Complement C3 in Bernese Mountain dogs.

BACKGROUND: Previous research suggests that low serum concentrations of the third component of complement (C3) are associated with both the susceptibility to infectious agents such as Borrelia burgdorferi and the development of glomerular disease. We hypothesized that low levels of C3 are associated with the coincident occurrence of B. burgdorferi infection and glomerulonephritis in Bernese Mountain dogs. OBJECTIVES: The aims of this study were to evaluate the serum concentration of C3 in Bernese Mountain dogs with and without antibodies against B. burgdorferi and to compare this concentration with that of healthy control dogs. METHODS: Eighty-three clinically healthy Bernese Mountain dogs and 46 control dogs were included. Antibodies against B. burgdorferi were determined using an ELISA with a whole cell sonicate as antigen. Results were confirmed using Western blot. C3 was measured using a single radial immunodiffusion test. Results were reported as the percentage concentration of C3 compared with that in pooled preserved canine serum (100% C3 concentration). RESULTS: Median C3 concentration was 128.5% in Bernese Mountain dogs with antibodies against B. burgdorferi, 133.5% in B. burgdorferi-negative Bernese Mountain dogs, 87.8% in positive control dogs, and 102.2% in negative control dogs. Within Bernese Mountain and control groups, C3 was lower in dogs with antibodies against B. burgdorferi compared with those without. Percentage concentration of C3 was higher in healthy Bernese Mountain dogs compared with control dogs. CONCLUSION: Low C3 concentration is not an explanation for the high prevalence of B. burgdorferi infections and glomerular disease in Bernese Mountain dogs.

Functional C1-inhibitor diagnostics in hereditary angioedema: assay evaluation and recommendations.

Hereditary angioedema (HAE) is an autosomal dominant disease characterized by recurrent episodes of potentially life-threatening angioedema. The most widespread underlying genetic deficiency is a heterozygous deficiency of the serine protease inhibitor C1 esterase inhibitor (C1-Inh). In addition to low C4 levels, the most important laboratory parameter for correct diagnosis of HAE or angioedema due to acquired C1-Inh deficiency is reduced C1-Inh function (fC1-Inh). No direct recommendations about the assays for fC1-Inh or sample handling conditions are available, although this would prove especially useful when a laboratory first starts to offer assays on fC1-Inh for HAE diagnosis. In the present study we evaluated the performance of fC1-Inh assays in the 15 different laboratories that are specialised in HAE diagnostics and assessed inter-laboratory variation with each laboratory using their own assays and standards. A double-blind survey was conducted using plasma/serum samples from healthy donors and HAE patients and the uniformity of HAE diagnosis was evaluated. It can be concluded that the diagnosis of fC1-Inh deficiency was made correctly in most cases in this survey. We can recommend the chromogenic assay for the determination of fC1-Inh, while the complex ELISA needs further investigation.

S-100B and FDG-PET/CT in therapy response assessment of melanoma patients.

OBJECTIVE: To compare the value of the tumor marker S-100B protein and fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) in patients treated for melanoma metastases. METHODS: In 41 patients with proven melanoma metastases, S-100B measurements and FDG-PET/CT were performed before and after therapy. The change of S-100B levels (DeltaS-100B) was assessed. In all patients, therapy response was assessed with PET/CT using visual criteria and change of maximal standard uptake value (DeltaSUV(max.)) or total lesion glycolysis (DeltaTLG). RESULTS: In 15 of 41 patients (37%), S-100B values were not suitable because they were normal before and after therapy. In 26 patients, S-100B was suitable for therapy response assessment. PET/CT was suitable for response assessment in all patients. Correlations between DeltaS-100B and DeltaTLG (r = 0.850, p < 0.001) and between DeltaS-100B and DeltaSUV(max.) (r = 0.818, p < 0.001) were both excellent. A complete agreement between S-100B and PET/CT response assessment was achieved in 22 of 26 patients. In 4 patients, therapy response differed between the S-100B and PET/CT findings, but subsequent S-100B measurements realigned the S-100B results with the later PET/CT findings. CONCLUSION: In a third of our patients with metastases, the S-100B tumor marker was not suitable for therapy assessment. In these patients, imaging techniques remain necessary, and FDG-PET/CT can be used for response assessment.

Tumour assessment in advanced melanoma: value of FDG-PET/CT in patients with elevated serum S-100B.

PURPOSE: To evaluate the usefulness of PET/CT in melanoma patients with an elevated serum S-100B tumour marker level. METHODS: Out of 165 consecutive high-risk melanoma patients referred for PET/CT imaging, 47 had elevated (>0.2 microg/l) S-100B serum levels and a contemporaneous 18F-FDG PET/CT scan. PET/CT scans were evaluated for the presence of metastases. To produce a composite reference standard, we used cytological, histological, MRI and PET/CT follow-up findings as well as clinical and S-100B follow-up. RESULTS: Among the 47 patients with increased S-100B levels, PET/CT correctly identified metastases in 38 (30 distant metastases and eight lymph node metastases). In one patient with cervical lymph node metastases, PET/CT was negative. Eight patients had no metastases and PET/CT correctly excluded metastases in all of them. Overall sensitivity for metastases was 97% (38/39), specificity 100% (8/8) and accuracy 98% (46/47). S-100B was significantly higher in patients with distant metastases (mean 1.93 microg/l, range 0.3-14.3 microg/l) than in patients with lymph node metastases (mean 0.49 microg/l, range 0.3-1.6 microg/l, p=0.003) or patients without metastases (mean 0.625 microg/l, range 0.3-2.6 microg/l, p=0.007). However, 6 of 14 patients with a tumour marker level of 0.3 microg/l had no metastases. CONCLUSION: In melanoma patients with elevated S-100B tumour marker levels, FDG-PET/CT accurately identifies lymph node or distant metastases and reliably excludes metastases. Because of the significant number of false positive S-100B tumour marker determinations (17%), we recommend repetition of tumour marker measurements if elevated S-100B levels occur before extensive imaging is used.

Detection of melanoma relapse: first comparative analysis on imaging techniques versus S100 protein.

BACKGROUND: Early detection of melanoma recurrence is essential for the patient's prognosis. The serum S100 level may be a useful tool to detect relapse early. OBJECTIVE: To compare the efficacy of imaging techniques and serum S100 in the early detection of melanoma progression. This is the first report of a comparison of a serum marker with an imaging tool in the follow-up of melanoma patients. METHODS: From 1992 to 2003, we screened 192 patients suffering from melanoma recurrence after a disease-free interval. Of those, 127 patients were identified whose S100 levels had been assessed parallel to imaging procedures. RESULTS: Serum S100 was elevated in 37% of patients at the time of relapse. In stage III, 32% of the patients had elevated S100 levels whereas in case of progression to stage IV, 48% of the patients presented with increased S100. In 5.5% of patients, S100 was the first indicator of disease progression. Imaging procedures lead to detection of melanoma recurrence in 26.8%. CONCLUSION: A rising level of serum S100 is a specific and sensitive marker of melanoma progression.

Serological immunomarkers in cutaneous T cell lymphoma.

INTRODUCTION: As serological immunomarkers like neopterin, beta2-microglobulin, soluble IL-2 receptor (sIL-2R) and IL-6 have been described to be elevated in various malignancies, the aim of this study was to investigate whether they would be of diagnostic and prognostic value for leukemic and non-leukemic cutaneous T cell lymphoma (CTCL). PATIENTS AND METHODS: Forty-one CTCL patients from the lymphoma clinics of the Department of Dermatology, University of Zurich, were tested for the serum levels of the above-mentioned immunomarkers at several time points, and clinical status and clinical outcome were recorded. Thirty-nine patients with CBCL and T cell inflammatory diseases served as controls. RESULTS: The study revealed that neopterin, beta2-MG and sIL-2R are significantly elevated in Sezary syndrome, whereby sIL-2R seemed to be the most sensitive marker and is typically increased in Sezary syndrome. Moreover, there is a correlation between tumor burden index values and serum parameters. Concerning the outcome of the disease (progression versus non-progression), only neopterin showed a significant prognostic value in non-leukemic CTCL patients. CONCLUSION: Serological immunomarkers are helpful tools in determining the tumor burden in CTCL and thus might be useful for disease monitoring during treatment. They may have prognostic value for predicting the clinical course.

Statin-induced immunomodulatory effects on human T cells in vivo.

Statins are widely used for treatment of hypercholesterolemia. Recent experimental studies revealed that these drugs also exert anti-inflammatory effects. The aim of this study was to assess immunomodulatory effects of statins in humans in vivo. Twenty-seven healthy volunteers were analyzed for serum cytokines and acute phase proteins, HLA-DR and CD38 expression on T cells and superantigen-mediated T cell activation ex vivo before and after 14 days of statin treatment. First, simvastatin 40 mg was compared to atorvastatin 20 mg. Second, two different doses of simvastatin (20 and 40 mg) were tested. Atorvastatin treatment led to a significant down-regulation of HLA-DR and the CD38 activation marker on peripheral T cells, whereas simvastatin up-regulated both of these molecules. In contrast, superantigen-mediated T cell activation was inhibited by simvastatin and enhanced by atorvastatin. No significant effect of statin treatment on inflammatory serum markers was detected. Thus, immunomodulatory effects of statins on human T cells are first demonstrated in vivo and are differentially induced by two different statins: atorvastatin led to a major histocompatibility class II (MHC II) antigens down-regulation and may therefore be investigated for treatment of chronic transplant rejection; simvastatin inhibited superantigen-mediated T cell activation, which might explain reduced mortality of simvastatin-treated patients with staphylococcal bacteremia.

False-positive human serum chorionic gonadotropin in a patient with a history of germ cell cancer.

Tumor markers, including the beta-subunit of human chorionic gonadotropin (beta-hCG), and radiological imaging methods are commonly used for the diagnosis and monitoring of testicular cancer. We report of a patient with a history of classical seminoma stage I who had elevated serum levels of beta-hCG suggesting relapse 5 years after initial treatment. Radiological evaluation revealed a pericardial cyst, which was surgically removed. Histological evaluation did not demonstrate malignant tissue, suggesting a false-positive beta-hCG. Further workup confirmed this suspicion as we could demonstrate false-positive test results due to heterophilic antibodies detectable in the patient's serum. This case stresses the need for verification of beta-hCG levels in patients where clinical results are not in line with laboratory results.

Prevalence of human T-cell leukemia virus types I and II in Switzerland.

The retroviruses human immunodeficiency virus (HIV)-1/2 and human T-cell leukemia virus (HTLV)-I/II share modes of transmission, suggesting that efforts to monitor the current HIV-1 epidemic in Switzerland should be complemented by assessment of HTLV-I/II prevalence. This study presents an updated evaluation of HTLV-I/II infection among groups within the Swiss population polarized towards either low or increased risk of infection. Archived serum and peripheral blood mononuclear cell (PBMC) samples were examined for evidence of HTLV-I/II infection by enzyme-linked immunosorbant assay (ELISA), type-specific Western blot, type-specific polymerase chain reaction (PCR), DNA sequence analysis, and virus culture. Among blood donations obtained from low-risk Swiss donors, we report a complete lack of HTLV-II infection and the occurrence of HTLV-I infection limited to a prevalence of 0.079 per 100,000 (1/1,266,466). Among high-risk HIV-positive persons and HIV-negative persons at increased risk of HIV-infection, we report a focus of HTLV-I and HTLV-II infection at prevalence rates of 62 per 100,000 (1/1,620) and 309 per 100,000 (5/1,620), respectively. The finding of low HTLV-I/II prevalence among Swiss blood donors and containment of HTLV-I/II infection within known risk-groups does not support initiation of HTLV-I/II screening for Swiss blood, tissue, and organ donations.

Troponin as a risk factor for mortality in critically ill patients without acute coronary syndromes.

OBJECTIVES: We sought to assess the mechanism and prognostic value of elevated troponins in patients without acute coronary syndromes (ACS). BACKGROUND: Cardiac troponins are used as specific markers for the diagnosis of ACS. Recent studies reported a considerable number of critically ill patients without ACS as being troponin-positive, especially patients with sepsis, pulmonary embolism, renal failure, and stroke. METHODS: We analyzed 58 consecutive, critically ill patients admitted for reasons other than ACS, according to their troponin status. Thirty-day mortality, left ventricular ejection fraction (LVEF), and a panel of inflammatory cytokines were compared between troponin-positive and troponin-negative patients. Relevant coronary artery disease was excluded either by stress echocardiography or autopsy. RESULTS: Of the 58 critically ill patients, 32 (55%) without evidence of ACS were troponin-positive. Positive troponin levels were associated with higher mortality (22.4% vs. 5.2%, p < 0.018) and a lower LVEF (p = 0.0006). Troponin-positive patients had significantly higher median levels of tumor necrosis factor (TNF)-alpha, its soluble receptor, and interleukin (IL)-6. A subgroup of 10 aplastic patients was troponin-negative at study entry. Three became troponin-positive during leukocyte recovery and subsequently died, whereas all the others stayed troponin-negative and survived. Flow-limiting coronary artery disease was not demonstrable at autopsy or stress echocardiography in 72% of troponin-positive patients. CONCLUSIONS: Elevated troponin is a mortality risk factor for medical intensive care patients admitted for reasons other than ACS. It is associated with decreased left ventricular function and higher levels of TNF-alpha and IL-6.

Glucose-induced beta cell production of IL-1beta contributes to glucotoxicity in human pancreatic islets.

In type 2 diabetes, chronic hyperglycemia is suggested to be detrimental to pancreatic beta cells, causing impaired insulin secretion. IL-1beta is a proinflammatory cytokine acting during the autoimmune process of type 1 diabetes. IL-1beta inhibits beta cell function and promotes Fas-triggered apoptosis in part by activating the transcription factor NF-kappaB. Recently, we have shown that increased glucose concentrations also induce Fas expression and beta cell apoptosis in human islets. The aim of the present study was to test the hypothesis that IL-1beta may mediate the deleterious effects of high glucose on human beta cells. In vitro exposure of islets from nondiabetic organ donors to high glucose levels resulted in increased production and release of IL-1beta, followed by NF-kappaB activation, Fas upregulation, DNA fragmentation, and impaired beta cell function. The IL-1 receptor antagonist protected cultured human islets from these deleterious effects. beta cells themselves were identified as the islet cellular source of glucose-induced IL-1beta. In vivo, IL-1beta-producing beta cells were observed in pancreatic sections of type 2 diabetic patients but not in nondiabetic control subjects. Similarly, IL-1beta was induced in beta cells of the gerbil Psammomys obesus during development of diabetes. Treatment of the animals with phlorizin normalized plasma glucose and prevented beta cell expression of IL-1beta. These findings implicate an inflammatory process in the pathogenesis of glucotoxicity in type 2 diabetes and identify the IL-1beta/NF-kappaB pathway as a target to preserve beta cell mass and function in this condition.