Pulmonary thromboembolism and obesity in forensic pathologic case work.

328 autopsy cases of fatal pulmonary thromboembolism (PE) were compared to 984 age- and sex-matched controls to evaluate the association between obesity and PE in a forensic context. Both PE and control cases had a mean age of 67,8 years (male 62,9 years, females 71,7 years). The percentage of morbidly obese persons with a body mass index (BMI) of above 40 or abdominal subcutaneous adipose tissue of above 4 cm was higher in the PE group (8,39% vs. 4,67% and 29.45% vs. 23.40%, respectively). On the other side, that of very slim persons (BMI below 18.5 or adipose tissue below 3 cm) was significantly smaller (4,27% vs. 7,52% and 47.55% vs. 56,60%). We thus found a strong association between being overweight and death from PE, while slim persons seem to be at an advantage. As the group of underweight persons includes those suffering from chronic diseases with reduced mobility or hypercoagulability (e.g. tumor kachexia or sarkopenia due to immobilisation), this finding is to some extent unexpected.

Pulmonary immune profiling of SIDS: impaired immune maturation and age-related cytokine imbalance.

BACKGROUND: For sudden infant death syndrome (SIDS), an impaired immunocompetence has been discussed for a long time. Cytokines and chemokines are soluble immune mediators (SIM) whose balance is essential for the immune status. We hypothesized that an imbalanced immune response might contribute to the etiology of SIDS. METHODS: We investigated 27 cytokines, chemokines, and growth factors in protein lysates of lungs derived from 29 SIDS cases and 15 control children deceased for other reasons. RESULTS: Except for the CCL5, no significant differences were detected in the lungs between SIDS cases with and without mild upper respiratory tract infections. In contrast, IL-1RA, IL-7, IL-13, and G-CSF were decreased in the merged SIDS cases compared to control cases without evidence of infection. Plotting SIM concentrations against infant age resulted in increasing concentrations in control but not in SIDS lungs, indicating a disturbed immune maturation. Moreover, an age-dependent shift towards a Th2-related pattern was observed in SIDS. CONCLUSIONS: Our findings suggest that an impaired maturation of the immune system, an insufficient response to respiratory pathogens, and an immune response modulated by Th1/Th2 imbalance might play a possible role in triggering SIDS. These findings might in part be explained by chronic stress. IMPACT: Maturation of the cytokine and chemokine network may be impaired in SIDS. An imbalance between Th1- and Th2-related cytokines, which may reflect a state of chronic stress causing a more Th2 shift. An impaired immune maturation, an insufficient response to respiratory pathogens, and an immune response modulated by Th1/Th2 imbalance might play a possible role in SIDS.

Sudden infant death syndrome revisited: serotonin transporter gene, polymorphisms and promoter methylation.

BACKGROUND: Based on findings in the brain stems of SIDS victims, the serotonin transporter (5-HTT) gene has been discussed to be associated with SIDS. METHODS: In the largest study to date, we investigated the promoter length (5-HTTLPR) and intron 2 VNTR polymorphisms in 274 cases and 264 controls and the Ile425Val polymorphism in 65 cases and 64 controls. Moreover, the methylation of the internal promoter region was investigated in 35 cases and 14 controls. RESULTS: For 5-HTTLPR, we observed a trend towards an association of allele L (58.8% vs. 53.4%) with SIDS and significant results were observed after stratifying for age, season at death, and prone position. Nevertheless, when pooling all published data, a significant association of allele L with SIDS is confirmed (p: 0.001). For the intron 2 VNTR polymorphism, no significant differences were observed. After pooling, a significant accumulation of the rare allele 9 was observed in SIDS (2.1% vs. 0.6%; p: 0.018). For the Ile425Val polymorphism, no differences were observed. CONCLUSION: We conclude that genetic variation at this gene might be of some importance in SIDS. Epigenetic analysis of the internal promoter, however, revealed no influence on the relative risk to succumb to SIDS. IMPACT: This is the largest study published up to now on 5-HTT gene polymorphisms and SIDS. Polymorphisms in the 5-HTT gene appear to contribute (although to a small degree) to the risk to die from SIDS. There is no evidence that a methylation of the promoter region is of impact for the etiology of SIDS.

Linking Fibrotic Remodeling and Ultrastructural Alterations of Alveolar Epithelial Cells after Deletion of Nedd4-2.

Our previous study showed that in adult mice, conditional Nedd4-2-deficiency in club and alveolar epithelial type II (AE2) cells results in impaired mucociliary clearance, accumulation of Muc5b and progressive, terminal pulmonary fibrosis within 16 weeks. In the present study, we investigated ultrastructural alterations of the alveolar epithelium in relation to interstitial remodeling in alveolar septa as a function of disease progression. Two, eight and twelve weeks after induction of Nedd4-2 knockout, lungs were fixed and subjected to design-based stereological investigation at the light and electron microscopic level. Quantitative data did not show any abnormalities until 8 weeks compared to controls. At 12 weeks, however, volume of septal wall tissue increased while volume of acinar airspace and alveolar surface area significantly decreased. Volume and surface area of alveolar epithelial type I cells were reduced, which could not be compensated by a corresponding increase of AE2 cells. The volume of collagen fibrils in septal walls increased and was linked with an increase in blood-gas barrier thickness. A high correlation between parameters reflecting interstitial remodeling and abnormal AE2 cell ultrastructure could be established. Taken together, abnormal regeneration of the alveolar epithelium is correlated with interstitial septal wall remodeling.

Conditional deletion of Nedd4-2 in lung epithelial cells causes progressive pulmonary fibrosis in adult mice.

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive interstitial lung disease characterized by patchy scarring of the distal lung with limited therapeutic options and poor prognosis. Here, we show that conditional deletion of the ubiquitin ligase Nedd4-2 (Nedd4l) in lung epithelial cells in adult mice produces chronic lung disease sharing key features with IPF including progressive fibrosis and bronchiolization with increased expression of Muc5b in peripheral airways, honeycombing and characteristic alterations in the lung proteome. NEDD4-2 is implicated in the regulation of the epithelial Na+ channel critical for proper airway surface hydration and mucus clearance and the regulation of TGFß signaling, which promotes fibrotic remodeling. Our data support a role of mucociliary dysfunction and aberrant epithelial pro-fibrotic response in the multifactorial disease pathogenesis. Further, treatment with the anti-fibrotic drug pirfenidone reduced pulmonary fibrosis in this model. This model may therefore aid studies of the pathogenesis and therapy of IPF.