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.     

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.     

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.     

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.     

创伤失血后微循环多形核白细胞在毛细血管内皮附壁状态的性别差异

目的:在体实时观察创伤失血性休克复苏后微循环多形核白细胞在毛细血管后微静脉内皮的附壁是否存在性别差异,并测定多形核白细胞黏附因子CD11b的表达。方法:实验于2005-08/2006-03在解放军总医院基础所微循环室完成。①实验动物为发情前期的雌性和成年雄性SD大鼠30只,分为雄性,雌性和假手术3组,每组10只,其中假手术组雌雄各5只。②麻醉后通过放血的方法将平均动脉压降至(35±5)mmHg,并维持60min,然后在60min内用4倍于最大失血量的乳酸林格氏液进行复苏。假手术组不进行休克及液体复苏。③复苏后2h和6h在腹部正中作4cm切口,取出回盲部附近的肠系膜,显微镜下观察多形核白细胞在肠系膜毛细血管后小静脉内的附壁情况并录像。通过股动脉抽取外周血分离多形核白细胞,用流式细胞仪测定黏附分子CD11b的表达。复苏后6h将动物处死,测定肺组织髓过氧化物酶活性。结果:30只大鼠均进入结果分析。①活体微循环观测:复苏后2h,雄性组大鼠毛细血管后小静脉内多形核白细胞数量明显增多,形成附壁。复苏后6h,雄性组毛细血管后小静脉内血流出现时快时慢甚至逆流的现象,说明雄性大鼠创伤失血性休克后微循环出现紊乱。②多形核白细胞附壁的分析:复苏后2h,雌性组和假手术组的多形核白细胞附壁数低于雄性组[(1.8±0.3),(0.4±0.2),(4.2±0.9)个,P<0.05]。但6h后各组之间差异不明显。③多形核白细胞黏附分子CD11b表达的测定:复苏后2h和6h,多形核白细胞黏附分子CD11b的表达雄性组明显高于雌性组和假手术组(P<0.01),雌性组和假手术组间差异不明显。④肺组织髓过氧化物酶活性测定:休克复苏后6h,雄性及雌性肺组织髓过氧化物酶活性都与各自的假手术组相比有显著的升高(P<0.05),但雌性组升高低于雄性组(P<0.05)。结论:创伤失血性休克后雌性大鼠多形核白细胞黏附分子CD11b的表达和多形核白细胞在毛细血管后微静脉内皮的附壁数量与雄性相比明显降低,多形核白细胞在肺组织中的浸润明显减少。     

Mutations of the alpha2(V) chain of type V collagen impair matrix assembly and produce ehlers-danlos syndrome type I

Ehlers-Danlos syndrome (EDS) is a heterogeneous connective tissue disorder that severely impairs the structure and function of the skin, joints, eyes and blood vessels. We have identified mutations of the COL5A2 gene, which encodes the alpha2(V) chain of type V collagen, in two unrelated patients with the severe type I form of EDS. The first proband was heterozygous for a 7 bp deletion that resulted in skipping of exon 27 while the second proband was heterozygous for a single nucleotide substitution that resulted in skipping of exon 28. Cultured dermal fibroblasts from both probands produced about equal amounts of the normal and mutant alpha2(V) mRNAs and protein chains. The dermis from the first proband contained a sparse collagen fibrillar network with great variability in collagen fibril sizes and shapes. The dermal collagens were also abnormally soluble. Bone cells from the first proband also produced about equal amounts of the normal and mutant alpha2(V) mRNAs. However, the collagen fibrillar architecture and collagen solubility of the bone matrix were normal. Our findings show that heterozygous mutations of the COL5A2 gene can produce the EDS type I phenotype. They also suggest that type V collagen plays a more important role in collagen fibrillogenesis of dermis than that of bone.      

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.