FGF10 maintains distal lung bud epithelium and excessive signaling leads to progenitor state arrest, distalization, and goblet cell metaplasia

<p>Abstract</p> <p>Background</p> <p>Interaction with the surrounding mesenchyme is necessary for development of endodermal organs, and Fibroblast growth factors have recently emerged as mesenchymal-expressed morphogens that direct endodermal morphogenesis. The fibroblast growth factor 10 (<it>Fgf10</it>) null mouse is characterized by the absence of lung bud development. Previous studies have shown that this requirement for <it>Fgf10 </it>is due in part to its role as a chemotactic factor during branching morphogenesis. In other endodermal organs <it>Fgf10 </it>also plays a role in regulating differentiation.</p> <p>Results</p> <p>Through gain-of-function analysis, we here find that FGF10 inhibits differentiation of the lung epithelium and promotes distalization of the embryonic lung. Ectopic expression of FGF10 in the lung epithelium caused impaired lung development and perinatal lethality in a transgenic mouse model. Lung lobes were enlarged due to increased interlobular distance and hyperplasia of the airway epithelium. Differentiation of bronchial and alveolar cell lineages was inhibited. The transgenic epithelium consisted predominantly of proliferating progenitor-like cells expressing Pro-surfactant protein C, TTF1, PEA3 and Clusterin similarly to immature distal tip cells. Strikingly, goblet cells developed within this arrested epithelium leading to goblet cell hyperplasia.</p> <p>Conclusion</p> <p>We conclude that FGF10 inhibits terminal differentiation in the embryonic lung and maintains the distal epithelium, and that excessive levels of FGF10 leads to metaplastic differentiation of goblet cells similar to that seen in chronic inflammatory diseases.</p

The impact of comorbidity and stage on ovarian cancer mortality: A nationwide Danish cohort study

<p>Abstract</p> <p>Background</p> <p>The incidence of ovarian cancer increases sharply with age, and many elderly patients have coexisting diseases. If patients with comorbidities are diagnosed with advanced stages, this would explain the poor survival observed among ovarian cancer patients with severe comorbidity. Our aims were to examine the prevalence of comorbidity according to stage of cancer at diagnosis, to estimate the impact of comorbidity on survival, and to examine whether the impact of comorbidity on survival varies by stage.</p> <p>Methods</p> <p>From the Danish Cancer Registry we identified 5,213 patients (> 15 years old) with ovarian cancer diagnosed from 1995 to 2003. We obtained information on comorbidities from the Danish National Hospital Discharge Registry. Vital status was determined through linkage to the Civil Registration System. We estimated the prevalence of comorbidity by stage and computed absolute survival and relative mortality rate ratios (MRRs) by comorbidity level (Charlson Index score 0, 1–2, 3+), using patients with Charlson Index score 0 as the reference group. We then stratified by stage and computed the absolute survival and MRRs according to comorbidity level, using patients with Charlson score 0 and localized tumour/FIGO I as the reference group. We adjusted for age and calendar time.</p> <p>Results</p> <p>Comorbidity was more common among patients with an advanced stage of cancer. One- and five-year survival was higher in patients without comorbidity than in patients with registered comorbidity. After adjustment for age and calendar time, one-year MRRs declined from 1.8 to 1.4 and from 2.7 to 2.0, for patients with Charlson scores 1–2 and 3+, respectively. After adjustment for stage, the MRRs further declined to 1.3 and 1.8, respectively. Five-year MRRs declined similarly after adjustment for age, calendar time, and stage. The impact of severe comorbidity on mortality varied by stage, particularly among patients with tumours with regional spread/FIGO-stages II and III.</p> <p>Conclusion</p> <p>The presence of severe comorbidity was associated with an advanced stage of ovarian cancer. Mortality was higher among patients with comorbidities and the impact of comorbidity varied by stage.</p

Haematogenous Staphylococcus aureus meningitis. A 10-year nationwide study of 96 consecutive cases

BACKGROUND: Haematogenous Staphylococcus aureus meningitis is rare but associated with high mortality. Knowledge about the disease is still limited. The objective of this study was to evaluate demographic and clinical prognostic features of bacteraemic S. aureus meningitis. METHODS: Nationwide surveillance in Denmark from 1991 to 2000 with clinical and bacteriological data. Risks of death were estimated by Cox proportional hazards regression analysis. RESULTS: Among 12480 cases of S. aureus bacteraemia/sepsis, we identified 96 cases of non-surgical bacteraemic S. aureus meningitis (0.8%). Incidence rates were 0.24 (95% confidence interval [CI], 0.18 to 0.30)/100 000 population between 1991–1995 and 0.13 (CI, 0.08 to 0.17)/100 000 population between 1996–2000. Mortality was 56%. After adjustment, only co morbidity (hazard ratio [HR], 3.45; CI, 1.15 to 10.30) and critical illness (Pitt score ≥ 4) (HR, 2.14; CI, 1.09 to 4.19) remained independent predictors of mortality. CONCLUSION: The incidence, but not mortality of bacteraemic S. aureus meningitis decreased during the study period. Co morbidity and critical illness were independent predictors of a poor outcome

Polygenic transmission disequilibrium confirms that common and rare variation act additively to create risk for autism spectrum disorders

Autism spectrum disorder (ASD) risk is influenced by common polygenic and de novo variation. We aimed to clarify the influence of polygenic risk for ASD and to identify subgroups of ASD cases, including those with strongly acting de novo variants, in which polygenic risk is relevant. Using a novel approach called the polygenic transmission disequilibrium test and data from 6,454 families with a child with ASD, we show that polygenic risk for ASD, schizophrenia, and greater educational attainment is over-transmitted to children with ASD. These findings hold independent of proband IQ. We find that polygenic variation contributes additively to risk in ASD cases who carry a strongly acting de novo variant. Lastly, we show that elements of polygenic risk are independent and differ in their relationship with phenotype. These results confirm that the genetic influences on ASD are additive and suggest that they create risk through at least partially distinct etiologic pathways

The Response of Lemna minor to Mixtures of Pesticides That Are Commonly Used in Thailand

In the field, aquatic organisms are exposed to multiple contaminants rather than to single compounds. It is therefore important to understand the toxic interactions of co-occurring substances in the environment. The aim of the study was to assess the effects of individual herbicides (atrazine, 2,4-D, alachlor and paraquat) that are commonly used in Thailand and their mixtures on Lemna minor. Plants were exposed to individual and binary mixtures for 7 days and the effects on plant growth rate were assesed based on frond area measurements. Experimental observations of mixture toxicity were compared with predictions based on single herbicide exposure data using concentration addition and independent action models. The single compound studies showed that paraquat and alachlor were most toxic to L. minor, followed by atrazine and then 2,4-D. For the mixtures, atrazine with 2,4-D appeared to act antagonistically, whereas alachlor and paraquat showed synergism

Diethylstilboestrol exposure does not reduce testosterone production in human fetal testis xenografts

In rodents, in utero exposure to exogenous estrogens including diethylstilboestrol (DES) results in major suppression of steroidogenesis in fetal testes. Whether similar effects occur in the human fetal testis is equivocal. Based on the results of the rodent studies, we hypothesised that exposure of human fetal testes to DES would result in a reduction in testosterone production. We show, using a xenograft approach, that testosterone production is not reduced in human fetal testis following DES exposure. Human fetal testes (15-19 weeks' gestation, n = 6) were xenografted into castrate male nude mice which were then treated for 35 days with vehicle or 100 µg/kg DES three times a week. For comparison, similar treatment was applied to pregnant rats from e13.5-e20.5 and effects on fetal testes evaluated at e21.5. Xenograft testosterone production was assessed by measuring host seminal vesicle (SV) weights as an indirect measure over the entire grafting period, and single measurement of serum testosterone at termination. Human fetal testis xenografts showed similar survival in DES and vehicle-exposed hosts. SV weight (44.3 v 26.6 mg, p = 0.01) was significantly increased in DES compared to vehicle-exposed hosts, respectively, indicating an overall increase in xenograft testosterone production over the grafting period, whilst serum testosterone at termination was unchanged. In contrast intra-testicular testosterone levels were reduced by 89%, in fetal rats exposed to DES. In rats, DES effects are mediated via Estrogen Receptor α (ESR1). We determined ESR1 protein and mRNA expression in human and rat fetal testis. ESR1 was expressed in rat, but not in human, fetal Leydig cells. We conclude that human fetal testis exposure to DES does not impair testosterone production as it does in rats, probably because ESR1 is not expressed in human fetal Leydig cells. This indicates that DES exposure is likely to pose minimal risk to masculinization of the human fetus