The pharmacokinetic diversity of two von Willebrand factor (VWF)/ factor VIII (FVIII) concentrates in subjects with congenital von Willebrand disease. Results from a prospective, randomised crossover study

The pharmacokinetic (PK) profiles of von Willebrand factor (VWF) /factor VIII (FVIII) concentrates are important for treatment efficacy and safety of von Willebrand disease (VWD) patients. This prospective, head-to-head, randomised crossover study compared the PK profile of a new, high purity, human plasma-derived (pd)VWF/FVIII concentrate, Wilate, with the PK profile of an intermediate purity (pd)VWF/FVIII concentrate, Humate-P, in VWD patients. Subjects with inherited VWD were randomised to a single intravenous dose (40 IU/kg VWF ristocetin cofactor activity [VWF:RCo]) of Wilate or Humate-P in Period 1, and switched to the other study drug in Period 2. Each period was preceded by a washout time of ≥ 7 days. Coagulation factor parameters were analysed at multiple time-points. Of 22 randomised subjects, 20 had evaluable PK profiles, which indicated comparability for VWF antigen and VWF:RCo between Wilate and Humate-P. The reported VWF:RCo average and terminal t1/2 of 10.4 and 15.8 hours (h), respectively, for Wilate and 9.3 h and 12.8 h for Humate-P, were not statistically different. Also, the mean VWF:RCo in vivo recoveries (Wilate 1.89, Humate-P 1.99 IU/dl per IU/kg) were similar between the two replacement therapies. Wilate showed parallel decay curves for VWF:RCo and FVIII clotting activity (FVIII:C) over time, while FVIII:C of Humate-P displayed a plateau between 0 and 12-24 h. This study demonstrated bioequivalent PK properties for VWF between Wilate and Humate-P. The PK profile of Wilate, combined with the 1:1 VWF/FVIII ratio, theoretically should facilitate dosing and laboratory monitoring of VWF replacement to prevent bleeding in individuals with VWD.     

Heterologous expression in transgenic mosquitoes

Arthropod-borne diseases such as malaria and dengue virus afflict billions of people worldwide imposing major economic and social burdens. Control of such pathogens is mainly performed by vector management and treatment of affected individuals with drugs. The failure of these conventional approaches due to emergence of insecticide-resistant insects and drug-resistant parasites demonstrate the need of novel and efficacious control strategies to combat these diseases. Genetic modification (GM) of mosquito vectors to impair their ability to be infected and transmit pathogens has emerged as a new strategy to reduce transmission of many vector-borne diseases and deliver public health gains. Several advances in developing transgenic mosquitoes unable to transmit pathogens have gained support, some of them attempt to manipulate the naturally occurring endogenous refractory mechanisms, while others initiate the identification of an exogenous foreign gene which disrupt the pathogen development in insect vectors. Heterologous expression of transgenes under a native or heterologous promoter is important for the screening and effecting of the transgenic mosquitoes. The effect of the transgene on mosquito fitness is a crucial parameter influencing the success of this transgenic approach. This review examines these two aspects and describes the basic research work that has been accomplished towards understanding the complex relation between the parasite and its vector and focuses on recent advances and perspectives towards construction of transgenic mosquitoes refractory to vector-borne disease transmission.     

Audit of patient's waiting time to see their family doctor prior to referral to a fast-access breast clinic in the era of a guaranteed 2-week wait

PURPOSE: A prospective study aimed at assessing the effect of introduction of a fast-tract referral system for patients with suspected breast cancer and the quality of GP referrals in Barnsley. METHODS: Between February and April 2001, 70 consecutive patients with symptomatic breast disorders were seen in the fast-access breast clinic. Mean age=46 years (range 18-84). Ten non-urgent referrals seen in the study period were included in the analysis to determine the appropriateness of such referrals. Three screening criteria were used to select high-risk patients and data were recorded prospectively. Patients were classified as urgent, soon or routine based on symptomatology. RESULTS: Of the 70 patients seen, 20 were considered as urgent, 20 as soon and 30 as routine. Forty patients were seen within the '2-week wait' period. Twelve were classified on clinical grounds as malignant. Mean waiting time to see the GP was 2.2 days. Mean waiting time to see the specialist breast surgeon was 6.6 days. CONCLUSION: A fast-track system for suspected breast cancer has led to a significant reduction in the time to diagnosis and initiation of a definitive treatment, with most made within 2 weeks. Fast-track referrals is not appropriate in all cases.     

USEFULNESS OF EVALUATION OF ANTIMEASLES ANTIBODIES IN PRETERM BABIES

As per WHO recommendations, measles vaccine is administered at the age of 9 months which is based on studies demonstrating seroconversion (from positive to negative) at this age. However this contention may not hold good in preterm babies since they may have lower initial levels of passively transferred IgG antimeasles antibodies of maternal origin. To explore this possibility, 50 preterm babies (gestational age less than 37 weeks) were studied for antimeasles antibodies. Serum samples were collected at birth and then at 3 months and 5 months of age in all the cases. Antimeasles antibody assay was done in all the serum samples using ELISA kits. At birth 32% of infants were positive for antimeasles antibodies whereas 60% were weakly positive and 8% were negative. At 3 months of age 50% were sero negative, 2% positive and 40% weakly positive. The sero negativity was found to be 98% at 5 months with only 2% remaining positive. Since seroconversion is seen to occur in this vast majority of preterm infants at the age of 5 months, antimeasles vaccine should be administered at this age to this subset of more vulnerable babies.KEY WORDS: Antimeasles antibodies, Preterm babies, Seroconversion     

Prospective development of an individualised predictive model for treatment coverage using offline cone beam computed tomography surrogate measures in post‐prostatectomy radiotherapy

The aim of this study is to prospectively evaluate and model surrogate explanatory variables (SEVs) of target coverage and rectal dose pertaining to soft tissue anatomy visualised on cone beam computed tomography (CBCT) for incorporation into post‐prostatectomy treatment coverage verification protocols. Twenty post‐prostatectomy patients treated with conformal prostate bed radiotherapy (64–74 Gy) underwent CBCT daily at fractions 1 to 5, and then weekly. Treatment coverage was defined on each CBCT using ‘PTV95’, percentage of the CBCT PTV covered by original treatment fields, and ‘RECTD50’, dose delivered to 50% of CBCT rectal volume by original treatment fields. Three candidate SEVs for treatment coverage were defined for each scan: anterior rectal wall movement, change in bladder length and bladder base movement. Both anterior rectal wall movement and increase in bladder length predicted for the decreased PTV95 (P < 0.001 for each). Anterior movement of the anterior rectal wall predicted for increased RECTD50 (P < 0.001). Predictive models for the PTV95 and RECTD50 that accept the significant SEVs as inputs were developed. We developed simple CBCT‐acquired soft tissue anatomic surrogate measures that signal changes in target coverage and rectal dose during post‐prostatectomy radiotherapy. Conventional bony anatomy patient position verification protocols were inadequate in accounting for soft tissue target and organ variation seen with CBCT.     

常用抗高血压药物对血压的时间生物学特征的影响

目的 :探讨 3类常用抗高血压药物对非杓型的高血压病患者BP的时间生物学特征的影响。方法 :共入选非杓型BP分布的高血压病患者 16 1例 ,将其随机分为 3组 ,分别给予赖诺普利 (10mg·d-1) ,非洛地平 (2 5mg·d-1) ,或氢氯噻嗪 (5 0mg·d-1) ,并于治疗前后行 2 4h动态BP监测。采用余弦拟合方法分析治疗前后患者BP时间生物学特征的改变。结果 :赖诺普利组与非洛地平组治疗后 2 4hBP均值明显降低 ,但其振幅、峰值相位无变化 ;氢氯噻嗪治疗降压效果不甚理想 ,但显著增加了患者BP的夜间降低幅度 ,使患者BP由非杓型转变为杓型分布。结论 :氢氯噻嗪治疗可能使非杓型分布的高血压病患者的BP转变为杓型分布 ,从而有助于降低患者相关并发症的发生率。