Localization of clusterin in the epimembranous deposits of passive Heymann nephritis

Localization of clusterin in the epimembranous deposits of passive Heymann nephritis. The membrane attack complex of complement (MAC) plays an important role in the mediation of proteinuria in experimental membranous nephropathy induced by Heymann antiserum. SP-40,40 is a recently described serum protein which appears to inhibit the formation of cytolytic MAC in a manner analogous to S protein/vitronectin. SP-40,40 is homologous to proteins originally isolated from rat and ram seminal fluid (sulfated glycoprotein 2 and clusterin, respectively). By current convention, these proteins are considered clusterin homologues. The objective of this study was to examine the participation of rat clusterin in passive Heymann nephritis. Using an antibody to rat clusterin as an immunofluorescent probe, clusterin deposits were demonstrated along the glomerular capillary wall in an identical pattern to rat C3 and C5b-9. Decomplementation using cobra venom factor prevented proteinuria and intraglomerular MAC formation. The epimembranous clusterin were not detected in the complement-depleted animals. The role of clusterin in the mediation of glomerular injury remains unknown, but it is probably related to in situ formation of the terminal complement cascade where it may play a regulatory role

Interstitial inflammation and fibrosis in rats with diet-induced hypercholesterolemia

Interstitial inflammation and fibrosis in rats with diet-induced hypercholesterolemia. Abnormalities in lipid metabolism appear to play a pathogenic role in progressive renal disease. To elucidate the cellular and molecular basis of renal interstitial fibrosis in uninephrectomized rats with diet-induced hypercholesterolemia, we fed experimental rats with standard rat chow supplemented with 4% cholesterol and 1% cholic acid. Control rats were fed an isocaloric diet. Groups of 7 control and 7 experimental rats were killed after 4, 8, and 12 weeks. Hypercholesterolemic rats developed albuminuria; serum creatinine was elevated at 12 weeks. By 12 weeks numerous oil red O-positive cells were present throughout the interstitium and to a lesser extent in tubules. Total renal lipid-peroxidation products were significantly increased (172 ± 15, 198 ± 28, and 197 ± 13mmol malondialdehyde/kidney at 4, 8, and 12 weeks vs. 123 ± 17, 144 ± 6, and 125 ± 10mmol in controls). Immunostaining revealed oxidatively modified lipoproteins within tubular and interstitial cells. The interstitial disease was characterized by an interstitial infiltrate of monocytes. Significant increases were detected in renal cortical mRNA levels for monocyte chemoattractant protein-1 (MCP-1), osteopontin, and vascular cell adhesion molecule-1 (VCAM-1), associated with changes in the pattern of immunostaining for each encoded proteins. Total kidney collagen was significantly increased at 12 weeks (9.8 ± 0.9mg/kidney vs. 7.8 ± 0.9mg in controls). At 12 weeks there was a significant increase in interstitial immunostaining for collagen I, collagen III, collagen IV, fibronectin and tenascin. A significant threefold increase in renal cortical mRNA levels for transforming growth factor beta-1 (TGF-β1) at 4 and 12 weeks was associated with the appearance of TGF-β1-positive interstitial cells. Renal matrix protein mRNA levels were measured at 4, 8, and 12 weeks. The only statistically significant elevations were procollagen α1(I) and procollagen α1(III) at weeks 8 and 12. In contrast, renal cortical mRNA levels for the tissue inhibitor of metalloproteinases-1 (TIMP-1) were significantly increased at 4, 8 and 12 weeks (1.4 ± 0.5, 2.7 ± 0.9 and 2.7 ± 1.4 arbitrary densitometric units, respectively, vs. 1.0 ± 0.4, 1.0 ± 0.5 and 1.0 ± 0.4 units for controls), and urokinase-type plasminogen activator (μPA) mRNA levels were significantly decreased at 4, 8, and 12 weeks (0.4 ± 0.1 arbitrary densitometric units for all three experimental groups vs. 1.0 ± 0.4, 1.0 ± 0.3, and 1.0 ± 0.4 units for the control groups). In summary, rats with diet-induced hypercholesterolemia develop renal interstitial fibrosis over several weeks. Following the accumulation of lipids within tubulointerstitial cells, interstitial nephritis develops. The fibrotic phase is characterized by modest changes in matrix protein mRNA levels, up-regulated TIMP-1, and down-regulated μPA levels, suggesting that altered matrix degradation plays a role in the interstitial fibrogenesis in this model

The Canadian Childhood Nephrotic Syndrome (CHILDNEPH) project: Overview of design and methods

Background: Nephrotic syndrome is a commonly acquired kidney disease in children that causes significant morbidity due to recurrent episodes of heavy proteinuria. The management of childhood nephrotic syndrome is known to be highly variable among physicians and care centres. Objectives: The primary objective of the study is to determine centre-, physician-, and patient-level characteristics associated with steroid exposure and length of steroid treatment. We will also determine the association of dose and duration of steroid treatment and time to first relapse as a secondary aim. An embedded qualitative study utilizing focus groups with health care providers will enrich the quantitative results by providing an understanding of the attitudes, beliefs and local contextual factors driving variation in care. Design: Mixed-methods study; prospective observational cohort (quantitative component), with additional semi-structured focus groups of healthcare professionals (qualitative component). Setting: National study, comprised of all 13 Canadian pediatric nephrology clinics. Patients: 400 patients under 18 years of age to be recruited over 2.5 years. Measurements: Steroid doses for all episodes (first presentation, first and subsequent relapses) tracked over course of the study. Physician and centre-level characteristics catalogued, with reasons for treatment preferences documented during focus groups. Methods: All patients tracked prospectively over the course of the study, with data comprising a prospective registry. One focus group at each site to enrich understanding of variation in care. Limitations: Contamination of treatment protocols between physicians may occur as a result of concurrent focus groups. Conclusions: Quantitative and qualitative results will be integrated at end of study and will collectively inform strategies for the development and implementation of standardized evidence-based protocols across centres

As tests evolve and costs of cancer care rise: reappraising stool-based screening for colorectal neoplasia

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73533/1/j.1365-2036.2008.03632.x.pd

Phase 1 Trial of Adalimumab in Focal Segmental Glomerulosclerosis (FSGS): II. Report of the FONT (Novel Therapies for Resistant FSGS) Study Group

Patients with primary focal segmental glomerulosclerosis (FSGS) resistant to current treatment regimens are at high risk of progression to end stage kidney disease. Antifibrotic agents, such as tumor necrosis factor α (TNF-α) antagonists, are a promising strategy to slow or halt the decline in renal function, based on preclinical and clinical data

The Neural Correlates of Theory of Mindand their Role during Empathy and theGame of Chess: A functional MagneticResonance Imaging Study

Chess involves the capacity to reason iteratively about potential intentional choices of an opponent and therefore involves high levels of explicit theory of mind [ToM] (i.e. ability to infer mental states of others) alongside clear, strategic rule-based decision-making. Functional magnetic resonance imaging was used on 12 healthy male novice chess players to identify cortical regions associated with chess, ToM and empathizing. The blood-oxygenation-level-dependent (BOLD) response for chess and empathizing tasks was extracted from each ToM region. Results showed neural overlap between ToM, chess and empathizing tasks in right-hemisphere temporo-parietal junction (TPJ) [BA40], left-hemisphere superior temporal gyrus [BA22] and posterior cingulate gyrus [BA23/31]. TPJ is suggested to underlie the capacity to reason iteratively about another's internal state in a range of tasks. Areas activated by ToM and empathy included right-hemisphere orbitofrontal cortex and bilateral middle temporal gyrus: areas that become active when there is need to inhibit one's own experience when considering the internal state of another and for visual evaluation of action rationality. Results support previous findings, that ToM recruits a neural network with each region sub-serving a supporting role depending on the nature of the task itself. In contrast, a network of cortical regions primarily located within right- and left-hemisphere medial-frontal and parietal cortex, outside the internal representational network, was selectively recruited during the chess task. We hypothesize that in our cohort of novice chess players the strategy was to employ an iterative thinking pattern which in part involved mentalizing processes and recruited core ToM-related regions