Twelve weeks of protracted venous infusion of fluorouracil (5-FU) is as effective as 6 months of bolus 5-FU and folinic acid as adjuvant treatment in colorectal cancer.

We performed a multicentre randomised trial to compare the efficacy and toxicity of 12 weeks of 5-fluorouracil (5-FU) delivered by protracted intravenous infusion (PVI 5-FU) against the standard bolus regimen of 5-FU and folinic acid (5-FU/FA) given for 6 months as adjuvant treatment in colorectal cancer. A total of 716 patients with curatively resected Dukes' B or C colorectal cancer were randomised to 5-FU/FA (5-FU 425 mg m(-2) i.v. and FA 20 mg m(-2) i.v. bolus days 1-5 every 28 days for 6 months) or to PVI 5-FU alone (300 mg m(-2) day for 12 weeks). With a median follow-up of 19.8 months, 133 relapses and 77 deaths have been observed. Overall survival did not differ significantly (log rank P=0.764) between patients receiving 5-FU/FA and PVI 5-FU (3-year survival 83.2 vs 87.9%, respectively). Patients in the 5-FU/FA group had significantly worse relapse-free survival (RFS, log rank P=0.023) compared to those receiving PVI 5-FU (3-year RFS, 68.6 vs 80%, respectively). Grades 3-4 neutropenia, diarrhoea, stomatitis and severe alopecia were significantly less (P<0.0001) and global quality of life scores significantly better (P&<0.001) for patients in the PVI 5-FU treatment arm. In conclusion, infused 5-FU given over 12 weeks resulted in similar survival to bolus 5-FU and FA over a 6 month period, but with significantly less toxicity

Disparities and risks of sexually transmissible infections among men who have sex with men in China: a meta-analysis and data synthesis.

BACKGROUND: Sexually transmitted infections (STIs), including Hepatitis B and C virus, are emerging public health risks in China, especially among men who have sex with men (MSM). This study aims to assess the magnitude and risks of STIs among Chinese MSM. METHODS: Chinese and English peer-reviewed articles were searched in five electronic databases from January 2000 to February 2013. Pooled prevalence estimates for each STI infection were calculated using meta-analysis. Infection risks of STIs in MSM, HIV-positive MSM and male sex workers (MSW) were obtained. This review followed the PRISMA guidelines and was registered in PROSPERO. RESULTS: Eighty-eight articles (11 in English and 77 in Chinese) investigating 35,203 MSM in 28 provinces were included in this review. The prevalence levels of STIs among MSM were 6.3% (95% CI: 3.5-11.0%) for chlamydia, 1.5% (0.7-2.9%) for genital wart, 1.9% (1.3-2.7%) for gonorrhoea, 8.9% (7.8-10.2%) for hepatitis B (HBV), 1.2% (1.0-1.6%) for hepatitis C (HCV), 66.3% (57.4-74.1%) for human papillomavirus (HPV), 10.6% (6.2-17.6%) for herpes simplex virus (HSV-2) and 4.3% (3.2-5.8%) for Ureaplasma urealyticum. HIV-positive MSM have consistently higher odds of all these infections than the broader MSM population. As a subgroup of MSM, MSW were 2.5 (1.4-4.7), 5.7 (2.7-12.3), and 2.2 (1.4-3.7) times more likely to be infected with chlamydia, gonorrhoea and HCV than the broader MSM population, respectively. CONCLUSION: Prevalence levels of STIs among MSW were significantly higher than the broader MSM population. Co-infection of HIV and STIs were prevalent among Chinese MSM. Integration of HIV and STIs healthcare and surveillance systems is essential in providing effective HIV/STIs preventive measures and treatments. TRIAL REGISTRATION: PROSPERO NO: CRD42013003721

Phase II study of a triplet regimen in advanced colorectal cancer using methotrexate, oxaliplatin and 5-fluorouracil

Building upon the concept of schedule-specific biochemical modulation of 5-fluorouracil (FU), which alternates bolus and continuous infusion (CI) FU, we have incorporated oxaliplatin (l-OHP) following the bolus part of the regimen to explore the activity of this new combination. Patients with advanced, untreated, measurable colorectal cancer received sequential methotrexate (MTX) (days 1 and 15)-->l-OHP+FU (days 2 and 16) (200, 85 and 600 mg m(-2), respectively) followed by 3 weeks of CI FU (200 mg m(-2) day(-1)) given from day 29 to 50, modulated by weekly leucovorin (LV) (20 mg m(-2)). After 1 week of rest, the second cycle was started. The treatment was continued until progression or patient's refusal. According to the intention-to-treat analysis on all 46 patients accrued, the response rate was 42% (95% CL=28-55%), with three complete responses and 16 partial responses. The median overall survival was 15.9 months and the median progression-free survival 6.9 months. Toxicity was very mild, with the bolus part of the regimen more toxic than the infusional part (24 vs 7% of grade III-IV, respectively). This new combination of MTX -->l-OHP-FU followed by FU CI is well tolerated, feasible and produces activity results similar to other more simple, but more toxic, regimens. Pros and cons of the different fluoropyrimidines-l-OHP combinations are discussed

Natural and Vaccine-Mediated Immunity to Salmonella Typhimurium is Impaired by the Helminth Nippostrongylus brasiliensis

The impact of exposure to multiple pathogens concurrently or consecutively on immune function is unclear. Here, immune responses induced by combinations of the bacterium Salmonella Typhimurium (STm) and the helminth Nippostrongylus brasiliensis (Nb), which causes a murine hookworm infection and an experimental porin protein vaccine against STm, were examined. Mice infected with both STm and Nb induced similar numbers of Th1 and Th2 lymphocytes compared with singly infected mice, as determined by flow cytometry, although lower levels of secreted Th2, but not Th1 cytokines were detected by ELISA after re-stimulation of splenocytes. Furthermore, the density of FoxP3+ T cells in the T zone of co-infected mice was lower compared to mice that only received Nb, but was greater than those that received STm. This reflected the intermediate levels of IL-10 detected from splenocytes. Co-infection compromised clearance of both pathogens, with worms still detectable in mice weeks after they were cleared in the control group. Despite altered control of bacterial and helminth colonization in co-infected mice, robust extrafollicular Th1 and Th2-reflecting immunoglobulin-switching profiles were detected, with IgG2a, IgG1 and IgE plasma cells all detected in parallel. Whilst extrafollicular antibody responses were maintained in the first weeks after co-infection, the GC response was less than that in mice infected with Nb only. Nb infection resulted in some abrogation of the longer-term development of anti-STm IgG responses. This suggested that prior Nb infection may modulate the induction of protective antibody responses to vaccination. To assess this we immunized mice with porins, which confer protection in an antibody-dependent manner, before challenging with STm. Mice that had resolved a Nb infection prior to immunization induced less anti-porin IgG and had compromised protection against infection. These findings demonstrate that co-infection can radically alter the development of protective immunity during natural infection and in response to immunization

Theory of disk accretion onto supermassive black holes

Accretion onto supermassive black holes produces both the dramatic phenomena associated with active galactic nuclei and the underwhelming displays seen in the Galactic Center and most other nearby galaxies. I review selected aspects of the current theoretical understanding of black hole accretion, emphasizing the role of magnetohydrodynamic turbulence and gravitational instabilities in driving the actual accretion and the importance of the efficacy of cooling in determining the structure and observational appearance of the accretion flow. Ongoing investigations into the dynamics of the plunging region, the origin of variability in the accretion process, and the evolution of warped, twisted, or eccentric disks are summarized.Comment: Mostly introductory review, to appear in "Supermassive black holes in the distant Universe", ed. A.J. Barger, Kluwer Academic Publishers, in pres

HLA-A and -B alleles and haplotypes in 240 index patients with common variable immunodeficiency and selective IgG subclass deficiency in central Alabama

BACKGROUND: We wanted to quantify HLA-A and -B phenotype and haplotype frequencies in Alabama index patients with common variable immunodeficiency (CVID) and selective IgG subclass deficiency (IgGSD), and in control subjects. METHODS: Phenotypes were detected using DNA-based typing (index cases) and microlymphocytotoxicity typing (controls). RESULTS: A and B phenotypes were determined in 240 index cases (114 CVID, 126 IgGSD) and 1,321 controls and haplotypes in 195 index cases and 751 controls. Phenotyping revealed that the "uncorrected" frequencies of A*24, B*14, B*15, B*35, B*40, B*49, and B*50 were significantly greater in index cases, and frequencies of B*35, B*58, B*62 were significantly lower in index cases. After Bonferroni corrections, the frequencies of phenotypes A*24, B*14, and B*40 were significantly greater in index cases, and the frequency of B*62 was significantly lower in index cases. The most common haplotypes in index cases were A*02-B*44 (frequency 0.1385), A*01-B*08 (frequency 0.1308), and A*03-B*07 (frequency 0.1000), and the frequency of each was significantly greater in index cases than in control subjects ("uncorrected" values of p < 0.0001, 0.0252, and 0.0011, respectively). After performing Bonferroni corrections, however, the frequency of A*02-B*44 alone was significantly increased in probands (p < 0.0085). Three other haplotypes were also significantly more frequent in index cases (A*03-B*14, A*31-B*40, and A*32-B*14). The combined frequencies of three latter haplotypes in index patients and control subjects were 0.0411 and 0.0126, respectively ("uncorrected" value of p < 0.0002; "corrected" value of p = 0.0166). Most phenotype and haplotype frequencies in CVID and IgGSD were similar. 26.7% of index patients were HLA-haploidentical with one or more other index patients. We diagnosed CVID or IgGSD in first-degree or other relatives of 26 of 195 index patients for whom HLA-A and -B haplotypes had been ascertained; A*01-B*08, A*02-B*44, and A*29-B*44 were most frequently associated with CVID or IgGSD in these families. We conservatively estimated the combined population frequency of CVID and IgGSD to be 0.0092 in adults, based on the occurrence of CVID and IgGSD in spouses of the index cases. CONCLUSIONS: CVID and IgGSD in adults are significantly associated with several HLA haplotypes, many of which are also common in the Alabama Caucasian population. Immunoglobulin phenotype variability demonstrated in index cases and family studies herein suggests that there are multiple gene(s) on Ch6p or other chromosomes that modify immunoglobulin phenotypes of CVID and IgGSD. The estimated prevalence of CVID and IgGSD in central Alabama could be reasonably attributed to the fact that many HLA haplotypes significantly associated with these disorders are also common in the general population

Age-dependent effects of low-dose nicotine treatment on cocaine-induced behavioral plasticity in rats

Epidemiological evidence of early adolescent tobacco use, prior to that of marijuana and other illicit drugs, has led to the hypothesis that nicotine is a “gateway” drug that sensitizes reward pathways to the addictive effects of other psychostimulants. To test this hypothesis, we have compared the effect of a brief, low-dose nicotine pretreatment of adolescent and adult rats on subsequent locomotor response to acute and chronic cocaine. Adolescents, aged postnatal day (P) 28, and adults, aged P86, were given four daily injections of saline or nicotine (0.06&nbsp;mg/kg, i.v.). At P32 and P90, rats were given acute injections of cocaine (0, 0.4 or 1.0&nbsp;mg/kg, i.v.) and monitored for locomotor activity in either a habituated or novel test environment. To examine cocaine sensitization, rats were treated for 3&nbsp;days with saline or cocaine (0.4&nbsp;mg/kg, i.v.), and, after 1&nbsp;day of withdrawal, were given a challenge dose of cocaine (0.4&nbsp;mg/kg, i.v.). Nicotine pretreatment did not affect acute, drug-induced locomotor activity at either age. However, age differences in cocaine response were observed, with adolescent animals showing enhanced locomotor activity in the novel environment. Adolescent controls did not exhibit cocaine-induced locomotor sensitization, whereas adults did. Nicotine pretreatment during adolescence promoted the development and expression of a sensitized response to repeated cocaine exposure similar to that observed in saline-pretreated adult controls. These findings show that brief pretreatment with nicotine, in a low dose comparable to that inhaled in 2–4 cigarettes, enhances cocaine-induced behavioral plasticity in adolescent rats

Higher incidence of persistent chronic infection of Chlamydia pneumoniae among coronary artery disease patients in India is a cause of concern

<p>Abstract</p> <p>Background</p> <p>There is growing evidence that <it>Chlamydia pneumoniae </it>may be involved in the pathogenesis of atherosclerosis, as several studies have demonstrated the presence of the organism in atherosclerotic lesions. <it>C. pneumoniae </it>infections, which are especially persistent infections, have been difficult to diagnose either by serological methods or isolation of the organism from the tissue. Nucleic Acid Amplification tests (NAATs) has emerged as an important method for detecting <it>C. pneumoniae</it>. Inspite of high prevalence of <it>C. pneumoniae </it>specific antibodies in coronary heart disease patients, direct detection of <it>C. pneumoniae </it>in circulating blood of coronary artery disease (CAD) patients by sensitive nucleic acid amplification tests nested PCR (nPCR), multiplex PCR (mPCR) has not been carried out is required. Further correlation of the presence of <it>C. pneumoniae </it>in blood of CAD patients with <it>C. pneumoniae </it>specific IgA and IgG antibodies, which may indicative of the status of infection with the progression of atherosclerosis. This will help in order to prepare strategies for the antibiotic intervention to avoid the progression towards CAD.</p> <p>Methods</p> <p>Venous blood was obtained from 91 CAD patients and 46 healthy controls. Nucleic acid amplification tests <it>viz</it>. nested -, semi-nested – and multiplex PCR were used for detection of <it>C. pneumoniae</it>. ELISA carried out prevalence of <it>C. pneumoniae </it>specific IgG and IgA antibodies.</p> <p>Results</p> <p>29.67% (27/91) patients were positive for <it>C. pneumoniae </it>using nested PCR. The sensitivity and specificity of semi-nested and multiplex PCR were 37.03%, 96.96% and 22.22%, 100% with respect to nested PCR. Positive nPCR patients were compared with presence of <it>C. pneumoniae </it>specific IgA, IgA+IgG and IgG antibodies. Among 27 (29.67%) nPCR <it>C. pneumoniae </it>positive CAD patients, 11(12%) were IgA positive, 13(14.2%) were IgA+IgG positive and only1 (1.1%) was IgG positive. A significant presence of <it>C. pneumoniae </it>was detected in heavy smokers, non-alcoholics and with family histories of diabetes and blood pressure group of CAD patients by nPCR.</p> <p>Conclusion</p> <p>The results indicate synergistic association of <it>C. pneumoniae </it>infection and development of CAD with other risk factors. We also detected increased positivity for <it>C. pneumoniae </it>IgA than IgG in nPCR positive CAD patients. Positive nPCR findings in conjunction with persisting high <it>C. pneumoniae </it>specific antibody strongly suggest an ongoing infection.</p

Evaluation of pseudoephedrine pharmacy sales before and after mandatory recording requirements in Western Australia: a case study

Background: A community pharmacy real-time electronic recording program, ProjectSTOP, enables Australian community pharmacists to verify pseudoephedrine requests. In Western Australia the program was available for voluntary use from April 2007 and became mandatory November 2010. This case study explores the effectiveness of the program by reviewing the total requests for pseudoephedrine products, and the proportion of requests which were classified as ‘denied sales’ before and after mandatory implementation. Seasonal and annual trends in these measures are also evaluated. Methods: ProjectSTOP data recordings for Western Australia pharmacies between 1 December 2007 and 28 February 2014 were analysed. Data included a de-identified pharmacy number and date of each pseudoephedrine product request. The total number of requests and sale classification (allowed, denied, safety, or not recorded) were calculated for each month/pharmacy. The potential influence of mandatory reporting using ProjectSTOP was investigated using a Regression Discontinuity Design. Correlations between sales from the same pharmacy were taken into account by classifying the pharmacy number as a random effect. The main effects of year (continuous variable), and season (categorical variable) were also included in the model. Results: There was a small but steady decline in the total requests for pseudoephedrine per month per 100,000 population (per pharmacy) from the time of mandatory reporting. The number of denied sales showed a steady increase up until mandatory reporting, after which it showed a significant decline over time. Total sales were heavily influenced by season, as expected (highest in winter, least in summer). The seasonal pattern was less pronounced for denied sales, which were highest in winter and similar across other seasons. The pattern over time for safety sales was similar to that for denied sales, with a clear change occurring around the time of mandatory reporting. Conclusion: Results indicate a decrease in pseudoephedrine product requests in Western Australia community pharmacies. Findings suggest ProjectSTOP has been successful in addressing suspicious sales and potential diversion however ongoing data review is recommended

Connective tissue growth factor in tumor pathogenesis

Key roles for connective tissue growth factor (CTGF/CCN2) are demonstrated in the wound repair process where it promotes myofibroblast differentiation and angiogenesis. Similar mechanisms are active in tumor-reactive stroma where CTGF is expressed. Other potential roles include prevention of hypoxia-induced apoptosis and promoting epithelial-mesenchymal transistion (EMT). CTGF expression in tumors has been associated to both tumor suppression and progression. For example, CTGF expression in acute lymphoblastic leukemia, breast, pancreas and gastric cancer correlates to worse prognosis whereas the opposite is true for colorectal, lung and ovarian cancer. This discrepancy is not yet understood