Infant with congenital erosions of the skin of several fingers and gastroschisis.
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Abnormalities, Multiple↗
Biomedical subjects
C Weber
Publications and source records attributed to C Weber.
Coenzyme Q blocks biochemical but not receptor-mediated apoptosis by increasing mitochondrial antioxidant protection.
Generation of free radicals is often associated with the induction and progression of apoptosis. Therefore, antioxidants can prove anti-apoptotic, and can help to elucidate specific apoptotic pathways. Here we studied whether coenzyme Q, present in membranes in reduced (ubiquinol) or oxidised (ubiquinone) forms, can affect apoptosis induced by various stimuli. Exposure of Jurkat cells to alpha-tocopheryl succinate (alpha-TOS), hydrogen peroxide, anti-Fas IgM or TRAIL led to induction of apoptosis. Cell death due to the chemical agents was suppressed in cells enriched with the reduced form of coenzyme Q. However, coenzyme Q did not block cell death induced by the immunological agents. Ubiquinol-10 inhibited reactive oxygen species (ROS) generation in cells exposed to alpha-TOS, and a mitochondrially targeted coenzyme Q analogue also blocked apoptosis triggered by alpha-TOS or hydrogen peroxide. Therefore, it is plausible that ubiquinol-10 protects cells from chemically-induced apoptosis by acting as an antioxidant in mitochondria. Our results also indicate that generation of free radicals may not be a critical step in induction of apoptosis by immunological agents.
Antioxidants↗
Combinatorial model of chemokine involvement in glomerular monocyte recruitment: role of CXC chemokine receptor 2 in infiltration during nephrotoxic nephritis.
A sequential model involving chemokines has been proposed for leukocyte extravasation into areas of inflammation; however, site-specific aspects remain to be elucidated. Hence, we studied the role of chemokines produced by mesangial (MC) or glomerular endothelial cells (GEC) and their receptors in glomerular recruitment of monocytes. Stimulation of MC with TNF-alpha up-regulated mRNA and protein of CC and CXC chemokines but not constitutive expression of the CX(3)C chemokine fractalkine. While growth-related activity (GRO)-alpha was immobilized to MC proteoglycans, monocyte chemotactic protein (MCP)-1 was secreted into the soluble phase. Firm adhesion and sequestration of monocytes on activated MC was supported by the GRO-alpha receptor CXCR2 and to a lesser extent by CX(3)CR, whereas the MCP-1 receptor CCR2 contributed to their transendothelial chemotaxis toward activated MC. In contrast, fractalkine mRNA and protein was induced by TNF-alpha in transformed rat GEC, and both CXCR2 and CX(3)CR mediated monocyte arrest on GEC in shear flow. The relevance of these mechanisms was confirmed in a rat nephrotoxic nephritis model where acute glomerular macrophage recruitment was profoundly inhibited by blocking CXCR2 or CCR2. In conclusion, our results epitomize a combinatorial model in which chemokines play specialized roles in driving glomerular monocyte recruitment and emphasize an important role for CXCR2 in macrophage infiltration during early phases of nephrotoxic nephritis.
Animals↗
Analysis of Bordetella pertussis isolates collected in Japan before and after introduction of acellular pertussis vaccines.
Because of recent concern that whole-cell pertussis vaccination can drive antigenic divergence of circulating isolates of Bordetella pertussis, we compared 12 clinical isolates of B. pertussis collected in Japan, the first country to introduce acellular pertussis vaccines, with the vaccine strain. We used pulsed-field gel electrophoresis, sequencing of ptx and prn genes and expression of fimbriae. Most of the isolates collected before or after introduction of acellular vaccine possess similar restriction patterns. They contain ptx genes and prn alleles similar to the vaccine strain and to European isolates collected before the introduction of vaccination. Two recently collected isolates exhibiting a different pulsed-field gel electrophoresis pattern possess ptxS1 and prn alleles similar to the alleles harbored by European isolates circulating currently. Our preliminary results suggest that, if acellular pertussis vaccine-induced antigenic divergence exists, it is likely to be a slow or rare process.
Antigenic Variation↗
Inhibition of inflammatory endothelial responses by a pathway involving caspase activation and p65 cleavage.
Suppression of NF kappa B activation has been involved in the elimination of survival programs during endothelial cell (EC) apoptosis. We used alpha-tocopheryl succinate (alpha-TOS) to trigger apoptosome formation and the subsequent activation of executioner caspases. The level of bcl-2 was reduced by alpha-TOS, and its downregulation potentiated and its overexpression suppressed pro-apoptotic effects of alpha-TOS, indicating a mitochondrial role in alpha-TOS-induced apoptosis in EC. alpha-TOS treatment was associated with induction of TUNEL-positive apoptosis in EC with a high but not with a low proliferation index. The use of the pan-caspase inhibitor z-VAD.fmk suggested the involvement of caspases in cleavage of p65, and in inhibition of nuclear translocation of p65 and NF kappa B-dependent transactivation of a gene construct encoding the green fluorescence protein elicited by TNF alpha in contact-arrested EC. The suppression by alpha-TOS of inflammatory EC responses induced by TNF alpha such as VCAM-1 mRNA and surface protein expression and shear-resistant arrest of monocytic cells were also reversed by z-VAD.fmk. NF kappa B-dependent transactivation was preserved in alpha-TOS-treated EC stably transfected with a caspase-noncleavable p65 mutant but not with its truncated form, thus establishing a direct link between alpha-TOS-induced effects and p65 cleavage. Our data infer a pathway by which caspase activation in EC inhibits NF kappa B-dependent inflammatory activation and monocyte recruitment, and provide evidence for a relationship between pro-apoptotic and anti-inflammatory pathways.
Apoptosis↗
Lack of cross-species transmission of porcine endogenous retrovirus infection to nonhuman primate recipients of porcine cells, tissues, or organs.
BACKGROUND: Nonhuman primates (NHPs) have been widely used in different porcine xenograft procedures inevitably resulting in exposure to porcine endogenous retrovirus (PERV). Surveillance for PERV infection in these NHPs may provide information on the risks of cross-species transmission of PERV, particularly for recipients of vascularized organ xenografts for whom data from human clinical trials is unavailable. METHODS: We tested 21 Old World and 2 New World primates exposed to a variety of porcine xenografts for evidence of PERV infection. These NHPs included six baboon recipients of pig hearts, six bonnet macaque recipients of transgenic pig skin grafts, and nine rhesus macaque and two capuchin recipients of encapsulated pig islet cells. Serologic screening for PERV antibody was done by a validated Western blot assay, and molecular detection of PERV sequences in peripheral blood mononuclear cells (PBMCs) and plasma was performed using sensitive polymerase chain reaction and reverse transcriptase-polymerase chain reaction assays, respectively. Spleen and lymph node tissues available from six bonnet macaques and three rhesus macaques were also tested for PERV sequences. RESULTS: All plasma samples were negative for PERV RNA suggesting the absence of viremia in these xenografted animals. Similarly, PERV sequences were not detectable in any PBMC and tissue samples, arguing for the lack of latent infection of these compartments. In addition, all plasma samples were negative for PERV antibodies. CONCLUSION: These data suggest the absence of PERV infection in all 23 NHPs despite exposure to vascularized porcine organs or tissue xenografts and the use of immunosuppressive therapies in some animals. These findings suggest that PERV is not easily transmitted to these NHP species through these types of xenografts.
Animals↗
RANTES deposition by platelets triggers monocyte arrest on inflamed and atherosclerotic endothelium.
BACKGROUND: Circulating platelets and chemoattractant proteins, such as the CC chemokine RANTES, contribute to the activation and interaction of monocytes and endothelium and may thereby play a pivotal role in the pathogenesis of inflammatory and atherosclerotic disease. METHODS AND RESULTS: The binding of RANTES to human endothelial cells was detected by ELISA or immunofluorescence after perfusion with platelets or exposure to their supernatants. Monocyte arrest on endothelial monolayers or surface-adherent platelets was studied with a parallel-wall flow chamber and video microscopy. We show that RANTES secreted by thrombin-stimulated platelets is immobilized on the surface of inflamed microvascular or aortic endothelium and triggers shear-resistant monocyte arrest under flow conditions, as shown by inhibition with the RANTES receptor antagonist Met-RANTES or a blocking RANTES antibody. Deposition of RANTES and its effects requires endothelial activation, eg, by interleukin-1beta, and is not supported by venous endothelium or adherent platelets. Immunohistochemistry revealed that RANTES is present on the luminal surface of carotid arteries of apolipoprotein E-deficient mice with early atherosclerotic lesions after wire-induced injury or cytokine exposure. In a mechanistic model of atherogenesis, monocyte adherence on endothelium covering such lesions was studied in murine carotid arteries perfused ex vivo, showing that the accumulation of monocytic cells in these carotid arteries involved RANTES receptors. CONCLUSIONS: The deposition of RANTES by platelets triggers shear-resistant monocyte arrest on inflamed or atherosclerotic endothelium. Delivery of RANTES by platelets may epitomize a novel principle relevant to inflammatory or atherogenic monocyte recruitment from the circulation.
Animals↗
Specialized roles of the chemokine receptors CCR1 and CCR5 in the recruitment of monocytes and T(H)1-like/CD45RO(+) T cells.
Chemokines and their receptors control the emigration of leukocytes during inflammation. The role of the RANTES (regulated on activation normal T-cell expressed and secreted) receptors CCR1 and CCR5 in the selective recruitment of monocytes, T(H)1-like T-cell clones, and peripheral T cells enriched for CD45RO(+) "memory" cells were tested in a system in which arrest under flow conditions is triggered by RANTES immobilized to activated endothelium. With the use of selective nonpeptide receptor antagonists or blocking antibodies, it was found that the RANTES-induced arrest of these cells was mediated predominantly by CCR1. In contrast, CCR5 mainly contributed to the spreading in shear flow, and both CCR1 and CCR5 supported transendothelial chemotaxis toward RANTES. The data in this study reveal specialized roles of apparently redundant receptors in distinct steps of leukocyte trafficking and suggest that not all receptors currently used to define mononuclear cell subsets are involved in their direct recruitment from the circulation.
Cell Adhesion↗
Selective cancer cell killing by alpha-tocopheryl succinate.
We report that alpha-tocopheryl succinate, a vitamin E analogue with pro-apoptotic properties, selectively kills cells with a malignant or transformed phenotype, i.e. multiple haematopoietic and carcinoma cell lines, while being non-toxic to normal, i.e. primary and non-transformed cells. These findings strongly suggest a potential of this micronutrient in the therapy and/or prevention of cancer without significant side-effects.
Apoptosis↗
Selective recruitment of Th2-type cells and evasion from a cytotoxic immune response mediated by viral macrophage inhibitory protein-II.
The viral CC chemokine macrophage inhibitory protein-II (vMIP-II) encoded by human herpes virus 8 (HHV-8) binds to multiple chemokine receptors, however, its ability to control the initial recruitment of specific leukocyte subtypes from the peripheral circulation has not been fully clarified. Here we show that vMIP-II blocks the firm arrest and transmigration of monocytes or Th1-like T lymphocytes triggered by RANTES immobilized on activated human microvascular endothelium (HMVEC) under flow conditions. The internalization of the receptors CCR1 and CCR5 that mediate arrest and transmigration of these cells in response to RANTES was prevented by vMIP-II, supporting its role as an antagonist of CCR1 and CCR5. In contrast, vMIP-II triggered the firm arrest of eosinophils and Th2-like T cells by engaging CCR3, as confirmed by its down-regulation. Immunohistochemical analysis of HHV-8-associated Kaposi's sarcoma lesions marked by vMIP-II expression and mononuclear cell infiltration revealed a predominance of Th2-type CCR3(+) lymphocytes over Th1-type CXCR3(+)/CCR5(+) leukocytes, indicating that as a CCR3 agonist vMIP-II can drive a Th2-type immune response in vivo. Thus, our data provide evidence for a immunomodulatory role of vMIP-II in directing inflammatory cell recruitment away from a Th1-type towards a Th2-type response and thereby facilitating evasion from cytotoxic reactions.
CCR5 Receptor Antagonists↗
Respiratory symptoms in Swiss farmers: an epidemiological study of risk factors.
BACKGROUND: The study was undertaken to assess the prevalence and risk factors of self-reported asthma, symptoms of chronic bronchitis, hay fever, and work-related respiratory symptoms in Swiss farmers as well as to compare the prevalence rates of respiratory symptoms with the Swiss population (SAPALDIA-Study). METHODS: An epidemiological study was performed with a representative sample of 1,542 Swiss farmers using a self-administered questionnaire. To investigate the effect of the type of farming on reported symptoms, the farmers were subdivided into seven groups according to the time farmers spent in different animal confinement buildings. A multivariate analysis was performed by the methods of binary and multivariate logistic regression adjusted for age and smoking habits. RESULTS: In farmers the prevalence rate was 16.0% for chronic bronchitis, 15.4% for asthma symptoms, and 42.0% for reporting at least one work-related symptom. Using logistic regression analysis, it was established that poultry farming and pig/cattle farming was a risk factor for reporting nasal irritation at work [OR 5.33, (1.57-18.0), OR 3.37 (1.04-10.87)]. Poultry farmers experienced the highest symptom rates. In crop farmers, the prevalence for chronic bronchitis was increased [OR 2.32 (1.03-5.23)]. Over 4 hr spent per day in animal confinement buildings more than doubled the risk for reporting chronic bronchitis [OR 2.61 (1.01-6.76)] and phlegm [OR 2.3 (0.99-5.4)] independent of the type of farming. The comparison of Swiss farmers with the Swiss population showed a twofold elevated risk of reporting chronic bronchitis [OR 1.89 (1.32-2.95)] and a 4.5-fold elevated risk for bringing up phlegm regularly [OR 4.5 (3.25-6.69)] in farmers. In contrast, the risk of farmers to report nasal allergies was less than half as high [OR 0.40 (0.29-0.56)] as that of the general population. CONCLUSIONS: This study shows that agricultural work in Switzerland is associated with an elevated risk for reporting symptoms of chronic bronchitis and chronic phlegm compared with the general Swiss population. These main results most likely indicate occupational disorders as the exposure-response relationship (hours spent in animal confinements) was particularly obvious for these symptoms.
Adolescent↗
Dyslexia and visual-spatial talents: compensation vs deficit model.
There are both theoretical and empirical reasons to support the hypothesis that dyslexia is associated with enhancement of right-hemisphere, visual-spatial skills. However, the neurological evidence is neutral with respect to whether dyslexic visual-spatial abilities should be superior (a compensation model) or inferior (a deficit model). In three studies we tested the hypothesis that dyslexia is associated with superior visual-spatial skills. Individuals with dyslexia not only failed to show superiority on a range of visual-spatial tasks, even when tasks were presented without time constraints, but also demonstrated a deficit on many tasks. Whereas we found attentional problems associated with dyslexia, these did not explain our findings. Results are discussed in terms of the apparent conflict between the failure to find any visual-spatial talent associated with dyslexia and the fact that dyslexia is overrepresented in certain visual-spatial professions.
Adult↗
[Intravascular ultrasound guided directional atherectomy and stent implantation of an unprotected main stem in a heart transplant patient with comorbidity].
Following orthotopic heart transplantation (HTx), development of transplant vasculopathy (TVP) is the limiting medical entity leading to significant morbidity and mortality beyond the first year after HTx. Selection of a suitable strategy for repeat revascularisation--transcatheter angioplasty, coronary artery bypass grafting or repeat HTx--depends on various parameters including coronary morphology, left ventricular performance, comorbidity, availability of graft material and donor organs. Catheter-based interventions on the main stem of the left coronary artery are feasible, but a relatively lower primary success rate and a higher complication rate and significantly increased mortality have to be expected. We report on a patient who underwent HTx 9 years ago and developed severe transplant vasculopathy revealing significant main stem stenosis, making reintervention necessary. Due to age, coronary artery morphology and comorbidity the patient was not considered for coronary artery bypass grafting or repeat HTx. We performed successful IVUS-guided directional coronary atherectomy and stent implantation on a distal stenosis of the unprotected main stem. Our case demonstrates a predictable procedural risk and favourable primary result of left main stem angioplasty procedures, thus providing a therapeutic option for patients who are poor candidates for operative revascularisation strategies.
Aged↗
The role of vitamin E in atherogenesis: linking the chemical, biological and clinical aspects of the disease.
Atherosclerosis is a disease involving both oxidative modifications and disbalance of the immune system. Vitamin E, an endogenous redox-active component of circulating lipoproteins and (sub)cellular membranes whose levels can be manipulated by supplementation, has been shown to play a role in the initiation and progression of the disease. Recent data reveal that the activities of vitamin E go beyond its redox function. Moreover, it has been shown that vitamin E can exacerbate certain processes associated with atherogenesis. In this essay we review the role of biology of atherosclerosis, and suggest that these two facets decide the clinical manifestation and outcome of the disease.
Animals↗
Transient increase of monocyte adhesion after a single dose of simvastatin.
Beneficial effects of HMG-CoA reductase inhibitors, such as simvastatin have been attributed to lipid lowering and cholesterol-independent mechanisms, for example a reduction of monocyte adhesion to endothelium. However, little is known about acute effects of statin intake. In an attempt to test for short-term effects of drug intake, we found that the adhesion of blood monocytes isolated from healthy volunteers or mildly hypercholesterolemic patients was increased after intake of simvastatin but not placebo at 0.5 h and declined to baseline levels at 3 h. Blood cholesterol levels were unaltered and the observed effects did not correlate with systemic concentrations of the pro-drug nor the active drug concentration in the peripheral circulation. In conclusion, the transient increase in adhesiveness of monocytes may be due to direct and/or enterohepatic metabolites of simvastatin, demonstrating the necessity of drug metabolism for exerting the beneficial effects of long-term treatment.
Cell Adhesion↗
Central retinal artery occlusion in association with an aneurysm of the internal carotid artery.
PURPOSE: To report an unusual case of central retinal artery occlusion in a 41-year-old woman. DESIGN: Interventional case report. METHODS: A 41-year-old woman presented with sudden and painless decrease of visual acuity of the left eye. Indirect ophthalmoscopy revealed the typical fundus findings of a central retinal artery occlusion. The fovea was spared by a cilioretinal arteriole. RESULTS: Cerebral angiography showed an aneurysm of the left internal carotid artery, measuring approximately 1.7 x 1.5 x 1.7 cm. The aneurysm was located in close proximity to the ophthalmic branch. CONCLUSION: Aneurysm of the intracranial arteries should be included in the differential diagnosis of central retinal artery occlusion in young patients.
Adult↗
Low prevalence of hepatitis C virus antibody among Swiss dental health care workers.
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Dental Auxiliaries↗
Lipophilic antioxidants and polyunsaturated fatty acids in lipoprotein classes: distribution and interaction.
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.
Adult↗