IS SALT-WASTING IN CONGENITAL ADRENAL HYPERPLASIA DUE TO THE SAME GENE AS THE FASCICULATA DEFECT?

Clinical studies in patients with 21-hydroxylase deficiency congenital adrenal hyperplasia (CAH) were designed to ascertain the genetics of the salt-wasting component of the disorder. The gene controlling aldosterone biosynthesis may not be the same gene that controls 21-hydroxylase in the adrenal zona fasciculata. This we infer from the following clinical observations: (1) concordance for salt-wasting is not observed in all HLA-identical sibs with CAH; (2) the defect in aldosterone biosynthesis does not persist throughout life as does the fasciculata defect; (3) there is a significantly increased gene frequency of B40 and Bw47 in salt-wasting CAH; (4) obligate heterozygote parents of patients with salt-wasting CAH do not express a partial defect in aldosterone biosynthesis, as they do in the fasciculata. These observations cast doubt on the accepted concept of the autosomal recessive transmission of the glomerulosa 21-hydroxylase deficiency.     

Prediction of residual time to AIDS and death based on markers and cofactors

A model was constructed that estimates the probability of an HIV-infected individual developing AIDS or dying within a certain time span if left untreated, based on the most recent CD4 lymphocyte count, HIV-1 RNA load, and HIV-1 phenotype, together with age, time since seroconversion, and two genetic cofactors. The model helps clinicians in deciding when to start highly active antiretroviral treatment (HAART). Data from the Amsterdam Cohort Study among homosexual men restricted to individuals with an estimated date of seroconversion (N = 280) were used. Individual predictions based on several combinations of marker and cofactor values were obtained, and their accuracy was measured using two indices of predictive value. CD4 lymphocyte count and HIV RNA load have the highest predictive value and act independently. The predictive value of the HIV phenotype is only slightly lower and greatly enhances predictions at high CD4 counts. The CCR5-Delta32 and CCR2-64I alleles have no additional predictive value. Some predictive value is lost by not knowing time since seroconversion, and some effect of calendar period is present. In summary, for prognosis, the markers CD4 count, HIV-1 RNA load, and HIV-1 phenotype (at a high CD4 count) are equally important, and the genetic cofactors considered are of no use.     

Development of a replication‐deficient adenoviral vector‐based vaccine candidate for the interception of HPV16‐ and HPV18‐induced infections and disease

High‐risk Human papilloma virus (HPV) types are the causative agents of cervical cancer and several other anogenital malignancies. The viral proteins expressed in the (pre)malignant cells are considered ideal targets for immunological intervention. Many approaches have been evaluated for this purpose, mostly aiming at the induction of HPV16 E7‐ and/or E6‐specific cellular immunogenicity. As clinical success has so far been limited, novel approaches are required. We describe the development and pre‐clinical testing of a vaccine candidate consisting of replication‐deficient adenovirus type 26 and 35 based vectors for the interception of HPV16‐ and HPV18‐related disease. We developed HPV16‐ and HPV18‐specific antigens consisting of fusion proteins of E2, E6 and E7. The vaccine will be suitable for every disease stage, from incident and persistent infections where E2 is predominantly expressed up to late stages where E6 and E7 expression are upregulated. Importantly E6 and E7 are present as reordered fragments to abrogate the transforming activity of these two proteins. Loss of transforming activity was demonstrated in different in vitro models. Robust T‐cell immunogenicity was induced upon immunization of mice with the vaccine candidate. Finally, the developed vaccine vectors showed considerable therapeutic efficacy in the TC‐1 mouse model. The absence of transforming activity of the antigens and the favorable immunogenicity profile of the adenovirus based vectors along with the fact that these vectors can be readily produced on a large scale makes this approach attractive for clinical evaluation.     

Maternal deaths after elective cesarean section for breech presentation in the Netherlands

BACKGROUND AND METHODS: The cesarean section rate for term singleton breech babies in the Netherlands rose from 57 to 81% after the Term Breech Trial in 2000. The Dutch Maternal Mortality Committee registered and evaluated maternal mortality due to elective cesarean section for breech. RESULTS: Four maternal deaths after elective cesarean section for breech presentation, from 2000 to 2002 inclusive, were registered, 7% of total direct maternal mortality in that period. Two women died due to massive pulmonary embolism, both were obese, and thromboprophylaxis was not adjusted to their weight. The other two women died from sepsis, one had not receive perioperative prophylactic antibiotics. The case fatality rate for elective cesarean section for breech presentation was 0.47/1,000 operations. No death after emergency cesarean section for breech presentation was registered at the committee. CONCLUSIONS: Elective cesarean section does not guarantee the improved outcome of the child, but may increase risks for the mother, compared to vaginal delivery.     

CCR5-restricted HIV type 2 variants from long-term aviremic individuals are less sensitive to inhibition by beta-chemokines than low pathogenic HIV type 1 variants

Many HIV-2-infected individuals maintain low, often undetectable, viral loads for prolonged periods. Virus and/or host factors that contribute to this high level of virus control are largely unknown. Previously we demonstrated that HIV-2 variants from long-term aviremic individuals have relatively low replication kinetics in vitro in comparison to HIV-1 variants. We hypothesized that the relatively low replication rates of HIV-2 in vitro as well as the high level of virus control in vivo might be explained by HIV-2 replication being more sensitive to inhibitory host factors like beta-chemokines or other CD8+ T cell-derived factors than HIV-1 replication. To test this we determined the effect of exogenously added beta-chemokines and healthy donor CD8+ T cells on the in vitro virus production of HIV-2 and HIV-1 variants from long-term nonprogressors (LTNPs). Contrary to expectations, HIV-2 replication was inhibited less efficiently by RANTES and MIP-1alpha than HIV-1 replication. CD8+ T cells from 8 of 12 healthy donors reduced HIV replication minimally 2-fold. Interestingly, cells from five of these donors inhibited HIV-1 but hardly affected HIV-2 replication, while the reverse was observed for cells from one donor. For HIV-1, but not HIV-2, the magnitude of the antiviral effect of CD8+ T cells correlated with their effect on RANTES levels in culture supernatants. Our findings indicate that RANTES is a more important factor of CD8+ T cell-associated anti-HIV-1 activity than it is of HIV-2 activity and that the benign clinical course of HIV-2 infection is not due to enhanced beta-chemokine sensitivity of HIV-2 variants.     

Variación de la baricidad en la mezcla de anestesia espinal para cesárea, ¿tiene algún efecto en la calidad anestésica? Estudio aleatorizado,doble ciego,controlado

IntroductionThis study was conducted to compare the effectiveness subarachnoid anaesthesia with bupivacaine plus fentanyl at different concentrations of dextrose for caesarean section.MethodsA double-blind, randomised study, which included 60 patients, aged between 18 and 40 years, ASA I-II for caesarean section class 3 or 4, divided into 3 groups, designated A, B, and C corresponding to dextrose 2, 4 and 6%, respectively, bupivacaine 6.25 mg plus fentanyl 25 μg. Demographic characteristics were quantified, episodes of hypotension and bradycardia onset and duration of sensory block and motor block, surgeon and maternal satisfaction, adverse events and the effect of anaesthesia on the foetus and neonate. A p < .05 was considered statistically significant.ResultsThere was no difference in the demographic data, the three-anaesthetic mixture with dextrose were sufficient to provide level and duration of anesthesia for surgery. Maternal hypotension events were lower in group C (p < 0.05), the same group had lower external malleolus deep sensitivity (p < 0.05), only 5 cases were consistent with neonatal asphyxia, however the Apgar scores values were greater than 7 points, with satisfactory development.ConclusionsThe three anaesthetic mixtures for subarachnoid anaesthesia with bupivacaine-fentanyl are clinically effective; however, the greater the amount of dextrose used the better block quality.