Search

Aims: Cell matrix modulating protein SPARCL-1 is highly expressed by astrocytes during CNS development and following acute CNS damage. Applying NanoLC-MS/MS to CSF of RRMS and SPMS patients, we identified SPARCL-1 as differentially expressed between these two stages of MS, suggesting a potential as CSF biomarker to differentiate RRMS from SPMS and a role in MS pathogenesis. Methods: This study examines the potential of SPARCL-1 as CSF biomarker discriminating RRMS from SPMS in three independent cohorts (n = 249), analyses its expression pattern in MS lesions (n = 26), and studies its regulation in cultured human brain microvasculature endothelial cells (BEC) after exposure to MS-relevant inflammatory mediators. Results: SPARCL-1 expression in CSF was significantly higher in SPMS compared to RRMS in a Dutch cohort of 76 patients. This finding was not replicated in 2 additional cohorts of MS patients from Sweden (n = 81) and Switzerland (n = 92). In chronic MS lesions, but not active lesions or NAWM, a vessel expression pattern of SPARCL-1 was observed in addition to the expression by astrocytes. EC were found to express SPARCL-1 in chronic MS lesions, and SPARCL-1 expression was regulated by MS-relevant inflammatory mediators in cultured human BEC. Conclusions: Conflicting results of SPARCL-10s differential expression in CSF of three independent cohorts of RRMS and SPMS patients precludes its use as biomarker for disease progression. The expression of SPARCL-1 by BEC in chronic MS lesions together with its regulation by inflammatory mediators in vitro suggest a role for SPARCL-1 in MS neuropathology, possibly at the brain vascular level. [ABSTRACT FROM AUTHOR]

Objective: To find out the frequency and predictors of osteoporotic fractures in late kidney graft patients. Methodology: Changes in spinal, hip, and total body bone mineral density were assessed using a DEXA Hologic QRD 1000 scanner and fractures were quantified in all kidney graft patients presenting for routine evaluation with a minimal follow-up of 5 years after transplantation (mean follow-up, 8.5 years). Biochemical markers of bone metabolism and clinical and dietary intake data were collected. Results: Fifty-none renal graft recipients were enrolled. Osteoporosis, according to the World Health Organization definition, was observed in 31 patients (53% of the total population) and fractures occurred in 26 patients (44% of the total population and 51.6% of patients with osteoporosis). Femoral neck bone mineral density was positively correlated with patient weight and cyclosporine current dosage. Steroid cumulative dosage correlated only to lumbar spine Z score. Dietary calcium, serum 25 hydroxyvitamin D, parathyroid hormone, and urinary N-telopeptides excretion were normal. Conclusion: There is a substantial prevalence of osteoporosis and fractures among very long-term kidney graft recipients. [ABSTRACT FROM AUTHOR]

Integrative medicine proposes a coordinated approach to conventional medicine and complementary treatments. This approach is of particular interest in the field of prevention and in comprehensive primary care. This article presents some key studies published in 2020, which highlight the potential benefits of an integrative approach in primary care medicine., Competing Interests: Les auteurs n’ont déclaré aucun conflit d’intérêts en relation avec cet article.

Traditionally, the doctor has focused his efforts on mastering medical knowledge. Given the challenges facing him, the medical institutions and the society, it becomes clear that his concern must also be about how this medical knowledge hits the patients and the general population. Knowing how to deliver our care is now as important as having the medical knowledge ! In this article, we present new models of healthcare delivery that we implemented or plan to implement in Geneva, Switzerland., Competing Interests: Les auteurs n’ont déclaré aucun conflit d’intérêts en relation avec cet article.

Background: Pyroglutamylation of truncated Aβ peptides, which is catalysed by enzyme glutaminyl cyclase (QC), generates pE-Aβ species with enhanced aggregation propensities and resistance to most amino-peptidases and endo-peptidases. pE-Aβ species have been identified as major constituents of Aβ plaques and reduction of pE-Aβ species is associated with improvement of cognitive tasks in animal models of Alzheimer's disease (AD). Pharmacological inhibition of QC has thus emerged as a promising therapeutic approach for AD. Here, we question whether cerebrospinal fluid (CSF) QC enzymatic activity differs between AD patients and controls and whether inflammatory or angiogenesis mediators, some of which are potential QC substrates, and/or Aβ peptides may serve as pharmacodynamic read-outs for QC inhibition., Methods: QC activity, Aβ peptides and inflammatory or angiogenesis mediators were measured in CSF of a clinically well-characterized cohort of 20 mild AD patients, 20 moderate AD patients and 20 subjective memory complaints (SMC) controls. Correlation of these parameters with core diagnostic CSF AD biomarkers (Aβ42, tau and p-tau) and clinical features was evaluated., Results: QC activity shows a tendency to decrease with AD progression (p = 0.129). The addition of QC activity to biomarkers tau and p-tau significantly increases diagnostic power (ROC-AUC TAU  = 0.878, ROC-AUC TAU & QC  = 0.939 and ROC-AUC pTAU  = 0.820, ROC-AUC pTAU & QC  = 0.948). In AD and controls, QC activity correlates with Aβ38 (r = 0.83, p < 0.0001) and Aβ40 (r = 0.84, p < 0.0001), angiogenesis mediators (Flt1, Tie2, VEGFD, VCAM-1 and ICAM-1, r > 0.5, p < 0.0001) and core diagnostic biomarkers (r > 0.35, p = <0.0057). QC activity does not correlate with MMSE or ApoE genotype., Conclusions: Aβ38, Aβ40 and angiogenesis mediators (Flt1, Tie2, VEGFD, VCAM-1 and ICAM-1) are potential pharmacodynamic markers of QC inhibition, because their levels closely correlate with QC activity in AD patients. The addition of QC activity to core diagnostic CSF biomarkers may be of specific interest in clinical cases with discordant imaging and biochemical biomarker results.

The development of Migrant Friendly Hospitals is an important first step towards eliminating health care disparities in Switzerland and an important reminder to health policy makers and practitioners across the health care system of their responsibility to provide non-discriminatory quality health care to all patients.

Following our studies of the melatoninergic receptors, we have developed new tetrahydronaphthalenic derivatives of melatonin that have been tested as selective melatonin receptors ligands. Regarding the role of the phenyl substituent to obtain selective ligands, modulation of selectivity and activity have been achieved by modifications of the acyl group and substitutions on the phenyl ring. Ten of the seventeen evaluated derivatives have MT(2) receptor affinity similar to that of melatonin. Moreover, we have achieved remarkable MT(2) selectivity over MT(1) (selectivity >100) and have been able to further extend the RSA of the tetrahydrophthalenic series. However, the compounds presented here display partial agonist or antagonist behavior instead of full agonist.

A series of naphthalenic analogues of melatonin were prepared and evaluated as melatonin receptor MT(2) selective ligands. Activity and MT(2) selectivity can be modulated with suitable variations of the C-3 phenyl and the acyl group on the C-1 side chain. Surprisingly, in contrast with what had been previously described in other series (2-benzylindoles, 2-benzylbenzofurans and 3-phenyltetralins), the presence of a C-3 phenyl with a functional group on the meta position seems to be primordial for MT(2) affinity and selectivity. Indeed, N-[2-(3-(3-hydroxymethylphenyl)-7-methoxynaphth-1-yl)ethyl]acetamide (21) is one of the best MT(2) selective ligands described until now and behaves as an antagonist.

The human CDC2L5 gene encodes a protein of unknown physiological function. This protein is closely related to the cyclin-dependent kinase (Cdks) family and contains an arginine/serine-rich (RS) domain. The Cdks were first identified as crucial regulators of cell-cycle progression, more recently they were found to be involved in transcription and mRNA processing. RS domains are mainly present in proteins regulating pre-mRNA splicing, suggesting CDC2L5 having a possible role in this process. In this study, we demonstrate that CDC2L5 is located in the nucleoplasm, at a higher concentration in speckles, the storage sites for splicing factors. Furthermore, this localization is dependent on the presence of the N-terminal sequence including the RS domain. Then, we report that CDC2L5 directly interacts with the ASF/SF2-associated protein p32, a protein involved in splicing regulation. Overexpression of CDC2L5 constructs disturbs constitutive splicing and switches alternative splice site selection in vivo. These results argue in favor of a functional role of the CDC2L5 kinase in splicing regulation., (2006 Wiley-Liss, Inc.)

Objective: The economic impact of rheumatoid arthritis (RA) is substantial, but most studies provide cost estimates specific to a US population. We performed a cost-of-illness analysis of patients with RA for French society., Methods: A cross-sectional study among rheumatologists in 148 hospitals in France was conducted between November and December 2000. Data were collected on health resource consumption associated with RA (treatments, medical devices, physician visits, examinations, hospitalization, other health professional care) during the previous 12 months. Direct costs and social costs were evaluated for 1109 RA patients. The relation of costs to disease activity and severity was analyzed., Results: The annual direct cost of RA per patient was over euro4000. The costs due to hospitalizations represented around 60% of the costs. The major reason for hospitalization was acute care for RA in a rheumatic disease ward. Patients visited a physician an average of 13 times during the 12 months, 7.7 +/- 8.6 visits to an office-based physician and 5.1 +/- 4.4 visits to a hospital-based physician. Among them, 37% of patients were receiving at least one disability pension (16.7%) or sick-leave allowance (11.9%), with an estimated cost of euro7328 per patient. The mean annual budget per patient was euro2742. Medical and social costs increased in patients with severe disease (2 times), longer disease duration since diagnosis (more than double for patients with a history longer than 10 yrs vs patients with less than 2 yrs), active disease (1.4 times), and functional status (4 times more for American College of Rheumatology class IV than for class I)., Conclusion: Direct costs represented 59% of the total costs for patients with active RA and 57% for patients with severe RA. Social costs represented 41% of the total costs on average.

Background: Renal transplantation triggers an early bone loss that increases the subsequent risk of osteoporosis and fractures. Little is known about the long-term outcome of bone status and fracture prevalence several years after transplantation. Therefore, we conducted a cross-sectional evaluation of bone status to find out the frequency and predictors of osteoporotic fractures in late kidney graft patients., Methods: Changes in spinal, hip, and total body bone mineral density were assessed using a DEXA Hologic QRD 1000 scanner, and fractures were quantified in all kidney graft patients presenting for routine evaluation with a minimal follow-up of 5 years after transplantation (with a mean follow-up 8.5+/-3.1 years). We measured biochemical markers of bone metabolism and collected clinical and dietary intake data., Results: Fifty-nine renal graft recipients were enrolled in the study within 9 months. Osteoporosis, according to the World Health Organization definition, was observed in 31 patients (53% of the total population) and fractures occurred in 26 patients (44% of the total population and 51.6% of patients with osteoporosis). Femoral neck bone mineral density was positively correlated with patient's weight and cyclosporin current dosage. Steroid cumulative dosage correlated only to lumbar spine Z score. Dietary calcium, serum 25 hydroxyvitamin D, parathyroid hormone, and urinary N-telopeptides excretion were normal., Conclusions: These data emphasize the substantial prevalence of osteoporosis and fractures among very long-term kidney graft recipients. Therapeutic intervention in these patients is urgently needed.

Objective: To determine how the use of trained and ad hoc interpreters during a medical screening interview affects referral to medical and psychiatric care., Methods: We reviewed 319 structured interviews conducted by nurses with asylum-seekers from Kosovo during a systematic medical screening at time of entry, consisting of questions about health conditions, past exposure to traumatic events, and posttraumatic symptoms., Results: The majority (72%) of asylum-seekers were male and the median age was 24 years. Forty-eight per cent were single and 55% declared having relatives already living in Switzerland. Screening interviews resulted in 36% of asylum-seekers being referred to a general practitioner and 6% to a psychiatrist. Relatives served as ad hoc interpreters in 18% of interviews and trained interpreters in 16%. The detection of traumatic events and psychological symptoms significantly improved when trained interpreters were present (traumatic events: no interpreters 55%, ad hoc interpreters 46%, trained interpreters 77%, P = 003; psychological symptoms: 12%, 14%, 33%, respectively, P = 0.001). Adjusted for traumatic events and posttraumatic symptoms, referral to medical care was more frequent when relatives served as ad hoc interpreter (OR: 1.9, 95% CI 1.0-3.6), while interviews conducted with trained interpreters were not significantly associated with increased referral to medical (OR: 1.3, 95% CI 0.6-2.6) and psychiatric care (OR: 2.3, 95% CI 0.7-7.0)., Conclusion: The use of trained interpreters improved the quality of communication, the detection of severe symptoms and traumatic situations, and facilitated therapeutic orientation of traumatized asylum-seekers.

Background: Although the existence of a motor defect in discogenic sciatica is a sign of severity, the literature does not provide evidence for an immediate requirement for surgery., Objective: To assess the course of sciatica with discogenic paresis and to determine possible prognostic factors for recovery or improvement., Study Design: This open prospective multicenter study included patients with discogenic sciatica with paresis that had been developing for less than 1 month and was rated < or =3 on a 5-grade scale. Pain, the strength of 11 muscles, return to work, and analgesic intake were assessed at 1, 3, and 6 months. Recovery and improvement were defined by pain not exceeding 20 mm or < or =50% of the initial pain score and a score of either 5 (recovery) or 4 (improvement) for the weakest muscle at inclusion., Results: Sixty-seven patients were enrolled; 39 (58%) patients were treated surgically and 28 (42%) medically. Surgically treated patients differed from medically treated patients by a higher rate of extruded herniation, a higher number of paretic muscles (6.3 vs. 5; P = 0.051), and a longer course of sciatica (31.4 vs. 17.3 days; P = 0.034). At 6 months, 7 (10.4%) patients were lost to follow-up; 32 (53.3%) had improved, including 18 (30%) recovered, 33 (85%) back to work and having a professional activity, and 22 (39%) still taking analgesics. The only significant difference between recovered and not recovered patients was mean age at inclusion (43 vs. 51 years, P = 0.034). There were no significant differences between improved and not improved patients. Moreover, the outcome was not different in the two treatment groups: there were 17 (53%) improvements in surgically treated patients, including 8 (25%) recoveries, and 14 (56%) improvements in medically treated patients, including 8 (40%) recoveries., Conclusion: This pilot study showed no difference between surgical or medical management for recovery or improvement in patients with discogenic paresis. These results need confirmation by a randomized study.

Cyclophilin B (CyPB), a cyclosporin A (CsA) binding protein, interacts with two types of binding sites at the surface of T-lymphocytes. The type I sites correspond to functional receptors involved in endocytosis and the type II sites to sulfated glycosaminoglycans (GAGs). Mutational analysis of CyPB has revealed that W128, which is part of the CsA-binding pocket, is implicated in the binding to the functional type I receptors and that two amino acid clusters located in the N-terminus ensure the binding to GAGs. The peptidyl-prolyl isomerase activity of CyPB is not required for receptor binding. We have recently demonstrated that CyPB enhances adhesion of peripheral blood T-lymphocytes to fibronectin, a component of the extracellular matrix. We intended to identify additional amino acids involved in the binding of CyPB to its functional type I receptor and to determine regions responsible for the stimulation of peripheral blood T-lymphocyte adhesion. We determined that residues R76, G77, K132, D155, and D158 of the calcineurin (CN) interacting region were implicated in the recognition of type I receptor but not of GAGs. We also found that two different changes in the N-terminal extension that abated binding to GAGs prevented adhesion of peripheral blood T-lymphocytes to coated CyPB, whereas abbrogation of the PPIase activity had no effect. On the other hand, the adhesion of peripheral blood T-lymphocytes to coated fibronectin was not stimulated by CyPB mutants devoid of either type I receptor or GAGs binding activity or by mutants of the PPIase site. Altogether, the results demonstrate that different regions of CyPB are involved in peripheral blood T-lymphocyte activation and imply a novel important physiological function for peptidyl-prolyl isomerase activity.

Cyclophilins A and B (CyPA and CyPB) are cyclosporin A-binding proteins that are involved in inflammatory events. We have reported that CyPB interacts with two types of cell-surface-binding sites. The first site corresponds to a functional receptor and requires interaction with the central core of CyPB. This region is highly conserved in cyclophilins, suggesting that CyPA and CyPB might share biological activities mediated by interaction with this receptor. The second site is identified with glycosaminoglycans (GAGs), the binding region located in the N terminus of CyPB. The difference in the N-terminal extensions of CyPA and CyPB suggests that a unique interaction with GAGs might account for selective activity of CyPB. To explore this hypothesis, we analyzed the lymphocyte responses triggered by CyPA, CyPB, and CyPB(KKK-), a mutant unable to interact with GAGs. The three ligands seemed capable enough to elicit calcium signal and chemotaxis by binding to the same signaling receptor. In contrast, only CyPB enhanced firm adhesion of T cells to the extracellular matrix. This activity depended on the interactions with GAGs and signaling receptor. CyPB-mediated adhesion required CD147 presumably because it was a costimulatory molecule and was related to an activation of alpha4beta1 and alpha4beta7 integrins. Finally, we showed that CyPB was capable mainly to enhance T cell adhesion of the CD4+CD45RO+ subset. The present data indicate that CyPB rather than CyPA is a proinflammatory factor for T lymphocytes and highlight the crucial role of CyPB-GAG interaction in the chemokine-like activity of this protein.

We have recently reported that cyclophilin B (CyPB), a secreted cyclosporine-binding protein, could bind to T lymphocytes through interactions with two types of binding sites. The first ones, referred to as type I, involve interactions with the conserved domain of CyPB and promote the endocytosis of surface-bound ligand, while the second type of binding sites, termed type II, are represented by glycosaminoglycans (GAG). Here, we further investigated the interactions of CyPB with blood cell populations. In addition to lymphocytes, CyPB was found to interact mainly with platelets. The binding is specific, with a dissociation constant (kd) of 9 +/- 3 nmol/L and the number of sites estimated at 960 +/- 60 per cell. Platelet glycosaminoglycans are not required for the interactions, but the binding is dramatically reduced by active cyclosporine derivatives. We then analyzed the biologic effects of CyPB and found a significant increase in platelet adhesion to collagen. Concurrently, CyPB initiates a transmembranous influx of Ca(2+) and induces the phosphorylation of the P-20 light chains of myosin. Taken together, the present results demonstrate for the first time that extracellular CyPB specifically interacts with platelets through a functional receptor related to the lymphocyte type I binding sites and might act by regulating the activity of a receptor-operated membrane Ca(2+) channel.

Cyclophilin B (CyPB) is a cyclosporin A (CsA)-binding protein mainly located in intracellular vesicles and secreted in biological fluids. In previous works, we demonstrated that CyPB interacts with T lymphocytes and enhances in vitro cellular incorporation and activity of CsA. In addition to its immunosuppressive activity, CsA is able to promote regeneration of damaged peripheral nerves. However, the crossing of the drug from plasma to neural tissue is restricted by the relative impermeability of the blood-brain barrier. To know whether CyPB might also participate in the delivery of CsA into the brain, we have analyzed the interactions of CyPB with brain capillary endothelial cells. First, we demonstrated that CyPB binds to two types of binding sites present at the surface of capillary endothelial cells from various species of tissues. The first type of binding sites (K(D) = 300 nM; number of sites = 3 x 10(6)) is related to interactions with negatively charged compounds such as proteoglycans. The second type of binding sites, approximately 50,000 per cell, exhibits a higher affinity for CyPB (K(D) = 15 nM) and is involved in an endocytosis process, indicating it might correspond to a functional receptor. Finally, the use of an in vitro model of blood-brain barrier allowed us to demonstrate that CyPB is transcytosed by a receptor-mediated pathway (flux = 16.5 fmol/cm2/h). In these conditions, CyPB did not significantly modify the passage of CsA, indicating that it is unlikely to provide a pathway for CsA brain delivery.

Introduction: Among the gastrointestinal adverse effects of nonsteroidal anti-inflammatory drugs (NSAID) and corticoids are mentioned complications of colonic diverticular disease. However, very few studies have described their consequences in rheumatoid arthritis., Exegesis: We report on seven patients who were admitted in our department between 1984 and 1997. All patients received corticoids and another antirheumatic drug (gold salts, hydroxychloroquine, immunosuppressive drugs); treatment also included NSAID in four cases. Two patients had a necrotizing vasculitis accompanying rheumatoid arthritis. Intestinal accompanying diseases were the following: one diverticulitis, three colonic perforations with pelviperitonitis, one colovesical fistula, one pelvic abscess, and one diverticular hemorrhage. All patients underwent surgery with positive results., Conclusion: Combination of the four following symptoms: fever, abdominal pain, diarrhea, and hemorrhage, can uncover a complication of colónic diverticular disease occurring in the course of rheumatoid arthritis. It should be investigated, even if no history of diverculosis may be evidenced.

In the Swiss context, the newly developed MPH programme at the University of Geneva is experimental in educational matters. Indeed the programme is fully learner-centered and community-oriented. Throughout the curriculum students plan, implement and evaluate intervention programmes or/and research projects related to health problems of the communities they are in charge of. In this article, we describe the educational strategies and tools used in this MPH curriculum (professional profile, mind-mapping procedures, field-work either on research projects or on intervention programmes, group work and evaluation procedures). These strategies and tools might assist some educational experimentation in MPH programmes in search of public health relevance and pedagogic efficacy.