Fecal calprotectin and platelet count predict histologic disease activity in pediatric ulcerative colitis: results from a projection-predictive feature selection.

Especially for pediatric patients, proxies of mucosal inflammation are needed. The Pediatric Ulcerative Colitis Activity Index (PUCAI) has been established to predict clinical and endoscopic disease activity. However, histologic inflammation might persist. We applied a special variable selection technique to predict histologic healing in pediatric ulcerative colitis (UC) as parsimoniously (but still as precisely) as possible. The retrospective analysis included data from two study cohorts, comprising 91 visits from 59 pediatric patients with UC. A Bayesian ordinal regression model was used in combination with a projection-predictive feature selection (PPFS) to identify a minimal subset of clinical and laboratory parameters sufficient for the prediction of histologic disease activity. Following the PPFS, CEDATA-GPGE patient registry data were analyzed to investigate the relevance of the selected predictors in relation to PUCAI and Physician Global Assessment (PGA) in up to 6697 patient visits. Fecal calprotectin (FC) and platelet count were identified as the minimal subset of predictors sufficient for prediction of histologic disease activity in pediatric UC. FC and platelet count also appeared to be associated with increasing disease activity as measured by PUCAI and PGA in the CEDATA-GPGE registry. Based on the selected model, predictions can be performed with a Shiny web app.  Conclusion: Our statistical approach constitutes a reproducible and objective tool to select a minimal subset of the most informative parameters to predict histologic inflammation in pediatric UC. A Shiny app shows how physicians may predict the histologic activity in a user-friendly way using FC and platelet count. To generalize the findings, further prospective studies will be needed. What is Known: • Histologic healing is a major endpoint in the therapy of ulcerative colitis (UC). • The PUCAI score has been established to predict disease activity in pediatric UC but is not suitable for the prediction of histologic healing. What is New: • Our Bayesian ordinal regression model in combination with a projection-predictive feature selection is a reproducible and objective tool to select the minimal subset of clinical and laboratory parameters to predict histologic inflammation in pediatric UC. • Histologic inflammation in pediatric UC can be non-invasively predicted based on the combination of fecal calprotectin levels and platelet count.

Molecular basis of hereditary C1q deficiency--revisited: identification of several novel disease-causing mutations.

C1q is the central pattern-recognition molecule in the classical pathway of the complement system and is known to have a key role in the crossroads between adaptive and innate immunity. Hereditary C1q deficiency is a rare genetic condition strongly associated with systemic lupus erythematosus and increased susceptibility to bacterial infections. However, the clinical symptoms may vary. For long, the molecular basis of C1q deficiency was ascribed to only six different mutations. In the present report, we describe five new patients with C1q deficiency, present the 12 causative mutations described till now and review the clinical spectrum of symptoms found in patients with C1q deficiency. With the results presented here, confirmed C1q deficiency is reported in 64 patients from at least 38 families.

Reticulocyte hemoglobin equivalent (Ret He) and assessment of iron-deficient states.

Direct measurement of the reticulocyte hemoglobin content provides useful information for the diagnosis and treatment of iron-deficient states. We have examined direct measurements of reticulocyte and red cell hemoglobin content on the Sysmex XE 2100 (Ret He and RBC He respectively) and the Bayer ADVIA 2120 (CHr and CH respectively) analyzers. Good agreement was found between Ret He and CHr (Y = 1.04X - 1.06; r2= 0.88) and between the RBC He and CH parameters (Y = 0.93X + 1; r2= 0.84 n = 200) in pediatric patients and in normal adults (Ret He and CHr; Y = 1.06X - 0.43; r2= 0.83; n = 126; RBC He and CH; Y = 0.94X + 1; r2= 0.87; n = 126). In 1500 blood samples from patients on chronic dialysis, Ret He was compared with traditional parameters for iron deficiency (serum iron <40 microg/dl, Tsat <20%, ferritin <100 ng/ml, hemoglobin <11 g/dl) for identifying iron-deficient states. Receiver operator characteristic (ROC) curve analysis revealed values of the area under the curve for Ret He of 0.913 (P < 0.0001). With a Ret He cutoff level of 27.2 pg, iron deficiency could be diagnosed with a sensitivity of 93.3%, and a specificity of 83.2%. Ret He is a reliable marker of cellular hemoglobin content and can be used to identify the presence of iron-deficient states.

Maximal aerobic capacity across age in healthy Hispanic and Caucasian women.

We tested the hypothesis that the age-related decline in maximal aerobic capacity, as measured by maximal oxygen uptake (VO(2 max)), is greater in Hispanic than in Caucasian women. We studied 146 healthy sedentary women aged 20-75 yr: 53 Hispanic (primarily of Mexican descent) and 93 Caucasian (non-Hispanic white). The groups did not differ in mean age, body mass, percent body fat, estimated physical activity-related energy expenditure, or education-based socioeconomic status (SES). During maximal exercise, respiratory exchange ratio, rating of perceived exertion, and percent predicted maximal heart rate were similar across age and ethnicity, suggesting equivalent maximum voluntary efforts in all subjects. VO(2 max) (ml x kg(-1) x min(-1)) was inversely related to age (P < 0.01) in Caucasian (r =-0.68) and Hispanic (r = -0.61) women. The absolute rate of decline in VO(2 max) with age was the same in the two groups (-0.31 ml x kg(-1) x min(-1) x yr(-1)). The relative rate of decline (% from age 25 yr) also was similar in the Caucasian (-9.0%) and Hispanic (-9.2%) women. When subjects of all ages were pooled, mean levels of VO(2 max) were similar in the two groups (approximately 28 ml x kg(-1) x min(-1)). These results, the first to our knowledge in Hispanics, indicate that mean levels of VO(2 max), as well as the rate of decline in VO(2 max) with age, are similar in healthy sedentary Hispanic and Caucasian women of similar SES. Thus it does not appear that Hispanic ethnicity per se modulates maximal aerobic capacity in this population.

Total and regional body composition across age in healthy Hispanic and white women of similar socioeconomic status.

BACKGROUND: Indirect measures of body composition suggest that Hispanic women have an excess prevalence of overweight and obesity compared with white women. Socioeconomic status (SES) is a potentially confounding factor in such studies. OBJECTIVE: Our aim was to determine whether Hispanic ethnicity is associated with higher total and regional adiposity and lower fat-free mass (FFM) in healthy women across the adult age range. DESIGN: We used a prospective cross-sectional design to examine total and regional body composition in 54 Hispanic women (primarily of Mexican descent) and 56 white women of similar SES. RESULTS: The groups were not significantly different in mean age, body mass, or SES, although the Hispanic women were shorter (P<0.05). Body mass index (in kg/m(2); 25.2+/-0.5 compared with 23.9+/-0.5; P<0.05), percentage body fat (38.4+/-0.8% compared with 34.9+/-1.3%; P<0.05), and total fat mass (25.0+/-1.0 compared with 23.0+/-1.2 kg; P = 0.10) were or tended to be higher in the Hispanic women. The greater total adiposity of the Hispanic women was primarily the result of higher percentage fat and fat mass in the trunk (P<0.05); within the trunk region, abdominal and subscapular skinfold thicknesses were 30-40% greater in the Hispanic women (P<0.01). Total FFM was slightly but significantly lower in the Hispanic women (38.9+/-0.6 compared with 40.9+/-0.6 kg; P = 0.01), primarily because of a smaller FFM in the trunk region (P<0.05). CONCLUSION: Among healthy women, Hispanic (Mexican American) ethnicity may be associated with modestly higher levels of adiposity and slightly lower amounts of FFM overall and in the trunk region in particular.

Age-related declines in knee extensor strength and physical performance in healthy Hispanic and Caucasian women.

Hispanic women may undergo greater age-related reductions in physical functional capacity compared with Caucasian women. If so, a greater rate of decline in muscle strength with age could contribute. We tested this hypothesis in 82 healthy sedentary Caucasian (n = 37) and Hispanic (n = 45) adult women aged 21-78 years of similar socioeconomic status. Absolute one-repetition maximum (1-RM) strength of the knee extensors (KE) declined with advancing age in the Caucasian (r = -.55, p < .01) and Hispanic (r = -.45, p < .01) women; the rates of decline were similar in the two groups (-7% to 8% x decade(-1), p = .60). KE strength normalized for thigh fat-free mass (FFM) also declined with age in the Caucasian (r = .52, p < .01) and Hispanic (r = -.41, p < .01) women, the rates of decline being similar (-6% to 7% x decade(-1), p = .66). For all functional performance tasks (10-m walk, stair ascent, stair descent, and chair stand), performance time increased with advancing age (mean of four tasks vs age: Caucasian, r = .64, p < .01; Hispanic, r = .56, p < .01). Absolute and normalized KE 1-RM were inversely related to the mean time for the four performance tasks (r = -.34 to -.58, all p < .01). Normalized KE 1-RM was the best independent predictor of the age-related decline in task performance in both groups. These cross-sectional findings do not support the hypothesis that Hispanic ethnicity per se is associated with a greater decline in KE strength and performance tasks associated with KE strength in healthy women.

Relation of leptin and insulin to adiposity-associated elevations in sympathetic activity with age in humans.

OBJECTIVE: To determine whether plasma leptin and insulin concentrations are related to adiposity-associated elevations in muscle sympathetic nerve activity (MSNA) with age in healthy adult humans. DESIGN: Cross-sectional investigation of young and older adult men. SUBJECTS: Thirty healthy adult men, 16 young (25+/-1 y, mean+/-s.e.) and 14 older (61+/-1 y). MEASUREMENTS/RESULTS: The older men had higher (P<0.05) levels of body mass, BMI, total fat mass and truncal fat mass (dual energy X-ray absorptiometry) than the young men. MSNA burst frequency (microneurography) was approximately 75% higher in the older men (P<0.001). Plasma leptin concentrations were approximately 150% higher (P<0.01), whereas plasma insulin concentrations were approximately 70% higher (P<0.05) in the older subjects. MSNA was related to both total (r=0.51, P<0.01) and truncal (r=0.56, P<0.01) fat mass. Plasma leptin concentrations were related to total and truncal fat mass (both r=0.83, P<0.001), and to MSNA (r=0.49, P<0.01). Plasma insulin concentrations were related to MSNA (r=0.38, P<0.05). We used partial correlation analyses to assess whether leptin and/or insulin are potential contributors to the relation between body fat and MSNA. Adjusting for the effects of plasma leptin, but not insulin, concentrations eliminated the significant relations between MSNA and total and truncal fat mass. CONCLUSION: Our results: (1) demonstrate a positive relation between MSNA and plasma leptin concentrations in young and older healthy men; and (2) support the concept that circulating leptin concentrations may act as a humoral signal contributing to adiposity-associated elevations in MSNA with age in adult humans.

Inflammatory parameters and soluble cell adhesion molecules in Swedish children with Kawasaki disease: relationship to cardiac lesions and intravenous immunoglobulin treatment.

The possible use of inflammatory parameters as a predictor of coronary artery lesions (CAL) and the effect of intravenous immunoglobulin (IVIG) treatment in 30 Swedish children with acute Kawasaki disease were investigated. All the patients were treated with IVIG (2 g/kg) and seven of them had CAL. Ten febrile children, hospitalized for treatment of severe infection, and 15 healthy children served as controls. The levels of soluble E-selectin and soluble intercellular adhesion molecule (ICAM)-1 in the Kawasaki patients were elevated in comparison to healthy, but not in comparison to febrile controls. Paired analysis of our patients before and after IVIG therapy during acute disease revealed lowered levels of C-reactive protein, interleukin-6, soluble E-selectin and soluble ICAM-1. We found no statistically significant relationships among any of these parameters as a possible predictor of CAL, but three patients with cardiac sequelae demonstrated high values for these inflammatory parameters. These findings may reflect endothelial activation in connection with vasculitis, and the anti-inflammatory effect of IVIG treatment lowering cytokine levels and subsequently decreasing the expression and shedding of adhesion molecules. In conclusion, we were unable to identify a predictor of CAL in the acute phase. The patients had higher levels of soluble E-selectin and soluble ICAM-1 than did afebrile controls, but not febrile controls. The patients' levels of C-reactive protein, interleukin-6, soluble E-selectin and soluble ICAM-1 were decreased after 1-2d of IVIG treatment.

Indicators of dysautonomia in severe Guillain-Barré syndrome.

This study sought to establish quantitative criteria for dysautonomia in artificially ventilated patients with Guillain-Barré syndrome (GBS). Such criteria would help to identify patients at risk for cardiovascular complications. This retrospective controlled clinical study compared hourly cardiovascular monitoring data from 36 successive, artificially ventilated GBS patients with that from 11 artificially ventilated control patients with myasthenia. Tolerance limits for daily means, extremes, and variations in heart rate (HR) and blood pressure (BP) were estimated from the most abnormal subgroups of the treatment days of our control patients. These exceeded previously suggested arbitrary cutoff values for dysautonomia. The range in systolic BP was increased in 27 GBS patients, despite an upper limit of normal (85 mmHg) that was double the value suggested in previous work. All 16 patients with mean systolic BP above 165 mmHg also had persistent tachycardia (mean HR > 125 bpm), or were treated with beta-blockers. This pattern of sympathetic hyperactivity was combined with probable vagal hyperactivity (bradycardia < 48 bpm) in 6 patients. Hypotension (minimal systolic BP < 85 mmHg) and unprovoked bradycardia indicated sympathetic hypoactivity in 3 patients. Except in one patient who suffered from asystole on his first day on the ICU, all episodes of bradycardia were preceded by increased daily systolic BP variation (> 85 mmHg), which thus proved to be a sensitive and prognostically valuable indicator of dysautonomia in GBS.

Characterization of the T-cell receptor V-beta repertoire in Kawasaki disease.

Kawasaki disease (KD) is a paediatric multisystem necrotizing vasculitis constituting the most frequent cause of acquired heart disease in childhood. Conflicting data have been reported regarding expanded T-cell populations using particular T-cell receptor (TCR) beta-chain variable (BV) gene segments, suggesting either a superantigen- or a conventional antigen-mediated immune response in this disease. In order to further investigate the role of T lymphocytes, cells were stained with an extensive panel of 21 different TCRBV specific monoclonal antibodies (MoAbs) covering almost 70% of all T-cells. Flow cytometry was employed to analyse the expression of the TCRBV repertoire in the CD4+ and CD8+ subsets separately, and of activation markers, in freshly isolated peripheral blood lymphocytes of 25 Kawasaki disease patients during the acute and convalescent phases of the disease. No abnormal usage of any TCRBV family was found, neither acutely nor during convalescence, compared with a control group of healthy children. However, a significant increase in interleukin-2 receptor (IL-2R)-expressing T lymphocytes restricted to the CD4+ subset was observed in KD patients. Our data confirm a strong immune activation in KD that might be of importance in the pathogenesis of the disease.

Inhibition of complement regulation is key to the pathogenesis of active Heymann nephritis.

Crry (complement receptor 1-related protein/gene y) is a key cellular complement regulator in rodents. It is also present in Fx1A, the renal tubular preparation used to immunize rats to induce active Heymann nephritis (HN), a model of membranous nephropathy. We hypothesized that rats immunized with anti-Fx1A develop autoantibodies (auto-Abs) to Crry as well as to the megalin-containing HN antigenic complex, and that anti-Crry Abs promote the development of injury in HN by neutralizing the complement regulatory activity of Crry. Rats immunized with Fx1A lacking Crry remained free of proteinuria and glomerular deposits of C3 during a 10-wk follow-up despite typical granular immunoglobulin (Ig)G deposits in glomeruli. Anti-Fx1A auto-Abs were present in their sera at levels that were not different from sera pooled from proteinuric rats with HN induced with nephritogenic Fx1A. Passive administration of sheep anti-Crry Abs to rats immunized with Crry-deficient Fx1A led to proteinuria and glomerular C3 deposition, which were not seen in such rats injected with preimmune IgG, nor in rats with collagen-induced arthritis injected with anti-Crry IgG. To directly examine the role of Crry in HN, rats were immunized with Crry-deficient Fx1A reconstituted with rCrry. This led to typical HN, with 8 out of 15 rats developing proteinuria within 14 wk. Moreover, the extent of glomerular C3 deposition correlated with proteinuria, and anti-Crry Abs were present in glomerular eluates. Thus, Crry is a key nephritogenic immunogen in Fx1A. Formation of neutralizing auto-Abs to Crry impairs its function, leading to unrestricted complement activation by Abs reactive with the HN antigenic complex on the epithelial cell surface.

Monoclonal immunoglobulin G1-kappa fibrillary glomerulonephritis.

We report here a case of fibrillary glomerulonephritis arising in a 43-year-old man with a polyclonal gammopathy, who presented with progressive renal insufficiency, microscopic hematuria, and mild proteinuria (0.7 g/d). Ultrastructural studies showed deposits of randomly oriented fibrils in the glomerular mesangium and adjacent portions of some glomerular basement membranes, with a mean fibril thickness of 14.3 nm, highly consistent with fibrillary glomerulonephritis. The Congo red stain was negative on histologic sections. Immunofluorescence studies revealed strong mesangial and focal glomerular capillary staining for immunoglobulin (Ig) G, complement (C) 3, and kappa light chains, with minimal staining for IgA, IgM, C1q, or lambda light chains. The IgG present was entirely of the IgG1 subclass. This case is quite unusual for fibrillary glomerulonephritis, which typically presents with polyclonal IgG deposits and IgG4 as the dominant IgG subclass present. Monoclonal deposits are more frequently associated with immunotactoid glomerulopathy, characterized ultrastructurally by microtubule-like structures 30 to 50 nmn thick, often in parallel arrays. The present case illustrates that although fibrillary glomerulonephritis and immunotactoid glomerulopathy might be distinguishable on ultrastructural grounds, there is overlap between these two entities with respect to the potential composition of the glomerular deposits present.

Focal glomerulosclerosis in the remnant kidney model--an inflammatory disease mediated by cytokines.

BACKGROUND: The mechanism of progression of established renal disease remains unclear. While a low protein diet slows this progression, the role of cytokines in this process has been little investigated. METHODS: We investigated cytokine expression by Northern blot and immunohistochemistry in two groups of 5/6 nephrectomized rats (5/6 Nx) fed a normal (24%) or low (6%) protein diet and compared them with sham operated controls. RESULTS: The rats on 6% protein diet had significantly less focal glomerulosclerosis (FGS) (17.4 +/- 4.4 vs 27.4 +/- 8.8%, P < 0.05) and global sclerosis (GGS) after 7 weeks (0.4 +/- 0.8 vs 3.5 +/- 2.1% of glomeruli P < 0.05). Both experimental groups showed three times control levels of MCP-I expression after 2 weeks. However in the 5/6 Nx 6% protein group the expression decreased at 4 weeks (1.5 times controls) and reached control levels after 7 weeks. In contrast, the 5/6 Nx 24% protein group exhibited a further marked increase after 4 weeks (5.6 times controls) and was still two-fold higher after 7 weeks. TGF-beta expression was modestly but consistently increased at all time points (120-160% of controls), with no difference between the two study groups. Neither IL-1 beta or TNF-alpha was detectable at any time. Immunohistochemistry demonstrated TGF-beta intracellularly in distal tubular cells in both experimental and control animals, while MCP-1 protein was found in the area of FGS and in the apical pole of distal tubular cells in both experimental groups. Glomerular and interstitial ED1 positive cells were significantly increased after four weeks in the 5/6 Nx 24% protein group (P < 0.05). CONCLUSIONS: A 'mechanical' injury to the kidney clearly results in an inflammatory response associated with the upregulation of MCP-1. A low protein diet modulates the expression of MCP-1 and improves the morphological sequelae seen after renal ablation.

Supplementation with L-2-oxothiazolidine-4-carboxylic acid, a cysteine precursor, does not protect against lipid peroxidation in puromycin aminonucleoside-induced nephropathy.

Lipid peroxidation in the kidney has been shown to precede proteinuria in puromycin aminonucleoside (PAN)-induced nephropathy. The aim of this study was to determine if L-2-oxothiazolidine-4-carboxylic acid (procysteine) would protect rats against PAN-induced nephrotoxicity. Male Sprague-Dawley rats were treated with procysteine (16 mg/100 g body weight i.p.) 24 h and 30 min prior to receiving a single injection of PAN (15 mg/100 g body weight i.v.) followed by procysteine in the drinking water (4 g/l). Control rats received procysteine alone (intraperitoneally and in drinking water) or PAN alone and then plain water. Proteinuria was not significantly different between PAN/ procysteine and PAN groups, reaching a maximum at day 14 and persisting at day 28. Lipid peroxidation was more severe in PAN/procysteine rats reaching a maximum at day 3 (253 +/- 30 ng/mg protein) compared to day 5 in PAN rats (196 +/- 20 ng/mg protein). Procysteine alone did not modulate proteinuria over 28 days or lipid peroxidation over 7 days. GSH levels over 7 days were not elevated by procysteine and were virtually zero in PAN and PAN/procysteine rats. Focal glomerulosclerosis (FGS) was worse at day 28 in PAN/procysteine rats than in PAN rats (39 +/- 8.2 vs. 23 +/- 4.5%; p < 0.05). This study shows that procysteine as a potential source of reducing equivalents does not protect against renal lipid peroxidation and FGS in this model. On the contrary, PAN/procysteine rats developed significantly more FGS through yet unknown mechanisms.

Alpha L beta 2 integrin/LFA-1 binding to ICAM-1 induced by cytohesin-1, a cytoplasmic regulatory molecule.

The avidity of integrin adhesion receptors for extracellular ligands is subject to dynamic regulation by intracellular programs that have yet to be elucidated. We describe here a protein, cytohesin-1, which specifically interacts with the intracellular portion of the integrin beta 2 chain (CD18). The molecule shows homology to the yeast SEC7 gene product and bears a pleckstrin homology (PH) domain. Overexpression of either the full-length cytohesin-1 or the SEC7 domain induces beta 2 integrin-dependent binding of Jurkat cells to ICAM-1, whereas expression of the isolated cytohesin-1 PH domain inhibits T cell receptor-stimulated adhesion. Similar inhibition is not exhibited by PH domains taken from other proteins, showing that the interaction is specific and that individual PH domains are capable of discriminating between alternative targets.

Experimental glomerulosclerosis: Defektheilung of the kidney.

Research in the role of cytokines in experimental glomerulonephritis has increased our understanding of the mechanisms that may be involved in the development of progressive renal disease. Glomerulosclerosis, the final common pathway in a variety of underlying kidney diseases, is characterized by increased extracellular matrix formation and cell proliferation. Transforming growth factor-beta (TGF-beta) and monocyte chemoattractant protein-1 (MCP-1) have been identified in animal models as mediators in the processes that follow renal injury. There is evidence of similar events occurring in other fibrotic disorders, suggesting that there is a common generic pathway of fibrosis. This review summarizes our knowledge of TGF-beta and MCP-1 in experimental kidney disease and compares these results with mechanisms described in other organs. We propose that glomerulosclerosis represents Defektheilung (healing by secondary intention) of the kidney after various injuries. The growing knowledge of the mechanisms involved will help advance future therapeutic interventions by directing the healing process toward primary healing.