Area deprivation and demographic factors associated with diabetes technology use in adults with type 1 diabetes in Germany.

Introduction: Diabetes technology improves glycemic control and quality of life for many people with type 1 diabetes (T1D). However, inequalities in access to diabetes technology exist in many countries. In Germany, disparities in technology use have been described in pediatric T1D, but no data for adults are available so far. We therefore aimed to analyze whether demographic factors and area deprivation are associated with technology use in a representative population of adults with T1D. Materials and methods: In adults with T1D from the German prospective diabetes follow-up registry (DPV), we analyzed the use of continuous subcutaneous insulin infusion (CSII), continuous glucose monitoring (CGM), and sensor augmented pump therapy (SAP, with and without automated insulin delivery) in 2019-2021 by age group, gender, migration background, and area deprivation using multiple adjusted regression models. Area deprivation, defined as a relative lack of area-based resources, was measured by quintiles of the German index of Multiple Deprivation (GIMD 2015, from Q1, least deprived, to Q5, most deprived districts). Results: Among 13,351 adults with T1D, the use of technology decreased significantly with older age: CSII use fell from 56.1% in the 18-<25-year age group to 3.1% in the ≥80-year age group, CGM use from 75.3% to 28.2%, and SAP use from 45.1% to 1.5% (all p for trend <0.001). The use of technology was also significantly higher in women than in men (CSII: 39.2% vs. 27.6%; CGM: 61.9% vs. 58.0%; SAP: 28.7% vs. 19.6%, all p <0.001), and in individuals without migration background than in those with migration background (CSII: 38.8% vs. 27.6%; CGM: 71.1% vs. 61.4%; SAP: 30.5% vs. 21.3%, all p <0.001). Associations with area deprivation were not linear: the use of each technology decreased only from Q2 to Q4. Discussion: Our real-world data provide evidence that higher age, male gender, and migration background are currently associated with lower use of diabetes technology in adults with T1D in Germany. Associations with area deprivation are more complex, probably due to correlations with other factors, like the higher proportion of migrants in less deprived areas or the federal structure of the German health care system.

DIVE/DPV registries: benefits and risks of analog insulin use in individuals 75 years and older with type 2 diabetes mellitus.

INTRODUCTION: The aims of this study were to characterize insulin-treated individuals aged ≥75 years with type 2 diabetes using basal insulin analogs (BIA) or regular insulins (human insulin (HI)/neutral protamine Hagedorn (NPH)) and to compare the benefits and risks. RESEARCH DESIGN AND METHODS: The analysis was based on data from the DPV (Diabetes-Patienten-Verlaufsdokumentation) and DIVE (DIabetes Versorgungs-Evaluation) registries. To balance for confounders, propensity score matching for age, sex, diabetes duration, body mass index and hemoglobin A1c (HbA1c) as covariates was performed. RESULTS: Among 167 300 patients aged ≥75 years with type 2 diabetes (mean age, 80.3 years), 9601 subjects used insulin regimens with basal insulin (HI/NPH or BIA). Of these 8022 propensity score-matched subjects were identified. The mean diabetes duration was ~12 years and half of the patients were male. At the time of switch, patients provided with BIA experienced more dyslipidemia (89.3% vs 85.9%; p=0.002) and took a greater number of medications (4.3 vs 3.7; p<0.001) and depression was more prevalent (8.4% vs 6.5%; p=0.01). Aggregated to the most actual treatment year, BIA was associated with a higher percentage of patients using basal-supported oral therapy (42.6% vs 14.4%) and intensified conventional insulin therapy (44.3% vs 29.4%) and lower total daily insulin doses (0.24 IU/kg/day vs 0.30 IU/kg/day; p<0.001). The study did not reveal significant differences in efficacy (HbA1c 7.4% vs 7.3%; p=0.06), hospitalizations (0.7 vs 0.8 per patient-year (PY); p=0.15), length of stay (16.3 vs 16.1 days per PY; p=0.53), or rates of severe hypoglycemia (4.07 vs 4.40 per 100 PY; p=0.88), hypoglycemia with coma (3.64 vs 3.26 per 100 PY; p=0.88) and diabetic ketoacidosis (0.01 vs 0.03 per 100 PY; p=0.36). CONCLUSION: BIA were used in more individually and patient-centered therapy regimens compared with HI/NPH in patients with a mean age of 80 years. Both groups were slightly overtreated with mean HbA1c <7.5%. The risk of severe hypoglycemia was low and independent of insulin type. Further analyses of elderly patients with type 2 diabetes are needed to provide evidence for best practice approaches in this age group.

Clinical nutrition scores are superior for the prognosis of haemodialysis patients compared to lab markers and bioelectrical impedance.

BACKGROUND: Malnutrition is closely related to inflammation and atherosclerosis in uraemic patients. There is still debate on how to quantify nutritional status in order to achieve the best prediction of mortality and hospitalization. METHODS: Different methods to detect malnutrition were prospectively investigated for their prognostic impact on mortality and hospitalization of haemodialysis (HD) patients. We compared clinical nutrition scores (body mass index, BMI; subjective global assessment, SGA; malnutrition inflammation score, MIS; and nutritional risk screening, NRS) to lab parameters of protein and lipid metabolism, or bioelectrical impedance analysis (BIA) in 90 HD patients. Over a 3-year follow-up, all-cause mortality and hospitalization were evaluated using a Cox regression model. RESULTS: The scores SGA, NRS, MIS, serum albumin, prealbumin, transferrin and BIA were predictive of both mortality and hospitalization. Elevated CRP predicted only a significantly higher mortality. After adjustment for age, gender, dialysis vintage and diabetes status, the best prognostic parameters for mortality were the clinical nutrition scores, MIS-Index > or = 10 [HR 6.25 (2.82-13.87), P < 0.001], NRS [HR 4.24 (1.92-9.38), P < 0.001] and SGA B/C [HR 2.70 (1.14-6.41), P < 0.05]. CONCLUSIONS: In HD patients, serum markers of protein metabolism and BIA can be used for evaluation of the nutritional status. However, with regard to mortality and hospitalization risk, the individual clinical nutrition scores are superior compared to lab markers and BIA. To confirm malnutrition, we propose using clinical nutrition score generally or at least in the case of two malnutrition-positive parameters (lab, BIA, BMI).

Over-expression of IGF-related peptides in stenoses of native arteriovenous fistulas in hemodialysis patients.

INTRODUCTION: Insulin-like growth factors (IGFs) are known to play an important role in atherogenesis. The aim of our study was to assess the local expression of IGF-related peptides in stenosed hemodialysis fistulas and compare these with their respective serum levels. METHODS: We investigated 15 stenosed vein segments of primary arteriovenous fistulas, 29 non-stenosed control vein segments from uremic patients and 15 non-stenosed control saphenous vein segments. Immunohistochemistry was performed for IGF-I, insulin, IGF-binding proteins (IGFBPs)-1, -2, -3 and -4, the acid labile subunit (ALS) and type 1 IGF-receptor (IGF-R). Serum levels were measured by specific radioimmunoassays. RESULTS: Compared to both control groups, a significantly higher expression of the following IGF-related peptides was seen in the stenotic (neo)intima: IGF-I, IGFBP-1, -2, -3, -4 and IGF-R; in the stenotic media: IGF-I and IGFBP-3 and in the endothelium of stenotic fistulas: IGF-I (all p<0.05). Staining against ALS and insulin was negative in all vessels. Serum IGF-I levels did not differ. Serum levels of IGFBP-1, -2, -3 and -4 were significantly higher in patients with renal disease (all p<0.05). There were no correlations between local and systemic IGF-related peptide levels. There were correlations of neointimal expression of IGF-I, IGFBP-1, -2, -3, -4 and IGF-R with both hypercellularity and the presence of inflammatory cells (p<0.05). CONCLUSION: In the stenotic arteriovenous fistula of hemodialysis patients, expression of the peptides IGF-I, IGFBP-1, -2, -3, -4 and IGF-R was significantly increased and showed a positive correlation with neointimal inflammation and hypercellularity (all p<0.05). IGF-related peptides are most likely synthesized locally and might be involved in the initiation and/or progression of neointimal thickening of primary arteriovenous fistulas.

Trend of antihyperglycaemic therapy and glycaemic control in 184,864 adults with type 1 or 2 diabetes between 2002 and 2014: Analysis of real-life data from the DPV registry from Germany and Austria.

AIMS: To analyse time trends of antihyperglycaemic therapy and glycaemic control in adult subjects with type 1, or type 2 diabetes between 2002 and 2014 in Germany/Austria. METHODS: 184,864 adults with diabetes (35,144 type 1 diabetes (T1D), 149,720 type 2 diabetes (T2D)) from the DPV-database documented between 2002 and 2014 were included. Regression models were applied for antihyperglycaemic therapy in T2D (non-pharmacological, OADs only, insulin±OADs), insulin therapy in T1D (CT, ICT, CSII) and T2D (BOT, SIT, CT, ICT, CSII), for the use of insulin analogues, and for glycaemic control (HbA1C, severe hypoglycaemia), adjusting for confounders sex, age, and diabetes duration. RESULTS: In T1D, CT (2002:19.7%; 2014:16.0%) and ICT (2002:66.8%; 2014:52.4%) decreased, while CSII increased from 13.5% to 31.5%. In T2D, non-pharmacological treatment became less frequent (2002:36.0%, 2014:21.8%), the use of OADs (2002:19.3%, 2014:28.9%) and insulin±OADs (2002:44.6%, 2014:49.4%) increased. BOT increased from 7.9% to 18.9%, SIT decreased from 12.0% to 8.3%. ICT slightly increased (2002:44.0%, 2014:45.3%), CT decreased (2002:35.8%, 2014:27.2%). Insulin analogues were used more frequently in T1D (rapid-acting:2002:46.8%, 2014:84.8%; long-acting:2002:26.0%, 2014:54.8%) and in T2D (rapid-acting:2002:26.0%, 2014:43.5%; long-acting:2002:13.7%, 2014:53.6%). Until 2011, HbA1C increased in T1D and T2D, but then decreased again. High variability in the rate of hypoglycaemia was observed. CONCLUSIONS: This observational study indicates an increased use of insulin pumps in T1D. In T2D, non-pharmacological therapy decreased, and insulin therapy, particular as BOT, rose. An increase in the use of rapid- and long-acting insulin analogues was present in both patient-groups. Time trend was less clear in glycaemic control.

High rate of hypoglycemia in 6770 type 2 diabetes patients with comorbid dementia: A multicenter cohort study on 215,932 patients from the German/Austrian diabetes registry.

AIMS: Dementia and type 2 diabetes (T2D) are two major phenomena in older people. To compare anti-hyperglycemic therapy and diabetes-related comorbidities between elderly T2D patients with or without comorbid dementia. METHODS: 215,932 type 2 diabetes patients aged ≥ 40 years (median [Q1;Q3]: 70.4 [61.2;77.7] years) from the standardized, multicenter German/Austrian diabetes patient registry, DPV, were studied. To identify patients with comorbid dementia, the registry was searched by ICD-10 codes, DSM-IV/-5 codes, respective search terms and/or disease-specific medication. For group comparisons, multiple hierarchic regression modeling with adjustments for age, sex, and duration of diabetes was applied. RESULTS: 3.1% (n=6770; 57% females) of the eligible T2D patients had clinically recognized comorbid dementia. After adjustment for demographics, severe hypoglycemia (insulin group: 14.8 ± 0.6 vs. 10.4 ± 0.2 events per 100 patient-years, p<0.001), hypoglycemia with coma (insulin group: 7.6 ± 0.4 vs. 3.9 ± 0.1 events per 100 patient-years, p<0.001), depression (9.9 vs. 4.7%, p<0.001), hypertension (74.7 vs. 72.2%, p<0.001), stroke (25.3 vs. 6.5%, p<0.001), diabetic foot syndrome (6.0 vs. 5.2%, p=0.004), and microalbuminuria (34.7 vs. 32.2%, p<0.001) were more common in dementia patients compared to T2D without dementia. Moreover, patients with dementia received insulin therapy more frequently (59.3 vs. 54.7%, p<0.001), but metabolic control (7.7 ± 0.1 vs. 7.7 ± 0.1%) was comparable to T2D without dementia. CONCLUSIONS: In T2D with dementia, higher rates of hypoglycemia and other diabetes-related comorbidities were observed. Hence, the risks of a glucocentric and intense diabetes management with insulin and a focus on tight glycemic control without considering other factors may outweigh the benefits in elderly T2D patients with comorbid dementia.

The terminal complement complex inhibits apoptosis in vascular smooth muscle cells by activating an autocrine IGF-1 loop.

Two counteracting processes determine accumulation of human vascular smooth muscle cells (SMCs) in atherosclerotic lesions: cell proliferation and apoptosis. SMCs synthesize insulin-like growth factor-1 (IGF-1), which potently inhibits apoptosis. The terminal complement complex C5b-9 interacts with SMCs in early human atherogenesis. In this study, we investigated whether C5b-9 may activate the IGF-1 system in SMCs, resulting in the inhibition of SMC apoptosis. C5b-9 generation on SMCs in vitro markedly reduced CD95-mediated apoptosis as assessed by flowcytometric analysis of annexin V binding and in caspase 3 assays. C5b-9 induced both significant IGF-1 release and up-regulation of IGF-1 binding sites in SMCs. Immunoneutralization of IGF-1 with a monoclonal IGF-1 antibody abolished the antiapoptotic effects of C5b-9. We conclude that C5b-9 inhibits apoptosis in SMCs by inducing an autocrine IGF-1 loop. This mechanism may contribute to the accumulation of SMCs in early human atherosclerotic lesions.

Psoriasis and Diabetes: A Multicenter Study in 222078 Type 2 Diabetes Patients Reveals High Levels of Depression.

OBJECTIVE: This study aimed to investigate the association between psoriasis and disease outcome in type 2 diabetes (T2D). METHODS: 222078 T2D patients (≥10 years old) from the prospective, multicenter diabetes patient registry were analyzed. Specific search items were used to identify psoriasis patients. Multiple regression models were fitted and adjusted for demographic confounder. RESULTS: 232 T2D patients had comorbid psoriasis. After adjusting psoriasis patients revealed a higher BMI (31.8 [31.0; 32.6] versus 30.6 [30.5; 30.6] kg/m2, p = 0.004) and HbA1c (64.8 [62.1; 67.6] versus 59.0 [58.9; 59.1] mmol/mol, p < 0.0001). Insulin was used more frequently (62.3 [55.7; 68.5] versus 50.9 [50.7; 51.1] %, p = 0.001), only OAD/GLP-1 was similar, and nonpharmacological treatment was less common (13.3 [9.5; 18.3] versus 21.9 [21.7; 22.1] %, p = 0.002). Severe hypoglycemia (0.31 [0.238; 0.399] versus 0.06 [0.057; 0.060] events per patient-year, p < 0.0001), hypertension (86.1 [81.1; 90.0] versus 68.0 [67.8; 68.2] %, p < 0.0001), and thyroid disease (14.0 [10.1; 19.2] versus 4.6 [4.5; 4.7] %, p < 0.0001) were more prevalent. Depression occurred more often (10.5 [7.1; 15.2] versus 2.8 [2.7; 2.8] %, p < 0.0001). CONCLUSIONS: Clinical diabetes characteristics in psoriasis T2D patients were clearly worse compared to patients without psoriasis. Comorbid conditions and depression were more prevalent, and more intensive diabetes therapy was required.

Fibrillary glomerulonephritis associated with crescents as a therapeutic challenge.

Most cases of fibrillary glomerulonephritis (FG) terminate in end-stage renal disease within a few years. We report on two female patients (41 and 50 years old) with the diagnosis of FG associated with crescentic glomerulonephritis, a combination found in 20% to 25% of cases of FG. A broad spectrum of infectious disease and systemic immunologic disorders could be ruled out by specific assays. Both patients had severely impaired renal function, nephrotic syndrome, and hypertension. Based on the biopsy finding with necrotizing FG, treatment was started with corticosteroids and cyclophosphamide. In both patients, renal function recovered markedly within 6 months of treatment, in one case remaining stable for 3.5 years. Whether or not cyclophosphamide treatment changed the course of the FG itself or counteracted the acute crescentic process cannot be determined from these two patients. Based on these promising preliminary findings and the poor prognosis of FG, however, we recommend cyclophosphamide treatment of patients with FG and additional crescentic glomerulonephritis. For a systematic evaluation of the therapeutic options in FG, a multicenter clinical trial should be conducted.

Preoperative oral application of immunoglobulin-enriched colostrum milk and mediator response during abdominal surgery.

Our objective was to evaluate the influence of pre-operative oral application of an immunoglobulin-enriched milk preparation on endotoxin translocation and mediator release during and after abdominal surgery. Forty patients who had been treated by partial (n = 4) or total gastrectomy (n = 8) or pancreatic resection (n = 28) were enrolled in a placebo-controlled pilot study. Pre-operatively, patients were randomly treated for 3 days by oral application of a bovine milk preparation (lactobin 56g/day, n = 20) or placebo (n = 20). In both groups, endotoxin translocation and mediator release was studied pre- and intraoperatively by measuring endotoxin, endotoxin-neutralizing capacity (ENC), interleukin 6, C-reactive protein, transferrin, alpha-2-macroglobulin, albumin, apoliprotein-A1/-B, IgG, IgA, and IgM. The clinical course was followed up by daily evaluation of the Apache-II-score. Clinical data were comparable in both groups. The lactobin group showed significantly lower levels of endotoxin and ENC compared to the placebo group. Acute phase response, endotoxin-binding proteins, and clinical outcome did not differ between both groups. We conclude that prophylactic oral application of lactobin reduces perioperative endotoxemia and prevents reduction of ENC, suggesting a stabilization of gut barrier during abdominal surgery.

Effects of reduced dialysate calcium on calcium-phosphorus product and bone metabolism in hemodialysis patients.

BACKGROUND: The safety of using reduced calcium dialysate (RDC) in hemodialysis (HD) patients is controversial due to related changes in bone metabolism. In the present study we investigated whether an 18-month treatment period with RDC may induce significant changes in calcium-phosphorus product (CaxP), bone metabolism, and components of the insulin-like growth factor (IGF) system in HD patients. STUDY DESIGN: In this prospective study, 13 HD patients with biochemical signs of diminished or low-normal bone turnover and high CaxP due to high serum calcium level were treated by lowering dialysate calcium from 3.5 to 2.5 mEq/l for 18 months. By specific immunometric assays, serum levels of intact parathyroid hormone (PTH), bone alkaline phosphatase (B-ALP), pyridinoline (PYR), desoxypyridinoline (D-PYR), 25-OH-vitamin D(3) (25-vit D(3)), 1,25-(OH)(2)-vitamin D(3) (1,25-vit D(3)), free IGF-I, IGF-II, and IGF-binding protein (IGFBP)-1 to -6 were measured. RESULTS: CaxP decreased significantly from 5.62 (baseline) to 3.95 mmol(2)/l(2) (at 18 months), whereas PTH increased from 81 +/- 57 pg/ml at baseline to 236 +/- 188 at 12 months (p < 0.01), remaining in this range thereafter. Parameters of bone resorption (PYR) as well as formation (B-ALP) significantly increased during RDC, with peak levels after 12 months. Despite increasing doses of oral alfacalcidol, levels of 25-vit D(3) and 1,25-vit D(3) subsequently declined during RDC. In parallel with the changes in bone markers, free IGF-I levels decreased (baseline: 1.9 +/- 0.9 ng/ml, after 18 months: 1.1 +/- 0.7; p < 0.01). The decline of free IGF-I correlated with decreasing levels of IGFBP-3 and increasing levels of IGFBP-1/-4. CONCLUSION: The treatment with RDC effectively lowered CaxP and stimulated bone formation and resorption. The different changes in bone markers and IGF system components mirror the complex effects on bone metabolism.

Enteral application of an immunoglobulin-enriched colostrum milk preparation for reducing endotoxin translocation and acute phase response in patients undergoing coronary bypass surgery--a randomized placebo-controlled pilot trial.

OBJECTIVE: To evaluate the influence of enteral application of an immunoglobulin enriched bovine milk preparation on endotoxin plasma levels, endotoxin neutralizing capacity of plasma (ENC) and the acute phase response (IL-6, CRP) during and after cardiac surgery, in a pilot study. DESIGN, PATIENTS AND METHODS: 60 patients who underwent coronary bypass operations, were evenly enrolled in a placebo-controlled randomized study. The patients were treated by enteral application of either 42 g of a bovine colostrum milk preparation per day or placebo, for 2 days preoperatively. Endotoxin and ENC were sequentially determined intra- and postoperatively by a chromogenic modification of the limulus amebocyte lysate test. Interleukin-6, CRP, transferrin, alpha-2-macroglobulin, albumin, apo-A, apo-B, IgG, IgA, IgM were determined by ELISA and nephelometrically. The clinical course was followed up by daily evaluation of the Apache-II-score. MAIN RESULTS: Demographic data were comparable in both groups. No differences of the Apache-II-score (verum group: 6.5 +/- 1.9 vs. controls: 6.8 +/- 1.8 on admission) were observed. Endotoxin and ENC levels were elevated at the end of the operation and seemed to have a trigger function for the acute phase response. However, there was no reduction (calculated as the area under the curve) in patients receiving the colostrum milk preparation throughout the observation period. Plasma levels of endotoxin binding proteins did not differ. Plasma IL-6 concentrations increased to maximal median values of 655 pg/ml in the verum and 786 pg/ml in the control group, respectively 2 and 6 h after surgery. In the colostrum group, there was a tendency to reduced IL-6 levels throughout the observation period. CRP-levels of all patients peaked 48 h after the operation but were lower (p = 0.034) in the verum group. CONCLUSION: This study revealed that endotoxemia occurs early in an elective non-intestinal surgical intervention, and is followed by a subsequent increase in mediators of the acute phase reaction. The prophylactic enteral application of a bovine milk preparation for two days in cardiac patients did reduce postoperative CRP-plasma levels but, contrary to a former double-blind study in abdominal surgery, failed to curtail perioperative endotoxemia. One reason could be the amount of colostrum preparation administered was too small.

[Therapy of diffuse suppurative peritonitis with continuous peritoneal lavage]. / Therapie der diffusen eitrigen Peritonitis mit kontinuierlicher Peritoneallavage.

Peritonitis is a severe illness with a high mortality rate and different treatment modalities. Over a time period of 12 years 510 patients with peritonitis treated with continuous peritoneal lavage (CPL) were retrospectively analyzed. 315 of 510 patients with a mean age of 57.4 and a mean APACHE-II-Score of 10.2 on admission had a diffuse four quadrant peritonitis. 195 had a local and diffuse peritonitis due to perforation of the appendix. 232 of 315 patients with diffuse peritonitis (73.7%) had a secondary peritonitis, mostly due to organ perforation. The most frequent comorbidities were congestive heart failure (36.8%), pulmonary diseases (26%), diabetes mellitus (18.7%), chronic renal failure (16.8%), chronic liver diseases (9.5%) and a history of alcohol abuse (12.4%). On admission 18.7% had pulmonary insufficiency, 18.4% renal failure, 14.3% congestive heart failure and 13.3% hepatic insufficiency. 14% had one organ-, 6.7% two organ-, 2.5% three organ- and 5% four organ failure. The mean duration of lavage was 5.1 days with a fluid amount of 8-24 l/day. 81.3% of all patients could be treated successfully. 46 patients were reoperated due to persistent peritonitis. The mortality rate of the primarily treated patients was 15.6% compared to 37.0% of patients who had to be reoperated. The mortality rate of all patients was 18.7%. The prognosis of the clinical outcome was significantly influenced by preexisting organ failure and by the duration of the peritonitis on admission. Our results on CPL for diffuse peritonitis are in accordance with results from other treatment modalities; a direct comparison was not possible due to the different patient groups.

Different acute-phase response in newborns and infants undergoing surgery.

In a prospective clinical study, we investigated the inflammatory response in 88 neonatal subjects (43 boys and 45 girls) who underwent major abdominal surgery owing to congenital malformation involving the gastrointestinal tract and compared it with the response in 20 infants (8 boys, 12 girls; mean age, 4 mo) who underwent elective surgery for resolution of an existing temporary stoma. In both groups, plasma levels of endotoxin, IL-6, and C-reactive protein as well as leukocyte counts were determined during and after surgery. Endotoxin was measured by the Limulus amebocyte test, IL-6 by ELISA, and C-reactive protein by nephelometry. Statistical analyses were performed using the Wilcoxon signed-rank test. A significant increase in circulating endotoxin and a leukocyte shift was observed in the infant group only. Postoperatively, IL-6 levels peaked between 2 and 6 h and C-reactive protein after 24 h in the infant group. In contrast, no significant increase in the levels of endotoxin, IL-6, and C-reactive protein in plasma were observed during and after surgery in the neonatal subjects, except those with gastroschisis. Newborns with gastroschisis developed an inflammatory response after surgery that was less pronounced than the response of infants older than 4 mo. The finding that endotoxemia in newborns does not follow surgical trauma is most likely because of the absence of bacterial colonization of the gastrointestinal tract.

Increased expression of TGF-beta1 and IGF-I in inflammatory stenotic lesions of hemodialysis fistulas.

BACKGROUND: Hemodialysis fistula dysfunction due to stenotic lesions remains a frequent cause of hospitalization for hemodialysis patients. Transforming growth factor-beta(TGF-beta) and insulin-like growth factor-I (IGF-I) are known to be involved in atherogenesis. The latent TGF-beta1 binding protein-1 (LTBP-1) targets extracellular matrix (ECM) interactions and is involved in the regulation of TGF-beta latency. METHODS: We investigated the expression of TGF-beta1, LTBP-1 and IGF-I in 15 occluded or severely narrowed vein segments of primary arteriovenous fistulas, in 29 non-stenosed control veins from uremic, pre-dialysis patients, and in 15 non-stenosed control saphenous veins obtained from patients undergoing aortocoronary bypass grafting. Immunohistochemistry was performed on snap-frozen tissue specimens using antibodies recognizing either the latency-associated peptide of TGF-beta1 (96-1), LTBP-1 (Ab39) or IGF-I. Serum levels of TGF-beta1 and IGF-I were determined by commercially available IRMA. RESULTS: In stenosed hemodialysis fistulas, a pronounced intimal thickening with deposition of ECM was observed with light and electron microscopy. Infiltrating cells were seen in stenosed vessels, mostly in areas of intimal hyperplasia and in the media. TGF-beta1, LTBP-1 and IGF-I expression were mostly localized in the neointimal and medial layers, and were significantly higher than in the control groups. A positive correlation between the presence of inflammatory cells and the staining intensity for TGF-beta1, LTBP-1 and IGF-I was found in all vessels analyzed. CONCLUSION: Neointimal thickening of primary arteriovenous fistulas represents a local inflammatory process and appears to be associated with increased protein expression of TGF-beta1 and IGF-I. While local IGF-I is likely to stimulate smooth muscle cell proliferation in this setting, TGF-beta1 may be an important trigger of ECM production and deposition.

The immunosuppressive drug mycophenolic acid reduces endothelin-1 synthesis in endothelial cells and renal epithelial cells.

Several studies have demonstrated that endothelin-1 (ET-1) plays an important pathophysiological role in ischaemic renal failure and drug-induced renal injury, such as cyclosporine A (CsA)- and tacrolimus-associated nephrotoxicity. This study aimed to investigate whether the new immunosuppressive drug mycophenolic acid (MPA), which in contrast with CsA and tacrolimus lacks nephrotoxic side effects, modulates ET-1 synthesis in endothelial cells and renal epithelial cells. ET-1 release by cultured human umbilical vein endothelial cells (HUVEC), human renal artery endothelial cells (RAEC) and rabbit proximal tubule cells was measured with a specific ELISA. ET-1 mRNA expression was investigated by reverse transcription-PCR. MPA (2.5-50 microg/ml) induced a significant decrease in ET-1 mRNA expression (minimum 51.8+/-3.8% of control; P<0.001) in HUVEC and RAEC. After a 48 h incubation with MPA (1-50 microg/ml), a significant decrease in ET-1 release per culture well (minimum 56.8+/-1.7%; P<0.001) and DNA content per culture well (minimum 58.7+/-1.9%; P<0.001) was observed with HUVEC and RAEC, whereas ET-1 release referred to the DNA content in the corresponding culture well did not differ significantly from controls. In rabbit proximal tubule cells, ET-1 release referred to the cell number in the corresponding culture well was also reduced after incubation with MPA (minimum 86.2+/-2.4%; P<0.05). This study provides evidence that, in contrast with CsA and tacrolimus, MPA does not stimulate ET-1 synthesis. The present results might explain the clinical observation that renal function often improves when CsA or tacrolimus is replaced by mycophenolate mofetil.

Serum levels of insulin-like growth factor (IGF)-I and IGF binding protein (IGFBP)-1 to -6 and their relationship to bone metabolism in osteoporosis patients.

BACKGROUND: Insulin-like growth factor (IGF) system components are important regulators of bone formation. Alterations of individual IGF system components have been described in osteoporosis (OP) patients; however, no study has addressed changes in free IGF-I and in all six IGF binding proteins (IGFBPs). METHODS: A cross-sectional study was performed in 45 OP patients and 100 healthy matched controls. Serum levels of free and total insulin-like growth factor I (IGF-I), IGFBP-1 through -6, intact parathyroid hormone (PTH), 25-OH-vitamin D(3) (25OHD(3)), 1,25-(OH)(2)-vitamin D(3) (1,25-(OH)(2)D(3)), osteocalcin (OSC), bone alkaline phosphatase (B-ALP), and carboxyterminal propeptide of type-I procollagen (PICP) were measured with specific assays. Bone mineral density (BMD) of the lumbar spine was determined by dual-energy X-ray absorptiometry (DEXA). RESULTS: Compared with age- and sex-matched control subjects, OP patients showed a 73% decrease in free IGF-I, a 29% decrease in total IGF-I, a 10% decrease in IGFBP-3, and a 52% decrease in IGFBP-5 levels; they had higher levels of IGFBP-1 (4.1-fold), IGFBP-2 (1.8-fold), IGFBP-4 (1.3-fold), and IGFBP-6 (2.1-fold). Alterations in IGF system components were most evident in 13 OP patients with vertebral fractures in the past 4 years compared to patients without fractures. In OP patients with fractures, the ratio between IGFBP-4 and IGFBP-5 was increased whereas levels of OSC were decreased. CONCLUSIONS: Our data provide strong indirect evidence for a functional connection between circulating IGF system components and bone metabolism and the susceptibility to fractures in OP patients.