Elastin accumulation is regulated at the level of degradation by macrophage metalloelastase (MMP-12) during experimental liver fibrosis

Elastin has been linked to maturity of liver fibrosis. To date, the regulation of elastin secretion and its degradation in liver fibrosis has not been characterized. The aim of this work was to define elastin accumulation and the role of the paradigm elastase macrophage metalloelastase (MMP-12) in its turnover during fibrosis. Liver fibrosis was induced by either intraperitoneal injections of carbon tetrachloride (CCl(4) ) for up to 12 weeks (rat and mouse) or oral administration of thioacetamide (TAA) for 1 year (mouse). Elastin synthesis, deposition, and degradation were investigated by immunohistochemistry, quantitative polymerase chain reaction (qPCR), western blotting, and casein zymography. The regulation of MMP-12 elastin degradation was defined mechanistically using CD11b-DTR and MMP-12 knockout mice. In a CCl(4) model of fibrosis in rat, elastin deposition was significantly increased only in advanced fibrosis. Tropoelastin expression increased with duration of injury. MMP-12 protein levels were only modestly changed and in coimmunoprecipitation experiments MMP-12 was bound in greater quantities to its inhibitor TIMP-1 in advanced versus early fibrosis. Immunohistochemistry and macrophage depletion experiments indicated that macrophages were the sole source of MMP-12. Exposure of CCl(4) in MMP-12(-/-) mice led to a similar degree of overall fibrosis compared to wildtype (WT) but increased perisinusoidal elastin. Conversely, oral administration of TAA caused both higher elastin accumulation and higher fibrosis in MMP-12(-/-) mice compared with WT. Conclusion: Elastin is regulated at the level of degradation during liver fibrosis. Macrophage-derived MMP-12 regulates elastin degradation even in progressive experimental liver fibrosis. These observations have important implications for the design of antifibrotic therapies.     

Chronic idiopathic orofacial pain. A long‐term follow‐up study

Patients suffering facial pain that does not fit with the traditional diagnostic criteria and which does not respond to dental treatment constitute a clinical problem. These patients lack a proper diagnosis and are frequently exposed to excessive and inadequate invasive treatment. The aim of this investigation was to study the long‐term development of pain and the result of treatment in a cohort of patients suffering chronic idiopathic facial pain. The 74 patients referred to the Facial Pain Diagnostic Group at the Karolinska Institute School of Dentistry between 1981 and 1992 were invited to take part in a follow‐up study. As 16 subjects were unwilling or unable to take part in the study and 13 had died, the remaining 45 were interviewed either in accordance with a standard protocol or by filling out a questionnaire mailed to them. The interview revealed that 10 were free of orofacial pain, but only 2 were totally free of pain. Over the 9–19 years' follow‐up period the relationship between facial pain and pain in the rest of the body had changed substantially. Of 14 patients and more than 100 extractions, permanent pain relief was felt by only 3 patients. It is concluded that a diagnosis was given in only 2 cases. The distribution of the pain has changed dramatically. The low success rate of invasive treatments suggests that such therapeutic methods are to be considered contraindicated in patients suffering from idiopathic orofacial pain.     

Timing of Return to Dialysis in Patients with Failing Kidney Transplants

In the last decade, the number of patients starting dialysis after a failed kidney transplant has increased substantially. These patients appear to be different from their transplant‐naïve counterparts, and so may be the timing of dialysis therapy initiation. An increasing number of studies suggest that in transplant‐naïve patients, later dialysis initiation is associated with better outcomes. Very few data are available on timing of dialysis reinitiation in failed transplant recipients, and they suggest that an earlier return to dialysis therapy tended to be associated with worse survival, especially among healthier and younger patients and women. Failed transplant patients may also have unique issues such as continuation of immunosuppression versus withdrawal or the need for remnant allograft nephrectomy with regard to dialysis reinitiation. These patients may have a different predialysis preparation work‐up, worse blood pressure control, higher or lower serum phosphorus levels, lower serum bicarbonate concentration, and worse anemia management. The choice of dialysis modality may also represent an important question for these patients, even though there appears to be no difference in mortality between patients starting peritoneal versus hemodialysis. Finally, failed transplant patients returning to dialysis appear to have a higher mortality rate compared with transplant‐naïve incident dialysis patients, especially in the first several months of dialysis therapy. In this review, we will summarize the available data related to the timing of dialysis initiation and outcomes in failed kidney transplant patients after returning to dialysis.     

Socio‐economic status and quality of life in children with chronic disease: A systematic review

Reduced quality of life (QoL) is a known consequence of chronic disease in children, and this association may be more evident in those who are socio‐economically disadvantaged. The aims of this systematic review were to assess the association between socio‐economic disadvantage and QoL among children with chronic disease, and to identify the specific socio‐economic factors that are most influential. MEDLINE, Embase and PsycINFO were searched to March 2015. Observational studies that reported the association between at least one measure of social disadvantage in caregivers and at least one QoL measure in children and young people (age 2–21 years) with a debilitating non‐communicable childhood disease (asthma, chronic kidney disease, type 1 diabetes mellitus and epilepsy) were eligible. A total of 30 studies involving 6957 patients were included (asthma (six studies, n = 576), chronic kidney disease (four studies, n = 796), epilepsy (14 studies, n = 2121), type 1 diabetes mellitus (six studies, n = 3464)). A total of 22 (73%) studies reported a statistically significant association between at least one socio‐economic determinant and QoL. Parental education, occupation, marital status, income and health insurance coverage were associated with reduced QoL in children with chronic disease. The quality of the included studies varied widely and there was a high risk of reporting bias. Children with chronic disease from lower socio‐economic backgrounds experience reduced QoL compared with their wealthier counterparts. Initiatives to improve access to and usage of medical and psychological services by children and their families who are socio‐economically disadvantaged may help to mitigate the disparities and improve outcomes in children with chronic illnesses.