Kainate Receptor Activation Enhances Amyloidogenic Processing of APP in Astrocytes.

Kainic acid (KA) is an analogue of the excitatory neurotransmitter glutamate that, when injected systemically into adult rats, can trigger seizures and progressive neuronal loss in a manner that mirrors the neuropathology of human mesial temporal lobe epilepsy. However, biomolecular mechanisms responsible for the neuronal loss that occurs as a consequence of this treatment remains elusive. We have recently reported that toxicity induced by KA can partly be mediated by astrocyte-derived amyloid ß (Aß) peptides, which are critical in the development of Alzheimer's disease (AD). Nonetheless, little is known how KA can influence amyloid precursor protein (APP) levels and processing in astrocytes. Thus, in the present study using human U-373 astrocytoma and rat primary astrocytes, we evaluated the role of KA on APP metabolism. Our results revealed that KA treatment increased the levels of APP and its cleaved products (α-/ß-CTFs) in cultured U-373 astrocytoma and primary astrocytes, without altering the cell viability. The cellular and secretory levels of Aß1-40/Aß1-42 were markedly increased in KA-treated astrocytes. We also demonstrated that the steady-state levels of APP-secretases were not altered but the activity of γ-secretase is enhanced in KA-treated U-373 astrocytoma. Furthermore, using selective receptor antagonists, we showed that the effects of KA is mediated by activation of kainate receptors and not NMDA or AMPA receptors. These results suggest that KA can enhance amyloidogenic processing of APP by activating its own receptor leading to increased production/secretion of Aß-related peptides from activated astrocytes which may contribute to the pathogenesis of temporal lobe epilepsy.

Accumulation of small hyaluronan oligosaccharides in tumour interstitial fluid correlates with lymphatic invasion and lymph node metastasis.

BACKGROUND: Association studies have implicated the glycosaminoglycan hyaluronan (hyaluronic acid, HA) and its degrading enzymes the hyaluronidases in tumour progression and metastasis. Oligosaccharides of degraded HA have been ascribed a number of biological functions that are not exerted by high-molecular-weight HA (HMW-HA). However, whether these small HA oligosaccharides (sHA) have a role in tumour progression currently remains uncertain due to an inability to analyse their concentration in tumours. METHODS: We report a novel method to determine the concentration of sHA ranging from 6 to 25 disaccharides in tumour interstitial fluid (TIF). Levels of sHA were measured in TIF from experimental rat tumours and human colorectal tumours. RESULTS: While the majority of HA in TIF is HMW-HA, concentrations of sHA up to 6 µg ml(-1) were detected in a subset of tumours, but not in interstitial fluid from healthy tissues. In a cohort of 72 colorectal cancer patients we found that increased sHA concentrations in TIF are associated with lymphatic vessel invasion by tumour cells and the formation of lymph node metastasis. CONCLUSIONS: These data document for the first time the pathophysiological concentration of sHA in tumours, and provide evidence of a role for sHA in tumour progression.

Heavy smoking and lung cancer: are women at higher risk? Result of the ICARE study.

BACKGROUND: Whether women are more or equally susceptible to the carcinogenic effects of cigarette smoke on the lungs compared with men is a matter of controversy. Using a large French population-based case-control study, we compared the lung cancer risk associated with cigarette smoking by gender. METHODS: The study included 2276 male and 650 female cases and 2780 male and 775 female controls. Lifetime smoking exposure was represented by the comprehensive smoking index (CSI), which combines the duration, intensity and time since cessation of smoking habits. The analysis was conducted among the ever smokers. All of the models were adjusted for age, department (a regional administrative unit), education and occupational exposures. RESULTS: Overall, we found that the lung cancer risk was similar among men and women. However, we found that women had a two-fold greater risk associated with a one-unit increase in CSI than men of developing either small cell carcinoma (OR=15.9, 95% confidence interval (95% CI) 7.6, 33.3 and 6.6, 95% CI 5.1, 8.5, respectively; P<0.05) or squamous cell carcinoma (OR=13.1, 95% CI 6.3, 27.3 and 6.1, 95% CI 5.0, 7.3, respectively; P<0.05). The association was similar between men and women for adenocarcinoma. CONCLUSION: Our findings suggest that heavy smoking might confer to women a higher risk of lung cancer as compared with men.

Flow cytometry-based isolation of dermal lymphatic endothelial cells from newborn rats.

The lymphatic system plays a key role in tissue homeostasis, fatty acid transport, and immune surveillance. Pathologically, dysfunction of the lymphatic system results in edema, and increased lymphangiogenesis can contribute to tumor metastasis. Lymphatic vessels are composed of lymphatic endothelial cells (LECs) that can be identified by distinct marker molecules such as Prox-1, podoplanin, VEGFR-3 and LYVE-1. Primary LECs represent a valuable tool for the study of basic functions of the lymphatic system. However, their isolation remains a challenge, particularly if rodent tissues are used as a source. We developed a method for the isolation of rat dermal LECs from the skin of newborn rats based on sequential enzymatic digestion with trypsin and Liberase followed by flow cytometric sorting using LYVE-1 specific antibodies. Cells isolated according to this protocol expressed the lymphatic markers Prox-1, podoplanin, LYVE-1 and VEGFR-3, and displayed an endothelial-like morphology when taken into culture. These primary cells can be used for studying lymphatic biology in rat models, and the protocol we describe here therefore represents an important extension of the experimental repertoire available for rats and for modeling the human lymphatic system.

Opposing effects of high- and low-molecular weight hyaluronan on CXCL12-induced CXCR4 signaling depend on CD44.

The tumor microenvironment makes a decisive contribution to the development and dissemination of cancer, for example, through extracellular matrix components such as hyaluronan (HA), and through chemokines that regulate tumor cell behavior and angiogenesis. Here we report a molecular link between HA, its receptor CD44 and the chemokine CXCL12 in the regulation of cell motility and angiogenesis. High-molecular-weight HA (hHA) was found to augment CXCL12-induced CXCR4 signaling in both HepG2iso cells and primary human umbilical vein endothelial cells, as evidenced by enhanced ERK phosphorylation and increased cell motility. The augmentation of CXCR4 signaling translated into increased vessel sprouting and angiogenesis in a variety of assays. Small HA oligosaccharides (sHA) efficiently inhibited these effects. Both siRNA-mediated reduction of CD44 expression and antibodies that block the interaction of CD44 with HA provided evidence that CXCL12-induced CXCR4 signaling depends on the binding of hHA to CD44. Consistently, CD44 and CXCR4 were found to physically interact in the presence of CXCL12, an interaction that could be inhibited by sHA. These findings provide novel insights into how microenvironmental components interact with cell surface receptors in multi-component complexes to regulate key aspects of tumor growth and progression.

Evaluation of the quality of coding of job episodes collected by self questionnaires among French retired men for use in a job-exposure matrix.

BACKGROUND: and AIMS: The ESPACES study was intended to identify retirees who may have been, according to their job descriptions, exposed to asbestos during their working lives. As part of this study, we analysed the quality of the occupation and activity sector coding as well as its effect on the subjects' exposure status. METHODS: The occupation and activity sector for a sample of 450 retired men were coded twice (with the second coder blinded to the first result), according to the international codes for industries (ISIC-1975) and occupations (ISCO-1968). For each series, linking the information about a job episode (dates, ISIC code, ISCO code) with the matrix allowed attribution of a probability of asbestos exposure to each episode and each subject. The asbestos exposure in the two series was compared by the kappa reproducibility coefficient. RESULTS: The analysis concerned 425 questionnaires. There was at least one difference in the code for either activity sector (ISIC) or occupation (ISCO) in half the episodes (50.2%). The exposure status estimated by the job-exposure matrix did not change between the series for 84.7% of the subjects. The kappa coefficient was 0.64 for all questionnaires, 0.70 when the questionnaire was coded twice by the same coder, and 0.62 when coded by two different coders. CONCLUSIONS: Despite intra- and inter-differences between coders, the coding of job episodes for the ESPACES study appears satisfactory and hence indicates that the assessment of the subjects' asbestos exposure was assessed without major distortions. This study underlines the usefulness of employing coders specifically trained for this technique.

Socioeconomic position, health, and possible explanations: a tale of two cohorts.

OBJECTIVES: We examined whether the social gradient for measures of morbidity is comparable in English and French public employees and investigated risk factors that may explain this gradient. METHODS: This longitudinal study of 2 occupational cohorts-5825 London civil servants and 6818 French office-based employees-used 2 health outcomes: long spells of sickness absence during a 4-year follow-up and self-reported health. RESULTS: Strong social gradients in health were observed in both cohorts. Health behaviors showed different relations with socioeconomic position in the 2 samples. Psychosocial work characteristics showed strong gradients in both cohorts. Cohort-specific significant risk factors explained between 12% and 56% of the gradient in sickness absence and self-reported health. CONCLUSIONS: Our cross-cultural comparison suggests that some common susceptibility may underlie the social gradient in health and disease, which explains why inequalities occur in cultures with different patterns of morbidity and mortality.

Socioeconomic, demographic, occupational, and health factors associated with participation in a long-term epidemiologic survey: a prospective study of the French GAZEL cohort and its target population.

The purpose of this paper is to examine personal and health factors, both at the beginning of the study and thereafter, associated with participation in the GAZEL cohort, set up in 1989 in a large French company. The authors used logistic regression to analyze the associations between participation and data available for both participants (n = 20,093) and nonparticipants (n = 24,829). Higher participation was associated with male sex, marriage, children, managerial status, and residence in particular regions. Among men, lower participation was associated with sick leave in the year before recruitment and afterwards. During follow-up, participation was negatively associated with several groups of diseases, especially those associated with alcohol consumption. The risk of upper respiratory and digestive tract and lung cancer during follow-up was higher among nonparticipants. The same phenomenon occurred among women, but less markedly, for cancers of the breast and genital organs. During follow-up, mortality among men was higher among nonparticipants, especially for alcohol-related diseases. The association among women was less strong. Among men, but not among women, diseases caused by alcohol, smoking, or dangerous behavior were the primary reason for the health differences observed between participants and nonparticipants. Overall, the most important determinants of participation were cultural factors and lifestyle behaviors.

Longitudinal study of associations between perceived health status and self reported diseases in the French Gazel cohort.

STUDY OBJECTIVE: Although perceived health status is an indicator widely used in epidemiological studies, its relation to various diseases is not well known. The objective of this study is to examine these relations in detail. DESIGN: Marginal models used for a longitudinal study of the association between three health scales and 47 diseases among 12 164 men and 44 diseases among 4415 women. SETTING: French Gazel cohort during the period from 1991 to 1996. MAIN RESULTS: The general health status scale was significantly associated with 43 diseases among men, and 31 among women. Some of these significantly associated diseases were physical (for example, cancer and cerebrovascular accident) and others, psychological (for example, depression). The mental fatigue scale was more specifically associated with psychological disorders, including sleep problems, depression, and nervous diseases. Moreover, modifications in subjects' assessment of their health from one year to the next were generally associated with modifications in reported diseases. CONCLUSION: Although the mechanism that relates the presence of a disease to perceived health status remains in question, these results show clearly that there is a close association between these two domains that justifies the use of perceived health as a proxy for self reported diseases.

Shoulder disorders related to work organization and other occupational factors among supermarket cashiers.

The study was designed to examine, in 210 supermarket cashiers, the cross-sectional relationships between shoulder disorders according to location and chronicity of pain as well as personal and occupational factors and store and workstation characteristics. The factors associated with shoulder disorders differed for the right and left sides. Age and psychological disorders were significant risk factors. Among occupational factors, duration of employment, job control, wage dependence on efficiency, exposure to cold, movements and postures such as stooping, working with arms above shoulder level and holding heavy loads in position, and using a laser scanner were associated with shoulder disorders, especially on the left. These results confirm the multifactorial origin of shoulder disorders, and show the importance of psychosocial work factors, movements and postures, and the laser scanner as occupational risk factors, and the need to consider right and left shoulder disorders in cashiers separately.