Progression of Epididymal Maldevelopment Into Hamartoma-like Neoplasia in VHL Disease

Inactivation of the von Hippel-Lindau (VHL) gene and activation of the hypoxia-inducible factor (HIF) in susceptible cells precedes formation of tumorlets and frank tumor in the epididymis of male VHL patients. We performed detailed histologic and molecular pathologic analysis of tumor-free epididymal tissues from VHL patients to obtain further insight into early epididymal tumorigenesis. Four epididymides from two VHL patients were serially sectioned to allow for three-dimensional visualization of morphologic changes. Areas of interest were genetically analyzed by tissue microdissection, immunohistochemistry for HIF and markers for mesonephric differentiation, and in situ hybridization for HIF downstream target vascular endothelial growth factor. Structural analysis of the epididymides revealed marked deviations from the regular anatomic structure resulting from impaired organogenesis. Selected efferent ductules were represented by disorganized mesonephric cells, and the maldeveloped mesonephric material was VHL-deficient by allelic deletion analysis. Furthermore, we observed maldeveloped mesonephric material near cystic structures, which were also VHL-deficient and were apparent derivatives of maldeveloped material. Finally, a subset of VHL-deficient cells was structurally integrated in regular efferent ductules; proliferation of intraductular VHL-deficient cells manifests itself as papillary growth into the ductular lumen. Furthermore, we clarify that that there is a pathogenetic continuum between microscopic tumorlets and formation of tumor. In multiple locations, three-dimensional reconstruction revealed papillary growth to extend deeply into ductular lumina, indicative of progression into early hamartoma-like neoplasia. We conclude epididymal tumorigenesis in VHL disease to occur in two distinct sequential steps: maldevelopment of VHL-deficient mesonephric cells, followed by neoplastic papillary proliferation.     

Risk factors for development of dehydration in young children with acute watery diarrhoea: a case-control study

In a case-control study to understand the risk factors for development of life-threatening dehydration, a total of 379 children comprising 243 cases (moderate or severe dehydration) and 136 controls (non or mild dehydration) up to 2 years of age suffering from acute watery diarrhoea were studied. By univariate analysis, the presence of vibrios in stool, withdrawal of breast feeding during diarrhoea, not giving fluids, including oral rehydration solution (ORS), during diarrhoea, frequent purging (> 8/ day), vomiting (> 2/day) and undernutrition were identified as risk factors. However, by multivariate analysis after controlling for confounders, withdrawal of breast feeding during diarrhoea (odds ratio (OR) = 6.8, p < 0.00001) and not giving ORS during diarrhoea (OR = 2.1, p < 0.006) were identified as significant risk factors. The confounding variables which also contributed significantly to increasing the risk were age (≤ 12 months; OR = 2.7, p = 0.001), frequent purging (> 8/day; OR = 4.1, p < 0.00001), vomiting (> 2/day; OR = 2.4, p = 0.001) and severe undernutrition (%median <60 weight-for-age of Indian Academy of Paediatrics classification; OR = 3.1, p = 0.001). We feel that these findings will be useful for Global and National Diarrhoeal Diseases Control Programmes for formulating intervention strategies for preventing death due to diarrhoeal dehydration.     

Emotional quality-of-life and outcomes in adolescents with asthma

OBJECTIVE: Examine the association between emotional quality-of-life (QOL) and asthma morbidity in adolescents with asthma. STUDY DESIGN: Cross-sectional survey of 185 adolescents with asthma 11 to 17 years of age cared for in three managed care organizations (MCOs) in the United States. The asthma-specific Pediatric Asthma Quality of Life Questionnaire (PAQLQ) and a short version of the generic Child Health and Illness Profile-Adolescent Edition (CHIP-AE) were used to assess emotional QOL. Asthma morbidity measures were: asthma control, emergency department (ED) visits, hospitalizations, doctor visits for worsening asthma, and missed school because of asthma. RESULTS: Of the adolescents surveyed, 45% reported feeling depressed, 41% had ED visits, and 30% missed >or=1 day of school because of asthma. Poorer asthma-specific emotional QOL was associated with poorer control of asthma symptoms ( P < .0001), missed school (OR 7.1, P < .05), and doctor visits for worsened asthma (OR = 7.0, P < .05). CONCLUSIONS: Emotional symptoms related to asthma are common in adolescents with persistent asthma and asthma-specific QOL is related to increased asthma morbidity, healthcare use, and school absenteeism. Adolescents with high morbidity from asthma exhibit poorer QOL. Therefore, the evaluation of asthma-specific emotional QOL should be included in the assessment of adolescents with asthma.     

Decellularized dermis in combination with cultivated keratinocytes in a short- and long-term animal experimental investigation

Decellularized human dermis as a potentially ideal scaffold for dermal substitution in severe burns was examined in a two‐staged animal experiment. In an initial step, an in vitro generated composite graft consisting of human keratinocytes and decellularized dermis (AlloDerm®) was transplanted onto nude mice in a short‐term trial (n = 20, 14 days). Subsequently, a combined one‐step grafting of full thickness wounds with both decellularized dermis (in part preincubated with fibroblasts) and cultivated autologous keratinocytes as a cell suspension in fibrin glue was done in a long‐term porcine animal model (n = 10, 6 months). In both series, macroscopic wound healing was evaluated by planimetry. Histological investigations included morphological as well as immunohistochemical parameters. The short‐term study showed both successful integration of the composite grafts and reduction of wound contraction compared with the control group (epithelial grafts). The long‐term porcine study displayed reduced myofibroblast formation and contraction in the wounds that had been treated with fibroblast‐preincubated dermis. After 4 weeks, a decline of the structural integrity of the dermal matrix could be noticed. The utility of decellularized dermis as template for both dermal reconstitution and keratinocyte delivery vehicle was shown. The closure of full thickness wounds by a single‐step combination of an autologous keratinocyte fibrin sealant suspension and acellular dermis in a pig animal model could be shown. Incorporation of fibroblasts led to reduced wound contraction but could not prevent the loss of dermal integrity. The engineered ‘skin’ remained viable and stable over a period of 6 months.     

Results from the National Sepsis Practice Survey: Use of drotrecogin α (activated) and other therapeutic decisions

PurposeWe sought to evaluate factors associated with choices about provided care for patients with septic shock, including the use of drotrecogin α (activated) (DAA).Materials and MethodsWe administered a mail-based survey to a random sample of intensivists. Study vignettes presented patients with septic shock with identical severity of illness scores but different ages, body mass indices, and comorbidities. Respondents estimated outcomes and selected care beyond standardized initial care (eg, antibiotics) for each hypothetical patient.ResultsFor most vignettes (99.1%), respondents added care, most commonly low tidal volume ventilation (87.6%) and enteral nutrition (73.3%). Choosing to administer DAA was not associated with predictions about mortality or bleeding. Vignettes with early-stage lung cancer were less likely to receive DAA. Time since medical school graduation was also associated with lower odds of selecting DAA. Most respondents (52.6%) chose identical care for all 4 completed vignettes.ConclusionsThere was wide variability in the therapeutic choices of respondents. The use of DAA was not associated with perceived risk of mortality or bleeding, as recommended by consensus guidelines. Physicians appear to base treatment decisions in septic shock on a consistent pattern of practice rather than estimates of patient outcome.