Changes in Astroglial Water Flow in the Pre-amyloid Phase of the STZ Model of AD Dementia.

Alzheimer's disease (AD) is an age-dependent neurodegenerative disease that is typically sporadic and has a high social and economic cost. We utilized the intracerebroventricular administration of streptozotocin (STZ), an established preclinical model for sporadic AD, to investigate hippocampal astroglial changes during the first 4 weeks post-STZ, a period during which amyloid deposition has yet to occur. Astroglial proteins aquaporin 4 (AQP-4) and connexin-43 (Cx-43) were evaluated, as well as claudins, which are tight junction (TJ) proteins in brain barriers, to try to identify changes in the glymphatic system and brain barrier during the pre-amyloid phase. Glial commitment, glucose hypometabolism and cognitive impairment were characterized during this phase. Astroglial involvement was confirmed by an increase in glial fibrillary acidic protein (GFAP); concurrent proteolysis was also observed, possibly mediated by calpain. Levels of AQP-4 and Cx-43 were elevated in the fourth week post-STZ, possibly accelerating the clearance of extracellular proteins, since these proteins actively participate in the glymphatic system. Moreover, although we did not see a functional disruption of the blood-brain barrier (BBB) at this time, claudin 5 (present in the TJ of the BBB) and claudin 2 (present in the TJ of the blood-cerebrospinal fluid barrier) were reduced. Taken together, data support a role for astrocytes in STZ brain damage, and suggest that astroglial dysfunction accompanies or precedes neuronal damage in AD.

Calorie restriction protects against acute systemic LPS-induced inflammation.

Caloric restriction (CR) has been proposed as a nutritional strategy to combat chronic diseases, including neurodegenerative diseases, as well as to delay aging. However, despite the benefits of CR, questions remain about its underlying mechanisms and cellular and molecular targets.Objective: As inflammatory processes are the basis or accompany chronic diseases and aging, we investigated the protective role of CR in the event of an acute inflammatory stimulus.Methods: Peripheral inflammatory and metabolic parameters were evaluated in Wistar rats following CR and/or acute lipopolysaccharide (LPS) administration, as well as glial changes (microglia and astrocytes), in two regions of the brain (hippocampus and hypothalamus) involved in the inflammatory response. We used a protocol of 30% CR, for 4 or 8 weeks. Serum and brain parameters were analyzed by biochemical or immunological assays.Results: Benefits of CR were observed during the inflammatory challenge, where the partial reduction of serum interleukin-6, mediated by CR, attenuated the systemic response. In the central nervous system (CNS), specifically in the hippocampus, CR attenuated the response to the LPS, as evaluated by tumor necrosis factor alpha (TNFα) levels. Furthermore, in the hippocampus, CR increased the glutathione (GSH) levels, resulting in a better antioxidant response.Discussion: This study contributes to the understanding of the effects of CR, particularly in the CNS, and expands knowledge about glial cells, emphasizing their importance in neuroprotection strategies.

Two Years' Experience of Intensive Home Hemodialysis with the Physidia S3 System: Results from the RECAP Study.

The RECAP study reports results and outcomes (clinical performances, patient acceptance, cardiac outcomes, and technical survival) achieved with the S3 system used as an intensive home hemodialysis (HHD) platform over a three-year French multicenter study. Ninety-four dialysis patients issued from ten dialysis centers and treated more than 6 months (mean follow-up: 24 months) with S3 were included. A two-hour treatment time was maintained in 2/3 of patients to deliver 25 L of dialysis fluid, while 1/3 required up to 3 h to achieve 30 L. The additional convection volume produced by means of the SeCoHD tool (internal filtration backfiltration) was 3 L/session, and the net ultrafiltration produced to achieve dry weight was 1.4 L/session. On a weekly basis, an average 156 L of dialysate corresponding to 94 L of urea clearance when considering 85% dialysate saturation under low flow conditions was delivered. Such urea clearance was equivalent to 9.2 [8.0-13.0] mL/min weekly urea clearance and a standardized Kt/V of 2.5 [1.1-4.5]. The predialysis concentration of selected uremic markers remained remarkably stable over time. Fluid volume status and blood pressure were adequately controlled by means of a relatively low ultrafiltration rate (7.9 mL/h/kg). Technical survival on S3 was 72% and 58% at 1 and 2 years, respectively. The S3 system was easily handled and kept by patients at home, as indicated by technical survival. Patient perception was improved, while treatment burden was reduced. Cardiac features (assessed in a subset of patients) tended to improve over time. Intensive hemodialysis relying on the S3 system offers a very appealing option for home treatment with quite satisfactory results, as shown in the RECAP study throughout a two-year follow-up time, and offers the best bridging solution to kidney transplantation.

Safety and Efficacy of Short Daily Hemodialysis with Physidia S3 System: Clinical Performance Assessment during the Training Period.

BACKGROUND: A growing body of scientific evidence indicates that clinical outcomes of hemodialysis patients can be improved with short daily dialysis treatment. Current in-center hemodialysis machines do not fulfill the requirements needed for self-care home hemodialysis (HHD) treatment. In line with the reviviscence of home therapy, several hemodialysis devices have been developed and deployed for treatment. Physidia S3 is one of these new dialysis delivery systems featuring an appealing design and functionalities intended for daily HHD treatment. METHODS: In this French multicenter proof-of-concept study enrolling 13 training centers, we report our preliminary experience with a special focus on quantifying clinical performances in short daily HHD treatment performed during the training period of the patients. RESULTS: Among the 80 patients included in this study, a total of 249 sessions could be analyzed. Dialysis dose, estimated from weekly standardized Kt/V, was maintained at 2.22 [1.95-2.61] with a normalized protein catabolic rate of 0.93 [0.73-1.18] g/kg/24 h. Furthermore, anemia and nutritional status were adequately controlled as indicated by 11.6 ± 1.4 g/dL of hemoglobin level and 39.4 ± 5.7 g/L of serum albumin as well as electrolyte disorders. CONCLUSIONS: The safety and efficacy of the S3 therapy concept relying on a short daily hemodialysis treatment using a bagged delivery system are in total agreement with daily HHD recommendations. Clinical performances are aligned to the metabolic needs of the vast majority of HHD patients. Currently ongoing studies at home will provide further evidence and value of this therapeutic approach.

Design, synthesis, and biological evaluation of multiple targeting antimalarials

Malaria still threatens global health seriously today. While the current discoveries of antimalarials are almost totally focused on single mode-of-action inhibitors, multi-targeting inhibitors are highly desired to overcome the increasingly serious drug resistance. Here, we performed a structure-based drug design on mitochondrial respiratory chain of

Comparison of physical activity and quality of life in home haemodialysis (HHD) patients versus conventional in-centre haemodialysis (ICHD) patients: the observational, longitudinal, prospective, international, multicentric SeCoIA study protocol.

BACKGROUND: Home haemodialysis (HHD), has shown improved clinical outcomes, as well as a better quality of life, compared to conventional in-centre haemodialysis (ICHD) but still has a global low prevalence among end-stage renal disease patients. Haemodialysis (HD) patients tend to be sedentary but only few studies, mainly in North American ICHD patients, have evaluated the level of activity in HD patients. METHODS: SeCoIA is an observational, longitudinal, prospective, international, multicentric, study, conducted in metropolitan France and Belgium. The main objective of the study is to quantify the physical activity measured by the total daily number of steps, in HHD patients compared to ICHD patients. The SeCoIA study will include 80 HHD patients and 80 ICHD patients,. Secondary objectives will be to characterize the HHD population and to confirm HHD efficiency on clinical parameters, as well as quality of life (QoL), in current practice. Physical activity will be measured by a 3-axis accelerometer. Accelerometers have been shown to provide accurate information, on both physical activity and sedentary behaviour. Patients will be instructed to wear the device and complete a patient diary 7 consecutive days after inclusion and the first week of each month for 12 months. Decision to undergo HDD or ICHD is independent of the study and follow-up frequency remains at the discretion of the physician/centre. QoL and quality of sleep will be respectively assessed by the Kidney Disease Quality of Life 1.2 (KDQOL™) and the Pittsburg Sleep Quality index (PSQI) questionnaires at inclusion, 6- and 12-month visits. Patients presenting a restless leg syndrome (RLS) will also complete the International Restless Legs Syndrome rating scale (IRLS) questionnaire. DISCUSSION: The SeCoIA study will be the first large cohort study (160 patients) evaluating physical activity, objectively measured with a 3-axis accelerometer, in HHD versus ICHD patients. The present study will also include a comparison of QoL with a focus on RLS between HHD and ICHD. It is anticipated that HHD patients will have an improved physical activity and QoL which should encourage physicians to further promote HHD. TRIAL REGISTRATION: Clinical trial NCT03737578 study registered on November 9, 2018 (Retrospectively registered).

Prevalence and risk factors to HIV-infection amongst health care workers within public and private health facilities in Cameroon.

INTRODUCTION: This study aimed at assessing the prevalence of Human Immunodeficiency Virus (HIV) among health care workers (HCWs) and to evaluate some risks factors for HCWs. METHODS: We conducted a cross sectional study amongst HCWs in public and private healthcare facilities within seven regions amongst the 10 found in Cameroon. We collected data from 446 HCWs within 150 healthcare facilities. We used questionnaires for interviews and biological sampling for HIV test. RESULTS: HIV prevalence was 2.61% (95% CI: 1.32% - 4.61%) regardless of gender and age. HCWs in private health facilities were more infected compared to those in public health facilities 5.00% vs 1.40% (p = 0.028); OR = 3.7 (95% CI: 1.01-12.90). HCWs who had never screened for HIV had a high risk of being infected OR = 7.05 (95% CI: 2.05-24.47). 44.62% of HCWs reported to have been victim of an Accidental Exposure to Blood (AEB). Amongst them, 45.80% in public HF versus 32.1% in private HF reported to have received an HIV screening and Post Exposure Prophylaxis following this incident. 4.20% of HCW victim of AEB were HIV positive, and 36.40% of HCWs had appropriate capacity training for HIV patient care. CONCLUSION: Though the HIV prevalence in HCWs is lower than in the general population 2.61% vs 4.3%, there is a high risk of infection as we observed a relatively high percentage of AEB amongst HCWs with an HIV prevalence of 4.20%. There is thus, a need in strengthening the capacity and provide psychosocial support to HCWs.

Acquired C1-inhibitor deficiency: 7 patients treated with rituximab.

BACKGROUND: Acquired C1-inhibitor deficiency can occur secondary to excessive C1-inhibitor consumption (type I) and be associated with a lymphoid hemopathy, or linked to the presence of anti-C1-inhibitor autoantibodies (type II) in a context of an isolated monoclonal gammopathy, sometimes associated with lymphoproliferation. Efficacy of danazol, tranexamic acid and/or corticosteroids is inconstant. Rituximab efficacy against type II angioedema has been reported. METHODS: Description of 7 rituximab-treated patients, 6 with type II acquired angioedema and 1 with type I. RESULTS: Clinical efficacy (only for type II) was complete for 3, partial for 2 and 2 were therapeutic failures. Only 2 patients had improved biological parameters, with normalization of their C1-inhibitor levels and diminished anti-C1-inhibitor autoantibodies, observed 1-9 months after the last infusion of the second rituximab cycle. An associated lymphoproliferation did not affect the response to treatment. CONCLUSION: Rituximab efficacy in the treatment of acquired angioedema is inconstant and might require repeated cycles.

Effect of alcaline cations in zeolites on their dielectric properties.

The effect on dielectric properties of alkaline cations Li+, Na+ and K+ incorporated in a zeolite Faujasite structure X or Y, has been investigated. Two major phenomena have been proved to occur: ionic conductivity and rotational polarization of the water molecules adsorbed. The polarizability of the cation which is directly linked to its radius, affects ionic conductivity as well as rotational polarization. Li cations are more strongly Linked to the framework than K+ and Na+ and induce a lower ionic conductivity. K+ is weakly fixed and induces a ionic conductivity even at low solvation level. At low water content, the cation nature and number mainly control the free rotation of the water molecules and affect the relaxation frequency. Close to saturation, the water molecules are mainly linked together by H bonds: the cation nature and number do not really affect the global dielectric properties anymore.

AN69: Evolution of the world's first high permeability membrane.

In response to a request from the French government, Rhône-Poulenc started development of a synthetic membrane for dialysis in 1969. When used for patients the new membrane, AN69, showed improved efficiency and clinical outcome. Treatment times could be reduced, peripheral neuropathy improved and patients expressed improved quality of life. This was the introduction of high-flux, volume-controlled dialysis. The polymer used for the AN69 membrane is a copolymer of acrylonitrile and sodium methallylsulfonate, specially selected for the dialysis application. Contrary to most synthetic membranes AN69 is hydrophilic, because the numerous sulfonate groups attract water and create a hydrogel structure which provides high diffusive and hydraulic permeability. In the AN69 membrane the microstructure and the chemical composition offer a unique context for bulk adsorption of low-molecular-weight proteins, the high water content of the hydrogel making the polymer chains easily accessible. The highly specific adsorptive properties - limited on the surface and favored in the membrane structure and with high specificity for basic, medium-sized proteins - distinguish AN69 from other synthetic high-flux membranes as well as from other so-called adsorptive membranes in the field of dialysis. Since its creation in the early 1970s the AN69 membrane has evolved to meet the requirements and challenges of dialysis therapy. Still the basic characteristics of high permeability to fluid and to a wide range of relevant uremic retention products combined with excellent biocompatibility, whether measured by traditional or novel indicators, have remained the hallmark of the membrane. The unique adsorptive capacity has provided a base for further development. The latest version of AN69, HeprAN, has heparin grafting on the inner surface and enhanced adsorption of bacterial products on the outer surface. Modern versions of AN69 are today used in hemodialysis and contemporary modes of convective therapies for a large number of chronic as well as acute renal patients around the world.

Biocompatibility of heparin-grafted hemodialysis membranes: impact on monocyte chemoattractant protein-1 circulating level and oxidative status.

This prospective observational study aimed at evaluating efficacy and biocompatibility performances of the new heparin-coated Evodial dialyzers with/without systemic heparin reduction. After a 4-week wash-out period with reference polysulfone F70S dialyzers, 6 hemodialysis patients were sequentially dialyzed with Evodial, F70S, and Evodial dialyzers using 30% heparin reduction, each period of treatment was 4 weeks. Removal rates (RR) (urea, creatinine, and ß2-microglobulin), dialysis dose, and instantaneous clearances (urea and creatinine) were measured as well as inflammatory (C-reactive protein, fibrinogen, interleukin 6, tumor necrosis factor α, and monocyte chemoattractant protein-1) and oxidative stress (OS) (superoxide anion, homocysteine, and isoprostanes) parameters at the end of each study period. Patients treated with Evodial or F70S dialyzers for 4 weeks presented comparable dialysis efficacy parameters including urea and creatinine RR, dialysis dose and instantaneous clearances. By contrast, a significantly lower but reasonably good ß2-microglobulin RR was achieved with Evodial dialyzers. Regarding biocompatibility, no significant difference was observed with inflammation and OS except for postdialysis monocyte chemoattractant protein-1 which significantly decreased with Evodial dialyzers. Thirty percent heparinization reduction with Evodial dialyzers did not induce any change in inflammation but led to an improvement in OS as demonstrated by a decrease in postdialysis superoxide production and predialysis homocysteine and isoprostane. This bioactive dialyzer together with heparin dose reduction represents a good trade-off between efficacy and biocompatibility performance (improvement in OS with a weak decrease in efficacy) and its use is encouraging for hemodialysis patients not only in reducing OS but also in improving patient comorbid conditions due to lesser heparin side effects.

[Membrane roughness: A relevant concept in haemodialysis]. / Le concept de rugosité membranaire en hémodialyse.

The molecular process that occurs at the interface between blood and a haemodialysis membrane determines the host response. The resulting reactions define the degree of membrane biocompatibility. These reactions are triggered by plasma protein adsorption onto the membrane and blood cell stress. Over the past decade, atomic force microscopy (AFM) has provided mechanistic insights into the molecular level of interactions that occur at the biomaterial surface. AFM provides tridimentional images produced by both changes in applied shear nanoforces and dynamic imaging through the molecular analysis of attraction and repulsion forces. The aim of the present brief review is to shortly present the technique of AFM and its emerging applications in haemodialysis, comparing hydrophilic and hydrophobic structures. Dialysis membrane roughness and protein adsorption mapping can be quantitatively estimated, since AFM resolution power is in the range of a nanometer. It is suggested that estimation of roughness and force mapping determining structure/function relationship should be proposed for the best understanding of membrane biocompatibility.

Assessment of heparin binding to the AN69 ST hemodialysis membrane: I. Preclinical studies.

The AN69 ST membrane was designed to render the surface of the native polyacrylonitrile polymer less cationic. This was achieved by layering the membrane with the polycationic biopolymer polyethyleneimine. This new membrane is able to bind heparin to its surface, through electrical interactions, without altering the reactivity of the sulfonate groups of the membrane, regularly distributed in the membrane bulk. The kinetics of unfractionated or low-molecular-weight heparins were studied in vitro and in vivo in sheep. Encouraging results were obtained indicating that heparin-coated hemodialyzers are potent anticoagulants. Priming the AN69 ST membrane-equipped hemodialyzer with heparin, as in regular hemodialysis, could allow drastic reduction of heparin consumption in hemodialysis.

Clinical and biological features associated with taste loss in internal medicine patients. A cross-sectional study of 100 cases.

Which are the main features associated with taste loss in patients exposed to a wide range of drugs and diseases? In 100 consecutive patients admitted to a ward of internal medicine, we assessed taste complaints, performance status, alcohol and tobacco consumptions, diseases, drugs and laboratory data, measuring the electrical taste threshold as primary outcome. After adjusting for age, taste thresholds were not associated with sex, body mass index, tobacco, thrush, drugs, aliageusia and phantogeusia. Features associated with threshold increase included alcohol intake>or=10 gd-1, impaired performance status, complaint of taste loss, atrophic glossitis, cerebral disease, and an erythrocyte mean corpuscular volume. A multivariate analysis identified age, alcohol intake, complaint of loss or altered taste, mean corpuscular volume, and performance status as independent factors associated with taste loss. Inpatients may be screened for taste loss by a few features, to identify those for whom a nutritional intervention should be focused.

Esophageal function and Sjögren's syndrome.

The frequency and characteristics of esophageal dysmotility in Sjögren's syndrome (SS) are as controversial as their related symptoms. We evaluated esophageal function and gastroesophageal reflux (GER) in 21 SS patients using manometry and 24-hr esophageal pH monitoring. All patients complained of xerostomia, 33% of dysphagia, and 62% of heartburn. Compared to controls, the mean percentage abdominal length of their lower esophageal sphincters (LES) and resting LES pressures were significantly lower, with no difference in primary esophageal peristalsis. Tertiary waves without swallowing were detected in 29% of them and pathological GER in 67%. Symptoms, esophageal motor abnormalities, and reflux features were similar in primary and secondary SS. ANOVA indicated that dysphagia was unrelated to the esophageal impairments and GER analysis results, while heartburn was significantly associated with GER severity. Esophageal acid-exposure time was significantly longer in SS patients with distal tertiary waves, while proximal esophagus wave velocity was significantly lower. While SS patients have nonspecific esophageal motility disorders and frequently GER disease, early and accurate diagnosis of GER is essential to identify SS patients at risk for acidic reflux, especially because the acid-clearance capacity of the esophagus is already diminished by the lack of saliva.

Hypovitaminosis C in hospitalized patients.

BACKGROUND: In recent years, cases of scurvy have mainly been described in populations at risk. The prevalence and risk factors for hypovitaminosis C among hospitalized patients in a department of internal medicine are largely unknown. METHODS: We determined serum ascorbic acid level (SAAL) and searched for clinical and biological signs of scurvy in 184 patients hospitalized during a 2-month period. RESULTS: The prevalence of hypovitaminosis C (depletion: SAAL<5 mg/l or deficiency: SAAL<2 mg/l ) was 47.3%. Some 16.9% of the patients had vitamin C deficiency. There was a strong association between hypovitaminosis C and the presence of an acute phase response (p=0.002). Other univariate risk factors for vitamin C depletion were male sex (p=0.02), being retired (p=0.037), and infectious diseases (p=0.002). For vitamin C deficiency, the significant univariate risk factors included the same ones found for vitamin C depletion, plus being unemployed (p=0.003) and concomitant excessive alcohol and tobacco consumption (p<0.0001). Logistic regression showed that being retired (p=0.015) and concomitant excessive alcohol and tobacco consumption (p=0.0003) were significant independent risk factors. Hemorrhagic syndrome and edema were described more often in patients with vitamin C deficiency than in those with vitamin C depletion or without hypovitaminosis. Clinical signs were more frequent for an ascorbic acid level below 2.5 mg/l. CONCLUSION: Hypovitaminosis C is frequent in hospitalized patients but should be interpreted according to the presence or absence of an acute phase response. The main risk factors are living conditions and excessive alcohol and tobacco consumption.

Utilization of 16S ribosomal DNA sequencing for diagnosis of septicemia due to Neisseria elongata subsp. glycolytica in a neutropenic patient.

Septicemia due to Neisseria elongata subsp. glycolytica occurs infrequently. We report a case of septicemia in a patient undergoing antimitotic chemotherapy. Gram-negative coccobacilli were isolated from blood cultures. The identity of the isolate by phenotypic methods was uncertain. In contrast, identity was confirmed by 16S ribosomal DNA sequencing, which appeared to be very useful for correct identification.

Septic shock caused by Ochrobactrum anthropi in an otherwise healthy host.

Reported is a case of life-threatening septic shock that occurred in an otherwise healthy host after administration of a peripheral venous infusion of a solution contaminated with Ochrobactrum anthropi, an unusual human pathogen. The rapid onset of shock may have been due to a large inoculum caused by nonsterile practices at the time of reconstitution.