New live mycobacterial vaccines: the Geneva consensus on essential steps towards clinical development

As the disease caused by Mycobacterium tuberculosis continues to be a burden, which the world continues to suffer, there is a concerted effort to find new vaccines to combat this problem. Of the various vaccines strategies, one viable option is the development of live mycobacterial vaccines. A meeting with researchers, regulatory bodies, vaccines developers and manufactures was held to consider the challenges and progress, which has been achieved with live mycobacterial vaccines (either modified BCG or attenuated M. tuberculosis). Discussion led to the production of a consensus document of the proposed entry criteria for Phase I clinical trials of candidate live mycobacterial vaccines. The vaccine must be characterised thoroughly to prove identity and consistency, as clinical trial lots are prepared. In pre-clinical studies, greater protective efficacy as well as improved safety potential relative to BCG should be considered when assessing potential vaccine candidates. A standard way to measure the protective efficacy to facilitate comparison between vaccine candidates was suggested. Additional safety criteria and verification of attenuation must be considered for attenuated M. tuberculosis. Two non-reverting independent mutations are recommended for such vaccines. When entering Phase I trials, enrollment should be based upon an acceptable characterisation of the study population regarding mycobacterium status and exclude HIV(+) individuals. BCG could be used as a comparator for blinding during the trials and to properly assess vaccine-specific adverse reactions, while assays are being developed to assess immunogenicity of vaccines. The proposed criteria suggested in this consensus document may facilitate the movement of the most promising vaccine candidates to the clinic and towards control of tuberculosis.     

Positional cloning of a gene involved in hereditary multiple exostoses

Hereditary multiple exostosis (EXT) is an autosomal dominant condition mainly characterized by the presence of multiple exostoses on the long bones. These exostoses are benign cartilaginous tumors (enchondromata). Three different EXT loci on chromosomes 8q (EXT1), 11p (EXT2) and 19p (EXT3) have been reported, and recently the EXT1 gene was identified by positional cloning. To isolate the EXT2 gene, we constructed a contig of yeast artificial chromosomes (YAC) and P1 clones covering the complete EXT2 candidate region on chromosome 11p11-p12. One of the transcribed sequences isolated from this region corresponds to a novel gene with homology to the EXT1 gene, and harbours inactivating mutations in different patients with hereditary multiple exostoses. This indicates that this gene is the EXT2 gene. EXT2 has an open reading frame encoding 718 amino acids with an overall homology of 30.9% with EXT1, suggesting that a family of related genes might be responsible for the development of EXT.      

结核病控制策略对患者涂阳率的影响

目的：探讨不同结核病控制策略与复治涂阳患形成的关系。方法：对宁夏实施世界银行贷款结构病控制项目前后两个不同时期结核病统计报表进行统计学X^2检验及直线相关分析。结果：宁夏实施项目以前的结核病控制策略导致新发涂阳肺结核患治愈率仅为34．33％，同期复治涂阳结核患比例高达68．79％，实施直接面视下短程化学疗法策略，使新发涂阳患治愈率提高到95％以上，同期复治涂阳肺结核患比例最低下降到18．27％，经相关处理，新发涂阳肺结核患的治愈率与复治涂阳患的比例之间呈明显的负相关。结论：现代结核商控制的直接面视下短程化学疗法策略能大幅度地养活复治涂阳患和耐多药结核患的产生。     

Supratheraputic rivaroxaban levels: A persistent drug‐drug interaction after discontinuation of amiodarone

We report the case of an 88‐year old woman referred for evaluation of increased INR. Surprisingly supratherapeutic levels of rivaroxaban was detected. Upon scrutiny of the patient's medical history, a drug‐drug interaction between amiodarone and rivaroxaban persisting 3 weeks after cessation of amiodaron remains the prime suspect causing the clinical picture. Both INR and rivaroxaban levels returned to normal within 3 days of cessation of rivaroxaban. The case highlights that rivaroxaban, although highly variably, does affect INR. Furthermore, it highlights that the potential for DDIs involving amiodarone may persists for weeks or months after discontinuation. Amiodarone is predicted to increase rivaroxaban exposure, through inhibition of rivaroxaban elimination via CYP3A4 and P‐gp. Elderly patients and patients with declining renal function are especially at risk of increased rivaroxaban exposure when a DDI with amiodarone occurs.     

Syntheses of the tricyclic cores of clozapine,dibenzo[b,f][1,4]thiazepin‐11(10H)‐one,and dibenzo[b,f][1,4]oxazepin‐11(10H)‐one in C‐14 labeled form by [14C]carbonylation

Clozapine has been demonstrated to bind covalently to proteins as a result of metabolic activation that has been proposed to be a precursor to the serious side effects including death that occur in a small percentage of the population. The covalent modification of proteins by clozapine has been studied by several groups and is well documented; therefore, the department of drug metabolism desired to use [¹⁴C]clozapine as a positive control for covalent binding assays. The preparation of [¹⁴C]clozapine was first conducted using a previous reported route and then using a new route that utilized [¹⁴C]carbonylation as the isotope incorporating step. While this route worked, it was not deemed superior to the previous route. However, this methodology proved quite effective in preparing C‐14 labeled dibenzothiazepine and dibenzoxapine ring systems. Copyright © 2010 John Wiley & Sons, Ltd.     

The antimicrobial resistance patterns and associated determinants in Streptococcus suis isolated from humans in southern Vietnam, 1997-2008

Background

Our objective was to determine the frequency and determinants of presentation to care with advanced HIV disease in patients who discover their HIV diagnosis at this stage as well as those with delayed presentation to care after HIV diagnosis in earlier stages.

Methods

We collected data on 1,819 HIV-infected patients in Brussels (Belgium) and Northern France from January 1997 to December 2007. "Advanced HIV disease" was defined as CD4 count <200/mm³ or clinically-defined AIDS at study inclusion and was stratified into two groups: (a) late testing, defined as presentation to care with advanced HIV disease and HIV diagnosis ≤6 months before initiation of HIV care; and (b) delayed presentation to care, defined as presentation to care with advanced HIV disease and HIV diagnosis >6 months before initiation of HIV care. We used multinomial logistic regression to determine the factors associated with delayed presentation to care and late testing.

Results

Of the 570 patients initiating care with advanced HIV disease, 475 (83.3%) were tested late and 95 (16.7%) had delayed presentation to care. Risk factors for delayed presentation to care were: age 30-50 years, injection drug use, and follow-up in Brussels. Risk factors for late testing were: sub-Saharan African origin, male gender, and older age. HIV transmission through heterosexual contact was associated with an increased risk of both delayed presentation to care and late testing. Patients who initiated HIV care in 2003-2007 were less likely to have been tested late or to have a delayed presentation to care than patients who initiated care before 2003.

Conclusion

A considerable proportion of HIV-infected patients present to care with advanced HIV disease. Late testing, rather than a delay in initiating care after earlier HIV testing, is the main determinant of presentation to care with advanced HIV disease. The factors associated with delay presentation to care differ from those associated with late testing. Different strategies should be developed to optimize early access to care in these two groups.     

Use of Testosterone Replacement Therapy in Patients with Prostate Cancer

Prostate cancer is among the more common and less lethal malignancies, yielding a large population of survivors. The incidence of hypogonadism increases in the same elderly population of men who most frequently develop prostate cancer, and the risk of becoming hypogonadal is increased further by prostate cancer therapy. The relative safety of replacing testosterone to reduce symptoms of hypogonadism in men who have been treated for prostate cancer is not well established. We review the available data, provide suggestions for approaching the management of prostate cancer survivors who suffer hypogonadal symptoms, and describe other diagnostic and therapeutic uses of testosterone that have been employed in patients with prostate cancer.     

Blood cells and their use in active immunotherapy of prostate cancer

Immune therapy has traditionally had a limited role in the treatment of solid malignancies, outside of renal cancer and melanoma. However, early evidence of the ability to provoke an effective anti-tumor immune response in prostate cancer has led to interest in developing a variety of immune activating strategies in this disease. The first immune therapy to attain success in prolonging survival for metastatic prostate cancer patients is Sipuleucel-T. Rather than utilizing a typical vaccine approach in which antigens and immune activators are injected into the cancer host, sipuleucel-T was developed to stimulate autologous dendritic cells ex vivo, in order to evade the immune suppressive environment created by the cancer. We review the components of the immune system which may be harnessed in the development of immunotherapy in the setting of the recent success with sipuleucel-T.