Do androgens enhance the response to antithymocyte globulin in patients with aplastic anemia? A prospective randomized trial

We analyzed the effect of antithymocyte globulin (ATG) with or without androgens in 121 patients with aplastic anemia. Fifty-three patients with moderate to severe aplastic anemia were prospectively randomized to receive ATG with or without oral androgens. Eleven of 26 patients (42%) receiving ATG plus androgen responded, including three complete and eight partial responses. Twelve of 27 patients (44%) receiving ATG plus placebo responded, including five complete and seven partial responses. The difference in response rates was not significant (P greater than .9). Survival was also comparable in the two groups; for patients with severe aplastic anemia, actuarial survival at two years was 55% +/- 24% (95% confidence interval) in patients receiving ATG plus androgen compared with 50% +/- 24% in the ATG plus placebo group (P = .65). Furthermore, results in both groups were indistinguishable from those obtained in 68 historical controls receiving ATG without androgens. These data indicate that androgens are not required in order to respond to antithymocyte globulin and the addition of androgens, as used in this trial, did not significantly improve response rates to ATG treatment.     

Wait times for gastroenterology consultation in Canada: The patients�� perspective

Long wait times for health care have become a significant issue in Canada. As part of the Canadian Association of Gastroenterology’s Human Resource initiative, a questionnaire was developed to survey patients regarding wait times for initial gastroenterology consultation and its impact. A total of 916 patients in six cities from across Canada completed the questionnaire at the time of initial consultation. Self-reported wait times varied widely, with 26.8% of respondents reporting waiting less than two weeks, 52.4% less than one month, 77.1% less than three months, 12.5% reported waiting longer than six months and 3.6% longer than one year. One-third of patients believed their wait time was too long, with 9% rating their wait time as ‘far too long’; 96.4% believed that maximal wait time should be less than three months, 78.9% believed it should be less than one month and 40.3% believed it should be less than two weeks. Of those working or attending school, 22.6% reported missing at least one day of work or school because of their symptoms in the month before their appointment, and 9.0% reported missing five or more days in the preceding month. A total of 20.2% of respondents reported being very worried about having a serious disease (ie, scored 6 or higher on 7-point Likert scale), and 17.6% and 14.8%, respectively, reported that their symptoms caused major impairment of social functioning and with the activities of daily living. These data suggest that a significant proportion of Canadians with digestive problems are not satisfied with their wait time for gastroenterology consultation. Furthermore, while awaiting consultation, many patients experience an impaired quality of life because of their gastrointestinal symptoms.     

HIV1 protease inhibitors selectively induce inflammatory chemokine expression in primary human osteoblasts

HIV-infected patients are at increased risk of decreased bone mineral density. Several studies have implicated antiretroviral therapy as a contributor to the decreased bone mineral density seen in treated HIV-1 patients. Whilst the exact molecular mechanisms underlying decreased bone density remain to be elucidated, inflammation has been postulated to be an important pathogenomic mechanism. In this study, we have explored primary human osteoblast gene expression in response to protease inhibitors (PIs), by oligonucleotide microarray analysis. A list of dysregulated genes, correlated with the inflammatory response, increased significantly after NFV and RTV exposure. Analysis of gene and protein expression determined a selectively increase of the pro-inflammatory cytokines monocyte chemoattractant protein (MCP)-1 and interleukin-8 (IL-8) following exposure to a pharmacological concentration of NFV and RTV. These data suggested that generation of local inflammatory cascades may contribute to the development of decreased bone mineral density in highly active antiretroviral therapy (HAART)-treated HIV patients.     

Carcinoma of endocrine organs: results of the RARECARE project

The rarity or the asymptomatic character of endocrine tumours results in a lack of epidemiological studies on their incidence and survival patterns. The aim of this study was to describe the incidence, prevalence and survival of endocrine tumours using a large database, which includes cancer patients diagnosed from 1978 to 2002, registered in 89 population-based cancer registries (CRs) with follow-up until 31st December 2003. These data give an unique overview of the burden of endocrine carcinomas in Europe. A list of tumour entities based on the third International Classification of Diseases for Oncology was provided by the project Surveillance of rare cancer in Europe (RARECARE) project. Over 33,594 cases of endocrine carcinomas were analysed in this study. Incidence rates increased with age and were highest in patients 65 years of age or older. In 2003, more than 315,000 persons in the EU (27 countries) were alive with a past diagnosis of a carcinoma of endocrine organs. The incidence of pituitary carcinoma equalled four per 1,000,000 person years and showed the strongest decline in survival with increasing age. Thyroid cancer showed the highest crude incidence rates (four per 100,000 person years) and was the only entity with a gender difference: (female-to-male ratio: 2:9). Parathyroid carcinoma was the rarest endocrine entity with two new cases per 10,000,000 person years. For adrenal carcinoma, the most remarkable observations were a higher survival for women compared to men (40% compared to 32%, respectively) and a particularly low relative survival of 24% in patients 65 years of age or older. More high quality studies on rare cancers, with additional information, e.g. on stage and therapeutic approach, are needed and may be of help in partly explaining the observed variation in survival.     

Predictors of immunity after hepatitis A vaccination in HIV-infected persons

Hepatitis A virus (HAV) infection remains a health risk for human immunodeficiency virus (HIV)-infected persons. While the inactivated HAV vaccine affords protection to immunocompetent persons >95% of the time, rates of developing protective antibody (anti-HAV) in HIV+ persons are considerably lower. Although low CD4+ T-cell counts have previously been reported to be correlated with this poor response, the effect of HIV viraemia on HAV vaccine response has not previously been reported. The medical records of HIV-infected patients who had received at least one dose of HAV vaccine (Havrix, 1440 EIU) were reviewed for factors associated with the development of a protective anti-HAV response. Serological data with regard to anti-HAV status after vaccination were available in 238 patients with 133 individuals (49.6%) developing immunity after vaccination. In a logistic regression model, the only factors associated with a protective antibody response were an HIV plasma RNA level <1000 copies/mL at the time of vaccination (P = 0.011) and male gender (P = 0.016). Neither nadir CD4+ T cell count nor CD4+ T-cell count at time of vaccination were predictive of the development of anti-HAV. Suppression of HIV replication at time of vaccination is associated with a protective antibody response to HAV vaccination in HIV-infected adults. The low rate of response warrants further research in alternative strategies for HAV vaccination among HIV-infected persons.     

HIV protease inhibitors selectively induce gene expression alterations associated with reduced calcium deposition in primary human osteoblasts

HIV-infected patients are at increased risk of decreased bone mineral density. Some studies have implicated antiretroviral therapy as a contributor to the decreased bone mineral density seen in treated HIV-1 patients. In this study we explore the interactions between protease inhibitors (PI) and primary human osteoblast gene expression, highlighting a group of dysregulated genes that potentially are key factors in reducing bone formation. Runx-2 mRNA expression, calcium deposition, and alkaline phosphatase (ALP) activity decreased significantly in human osteoblast cultures after exposure to the PIs nelfinavir (NFV) and indinavir (IDV). Saquinavir (SQV), ritonavir (RTV), indinavir (IDV), or nelfinavir (NFV) exposure induced significant changes in genotypic expression as assessed by gene-chip microarray analysis. The altered genes from each group were compared to each other and a list of 8 upregulated and 13 downregulated genes only after NFV and IDV exposure was identified. This set includes TIMP-3, which has previously been demonstrated to be involved in osteoblast differentiation and extracellular matrix development processes. Silencing TIMP-3 mRNA expression using siRNA duplexes enhanced calcium deposition and ALP activity significantly, even after exposure to NFV and IDV. Our data suggest a link between reduced osteoblastic phenotype and a group of 21 altered genes following NFV and IDV treatment, and also suggest TIMP-3 may be involved in the PI-induced inhibition of osteoblast function.     

Antiviral activity and safety of aplaviroc,a CCR5 antagonist,in combination with lopinavir/ritonavir in HIV‐infected,therapy‐naïve patients: results of the EPIC study (CCR100136)*

Background

This phase IIb study explored the antiviral activity and safety of the investigational CC chemokine receptor 5 (CCR5) antagonist aplaviroc (APL) in antiretroviral‐naïve patients harbouring R5‐ or R5X4‐tropic virus.

Methods

A total of 191 patients were randomized 2:2:2:1 to one of three APL dosing regimens or to lamivudine (3TC)/zidovudine (ZDV) twice daily (bid), each in combination with lopinavir/ritonavir (LPV/r) 400 mg/100 mg bid. Efficacy, safety and pharmacokinetic parameters were assessed.

Results

This study was terminated prematurely because of APL‐associated idiosyncratic hepatotoxicity. A total of 141 patients initiated treatment early enough to have been able to complete 12 weeks on treatment [modified intent‐to‐treat (M‐ITT) population]; of these, 133 completed the 12‐week treatment phase. The proportion of subjects in the M‐ITT population with HIV‐1 RNA <400 copies/mL at week 12 was 50, 48, 54 and 75% in the APL 200 mg bid, APL 400 mg bid, APL 800 mg once a day (qd) and 3TC/ZDV arms, respectively. Similar responses were seen in the few subjects harbouring R5X4‐tropic virus (n=17). Common clinical adverse events (AEs) were diarrhoea, nausea, fatigue and headache. APL demonstrated nonlinear pharmacokinetics with high interpatient variability.

Conclusions

While target plasma concentrations of APL were achieved, the antiviral activity of APL+LPV/r did not appear to be comparable to that of 3TC/ZDV+LPV/r.     

Effect of exercise on the reproductive outcome and fetal development of diabetic rats

The aim of this study was to evaluate the effect of exercise on pregnancy outcome in streptozotocin-induced diabetic Wistar rats (n = 11 animals/group). These animals were randomly assigned to sedentary (G1) and exercised groups, beginning from day 0 (G2) or 7 (G3) to day 20 of pregnancy. The moderate exercise was a swimming programme. At day 21 of pregnancy, all rats were anaesthetized and killed to obtain pregnancy outcome data. All rats presented glycaemia higher than 300 mg/dl, regardless of the exercise training. The G3 group showed higher live fetus number per implantation site and lower resorption number per implantation site compared with the G1 group. The fetal and placental mean weights per litter and the total number of ossification sites were significantly lower in the exercised groups (P < 0.05). Placental index was lower in the G2 and G3 groups compared with the G1 group. The occurrence of skeletal anomalies indicated that exercise increased the number of altered fetuses. Thus, moderate exercise achieved better outcomes by increasing the number of live births and decreasing resorption. However, exercise increased skeletal anomalies and decreased fetal and placental weights.