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Biomedical subjects

T Sitter

Publications and source records attributed to T Sitter.

At least 19 recordsLinked to original sources
PubMed2002

[Primary hypertrophic osteoarthropathy (Touraine-Solente-Golé syndrome)].

HISTORY: A 29-year-old man had finger clubbing since the age of 15 years, and for the last 10 years his hands and feet had grown disproportionately. In addition he suffered from marked whole-body sweating, especially of the hands and feet, as well as persistent pain in the limbs and joints. INVESTIGATIONS: Biochemical and endocrinological tests were normal. Radiology of the hands and lower legs revealed marked periosteal thickening, while the substantia trabeculosa was unremarkable. Secondary causes having been excluded primary hypertrophic osteoarthropathy was diagnosed. TREATMENT AND COURSE: While there is no causal treatment, physio- and balneotherapy improved the symptoms. CONCLUSION: Early and accurate diagnosis of primary hypertrophic osteoarthropathy is essential, if only because of its favourable long-term prognosis.

Adult↗
PubMed2001

[Acute renal failure due to rhabdomyolysis in McArdle's disease following binge drinking with seizures].

HISTORY AND ADMISSION FINDINGS: A 36-year-old gardener was admitted for tonic-clonic seizures after binge drinking. The next days he developed massive rhabdomyolysis with acute renal failure. Past medical history was unremarkable except for a similar episode of acute renal failure 14 years ago. At that time he had consumed alcohol as well. Furthermore, the patient complained of exercise-related painful muscle cramping and swelling. INVESTIGATIONS: The serum creatinine peaked at 8.5 mg/dl, blood urea at 126 mg/dl and the maximal level of serum creatinine kinase was 108 300 U/l. Because of the massive rhabdomyolysis and the patient inverted question marks past medical history a metabolic myopathy was suspected and a muscle biopsy was performed. Histochemical staining of muscle frozen sections for phosphorylase revealed no activity which is typical for myophosphorylase deficiency (McArdle inverted question marks disease). Additional biochemical analysis of the muscle biopsy specimen confirmed the diagnosis. TREATMENT AND COURSE: By vigorous intravenous hydration and forced alkaline diuresis, the patient had a sufficient urinary output and lacked uremic signs. The serum creatinine and urea fell continuously and reached normal levels after 6 weeks. At that time serum creatinine kinase was still elevated (867 U/l), which is typical for McArdle inverted question marks disease. Avoiding alcohol, a new episode of rhabdomyolysis and acute renal failure did not occur. CONCLUSIONS: Besides exercise alcohol is likely to be a further possible trigger of rhabdomyolysis and acute renal failure in McArdle inverted question marks disease. Postulated mechanisms by which alcohol induces muscle injury include direct muscle toxicity and inhibition of gluconeogenesis, as these patients are probably more dependent on the gluconeogenetic pathway for muscle cell metabolism.

Acute Kidney Injury↗
PubMed2001

A linkage disequilibrium between genes at the serine protease inhibitor gene cluster on chromosome 14q32.1 is associated with Wegener's granulomatosis.

The frequency of carriers of the alpha1-antitrypsin (alpha1-AT) deficiency allele PI*Z is increased in patients with Wegener's granulomatosis (WG). The polymorphic protease inhibitor (PI) gene is part of a cluster of serine protease inhibitor (serpin) genes (AACT; alpha1-antichymotrypsin, PCI; protein C inhibitor, CBG; corticosteroid binding globulin, PIL; PI-like pseudogene) at chromosome 14q32.1. In this study we investigated whether the serpin gene cluster contributes to the background of Wegener's granulomatosis. Therefore, phenotyping of alpha1-AT was performed and simple tandem repeat polymorphisms (STRP) in the genes for CBG, PI, and PCI as well as two STRP (D14S55 and D14S48) flanking the centromeric and one (D14S51) flanking the telomeric region of the gene cluster were examined in a population of 79 patients with WG and 128 unrelated healthy controls. In WG patients an increased frequency of the PI*Z defective allele is demonstrated as well as a linkage disequilibrium between all members of this gene cluster plus the centromeric and telomeric STRP. These results indicate an involvement of the serpin genes in the pathogenesis of Wegener's granulomatosis and it is possible that other genes located in the vicinity of D14S55 or D14S51 contribute to the genetic background of the disease.

Alleles↗
PubMed2001

Hyaluronan fragments induce the synthesis of MCP-1 and IL-8 in cultured human peritoneal mesothelial cells.

Human peritoneal mesothelial cells (HMC) play an important role in inflammatory processes by their ability to produce various cytokines and chemokines, such as monocyte chemoattractant protein 1 (MCP-1) and interleukin 8 (IL-8). In this study we investigated the effect of experimentally generated hyaluronan (HA) fragments, degradation products of the extracellular matrix component hyaluronan, which accumulate at inflammatory sites, on the expression of MCP-1 and IL-8 in cultured HMC. MCP-1 and IL-8 mRNA expression was determined by RNase protection assays, and protein levels in the supernatants were measured by enzyme-linked immunosorbent assays. HA fragments with a molecular mass of approximately 1-7x10(5) daltons upregulate MCP-1 and IL-8 synthesis in HMC dose and time dependently. The effect of HA fragments could be blocked by Ro31-8220, a specific protein kinase C inhibitor, and by PD98059, an inhibitor of the mitogen-activated protein kinase/extracellular signal-regulated kinase pathway. Upregulation of chemokine synthesis was preceded by an increase in NF-kappaB and AP-1 DNA-binding activity, suggesting that these transcription factors are activated to increase MCP-1 and IL-8 expression by HA fragments. These data demonstrate that HA fragments markedly enhance the mRNA expression and protein synthesis of MCP-1 and IL-8 in HMC. In concert with previous findings, our observations indicate that enhanced levels of HA, which are present in the peritoneal cavity of peritoneal dialysis patients, may account for a locally increased chemokine production.

Adjuvants, Immunologic↗
PubMed2001

Heat-killed microorganisms induce PAI-1 expression in human peritoneal mesothelial cells: role of interleukin-1alpha.

Human peritoneal mesothelial cells (HMCs) have a critical role in maintaining the intraperitoneal balance between fibrinolysis and coagulation by expressing the fibrinolytic enzyme, tissue-type plasminogen activator (tPA), as well as a specific plasminogen activator inhibitor (type 1; PAI-1). During bacterial peritonitis, the balance between intraperitoneal generation and degradation of fibrin is disturbed. As a consequence, severe peritoneal damage occurs, which is one of the leading causes of patient dropout from continuous ambulatory peritoneal dialysis (CAPD) therapy. Cultured HMCs isolated from omental biopsy specimens were used to study the effect of heat-killed strains (2 x 10(8)/mL) of Staphylococcus aureus, Staphylococcus epidermidis, and Escherichia coli on the synthesis of tPA and PAI-1. Conditioned media were obtained by incubating cells with the different bacterial strains. tPA and PAI-1 antigen concentrations were measured in the cell supernatants by enzyme-linked immunosorbent assay. Each of the three heat-killed microorganisms induced a time-dependent increase in PAI-1 synthesis. After a 48-hour incubation period, the strongest effect was seen in the presence of S aureus (3.5-fold versus control), followed by S epidermidis (2.5-fold versus control) and E coli (1.5-fold versus control). Under the same conditions, tPA antigen levels did not change after exposure to S aureus or E coli, whereas the addition of S epidermidis resulted in enhanced tPA antigen production (2-fold versus control). The increase in PAI-1 synthesis in the presence of the heat-killed microorganisms was preceded by similar changes in interleukin-1alpha (IL-1alpha) levels. Inhibiting the activity of IL-1alpha with a neutralizing antibody significantly reduced bacterial-induced PAI-1 production. Our results indicate that the fibrinolytic imbalance during bacterial peritonitis depends on the bacterial species. The increase in PAI-1 synthesis, not the decrease in the production of tPA, alters mesothelial fibrinolytic activity. Because the increase in PAI-1 expression is significantly quenched by blocking the activity of IL-1alpha, the mesothelial release of this cytokine is involved in bacterial-induced changes in the fibrinolytic system.

Bacterial Vaccines↗
PubMed2001

Adenovirus-mediated transfer of the 39 kD receptor-associated protein increases fibrinolytic capacity.

BACKGROUND: The mesothelium has an important role in maintaining an adequate fibrinolytic capacity in the peritoneal cavity and thus in preventing the formation of fibrinous peritoneal adhesions by secreting the fibrinolytic enzyme tissue-type plasminogen activator (t-PA). The fibrinolytic activity of human mesothelial cells (HMCs) is counteracted by rapid uptake of t-PA via the low-density lipoprotein receptor-related protein (LRP). The 39 kD receptor-associated protein (RAP) is an inhibitor of binding of t-PA to LRP, but RAP itself is also rapidly degraded via LRP. METHODS: Adenovirus-mediated RAP gene transfer technology was used to evaluate the effect of prolonged overexpression of RAP on t-PA accumulation in conditioned medium of HMCs under basal and inflammatory conditions. RESULTS: Infection of HMCs with a recombinant adenovirus carrying the RAP cDNA resulted within one day in t-PA levels that were maximally twofold to threefold increased as compared with noninfected or adenovirus-beta-galactosidase-infected cells. Whereas upon prolonged incubation, t-PA levels in the conditioned medium of uninfected cells leveled off because of rapid uptake and degradation via LRP, t-PA concentrations in the medium of adenovirus-RAP-infected cells continued to increase, reaching fivefold control levels after 72 hours. The increased t-PA accumulation persisted for seven days and then slowly returned to control values over the next few weeks. In contrast, the production of a specific inhibitor of t-PA, plasminogen activator inhibitor-1 (PAI-1), was not affected by adenoviral RAP gene transfer. Northern blotting analysis showed that t-PA, PAI-1, and LRP mRNA concentrations were not changed after adenoviral infection, underlining that the elevated t-PA levels are the result of RAP-blocked uptake and degradation of t-PA rather than increased t-PA synthesis. RAP gene transfer also restored diminished fibrinolytic activity of cytokine-treated mesothelial cells. CONCLUSIONS: Adenovirus-mediated transfer of the RAP gene provides an efficient way of transiently increasing the fibrinolytic capacity of mesothelial cells.

Adenoviridae↗
PubMed2001

Effect of high glucose concentration on the synthesis of monocyte chemoattractant protein-1 in human peritoneal mesothelial cells: involvement of protein kinase C.

Human peritoneal mesothelial cells (HMC) contribute to the activation and control of inflammatory processes in the peritoneum by their potential to produce various inflammatory mediators. The present study was designed to assess the effect of glucose, the osmotic active compound in most commercially available peritoneal dialysis fluids, on the synthesis of the C-C chemokine monocyte chemoattractant protein-1 (MCP-1) in cultured HMC. The MCP-1 concentration in the cell supernatants was determined by enzyme-linked immunosorbent assay and the MCP-1 mRNA expression was examined using Northern blot analysis. Incubation of HMC with glucose (30-120 mM) resulted in a time- and concentration-dependent increase in MCP-1 protein secretion and mRNA expression. After 24 h the MCP-1 synthesis was increased from 2.8 +/- 0.46 to 4.2 +/- 0.32 ng/10(5) cells (n = 5, p < 0.05) in HMC treated with 60 mM glucose. In contrast, osmotic control media containing either the metabolically inert monosaccharide mannitol or NaCl did not influence MCP-1 production. The stimulating effect of high glucose on MCP-1 expression in HMC was mimicked by activation of protein kinase C (PKC) with the phorbol ester PMA (20 nM). Coincubation of the cells with glucose and the specific PKC inhibitor Ro 31-8220 completely blunted glucose-mediated MCP-1 expression. In summary, our results indicate that glucose induces MCP-1 synthesis by a PKC-dependent pathway. Since osmotic control media did not increase MCP-1 release, it is suggested that the effect of glucose is mainly related to metabolism and not to hyperosmolarity. These data may in part explain elevated steady-state levels of MCP-1 found in the dialysis effluent of continuous ambulatory peritoneal dialysis patients.

Cells, Cultured↗
PubMed2000

The association of CD18 alleles with anti-myeloperoxidase subtypes of ANCA-associated systemic vasculitides.

Wegener granulomatosis (WG), microscopic polyangiitis (MP), and Churg Strauss syndrome (CSS) are rare systemic autoimmune disorders. Common features are anti-neutrophil cytoplasmic antibodies (ANCA) in patient sera. Whereas WG patients show mainly anti-proteinase 3 ANCA, MP and CSS patients typically present anti-myeloperoxidase (MPO) ANCA. ANCA play an important role in the pathogenesis in the vessel wall by activating polymorphonuclear cells (PMN) and increased adhesivity between PMN and endothelial cells via adhesion molecules. Here we investigated major adhesion molecules as predisposition factors via common polymorphisms in or in the vicinity of the candidate genes ICAM-1, e-selectin, PLAUR, CD11b, and CD18. A restriction fragment-length polymorphism in exon 11 of the CD18 gene was associated with MPO-ANCA(+) systemic vasculitis. Our data indicate that a common variant of the CD18 gene confers increased risk for CSS and MP, supporting that genetic factors are involved in the etiology and pathogenesis of ANCA-associated systemic vasculitides.

Alleles↗
PubMed2000

Dialysate related cytokine induction and response to recombinant human erythropoietin in haemodialysis patients.

BACKGROUND: Chronic inflammatory disorders or infections represent a major cause of hyporesponsiveness to recombinant human erythropoietin (rHuEpo). To test the hypothesis that dialysate-related cytokine induction alters the response to rHuEpo, we conducted a prospective study with matched pairs of chronic haemodialysis patients. We compared the effect of two dialysis fluids, differing in their microbiological quality, on the rHuEpo therapy. METHODS: Thirty male patients with end-stage renal disease maintained on regular haemodialysis were assigned either to a group treated with conventional (potentially microbiologically contaminated) dialysate (group I) or to a group treated with online-produced ultrapure dialysate (group II). Randomization was stratified according to the maintenance dose of rHuEpo necessary to maintain a target haemoglobin level of 10-10.5 g/dl. Patients were followed for 12 months. Kt/V was calculated by the formula of Daugirdas. Haemoglobin levels were measured weekly and serum ferritin concentrations were determined at 6-week intervals. C-reactive protein (CRP) and interleukin-6 (IL-6) was measured by an ELISA at the start of the study and after 3, 6 and 12 months. RESULTS: In group I, continuous use of bicarbonate dialysate did not change the rHuEpo dosage given to achieve the target haemoglobin level and was associated with elevated surrogate markers (CRP, IL-6) of cytokine-induced inflammation. The switch from conventional to online-produced ultrapure dialysate in group II resulted in a lower bacterial contamination with a significant decrease of CRP and IL-6 blood levels. It was accompanied by a significant and sustained reduction of the rHuEpo dosage, which was required to correct the anaemia. Using multiple regression analysis, IL-6 levels are shown to have a strong predictive value for rHuEpo dosage in both groups. CONCLUSIONS: Our data demonstrate that dialysate-related factors such as low bacterial contamination can induce the activation of monocytes, resulting in elevated serum levels of IL-6. Dialysate-related cytokine induction might diminish erythropoiesis. The use of pyrogen free ultrapure dialysate resulted in a better response to rHuEpo. Not only would it save money, but it would also help to maintain an optimal haemoglobin level without further increase in rHuEpo dosage.

Bacteria↗
PubMed2000

Successful management of polyneuropathy associated with IgM gammopathy of undetermined significance with antibody-based immunoadsorption.

Peripheral polyneuropathies associated with monoclonal IgM gammopathy of undetermined significance often have a progressive course and optimal treatment has not been established. We report on a patient diagnosed with polyneuropathy associated with benign IgM gammopathy, who was successfully treated with antibody-based immunoadsorption only. The neurological symptoms of the patient improved continuously over six months of treatment. Controlled trials should be performed to define this indication for antibody-based immunoadsorption therapy.

Humans↗
PubMed1999

[Skin necrosis in the front foot area during anticoagulation with phenprocoumon].

HISTORY AND ADMISSION FINDINGS: A 52-year-old woman was admitted because of pain for several days in the lower left leg and increasing pretibial swelling with livid discoloration. Six months before she had undergone a bilateral adnexectomy with removal of the omentum and subsequent chemotherapy for ovarian cancer. INVESTIGATIONS: Duplex sonography on the day of admission revealed thrombosis of the left popliteal vein with an unobstructed femoral vein. Both the quick value (89%) and partial thromboplastin time (PTT, 35.9 s) were within normal limits. Computed tomography and sonography were highly suspicious of a local recurrence of the ovarian cancer with peritoneal carcinomatosis. TREATMENT AND COURSE: PTT-effective heparinization (heparin-Na) was initiated together with overlapping anticoagulation with phenprocoumon (thromboplastin time 20-30%). On the 9th day after starting phenprocoumon painful, black necrotic changes began to appear on the skin of the left first to fourth toes. Assuming these to be due to phenprocoumon, anticoagulation was switched to low-molecular heparin (Enoxaparin), and antithrombin III and protein C were administered. A few days later thrombosis of the right iliac vein occurred, probably caused by local recurrence of the ovarian cancer. No palliative chemotherapy was undertaken in view of the thrombotic complications. The patient died a few months later from the cancer. CONCLUSION: If there is an underlying malignancy, chemotherapy and therapeutic vitamin-K antagonism in the presence of thromboembolic complications increases the risk of lowering protein C activity and may cause the rare complication of skin necrosis, induced by phenprocoumon.

Anticoagulants↗
PubMed1999

Immunogenetic risk factors for anti-neutrophil cytoplasmic antibody (ANCA)-associated systemic vasculitis.

Wegener's granulomatosis (WG) and microscopic polyangiitis are systemic autoimmune diseases characterized by the presence of ANCA in the sera of patients. Little is known about the aetiologic factors and genetic predisposition as well as the pathogenesis of these disease entities. A slightly decreased representation of HLA-DRB1*13 and HLA-DQB1*0603 individuals was observed in our cohort of ANCA-associated systemic vasculitis (AASV) patients compared with controls. In addition, HLA-DRB1*04 individuals were over-represented in a subgroup of patients with WG in end-stage renal disease as a result of renal vasculitis. In order to identify other genes relevant for these diseases, we investigated highly polymorphic markers in the vicinity of several immunorelevant genes, i.e. tumour necrosis factor (TNF)alpha, IL-2, IL-5 receptor alpha (IL-5RA), in a group of 102 patients with AASV and compared the representation with controls. Furthermore, functional polymorphisms were directly analysed in the promotor region of TNFalpha as well as in the coding region of the FcgammaIIRA genes. Polymorphisms of the TNFalpha promotor (TNF-308) as well as in the FcgammaIIRA gene were excluded as risk factors for the disease in our cohort. No major phenotype distribution differences were observed between patients and controls for the IL-2 and IL-5RA microsatellites. Most importantly, several haplotypes on chromosome 6p appeared strongly associated with proteinase 3 (PR3)-ANCA+ AASV. Thus, as in other autoimmune diseases, different predisposing factors play differential aetiopathogenic roles in various groups of AASV patients.

Adolescent↗