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Using an original technique permitting repeated plasma exchange in the rat, we have tested this therapeutic approach in animals actively immunised with horseradish peroxidase, and in rats with HgCl-induced autoimmune glomerulonephritis. Plasma exchange effectively removes circulating JgG anti-horseradish peroxidase antibodies from the sera of immunised rats. When applied to the model of HgCl antiglomerular basement membrane glomerulonephritis in Brown-Norway rats, this technique is also remarkably effective. In these rats, proteinuria is abolished during the plasma exchange treatment period and no circulating antiglomerular basement membrane antibodies can be detected. These antibodies are, however, found in the ultrafiltrates of exchanged rats. Serum IgE, characteristically elevated in HgCl-treated rats, is also markedly diminished in exchanged rats. Control rats treated with infusions of fresh frozen plasma or with heparin alone did not show any improvement in disease severity. These results suggest that plasma exchange alone can attenuate antiglomerular basement membrane nephritis in HgCl-treated rats. This observation may be of relevance for the treatment of human antiglomerular-basement membrane-mediated glomerulonephritis. [ABSTRACT FROM PUBLISHER]

Introduction: The current medical shortage and increasing healthcare needs lead to the overcrowding of primary care services. In an effort to cope with this, task sharing models of care have been implemented between healthcare professionals. Varied terms are used to describe these models. In France, “cooperation protocol” pathways have been established between general practitioners and physiotherapists., Objective: The aim of this narrative review is to define the terms used to describe models of task sharing involving physiotherapists for musculoskeletal care and to describe these models and their impact in order to suggest evolution prospects of French experimentations., Results: Delegation, task shifting, substitution, supplementation and advanced practice terms were found in the literature. A clear distinction is suggested between substitution and supplementation. Advanced practice physiotherapy is internationally defined and recognized. Advanced practice physiotherapy models of care seem to improve care access and quality of care without increasing costs. In France, two cooperation protocols have been implemented between general practitioners and physiotherapists for musculoskeletal disorders. Regarding the obstacles to their deployment, these models could evolve considering the international and formally defined framework of advanced practice physiotherapy., Conclusions: Task sharing models of care involving physiotherapists could be promising strategies to improve access to care for patients with musculoskeletal disorders. Further studies are needed to better define the models, their objectives and to evaluate their impact in the French context.

The small ubiquitin-like modifier (SUMO) system regulates numerous biological processes, including protein localization, stability and/or activity, transcription, and DNA repair. SUMO also plays critical roles in innate immunity and antiviral defense by mediating interferon (IFN) synthesis and signaling, as well as the expression and function of IFN-stimulated gene products. Viruses including human immunodeficiency virus-1, Zika virus, herpesviruses, and coronaviruses have evolved to exploit the host SUMOylation system to counteract the antiviral activities of SUMO proteins and to modify their own proteins for viral persistence and pathogenesis. Understanding the exploitation of SUMO is necessary for the development of effective antiviral therapies. This review summarizes the interplay between viruses and the host SUMOylation system, with a special emphasis on viruses with neuro-invasive properties that have pathogenic consequences on the central nervous system.

The conjugation of small ubiquitin-like modifier (SUMO) proteins to substrates is a well-described post-translational modification that regulates protein activity, subcellular localization, and protein-protein interactions for a variety of downstream cellular activities. Several studies describe SUMOylation as an essential post-translational modification for successful viral infection across a broad range of viruses, including RNA and DNA viruses, both enveloped and un-enveloped. These viruses include but are not limited to herpes viruses, human immunodeficiency virus-1, and coronaviruses. In addition to the SUMOylation of viral proteins during infection, evidence shows that viruses manipulate the SUMO pathway for host protein SUMOylation. SUMOylation of host and viral proteins greatly impacts host innate immunity through viral manipulation of the host SUMOylation machinery to promote viral replication and pathogenesis. Other post-translational modifications like phosphorylation can also modulate SUMO function. For example, phosphorylation of COUP-TF interacting protein 2 (CTIP2) leads to its SUMOylation and subsequent proteasomal degradation. The SUMOylation of CTIP2 and subsequent degradation prevents CTIP2-mediated recruitment of a multi-enzymatic complex to the HIV-1 promoter that usually prevents the transcription of integrated viral DNA. Thus, the "SUMO switch" could have implications for CTIP2-mediated transcriptional repression of HIV-1 in latency and viral persistence. In this review, we describe the consequences of SUMO in innate immunity and then focus on the various ways that viral pathogens have evolved to hijack the conserved SUMO machinery. Increased understanding of the many roles of SUMOylation in viral infections can lead to novel insight into the regulation of viral pathogenesis with the potential to uncover new targets for antiviral therapies., (© 2021. Journal of NeuroVirology, Inc.)

Background: The strong geographic variations in the incidence rates of renal replacement therapy (RRT) for end-stage renal disease are not solely related to variations in the population's needs, such as the prevalence of diabetes or the deprivation level. Inequitable geographic access to health services has been involved in different countries but never in France, a country with a generous supply of health services and where the effect of the variability of medical practices was highlighted in an analysis conducted at the geographic scale of districts. Our ecological study, performed at the finer scale of townships in a French area of 8,370,616 inhabitants, investigated the association between RRT incidence rates, socioeconomic environment and geographic accessibility to healthcare while adjusting for morbidity level and medical practice patterns., Methods: Using data from the Renal Epidemiology and Information Network registry, we estimated age-adjusted RRT incidence rates during 2010-2014 for the 282 townships of the area. A hierarchical Bayesian Poisson model was used to examine the association between incidence rates and 18 contextual variables describing population health status, socioeconomic level and health services characteristics. Relative risks (RRs) and 95% credible intervals (95% CrIs) for each variable were estimated for a 1-SD increase in incidence rate., Results: During 2010-2014, 6,835 new patients ≥18 years old (4231 men, 2604 women) living in the study area started RRT; the RRT incidence rates by townships ranged from 21 to 499 per million inhabitants. In multivariate analysis, rates were related to the prevalence of diabetes [RR (95% CrI): 1.05 (1.04-1.11)], the median estimated glomerular filtration rate at dialysis initiation [1.14 (1.08-1.20)], and the proportion of incident patients ≥ 85 years old [1.08 (1.03-1.14)]. After adjusting for these factors, rates in townships increased with increasing French deprivation index [1.05 (1.01-1.08)] and decreased with increasing mean travel time to reach the closest nephrologist [0.92 (0.89-0.95])., Conclusion: These data confirm the influence of deprivation level, the prevalence of diabetes and medical practices on RRT incidence rates across a large French area. For the first time, an association was found with the distance to nephrology services. These data suggest possible inequitable geographic access to RRT within the French health system., Competing Interests: The authors have declared that no competing interests exist.

We have used a protein-based vaccine, a live virus vaccine, and an experimental adjuvant to evaluate the utility of an advanced kinetic modeling approach for stability prediction. The modeling approach uses a systematic and simple procedure for the selection of the most appropriate kinetic equation to describe the degradation rate of compounds subjected to accelerated conditions. One-step and two-step reactions with unlimited combinations of kinetic models were screened for the three products under evaluation. The most appropriate mathematical model for a given product was chosen based on the values of residual sum of squares and the weight parameter w. A relatively simple n-th order kinetic model best fitted the degradation of an adjuvanted protein vaccine with a prediction error lower than 10%. A more complex two-step model was required to describe inactivation of a live virus vaccine under normal and elevated storage temperatures. Finally, an autocatalytic-type kinetic model best fitted the degradation of an oil-in-water adjuvant formulation. The modeling approach described here could be used for vaccine stability prediction, expiry date estimation, and formulation selection. To the best of our knowledge, this is the first report describing a global kinetic analysis of degradation of vaccine components with high prediction accuracy., (© 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.)

Purpose: To describe the patterns of care of elderly cancer patients (ECPs) (>70 years old) and the factors affecting the referral by general practitioners (GPs) of patients to cancer specialists (SPs), in Alsace France., Methods: A postal mail questionnaire was sent to a total of 2818 physicians including primary care physicians and specialists. The factors possibly responsible for a poor referral rate of ECPs and the factors affecting treatment implementation by specialists were explored. We also searched for unmet needs such as the incorporation of geriatric assessment into routine practice and continuous medical education (CME) programs., Results: A total of 1217 questionnaires were returned (46.9%) from 1053 GPs and 214 SPs. Patients' age did not negatively impact referral to SPs as opposed to patients' performance status, wishes, and co-morbidities. Conversely, a significant decrease in patients' file presentation by SPs to tumor boards was observed for patients over 80 years old. Neither reimbursement nor SPs' waiting lists were an issue. The need for CME programs in geriatric oncology was emphasized by both GPs and SPs., Conclusions: Age was not the governing variable that impacted patient referral. The need for CME in geriatrics was highlighted for both GPs and SPs., (Copyright (c) 2009 Elsevier Ireland Ltd. All rights reserved.)

Background: Most comparisons of health data in Europe take place at the national level. However, there is increased interest in looking at health data at a sub-national level. This is because of the increased importance in many European countries, of regions and devolved powers to them. This study aimed to establish the availability of health data at a regional level and to construct an experimental database., Methods: Using a network of country correspondents, data were collected on a series of topics from all the regions of that country. In addition, a supplementary list of data was collected from one region of each country., Results: Out of the then 15 Member States of the European Union (EU), 14 countries participated in the study. Thirteen countries were able to supply data. Where data were available, using the criteria we developed, these were of relatively good quality. Data on mortality was most readily available, but data on the important public health topics such as obesity was much more difficult to obtain, and absent in many cases., Conclusions: It is possible to construct a database and a resultant set of indicators for relevant sub-national areas of Member States in the EU. This is not likely to be achieved through current routine data collection systems unless significant changes are made to the data collection processes such as those undertaken by Eurostat. There is, also, an urgent need to introduce comprehensive sub-national data collections on important public health topics such as obesity and smoking.

Objective: Our aim was to describe the living conditions of disabled elderly subjects aged 75 years and more living at home., Design: This study was conducted in 1996-97 in the Alsace region in France and included two parts. First, a sample survey was mailed to 15,600 subjects randomly selected from a pension funds list. This survey provided with a reliable representation of the study population in terms of disabilities using the Colvez classification. In the second part, the most disabled individuals were selected and, among them, 1,259 subjects were visited at home. Their disabilities and living conditions were noted using a predefined set of questions., Results: An estimated 71,000 subjects aged 75 years and more lived at home in the study region. The vast majority were free of significant disability. Help to wash and dress was needed by 6,000 until 1,500 were bedridden or confined to an armchair. Between 4,350 and 5,400 met the criteria for iso-resource grades (IRG) 1 to 3. Disability was associated with age, female gender, cognitive impairment and some social and professional characteristics. Family support was routine in almost every aspect of everyday life including personal hygiene. Professional support was mostly limited to technical interventions. Professional nursing care concerned only the most dependent persons. Nevertheless, needs for help in home and social activities remained high even in the least dependent individuals and were strongly age-dependent. Only 10% of individuals with IRG 1 to 3 complained of inadequate help. More than 80% of the elderly felt comfortable with their living conditions at home and were not thinking of moving from home to an institution for old people., Conclusion: The present study confirms the important commitment of family members and their close relationships toward their elderly.

Itraconazole is a fungistatic agent that, although highly lipophilic, shows poor transport through the blood brain barrier that may be due to efflux proteins. The combined administration of an efflux inhibitor with itraconazole should increase cerebral itraconazole concentrations and therefore, improve the treatment of Cryptococcus neoformans meningitis with this antifungal agent. To test this hypothesis, we have studied the influence of murine cerebral infection with C. neoformans and the inhibition of efflux by intraperitoneal injection of a P-glycoprotein inhibitor, GF120918 [N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)-ethyl]-phenyl)9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide], on the pharmacokinetics of itraconazole in plasma and brain after a single intraperitoneal itraconazole injection. We also investigated the influence of efflux inhibition on the efficacy of repeated doses of itraconazole in this murine model. The results showed that in healthy and infected mice pretreated or not with GF120918, plasma itraconazole values of area under the curve (AUC) were similar. In contrast, cerebral values of AUC were higher in infected mice compared with healthy mice. Moreover, the pretreatment of infected mice with GF120918 significantly increased cerebral itraconazole values of area under the curve and decreased weight loss in the treatment with itraconazole of a cerebral infection with C. neoformans.

An original model of experimental proliferative vitreoretinopathy consisting of an intravitreal injection of 10(7) human platelets and 1 IU of hyaluronidase was developed in pigmented rabbits. One group of 11 eyes served as non-treated controls. Two other groups of 11 eyes each received Ginkgo Biloba extracts which are known free radical scavengers (EGb761, Ipsen, France), given orally in two doses, 50 mg kg-1 day-1 and 100 mg kg-1 day-1 respectively, from the day after the platelet injection to the end of the first month. The fourth group (11 eyes) was intravenously injected with a unique dose of 15000 U kg-1 of superoxide dismutase the day after platelet injection. All animals were ophthalmoscopically examined in a masked fashion twice a week for 1 month and killed at the end of the experiment for histological analysis. Vitreoretinal proliferation was graded according to a six-stage classification. The non-treated eyes showed a high rate of retinal detachment (11/11 eyes), with a mean final score of 3.91 +/- 0.94. Histologic examinations consistently showed retinal retraction by fibrocellular preretinal membranes spreading to both surfaces of the retina as well as preretinal neovascularization. Many cells positively reacted with anti-cytokeratin or anti-vimentin monoclonal antibodies. All three groups of treated eyes showed significantly lower scores of vitreoretinal proliferation at almost each time point of examination. At the end of the study, five retinal detachments were found in the EGb761 group at 50 mg kg-1 day-1 (mean final score 2.45 +/- 1.37), only one in the group receiving 100 mg kg-1 day-1 (mean score 1.64 +/- 1.03), and one in the SOD treated eyes. The lowest mean score found at day 28 was observed in the group receiving SOD (1.36 +/- 1.43), although this group presented during the first 3 weeks with an intense vitreous and sometimes anterior chamber inflammation. Statistical comparison between treatments did not show significant differences at most time points of the study. These results demonstrate that antioxidants may efficiently prevent preretinal proliferation, in clinicopathological entities where free radicals had not yet been shown to play a direct pathogenetic role. They are also among the first attempts for inhibiting preretinal proliferations with non-cytotoxic agents and using a non-ocular route.