Role of tumour necrosis factor-alpha receptor p75 in cigarette smoke-induced pulmonary inflammation and emphysema.

Chronic obstructive pulmonary disease (COPD) is characterised by a local pulmonary inflammatory response to respiratory pollutants and by systemic inflammation. Tumour necrosis factor (TNF)-alpha has been implicated in systemic effects of COPD and operates by binding the p55 (R1) and p75 (R2) TNF-alpha receptors. To investigate the contribution of each TNF-alpha receptor in the pathogenesis of COPD, the present study examined the effects of chronic air or cigarette smoke (CS) exposure in TNF-alpha R1 knockout (KO) mice, TNF-alpha R2 KO mice and wild type (WT) mice. CS was found to significantly increase the protein levels of soluble TNF-alpha R1 (by four-fold) and TNF-alpha R2 (by 10-fold) in the bronchoalveolar lavage of WT mice. After 3 months, CS induced a prominent pulmonary inflammatory cell influx in WT and TNF-alpha R1 KO mice. In TNF-alpha R2 KO mice, CS-induced pulmonary inflammation was clearly attenuated. After 6 months, no emphysema was observed in CS-exposed TNF-alpha R2 KO mice in contrast to WT and TNF-alpha R1 KO mice. CS-exposed WT and TNF-alpha R1 KO mice failed to gain weight, whereas the body mass of TNF-alpha R2 KO mice was not affected. These current findings suggest that both tumour necrosis factor-alpha receptors contribute to the pathogenesis of chronic obstructive pulmonary disease, but tumour necrosis factor-alpha receptor-2 is the most active receptor in the development of inflammation, emphysema and systemic weight loss in this murine model of chronic obstructive pulmonary disease.     

Renal impairment after spontaneous bacterial peritonitis: incidence and prognosis.

BACKGROUND/AIMS: Spontaneous bacterial peritonitis (SBP) is an important complication in cirrhotic patients. The aim of the present study was to assess the incidence, predictive factors and prognosis for renal impairment (RI) after SBP in cirrhotic patients from southern Brazil. METHODS: Of the 1030 hospitalizations evaluated, 114 episodes of SBP were diagnosed in 94 patients (mean age 49 years; 76.59% men). SBP diagnosis was established when the ascitic fluid polymorphonuclear cell count was equal to or greater than 250 cells/mm3. Five cases were excluded. The variables assessed as possible predictors of steady or progressive RI were blood urea nitrogen and creatinine levels before the diagnosis of SBP; type of infection, antibiotic prophylaxis, first episode or recurrent SBP, presence of gastrointestinal bleeding and hepatic encephalopathy during hospitalization, SBP resolution, Child-Pugh classification, levels of blood pressure, ascitic fluid and blood polymorphonuclear cell count, bacteriological data (positive and negative ascitic fluid culture), albumin, bilirubin, sodium and prothrombin time at the moment of diagnosis. RESULTS: The incidence of SBP was 11.07%. In 61 (55.96%) episodes, SBP was associated with RI (transient in 57.37%; steady in 19.67%; and progressive in 22.95%). The mortality rate associated with progressive RI was 100%; 58.33% with steady RI; and 2.85% with transient RI. The mortality rate in patients with or without RI was 36.07% and 6.25%, respectively (P<0.001). The level of creatinine (greater than or equal to 1.3mg/dL) before the diagnosis of SBP and the rate of infection resolution were the only predictors of RI in the multivariate analysis. CONCLUSIONS: RI after SBP is a common complication, and indicates a poor prognosis for this infection. High levels of creatinine before infection and the rate of infection resolution are independent predictors of RI.     

Energy cost of activity and exercise in children and adolescents with cystic fibrosis.

In cystic fibrosis (CF), perturbations of total daily energy expenditure (TDEE) may be a major determinant of altered nutrition and growth. Measurement of TDEE is problematic, though the flex-heart rate method (FHRM) provides a close estimation of TDEE, as compared to the cost-prohibitive, gold standard, the double-labeled water method, and permits estimates of the energy cost of daily activities (ECA) above resting energy expenditure (REE). We hypothesize that alterations in ECA affects TDEE in CF. PURPOSE: To measure components of TDEE in adolescents with CF and normal lung function compared with controls, and to determine whether ECA can be improved by diet and exercise. METHODS: Clinically stable CF subjects (aged 9-13, n=12) and age- and gender-matched controls (n=13) had repeated measurements of TDEE by FHRM, REE, and maximal cardiopulmonary exercise testing (CPET) during a 6-week exercise and diet program. RESULTS: While the mean REE was similar in both groups, ECA was significantly lower in CF adolescents as compared to controls (p=0.02). During CPET, maximal exercise in CF was characterized by hyperventilation, which was unrelated to ventilation-perfusion mismatching. There were no changes in REE after dietary intervention. CONCLUSION: ECA in CF adolescents with normal lung function is lower when compared to healthy controls. These findings support the hypothesis that clinically stable patients with CF have inefficient energy metabolism or alternatively conserve energy during activities of daily living.     

Evaluation of a strict protocol approach in managing women with severe disease due to abortion.

AIM: To evaluate whether the introduction of a strict protocol approach based on the systemic evaluation of critically ill pregnant women with complications of abortion affected outcome. SETTING: Indigent South Africans managed in the regional and tertiary hospitals of the Pretoria Academic Complex. METHOD: Since 1997 a standard definition of severe acute maternal morbidity (SAMM) has been used in the Pretoria Academic Complex. All cases of SAMM and maternal deaths were entered on the Maternal Morbidity and Mortality Audit System programme. A comparison of outcome of severely ill women who had complications of abortion was made between 1997-1998 (original protocol) and 2002-2004 (strict protocol). OUTCOME MEASURES: The mortality index and prevalence of organ system failure or dysfunction. RESULTS: In 1997-1998 there were 43 women with SAMM who survived and a further 10 maternal deaths due to complications of abortion, compared with 107 women with SAMM and 7 maternal deaths during 2002-2004. The mortality index declined from 18.9% in 1997-1998 to 6.1% in 2002-2004 (p = 0.02, odds ratio 0.28, 95% confidence limits 0.10 - 0.79). Significantly more women had hypovolaemic shock in 2002-2004 compared with 1997-1998 (54.4% v. 35.8%, p = 0.04), but fewer women had immune system failure including septic shock (18.4% v. 47.2%, p = 0.0002) and metabolic dysfunction (0 v. 5.7%, p = 0.03) and there was a trend to less renal failure (10.5% v. 22.6%, p = 0.06) and cardiac failure (4.4% v. 13.2%, p = 0.08). CONCLUSION: The strict protocol approach based on systemic evaluation in managing critically ill pregnant women with complications of abortion, coupled with an intensive, regular feedback mechanism, has been associated with a reduction in the mortality index.     

Did the gradual loss of GLUT2 cause a shift to diabetic disorders in the New Zealand obese mouse (NZO/Hl)?

The New Zealand obese mouse (NZO/Hl) is characterised by hereditary obesity and type-2 diabetes, including insulin resistance, hyperinsulinaemia, and glucose intolerance. In other diabetic models, it has been revealed that the proper functioning of the glucose transporter isoform 2 (GLUT2) is essential for adequate secretion of insulin. The aim of this study was to compare the distribution of islet cells and GLUT2, as well as the expression of GLUT2-mRNA, in the pancreas of NZO mice and metabolically unimpaired NMRI (Naval Medical Research Institute) mice. Pancreas tissue was obtained from different stages of development. For molecular determination of the expression level of GLUT2-mRNA, total-RNA was extracted from the pancreas and analysed by quantitative real-time RT-PCR. All investigated NZO mice displayed increased weight, elevated hyperinsulinaemia, and slightly enhanced blood glucose levels compared with the NMRI control mice. By means of immunofluorescence microscopy drastically reduced insulin levels were detected, which might be compensated by the observed islet cell hyperplasia and hypertrophy. Furthermore, the normally peripheral localisation of the alpha-cells within islets was disturbed. By contrast, there were no changes in somatostatin cell distribution. However, considerable differences appeared with regard to GLUT2: whereas the beta-cells of NMRI mice showed dense immunostaining of the GLUT2 transporter on the cell surface, in all age groups of NZO mice, GLUT2 on the plasma membranes was reduced and dispersed in the cytoplasm. These findings agree with the molecular biological results, which displayed decreased mRNA-expression of GLUT2. In summary, the observed alteration of islet morphology and of GLUT2 expression in diabetic mice complements our previous results from a superfusion protocol and further clarifies the mechanisms of diabetogenesis in NZO mice.