Timeliness of infant vaccination and factors related with delay in Flanders,Belgium

Achieving high vaccination coverage is a necessary, but not a sufficient indicator of the quality of a vaccination programme, in terms of control and prevention of childhood infectious diseases. For optimal protection of infants, timeliness of vaccination is increasingly recognized as another important target.     

Inhibition of histone deacetylases by chlamydocin induces apoptosis and proteasome-mediated degradation of survivin

The naturally occurring cyclic tetrapeptide chlamydocin is a very potent inhibitor of cell proliferation. Here we show that chlamydocin is a highly potent histone deacetylase (HDAC) inhibitor, inhibiting HDAC activity in vitro with an IC(50) of 1.3 nM. Like other HDAC inhibitors, chlamydocin induces the accumulation of hyperacetylated histones H3 and H4 in A2780 ovarian cancer cells, increases the expression of p21(cip1/waf1), and causes an accumulation of cells in G(2)/M phase of the cell cycle. In addition, chlamydocin induces apoptosis by activating caspase-3, which in turn leads to the cleavage of p21(cip1/waf1) into a 15-kDa breakdown product and drives cells from growth arrest into apoptosis. Concomitant with the activation of caspase-3 and cleavage of p21(cip1/waf1), chlamydocin decreases the protein level of survivin, a member of the inhibitor of apoptosis protein family that is selectively expressed in tumors. Although our data indicate a potential link between degradation of survivin and activation of the apoptotic pathway induced by HDAC inhibitors, stable overexpression of survivin does not suppress the activation of caspase-3 or cleavage of p21(cip1/waf1) induced by chlamydocin treatment. The decrease of survivin protein level is mediated by degradation via proteasomes since it can be inhibited by specific proteasome inhibitors. Taken together, our results show that induction of apoptosis by chlamydocin involves caspase-dependent cleavage of p21(cip1/waf1), which is strikingly associated with proteasome-mediated degradation of survivin.     

Comparisons between in vitro whole cell imaging and in vivo zebrafish-based approaches for identifying potential human hepatotoxicants earlier in pharmaceutical development

Drug-induced liver injury (DILI) is a major cause of attrition during both the early and later stages of the drug development and marketing process. Reducing or eliminating drug-induced severe liver injury, especially those that lead to liver transplants or death, would be tremendously beneficial for patients. Therefore, developing new pharmaceuticals that have the highest margins and attributes of hepatic safety would be a great accomplishment. Given the current low productivity of pharmaceutical companies and the high costs of bringing new medicines to market, any early screening assay(s) to identify and eliminate pharmaceuticals with the potential to cause severe liver injury in humans would be of economic value as well. The present review discusses the background, proof-of-concept, and validation studies associated with high-content screening (HCS) by two major pharmaceutical companies (Pfizer Inc and Jansen Pharmaceutical Companies of Johnson & Johnson) for detecting compounds with the potential to cause human DILI. These HCS assays use fluorescent-based markers of cell injury in either human hepatocytes or HepG2 cells. In collaboration with Evotec, an independent contract lab, these two companies also independently evaluated larval zebrafish as an early-stage in vivo screen for hepatotoxicity in independently conducted, blinded assessments. Details about this model species, the need for bioanalysis, and, specifically, the outcome of the phenotypic-based zebrafish screens are presented. Comparing outcomes in zebrafish against both HCS assays suggests an enhanced detection for hepatotoxicants of most DILI concern when used in combination with each other, based on the U.S. Food and Drug Administration DILI classification list.     

Late erosions of mid-urethral tapes for stress urinary incontinence—need for long-term follow-up?

Tension-free vaginal tape (TVT) procedure has become one of the most common treatments of female urinary stress incontinence. Success rates as high as 81.3% were reported over a follow-up period of 7 years. Erosion of the synthetic mesh is a well-described complication. The mean time for the onset of erosion after sling insertion was 11.2 months. These case reports describe an erosion of a mid-urethral tape after 18 and 28 months, which is uncommon. There is a need for long-term follow-up of patients with TVT.     

Cultural differences affecting euthanasia practice in Belgium: one law but different attitudes and practices in Flanders and Wallonia

Since 2002, Belgium has had a national law legalising euthanasia. The law prescribes several substantive due care requirements and two procedural due care requirements, i.e. consultation with an independent physician and reporting of euthanasia to a Federal Control Committee. A large discrepancy in reporting rates between the Dutch-speaking (Flanders) and the French-speaking (Wallonia) parts of Belgium has led to speculation about cultural differences affecting the practice of euthanasia in both regions. Using Belgian data from the European Values Study conducted in 2008 among a representative sample of the general public and data from a large-scale mail questionnaire survey on euthanasia of 480 physicians from Flanders and 305 from Wallonia (conducted in 2009), this study presents empirical evidence of differences between both regions in attitudes towards and practice of euthanasia. Acceptance of euthanasia by the general population was found to be slightly higher in Flanders than in Wallonia. Compared with their Flemish counterparts, Walloon physicians held more negative attitudes towards performing euthanasia and towards the reporting obligation, less often labelled hypothetical cases correctly as euthanasia, and less often defined a case of euthanasia having to be reported. A higher proportion of Flemish physicians had received a euthanasia request since the introduction of the law. In cases of a euthanasia request, Walloon physicians consulted less often with an independent physician. Requests were more often granted in Flanders than in Wallonia (51% vs 38%), and performed euthanasia cases were more often reported (73% vs 58%). The study points out some significant differences between Flanders and Wallonia in practice, knowledge and attitudes regarding euthanasia and its legal requirements which are likely to explain the discrepancy between Wallonia and Flanders in the number of euthanasia cases reported. Cultural factors seem to play an important role in the practice of (legal) euthanasia and the extent to which legal safeguards are followed.     

Clinical study of solid dispersions of itraconazole prepared by hot-stage extrusion.

The aim of this study was to investigate the performance of three new solid dispersion formulations of itraconazole in human volunteers in comparison with Sporanox, the marketed form. Solid dispersions made up of itraconazole (40%, w/w) and HPMC 2910, Eudragit E100 or a mixture of Eudragit E100-PVPVA64 were manufactured by hot-stage extrusion and filled in gelatin capsules. The formulations were tested in eight human volunteers in a double blind, single dose, and cross-over study. Concentrations of the drug and its metabolite hydroxyitraconazole in the plasma were determined using HPLC. The in vivo performance was evaluated by comparing the mean area under the plasma concentration-time curves (AUC), the mean maximum plasma concentration (C(max)), and the mean time to reach C(max) (T(max)). The mean bioavailability of itraconazole was comparable after administration of the HPMC solid dispersion, compared to Sporanox, while it was lower after administration of the Eudragit E100 or Eudragit E100-PVPVA64 dispersions. Due to high variability, a significant decrease in AUC and C(max) was only observed for the Eudragit E100-PVPVA formulation. Although the solid dispersions showed different in vitro dissolution behaviour, T(max) values were comparable. The same observations with respect to AUC, C(max) and T(max) could be made for hydroxyitraconazole. The present results indicate that hot-stage extrusion can be considered as a valuable alternative for manufacturing solid dispersions of itraconazole.