tbuckley/cabot-search huggingface dataset:
The influence of human immunodeficiency virus coinfection on chronic hepatitis C in injection drug users: A long-term retrospective cohort study
Authors: Vincent Di Martino, Pierre Rufat, Nathalie Boyer, Philippe Renard, Françoise Degos, Michèle Martinot-Peignoux, Sophie Matheron, Vincent Le Moing, François Vachon, Claude Degott, Dominique Valla, Patrick Marcellin
Journal: Hepatology (2001)

In this study we analyzed the influence of human immunodeficiency virus (HIV) infection on the course of chronic hepatitis C through multivariate analysis including age, alcohol consumption, immune status, and hepatitis C virus (HCV)-related virologic factors. Eighty HIV-positive and 80 HIV-negative injection drug users included between 1980 and 1995 were matched according to age, gender, and duration of HCV infection and followed-up during 52 months. The progression to cirrhosis was the primary outcome measure. The impact of HIV on HCV-RNA load, histologic activity index, response to interferon therapy, and liver-related death was also considered. In HIV-positive patients, chronic hepatitis C was characterized by higher serum HCV-RNA levels (P =.012), higher total Knodell score (P =.011), and poorer sustained response to interferon therapy (P =.009). High serum HCV-RNA level was associated with low CD4-lymphocyte count (P =.001). Necroinflamatory score was higher in HIV-positive patients (P =.023) independently of the CD4-lymphocyte count, whereas increased fibrosis was related to decreased CD4-lymphocyte count (P =.011). The progression to cirrhosis was accelerated in HIV-positive patients with low CD4 cell count (RR = 4.06, P =.024) and in interferon-untreated patients (RR = 4.76, P =.001), independently of age at HCV infection (P =.001). Cirrhosis caused death in 5 HIV-positive patients. The risk of death related to cirrhosis was increased in heavy drinkers (RR = 10.8, P =.001) and in HIV-positive patients with CD4 cell count less than 200/mm(3) (RR = 11.9, P =.007). In this retrospective cohort study, HIV coinfection worsened the outcome of chronic hepatitis C, increasing both serum HCV-RNA level and liver damage and decreasing sustained response to interferon therapy. Age and alcohol were cofactors associated with cirrhosis and mortality. Interferon therapy had a protective effect against HCV-related cirrhosis no matter what the patient's HIV status was.
Clinical Use of Inotropic Therapy for Heart Failure: Looking Backward or Forward?
Authors: Lynne Warner Stevenson
Journal: Circulation (2003)

T herapy with intravenous inotropic agents is most often initiated as short-term therapy during hospitalization to achieve one of several goals for acute management of decompensation, as described in part I of this report (Table ). 1 However, it may become difficult to wean these infusions in some patients as a heart failure progresses to late stages.
Molecular, Pathologic, and Clinical Features of Early-Onset Endometrial Cancer: Identifying Presumptive Lynch Syndrome Patients
Authors: Michael D. Walsh, Margaret C. Cummings, Daniel D. Buchanan, Wendy M. Dambacher, Sven Arnold, Diane McKeone, Rebecca Byrnes, Melissa A. Barker, Barbara A. Leggett, Michael Gattas, Jeremy R. Jass, Amanda B. Spurdle, Joanne Young, Andreas Obermair
Journal: Clinical Cancer Research (2008)

A woman with early-onset endometrial cancer (EC) may represent the "sentinel" cancer event in a Lynch syndrome kindred. The aim of this study was to determine the incidence of Lynch syndrome in a series of young-onset EC, and to identify molecular, clinical, and pathologic features that may alert clinicians to the presence of this disorder.Patients with EC, ages < or =50 years, were identified from the Queensland Centre for Gynaecological Cancer. Tumor sections underwent histopathology review and were immunostained for mismatch repair proteins. Tumor DNA was tested for microsatellite instability and methylation of MLH1. Patients were conservatively classified as presumptive Lynch syndrome if their tumors showed loss of at least one mismatch repair protein and were negative for methylation of MLH1. Personal and family history of cancer was reviewed where available.Presumptive Lynch syndrome was seen in 26 of 146 (18%) tumors. These tumors were more likely to be poorly differentiated, International Federation of Gynecology and Obstetrics stage II and above, have tumor-infiltrating lymphocytes, have higher mitotic rate, and have deeper myometrial invasion (P < 0.05). Lynch syndrome cases were more likely to be associated with a positive family history when analyzed for Amsterdam criteria II, diagnosis of a Lynch syndrome spectrum cancer in at least one first-degree relative, and family history of any cancer (P < 0.05).Presumptive Lynch syndrome was identified in 18% of early-onset EC. A risk of this magnitude would argue for routine immunohistochemical testing of tumors in patients diagnosed with EC at or before the age of 50 years.
Genetically designing a more potent antipancreatic cancer agent by simultaneously co-targeting human IL13 and EGF receptors in a mouse xenograft model
Authors: D. A. Vallera, B. J. Stish, Y. Shu, H. Chen, A. Saluja, D. J. Buchsbaum, S. M. Vickers
Journal: Gut (2008)

<h3>Objective:</h3> Investigators are currently interested in the epidermal growth factor receptor (EGFR) and interleukin 13 receptor (IL13R) as potential targets in the development of new biologicals for pancreatic cancer. Attempts to develop successful agents have met with difficulty. The novel approach used here was to target these receptors simultaneously with EGF and IL13 cloned on the same bispecific single-chain molecule with truncated diphtheria toxin (DT<sub>390</sub>) to determine if co-targeting with DTEGF13 had any advantages. <h3>Design:</h3> Proliferation experiments were performed to measure the potency and selectivity of bispecific DTEGF13 and its monospecific counterparts against pancreatic cancer cell lines PANC-1 and MiaPaCa-2 in vitro. DTEGF13 was then administered intratumourally to nude mice with MiaPaCa-2 flank tumours to measure efficacy and toxicity (weight loss). <h3>Results:</h3> In vitro, bispecific DTEGF13 was 2800-fold more toxic than monospecific DTEGF or DTIL13 against PANC-1. A similar enhancement was observed in vitro when MiaPaCa-2 pancreatic cancer cells or H2981-T3 lung adenocarcinoma cells were studied. DTEGF13 activity was blockable with recombinant EGF13. DTEGF13 was potent (IC<sub>50</sub> = 0.00017 nM) against MiaPaCa-2, receptor specific and significantly inhibited MiaPaCa-2 tumours in nude mice (p&lt;0.008). <h3>Conclusions:</h3> In vitro studies show that the presence of both ligands on the same bispecific molecule is responsible for the superior activity of DTEGF13. Intratumoural administration showed that DTEGF13 was highly effective in checking aggressive tumour progression in mice. Lack of weight loss in these mice indicated that the drug was tolerated and a therapeutic index exists in an "on target" model in which DTEGF13 is cross-reactive with native mouse receptors.
The PlA2 Polymorphism of the Platelet Glycoprotein IIIA Gene as a Risk Factor for Acute Renal Allograft Rejection
Authors: EDUARDO SALIDO, BASILIO MARTÍN, YSAMAR BARRIOS, JOSÉ D. LINARES, DOMINGO HERNÁNDEZ, MARIAN COBOS, MARÍA D. CHECA, LUIS HORTAL, ANA FERNÁNDEZ, JOSÉ J. GARCÍA, ARMANDO TORRES
Journal: Journal of the American Society of Nephrology (1999)

Glycoprotein IIIa/IIb is a membrane receptor for fibrinogen and von Willebrand factor that plays an important role in platelet aggregation. The beta integrin chain of this receptor, GPIIIa, is polymorphic, and the allele known as PlA2 has been associated with coronary thrombosis. The GPIIIa genotype of a cohort of 119 consecutive renal allograft recipients (46.3 +/- 13 yr; 85 M/34 F; 24.4% diabetic patients) was determined by PCR-restriction fragment length polymorphism, and those patients were followed for at least 12 mo. From 119 patients with at least 1 yr of follow-up, those who suffered an acute rejection (n = 52) showed a lower proportion of HLA-DR beta1 identity with the donor (7.7% versus 23.9%; P = 0.03), a higher proportion of cytomegalovirus-positive (CMV+) donors/CMV- recipients (21% versus 7.5%; P = 0.05), and the PlA2 allele was more frequent (48.1% versus 26.9%; P = 0.02) compared with patients free of acute rejection (n = 67). No other variable was associated with acute rejection in the univariate analysis. The impact of the three above-mentioned significant variables on acute rejection was analyzed by stepwise logistic regression. The presence of the PlA2 allele yielded an odds ratio of 2.75 (95% confidence interval, 1.01 to 7.93) and an HLA-DR beta1 identity of 0.2 (95% confidence interval, 0.06 to 0.99) for suffering an acute rejection episode. In addition, the serum creatinine at discharge was higher in PlA2-positive versus PlA2-negative patients (2.2 +/- 1.6 versus 1.5 +/- 0.6 mg/dl, respectively; P = 0.01), and the prevalence of proteinuria >1.5 g/d 1 yr after transplantation was significantly higher among patients showing the PlA2 allele (16% versus 3%; P = 0.02). Finally, in the entire cohort of patients, the 2-yr graft survival was significantly lower in PlA2-positive (n = 43) compared with PlA2-negative (n = 76) patients (85.7% versus 97.2%; P = 0.015). No differences were found in patient survival (95.2% versus 98.7%, respectively). Proportional hazards regression analysis (Cox regression model) confirmed that serum creatinine level at discharge is the best predictor of allograft survival, followed by CMV status, delayed graft function, and the glycoprotein IIIa/IIb genotype. The PlA2 polymorphism is an independent risk factor for acute renal graft rejection, affecting short-term graft survival. Future studies aimed at preventing the hemostatic imbalance favoring platelet aggregation associated with this polymorphism may be important in preventing acute rejection and its impact on chronic rejection.
CT in COPD: just a pretty picture or really worth a thousand words (or dollars)?
Authors: D. D. Sin, J. Leipsic, S. F. P. Man
Journal: Thorax (2011)

We like pretty pictures and, in pulmonary medicine, we use computed axial tomography (CT) to generate pretty pictures to help us diagnose and manage patients with respiratory complaints. In 2007 more than 10 million chest CT scans were performed across the USA, representing an astounding 11 000% increase in the CT rate since 1980.1 CT scans rely on ionising radiation to generate images, and recent estimates suggest that CT scans may be responsible for 24% of the total ‘background’ radiation to which the population is exposed in a given year.2 Thankfully, there are several large-scale efforts to reduce the radiation exposure related to CT scans and to mitigate the health risks imposed by ionising radiation.3 What is not being adequately addressed is the issue of economic costs (and benefits) of CT scans. CT scans are expensive for patients and to the healthcare system, with prices ranging from $500 to $1500 per scan.4 Recently, the cost-effectiveness ratio of lung cancer screening with CT scans was reported to be $2.3 million dollars per quality-adjusted life saved,5 providing us with a sobering reminder that these ‘pretty pictures’ are not without significant costs.

Chronic obstructive pulmonary disease (COPD) is a condition that lends itself to anatomical medical imaging. For practical reasons, COPD is largely defined based on spirometric criteria. However, there is general discontent with this approach because spirometric measurements are relatively insensitive and correlate only very loosely with histological abnormalities or with patient symptoms or …
Communicating the risk reduction achieved by cholesterol reducing drugs
Authors: J. A. Skolbekken
Journal: BMJ (1998)

“When the facts change, I change my mind. What do you do?” asked Professor Michael Oliver at a presentation held in Stockholm on 6 June 1996. This is what readers of the New England Journal of Medicine were told in an advertisement for the cholesterol lowering drug simvastatin during the winter of 1996-7. Oliver's statement is accompanied in the advertisement by the following facts: “In post MI and angina patients with cholesterol levels in the range of 5.5 to 8.0 mmol/l (212-309 mg/dl). Proven to reduce the risk of total mortality by 30% (P=0.0003),1 coronary mortality by 42% (P=0.00001).2 “These facts are followed by another statement from Oliver et al: “Lower patients' cholesterol now.”3 This second statement represents Oliver's change of mind since he, in 1992, stated his “Doubts about preventing coronary heart disease: multiple interventions in middle aged men may do more harm than good,”4 which contributed to the controversy over the importance of lowering serum cholesterol concentrations.5

In a similar advertisement, readers of the Lancet have been informed of the same facts, but unaccompanied by Professor Oliver's statements. Instead, these readers are provided with more facts: “Projected 6-year benefits in 1000 patients with coronary heart disease (CHD). 35 lives saved, 67 MIs prevented, 59 procedures avoided.”

At first sight, a negative response to Oliver's rhetorical question may seem perverse or prejudiced. On second thoughts, given its rhetorical nature and considering that it is being used in a commercial presentation, you might suspect that there is something more to it. Indeed there is, and the aim of this article is to shed some light on the presentation of facts from clinical trials like the Scandinavian simvastatin survival study (4S) and the West of Scotland coronary prevention study (WOSCOPS).6

Facts from WOSCOPS were presented …
Evaluation of Trends in the Cost of Initial Cancer Treatment
Authors: J. L. Warren, K. R. Yabroff, A. Meekins, M. Topor, E. B. Lamont, M. L. Brown
Journal: JNCI Journal of the National Cancer Institute (2008)

BackgroundDespite reports of increases in the cost of cancer treatment, little is known about how costs of cancer treatment have changed over time and what services have contributed to the increases.
Actual 10-Year Survival After Resection of Colorectal Liver Metastases Defines Cure
Authors: James S. Tomlinson, William R. Jarnagin, Ronald P. DeMatteo, Yuman Fong, Peter Kornprat, Mithat Gonen, Nancy Kemeny, Murray F. Brennan, Leslie H. Blumgart, Michael D'Angelica
Journal: Journal of Clinical Oncology (2007)

Resection of colorectal liver metastases (CLM) in selected patients has evolved as the standard of care during the last 20 years. In the absence of prospective randomized clinical trials, a survival benefit has been deduced relative to historical controls based on actuarial data. There is now sufficient follow-up on a significant number of patients to address the curative intent of resecting CLM.Retrospective review of a prospectively maintained database was performed on patients who underwent resection of CLM from 1985 to 1994. Postoperative deaths were excluded. Disease-specific survival (DSS) was calculated from the time of hepatectomy using the Kaplan-Meier method.There were 612 consecutive patients identified with 10-year follow-up. Median DSS was 44 months. There were 102 actual 10-year survivors. Ninety-nine (97%) of the 102 were disease free at last follow-up. Only one patient experienced a disease-specific death after 10 years of survival. In contrast, 34% of the 5-year survivors suffered a cancer-related death. Previously identified poor prognostic factors found among the 102 actual 10-year survivors included 7% synchronous disease, 36% disease-free interval less than 12 months, 25% bilobar metastases, 50% node-positive primary, 39% more than one metastasis, and 35% tumor size more than 5 cm.Patients who survive 10 years appear to be cured of their disease, whereas approximately one third of actual 5-year survivors succumb to a cancer-related death. In well-selected patients, there is at least a one in six chance of cure after hepatectomy for CLM. The presence of poor prognostic factors does not preclude the possibility of long-term survival and cure.
Pharmacokinetics of antibiotics in the lungs
Authors: Y Valcke, R Pauwels, M Van der Straeten
Journal: European Respiratory Journal (1990)

This paper reviews current knowledge on the relationship between local penetration or antibiotics and therapeutic efficacy in pulmonary and bronchial infections. The antimicrobial drug concentration at the site of infection is supposedly determinative for the efficacy of the antibiotic treatment but the number of studies in respiratory infections supporting this hypothesis is limited. The mechanisms responsible for the pulmonary deposition or orally or systemically administered antibiotics include passive diffusion, active transport, bulk flow and permeation. The penetration of antimicrobial drugs into the respiratory tract is influenced by both host-related factors, such as inflammation or mechanical injury, and drug-related factors, such as molecular weight. In addition, local bio-inactivation can occur. The final bioactive antibiotic concentration at the site of the respiratory infection is, therefore, the result or a very complex dynamic process. Different sampling and measuring methods have been used for the assessment of antibiotic concentrations at the site of respiratory infections. Concentrations in sputum, bronchial secretions and biopsy specimens have been correlated with serum concentrations and clinical outcome. Bronchoalveolar lavage could be a promising technique for evaluating antibiotic drug concentrations in alveolar lining fluid. For many antibiotics, data concerning penetration and pharmacokinetic behaviour in the respiratory tract are lacking.
Reduction in cholesterol and low density lipoprotein synthesis after portacaval shunt surgery in a patient with homozygous familial hypercholesterolemia.
Authors: D W Bilheimer, J L Goldstein, S M Grundy, M S Brown
Journal: Journal of Clinical Investigation (1975)

The turnover of 125I-labeled low density lipoprotein (LDL) and the total body balance of cholestrol were studied in a 6-yr-old girl with the homozygous form of familial hypercholesterolemia (FH) before and after the surgical creation of an end-to-side portacaval shunt. The results were compared with those of similar studies simultaneously performed in untreated patients with the heterozygous form of FH and with the results of earlier studies performed on normolipidemic subjects. Before shunt surgery, the rate of synthesis of LDL in the FH homozygote (mg/kg per day) was fourfold higher than in normolipidemic subjects and twofold higher than in her heterozygous mother. The fractional catabolic rate for LDL in the homozygote was decreased to 33% of normal control values. The rate of cholesterol synthesis, estimated by chemical sterol balance, was higher in the FH homozygote than in two FH heterozygotes of similar age studied simultaneously. When considered in relation to the markedly elevated level of plasma cholesterol, the observed rate of cholesterol synthesis in the FH homozygote was inappropriately elevated. Bile acid production was normal in all three children. 5 mo after shunt surgery, the rate of LDL synthesis in the homozygote had declined by 48% as compared with the preoperative value, and this caused a 39% drop in the plasma LDL cholesterol level despite a 17% reduction in the fractional catabolic rate of the lipoprotein. The rate of cholesterol synthesis fell by 62% as compared with the preoperative value. The findings of an inappropriately elevated rate of production of both cholesterol and LDL as well as a reduced fractional catabolic rate for the lipoprotein in the untreated FH homozygote are consistent with results of studies in cultured fibroblasts indicating that the primary genetic defect in FH involves a deficiency in a cell-surface receptor for LDL that regulates both cholesterol synthesis and LDL degradation. Although the mechanism for the decline in production of cholesterol and LDL after portacaval shunt surgery is unknown, it was observed that these changes were associated with marked increases in the plasma concentrations of bile acids and glucagon.
Vasopressin Receptor Antagonists, Heart Failure, and Polycystic Kidney Disease
Authors: Vicente E. Torres
Journal: Annual Review of Medicine (2014)

The synthesis of nonpeptide orally bioavailable vasopressin antagonists devoid of agonistic activity (vaptans) has made possible the selective blockade of vasopressin receptor subtypes for therapeutic purposes. Vaptans acting on the vasopressin V2 receptors (aquaretics) have attracted attention as a possible therapy for heart failure and polycystic kidney disease. Despite a solid rationale and encouraging preclinical testing, aquaretics have not improved clinical outcomes in randomized clinical trials for heart failure. Additional clinical trials with select population targets, more flexible dosing schedules, and possibly a different drug type or combination (balanced V1a/V2 receptor antagonism) may be warranted. Aquaretics are promising for the treatment of autosomal dominant polycystic kidney disease and have been approved in Japan for this indication. More studies are needed to better define their long-term safety and efficacy and optimize their utilization.
Deranged smooth muscle -actin as a biomarker of intestinal pseudo-obstruction: a controlled multinational case series
Authors: CH Knowles, Dba Silk, A Darzi, Bela Veress, R Feakins, AH Raimundo, T Crompton, EC Browning, G Lindberg, JE Martin
Journal: Gut (2004)

<b>Background and aims:</b> Chronic idiopathic intestinal pseudo-obstruction (CIIP) is a severe motility disorder associated with significant morbidity. Several histopathological (neuropathic and myopathic) phenotypes have been described but only a single adult with jejunal smooth (circular) muscle α-actin deficiency. We present a prospective multinational case series investigating smooth muscle α-actin deficiency as a biomarker of this disease. <b>Methods:</b> A total of 115 fully clinically and physiologically (including prolonged (24 hour) ambulatory jejunal manometry) characterised CIIP patients from three European centres were studied. Immunohistochemical localisation of actins and other cytoskeletal proteins were performed on laparoscopic full thickness jejunal biopsies and compared with adult controls. Distribution of α-actin was also characterised in other gut regions and in the developing human alimentary tract. <b>Results:</b> Twenty eight of 115 (24%) CIIP patient biopsies had absent (n = 22) or partial (n = 6) jejunal smooth muscle α-actin immunostaining in the circular muscle layer. In contrast, smooth muscle α-actin staining was preserved in the longitudinal muscle and in adult jejunal controls (n = 20). Comparative study of other adult alimentary tract regions and fetal small intestine, suggested significant spatial and temporal variations in smooth muscle α-actin expression. <b>Conclusions:</b> The ability to modulate α-smooth muscle actin expression, evident in development, is maintained in adult life and may be influenced by disease, rendering it a valuable biomarker even in the absence of other structural abnormalities.