A one-year trial of lamivudine for chronic hepatitis B

Background and Methods: In preliminary trials, lamivudine, an oral nucleoside analogue, has shown promise for the treatment of chronic hepatitis B. We conducted a one-year double-blind trial of lamivudine in 358 Chinese patients with chronic hepatitis B. The patients were randomly assigned to receive 25 mg of lamivudine (142 patients), 100 mg of lamivudine (143), or placebo (73) orally once daily. The patients underwent liver biopsies before entering the study and after completing the assigned treatment regimen. The primary end point was a reduction of at least two points in the Knodell necroinflammatory score. Results: Hepatic necroinflammatory activity improved by two points or more in 56 percent of the patients receiving 100 mg of lamivudine, 49 percent of those receiving 25 mg of lamivudine, and 25 percent of those receiving placebo (P<0.001 and P=0.001, respectively, for the comparisons of lamivudine treatment with placebo). Necroinflammatory activity worsened in 7 percent of the patients receiving 100 mg of lamivudine, 8 percent of those receiving 25 mg, and 26 percent of those receiving placebo. The 100mg dose of lamivudine was associated with a reduced progression of fibrosis (P=0.01 for the comparison with placebo) and with the highest rate of hepatitis B e antigen (HBeAg) seroconversion (loss of HBeAg, development of antibody to HBeAg, and undetectable HBV DNA) (16 percent), the greatest suppression of HBV DNA (98 percent reduction at week 52 as compared with the base-line value), and the highest rate of sustained normalization of alanine aminotransferase levels (72 percent). Ninety-six percent of the patients completed the study. The incidence of adverse events was similar in all groups, and there were few serious events. Conclusions: In a one-year study, lamivudine was associated with substantial histologic improvement in many patients with chronic hepatitis B. A daily dose of 100 mg was more effective than a daily dose of 25 mg.published_or_final_versio

Analysis of Dense Gas Effects in Compressible Turbulent Channel Flows

In this work we investigate the influence of dense gas effects on compressible wall-bounded turbulence. Turbulent flows of dense gases represent a research field of great importance for a wide range of applications in engineering. Dense gases are single-phase fluids with a molecular complexity such that the fundamental derivative of gas dynamics [1], which measures the rate of change of the sound speed in isentropic transformations, is less than one in a range of thermodynamic conditions close to the saturation curve. In such conditions, the speed of sound increases in isentropic expansions and decreases in isentropic compressions, unlike the case of perfect gases. For dense gases, the perfect gas model is no longer valid, and more complex equations of state must be used to account for their peculiar thermodynamic behavior. Moreover, in the dense gas regime, the dynamic viscosity μ and the thermal conductivity λ depend on temperature and pressure through complex relationships. Similarly, the approximation of nearly constant Prandtl number Pr= μ c p / λ is no longer valid. Numerical simulations of turbulent dense gas flows of engineering interest are based on the (Reynolds-Averaged Navier–Stokes) RANS equations, which need to be supplemented by a model for the Reynolds stress tensor and turbulent heat flux. The accuracy of RANS models for dense-gas flows has not been properly assessed up to date, due to the lack of both experimental and numerical reference data. DNS databases [2, 3] are then needed to quantify the deficiencies of existing turbulence models and to develop and calibrate improved ones. In this work we first summarize some recent direct numerical simulation (DNS) results [4] for supersonic turbulent channel flows (TCF) of PP11, a heavy fluorocarbon representative of dense gases, at various bulk Mach and Reynolds numbers. The most relevant effects are represented by non-conventional variations of the fluctuating thermodynamic quantities, compared to perfect gases and a strong decoupling between thermal and dynamic effects almost everywhere in the flow, except in the immediate vicinity of the solid wall. Preliminary considerations about the validity of some currently-used models for the turbulent stresses and heat flux are carried out based on a priori comparisons between the exact terms computed from the DNS and their modeled counterparts

A transient homotypic interaction model for the influenza A virus NS1 protein effector domain

Influenza A virus NS1 protein is a multifunctional virulence factor consisting of an RNA binding domain (RBD), a short linker, an effector domain (ED), and a C-terminal 'tail'. Although poorly understood, NS1 multimerization may autoregulate its actions. While RBD dimerization seems functionally conserved, two possible apo ED dimers have been proposed (helix-helix and strand-strand). Here, we analyze all available RBD, ED, and full-length NS1 structures, including four novel crystal structures obtained using EDs from divergent human and avian viruses, as well as two forms of a monomeric ED mutant. The data reveal the helix-helix interface as the only strictly conserved ED homodimeric contact. Furthermore, a mutant NS1 unable to form the helix-helix dimer is compromised in its ability to bind dsRNA efficiently, implying that ED multimerization influences RBD activity. Our bioinformatical work also suggests that the helix-helix interface is variable and transient, thereby allowing two ED monomers to twist relative to one another and possibly separate. In this regard, we found a mAb that recognizes NS1 via a residue completely buried within the ED helix-helix interface, and which may help highlight potential different conformational populations of NS1 (putatively termed 'helix-closed' and 'helix-open') in virus-infected cells. 'Helix-closed' conformations appear to enhance dsRNA binding, and 'helix-open' conformations allow otherwise inaccessible interactions with host factors. Our data support a new model of NS1 regulation in which the RBD remains dimeric throughout infection, while the ED switches between several quaternary states in order to expand its functional space. Such a concept may be applicable to other small multifunctional proteins

Epstein–Barr virus antibody level and gastric cancer risk in Korea: a nested case–control study

BACKGROUND: Few cohort studies have investigated Epstein-Barr virus (EBV) infection before the occurrence of gastric cancer. METHODS: Among 14 440 cohort participants, 100 incident gastric cancer cases were individually matched to two controls. Epstein-Barr virus antibodies IgG and IgA against viral capsid antigen (VCA), EBV nuclear antigen (EBNA) antibody IgG, and early antigen (EA) antibody IgG were measured using enzyme immunoassays (EIAs). RESULTS: The highest titres of VCA IgG (odds ratio (OR): 1.37, 95% confidence interval (CI): 0.62-3.06) or EBNA IgG (OR: 0.87, 95% CI: 0.51-1.46) were not associated with gastric cancer risk. CONCLUSION: Higher levels of VCA IgG or EBNA IgG were not associated with increased risk of gastric adenocarcinoma in Koreans.Akiba S, 2008, CANCER SCI, V99, P195, DOI 10.1111/j.1349-7006.2007.00674.xKoshiol J, 2007, BRIT J CANCER, V97, P1567, DOI 10.1038/sj.bjc.6604063Tedeschi R, 2007, AM J EPIDEMIOL, V165, P134, DOI 10.1093/aje/kwj332Gwack J, 2006, BRIT J CANCER, V95, P639, DOI 10.1038/sj.bjc.6603309Ouburg S, 2005, EUR J GASTROEN HEPAT, V17, P1213Chan D, 2005, J RES PRACT INF TECH, V37, P267HERRERAGOEPFERT R, 2005, WORLD J GASTROENTERO, V11, P6096CORREA P, 2004, GASTRIC CANCER, V7, P9Macsween KF, 2003, LANCET INFECT DIS, V3, P131Gartner BC, 2003, CLIN DIAGN LAB IMMUN, V10, P78, DOI 10.1128/CDLI.10.1.78-82.2003Burgess DE, 2002, BRIT J CANCER, V86, P702, DOI 10.1038/sj/bjc/6600107YOO KY, 2002, ASIAN PAC J CANCER P, V3, P85Chien YC, 2001, NEW ENGL J MED, V345, P1877Bruu AL, 2000, CLIN DIAGN LAB IMMUN, V7, P451Shinkura R, 2000, J MED VIROL, V60, P411Akre O, 1999, INT J CANCER, V82, P1Tokunaga M, 1998, CANCER EPIDEM BIOMAR, V7, P449*IARC, 1997, EPSTEINBARR VIR KAP, V8LEVINE PH, 1995, INT J CANCER, V60, P642LEHTINEN T, 1993, CANCER CAUSE CONTROL, V4, P187GESER A, 1982, INT J CANCER, V29, P397

Tumor-Targeted Delivery of IL-2 by NKG2D Leads to Accumulation of Antigen-Specific CD8+ T Cells in the Tumor Loci and Enhanced Anti-Tumor Effects

Interleukin-2 (IL-2) has been shown to promote tumor-specific T-cell proliferation and differentiation but systemic administration of IL-2 results in significant toxicity. Therefore, a strategy that can specifically deliver IL-2 to the tumor location may alleviate concerns of toxicity. Because NKG2D ligands have been shown to be highly expressed in many cancer cells but not in healthy cells, we reason that a chimeric protein consisting of NKG2D linked to IL-2 will lead to the specific targeting of IL-2 to the tumor location. Therefore, we created chimeric proteins consisting of NKG2D linked to Gaussia luciferase (GLuc; a marker protein) or IL-2 to form NKG2D-Fc-GLuc and NKG2D-Fc-IL2, respectively. We demonstrated that NKG2D linked to GLuc was able to deliver GLuc to the tumor location in vivo. Furthermore, we showed that TC-1 tumor-bearing mice intramuscularly injected with DNA encoding NKG2D-Fc-IL2, followed by electroporation, exhibited an increased number of luciferase-expressing E7-specific CD8+ T cells at the tumor location. More importantly, treatment with the DNA construct encoding NKG2D-Fc-IL2 significantly enhanced the therapeutic anti-tumor effects generated by intradermal vaccination with therapeutic HPV DNA in tumor-bearing mice. Therefore, by linking NKG2D to IL2, we are able to specifically deliver IL-2 to the tumor location, enhancing antigen-specific T-cell immune response and controlling tumor growth. Our approach represents a platform technology to specifically deliver proteins of interest to tumor loci

Hepatobiliary and pancreatic tuberculosis: A two decade experience

<p>Abstract</p> <p>Background</p> <p>Isolated hepatobiliary or pancreatic tuberculosis (TB) is rare and preoperative diagnosis is difficult. We reviewed our experience over a period two decades with this rare site of abdominal tuberculosis.</p> <p>Methods</p> <p>The records of 18 patients with proven histological diagnosis of hepatobiliary and pancreatic tuberculosis were reviewed retrospectively. The demographic features, sign and symptoms, imaging, cytology/histopathology, procedures performed, outcome and follow up data were obtained from the departmental records. The diagnosis of tuberculosis was based on granuloma with caseation necrosis on histopathology or presence of acid fast bacilli.</p> <p>Results</p> <p>Of 18 patients (11 men), 11 had hepatobiliary TB while 7 had pancreatic TB. Two-thirds of the patients were < 40 years (mean: 42 yrs; range 19–70 yrs). The duration of the symptoms varied between 2 weeks to 104 weeks (mean: 20 weeks). The most common symptom was pain in the abdomen (n = 13), followed by jaundice (n = 10), fever, anorexia and weight loss (n = 9). Five patients (28%) had associated extra-abdominal TB which helped in preoperative diagnosis in 3 patients. Imaging demonstrated extrahepatic bile duct obstruction in the patients with jaundice and in addition picked up liver, gallbladder and pancreatic masses with or without lymphadenopathy (peripancreatic/periportal). Preoperative diagnosis was made in 4 patients and the other 14 were diagnosed after surgery. Two patients developed significant postoperative complications (pancreaticojejunostomy leak <abbrgrp><abbr bid="B1">1</abbr></abbrgrp> intraabdominal abscess <abbrgrp><abbr bid="B1">1</abbr></abbrgrp>) and 3 developed ATT induced hepatotoxicity. No patient died. The median follow up period was 12 months (9 – 96 months).</p> <p>Conclusion</p> <p>Tuberculosis should be considered as a differential diagnosis, particularly in young patients, with atypical signs and symptoms coming from areas where tuberculosis is endemic and preoperative tissue and/or cytological diagnosis should be attempted before labeling them as hepatobiliary and pancreatic malignancy.</p

Is quality of colorectal cancer care good enough? Core measures development and its application for comparing hospitals in Taiwan

<p>Abstract</p> <p>Background</p> <p>Although performance measurement for assessing care quality is an emerging area, a system for measuring the quality of cancer care at the hospital level has not been well developed. The purpose of this study was to develop organization-based core measures for colorectal cancer patient care and apply these measures to compare hospital performance.</p> <p>Methods</p> <p>The development of core measures for colorectal cancer has undergone three stages including a modified Delphi method. The study sample originated from 2004 data in the Taiwan Cancer Database, a national cancer data registry. Eighteen hospitals and 5585 newly diagnosed colorectal cancer patients were enrolled in this study. We used indicator-based and case-based approaches to examine adherences simultaneously.</p> <p>Results</p> <p>The final core measure set included seventeen indicators (1 pre-treatment, 11 treatment-related and 5 monitoring-related). There were data available for ten indicators. Indicator-based adherence possesses more meaningful application than case-based adherence for hospital comparisons. Mean adherence was 85.8% (79.8% to 91%) for indicator-based and 82.8% (77.6% to 88.9%) for case-based approaches. Hospitals performed well (>90%) for five out of eleven indicators. Still, the performance across hospitals varied for many indicators. The best and poorest system performance was reflected in indicators T5-negative surgical margin (99.3%, 97.2% - 100.0%) and T7-lymph nodes harvest more than twelve(62.7%, 27.6% - 92.2%), both of which related to surgical specimens.</p> <p>Conclusions</p> <p>In this nationwide study, quality of colorectal cancer care still shows room for improvement. These preliminary results indicate that core measures for cancer can be developed systematically and applied for internal quality improvement.</p

Systemic delivery of E6/7 siRNA using novel lipidic particles and its application with cisplatin in cervical cancer mouse models

Small interfering RNA (siRNA) shows great promise in cancer therapy, but its effectiveness in vivo still remains a crucial issue for its transition into the clinics. Although the successful use of polyethylene glycol (PEG)ylated lipidic delivery systems have already been reported, most of the formulation procedures used are labour intensive and also result in unstable end products. We have previously developed a simple yet efficient hydration-of-freeze-dried- matrix (HFDM) method to entrap siRNA within lipid particles, in which the products exhibited superior stability. Here, we show that these HFDM-formulated particles are stable in the presence of serum and can deliver siRNA efficiently to tumours after intravenous administration. Using these particles, around 50% knockdown of the target gene expression was observed in tumours. With the use of siRNA targeting the E6/7 oncogenes expressed in cervical cancer, we showed a 50% reduction in tumour size. This level of tumour growth suppression was comparable to that achieved from cisplatin at the clinically used dose. Overall, our results demonstrate the feasibility of using HFDM-formulated particles to systematically administer E6/7-targeted siRNA for cervical cancer treatment. The simplicity of preparation procedure along with superior product stability obtained from our method offers an innovative approach for the in vivo delivery of siRNA

Effects of air pollution on neonatal prematurity in guangzhou of china: a time-series study

<p>Abstract</p> <p>Background</p> <p>Over the last decade, a few studies have investigated the possible adverse effects of ambient air pollution on preterm birth. However, the correlation between them still remains unclear, due to insufficient evidences.</p> <p>Methods</p> <p>The correlation between air pollution and preterm birth in Guangzhou city was examined by using the Generalized Additive Model (GAM) extended Poisson regression model in which we controlled the confounding factors such as meteorological factors, time trends, weather and day of the week (DOW). We also adjusted the co linearity of air pollutants by using Principal Component Analysis. The meteorological data and air pollution data were obtained from the Meteorological Bureau and the Environmental Monitoring Centre, while the medical records of newborns were collected from the perinatal health database of all obstetric institutions in Guangzhou, China in 2007.</p> <p>Results</p> <p>In 2007, the average daily concentrations of NO₂, PM₁₀and SO₂in Guangzhou, were 61.04, 82.51 and 51.67 μg/m³respectively, where each day an average of 21.47 preterm babies were delivered. Pearson correlation analysis suggested a negative correlation between the concentrations of NO₂, PM₁₀, SO_2,and temperature as well as relative humidity. As for the time-series GAM analysis, the results of single air pollutant model suggested that the cumulative effects of NO₂, PM₁₀and SO₂reached its peak on day 3, day 4 and day 3 respectively. An increase of 100 μg/m³of air pollutants corresponded to relative risks (RRs) of 1.0542 (95%CI: 1.0080 ~1.1003), 1.0688 (95%CI: 1.0074 ~1.1301) and 1.1298 (95%CI: 1.0480 ~1.2116) respectively. After adjusting co linearity by using the Principal Component Analysis, the GAM model of the three air pollutants suggested that an increase of 100 μg/m³of air pollutants corresponded to RRs of 1.0185 (95%CI: 1.0056~1.0313), 1.0215 (95%CI: 1.0066 ~1.0365) and 1.0326 (95%CI: 1.0101 ~1.0552) on day 0; and RRs of the three air pollutants, at their strongest cumulative effects, were 1.0219 (95%CI: 1.0053~1.0386), 1.0274 (95%CI: 1.0066~1.0482) and 1.0388 (95%CI: 1.0096 ~1.0681) respectively.</p> <p>Conclusions</p> <p>This study indicates that the daily concentrations of air pollutants such as NO₂, PM₁₀and SO₂have a positive correlation with the preterm births in Guangzhou, China.</p