Pathophysiological lessons from rare associations of immunological disorders

Rare associations of immunological disorders can often tell more than mice and rats about the pathogenesis of immunologically mediated human kidney disease. Cases of glomerular disease with thyroiditis and Graves’ disease and of minimal change disease with lymphoepithelioma-like thymic carcinoma and lymphomatoid papulosis were recently reported in Pediatric Nephrology. These rare associations can contribute to the unraveling of the pathogenesis of membranous nephropathy (MN) and minimal change disease (MCD) and lead to the testing of novel research hypotheses. In MN, the target antigen may be thyroglobulin or another thyroid-released antigen that becomes planted in the glomerulus, but other scenarios can be envisaged, including epitope spreading, polyreactivity of pathogenic antibodies, and dysregulation of T regulatory cells, leading to the production of a variety of auto-antibodies with different specificities [immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX syndrome)]. The occurrence of MCD with hemopathies supports the role of T cells in the pathogenesis of proteinuria, although the characteristics of those T cells remain to be established and the glomerular permeability factor(s) identified

Cellular mechanisms of bone resorption in breast carcinoma

The cellular mechanisms that account for the increase in osteoclast numbers and bone resorption in skeletal breast cancer metastasis are unclear. Osteoclasts are marrow-derived cells which form by fusion of mononuclear phagocyte precursors that circulate in the monocyte fraction. In this study we have determined whether circulating osteoclast precursors are increased in number or have an increased sensitivity to humoral factors for osteoclastogenesis in breast cancer patients with skeletal metastases (± hypercalcaemia) compared to patients with primary breast cancer and age-matched normal controls. Monocytes were isolated and cocultured with UMR 106 osteoblastic cells in the presence of 1,25 dihydroxyvitamin D3[1,25(OH)2D3] and human macrophage colony stimulating factor (M-CSF) on coverslips and dentine slices. Limiting dilution experiments showed that there was no increase in the number of circulating osteoclast precursors in breast cancer patients with skeletal metastases (± hypercalcaemia) compared to controls. Osteoclast precursors in these patients also did not exhibit increased sensitivity to 1,25(OH)2D3 or M-CSF in terms of osteoclast formation. The addition of parathyroid hormone-related protein and interleukin-6 did not increase osteoclast formation. The addition of the supernatant of cultured breast cancer cell lines (MCF-7 and MDA-MB-435), however, significantly increased monocyte-osteoclast formation in a dose-dependent fashion. These results indicate that the increase in osteoclast formation in breast cancer is not due to an increase in the number/nature of circulating osteoclast precursors. They also suggest that tumour cells promote osteoclast formation in the bone microenvironment by secreting soluble osteoclastogenic factor(s). © 2001 Cancer Research Campaign http://www.bjcancer.co

Global variation in anastomosis and end colostomy formation following left-sided colorectal resection

Background End colostomy rates following colorectal resection vary across institutions in high-income settings, being influenced by patient, disease, surgeon and system factors. This study aimed to assess global variation in end colostomy rates after left-sided colorectal resection. Methods This study comprised an analysis of GlobalSurg-1 and -2 international, prospective, observational cohort studies (2014, 2016), including consecutive adult patients undergoing elective or emergency left-sided colorectal resection within discrete 2-week windows. Countries were grouped into high-, middle- and low-income tertiles according to the United Nations Human Development Index (HDI). Factors associated with colostomy formation versus primary anastomosis were explored using a multilevel, multivariable logistic regression model. Results In total, 1635 patients from 242 hospitals in 57 countries undergoing left-sided colorectal resection were included: 113 (6·9 per cent) from low-HDI, 254 (15·5 per cent) from middle-HDI and 1268 (77·6 per cent) from high-HDI countries. There was a higher proportion of patients with perforated disease (57·5, 40·9 and 35·4 per cent; P < 0·001) and subsequent use of end colostomy (52·2, 24·8 and 18·9 per cent; P < 0·001) in low- compared with middle- and high-HDI settings. The association with colostomy use in low-HDI settings persisted (odds ratio (OR) 3·20, 95 per cent c.i. 1·35 to 7·57; P = 0·008) after risk adjustment for malignant disease (OR 2·34, 1·65 to 3·32; P < 0·001), emergency surgery (OR 4·08, 2·73 to 6·10; P < 0·001), time to operation at least 48 h (OR 1·99, 1·28 to 3·09; P = 0·002) and disease perforation (OR 4·00, 2·81 to 5·69; P < 0·001). Conclusion Global differences existed in the proportion of patients receiving end stomas after left-sided colorectal resection based on income, which went beyond case mix alone

The association between sodium fluctuations and mortality in surgical patients requiring intensive care

Purpose: Serum sodium derangement is the most common electrolyte disturbance amongst patients admitted to intensive care. This study aims to validate the association between dysnatraemia and serum sodium fluctuation with mortality in surgical intensive care patients. Method: We performed a retrospective analysis of the Medical Information Mart for Intensive Care (MIMIC-II) database. Dysnatraemia was defined as a sodium concentration outside physiologic range (135–145 mmol/L) and subjects were categorized by severity of dysnatraemia and sodium fluctuation. Univariate and multivariable logistic regression was used to test for associations between sodium fluctuations and mortality. Results: We identified 8600 subjects, 39% female with a median age of 66 years for analysis. Subjects with dysnatraemia were more likely to be dead at 28-days (17% vs 7%; p<0.001). There was a significant association between sodium fluctuation and mortality at 28-days (adjusted OR per 1 mmol/L change: 1.10 (95% CI 1.08-1.12; p <0.001)) even in patients who remained normotraemic during their ICU stay (1.12 (95% CI 1.09-1.16; p<0.001)) Conclusions: This observational study validates previous findings of an association between serum sodium fluctuations and mortality in surgical intensive care patients. This association was also present in subjects who remained normonatraemic throughout their ICU admission

The association between sodium fluctuations and mortality in surgical patients requiring intensive care

Purpose Serum sodium derangement is the most common electrolyte disturbance among patients admitted to intensive care. This study aims to validate the association between dysnatremia and serum sodium fluctuation with mortality in surgical intensive care patients. Method We performed a retrospective analysis of the Medical Information Mart for Intensive Care II database. Dysnatremia was defined as a sodium concentration outside physiologic range (135–145 mmol/L) and subjects were categorized by severity of dysnatremia and sodium fluctuation. Univariate and multivariable logistic regressions were used to test for associations between sodium fluctuations and mortality. Results We identified 8600 subjects, 39% of whom were female, with a median age of 66 years for analysis. Subjects with dysnatremia were more likely to be dead at 28 days (17% vs 7%; P &lt; .001). There was a significant association between sodium fluctuation and mortality at 28 days (adjusted odds ratio per 1 mmol/L change, 1.10 [95% confidence interval, 1.08–1.12; P &lt; .001]), even in patients who remained normotremic during their intensive care unit stay (1.12 [95% confidence interval, 1.09–1.16; P &lt; .001]) Conclusions This observational study validates previous findings of an association between serum sodium fluctuations and mortality in surgical intensive care patients. This association was also present in subjects who remained normonatremic throughout their intensive care unit admission.</p