Vascular endothelial growth factor acts in an autocrine manner in rhabdomyosarcoma cell lines and can be inhibited with all-trans-retinoic acid

Vascular endothelial growth factor (VEGF) is a potent signalling molecule that acts through two tyrosine kinase receptors, VEGFR1 and VEGFR2. The upregulation of VEGF and its receptors is important in tumour-associated angiogenesis; however, recent studies suggest that several tumour cells express VEGF receptors and may be influenced by autocrine VEGF signalling. Rhabdomyosarcoma (RMS) is the most common paediatric soft-tissue sarcoma, and is dependent on autocrine signalling for its growth. The alveolar subtype of RMS is often characterized by the presence of a PAX3-FKHR translocation, and when introduced into non-RMS cells, the resultant fusion protein induces expression of VEGFR1. In our study, we examined the expression of VEGF and its receptors in RMS, and autocrine effects of VEGF on cell growth. VEGF and receptor mRNA and protein were found to be expressed in RMS cells. Exogenous VEGF addition resulted in extracellular signal-regulated kinase-1/2 phosphorylation and cell proliferation, and both were reduced by VEGFR1 blockade. Growth was also slowed by VEGFR1 inhibitor alone. Treatment of RMS cells with all-trans-retinoic acid decreased VEGF secretion and slowed cell growth, which was rescued by VEGF. These data suggest that autocrine VEGF signalling likely influences RMS growth and its inhibition may be an effective treatment for RMS.     

Association of ANKH gene polymorphisms with radiographic hand bone size and geometry in a Chuvasha population

We performed a family-based association study to test the hypothesis that genetic variation at the human orthologue of the mouse progressive ankylosis gene (ANKH) is involved in determining bone size (BS) and bone geometry (BG). The study population comprised 126 nuclear families with 574 adult Chuvashian individuals living in small villages in the Russian Federation. Quantitative bone traits were determined by analyzing plain hand radiographs. Familial correlations for all studied traits revealed a high degree of heritability in this ethnically homogeneous population. Three simple tandem repeat (STR) polymorphisms, one intragenic and two flanking markers, as well as six single nucleotide polymorphisms (SNPs) were tested. The SNPs were detected by re-sequencing experiments and covered ANKH exons with their flanking splice sites and the promoter region. We used three different transmission disequilibrium tests (TDTs) and obtained multiple significant association signals for all investigated bone traits. Alleles of several markers located at different positions of the ANKH locus, including the promoter, consistently revealed the association. The bone traits tested are closely related to bone fragility suggesting a role for ANKH in osteoporosis.     

Factors influencing survival in children with recurrent neuroblastoma

Despite advances in multimodal therapy for neuroblastoma, survival from advanced disease remains poor. Children are now offered a wide variety of salvage regimens following relapse. A retrospective review was performed on 31 patients with recurrent neuroblastoma treated at one institution between 1995 and 2001. At initial diagnosis, 27 patients had metastatic disease and 11 had N-myc amplification (NMA). The median time to recurrence from diagnosis was 16.1 months. Seventeen patients received salvage therapy, with a median of three salvage regimens per patient. The median survival time from relapse was 8.4 months. The median survival time was significantly shorter for recurrence less than 6 months after stem cell transplantation (2.9 vs. 13.3 months; P = 0.003) and for patients with NMA (2.7 vs. 15.1 months; P < 0.0001). Overall, salvage therapy led to a significantly longer median survival time (22.4 vs. 3.3 months; P = 0.0003); however, salvage therapy extended the median survival time only from 2.2 to 3.2 months for patients with NMA and from 0.7 to 5.8 months for patients with early relapse after stem cell transplantation. Multiple salvage regimens prolong survival significantly, especially for patients with no NMA and for relapses more than 6 months after stem cell transplantation, but the long-term disease-free survival after recurrent disease remains dismal.     

A mathematical comparison of techniques to predict biologically available testosterone in a cohort of 1072 men

OBJECTIVE: In the absence of widely available measures of determining free and/or bioavailable testosterone (BioT) physicians may use formulae such as the free androgen index (FAI) to estimate free testosterone. We compared the efficacy of calculated markers of androgen status in predicting serum BioT and hypogonadism. DESIGN: Total testosterone (TT), sex hormone binding globulin (SHBG) and BioT were determined in a large cohort of men. Comparison of calculated androgen levels was performed following endocrine assessment. METHODS: TT and SHBG were determined by ELISA, and BioT was determined by ammonium sulphate precipitation. From these data we calculated FAI and free testosterone using two other published formulae - FTnw (free testosterone as calculated by the method of Nanjeee and Wheeler) and FTv (free testosterone as calculated by the method of Vermeulen). A novel formula was derived to calculate BioT from given levels of TT and SHBG (BTcalculated). The ability of the methods (FAI, FTnw, FTv, BTcalc) to predict BioT were compared using regression analysis. The ability of these markers of androgen status to predict biochemical hypogonadism was compared using area under receiver operator curve (auROC). RESULTS: The equation derived from our data was the best predictor of BioT (R(2)=0.73, P<0.0001) although TT was also a good marker (R(2)=0.68, P=0.0001). In the determination of hypogonadism, of all currently available formulae none were better that the TT (auROC: TT=0.93, FAI=0.72, FTnw=0.91, FTv=0.88) although when TT is borderline (7.5相似文献   

T wave alternans: a marker of myocardial instability

T wave alternans is an electrocardiographic marker of myocardial electrical instability considered predictive for the development of lethal ventricular rhythms. Direct observation of this phenomenon on the electrocardiogram is rare. Subtle, nonvisible alternation of the T wave may be detected at the microvolt level using advanced signal processing techniques. This technology has enabled investigators and clinicians to identify and risk-stratify certain groups at high risk for sudden cardiac death. The purpose of this review is to discuss the concept of T wave alternans in relation to all cardiac alternans, provide an overview of its proposed mechanisms, and address the clinical utility of this electrocardiographic marker of myocardial electrical instability.     

Herpes as viewed by the French: result of a survey conducted on 10,000 persons

Herpes is a viral infection which increases, specifically genital herpes. The aim of this survey was to assess the perception of herpes in the general population and in patients with herpes in France using a self-administered questionnaire. A total of 10,000 persons answered the questionnaire among which 128 patients presented herpes. This study showed that only 5% of the French population knew that herpes was a viral infection, and 7% a sexually transmitted disease. Among patients with genital herpes only 34% indicated a sexual relationship and a mode of contamination. The interference with sexual and social life is important. Development of information and communication on herpes appears crucial.     

Modelling of age-related bone loss using cross-sectional data

BACKGROUND: Current applications of bone mineral density (BMD) data in age studies are not free of certain drawbacks. Since it is well established that age-related patterns of BMD changes involve three distinct periods (bone acquisition in youth, stabilization at maturity, and decrease with ageing), adjusting for age via an inappropriate mathematical function may lead to inconsistencies and wrong conclusions. HYPOTHESIS: The piecewise model, which encompasses the above three periods, will accurately describe the BMD dependence on age. OBJECTIVE: To examine age-related patterns of BMD changes using a number of possible mathematical functions and to find among them the best-fitting function. Next, to test whether the chosen function is universally applicable or if there are diverse population-specific functions. MATERIAL AND METHODS: Thirteen ethnic samples from various regions of Europe and Asia, assigned into five ethnic-geographic groups, were examined. The total sample included 2430 males and 2515 females. Compact BMD of hand phalanges was measured by photodensitometry from plain radiographs of each individual studied. Statistical software was developed for the purposes of the present study; this software gave a maximum likelihood of the parameter estimates for various statistical models (functions). RESULTS: In all samples of sufficient size and representative age range, a two-interval function was found as the best fitting and most parsimonious model to describe the BMD age-related changes. This two-interval function was characterized by age-related bone mass increase, positive slope beta(1s) in young age or a plateau (beta(1s) = 0, i.e. no age-related changes) until a sex-specific age threshold, T(0), after which annual bone loss ensued with a slope coefficient beta(2s). Threshold of BMD loss in women of different ethnic groups ranged between 37.85 and 47.77 years, and roughly coincided with perimenopausal age. In males, the age T(0) varied between 27.85 and 49.07 years. The ensuing cortical bone loss appeared to be linear in both sexes, averaging between 0.51% and 1.15% in men and between 0.74% and 1.77% per year of young age BMD value in females. CONCLUSIONS: The change of phalangeal BMD with age may be best described by a two-interval function, regardless of sex and ethnic background. However, specific parameter estimates depend both on gender and ethnic affiliation. This study has yielded a well-fitted model of BMD dependence on age suitable for further use in population studies.