angiogenesis and the blood vasculature in human physiology, the lymphatic vascular system has until recently attracted very little attention. In this review, we will discuss recent advances in angiogenesis research and provide an overview of the molecular players involved in lymphangiogenesis.
A Pharmacodynamic/Pharmacokinetic Study of Ficlatuzumab in Patients with Advanced Solid Tumors and Liver Metastases
Authors: Josep Tabernero, Maria Elena Elez, Maria Herranz, Isabel Rico, Ludmila Prudkin, Jordi Andreu, Jose Mateos, Maria Josep Carreras, May Han, James Gifford, Marc Credi, Wei Yin, Shefali Agarwal, Philip Komarnitsky, Jose Baselga
Journal: Clinical Cancer Research (2014)

This study evaluated the safety, tolerability, pharmacodynamics, pharmacokinetics, and antitumor activity of ficlatuzumab, a humanized hepatocyte growth factor (HGF) inhibitory monoclonal antibody, as monotherapy in patients with advanced solid tumors and liver metastases.Patients with p-Met (phosphorylated c-Met)-positive tumors enrolled in three dose-escalation cohorts, receiving ficlatuzumab 2, 10, or 20 mg/kg once per 14-day cycle. Pharmacodynamic changes in liver tumor biopsies and serum, pharmacokinetics, safety, and clinical activity were assessed.No dose-limiting toxicities occurred in the 19 patients enrolled (n = 6, 2 mg/kg; n = 7, 10 mg/kg; n = 6, 20 mg/kg). The most frequent diagnosis was colorectal cancer (n = 15; 79%). The most common treatment-emergent adverse events were asthenia, peripheral edema, hepatic pain (32% each), and cough (26%). Laboratory abnormalities of decreased serum albumin were present in all patients. Ficlatuzumab at 20 mg/kg lowered median levels of tumor p-Met (-53%), p-ERK (-43%), p-Akt (-2%), and increased median HGF levels (+33%), at the last on-study time point relative to baseline. Mean serum HGF levels increased with ficlatuzumab dose and number of treatment cycles. Ficlatuzumab exhibited linear pharmacokinetics and long terminal half-life (7.4-10 days). Best overall response was stable disease in 28% of patients, including 1 patient with pancreatic cancer with stable disease >1 year.Ficlatuzumab exhibited good safety/tolerability and demonstrated ability to modulate the HGF/c-Met pathway and downstream signaling in the tumor in patients with advanced solid tumors. Safety, pharmacodynamic, and pharmacokinetic data for ficlatuzumab confirmed the recommended phase II dose of 20 mg/kg once per 14-day cycle.
Retinal toxicity in long term hydroxychloroquine treatment.
Authors: M Mavrikakis, S Papazoglou, P P Sfikakis, G Vaiopoulos, K Rougas
Journal: Annals of the Rheumatic Diseases (1996)

To report clinical experience from patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) who were receiving recommended doses of hydroxychloroquine for more than six years, and were monitored for evidence of hydroxychloroquine related retinopathy every six months.A prospective (and continuing) evaluation was made of the potential retinal toxicity of hydroxychloroquine in a cohort of 360 Greek patients followed for RA and SLE, 58 of whom have received long term treatment ( > six years). Fundoscopy, colour vision tests, dark adaptation tests, visual field testing, automated perimetry, and electroretinogram were performed every six months.Among 58 patients receiving hydroxychloroquine for more than six years, two relatively young women (3.5%), one treated for RA and the other treated for SLE, developed characteristic hydroxychloroquine related toxic retinal lesions after cumulative doses of 700 g (6.5 years) and 730 g (8 years) of hydroxychloroquine, respectively. Bilateral visual acuity was 6/6 and 6/7.5, respectively; both patients had normal colour perception. Despite an early diagnosis and cessation of treatment, permanent visual field paracentral scotomata in both patients, and persisting lesions in fluorescein angiography in the patient with SLE, were observed at 4.5 and 3 years of follow up, respectively. No other specific cases of hydroxychloroquine related retinopathy have to date been identified in the remaining 302 patients.Cases of irreversible, hydroxychloroquine related retinopathy in patients who did not receive overdoses have not been reported previously. The present observations in two relatively young patients should raise our concern regarding the long term usage of an increasingly popular medication in rheumatology practice.
Building on the GMC's achievements
Authors: Graeme Catto
Journal: BMJ (2005)

Revalidation is under scrutiny. The GMC plans to play an important part in developing an effective system 

The fifth report of the Shipman inquiry provided a thorough and considered analysis of the issues surrounding fitness to practise.1 We must all approach the report in the spirit of learning from the past and as a source of ideas for improving the protection of patients in the future. The government's proposals to improve death certification and for tighter regulation of controlled drugs2 will, alongside clinical governance, help stop another Harold Shipman. Nevertheless, the General Medical Council recognises that further changes are required to our processes.

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How can we ensure new doctors remain fit to practise?

Credit: www.topfoto.co.uk

Some have argued that no general lessons can be drawn from the Shipman case. I believe that view is mistaken. Of course many of the circumstances were specific, but much broader, historical issues were raised. These include:

Dame Janet Smith, the chairman of the inquiry, acknowledged that much has changed for the better, but we all have more to do, whether within our regulatory bodies, healthcare organisations, or clinical teams or as individual healthcare professionals. We need to ensure that further …

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Interaction between Arsenic Exposure from Drinking Water and Genetic Polymorphisms on Cardiovascular Disease in Bangladesh: A Prospective Case-Cohort Study
Authors: Fen Wu, Farzana Jasmine, Muhammad G. Kibriya, Mengling Liu, Xin Cheng, Faruque Parvez, Tariqul Islam, Alauddin Ahmed, Muhammad Rakibuz-Zaman, Jieying Jiang, Shantanu Roy, Rachelle Paul-Brutus, Vesna Slavkovich, Tariqul Islam, Diane Levy, Tyler J. VanderWeele, Brandon L. Pierce, Joseph H. Graziano, Habibul Ahsan, Yu Chen
Journal: Environmental Health Perspectives (2015)

Background: Epidemiologic data on genetic susceptibility to cardiovascular effects of arsenic exposure from drinking water are limited.Objective: We investigated whether the association between well-water arsenic and cardiovascular disease (CVD) differed by 170 single nucleotide polymorphisms (SNPs) in 17 genes related to arsenic metabolism, oxidative stress, inflammation, and endothelial dysfunction.Method: We conducted a prospective case-cohort study nested in the Health Effects of Arsenic Longitudinal Study, with a random subcohort of 1,375 subjects and 447 incident fatal and nonfatal cases of CVD. Well-water arsenic was measured in 2000 at baseline. The CVD cases, 56 of which occurred in the subcohort, included 238 coronary heart disease cases, 165 stroke cases, and 44 deaths due to other CVD identified during follow-up from 2000 to 2012.Results: Of the 170 SNPs tested, multiplicative interactions between well-water arsenic and two SNPs, rs281432 in ICAM1 (padj = 0.0002) and rs3176867 in VCAM1 (padj = 0.035), were significant for CVD after adjustment for multiple testing. Compared with those with GC or CC genotype in rs281432 and lower well-water arsenic, the adjusted hazard ratio (aHR) for CVD was 1.82 (95% CI: 1.31, 2.54) for a 1-SD increase in well-water arsenic combined with the GG genotype, which was greater than expected given aHRs of 1.08 and 0.96 for separate effects of arsenic and the genotype alone, respectively. Similarly, the joint aHR for arsenic and the rs3176867 CC genotype was 1.34 (95% CI: 0.95, 1.87), greater than expected given aHRs for their separate effects of 1.02 and 0.84, respectively.Conclusions: Associations between CVD and arsenic exposure may be modified by genetic variants related to endothelial dysfunction.Citation: Wu F, Jasmine F, Kibriya MG, Liu M, Cheng X, Parvez F, Islam T, Ahmed A, Rakibuz-Zaman M, Jiang J, Roy S, Paul-Brutus R, Slavkovich V, Islam T, Levy D, VanderWeele TJ, Pierce BL, Graziano JH, Ahsan H, Chen Y. 2015. Interaction between arsenic exposure from drinking water and genetic polymorphisms on cardiovascular disease in Bangladesh: a prospective case-cohort study. Environ Health Perspect 123:451–457; http://dx.doi.org/10.1289/ehp.1307883
Preclinical characterization of CPL-302-201, a novel, highly potent and selective PI3Kδ inhibitor for the treatment of inflammatory disorders
Authors: Pawel Gunerka, Barbara Dymek, Daria Zdzalik, Marcin Zagozda, Maciej Dziachan, Maciej Malczyk, Anna Bujak, Paulina Grygielewicz, Olga Musielak, Monika Skupinska, Joanna Hucz-Kalitowska, Krzysztof Dubiel, Monika Lamparska-Przybysz, Maciej Wierczorek, Aleksandra Stanczak
Journal: European Respiratory Journal (2014)

Background:  PI3Kδ is predominantly expressed in hematopoietic cells where it is the key enzyme involved in BCR, TCR and FceR signaling essential for immune response. Inhibition of PI3Kδ has been proposed as a new anti-inflammatory therapeutic approach in pulmonary or autoimmune disorders and there is an intense effort to develop selective PI3Kδ inhibitors.  Materials and methods:  Using the knowledge-based drug design we developed a novel PI3Kδ inhibitor - CPL-302-201. Its activity among the class I of PI3K lipid kinases and selected protein kinases was assessed by ATP-based enzymatic assay. Additionally, its biological potency and selectivity was evaluated in a number of cell-based models by Western blot.  Results:  CPL-302-201 inhibits PI3Kδ kinase activity at low nanomolar concentrations (IC 50  = 6,6 nM) and exhibits outstanding selectivity over α, β and γ isoforms of PI3K (1890, 830 and 9000-fold, respectively) and among panel of diverse protein kinases. Western blot has revealed that CPL-302-201 significantly inhibits phosphorylation of Akt in Raji cell line after anti-IgM stimulation (IC 50   Conclusions:  We have designed CPL-302-201 - a novel PI3Kδ inhibitor with high potency and outstanding selectivity and preclinical data indicate its therapeutic potential in inflammatory diseases including asthma.
Mechanical Pre-Conditioning With Acute Circulatory Support Before Reperfusion Limits Infarct Size in Acute Myocardial Infarction
Authors: Navin K. Kapur, Xiaoying Qiao, Vikram Paruchuri, Kevin J. Morine, Wajih Syed, Sam Dow, Nimish Shah, Natesa Pandian, Richard H. Karas
Journal: JACC Heart Failure (2015)
Studies of the macrophage complement receptor. Alteration of receptor function upon macrophage activation.
Authors: C Bianco, F M Griffin, S C Silverstein
Journal: The Journal of Experimental Medicine (1975)

We have examined the roles of Fc receptors and complement receptors in mediating the interaction of sensitized sheep erythrocytes (E) with activated and with nonactivated mouse peritoneal macrophages. Both activated and nonactivated macrophages ingest IgG-coated erythrocytes [E(IgG)]; activated cells intest 1.5-2 times as man E(IgG) as do nonactivated macrophages. Thus, there is a quantitative difference in Fc receptor-mediated ingestion between activated and nonactivated macrophages. There is, however, a qualitative difference in function of complement receptors of activated and nonactivated macrophages. Nonactivated macrophages avidly bind complement-coated E [E(IgM)Ia1, but do not ingest them to a significant degree. Activated macrophages, on the other hand, bind and ingest E(IgM)C. The possibility of Fc receptor participation in mediating ingestion of E(IgM)C by activated macrophages was eliminated by blocking Fc receptors with an antimacrophage IgG fraction. Activated macrophages treated with antimacrophage IgG did not ingest E(igG) but did ingest both E(IgM)C AND E(IgM)C. Nonactivated macrophages treated with antimacrophage IgG did not interact at all with E(IgG). These cells bound, but did not ingest, E(IgM)C and E(IgM)C. Complement receptor-mediated ingestion is a marker for macrophage activation and may be physiologically important in the elimination of complement-coated particles.