The contribution of genetic variants of SLC2A1 gene in T2DM and T2DM-nephropathy: association study and meta-analysis.

An association study was conducted to investigate the relation between 14 variants of glucose transporter 1 gene (SLC2A1) and the risk of type 2 diabetes (T2DM) leading to nephropathy. We also performed a meta-analysis of 11 studies investigating association between diabetic nephropathy (DN) and SLC2A1 variants. The cohort included 197 cases (T2DM with nephropathy), 155 diseased controls (T2DM without nephropathy) and 246 healthy controls. The association of variants with disease progression was tested using generalized odds ratio (ORG). The risk of type 2 diabetes leading to nephropathy was estimated by the OR of additive and co-dominant models. The mode of inheritance was assessed using the degree of dominance index (h-index). We synthesized results of 11 studies examining association between 5 SLC2A1 variants and DN. ORG was used to assess the association between variants and DN using random effects models. Significant results were derived for co-dominant model of rs12407920 [OR = 2.01 (1.17-3.45)], rs841847 [OR = 1.73 (1.17-2.56)] and rs841853 [OR = 1.74 (1.18-2.55)] and for additive model of rs3729548 [OR = 0.52 (0.29-0.90)]. The mode of inheritance for rs12407920, rs841847 and rs841853 was 'dominance of each minor allele' and for rs3729548 'non-dominance'. Frequency of one haplotype (C-G-G-A-T-C-C-T-G-T-C-C-A-G) differed significantly between cases and healthy controls [p = .014]. Regarding meta-analysis, rs841853 contributed to an increased risk of DN [(ORG = 1.43 (1.09-1.88); ORG = 1.58 (1.01-2.48)] between diseased controls versus cases and healthy controls versus cases, respectively. Further studies confirm the association of rs12407920, rs841847, rs841853, as well as rs3729548 and the risk of T2DM leading to nephropathy.

Case series of idiopathic membranous nephropathy with long-term beneficial effects of ACTH peptide 1-24.

BACKGROUND: In patients with idiopathic membranous nephropathy (IMN), immunosuppressive therapy is usually considered when severe nephrotic syndrome or risk for progressive renal failure exist. Recently, several studies showing beneficial effects of synthetic adrenocorticotropic hormone (ACTH) under such circumstances have been published. The objective of the present case series was to evaluate long-term ACTH effects on proteinuria and renal function. METHODS: Four patients with biopsy-proven membranous nephropathy and nephrotic syndrome were enrolled (median age 50 years (range 38 - 61), median GFR 39.5 ml/min (range 20 - 62), median proteinuria 9.6 g/d (range 6.0 - 20.0). Prior immunosuppressive treatment regimens included steroids, cyclosporine A, cyclophosphamide, mycophenolate mofetil or azathioprine. The patients received a synthetic ACTH analogue intramuscularly for a median duration of 8 months (range 3 - 24). ACTH dosage was adjusted according to side effects between 0.25 and 2.25 mg/week. Follow-up lasted between 24 and 82 months after therapy initiation. RESULTS: All 4 patients exhibited partial (n = 2) or complete (n = 2) remissions of their nephrotic syndrome within the first year. After discontinuation of ACTH therapy, proteinuria remained low in 3 of 4 cases, whereas 1 patient exhibited undulating proteinuria. Glomerular function (as assessed by glomerular filtration rate, GFR) was maintained in all patients. Side effects were minor and included weight gain, elevated blood pressure and hyperglycemia. CONCLUSION: In all 4 cases with IMN, ACTH treatment induced a lasting disease remission with relatively few side effects.

Predictors of Outcomes of Living Kidney Donation: Impact of Sex, Age and Preexistent Hypertension.

CONTEXT: Living kidney donation is considered a safe procedure with excellent outcomes. The great demand for organs has changed the suitability criteria for donation and older or hypertensive donors are increasingly accepted. METHODS: We reviewed the charts of 200 adults who donated a kidney at the University Hospital Hannover. Data regarding diastolic, systolic, mean blood pressure, renal function, and proteinuria at baseline and post-donation follow-up visits were recorded. A Mann-Whitney U test was performed to compare the post-nephrectomy development of blood pressure, estimated glomerular filtration rate (eGFR), and proteinuria between men and women, hypertensives and normotensives, and older (≥65 years) and younger (<65 years) donors. Multivariable time-dependent Cox regression models were used to evaluate eGFR decline post-donation, after adjustment for covariates. RESULTS: The majority of donors were female (64.5%), and 29.0% had pre-existing hypertension. The mean age at donation was 49 years, and 9.5% were older than 65 years. During a median follow-up of 3 years, no significant differences in proteinuria and change in renal function were observed between both sexes or hypertensive and normotensive donors. In contrast, older donors exhibited a faster decline in renal function. Mean eGFR (chronic kidney disease epidemiology collaboration equation) pre-donation was 99.6 ± 21.9 mL/min in younger donors and 77.6 ± 17.7 mL/min in older donors (P < .001). The respective mean values at the last follow-up visit were 81.3 ± 24.0 and 46.8 ± 17.9 mL/min (P < .001). After adjustment for sex and preexisting hypertension, compared to younger donors, older donors had a 2.39 hazard ratio for eGFR decline. CONCLUSION: Older adults display a faster decline in renal function after donation and thus should be carefully evaluated for suitability before donation.

Y-box protein-1 controls transforming growth factor-beta1 translation in proximal tubular cells.

Transforming growth factor-beta1 (TGF-beta1) mRNA has low basal translational efficiency in proximal tubule cells; however, its translation is stimulated by profibrotic cytokines. We studied the role of the multifunctional Y-box protein-1 (YB-1) in regulating proximal tubule cell TGF-beta1 translation. Using RNA-electrophoretic mobility shift assays and ultraviolet crosslinking, we found two protein complexes of 50 and 100 kDa, which bound to the TGF-beta1 mRNA 5'-untranslated region. Supershift studies using antibodies to YB-1 showed that both sites contained YB-1 as did studies with recombinant YB-1, which demonstrated that it was sufficient to form both complexes. RNA competition experiments confirmed YB-1 binding to the two predicted binding sites; one with high affinity and the other with lower affinity. Strong basal YB-1 association with TGF-beta1 mRNA was found in proximal tubule cells, which decreased when platelet-derived growth factor was used to activate TGF-beta1 translation. In contrast, knockdown of proximal tubule cell YB-1 expression abrogated TGF-beta1 synthesis. Our results suggest that TGF-beta1 translation in proximal tubule cells requires YB-1 binding to a high-affinity site in the 5'-untranslated region of its mRNA; however, binding to a low-affinity site inhibits basal translation.

Analysis of c-myc, PAI-1 and uPAR in patients with incisional hernias.

BACKGROUND: Disturbed wound healing leading to alterations in collagen composition has been thought to play a key role in the pathogenesis of incisional hernia formation. The aim of the present study was to further characterise the scarring process in such patients. METHODS: Mature skin scars from patients with either primary or recurrent incisional hernias were compared to mature abdominal skin scars from patients without hernias. The distribution of collagen types I and III was analysed using crosspolarisation microscopy. Expression of c-myc--a parameter for cell differentiation and proliferation--and of PAI-1 and uPAR--parameters of the proteolytic cascade in wound healing--were determined by immunohistochemistry. RESULTS: In agreement with previous studies, decreased collagen I/III ratios were found in patients with incisional hernias. In these patients, c-myc levels were significantly elevated whereas plasminogen activator inhibitor-1 (PAI-1) and urokinase-plasminogen activator receptor (uPAR) levels were only slightly increased. In contrast to controls, a significant correlation between c-myc, PAI-1 and uPAR expression and collagen I/III ratios was found in patients with incisional hernias. CONCLUSION: The differential correlation of collagen types and expression of c-myc, PAI-1 and uPAR within the scar tissue might represent a causal factor in incisional hernia formation.

Are collagens the culprits in the development of incisional and inguinal hernia disease?

Incidence curves for the development of inguinal hernia disease and recurrences thereof exhibit a linear rise over the years and therefore suggest multi-factorial underlying causes. Several studies have revealed marked changes in the abundance and composition of interstitial collagens in patients with (recurrent) hernia diseases, adult groin hernia and incisional hernia. These observations led to the hypothesis that hernia formation and the recurrence of incisional hernia may be explained by disordered tissue renewal and by abnormal wound healing, respectively. Interstitial collagens, owing to their long half-lives and biomechanical strength, are most likely critical components of the biological system of tissue remodelling. An overview of the literature is provided, and the consequences for surgical practice are discussed.

Biomaterial-dependent MMP-2 expression in fibroblasts from patients with recurrent incisional hernias.

With regard to the pathogenesis of recurrent incisional hernia, an impaired connective tissue quality leading to an aberrant scarring process has been proposed. For the matrix metalloproteinase (MMP-2) a pathogenetic involvement in direct inguinal hernia development is reported. With mesh implantation as the gold standard treatment for incisional hernias, the aim of the present study was to investigate the MMP-2 expression in patients with recurrent incisional hernias with and without mesh-materials. In primary fibroblast cultures obtained from skin scars in patients with and without recurrent incisional hernias, MMP-2 synthesis and gene expression were investigated. Furthermore, MMP-2 synthesis and gene expression of fibroblasts were compared after incubation with two different mesh materials: polypropylene and absorbable polyglactin filaments. MMP-2 enzyme activity was determined by semiquantitative zymography and mRNA synthesis by quantitative RT-PCR. Both MMP-2 enzyme activity and mRNA expression were similar in hernia and control fibroblasts in vitro. In control fibroblasts mesh incubation did not significantly affect MMP-2 expression, whereas polypropylene mesh contact of fibroblasts from patients with recurrent incisional hernias led to a major decrease of MMP-2 activity and of mRNA expression. In the absence of biomaterials fibroblasts from recurrent incisional hernia, patients have no alterations of their MMP-2 synthesis compared to control fibroblasts, whereas a specific response was found after biomaterial contact hereby indicating differences in fibroblast phenotype.

Expression of transforming growth factor-beta receptor II mRNA in cyclosporine-induced gingival overgrowth.

Gingival overgrowth (GO), characterized by increased cellular and extracellular matrix components in gingival tissue, is a frequent side effect of cyclosporine (CsA). In previous studies, elevated levels of transforming growth factor-beta (TGF-beta) have been detected in GO tissue, which led to the conclusion that TGF-beta plays a major part in the pathogenesis. TGF-beta activity is mediated by three receptors; TGF-beta receptor II (TGF-beta RII), the most important, has been immunohistochemically detected in GO and normal gingival tissue. The aim of this study was to clarify whether TGF-beta RII is overexpressed in CsA-induced GO. The expression of TGF-beta RII mRNA in GO tissue of patients on CsA (n = 10, 5 women, aged 42.5 +/- 14.9 years) with renal transplantation (transplant duration 3.6 +/- 0.96 years) was compared with that in healthy gingiva of control subjects (n = 10, 5 women, aged 42.5 +/- 7.6 years). Semiquantitative reverse transcribed-polymerase chain reactions (RT-PCR) were applied with glyceraldehyde-3-phosphate dehydrogenase (GAPDH) as an internal standard. TGF-beta RII mRNA was readily detected in the GO tissue of patients on CsA. The level of TGF-beta RII mRNA relative to GAPDH in GO cases was not significantly higher than the relative TGF-beta mRNA level in normal gingiva (0.60 +/- 0.16 vs 0.52 +/- 0.19; P = .575). The precise mechanism of CsA-induced GO remains uncertain. According to our results, TGF-beta RII was not upregulated in CsA-induced GO, and may have no important role in this disorder. However, the involvement of TGF-beta in the molecular pathology of GO may be mediated via TGF-beta RI or RIII.

The kidney regulates regeneration, but don't upset the balance.

Better understanding of the cellular pathophysiological process undergoing kidney injury and repair will be hopefully result in the design of more targeted therapies to prevent injury, hasten repair, and minimize chronic progressive kidney diseases. The relevance of CSF-1 signalling for kidney organ development and inflammatory disease has been highlighted by numerous studies. Interestingly, there are different functions of CSF-1 in acute kidney injury versus chronic kidney disease (CKD). Within CKD, an enhanced expression of CSF-1 results in more damage, and thus disruption of the CSF-1/CSF-1R interaction/activation is protective. A reverse scenario is seen during acute kidney injury, where inhibition of CSF-1 leads to delayed recovery of kidney function and less regenerative (M2) macrophages. However, the major factor to stimulate epithelial cell repair and the cell type(s) generating the factor in response to acute kidney injury remained unclear. In their recent report Wang et al. used a specific CSF-1 knockout in the proximal tubular cells, induced acute kidney injury, and analyzed the recovery of kidney function. They nicely demonstrated a strong positive effect of renal and proximal tubular secreted CSF-1. It mediates the differentiation of infiltrated monocytes into M2 macrophages, also denoted as reparative macrophages. Mice with a deletion of CSF-1 within the proximal tubular cells exhibited a delayed recovery from acute kidney injury. These findings may pave the path to therapeutic intervention in acute kidney injury.

Renal Sympathetic Denervation by CT-Guided Ethanol Injection: A Phase II Pilot Trial of a Novel Technique.

OBJECTIVES: CT-guided ethanol-mediated renal sympathetic denervation in treatment of therapy-resistant hypertension was performed to assess patient safety and collect preliminary data on treatment efficacy. MATERIALS AND METHODS: Eleven patients with therapy-resistant hypertension (blood pressure of >160 mmHg despite three different antihypertensive drugs including a diuretic) and following screening for secondary causes were enrolled in a phase II single arm open label pilot trial of CT-guided neurolysis of sympathetic renal innervation. Primary endpoint was safety, and secondary endpoint was a decrease of the mean office as well as 24-h systolic blood pressure in follow-up. Follow-up visits at 4 weeks, 3, and 6 months included 24-h blood pressure assessments, office blood pressure, laboratory values, as well as full clinical and quality of life assessments. RESULTS: No toxicities ≥3° occurred. Three patients exhibited worsened kidney function in follow-up analyses. When accounting all patients, office systolic blood pressure decreased significantly at all follow-up visits (maximal mean decrease -41.2 mmHg at 3 months). The mean 24-h systolic blood pressure values decreased significantly at 3 months, but not at 6 months (mean: -9.7 and -6.3 mmHg, respectively). Exclusion of five patients who had failed catheter-based endovascular denervation and/or were incompliant for antihypertensive drug intake revealed a more pronounced decrease of 24-h systolic blood pressure (mean: -18.3 and -15.2 mmHg at 3 and 6 months, p = 0.03 and 0.06). CONCLUSION: CT-guided sympathetic denervation proved to be safe and applicable under various anatomical conditions with more renal arteries and such of small diameter.

Influence of hemodialysis on the mean blood flow velocity in the middle cerebral artery.

BACKGROUND: Several effects of hemodialysis, including hemoconcentration, alterations of hemostasis or hemorheology and endothelial activation, could potentially interfere with cerebral blood flow (CBF) regulation. These treatment-specific changes may also be crucial for the enhanced incidence of stroke in uremic patients. Nevertheless, the influence of hemodialysis on CBF has not been yet adequately studied. PATIENTS AND METHODS: We registered mean blood flow velocity (MFV) in the middle cerebral artery (MCA) during hemodialysis treatment in order to evaluate its contribution on CBF changes. Transcranial Doppler ultrasonography (TCD) of the MCA was performed continuously during hemodialysis treatment in 18 stable patients (10 males and 8 females, mean age 62 +/- 11 years) with end-stage renal disease of various origin. Blood pressure (mmHg), heart rate (/min), ultrafiltration volume (ml), BV changes (deltaBV by hemoglobinometry, %), arterial blood gases (pO2, blood oxygen content, pCO2), hemostasis activation (thrombin-antithrombin III complex, ELISA) and fibrinogen (Clauss) were measured simultaneously at the beginning of treatment and every hour thereafter. RESULTS: Before the hemodialysis session the MFV in the MCA was within normal range (57.5 +/- 13.0 cm/s, ref. 60 +/- 12) and was mainly dependent on the patients' age (r = -0.697, p < 0.01). The blood flow velocity in the MCA decreased significantly from 57.5 +/- 13.0 cm/s before the beginning to 48.3 +/- 11.1 cm/s after four hours (n = 18, p < 0.05) and to 43.9 +/- 8.9 cm/s after five hours (n = 9, p < 0.05) of hemodialysis treatment. During hemodialysis treatment, the percentual changes of MFV in the MCA (delta%MFV) were interrelated to the ultrafiltration volume (r = -0.486, p < 0.01), the blood volume (BV%, r = 0.369, p < 0.01) and the percentual changes of the hematocrit (r = -0.358, p < 0.01), of the arterial blood oxygen content (delta%acO2, r = -0.420, p < 0.01) and of the plasma fibrinogen levels (delta%fibrinogen, r = 0.244, p < 0.05). CONCLUSION: A significant continuous decrease of the MFV in the MCA was observed during hemodialysis treatment, which inversely correlated both with ultrafiltration volume, BV changes and changes of plasma fibrinogen. The ultrafiltration-induced hemoconcentration with concomitant rise of hematocrit and oxygen transport capacity, may partly explain the alterations in the cerebral MFV observed during hemodialysis.

Influence of polyglecaprone 25 (Monocryl) supplementation on the biocompatibility of a polypropylene mesh for hernia repair.

BACKGROUND: Supplementary polyglecaprone 25 (Monocryl) monofilaments were added to a lightweight pure monofilament polypropylene mesh (PP mesh) to improve intraoperative handling (PP+M mesh). This study was designed to evaluate the influence of this additional supplementation on the biocompatibility in a rodent animal model. METHODS: Two mesh materials, a composite mesh (PP+M) and the pure polypropylene variant (PP), were compared after subcutaneous implantation in a standardized rat model. Histological analysis of the inflammatory response was performed after 28, 56 and 84 days of implantation. Material absorption, inflammatory tissue reaction, fibrosis and granuloma formation were investigated, as well as the percentage of proliferating and apoptotic cells at the interface. RESULTS: Both mesh materials showed a slight foreign body reaction involving mainly macrophages and foreign body giant cells. Total absorption of the Monocryl filaments of the PP+M mesh occurred between 56 and 84 days of implantation. Both the inflammatory and the fibrotic reaction were decreased (n.s.) in the PP+M mesh group compared to the pure PP mesh. Whereas the percentage of proliferating cells showed no significant difference, the rate of apoptotic cells was significantly decreased in the PP+M mesh group over the whole implantation period. CONCLUSION: Compared to the pure polypropylene mesh, our data confirm that the use of a polypropylene mesh supplemented with absorbable Monocryl filaments is feasible without additional short-term mesh-related complications in the experimental model or negative side effects on biocompatibility.

Pressure oscillation regulates human mesangial cell growth and collagen synthesis.

Experimental renal disease models establish glomerular hypertension as a crucial determinant in glomerulosclerosis progression and demonstrate that glomerular capillary pressure reduction delays sclerosis development. An oscillating pressure (OP) chamber was constructed as an in vitro model to study human mesangial cells. Cell cultures were grown under atmospheric pressure (AP) and a controlled OP corresponding to intraglomerular capillary pressure. We show that OP significantly decreases mesangial cell proliferation within 24 hours and attenuates DNA synthesis throughout a 7-day period. To explore the effects of OP on cell metabolism, cell-associated and medium-secreted extracellular (CA and EC, respectively) collagen synthesis were measured by [3H]proline incorporation. In subconfluent cultures, total CA and EC collagen synthesis was unaffected by OP, while in confluent cultures total EC collagen [3H]proline incorporation was increased. To determine whether OP influenced mesangial cell growth induction, the effects of increasing glucose in the cell culture media were investigated. Our data show that the high glucose growth stimulatory effect on cell number and DNA synthesis was suppressed by OP. Under high glucose conditions, total CA collagen synthesis was increased in confluent cultures, whereas the EC collagen fraction remained unchanged. In these cultures, OP caused an additional increase in CA collagen synthesis. This study shows that mesangial cell growth and collagen synthesis are influenced by hyperbaric OP, supporting the hypothesis that glomerular capillary pressure plays a role in progressive glomerulosclerosis development.

Influence of hematocrit on hemostasis in continuous venovenous hemofiltration during acute renal failure.

BACKGROUND: Hematocrit plays a major role in primary hemostasis by influencing blood viscosity and platelet adhesion. During continuous venovenous hemofiltration (CVVH), it is suspected that an increased hematocrit is accompanied by an activation of hemostasis and frequently leads to thromboses in the extracorporeal system. In order to examine this hypothesis, we studied the influence of hematocrit on hemostasis during CVVH. METHODS: Fourteen patients (8 men and 6 women, mean age 65+/-10 years) with acute renal failure undergoing CVVH were prospectively enrolled. Polysulfone hemofilters (AV 600; Fresenius, Oberursel, Germany) were used in all of the patients; blood flow rates were adjusted to 120 ml/min. No blood products and coagulation-related medication, except unfractionated heparin, were applied. Study exclusion criteria included a history of thromboembolism and artificial heart valves. Hemostasis activation markers (fibrinopeptide A, thrombin-antithrombin III complex, beta-thromboglobulin, platelet retention) and hematocrit values were determined before and at three-day intervals during the course of CVVH treatment. RESULTS: The mean hematocrit value (mean +/- SEM) was 29+/-1% (range, 22 to 35%). Patients with hematocrit values of less than 30% (N = 7) were compared with patients with higher hematocrit values (>30%, N = 7). The patients with a lower hematocrit (<30%) showed a stronger activation of hemostasis during CVVH when compared with those with a higher hematocrit (>30%), as indicated by a tendency toward higher values for fibrinopeptide A (25+/-8 vs. 14+/-5 ng/ml, P = 0.35), thrombin-antithrombin III complex (15+/-4 vs. 10+/-2 ng/ml, P = 0.66), and a higher beta-thromboglobulin/creatinine ratio (0.62+/-0.17 vs. 0.48+/-0.12, P = 0.8). CONCLUSION: Contrary to our hypothesis, hematocrit values of more than 30% are not accompanied by an increased hemostasis activation during CVVH. Concerning hemostasis activation, hematocrit values between 30 and 35% may be suitable for patients on CVVH.

cAMP-synthesis in a medullary thyroid carcinoma cell line: response to adrenergic agents and prostaglandines.

Calcitonin secretion by C-cells is mediated through intracellular 3'5'-cyclic adenosine monophosphate (cAMP) and calcium signaling. Calcitonin release stimulation tests may take advantage of both signaling cascades in screening for medullary thyroid carcinomas (MTC). To elucidate the regulation of the adenylyl cyclase system we have determined cAMP levels of a calcitonin-expressing MTC cell line (RG) after exposure to adrenergic agents and prostaglandines. In early passages (20-30) cAMP concentrations were significantly elevated in RG cells after exposure to beta-adrenergic agents and prostaglandines E1 and E2. In advanced passages (60-80) the beta-adrenergic response was no longer detectable and adrenergic receptors were uncoupled from the adenylyl cyclase complex; while the effect of prostaglandines E1 and E2 remained unaffected. Preincubation with dexamethasone, in a process requiring protein new synthesis, re-established the adrenergic response in later passages, indicating that RG cells dedifferentiated in culture over time. Our in vitro findings suggest that MTC cell dedifferentiation may be accompanied by adrenergic receptor-uncoupling from the adenylate cyclase system and that this process may be reversed by dexamethasone incubation.

Tacrolimus- (FK 506) based immunosuppression in severe systemic lupus erythematosus.

In a 30-year-old male patient systemic lupus erythematosus was diagnosed based on the presence of 8 out of 11 ARA criteria. Disease onset was acute and included renal function impairment with biopsy-proven lupus nephritis (WHO class IV) requiring renal replacement therapy. Although conventional immunosuppressive therapy regimens proved effective in controlling disease activity, all of the administered drugs were accompanied by serious side effects: bilateral femur head necrosis with corticosteroids, allergic skin reaction in response to azathioprine, nephrotoxicity with cyclosporine, nausea and abdominal pain with mycophenolate mofetil and life-threatening septicemia with cyclophosphamide treatment. In search for alternative treatment options, tacrolimus (FK506, trough serum levels 3-6 ng/ml) was started. FK506 was well-tolerated and lupus activity completely resolved within 7 months after initiation of therapy. During 36 months of follow-up no arthritic complaints occurred and renal function stabilized at a serum creatinine of 2.1 mg/dl with negative anti-ds-DNA antibodies and ANA titers. In conclusion, FK506 may be considered as alternative immunosuppressive for maintenance treatment in patients with severe lupus erythematosus and side effects to conventional regimens.

Group B Streptococcus (Streptococcus agalactiae) peritonitis associated with continuous ambulatory peritoneal dialysis (CAPD).

Streptococcus agalactiae typically induces serious infections in pregnant women and newborns. Nonpregnant adult patients can also be infected and mortality rate exceeds 40%. CAPD peritonitis is very rarely induced by S. agalactiae. Seven cases have been described previously and all had a very severe course, which included bacteremia, septic shock and death. A 27-year-old male with end-stage renal disease due to membranoprolipherative glomerulonephritis type I, who was on CAPD for 17 months, was admitted with the clinical and laboratory picture of CAPD peritonitis. Severe abdominal pain, shaking chills and fever 38.5 microC were also observed at presentation. Streptococcus agalactiae was isolated from the peritoneal fluid and blood culture was sterile. Under treatment with ceftazidime and tobramycin (i.p.) and vancomycin (i.v.) cultures became negative after 48 hours, abdominal symptoms resolved after 12 days and WBC count in the dialysate normalized after 14 days. As a possible source of infection the patient's partner was shown to be a vaginal carrier of a clone of S. agalactiae identical to that isolated in the peritoneal fluid. S. agalactiae is a rare cause of CAPD peritonitis with potentially very serious consequences. Anal or genital tract colonization is, in general, the source of contamination with S. agalactiae. The microbiological findings in the case presented here suggest that colonization of the patient or of his close environment may be important in the pathogenesis of S. agalactiae-induced CAPD peritonitis.

32-year old patient presenting with autoimmune polyglandular syndrome.

A 32-year-old student reported fatigue and malaise since two months in the absence of specific symptoms. Clinical examination and extensive laboratory testing revealed no abnormalities at his first presentation. Some weeks thereafter, on re-admission, hyperpigmentation suggestive of Addison's disease was observed and pathognomonic autoantibodies directed against the thyroid gland and the adrenal cortex were detected. Further evaluation led to the diagnosis autoimmune polyglandular deficiency syndrome, also named "Schmidt syndrome", comprising adrenocortical insufficiency (Addison's disease) and lymphocytic thyroiditis (Hashimoto thyroiditis). The diagnosis of polyglandular insufficiency is often delayed due to non-specific symptoms at early disease stages and progression may be rapid, culminating in Addisonian crisis under physical stress or infection, requiring immediate high-dose hormone replacement therapy. Hence, careful re-examination is mandatory to ensure adequate treatment before life-threatening complications occur. Nowadays this type of disease is classified as autoimmune polyglandular syndrome type II (APS type II) with an increased risk of developing insulin-dependent diabetes mellitus (IDDM), vitiligo, alopecia, pernicious anaemia, coeliac disease, myasthenia gravis and primary hypogonadism. The cause of the disease remains obscure but in addition to an autosomal dominant trait with variable penetrance some hints at viral infection triggering the disease process exist.

Influence of mesh materials on collagen deposition in a rat model.

Alterations of the extracellular matrix (ECM) with its major component collagen are increasingly discussed as possible risk factors implicated in the development of abdominal-wall herniation. Because of the widespread use of alloplastic meshes for the surgical repair of hernias, an animal study was performed to analyze the influence of various mesh materials on the quantity and quality of collagen deposition. In 60 male Sprague-Dawley rats an abdominal replacement was performed using three different kinds of mesh materials: polyester (PE), a pure polypropylene (PP), and a composite mesh made of polypropylene and polyglactin (PG). A simple fascia suture repair served as control. The count of fibroblasts, the collagen/protein ratio, the type I/III collagen ratio, and the expression of basic fibroblast growth factor (b-FGF) at the interface were analyzed after 7, 21, and 90 days. The ratio of collagen to overall protein (microg/mg) showed significant differences comparing different mesh materials (sham controls 38.44 +/- 16.33 microg/mg, PE 68.5 +/- 23.8 microg/mg, PP 101.6 +/- 32.3 microg/mg, PG 49.6 +/- 11.6 microg/mg at day 90). The ratio of collagen type I/III increased over time in all groups. However, 90 days after mesh implantation the ratio was always significantly lowered compared to the controls. No significant difference was found comparing different mesh materials. The alteration of the scar composition is closely connected to an increased b-FGF expression. b-FGF and count of fibroblasts highly correlated (r =.95) and showed significant elevated levels compared to simple suture repair. The results of our study strongly support the notion that wound healing is affected by mesh implantation. The quality of the ECM deposition as determined by collagen type I/III ratio is impaired in general, whereas the quantity of ECM deposition is markedly influenced by the kind of mesh material.

Influence of recombinant human erythropoietin therapy on plasma endothelin-1 levels during hemodialysis.

The correction of anemia with human recombinant erythropoietin (rHuEPO) in end stage renal disease is associated with hypertension in about one third of hemodialysis patients. The pathogenesis of the rHuEPO-induced hypertension is still uncertain, though evidence of the involvement of endothelial cells has emerged. The aim of this study was to determine plasma endothelin-1 during hemodialysis and to compare the endothelin-1 levels in hemodialysis patients with and without rHuEPO substitution. Nineteen stable patients (13 male and 6 female, mean age 62 +/- 11 years) with end stage renal disease were studied. Cuprophan dialysers (GFS 12, Gambro, Lund, Sweden) were used for hemodialysis in all cases. rHuEPO (40 U/kg s.c.) was administered to 10 patients. Blood pressure (BP; RR mmHg) and blood volume changes (deltaBV; hemoglobinometry %) were serially measured. Samples were taken before and every hour during hemodialysis. Plasma endothelin-1 was measured by ELISA (R&D Systems, Minneapolis, USA) and corrected for hemoconcentration. Endothelin-1 concentration was elevated before commencement of hemodialysis (1.16 +/- 0.36 pg/ml) when compared to healthy controls (ref. 0.3-0.9) and increased to 1.47 +/- 0.51 pg/ml by the end of the session (p<0.05). In patients under rHuEPO-substitution plasma endothelin-1 was higher when compared to patients without substitution before (1.25 +/- 0.3 vs. 1.05 +/- 0.3 pg/ml) and at the end of HD (1.62 +/- 0.5 vs. 1.28 +/- 0.3 pg/ml, p<0.05). There was no difference in BP and deltaBV between the two groups during treatment. Plasma endothelin-1 was higher in hemodialysis patients and there was a continuous rise in plasma endothelin-1 during a session. Comparison of two groups of hemodialysis patients with and without s.c. rHuEPO-replacement treatment revealed a significantly higher plasma endothelin-1 concentration in patients with s.c. rHuEPO treatment. However, the elevated endothelin-1 levels were not accompanied by arterial hypertension.