Improved general health of international adoptees, but immunization status still insufficient

We studied the demographic and clinical data from 495 adopted children seen between January 2002 and January 2007 to evaluate the medical condition and immunization status of international adoptees. The data of children from Chinese origin (53.5%) were compared to children arriving from other countries. Medical problems requiring treatment were present in 42.8% of the children. Parasitic gastrointestinal infection (22.0%) and skin abnormalities (22.4%) were diagnosed most often. Hepatitis B (1.2%) and tuberculosis (1%) were documented in some children; HIV, hepatitis C, and syphilis were not seen in any of the children. Antibody levels against diphtheria and tetanus were insufficient in about half of all children, particularly in those from China. In conclusion, most adoptive children had a good general health, with only a few having major medical problems. Many adoptive children had an inadequate immunization status

Use of radiolabelled choline as a pharmacodynamic marker for the signal transduction inhibitor geldanamycin

There is an urgent need to develop non-invasive pharmacodynamic endpoints for the evaluation of new molecular therapeutics that inhibit signal transduction. We hypothesised that, when labelled appropriately, changes in choline kinetics could be used to assess geldanamycin pharmacodynamics, which involves inhibition of the HSP90 molecular chaperone→Raf1→Mitogenic Extracellular Kinase→Extracellular Signal-Regulated Kinase 1 and 2 signal transduction pathway. Towards identifying a potential pharmacodynamic marker response, we have studied radiolabelled choline metabolism in HT29 human colon carcinoma cells following treatment with geldanamycin. We studied the effects of geldanamycin, on net cellular accumulation of (methyl-14C)choline and (methyl-14C)phosphocholine production. In parallel experiments, the effects of geldanamycin on extracellular signal-regulated kinase 1 and 2 phosphorylation and cell viability were also assessed. Additional validation studies were carried out with the mitogenic extracellular kinase inhibitor U0126 as a positive control; a cyclin-dependent kinase-2 inhibitor roscovitine and the phosphatidylinositol 3-kinase inhibitor LY294002 as negative controls. Hemicholinium-3, an inhibitor of choline transport and choline kinase activity was included as an additional control. In exponentially growing HT29 cells, geldanamycin inhibited extracellular signal-regulated kinase 1 and 2 phosphorylation in a concentration- and time-dependent manner. These changes were associated with a reduction in (methyl-14C)choline uptake, (methyl-14C) phosphocholine production and cell viability. Brief exposure to U0126, suppressed phosphocholine production to the same extent as Hemicholinium-3. In contrast to geldanamycin and U0126, which act upstream of extracellular signal-regulated kinase 1 and 2, roscovitine and LY294002 failed to suppress phosphocholine production. Our results suggest that when labelled with carbon-11 isotope, (methyl-11C)choline may be a useful pharmacodynamic marker for the non-invasive evaluation of geldanamycin analogues

Sexual Size Dimorphism and Body Condition in the Australasian Gannet

Funding: The research was financially supported by the Holsworth Wildlife Research Endowment. Acknowledgments We thank the Victorian Marine Science Consortium, Sea All Dolphin Swim, Parks Victoria, and the Point Danger Management Committee for logistical support. We are grateful for the assistance of the many field volunteers involved in the study.Peer reviewedPublisher PD

Systematically missing confounders in individual participant data meta-analysis of observational cohort studies.

One difficulty in performing meta-analyses of observational cohort studies is that the availability of confounders may vary between cohorts, so that some cohorts provide fully adjusted analyses while others only provide partially adjusted analyses. Commonly, analyses of the association between an exposure and disease either are restricted to cohorts with full confounder information, or use all cohorts but do not fully adjust for confounding. We propose using a bivariate random-effects meta-analysis model to use information from all available cohorts while still adjusting for all the potential confounders. Our method uses both the fully adjusted and the partially adjusted estimated effects in the cohorts with full confounder information, together with an estimate of their within-cohort correlation. The method is applied to estimate the association between fibrinogen level and coronary heart disease incidence using data from 154,012 participants in 31 cohort

Gap Junction Mediated Intercellular Metabolite Transfer in the Cochlea Is Compromised in Connexin30 Null Mice

Connexin26 (Cx26) and connexin30 (Cx30) are two major protein subunits that co-assemble to form gap junctions (GJs) in the cochlea. Mutations in either one of them are the major cause of non-syndromic prelingual deafness in humans. Because the mechanisms of cochlear pathogenesis caused by Cx mutations are unclear, we investigated effects of Cx30 null mutation on GJ-mediated ionic and metabolic coupling in the cochlea of mice. A novel flattened cochlear preparation was used to directly assess intercellular coupling in the sensory epithelium of the cochlea. Double-electrode patch clamp recordings revealed that the absence of Cx30 did not significantly change GJ conductance among the cochlear supporting cells. The preserved electrical coupling is consistent with immunolabeling data showing extensive Cx26 GJs in the cochlea of the mutant mice. In contrast, dye diffusion assays showed that the rate and extent of intercellular transfer of multiple fluorescent dyes (including a non-metabolizable D-glucose analogue, 2-NBDG) among cochlear supporting cells were severely reduced in Cx30 null mice. Since the sensory epithelium in the cochlea is an avascular organ, GJ-facilitated intercellular transfer of nutrient and signaling molecules may play essential roles in cellular homeostasis. To test this possibility, NBDG was used as a tracer to study the contribution of GJs in transporting glucose into the cochlear sensory epithelium when delivered systemically. NBDG uptake in cochlear supporting cells was significantly reduced in Cx30 null mice. The decrease was also observed with GJ blockers or glucose competition, supporting the specificity of our tests. These data indicate that GJs facilitate efficient uptake of glucose in the supporting cells. This study provides the first direct experimental evidence showing that the transfer of metabolically-important molecules in cochlear supporting cells is dependent on the normal function of GJs, thereby suggesting a novel pathogenesis process in the cochlea for Cx-mutation-linked deafness

Unexpected combination of acute croup and myocarditis: Case report

BACKGROUND: Lower vaccination coverage among foreign-born children is of concern because they live in households and communities characterized by more intense exposure to infectious diseases. Because of their higher prevalence rates, there is an increasing occurrence of infectious diseases imported into developed countries. This case report emphasizes the emerging necessity for new clinicians and pathologists of having competence with old infectious disease pathology. CASE PRESENTATION: A three and a half year old girl, who presented with croup history of 5 days and has been in severe respiratory distress, was admitted to the Pediatric Intensive Care Unit in shock and acute respiratory failure. The patient was immediately intubated, and a grayish nonadherent membrane extending through the glottis down into the larynx was apparent during the procedure. Echocardiographic findings, which were consistent with acute myocarditis, confirmed poor left ventricular contractility despite escalating high doses of inotropes. Autopsy showed numerous strains of toxigenic corynobacterium diphtheriae, which also grew on the Loeffler cultures of membranes received during the intubation. CONCLUSION: It is critical that new generations of clinicians and bio-pathologists not only be trained in the subspecialty of infectious disease pathology, but that they also be willing participants in the diagnosis and investigation of infectious diseases

In Vivo Analysis of the Role of O-Glycosylations of Von Willebrand Factor

The objective of this project was to study the function of O-glycosylations in von Willebrand factor (VWF) life cycle. In total, 14 different murine Vwf cDNAs mutated on one or several O-glycosylations sites were generated: 9 individual mutants, 2 doublets, 2 clusters and 1 mutant with all 9 murine glycosylation sites mutated (Del-O-Gly). We expressed each mutated cDNA in VWF deficient-mice by hydrodynamic injection. An immunosorbent assay with Peanut Agglutinin (PNA) was used to verify the O-glycosylation status. Wild-type (WT) VWF expressed by hepatocytes after hydrodynamic injection was able to bind PNA with slightly higher affinity than endothelial-derived VWF. In contrast, the Del-O-Gly VWF mutant did not bind PNA, demonstrating removal of O-linked glycans. All mutants displayed a normal multimeric pattern. Two mutants, Del-O-Gly and T1255A/T1256A, led to expression levels 50% lower than those induced by WT VWF and their half-life in vivo was significantly reduced. When testing the capacity of each mutant to correct the bleeding time of VWF-deficient mice, we found that S1486A, T1255A, T1256A and the doublet T1255A/T1256A were unable to do so. In conclusion we have shown that O-glycosylations are dispensable for normal VWF multimerization and biosynthesis. It also appears that some O-glycosylation sites, particularly the T1255 and T1256 residues, are involved in the maintenance of VWF plasma levels and are essential for normal haemostasis. As for the S1486 residue, it seems to be important for platelet binding as demonstrated in vitro using perfusion experiments

Impaired Heat Shock Response in Cells Expressing Full-Length Polyglutamine-Expanded Huntingtin

The molecular mechanisms by which polyglutamine (polyQ)-expanded huntingtin (Htt) causes neurodegeneration in Huntington's disease (HD) remain unclear. The malfunction of cellular proteostasis has been suggested as central in HD pathogenesis and also as a target of therapeutic interventions for the treatment of HD. We present results that offer a previously unexplored perspective regarding impaired proteostasis in HD. We find that, under non-stress conditions, the proteostatic capacity of cells expressing full length polyQ-expanded Htt is adequate. Yet, under stress conditions, the presence of polyQ-expanded Htt impairs the heat shock response, a key component of cellular proteostasis. This impaired heat shock response results in a reduced capacity to withstand the damage caused by cellular stress. We demonstrate that in cells expressing polyQ-expanded Htt the levels of heat shock transcription factor 1 (HSF1) are reduced, and, as a consequence, these cells have an impaired a heat shock response. Also, we found reduced HSF1 and HSP70 levels in the striata of HD knock-in mice when compared to wild-type mice. Our results suggests that full length, non-aggregated polyQ-expanded Htt blocks the effective induction of the heat shock response under stress conditions and may thus trigger the accumulation of cellular damage during the course of HD pathogenesis

Treatment success for overactive bladder with urinary urge incontinence refractory to oral antimuscarinics: a review of published evidence

<p>Abstract</p> <p>Background</p> <p>Treatment options for overactive bladder (OAB) with urinary urge incontinence (UUI) refractory to oral antimuscarinics include: botulinum toxin type A (BoNTA), sacral neuromodulation (SNM), and augmentation cystoplasty (AC). A standard treatment success metric that can be used in both clinical and economic evaluations of the above interventions has not emerged. Our objective was to conduct a literature review and synthesis of published measures of treatment success for OAB with UUI interventions and to identify a treatment success outcome.</p> <p>Methods</p> <p>We performed a literature review of primary studies that used a definition of treatment success in the OAB with UUI population receiving BoNTA, SNM, or AC. The recommended success outcome was compared to generic and disease-specific health-related quality-of-life (HRQoL) measures using data from a BoNTA treatment study of neurogenic incontinent patients.</p> <p>Results</p> <p>Across all interventions, success outcomes included: complete continence (n = 23, 44%), ≥ 50% improvement in incontinence episodes (n = 16, 31%), and subjective improvement (n = 13, 25%). We recommend the OAB with UUI treatment success outcome of ≥ 50% improvement in incontinence episodes from baseline. Using data from a neurogenic BoNTA treatment study, the average change in the Incontinence Quality of Life questionnaire was 8.8 (95% CI: -4.7, 22.3) higher for those that succeeded (N = 25) versus those that failed (N = 26). The average change in the SF-6D preference score was 0.07 (95% CI: 0.02, 0.12) higher for those that succeeded versus those that failed.</p> <p>Conclusion</p> <p>A treatment success definition that encompasses the many components of underlying OAB with UUI symptoms is currently not practical as a consequence of difficulties in measuring urgency. The treatment success outcome of ≥ 50% improvement in incontinence episodes was associated with a clinically meaningful improvement in disease-specific HRQoL for those with neurogenic OAB with UUI. The recommended success definition is less restrictive than a measure such as complete continence but includes patients who are satisfied with treatment and experience meaningful improvement in symptoms. A standardized measure of treatment success will be useful in clinical and health economic applications.</p