Low prevalence of hepatitis C virus antibody among Swiss dental health care workers.
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Biomedical subjects
Publications and source records attributed to C Weber.
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OBJECTIVE: To study the lipoprotein distribution of supplemented coenzyme Q10 (CoQ10), vitamin E, and polyunsaturated fatty acids (PUFA). DESIGN: Balanced three-period crossover study. SETTING: University research unit. SUBJECTS: Eighteen apparently healthy free-living non-smoking volunteers (nine women, nine men), mean age 26 +/- 3 y, recruited among the university students; no dropouts. INTERVENTIONS: Three supplementation periods of 10 days: 100 mg/day CoQ10, 350 mg/day D-alpha-tocopherol, and 2 g/day concentrated fish oil. Fasting venous blood samples were collected twice before the first period and then after each period. Plasma and isolated lipoproteins were analysed for cholesterol, triacylglycerol, alpha- and gamma-tocopherol, CoQ10, and fatty acid composition. RESULTS: Significant (P < 0.05) increase in CoQ10 and alpha-tocopherol occurred in all lipoprotein classes after supplementation. CoQ10 was primarily incorporated into low-density lipoprotein (LDL). alpha-tocopherol and fish oil n-3 PUFAs had similar patterns. They were equally distributed between LDL and high-density lipoprotein (HDL), with a smaller part in VLDL. The total sum of PUFA was unchanged following all supplementations, but fish oil increased the amount of n-3 fatty acids at the expense of n-6 fatty acids. CONCLUSION: Lipoprotein distribution of CoQ10 is markedly different from that of alpha-tocopherol, suggesting that they may be metabolised by distinct routes. alpha-Tocopherol is distributed similarly to n-3 fatty acids, thus providing protection on location for the oxidatively labile PUFAs.
PURPOSE: Evaluation of MRI first-pass myocardial perfusion pre- and post-percutaneous myocardial laser revascularisation (PMR). PATIENTS AND METHODS: MRI was performed in 10 patients with coronary heart disease grade III-IV, 1-4 days prior to PMR, as well as 1-5 days and 6 months after PMR. Contrast enhanced (0.1 ml/kgBw; 4 ml/s) "first-pass" MRI imaging was obtained by breath-hold, ECG-triggered, multislice Turbo-FLASH GRE. For quantitative analysis the absolute and percentual signal-to-noise (S/N)-measurements were calculated. Positron emission tomography (PET) was regarded as the gold standard for myocardial perfusion. RESULTS: The mean values of absolute and % S/N increase revealed no statistical difference between pre- and immediately post-PMR imaging. 6 months following PMR both values were significantly elevated (14.1 vs. 24.4 and 127 vs. 176; p = 0.03 and p = 0.01). However, the non-treated myocardial segments revealed a similar S/N pattern. Intraindividual analysis showed a significant S/N increase post PMR in one patient, and in additional 4 patients 6 months later. PET revealed increased myocardial perfusion in only two patients. Following PMR 5/10 patients experienced a significant reduction of chest pain equivalent to two CCS grades. Two of these had significant S/N elevations but no evidence of increased perfusion by PET. CONCLUSION: S/N first-pass calculations following PMR do not correlate well with the true situation of myocardial perfusion. They seem to be more closely associated with other histological phenomena and possible explanations for the improved clinical symptomatology.
BACKGROUND: During clinical trials bosentan, the first orally active endothelin receptor antagonist, caused asymptomatic transaminase elevations in some patients. In this study we investigated whether inhibition of the hepatocanalicular bile salt export pump (rodents, Bsep; humans, BSEP ABCB11) could account for bosentan-induced liver injury. METHODS: We reanalyzed the safety database of the bosentan trials for cholestatic liver injury, determined the cholestatic potency of bosentan in the rat, and studied the effects of bosentan and its metabolites on Bsep-mediated taurocholate transport in vitro. RESULTS: Bosentan caused dose-dependent and reversible liver injury in 2% to 18% of patients and caused a significant increase of serum bile salt levels (P <.01). Concomitant administration of glyburide (INN, glibenclamide) enhanced the cholestatic potency of bosentan. Similar effects were seen in rats, in which serum bile salt levels were increased by glyburide less than by bosentan, which increased the levels less than a combination of bosentan and glyburide. In vitro, Bsep-mediated taurocholate transport was inhibited by bosentan (inhibition constant, approximately 12 micromol/L) and metabolites (inhibition constant, approximately 8.5 micromol/L for metabolite Ro 47-8634). CONCLUSIONS: These results indicate that bosentan-induced liver injury is mediated, at least in part, by inhibition of Bsep/BSEP-causing intracellular accumulation of cytotoxic bile salts and bile salt induced liver cell damage. The data further emphasize the pathophysiologic importance of drug-Bsep interactions in acquired forms of cholestatic liver injury.
We report the case of a young white woman in whom cerebrovascular moyamoya disease, which was associated with nonarteriosclerotic peripheral artery disease of the subclavian, iliac, and femoropopliteal arteries, was diagnosed by means of angiography. During 8 years of follow-up, the peripheral artery disease progressed, without any signs characteristic of systemic inflammation or vasculitis, leading to severe calf and arm claudication. Despite the absence of histologic confirmation, this observation strongly suggests that peripheral artery involvement may be a feature of moyamoya disease. To our knowledge, this is the first report of an association of classical cerebrovascular moyamoya disease with peripheral artery disease.
We investigated the role of H-Ras in chemokine-induced integrin regulation in leukocytes. Stimulation of Jurkat T cells with the CXC chemokine stromal cell-derived factor-1alpha (SDF-1alpha) resulted in a rapid increase in the phosphorylation, i.e., activation of extracellular signal receptor-activated kinase (ERK) but not c-Jun NH(2)-terminal kinase or p38 kinase, and phosphorylation of Akt, reflecting phosphatidylinositol 3-kinase (PI3-K) activation. Phosphorylation of ERK in Jurkat cells was enhanced and attenuated by expression of dominant active (D12) or inactive (N17) forms of H-Ras, respectively, while N17 H-Ras abrogated SDF-1alpha-induced Akt phosphorylation. SDF-1alpha triggered a transient regulation of adhesion to intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 mediated by lymphocyte function antigen-1 (LFA-1) and very late antigen-4 (VLA-4), respectively, and a rapid increase in LFA-1 binding to soluble ICAM-1.Ig, which was inhibited by D12 but not N17 H-Ras. Both D12 and N17 H-Ras abrogated the regulation of LFA-1 but not VLA-4 avidity, and impaired LFA-1-mediated transendothelial chemotaxis but not VLA-4-dependent transmigration induced by SDF-1alpha. Analysis of the mutant Jurkat J19 clone revealed LFA-1 with constitutively high affinity and reduced ERK phosphorylation, which were partially restored by expression of active H-Ras. Inhibition of PI3-K blocked the up-regulation of Jurkat cell adhesion to ICAM-1 by SDF-1alpha, whereas inhibition of mitogen-activated protein kinase kinase impaired the subsequent down-regulation and blocking both pathways abrogated LFA-1 regulation. Our data suggest that inhibition of initial PI3-K activation by inactive H-Ras or sustained activation of an inhibitory ERK pathway by active H-Ras prevail to abolish LFA-1 regulation and transendothelial migration induced by SDF-1alpha in leukocytes, establishing a complex and bimodal involvement of H-Ras.
BACKGROUND: Repetitive exposure to cytokine-inducing substances (pyrogens) results in chronic inflammation, which may significantly contribute to some of the long-term complications in dialysis patients. On-line dialysis modalities, such as on-line haemodiafiltration (HDF), raise particular concerns because of the administration of infusate prepared from potentially contaminated dialysis fluid. Hence, great retention capability for pyrogens is of critical importance for the safe performance of on-line systems. METHODS: The microbiological safety of a novel on-line system, ONLINEplus(TM), was assessed in clinical practice in five centres for 3 months. Infusate and dialysis fluid were regularly monitored for microbial counts, endotoxins, and cytokine-inducing activity. Levels of interleukin-1 receptor antagonist (IL-1Ra) were determined in supernatants of whole blood incubated either under pyrogen-free conditions (spontaneous cytokine production) or following low-dose endotoxin exposure (LPS-stimulated cytokine production). RESULTS: We failed to detect microorganisms or endotoxin contamination of infusate during the entire study period. Moreover, neither infusate nor dialysis fluid demonstrated cytokine-inducing activity. Intradialytic IL-1Ra induction was not detected, as there was no difference between pre- and post-session values for both spontaneous and LPS-stimulated IL-1Ra production (115+/-26 vs 119+/-27 and 2445+/-353 vs 2724+/-362 pg/10(6) white blood cells (WBC), respectively). Neither the number of immunocompetent cells nor their capacity to produce IL-1Ra declined during this period, indicating that cells were not significantly stimulated during treatment. Spontaneous and LPS-induced exvivo IL-1Ra generation remained unchanged after 3 months of on-line HDF therapy as compared with the start of the study (71+/-30 pre- vs 48+/-14 post-study, and 2559+/-811 vs 2384+/-744 pg/10(6) WBC, respectively). CONCLUSIONS: The present on-line system performed safely from a microbiological view-point as both the dialysis fluid and infusate were consistently free of microorganisms, endotoxins, and cytokine-inducing substances. As a result, on-line HDF therapy had no effect upon the chronic inflammatory responses in end-stage renal disease patients.
The vitamin E analog alpha-tocopheryl succinate (alpha-TOS) can induce apoptosis. We show that the proapoptotic activity of alpha-TOS in hematopoietic and cancer cell lines involves inhibition of protein kinase C (PKC), since phorbol myristyl acetate prevented alpha-TOS-triggered apoptosis. More selective effectors indicated that alpha-TOS reduced PKCalpha isotype activity by increasing protein phosphatase 2A (PP2A) activity. The role of PKCalpha inhibition in alpha-TOS-induced apoptosis was confirmed using antisense oligonucleotides or PKCalpha overexpression. Gain- or loss-of-function bcl-2 mutants implied modulation of bcl-2 activity by PKC/PP2A as a mitochondrial target of alpha-TOS-induced proapoptotic signals. Structural analogs revealed that alpha-tocopheryl and succinyl moieties are both required for maximizing these effects. In mice with colon cancer xenografts, alpha-TOS suppressed tumor growth by 80%. This epitomizes cancer cell killing by a pharmacologically relevant compound without known side effects.
Monitoring biochemical processes relevant to the function, survival, and longevity of tissue-engineered pancreatic constructs is important for the development of an optimum construct design as well as patient care management after implantation. In this report we demonstrate the ability of nuclear magnetic resonance (NMR) techniques to monitor aspects of intracellular metabolism, overall morphology, and distribution of a microencapsulation based bioartificial pancreas in vitro and in vivo.
We compared Bordetella pertussis isolates collected in France over the last 10 years, the vaccine strains used for more than 30 years, and isolates collected before the introduction of generalized vaccination. The analysis included serotyping, pulsed-field gel electrophoresis of chromosomal DNA after digestion with XbaI and SpeI, and sequencing of the pt S1 gene, encoding the S1 subunit of pertussis toxin, and the prn gene, encoding the adhesin pertactin. We found that the incidence of infection increases every 3 years. Ninety-five per cent of the isolates analyzed express type 3 fimbriae. Most of the isolates circulating since 1991, unlike the vaccinal strains, express a type A pertussis toxin and a type 2 pertactin. The isolates could be classified into five major groups by pulsed-field gel electrophoresis. Most of these groups correlated with the pertactin type expressed by the isolates. Pulsed-field gel electrophoresis is more discriminative than sequencing particular genes since it could differentiate isolates expressing type 2 pertactin into two subgroups: those circulating in 1993 to 1997 and those circulating in 1997 to 2001. This observation suggests that there has been continuous evolution of the B. pertussis population.
OBJECTIVES: To describe the relation between spirometric findings and farming characteristics and variables of exposure to organic dust measured during work in animal buildings. Farmers have traditionally been described as having one of the most dangerous occupations, so a large scale study on European farmers was carried out. This is the report of the second part of that study. METHODS: 40 pig farmers in Denmark and 36 poultry farmers in Switzerland were chosen randomly and were assessed over 1 working day. RESULTS: Mean (SD) baseline spirometric results in pig farmers were higher than in poultry farmers (forced expiratory volume in 1 second (FEV(1)) (% of reference value) 108.3 (16.7) v 100.2 (14.2); p=0.04). Baseline lung function results were significantly associated with ventilation of the animal houses. Furthermore, temperature was related to spirometric findings in pig farmers. CONCLUSIONS: Ventilation of the animal house and temperature might influence respiratory morbidity in farmers.
The activation of nuclear factor-kappaB (NF-kappaB) is required for the induction of many of the adhesion molecules and chemokines involved in the inflammatory leukocyte recruitment to the kidney. Here we studied the effects of NF-kappaB inhibition on the machinery crucial for monocyte infiltration of the glomerulus during inflammation. In mesangial cells (MC), the protease inhibitors MG-132 and N-alpha-tosyl-L-lysine chloromethyl ketone or adenoviral overexpression of IkappaB-alpha prevented the complete IkappaB-alpha degradation following tumor necrosis factor-alpha (TNF-alpha) stimulation. This resulted in a marked inhibition of TNF-alpha-induced expression of mRNA and protein for the immunoglobulin molecules intracellular adhesion molecule-1 and vascular cell adhesion molecule-1 and the chemokines growth-related oncogene-alpha, monocyte chemoattractant protein-1, interleukin-8, or fractalkine in MC. Finally, the inhibition of IkappaB-alpha degradation or IkappaB-alpha overexpression suppressed the chemokine-induced transendothelial monocyte chemotaxis toward MC and the chemokine-triggered firm adhesion of monocytic cells to MC. The inhibition of NF-kappaB by pharmacological intervention or gene transfer may present a multimodal approach to control the machinery propagating inflammatory recruitment of monocytes during glomerular disease.
In a reconstituted flow chamber system, preincubation with chemokines can trigger the arrest of rolling monocytes, suggesting that this interaction could help recruit these cells to early atherosclerotic lesions. To date, however, the contribution of endothelium-derived chemokines found in these lesion to monocyte arrests has not been investigated. The endothelium of lesion-prone carotid arteries from apolipoprotein E-deficient (ApoE(-/-)) mice, but not control mice, presents the chemokines KC (mouse GRO-alpha) and JE (mouse monocyte chemoattractant protein-1 [MCP-1]). Arrest of a monocytic cell line or mouse blood monocytes perfused through carotid arteries of ApoE(-/-) mice was reduced by treating with either pertussis toxin, an antagonist of CXCR2, or an antibody to KC, but this process was insensitive to agents that blocked CCR-2 or JE. Conversely, monocyte accumulation more than doubled upon pre-perfusion of the carotid artery with KC but not with mouse MCP-1. Blockade of alpha(4)beta(1) integrin (VLA-4) or vascular cell adhesion molecule-1, but not CD18 or intercellular adhesion molecule-1, almost completely inhibited the arrest of monocytes. We conclude that when presented by early atherosclerotic lesions, KC but not murine MCP-1 triggers VLA-4-dependent monocyte recruitment.
Recent evidence suggests that vitamin E and its analogues, which have been used for many years as antioxidants, may not only protect cells from free radical damage but also induce apoptotic cell death in various cell types. While alpha-tocopherol (alpha-TOH) is mainly known as an anti-apoptotic agent, its redox-silent analogues either have no influence on cell survival (alpha-tocopheryl acetate, alpha-TOA), or induce apoptosis (alpha-tocopheryl succinate, alpha-TOS). Although precise mechanisms of apoptosis induction by alpha-TOS remain to be elucidated, there is evidence that this process involves both the antiproliferative and membrane destabilising activities of the agent. Alpha-TOS has been shown to induce apoptosis in malignant cell lines but not, in general, in normal cells, and to inhibit tumorigenesis in vivo. These features suggest that this semi-synthetic analogue of vitamin E could be a promising antineoplastic agent.
Farmers are known to be at high risk for the development of occupational airway disease. The aim of this European study was to determine which airway symptoms predominate in different types of animal farmers (cattle, pigs, poultry, sheep) and to compare the prevalence of symptoms to the general population. A total of 6,156 randomly selected animal farmers in Denmark, Germany (Schleswig-Holstein, Niedersachsen), Switzerland, and Spain completed a questionnaire on respiratory symptoms and farming characteristics in 1995-1997. The prevalence of general respiratory symptoms was compared to the results of the European Community Respiratory Health Survey (ECRHS) obtained in the same regions. Pig farmers were at highest risk for the development of work-related symptoms. A significant dose-response relationship between daily hours worked inside animal houses and symptoms was established for pig and poultry farmers. Additionally, self-reported nasal allergies (odds ratio (95% confidence interval): 3.92 (3.26-4.71)) and nasal irritation during work (3.98 (3.35-4.73)) were shown to be associated with the development of chronic phlegm. The prevalence of wheezing, shortness of breath, asthma and nasal allergies was signficantly lower among all farmers in the age group 20-44 yrs than among the general population. However, the prevalence of usually bringing up phlegm in winter among farmers was significantly higher than in the general population (9.4 (8.3-10.5%) versus 7.5 (6.5-8.5%)). Individual factors have been shown to be related to the prevalence of chronic phlegm among farmers. Additionally, this study could support the hypothesis that farming could be negatively related to allergic diseases.
The antiphospholipid antibody syndrome (APS) is characterized by arterial or venous thromboses and recurrent foetal loss. It occurs as primary disease, but also in the context of systemic lupus erythematosus (SLE). Whereas primary APS induces a thrombotic microangiopathy without significant inflammatory reaction, secondary APS in SLE is usually associated with vasculitis. Here we report a patient with APS who presented with acute diarrhoea and then developed a HELLP-like syndrome characterized by a spontaneous abortion, multifocal hepatic necroses and thrombocytopenia. Thereafter an acute flare of SLE with arthralgias, pleuritis, skin rash and glomerulitis occurred. Clinical amelioration was only achieved by combining curettage, anticoagulation and immunosuppression, a treatment taking into account the pathogenesis of HELLP-like disease, APS and SLE. To our knowledge this is the first reported case of APS associated with combined acute manifestations of these three syndromes triggered by a presumable intestinal infection.
The domain of body image plays a central role in the quality of life of patients with haematological malignancies and metastasized cancer, since the disease itself as well as the enrolled therapies interfere with psychological and bodily well-being. We approached this highly subjective field by using the repertory grid technique and hypothesized that patients would display a restricted body image, focusing on functional aspects of the body. In all, 55 in-patients (27 men, 28 women, M age = 45.7 yrs, N = 46 with haematological malignancies, N = 9 with metastasized cancer), at the time of initial diagnosis, were included in the study and assessed with the Body Grid, an instrument specifically designed by us for the exploration of body image. The data were analysed by principal component analysis (PCA) and construct categorization. Further, 42 chronic tinnitus sufferers (20 male, 22 female, M age = 46.5 yrs) served as a comparison group. Based on the constructs elicited, six construct categories were formulated in the sense of a first attempt of a hierarchical model (emotion, control, activity, strength, function, appearance). The central constructs (373 construct pairs) were assigned to these categories by three inter-raters. The categories appeared in the following order of frequency: function (27.1%), emotion (20.4%), strength (20.1%), activity (15%), control (10.2%) and appearance (7.2%). PCA indicated that the patients mainly demonstrated a restricted view of their body. In the tinnitus group, the most frequent category proved to be activity (21.3%), closely followed by function (21.1%) and control (20.9%). The body image was also restricted (PCA). The restriction of body image, together with the specific construct choice, seen in the haematology and cancer patients reflects the existential threat of the disease and may serve as a coping strategy. The high percentage of emotional constructs may mirror the patients' need for further support. The distinct distribution of construct categories in the two different patient samples supports the applicability of the proposed preliminary model.
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