Antimicrobial for 7 or 14 Days for Febrile Urinary Tract Infection in Men: A Multicenter Noninferiority Double-Blind, Placebo-Controlled, Randomized Clinical Trial.

BACKGROUND: The optimal duration of antimicrobial therapy for urinary tract infections (UTIs) in men remains controversial. METHODS: To compare 7 days to 14 days of total antibiotic treatment for febrile UTIs in men, this multicenter randomized, double-blind. placebo-controlled noninferiority trial enrolled 282 men from 27 centers in France. Men were eligible if they had a febrile UTI and urine culture showing a single uropathogen. Participants were treated with ofloxacin or a third-generation cephalosporin at day 1, then randomized at day 3-4 to either continue ofloxacin for 14 days total treatment, or for 7 days followed by placebo until day 14. The primary endpoint was treatment success, defined as a negative urine culture and the absence of fever and of subsequent antibiotic treatment between the end of treatment and 6 weeks after day 1. Secondary endpoints included recurrent UTI within weeks 6 and 12 after day 1, rectal carriage of antimicrobial-resistant Enterobacterales, and drug-related events. RESULTS: Two hundred forty participants were randomly assigned to receive antibiotic therapy for 7 days (115 participants) or 14 days (125 participants). In the intention-to-treat analysis, treatment success occurred in 64 participants (55.7%) in the 7-day group and in 97 participants (77.6%) in the 14-day group (risk difference, -21.9 [95% confidence interval, -33.3 to -10.1]), demonstrating inferiority. Adverse events during antibiotic therapy were reported in 4 participants in the 7-day arm and 7 in the 14-day arm. Rectal carriage of resistant Enterobacterales did not differ between both groups. CONCLUSIONS: A treatment with ofloxacin for 7 days was inferior to 14 days for febrile UTI in men and should therefore not be recommended. CLINICAL TRIALS REGISTRATION: NCT02424461; Eudra-CT: 2013-001647-32.

Clinical and pathological impact of an optimal assessment of brain invasion for grade 2 meningioma diagnosis: lessons from a series of 291 cases.

Brain invasion has not been recognized as a standalone criterion for atypical meningioma by the WHO classification until 2016. Since the 2007 edition suggested that meningiomas harboring brain invasion could be classified as grade 2, brain invasion study was progressively strengthened in our center, based on a strong collaboration between neurosurgeons and neuropathologists regarding sample orientation and examination. Practice changes were considered homogeneous enough in 2011. The aim of the present study was to evaluate the impact of gross practice change on the clinical and pathological characteristics of intracranial meningiomas classified as grade 2.The characteristics of consecutive patients with a grade 2 meningioma surgically managed before (1998-2005, n = 125, group A) and after (2011-2014, n = 166, group B) practices changed were retrospectively reviewed.Sociodemographical and clinical parameters were comparable in groups A and B, and the median age was 62 years in both groups (p = 0.18). The 5-year recurrence rates (23.2% vs 29.5%, p = 0.23) were similar. In group A, brain invasion was present in 48/125 (38.4%) cases and was more frequent than in group B (14/166, 8.4%, p < 0.001). In group A, 33 (26.4%) meningiomas were classified as grade 2 solely based on brain invasion (group ASBI), and 92 harbored other grade 2 criteria (group AOCA). Group ASBI meningiomas had a similar median progression-free survival compared to groups AOCA (68 vs 80 months, p = 0.24) and to AOCA and B pooled together (n = 258, 68 vs 90 months, p = 0.42).An accurate assessment of brain invasion is mandatory as brain invasion is a strong predictor of meningioma progression.

Perceived Health and Quality of Life in Patients With CKD, Including Those With Kidney Failure: Findings From National Surveys in France.

RATIONALE & OBJECTIVE: Health-related quality of life (HRQoL) is a major outcome measure increasingly used in patients with chronic kidney disease (CKD). We evaluated the association between different stages of CKD and the physical and mental health domains of HRQoL. STUDY DESIGN: Cross-sectional study. SETTING & PARTICIPANTS: 2,693 outpatients with moderate (stage 3, estimated glomerular filtration rate [eGFR], 30-60mL/min/1.73m2) or advanced (stages 4-5, estimated glomerular filtration rate<30mL/min/1.73m2, not on kidney replacement therapy [KRT]) CKD under the care of a nephrologist at 1 of 40 nationally representative facilities, 1,658 patients with a functioning kidney transplant, 1,251 patients on maintenance dialysis randomly selected from the national Renal Epidemiology and Information Network registry, and 20,574 participants in the French Decennial Health Survey, representative of the general population. PREDICTOR: Severity of kidney disease (moderate CKD, advanced CKD, maintenance dialysis as KRT, and functioning kidney transplant as KRT), compared with a sample of the general population. OUTCOMES: HRQoL scores assessed using the Medical Outcomes Study 36-Item Short Form Health Survey or the Kidney Disease Quality of Life 36 scale. ANALYTICAL APPROACH: Age- and sex-standardized (to the general population) prevalence of poor or fair health status was estimated for each study kidney disease group. Analysis of variance was used to estimate adjusted differences in mean physical and mental health scores between the kidney disease subgroups and the general population. RESULTS: Mean age was 67.2±12.6 (SD) years for patients with non-KRT-requiring CKD, 69.3±17.7 years for dialysis patients, and 55.3±14.2 years for those with functioning kidney transplants; 60% were men. Age- and sex-standardized health status was perceived as fair or poor in 27% of those with moderate CKD,>40% of those with advanced CKD or receiving dialysis, 12% with a functioning transplant, and 3% of the general population sample. HRQoL physical scores (adjusted for age, sex, education, obesity, and diabetes) were significantly lower in patients in all CKD subgroups than in the general population. For patients receiving dialysis, the magnitude of the difference in physical score versus the general population exceeded 4.5 points, the minimal clinically important difference for this score in this study; for both kidney transplant recipients and patients with advanced CKD, the magnitude of the difference was close to this threshold. For mental score, only dialysis patients had a score that differed from that of the general population by more than the minimal clinically important difference. LIMITATIONS: Cross-sectional study design for each subpopulation. CONCLUSIONS: This study highlights the degree to which perceived physical health is lower in the setting of CKD than in the general population, even in the absence of kidney failure, and calls for greater attention to CKD-related quality of life.

Thoracic aorta involvement in giant cell arteritis: a case-control analysis of morphological data at diagnosis.

OBJECTIVES: Giant cell arteritis (GCA) is a cause of potentially fatal aortic aneurysms. Descriptive data on thoracic aorta measurements at the beginning of the disease are lacking. We aimed to compare aortic diameters between a recently diagnosed GCA population and an age- and sex-matched control group. METHODS: Patients with GCA and with an available thoracic CT concomitant with diagnosis were included. Controls were patients matched for age and sex and hospitalised in the same care centre for pneumonia. The main criteria were the anteroposterior and lateral diameters of the ascending thoracic aorta, which were measured by a blinded evaluator. RESULTS: 90 cases and 90 controls were included. Each group comprised 30 males and 60 females for a mean age of 75.1±9 and 75.7±10.1 years old. At the time of GCA diagnosis no difference was found between the two groups (anteroposterior diameter 37.1±5 mm for cases vs. 36.7±5 mm for controls, p=0.6; lateral diameter 36.6±5 mm for cases vs. 35.9±4 mm for controls, p=0.3). Thoracic aorta diameter was not significantly higher in patients with aortitis at diagnosis (n=44) than in cases without aortitis (n=46). CONCLUSIONS: Morphologic comparison of thoracic aorta at diagnosis of GCA with an age- and sex-matched control population showed no significant difference. Morphologic evaluation of aorta cannot predict accurately the occurrence of aortic aneurysm. Systematic follow-up according to current recommendations is thus justified.

The Lysine Specific Demethylase-1 Negatively Regulates the COL9A1 Gene in Human Articular Chondrocytes.

Osteoarthritis (OA) is a degenerative disease of the joints which is associated with an impaired production of the cartilage matrix by the chondrocytes. Here, we investigated the role of Lysine-Specific Demethylase-1 (LSD1), a chromatin remodeling enzyme whose role in articular chondrocytes was previously associated with a catabolic activity and which is potentially involved during OA. Following a loss of function strategy and RNA sequencing analysis, we detail the genes which are targeted by LSD1 in human articular chondrocytes and identify COL9A1, a gene encoding the α1 chain of the cartilage-specific type IX collagen, as negatively regulated by LSD1. We show that LSD1 interacts with the transcription factor SOX9 and is recruited to the promoter of COL9A1. Interestingly, we observe that OA cartilage displays stronger LSD1 immunostaining compared with normal, and we demonstrate that the depletion of LSD1 in OA chondrocytes prevents the decrease in COL9A1 following Il-1ß treatment. These results suggest LSD1 is a new regulator of the anabolic activity of articular chondrocytes potentially destabilizing the cartilage matrix, since it negatively regulates COL9A1, a gene encoding a crucial anchoring collagen molecule. This newly identified role played by LSD1 may thus participate in the alteration of the cartilage matrix during OA.

Biogenesis of the bacterial cbb3 cytochrome c oxidase: Active subcomplexes support a sequential assembly model.

The cbb3 oxidase has a high affinity for oxygen and is required for growth of bacteria, including pathogens, in oxygen-limited environments. However, the assembly of this oxidase is poorly understood. Most cbb3 are composed of four subunits: the catalytic CcoN subunit, the two cytochrome c subunits (CcoO and CcoP) involved in electron transfer, and the small CcoQ subunit with an unclear function. Here, we address the role of these four subunits in cbb3 biogenesis in the purple bacterium Rubrivivax gelatinosus Analyses of membrane proteins from different mutants revealed the presence of active CcoNQO and CcoNO subcomplexes and also showed that the CcoP subunit is not essential for their assembly. However, CcoP was required for the oxygen reduction activity in the absence of CcoQ. We also found that CcoQ is dispensable for forming an active CcoNOP subcomplex in membranes. CcoNOP exhibited oxygen reductase activity, indicating that the cofactors (hemes b and copper for CcoN and cytochromes c for CcoO and CcoP) were present within the subunits. Finally, we discovered the presence of a CcoNQ subcomplex and showed that CcoN is the required anchor for the assembly of the full CcoNQOP complex. On the basis of these findings, we propose a sequential assembly model in which the CcoQ subunit is required for the early maturation step: CcoQ first associates with CcoN before the CcoNQ-CcoO interaction. CcoP associates to CcoNQO subcomplex in the late maturation step, and once the CcoNQOP complex is fully formed, CcoQ is released for degradation by the FtsH protease. This model could be conserved in other bacteria, including the pathogenic bacteria lacking the assembly factor CcoH as in R. gelatinosus.

End-stage renal disease treated in Provence-Alpes Côte d'Azur: 12-years follow-up and forecast to the year 2030.

BACKGROUND: This study describes the time trend of renal replacement therapy for end-stage renal disease (ESRD) in the Provence-Alpes Côte d'Azur region (PACA) between 2004 and 2015, and forecasts up to 2030. METHODS: A longitudinal study was conducted on all ESRD patients treated in PACA and recorded in the French Renal Epidemiology and Information Network (REIN) during this period. Time trends and forecasts to 2030 were analyzed using Poisson regression models. RESULTS: Since 2004, the number of new patients has steadily increased by 3.4% per year (95% CI, 2.8-3.9, p < 0.001) and the number of patients receiving RRT has increased by 3.7% per year (RR 1.037, 95% CI: 1.034-1.039, p < 0.001). If these trends continue, the PACA region will be face with 7371 patients on dialysis and 3891 with a functional renal transplant who will need to be managed in 2030. The two most significant growth rates were the percentage of obese people (RR 1.140, 95% CI: 1.131-1.149, p < 0.001) and those with diabetes (RR 1.070, 95% CI; 1.064-1.075, p < 0.001). CONCLUSION: This study highlights the increase in the number of ESRD patients over 12 years, with no prospect of stabilization. These findings allow us to anticipate the quality and quantity of care offered and to propose more preventive measures to combat obesity and diabetes.

Efficacy of Alteplase in a Mouse Model of Acute Ischemic Stroke: A Retrospective Pooled Analysis.

BACKGROUND AND PURPOSE: The debate over the fact that experimental drugs proposed for the treatment of stroke fail in the translation to the clinical situation has attracted considerable attention in the literature. In this context, we present a retrospective pooled analysis of a large data set from preclinical studies, to examine the effects of early versus late administration of intravenous recombinant tissue-type plasminogen activator. METHODS: We collected data from 26 individual studies from 9 international centers (13 researchers; 716 animals) that compared recombinant tissue-type plasminogen activator with controls, in a unique mouse model of thromboembolic stroke induced by an in situ injection of thrombin into the middle cerebral artery. Studies were classified into early (<3 hours) versus late (≥3 hours) drug administration. Final infarct volumes, assessed by histology or magnetic resonance imaging, were compared in each study, and the absolute differences were pooled in a random-effect meta-analysis. The influence of time of administration was tested. RESULTS: When compared with saline controls, early recombinant tissue-type plasminogen activator administration was associated with a significant benefit (absolute difference, -6.63 mm(3); 95% confidence interval, -9.08 to -4.17; I(2)=76%), whereas late recombinant tissue-type plasminogen activator treatment showed a deleterious effect (+5.06 mm(3); 95% confidence interval, +2.78 to +7.34; I(2)=42%; Pint<0.00001). Results remained unchanged after subgroup analyses. CONCLUSIONS: Our results provide the basis needed for the design of future preclinical studies on recanalization therapies using this model of thromboembolic stroke in mice. The power analysis reveals that a multicenter trial would require 123 animals per group instead of 40 for a single-center trial.

Oxygen-dependent copper toxicity: targets in the chlorophyll biosynthesis pathway identified in the copper efflux ATPase CopA deficient mutant.

Characterization of a copA(-) mutant in the purple photosynthetic bacterium Rubrivivax gelatinosus under low oxygen or anaerobic conditions, as well as in the human pathogen Neisseria gonorrhoeae identified HemN as a copper toxicity target enzyme in the porphyrin synthesis pathway. Heme synthesis is, however, unaffected by copper under high oxygen tension because of the aerobic coproporphyrinogen III oxidase HemF. Nevertheless, in the copA(-) mutant under aerobiosis, we show that the chlorophyll biosynthesis pathway is affected by excess copper resulting in a substantial decrease of the photosystem. Analyses of pigments and enzyme activity showed that under low copper concentrations, the mutant accumulated protochlorophyllide, suggesting that the protochlorophyllide reductase activity is affected by excess copper. Increase of copper concentration led to a complete lack of chlorophyll synthesis as a result of the loss of Mg-chelatase activity. Both enzymes are widely distributed from bacteria to plants; both are [4Fe-4S] proteins and oxygen sensitive; our data demonstrate their in vivo susceptibility to copper in the presence of oxygen. Additionally, our study provides the understanding of molecular mechanisms that may contribute to chlorosis in plants when exposed to metals. The role of copper efflux systems and the impact of copper on heme and chlorophyll biosynthesis in phototrophs are addressed.

Predictive factors for early unplanned rehospitalization of older adults after an ED visit: role of the caregiver burden.

BACKGROUND AND AIMS: For older adults, an Emergency Department (ED) visit represents a period of vulnerability that extends beyond the visit itself. This study aimed to determine the impact of the role of caregiver, and geriatric conditions of patients on early unplanned rehospitalization (EUR) within 3 months after an ED visit. METHODS: This prospective longitudinal experimental study included consecutively 173 patients aged 75 and older admitted in an ED over a 2-week period (18.7% of the total visits). Only older patients having a caregiver were analyzed (78.0%, n = 135). Medical conditions and a comprehensive geriatric assessment were recorded for each patient. All caregivers were interviewed about their tasks and emotional impact using the short Zarit Burden Inventory. Three months after, patients or their caregivers were called about the vital status, and EUR of patients. RESULTS: Among the patients included, 64.2% had an EUR and 28.9% of their caregivers reported a high level of burden. EUR was strongly associated with a high caregiver burden (OR 8.7, 95% CI 1.5-49.8). No association was found for patient's medical or geriatric status. Caregivers reported a significantly high burden when patients were malnourished, or were at risk of adverse health outcomes based on the ISAR scale, and when they had greater disabilities in IADLs and ADLs, or cognitive impairments. CONCLUSIONS: Many hospital readmissions after an ED visit may be preventable by identifying caregiver's high burden. Reasons that lead to this high burden should be checked at the first visit.

Coproporphyrin III excretion identifies the anaerobic coproporphyrinogen III oxidase HemN as a copper target in the Cu⁺-ATPase mutant copA⁻ of Rubrivivax gelatinosus.

Two genes encoding structurally similar Copper P1B -type ATPases can be identified in several genomes. Notwithstanding the high sequence and structural similarities these ATPases held, it has been suggested that they fulfil distinct physiological roles. In deed, we have shown that the Cu(+) -ATPase CtpA is required only for the activity of cuproproteins in the purple bacterium Rubrivivax gelatinosus; herein, we show that CopA is not directly required for cytochrome c oxidase but is vital for copper tolerance. Interestingly, excess copper in the copA(-) mutant resulted in a substantial decrease of the cytochrome c oxidase and the photosystem under microaerobic and anaerobic conditions together with the extrusion of coproporphyrin III. The data indicated that copper targeted the tetrapyrrole biosynthesis pathway at the level of the coproporphyrinogen III oxidase HemN and thereby affects the oxidase and the photosystem. This is the first in vivo demonstration that copper, like oxygen, affects tetrapyrrole biosynthesis presumably at the level of the SAM and [4Fe-4S] containing HemN enzyme. In light of these results and similar findings in Escherichia coli, the potential role of copper ions in the evolution of [4Fe-4S] enzymes and the Cu(+) -ATPases is discussed.

Effects of a TAFI-inhibitor combined with a suboptimal dose of rtPA in a murine thromboembolic model of stroke.

BACKGROUND: Since thrombolysis is the only approved intervention for ischemic stroke, improving its efficacy and safety is a therapeutic aim of considerable interest. The activated form of thrombin activatable fibrinolysis inhibitor (TAFI) has antifibrinolytic effects, and inhibition of TAFI might thus favor recanalization. The present study compared efficacy between TAFI inhibition alone and TAFI inhibition in combination with rtPA at a suboptimal dose, in a murine model of thromboembolic stroke. METHODS: Focal ischemia was induced in mice by thrombin injection in the middle cerebral artery. Animals were placed within the magnet immediately after surgery for baseline MRI (H0). MRI examination comprised diffusion-weighted imaging (DWI), perfusion-weighted imaging (PWI), and T2-weighted imaging (T2-WI). Animals were randomly assigned to 1 of 5 treatment groups: saline, rtPA 5 mg/kg (tPA(5): suboptimal or low dose), rtPA 10 mg/kg (tPA(10): standard dose), TAFI-I 100 mg/kg (TAFI-I), and rtPA 5 mg/kg + TAFI-I 100 mg/kg (tPA(5) + TAFI-I). Treatments were administered inside the magnet, via a catheter placed in the tail vein, using a power injector, as 10% bolus and 90% infusion over a period of 20 min. MRI examination was repeated at 3 h (H3) and 24 h (H24) after surgery. Therapeutic benefit was evaluated by: (1) improvement of reperfusion and (2) reduction in final lesion size. Microhemorrhages were assessed as black spots on T2-WI at H24. Animals were sacrificed after the last MR examination. The surgeon and all investigators were blinded to treatment allocation. RESULTS: A total of 104 mice were operated on. Forty four of these were excluded from the study and 27 from the analysis, according to a priori defined criteria (no lesion or no mismatch), leading to the following distribution: saline (n = 6), tPA(5) (n = 8), tPA(10) (n = 7), TAFI-I (n = 7), and TAFI-I + tPA(5) (n = 5). Standard-dose rtPA treatment (tPA(10)) significantly improved lesion regression between H0 and H24 compared to saline (-57 ± 18% vs. -36 ± 21%, p = 0.03), which treatment with rtPA(5) or TAFI-I alone did not. On the other hand, combined treatment with tPA(5) + TAFI-I showed only a trend toward lesion regression (-49 ± 26%), similarly to treatment with tPA(10), but not significantly different from saline (p = 0.46). Nine animals showed microhemorrhage on T2-WI at H24. These animals were evenly distributed between groups. CONCLUSIONS: The present study showed that the combination of TAFI-I with a suboptimal dose of rtPA is not as effective as the standard dose of rtPA, while TAFI inhibition alone is not effective at all. The thromboembolic model is of particular interest in assessing rtPA association to improve thrombolysis, especially when coupled with longitudinal MRI assessment.

The green cupredoxin CopI is a multicopper protein able to oxidize Cu(I).

Anthropogenic activities in agriculture and health use the antimicrobial properties of copper. This has led to copper accumulation in the environment and contributed to the emergence of copper resistant microorganisms. Understanding bacterial copper homeostasis diversity is therefore highly relevant since it could provide valuable targets for novel antimicrobial treatments. The periplasmic CopI protein is a monodomain cupredoxin comprising several copper binding sites and is directly involved in copper resistance in bacteria. However, its structure and mechanism of action are yet to be determined. To study the different binding sites for cupric and cuprous ions and to understand their possible interactions, we have used mutants of the putative copper binding modules of CopI and spectroscopic methods to characterize their properties. We show that CopI is able to bind a cuprous ion in its central histidine/methionine-rich region and oxidize it thanks to its cupredoxin center. The resulting cupric ion can bind to a third site at the N-terminus of the protein. Nuclear magnetic resonance spectroscopy revealed that the central histidine/methionine-rich region exhibits a dynamic behavior and interacts with the cupredoxin binding region. CopI is therefore likely to participate in copper resistance by detoxifying the cuprous ions from the periplasm.

Monitoring therapeutic effects in experimental stroke by serial USPIO-enhanced MRI.

OBJECTIVES: This study sought to evaluate whether the therapeutic effects of an anti-inflammatory drug such as minocycline could be monitored by serial ultrasmall superparamagnetic particles of iron oxide (USPIO)-enhanced MRI in experimental stroke. METHODS: Mice received a three-dose minocycline treatment (n = 12) or vehicle (n = 12) after permanent middle cerebral artery occlusion. USPIOs were administered 5 h post-surgery. MRI was performed before, 24 h and 48 h post-USPIO administration. MRI endpoints were the extent of signal abnormalities on R2 maps (=1/T2) and quantitative R2 changes over time (∆R2). Post-mortem brains were prepared either for immunohistology (n = 16) or for iron dosage (n = 8). RESULTS: As expected, treatment with minocycline significantly reduced infarct size, blood-brain barrier permeability and F4/80 immunostaining for microglia/macrophages. Areas of R2 maps > 35 ms(-1) also appeared significantly decreased in minocycline-treated mice (ANOVA for repeated measures, P = 0.017). There was a fair correlation between these areas and the amount of iron in the brain (R(2) = 0.69, P = 0.010), but no significant difference in ∆R2 was found between the two groups. CONCLUSIONS: This study showed that the extent of signal abnormalities on R2 maps can be used as a surrogate marker to detect minocycline effects in a murine experimental model of stroke.

A study comparing care between nurses and doctors in the French prehospital setting: the case of hypoglycemia.

INTRODUCTION: The objective of this study was to compare the quality of care between French nurses and physicians in the prehospital management of hypoglycemic patients. METHODS: Response times, concordance with medical protocols/recommendations, quality of medical records, and percentage of hospitalized patients were evaluated. RESULTS: A total of 33 patients were treated for hypoglycemia by the nurse group and 41 by the physician group. The groups were similar in terms of response rates (mean time of 00:08 ± 00:06 minutes for nurses and 00:10 ± 00:09 minutes for doctors). For 51 patients not requiring hospitalization, the proportion was similar in each group (47.1% and 52.9% for nurses and doctors, respectively). The nurse group showed significantly higher mean scores for concordance with recommendations (P < .001) and quality of medical records (P = .005). DISCUSSION: In the management of hypoglycemic patients, the quality of care of an emergency ambulance team composed of nurses was comparable to that of doctors.

The epigenetic players and the chromatin marks involved in the articular cartilage during osteoarthritis.

Epigenetics defines the modifications of the genome that do not involve a change in the nucleotide sequence of DNA. These modifications constitute a mechanism of gene regulation poorly explored in the context of cartilage physiology. They are now intensively studied by the scientific community working on articular cartilage and its related pathology such as osteoarthritis. Indeed, epigenetic regulations can control the expression of crucial gene in the chondrocytes, the only resident cells of cartilage. Some epigenetic changes are considered as a possible cause of the abnormal gene expression and the subsequent alteration of the chondrocyte phenotype (hypertrophy, proliferation, senescence…) as observed in osteoarthritic cartilage. Osteoarthritis is a joint pathology, which results in impaired extracellular matrix homeostasis and leads ultimately to the progressive destruction of cartilage. To date, there is no pharmacological treatment and the exact causes have yet to be defined. Given that the epigenetic modifying enzymes can be controlled by pharmacological inhibitors, it is thus crucial to describe the epigenetic marks that enable the normal expression of extracellular matrix encoding genes, and those associated with the abnormal gene expression such as degradative enzyme or inflammatory cytokines encoding genes. In this review, only the DNA methylation and histone modifications will be detailed with regard to normal and osteoarthritic cartilage. Although frequently referred as epigenetic mechanisms, the regulatory mechanisms involving microRNAs will not be discussed. Altogether, this review will show how this nascent field influences our understanding of the pathogenesis of OA in terms of diagnosis and how controlling the epigenetic marks can help defining epigenetic therapies.

Discriminating Susceptibility of Xanthine Oxidoreductase Family to Metals.

The xanthine oxidoreductase (XOR) family are metal-containing enzymes that use the molybdenum cofactor (Moco), 2Fe-2S clusters, and flavin adenine dinucleotide (FAD) for their catalytic activity. This large molybdoenzyme family includes xanthine, aldehyde, and CO dehydrogenases. XORs are widely distributed from bacteria to humans due to their key roles in the catabolism of purines, aldehydes, drugs, and xenobiotics, as well as interconversions between CO and CO2. Assessing the effect of excess metals on the Rubrivivax gelatinosus bacterium, we found that exposure to copper (Cu) or cadmium (Cd) caused a dramatic decrease in the activity of a high-molecular-weight soluble complex exhibiting nitroblue tetrazolium reductase activity. Mass spectrometry and genetic analyses showed that the complex corresponds to a putative CO dehydrogenase (pCOD). Using mutants that accumulate either Cu+ or Cd2+ in the cytoplasm, we show that Cu+ or Cd2+ is a potent inhibitor of XORs (pCOD and the xanthine dehydrogenase [XDH]) in vivo. This is the first in vivo demonstration that Cu+ affects Moco-containing enzymes. The specific inhibitory effect of these compounds on the XOR activity is further supported in vitro by direct addition of competing metals to protein extracts. Moreover, emphasis is given on the inhibitory effect of Cu on bovine XOR, showing that the XOR family could be a common target of Cu. Given the conservation of XOR structure and function across the tree of life, we anticipate that our findings could be transferable to other XORs and organisms. IMPORTANCE The high toxicity of Cu, Cd, Pb, As, and other metals arises from their ability to cross membranes and target metalloenzymes in the cytoplasm. Identifying these targets provides insights into the toxicity mechanisms. The vulnerability of metalloenzymes arises from the accessibility of their cofactors to ions. Accordingly, many enzymes whose cofactors are solvent exposed are likely to be targets of competing metals. Here, we describe for the first time, with in vivo and in vitro experiments, a direct effect of excess Cu on the xanthine oxidoreductase family (XOR/XDH/pCOD). We show that toxic metal affects these Moco enzymes, and we suggest that access to the Moco center by Cu ions could explain the Cu inhibition of XORs in living organisms. Human XOR activity is associated with hyperuricemia, xanthinuria, gout arthritis, and other diseases. Our findings in vivo highlight XOR as a Cu target and thus support the potential use of Cu in metal-based therapeutics against these diseases.

Caregiver Burden Is Reduced by Social Support Services for Non-Dependent Elderly Persons: Pre-Post Study of 569 Caregivers.

BACKGROUND: Informal care provided by family caregivers (FCGs) to elderly persons is associated with a high risk of burden and poor health status. Social support services (3S) for the elderly persons were characterized by assistance in various activities of daily living. This study aimed to analyze the impact of 3S on the burden of FCGs of elderly persons living in the community and identify factors associated with changes in their burden. METHODS: This pre-post study was performed in the southeast of France: FCGs of non-dependent elderly persons still living at home who received a 3S were consecutively included. FCG burden was assessed with the Mini-Zarit scale before the setting up of the 3S (pre-3S) and 6 months after (post-3S). RESULTS: A total of 569 FCGs were included in the study. Mean age of the FCGs was 62.9 years old (±13.3), 67% were women, 61.2% were children or stepchildren. Burden was present for 81% of FCGs. In most cases, 3S targeted household chores (95.8%); 59.8% of elderly persons and their FCGs were fully satisfied. The improvement in burden was greater for FCGs perceiving less obstacles post-3S in helping elderly persons (OR = 4.083) but also for FCGs fully satisfied with the 3S (OR = 2.809) and for FCGs whose perceived health status had improved post-3S (OR = 2.090). CONCLUSIONS: FCGs of non-dependent elderly persons experience a burden similar to those of dependent elderly persons. The implementation of a 3S in daily life helps to reduce their burden.

ED patients: how nonurgent are they? Systematic review of the emergency medicine literature.

Nonurgent visits to emergency departments (ED) are a controversial issue; they have been negatively associated with crowding and costs. We have conducted a critical review of the literature regarding methods for categorizing ED visits into urgent or nonurgent and analyzed the proportions of nonurgent ED visits. We found 51 methods of categorization. Seventeen categorizations conducted prospectively in triage areas were based on somatic complaint and/or vital sign collection. Categorizations conducted retrospectively (n = 34) were based on the diagnosis, the results of tests obtained during the ED visit, and hospital admission. The proportions of nonurgent ED visits varied considerably: 4.8% to 90%, with a median of 32%. Comparisons of methods of categorization in the same population showed variability in levels of agreement. Our review has highlighted the lack of reliability and reproducibility.