Recruitment and baseline epidemiologic profile of participants in the first phase 3 HIV vaccine efficacy trial

OBJECTIVE: To describe recruitment and baseline epidemiologic characteristics of volunteers in the first phase 3 placebo-controlled trial of a recombinant gp120 HIV vaccine (AIDSVAX B/B). METHODS: Volunteers were gay/bisexual men or women at risk for sexually transmitted HIV infection. Recruitment strategies, demographics, and risk factors were assessed. HIV status was determined by standard HIV-1 antibody assays. Seronegative/viremic HIV infection at enrollment was determined using the HIV-1 nucleic acid test. RESULTS: From June 1998 through October 1999, 5417 of 7185 volunteers screened were enrolled at 61 sites in the United States, Canada, and The Netherlands. Successful recruitment methods included distribution of study information at gay venues, advertising and media coverage, and referrals from volunteers. Most volunteers were altruistically motivated, men (98%), young (median, 36 years), white (83%), well educated (61% college education or more), and at high risk for HIV during the 6 months before enrollment. At baseline, 14 were HIV infected (12 were seronegative but viremic; 2 were seropositive and viremic). CONCLUSION: Men and women at high risk for sexually transmitted HIV infection were successfully recruited for the first phase 3 HIV vaccine efficacy trial. Knowledge of recruitment and baseline epidemiologic characteristics of participants in this trial will provide valuable guidance for designing and conducting future trials.     

Localization,structure and polymorphism of two paralogous <Emphasis Type="Italic">Xenopus laevis</Emphasis> mitochondrial malate dehydrogenase genes

Two paralogous mitochondrial malate dehydrogenase 2 (Mdh2) genes of Xenopus laevis have been cloned and sequenced, revealing 95% identity. Fluorescence in-situ hybridization (FISH) combined with tyramide amplification discriminates both genes; Mdh2a was localized into chromosome q3 and Mdh2b into chromosome q8. One kb cDNA probes detect both genes with 85% accuracy. The remaining signals were on the paralogous counterpart. Introns interrupt coding sequences at the same nucleotide as defined for mouse. Restriction polymorphism has been detected in the first intron of Mdh2a, while the individual variability in intron 6 of Mdh2b gene is represented by an insertion of incomplete retrotransposon L1Xl. Rates of nucleotide substitutions indicate that both genes are under similar evolutionary constraints. X. laevis Mdh2 genes can be used as markers for physical mapping and linkage analysis.     

Valoración de parámetros clínicos y analíticos preoperatorios en apendicitis aguda complicada. Score para predecir apendicitis complicada

BackgroundTo analyze whether clinical and analytical parameters differ according to histopathology in cases of acute appendicitis (AA).MethodsThis is a retrospective, observational study including patients (>14 years of age) admitted for suspicion of AA from 1 April 2014 to 31 July 2016. Histopathology was divided into complicated (including perforated and gangrenous AA) and uncomplicated appendicitis (phlegmonous). Sex, age, temperature of patients on admission to the Emergency Department, symptom duration, preoperative white blood cell (WBC) count, neutrophil percentage, mean platelet volume (MPV), platelet distribution width (PDW), C-reactive protein (CRP) and hospital stay were compared in the two groups.ResultsThree hundred and thirty-five patients were analyzed, and 284 were included. Appendicitis was uncomplicated in 194 (68.3%) and complicated in 90 (31.7%). Age, symptom duration, neutrophil percentage, CRP and hospital stay were higher in the complicated AA group (P < .05). The mean differences between uncomplicated and complicated AA were: age 13.2 years (95% CI: 8.2-18.2), symptom duration 14.1 hours (95% CI: 6.3-21.9), neutrophil percentage 5.0% (95% CI: 3.2-6.8), CRP 73.6 mg/l (95% CI: 50.0-97.2) and hospital stay 2.2 days (95% CI: 1.4-3.0), with p<0.05 for all these variables. A model based on the preoperative parameters (age, symptom duration, neutrophil percentage and CRP) was calculated to predict the likelihood of complicated AA. The receiver operating characteristic (ROC) of the model had an area under the curve of 0.80 (95% CI 0.75-0.85).ConclusionThis model is able to diagnose complicated AA without the need for imaging techniques, although it must be validated with prospective analysis.     

Zoledronic acid-related angiogenesis modifications and survival in advanced breast cancer patients.

The proven antiangiogenic activity of zoledronic acid, a third-generation bisphosphonate widely used in bone metastatic cancer patients, led us to investigate if the vascular endothelial growth factor (VEGF)-related zoledronic acid modifications are correlated with survival advantages in advanced breast cancer patients. Forty-two consecutive breast cancer patients with scintigraphic and radiographic evidence of bone metastases were treated with a single infusion of 4 mg zoledronic acid before anticancer chemotherapy. The patients were prospectively evaluated for circulating levels of VEGF and interferon-gamma (IFN-gamma) just before and at 1, 2, 7, and 21 days after zoledronic acid infusion. Afterward, clinical outcome was prospectively monitored. The basal serum VEGF median levels were significantly decreased at each time point, but the major reduction was recorded 21 days after the infusion. In particular, 25 patients of 42 (59.5%) experienced a reduction of at least 25% in the VEGF circulating levels. In contrast, no statistically significant modifications of the IFN-gamma serum levels were recorded. We stratified patients on the basis of this VEGF reduction 21 days after the infusion. No differences in patient features were recorded between those with or without the VEGF reduction. The analysis of survival showed that patients with a reduction in the VEGF circulating levels had a longer time to first skeletal-related event (p = 0.0002), time to bone progression disease (p = 0.0024), and time to performance status worsening (p = 0.0352) than those without the VEGF reduction. No statistically significant differences were recorded in terms of overall survival and time to visceral progression. This study confirms that zoledronic acid could have an in vivo antiangiogenic property and that the VEGF modifications may represent a surrogate marker able to predict time to first skeletal-related event, time to bone progression disease, and time to worsening of performance status.     

Pb2+ modulates the NMDA-receptor-channel complex

Summary The actions of Pb²⁺ on NMDA channel currents of acutely dissociated hippocampal CA1- and CA3-neurones from adult rats activated by aspartate plus glycine (asp/gly) were examined. A fast reversible and a slow irreversible response to Pb²⁺ were found. Pb²⁺ applied simultaneously with asp/gly decreased an inward current. The threshold concentration was below 2 M, the current was reduced > 90% at concentrations over 100 M, The decrease of the asp/gly activated current showed no voltage dependence. Opening of NMDA channels was not necessary for Pb²⁺-action, as preincubation in 50 M Pb²⁺-containing external solution for several seconds dramatically reduced the response to asp/gly/Pb²⁺. This effect was reversed within 2 to 5 s of wash. Presence of Pb²⁺ or asp/Pb²⁺ or glycine/Pb²⁺ in the external solution did not prevent recovery of the NMDA receptor/channel complex from desensitization. Prolonged perfusion of a cell with the asp/gly/Pb²⁺-containing external solution resulted in an irreversible decrease of the asp/gly current, whereas the amplitude of the asp/gly/Pb²⁺ response did not change over the duration of an experiment. We conclude that Pb²⁺ modulates NMDA channel activity via interaction with the NMDA/glycine receptor: as a result the channel current decreases.Abbreviations NMDA N-methyl-D-aspartate - LTP long-term potentiation - AP5 2-amino-5-phosphonovalerate - EGTA ethylene glycol bis(-aminoethylether)-N,N,N,N-tetraacetic acid - HEPES 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid Correspondence to H. L. Haas at the above address     

Pathogenetic role and clinical significance of interleukin-1β in cancer

In recent years, pro-oncogenic mechanisms of the tumour microenvironment (ТМЕ) have been actively discussed. One of the main cytokines of the TМЕ is interleukin-1 beta (IL-1β), which exhibits proinflammatory properties. Some studies have shown an association between an increase in IL-1β levels and tumour progression. The purpose of this review is to analyse the pathogenic mechanisms induced by IL-1β in the TМЕ, as well as the diagnostic significance of the presence of IL-1β in patients with cancer and the efficacy of treatment with IL-1β inhibitors. According to the literature, IL-1β can induce an increase in tumour angiogenesis due to its effects on the differentiation of epithelial cells, pro-angiogenic molecule secretion and expression of adhesion molecules, thus increasing tumour growth and metastasis. IL-1β is also involved in the suppression of anti-tumour immune responses. The expression and secretion of IL-1β has been noted in various types of tumours. In some clinical studies, an elevated level of IL-1β was found to be associated with low efficacy of anti-cancer therapy and a poor prognosis. In most experimental and clinical studies, the use of IL-1β inhibitors contributed to a decrease in tumour mass and an increase in the response to anti-tumour drugs.     

Molecular genetic studies of early breast cancer evolution

Summary In the past few years there has been an explosion in the number of patients diagnosed with hyperplastic breast disease andin situ breast cancer. Based on epidemiological data, these morphologically defined lesions may be categorized as those with little malignant potential (e.g. typical hyperplasia or proliferative disease without atypia [PDWA]), those with significant malignant potential which may already be initiated (e.g. atypical ductal hyperplasia [ADH]), and early transformed lesions which are malignant but not yet invasive (e.g. ductal carcinomain situ [DCIS]). They may represent sequential evolutionary stages in the ontogeny of invasive breast cancer, with each morphologically defined stage resulting from accumulating genetic changes culminating in a transformed clonal lineage capable of invasion and metastasis. Using loss-of-heterozygosity (LOH) analysis, we are studying the genetic changes associated with these lesions in archival tissue samples. 50% (6/12) of the proliferative lesions (PDWA and ADH) and 80% of the DCIS shared their LOH patterns with more advanced lesions from the same breast, strongly supporting a precursor/product relationship between these lesions and the cancers they accompany.     

A genetic study of idiopathic focal dystonias

The inheritance of focal dystonias was investigated in 43 families containing 43 index cases with torticollis (n = 21), blepharospasm (n = 18) and writer's cramp (n = 4). They generated a potential population of 235 first-degree relatives, and 168 out of 179 living first-degree relatives were examined. Ten relatives with dystonia were identified in ten families. Another two parents from two of the same group of ten families were affected according to the family history. The majority of the secondary cases (six patients, five siblings, and one child) were not aware of any dystonia. The tendency for affected relatives to have the same type of dystonia as index patients was observed only for torticollis. Overall, 23% of index patients had relatives with dystonia. Segregation analysis suggested the presence of an autosomal dominant gene or genes with reduced penetrante underlying focal dystonia.