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Biomedical subjects

L Raymond

Publications and source records attributed to L Raymond.

At least 19 recordsLinked to original sources
PubMed2006

RelA is required for IL-1beta stimulation of Matrix Metalloproteinase-1 expression in chondrocytes.

OBJECTIVE: Interleukin-1beta (IL-1beta) stimulates collagenase-1 (Matrix Metalloproteinase-1 (MMP-1)) expression in articular chondrocytes, leading to cleavage of type II collagen and irreversible cartilage degradation. The nuclear factor-kappa B (NF-kappaB) pathway is potently activated in IL-1beta-stimulated cells and has been implicated as an intermediate in MMP-1 gene expression. However, the roles of individual NF-kappaB family members during IL-1beta-induced MMP-1 gene expression have not been defined. RESULTS: To address the relationship between the NF-kappaB pathway and MMP-1 gene activation in chondrocytes, primary cultured human articular chondrocyte cultures (HAC) and SW-1353 cells were stimulated with IL-1beta over a 24-h time course and MMP-1, NF-kappaB1, NF-kappaB2 and RelA gene expression was assayed. IL-1beta-induced MMP-1 expression was comparable in HAC and SW-1353 cells both temporally and quantitatively. MMP-1 gene expression was mirrored by increases in NF-kappaB gene expression, and inhibition of NF-kappaB nuclear translocation with dominant-negative IkappaBalpha reduced IL-1beta-dependent MMP-1 gene expression. IL-1beta activated the NF-kappaB pathway in chondrocytes, both through phosphorylation and transient degradation of IkappaBalpha, as well as through sustained phosphorylation of RelA. Small inhibitory RNAs (siRNA) specific for RelA resulted in significant reduction of MMP-1 mRNA, whereas siRNA for NF-kappaB1 and NF-kappaB2 augmented IL-1beta-induced MMP-1 expression. CONCLUSIONS: Our data demonstrate that IL-1beta activation of the NF-kappaB pathway is required for IL-1beta induction of MMP-1 in chondrocytes and that RelA can work independently of NF-kappaB1 or NF-kappaB2 to activate this gene expression program.

Aggrecans↗
PubMed2004

The impact of coding process on observed cancer mortality trends in Switzerland.

Official cancer mortality in Switzerland decreased by about 16% over the 9-year period 1990-1998 and this trend has often been used to suggest that secondary prevention by screening for breast cancer could be useless. However, the clear downshift observed between 1994 and 1995 for some cancers, such as female breast and prostate, and the simultaneous change in ICD classification used by the Federal Office for Statistics in 1995 (ICD-8 to ICD-10) could be related, suggesting an impact of coding process on the observed trend. For every death occurred between 1980 and 1999, the death certificates have been retrieved, the cause of death has been recoded and site-specific mortality rates have been calculated again for each year during this period. As suggested, the trend appears to be overestimated: in order to be comparable with current rates, the mortality observed before 1995 should be lowered by about 7% for men and 5% for women. The error may be partially due to attributing the cause of death to co-morbidity factors not normally (and nowadays) defined as the underlying cause. Logically, the impact of such a miscoding is more important among older people and for cancer sites with long survival. For instance, the correction should be around 15% for female breast, 12% for prostate and up to 40% for testicular cancer.

Age Factors↗
PubMed2001

Adjuvant chemotherapy for colon carcinoma with positive lymph nodes: use and benefit in routine health care practice.

In 1990, an international consensus was reached on the efficacy of adjuvant chemotherapy for lymph node positive (stage III) colon carcinoma (CC). This study evaluates the use and benefit of such therapy in routine health care practice. The study includes all patients with stage III CC treated by putative curative surgery (n = 182) recorded at the Geneva cancer registry between 1990 and 1996. Factors modifying chemotherapy use were determined by logistic regression, considering patients with chemotherapy as cases (n = 55) and others as controls (n = 127). The effect of chemotherapy on the 5-year survival was evaluated by the Cox model. Analyses were adjusted for possible confounders. The use of chemotherapy increased over the period (P(trend) < 0.001). Age strongly modulated chemotherapy use. In 1996, 54% of eligible patients received chemotherapy, this proportion fell to 13% after age 70. Decisions to use chemotherapy significantly depended on stage, grade and cancer site. The chance to be treated was non-significantly lower among individuals of low social class, widowed and foreigners. Chemotherapy significantly decreased mortality rates (Hazard ratio: 0.35, 95%CI: 0.18-0.68), independently of the prognostic factors and with similar benefit regardless of stage and age group. Strong beneficial effect of adjuvant chemotherapy on stage III CC can be achieved in routine practice. However, this study shows that it is probably not optimally utilised in Switzerland, particularly among the elderly.

Adult↗
PubMed2001

Dishevelled regulates the metabolism of amyloid precursor protein via protein kinase C/mitogen-activated protein kinase and c-Jun terminal kinase.

Alzheimer's disease (AD) is a disorder of two pathologies: amyloid plaques, the core of which is a peptide derived from the amyloid precursor protein (APP), and neurofibrillary tangles composed of highly phosphorylated tau. Protein kinase C (PKC) is known to increase non-amyloidogenic alpha-secretase cleavage of APP, producing secreted APP (sAPPalpha), and glycogen synthase kinase (GSK)-3beta is known to increase tau phosphorylation. Both PKC and GSK-3beta are components of the wnt signaling cascade. Here we demonstrate that overexpression of another member of this pathway, dishevelled (dvl-1), increases sAPPalpha production. The dishevelled action on APP is mediated via both c-jun terminal kinase (JNK) and protein kinase C (PKC)/mitogen-activated protein (MAP) kinase but not via p38 MAP kinase. These data position dvl-1 upstream of both PKC and JNK, thereby explaining the previously observed dual signaling action of dvl-1. Furthermore, we show that human dvl-1 and wnt-1 also reduce the phosphorylation of tau by GSK-3beta. Therefore, both APP metabolism and tau phosphorylation are potentially linked through wnt signaling.

Adaptor Proteins, Signal Transducing↗
PubMed2001

Sulfated glycans and elevated temperature stimulate PrP(Sc)-dependent cell-free formation of protease-resistant prion protein.

A conformational conversion of the normal, protease- sensitive prion protein (PrP-sen or PrP(C)) to a protease-resistant form (PrP-res or PrP(Sc)) is commonly thought to be required in transmissible spongiform encephalopathies (TSEs). Endogenous sulfated glycosaminoglycans are associated with PrP-res deposits in vivo, suggesting that they may facilitate PrP-res formation. On the other hand, certain exogenous sulfated glycans can profoundly inhibit PrP-res accumulation and serve as prophylactic anti-TSE compounds in vivo. To investigate the seemingly paradoxical effects of sulfated glycans on PrP-res formation, we have assayed their direct effects on PrP conversion under physiologically compatible cell-free conditions. Heparan sulfate and pentosan polysulfate stimulated PrP-res formation. Conversion was stimulated further by increased temperature. Both elevated temperature and pentosan polysulfate promoted interspecies PrP conversion. Circular dichroism spectropolarimetry measurements showed that pentosan polysulfate induced a conformational change in PrP-sen that may potentiate its PrP-res-induced conversion. These results show that certain sulfated glycosaminoglycans can directly affect the PrP conversion reaction. Therefore, depending upon the circumstances, sulfated glycans may be either cofactors or inhibitors of this apparently pathogenic process.

Animals↗
PubMed2000

Huntingtin interacting protein 1 induces apoptosis via a novel caspase-dependent death effector domain.

Huntington disease is a devastating neurodegenerative disease caused by the expansion of a polymorphic glutamine tract in huntingtin. The huntingtin interacting protein (HIP-1) was identified by its altered interaction with mutant huntingtin. However, the function of HIP-1 was not known. In this study, we identify HIP-1 as a proapoptotic protein. Overexpression of HIP-1 resulted in rapid caspase 3-dependent cell death. Bioinformatics analyses identified a novel domain in HIP-1 with homology to death effector domains (DEDs) present in proteins involved in apoptosis. Expression of the HIP-1 DED alone resulted in cell death indistinguishable from HIP-1, indicating that the DED is responsible for HIP-1 toxicity. Furthermore, substitution of a conserved hydrophobic phenylalanine residue within the HIP-1 DED at position 398 eliminated HIP-1 toxicity entirely. HIP-1 activity was found to be independent of the DED-containing caspase 8 but was significantly inhibited by the antiapoptotic protein Bcl-x(L), implicating the intrinsic pathway of apoptosis in HIP-1-induced cell death. Co-expression of a normal huntingtin fragment capable of binding HIP-1 significantly reduced cell death. Our data identify HIP-1 as a novel proapoptotic mediator and suggest that HIP-1 may be a molecular accomplice in the pathogenesis of Huntington disease.

Amino Acid Sequence↗
PubMed1999

Disturbance of Notch-1 and Wnt signalling proteins in neuroglial balloon cells and abnormal large neurons in focal cortical dysplasia in human cortex.

Determination of neuroglial cell fate and neural tube development during embryogenesis is influenced by the Notch/Wnt signalling pathway. We have studied the localisation of several proteins in the Wnt pathway in focal cortical dysplasia (FCD). This disorder, thought to be due to abnormalities of neuronal migration and differentiation, contains regions of morphologically normal neocortex interrupted by areas of neuronal laminar disorganisation, heterotopic white matter neurons, abnormal large neurons and balloon cells of uncertain histogenesis. We found that the subcellular distribution of several proteins involved in the Wnt pathway differed in regions of FCD from normal cortex, and that within the areas of FCD, the pattern varied with cellular phenotype. Thus, in balloon cells, elevated cytoplasmic levels of dishevelled (Dvl-1) protein were accompanied by an absence of Notch-1, increased adenomatous poliposis coli (APC), altered cytoplasmic beta-catenin, and reduced nuclear expression of beta-catenin. A contrasting pattern of expression was found in abnormal large neurons, which demonstrated elevated levels of Notch-1, and glycogen synthase kinase-3beta (GSK-3beta), and normal levels of APC. Our results are consistent with the notion that Wnt/Notch signalling influences neuroglial cell fate, and suggest that a perturbation of Wnt/Notch signalling may contribute to the neuropathology of FCD.

Adaptor Proteins, Signal Transducing↗
PubMed1999

Influence of stage at diagnosis on survival differences for rectal cancer in three European populations.

Important differences have recently been highlighted between European countries in the survival of colorectal cancer patients. As data on stage at diagnosis were available for rectal cancers in three European population-based registries (Geneva Switzerland; Côte d'Or, France; Mallorca, Spain), we compared relative survival while assessing the effect of stage in a multiple regression model. We analysed 1005 rectal cancer cases diagnosed between 1982 and 1987 and followed up for at least 5 years. In the Mallorca registry, 16% of the patients were diagnosed in the TNM stage I (versus 21% in the Côte d'Or registry and 29% in the Geneva registry, P < 10(-4)) and the 5-year relative survival rate was lower (35%) than in the other two registries (Côte d'Or 47%, Geneva 48%, P = 0.01). In the multivariate analysis, stage was the only independent prognostic factor, whereas the excess death risk did not vary significantly among registries (compared to Geneva, Côte d'Or relative risk was 1.0, Mallorca relative risk 1.11, 95% confidence interval 0.76-1.32 and 0.85-1.44 respectively). Survival differences between the registries were mainly due to stage at diagnosis. Thus, diagnostic conditions appear to be the main determinant of the survival inequalities found in those three European populations.

Adult↗
PubMed1999

Inflammatory aetiology of primary oesophageal achalasia: an immunohistochemical and ultrastructural study of Auerbach's plexus.

AIM: Achalasia is a disease of the oesophagus characterized by increased lower oesophageal sphincter (LOS) tone, absence of LOS relaxation with swallowing and aperistalsis of the body of the oesophagus. The aetiology and pathogenesis of idiopathic achalasia is still controversial. METHODS AND RESULTS: We examined 16 oesophageal biopsies and one low oesophagectomy specimen from patients with achalasia. The control group was composed of five autopsy cases with no history of oesophageal disorders, three cases of diffuse oesophageal spasm, one of gastro-oesophageal reflux disease and one patient with oesophageal carcinoma. Sections were immunostained for neurofilaments NF70 and NF200, S100 protein and neurone-specific enolase. Biopsies with inflammatory infiltrates, were in addition immunostained with antibodies against leucocyte common antigen as well as for CD20, CD43, CD68 and CD45RO. All biopsies were examined after plastic embedding, and electron microscopy (EM) was performed on samples containing autonomic plexus. An inflammatory infiltrate of varying intensity was present along the nerve fascicles and around ganglion cells in 90% of the cases of achalasia. T-lymphocytes predominated in all these cases. The autonomic nerves showed loss of fibres and degenerative changes which were discernible only by EM. Although there was no convincing neuronal loss or signs of active neuronal degeneration in biopsied cases, the oesophagectomy specimen revealed total absence of neurones and significant loss of nerve fibres. The control group showed normal plexuses and no inflammation. CONCLUSION: Degeneration and significant loss of nerve fibres associated with predominant T-cell lymphocytic inflammatory infiltrate around the myenteric plexus support the concept for the inflammatory, probably autoimmune, aetiology of autonomic nervous system injury in primary achalasia.

Adult↗
PubMed1998

Primary CD30-positive anaplastic large cell lymphoma of the lip.

We report a case of primary CD30-positive anaplastic large cell lymphoma of the lip. While extranodal involvement is not uncommon in Ki-1(CD30) anaplastic large cell lymphoma, this is the first reported case of primary lip involvement. The clinical features and clinical outcome in Ki-1 anaplastic large cell lymphoma are discussed.

Aged↗
PubMed1998

Comparability of colorectal cancer survival data in three European population-based registries.

During the first part of a study that aimed to compare the survival of persons with colorectal cancers, the comparability of data collected by the Geneva Cancer Registry, the Côte d'Or Cancer Registry and the Mallorca Cancer Registry was investigated, as well as the feasibility of obtaining a common reliable stage classification at diagnosis. The validity of incidence and follow-up data was high in the three registries but completeness appeared to be slightly lower in the Mallorca Cancer Registry than in the other two registries. Comparison of incidence curves, by age, showed that a discrepancy appeared over 75 years, which could correspond to an under-diagnosis or an under-registration of some cases among the elderly in the Côte d'Or and the Mallorca Cancer Registries. Stage classification was stratified by surgical treatment in order to improve the homogeneity of investigations undergone by the patients in each class. Stage distribution and stage-specific survival were consistent with those observed in other population-based series. This study shows that it would be better to restrict comparisons of the survival of persons with colorectal cancer to patients under 75 years, and that stage specific survival comparisons are possible with data routinely collected by registries.

Adult↗
PubMed1997

Texture analysis of cerebral white matter in SIV-infected macaque monkeys.

Image texture analysis is used in a wide variety of applications in medical research. Neurovirulent simian immunodeficiency virus (SIV) infection in monkeys is considered a good model for HIV-1 infection in humans and causes neuropathological changes in white matter which can include diffuse myelin pallor, subtle white matter astrocytosis, perivascular macrophage infiltrates, and microglial nodules with multinucleated giant cells. The ability of image texture analysis to quantify these changes was evaluated. Sections of thionin-stained brain tissue from eight male rhesus macaques ranging in age from 42-59 months were used. Four animals served as controls and four animals were infected with neurovirulent SIVmac239/17E-R71 by bone marrow inoculation. Images of cerebral white matter were captured and analyzed by calculating 13 textural features based on statistical analysis of spatial co-occurrence matrices. Statistical analysis of the results included multiple comparisons using the Newman-Keuls multiple range test. The effect of variation in background illumination used at image acquisition was also evaluated. Ten of the 13 textural features used in this study successfully discriminated between tissue from control and SIV-infected animals and were consistent with independent neuropathological assessment. Three textural features were highly sensitive to variation in background illumination and found not useful in this application.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Mechanisms of amiloride stimulation of Mg2+ uptake in immortalized mouse distal convoluted tubule cells.

The distal convoluted tubule reabsorbs approximately 10% of the filtered magnesium, which is approximately 70% of that delivered to it from the loop of Henle. The cellular mechanisms of magnesium transport in the distal convoluted tubule are not known. Amiloride has been reported to promote magnesium conservation. Studies were performed on immortalized mouse distal convoluted tubule (MDCT) cells to characterize distal magnesium transport and the effects ofamiloride. Intracellular free Mg2+ concentration ([Mg2+]i) was determined on single MDCT cells using microfluorescence with mag-fura 2. Basal [Mg2+]i was 0.53 +/- 0.01 mM, which is approximately 2% of the total cellular magnesium. To assess Mg2+ uptake, MDCT cells were first Mg2+ depleted (0.22 +/- 0.01 mM) by culturing in Mg2+-free media for 8-16 h and then placed in 5 mM MgCl2, and the [Mg2+]i was determined. [Mg2+]i returned to basal levels (0.50 +/- 0.04 mM) with refill rate, d([Mg2+]i)/dt, of 181 +/- 33 nM/s. Mg2+ entry rate was concentration dependent; a concentration of approximately 0.1 mM resulted in half-maximal uptake rates. Mg2+ uptake was inhibited by La3+ (36 +/- 17 nM/s), Mn2+ (56 +/- 25 nM/s), and nitrendipine (52 +/- 18 nM/s), but not Ca2+ (225 +/- 70 nM/s). Mg2+ uptake was influenced by the transmembrane voltage; hyperpolarization either with the addition of valinomycin or the substitution of bath NaCl with NaSCN stimulated Mg2+ influx (205 +/- 3 and 561 +/- 54 nM/s, respectively). Depolarization with external KCl diminished Mg2+ uptake (57 +/- 25 nM/s). These data provide evidence for novel Mg2+ entry pathways in MDCT cells that are specific for Mg2+ and activated by an increase in transmembrane voltage. Because amiloride leads to a hyperpolarization of the apical membrane, we postulated that amiloride may enhance Mg2+ transport by influencing the membrane voltage. Amiloride (50 microM) increased Mg2+ uptake (235 +/- 79 nM/s) in a concentration-dependent manner (half-maximal concentration of 35 microM amiloride). Accordingly, the distal diuretic, amiloride, inhibits Na+ transport, hyperpolarizes the apical membrane, and results in a stimulation of Mg2+ uptake in MDCT cells. These results provide the cellular basis for the clinical use of amiloride to bring about renal magnesium conservation.

Amiloride↗