24-Hour Carotid Stent Patency and Outcomes After Endovascular Therapy: A Multicenter Study.

BACKGROUND: Management of extracranial internal carotid artery steno-occlusive lesion during endovascular therapy remains debated. Stent occlusion within 24 hours of endovascular therapy is a frequent event after acute carotid artery stenting, and we currently lack large population results. We investigated the incidence, predictors, and clinical impact of stent occlusion after acute carotid artery stenting in current clinical practice. METHODS: Patients treated by endovascular therapy with acute carotid artery stenting between 2015 and 2019 in 5 large-volume endovascular-capable centers were retrospectively analyzed. Patients were separated in 2 groups according to the stent patency at 24 hours after carotid artery stenting. We compared baseline characteristics, treatment modalities, and clinical outcome depending on 24-hour stent patency. Primary end point was favorable outcome, defined as a modified Rankin Scale score 0-2 at 3 months. RESULTS: A stent occlusion was observed in 47/225 patients (20.9%). Patients with stent patency had a lower baseline National Institutes of Health Stroke Scale (median [interquartile range]: 13 [7-17] versus 18 [12-21]) and had more often stroke of atherothrombotic origin (77.0% versus 53.2%). A higher stent patency rate was found for patients treated with P2Y12 antagonists at the acute phase (odds ratio [OR]' 2.95 [95% CI' 1.10-7.91]; P=0.026) and treated with angioplasty (OR' 2.42 [95% CI' 1.24-4.67]; P=0.008). A better intracranial angiographic reperfusion was observed in patients with 24-hour stent patency compared with patients without stent patency (OR' 8.38 [95% CI' 3.07-22.78]; P<0.001). Patients with a stent patency at 24 hours had a higher chance of favorable outcome (OR' 3.29 [95% CI, 1.66-6.52]; P<0.001) and a lower risk of death (OR' 0.32 [95% CI, 0.13-0.76]; P=0.009). CONCLUSIONS: One out of 5 patients treated with carotid artery stenting during endovascular therapy presented a stent occlusion within 24 hours. This event was associated with worse functional outcome. Stroke etiology, P2Y12 antagonist administration, quality of intracranial reperfusion, and angioplasty were associated with 24-hour stent patency.

Radial artery occlusion after aneurysm treatment using the rist guide catheter: Single center cohort study.

BACKGROUND AND PURPOSE: Delayed radial artery occlusion (dRAO) is a frequent complication after transradial access (TRA) for neurointervention when using standard large guide catheters. The RIST 079 guide catheter (RIST GC) is the first catheter designed for TRA in neurointervention. We aimed to assess the rate of dRAO after intracranial aneurysm (IA) treatment using the RIST GC. METHODS: Patients treated for an IA using TRA and the RIST GC between June 2021 and November 2022 were referred to a systematic US-doppler assessment of the radial artery patency at 3-month follow-up. Patients with and without dRAO were compared to identify risk factors. RESULTS: Twenty-two patients were included in the analysis. At 3-months follow up, 6 patients (27.3 %) presented with dRAO. Four patients were asymptomatic and 2 experienced post-operative radial hematoma and wrist pain. There was a tendency towards younger age, longer procedure duration and higher rate of forearm hematoma in patients with dRAO. Navigation using the RIST GC was successful in 90.9 % of cases. Intracranial access failures and navigation complications were all related to left internal carotid artery navigation. CONCLUSIONS: At 3-month follow up, 27.3 % of patients treated for IA using TRA with the RIST GC presented dRAO.

Temporal trends in living kidney donation in France between 2007 and 2017.

BACKGROUND: Long-term studies have demonstrated a slight increased risk for end-stage renal disease (ESRD) for living kidney donors (LKD). In France, living kidney donation doubled within the past 10 years. We investigated the change in characteristics of LKD between 2007 and 2017 and the adequacy of follow-up. METHODS: Data were obtained from the national registry for LKD. We compared characteristics of LKD between two study periods: 2007-11 and 2012-17, and stratified donors by age and relation to recipient. We aggregated four characteristics associated with higher ESRD risk [young age, first-degree relation to recipient, obesity, low glomerular filtration rate (GFR) for age] in a single risk indicator ranging from 0 to 4. RESULTS: We included 3483 donors. The proportion of unrelated donors >56 years of age increased significantly. The proportion of related donors <56 years of age decreased significantly. The body mass index and proportion of obese donors did not change significantly. The proportion of donors with low estimated GFR for age decreased significantly from 5% to 2.2% (P < 0.001). The proportion of donors with adequate follow-up after donation increased from 19.6% to 42.5% (P < 0.001). No donor had a risk indicator equal to 4, and the proportion of donors with a risk indicator equal to 0 increased significantly from 19.2% to 24.9% (P < 0.001). CONCLUSIONS: An increase in living kidney donation in France does not seem to be associated with the selection of donors at higher risk of ESRD and the proportion of donors with adequate annual follow-up significantly increased.

Drug-induced hepatic steatosis in absence of severe mitochondrial dysfunction in HepaRG cells: proof of multiple mechanism-based toxicity.

Steatosis is a liver lesion reported with numerous pharmaceuticals. Prior studies showed that severe impairment of mitochondrial fatty acid oxidation (mtFAO) constantly leads to lipid accretion in liver. However, much less is known about the mechanism(s) of drug-induced steatosis in the absence of severe mitochondrial dysfunction, although previous studies suggested the involvement of mild-to-moderate inhibition of mtFAO, increased de novo lipogenesis (DNL), and impairment of very low-density lipoprotein (VLDL) secretion. The objective of our study, mainly carried out in human hepatoma HepaRG cells, was to investigate these 3 mechanisms with 12 drugs able to induce steatosis in human: amiodarone (AMIO, used as positive control), allopurinol (ALLO), D-penicillamine (DPEN), 5-fluorouracil (5FU), indinavir (INDI), indomethacin (INDO), methimazole (METHI), methotrexate (METHO), nifedipine (NIF), rifampicin (RIF), sulindac (SUL), and troglitazone (TRO). Hepatic cells were exposed to drugs for 4 days with concentrations decreasing ATP level by less than 30% as compared to control and not exceeding 100 × Cmax. Among the 12 drugs, AMIO, ALLO, 5FU, INDI, INDO, METHO, RIF, SUL, and TRO induced steatosis in HepaRG cells. AMIO, INDO, and RIF decreased mtFAO. AMIO, INDO, and SUL enhanced DNL. ALLO, 5FU, INDI, INDO, SUL, RIF, and TRO impaired VLDL secretion. These seven drugs reduced the mRNA level of genes playing a major role in VLDL assembly and also induced endoplasmic reticulum (ER) stress. Thus, in the absence of severe mitochondrial dysfunction, drug-induced steatosis can be triggered by different mechanisms, although impairment of VLDL secretion seems more frequently involved, possibly as a consequence of ER stress.

Antiplatelet Therapy During Emergent Extracranial Internal Carotid Artery Stenting: Comparison of Three Intravenous Antiplatelet Perioperative Strategies.

INTRODUCTION: Guidelines for antiplatelet therapy administration, during emergent stenting for extra-cranial internal carotid artery (EC-ICA) occlusion in the setting of acute ischemic stroke (AIS) are lacking. Different antiplatelet regimen are used in association to endovascular therapy (EVT) for the treatment of EC-ICA lesions. We aimed to compare the clinical and radiological effects of three intravenous antiplatelet agents used during emergent EC-ICA stenting. MATERIAL AND METHODS: Clinical data were collected from January 2015 to December 2019 in a monocentric prospective registry of AIS patients treated by EVT. All patients who underwent emergent EC-ICA stenting were sorted regarding the intravenous antiplatelet agent used during the procedure. RESULTS: Among 218 patients treated by EVT for an EC-ICA occlusion of the anterior circulation during the study period, 70 underwent an emergent stenting of the EC-ICA. 60 were included in the present study, 9 received intravenous (IV) Cangrelor, 8 IV abciximab and 43 Aspirin. The rate of favorable neurological outcome, defined as modified Rankin Scale (mRS) ≤ 2 at three months were better in the Cangrelor and Aspirin groups (66,7% and 58,1%, respectively) than in the Abciximab group (37,5%), as well as, the rate of any intracranial ICH (22,2% and 37,2% vs 62,5%). The rate of acute stent reocclusion was similar between groups. CONCLUSION: When used as a rescue treatment during emergent stenting of EC-ICA, Cangrelor and Aspirin present a better safety profile than Abciximab, with less intracranial hemorrhages and a higher rate of good clinical outcome. Additional studies are needed to confirm these findings.

Population pharmacokinetics of gentamicin in haemodialysis patients: modelling, simulations and recommendations.

PURPOSE: The usual recommended dose for gentamicin is 3 to 7 mg/kg/day for patients with a normal renal function while 1.7 mg/kg/day is recommended for patients undergoing chronic haemodialysis. The objectives of this study were to develop a population pharmacokinetics model (POPPK) for gentamicin, designed for patients undergoing dialysis, and to investigate the best dosing scheme for different MIC clinical breakpoints using Monte Carlo simulations. METHODS: In this monocentric prospective interventional open clinical study, 23 patients (141 gentamicin samples) were included. The covariates investigated were weight, creatinine, dialysis (yes/no), dialysis flow and dialysis duration. The POPPK model was developed in Pmetrics and 1000 time-concentration profiles were simulated for 9 doses between 2 and 10 mg/kg/day, with an inter-dose period of 24, 48 or 96 h to predict the probability of having both a serum peak > 8*MIC and a trough < 1 mg/L for MIC values between 0.25 and 4 mg/L. RESULTS: A two-compartment model including the dialysis on the elimination constant and bodyweight on the volume of distribution best described the data. A 30-min gentamicin infusion of 2 mg/kg/day (for MIC = 1 mg/L) or 8 mg/kg/day (for MIC = 4 mg/L) just before dialysis eliminated by two dialysis sessions before the next administration (dose interval of at least 96 h) led to a peak > 8*MIC for > 90% of the simulations and a trough concentration < 1 mg/L at 96 h for 92% and 34% respectively. CONCLUSION: The gentamicin dose generally used to treat infections in dialysis patients is insufficient and might be increased to 3-8 mg/kg/day just before dialysis, taking into account the type of infection.

Resistance to Insulin in Patients with Gitelman Syndrome and a Subtle Intermediate Phenotype in Heterozygous Carriers: A Cross-Sectional Study.

BACKGROUND: Gitelman syndrome is a salt-losing tubulopathy caused by mutations in the SLC12A3 gene, which encodes the thiazide-sensitive sodium-chloride cotransporter. Previous studies suggested an intermediate phenotype for heterozygous carriers. METHODS: To evaluate the phenotype of heterozygous carriers of pathogenic SLC12A3 mutations, we performed a cross-sectional study of patients with Gitelman syndrome, heterozygous carriers, and healthy noncarriers. Participants measured their BP at home for three consecutive days before hospital admission for blood and urine sampling and an oral glucose tolerance test. RESULTS: We enrolled 242 participants, aged 18-75 years, including 81 heterozygous carriers, 82 healthy noncarriers, and 79 patients with Gitelman syndrome. The three groups had similar age, sex ratio, and body mass index. Compared with healthy noncarriers, heterozygous carriers showed significantly higher serum calcium concentration (P=0.01) and a trend for higher plasma aldosterone (P=0.06), but measures of home BP, plasma and urine electrolytes, renin, parathyroid hormone, vitamin D, and response to oral glucose tolerance testing were similar. Patients with Gitelman syndrome had lower systolic BP and higher heart rate than noncarriers and heterozygote carriers; they also had significantly higher fasting serum glucose concentration, higher levels of markers of insulin resistance, and a three-fold higher sensitivity to overweight. According to oral glucose tolerance testing, approximately 14% of patients with Gitelman syndrome were prediabetic, compared with 5% of heterozygous carriers and 4% of healthy noncarriers. CONCLUSIONS: Heterozygous carriers had a weak intermediate phenotype, between that of healthy noncarriers and patients with Gitelman syndrome. Moreover, the latter are at risk for development of type 2 diabetes, indicating the heightened importance of body weight control in these patients.

Physiological properties of the lamina I spinoparabrachial neurons in the mouse.

KEY POINTS: Spinal cord lamina I neurons receiving dense input from nociceptors and projecting to the parabrachial area at the ponto-mesencephalic junction form the major ascending pain-related pathway in rodents. Lamina I spinoparabrachial (SPB) neurons have never been characterized in mice, despite the growing and extensive use of this species to understand the contribution of lamina I SPB neurons in chronic pain. The electrophysiological properties of lamina I SPB neurons recorded here in anaesthetized mice are comparable to those of rat or cat, forming a nociceptive and thermoreceptive pathway. It was confirmed 'on line' that lamina I SPB neurons that normally encode noxious stimuli can receive input from low threshold mechanoreceptors in certain conditions. The present work indicates that the study of lamina I SPB neurons in vivo could take advantage of the use of genetically modified mice. ABSTRACT: Ongoing studies investigating the role of lamina I projection neurons in the generation of chronic pain are mainly based on the use of genetically modified mice. However, lamina I projection neurons have never been physiologically characterized in this species. The present work aimed to fill this gap, and to assess the effect of spinal 'disinhibition' that may occur in chronic pain states on the responses of these neurons to light touch. Seventy lamina I spinoparabrachial (SPB) neurons were characterized in anaesthetized mice. These neurons showed low central conduction velocities (<12.4 m s-1 ) and wide range of responses. Fifty-six neurons responded equally to noxious mechanical and thermal (heat) stimuli (16% responded consistently to light touch). Modality-specific neurons responded preferentially to thermal (cold) stimuli (n = 10) and pinch (n = 2), or specifically to heat (n = 2). Spinal bicuculline and strychnine application induced responses to brush in half of the neurons tested, confirming directly the potential connection between low threshold mechanoreceptors and nociceptive-specific neurons, responsible for mechanical allodynia. Remarkably, the effect of the treatment was highly variable and apparently independent of the initial profile of the neurons. The present data confirm that mice lamina I SPB neurons have the expected characteristics to form a nociceptive and thermoreceptive pathway, but they constitute a highly heterogeneous group. The differential effect of spinal disinhibition observed here suggests that a subgroup of lamina I SPB neurons might be responsible for abnormal pain in pathological conditions, and emphasizes the importance of in vivo recording, a neglected approach.

Identification of genetic causes for sporadic steroid-resistant nephrotic syndrome in adults.

Monogenic forms of Steroid-Resistant Nephrotic Syndrome (SRNS) have been widely characterized, but genetic screening paradigms preferentially address congenital, infantile onset, and familial cases. Our aim was to characterize the distribution of disease-causing gene mutations in adults with sporadic SRNS or focal segmental glomerulosclerosis (FSGS). We selected adult patients with non-syndromic, biopsy-proven FSGS or SRNS in the absence of known family history. Strict clinical criteria included lack of response to glucocorticoids and cyclosporine, and no recurrence after kidney transplantation. Mutations in SRNS genes were detected using a targeted gene panel. Sixteen of 135 tested participants (11.8%) carried pathogenic mutations in monogenic SRNS genes, and 14 others (10.4%) carried two APOL1 high-risk alleles. Autosomal recessive disease was diagnosed in 5 participants, autosomal dominant disease in 9, and X-linked disease in 2. Four participants carried a de novo heterozygous mutation. Among the 16 participants with identified mutations in monogenic SNRS genes, 7 (43.7%) had type IV collagen mutations. Mutations in monogenic SNRS genes were identified primarily in participants with proteinuria onset before 25 years of age, while the age at disease onset was variable in those with APOL1 high-risk genotype. Mean age at diagnosis was lower and renal survival was worse in participants with identified mutations in SNRS genes than in those without mutations. We found a significant rate of pathogenic mutations in adults with SRNS, with Type IV collagen mutations being the most frequent. These findings may have immediate impact on clinical practice.

Indomethacin, amiloride, or eplerenone for treating hypokalemia in Gitelman syndrome.

Patients with Gitelman syndrome (GS), an inherited salt-losing tubulopathy, are usually treated with potassium-sparing diuretics or nonsteroidal anti-inflammatory drugs and oral potassium and magnesium supplementations. However, evidence supporting these treatment options is limited to case series studies. We designed an open-label, randomized, crossover study with blind end point evaluation to compare the efficacy and safety of 6-week treatments with one time daily 75 mg slow-release indomethacin, 150 mg eplerenone, or 20 mg amiloride added to constant potassium and magnesium supplementation in 30 patients with GS (individual participation: 48 weeks). Baseline plasma potassium concentration was 2.8±0.4 mmol/L and increased by 0.38 mmol/L (95% confidence interval [95% CI], 0.23 to 0.53; P<0.001) with indomethacin, 0.15 mmol/L (95% CI, 0.02 to 0.29; P=0.03) with eplerenone, and 0.19 mmol/L (95% CI, 0.05 to 0.33; P<0.01) with amiloride. Fifteen patients became normokalemic: six with indomethacin, three with eplerenone, and six with amiloride. Indomethacin significantly reduced eGFR and plasma renin concentration. Eplerenone and amiloride each increased plasma aldosterone by 3-fold and renin concentration slightly but did not significantly change eGFR. BP did not significantly change. Eight patients discontinued treatment early because of gastrointestinal intolerance to indomethacin (six patients) and hypotension with eplerenone (two patients). In conclusion, each drug increases plasma potassium concentration in patients with GS. Indomethacin was the most effective but can cause gastrointestinal intolerance and decreased eGFR. Amiloride and eplerenone have similar but lower efficacies and increase sodium depletion. The benefit/risk ratio of each drug should be carefully evaluated for each patient.

Busulfan induces steatosis in HepaRG cells but not in primary human hepatocytes: Possible explanations and implication for the prediction of drug-induced liver injury.

BACKGROUND: The antineoplastic drug busulfan can induce different hepatic lesions including cholestasis and sinusoidal obstruction syndrome. However, hepatic steatosis has never been reported in patients. OBJECTIVES: This study aimed to determine whether busulfan could induce steatosis in primary human hepatocytes (PHH) and differentiated HepaRG cells. METHODS: Neutral lipids were determined in PHH and HepaRG cells. Mechanistic investigations were performed in HepaRG cells by measuring metabolic fluxes linked to lipid homeostasis, reduced glutathione (GSH) levels, and expression of genes involved in lipid metabolism and endoplasmic reticulum (ER) stress. Analysis of two previous transcriptomic datasets was carried out. RESULTS: Busulfan induced lipid accumulation in HepaRG cells but not in six different batches of PHH. In HepaRG cells, busulfan impaired VLDL secretion, increased fatty acid uptake, and induced ER stress. Transcriptomic data analysis and decreased GSH levels suggested that busulfan-induced steatosis might be linked to the high expression of glutathione S-transferase (GST) isoenzyme A1, which is responsible for the formation of the hepatotoxic sulfonium cation conjugate. In keeping with this, the GST inhibitor ethacrynic acid and the chemical chaperone tauroursodeoxycholic acid alleviated busulfan-induced lipid accumulation in HepaRG cells supporting the role of the sulfonium cation conjugate and ER stress in steatosis. CONCLUSION: While the HepaRG cell line is an invaluable tool for pharmacotoxicological studies, it might not be always an appropriate model to predict and mechanistically investigate drug-induced liver injury. Hence, we recommend carrying out toxicological investigations in both HepaRG cells and PHH to avoid drawing wrong conclusions on the potential hepatotoxicity of drugs and other xenobiotics.

Drug-induced impairment of mitochondrial fatty acid oxidation and steatosis: assessment of causal relationship with 45 pharmaceuticals.

Drug-induced liver injury (DILI) represents a major issue for pharmaceutical companies, being a potential cause of black-box warnings on marketed pharmaceuticals, or drug withdrawal from the market. Lipid accumulation in the liver also referred to as steatosis, may be secondary to impaired mitochondrial fatty acid oxidation (mtFAO). However, an overall causal relationship between drug-induced mtFAO inhibition and the occurrence of steatosis in patients has not yet been established with a high number of pharmaceuticals. Hence, 32 steatogenic and 13 non-steatogenic drugs were tested for their ability to inhibit mtFAO in isolated mouse liver mitochondria. To this end, mitochondrial respiration was measured with palmitoyl-L-carnitine, palmitoyl-CoA + L-carnitine, or octanoyl-L-carnitine. This mtFAO tri-parametric assay was able to predict the occurrence of steatosis in patients with a sensitivity and positive predictive value above 88%. To get further information regarding the mechanism of drug-induced mtFAO impairment, mitochondrial respiration was also measured with malate/glutamate or succinate. Drugs such as diclofenac, methotrexate and troglitazone could inhibit mtFAO secondary to an impairment of the mitochondrial respiratory chain, while dexamethasone, olanzapine and zidovudine appeared to impair mtFAO directly. Mitochondrial swelling, transmembrane potential and production of reactive oxygen species were also assessed for all compounds. Only the steatogenic drugs amiodarone, ketoconazole, lovastatin and toremifene altered all these 3 mitochondrial parameters. In conclusion, our tri-parametric mtFAO assay could be useful in predicting the occurrence of steatosis in patients. The combination of this assay with other mitochondrial parameters could also help to better understand the mechanism of drug-induced mtFAO inhibition.

Mechanisms of hepatocellular toxicity associated with the components of St. John's Wort extract hypericin and hyperforin in HepG2 and HepaRG cells.

St. John's Wort preparations are used for the treatment of mild to moderate depression. They are usually well tolerated but can cause adverse reactions including liver toxicity in rare cases. To date, the mechanism(s) underlying the hepatotoxicity of St. John's Wort extracts are poorly investigated. We studied the hepatocellular toxicity of hypericin and hyperforin as the two main ingredients of St. John's Wort extracts in HepG2 and HepaRG cells and compared the effects to citalopram (a synthetic serotonin uptake inhibitor) with a special focus on mitochondrial toxicity and oxidative stress. In HepG2 cells, hypericin was membrane-toxic at 100 µM and depleted ATP at 20 µM. In HepaRG cells, ATP depletion started at 5 µM. In comparison, hyperforin and citalopram were not toxic up to 100 µM. In HepG2 cells, hypericin decreased maximal respiration starting at 2 µM and mitochondrial ATP formation starting at 10 µM but did not affect glycolytic ATP production. Hypericin inhibited the activity of complex I, II and IV of the electron transfer system and caused mitochondrial superoxide accumulation in cells. The protein expression of mitochondrial superoxide dismutase 2 (SOD2) and thioredoxin 2 (TRX2) and total and reduced glutathione decreased in cells exposed to hypericin. Finally, hypericin diminished the mitochondrial DNA copy number and caused cell necrosis but not apoptosis. In conclusion, hypericin, but not hyperforin or citalopram, is a mitochondrial toxicant at low micromolar concentrations. This mechanism may contribute to the hepatotoxicity occasionally observed in susceptible patients treated with St. John's Wort preparations.

Angiographic Evolution of Brain Arteriovenous Malformation Angioarchitecture After Partial Endovascular Treatment.

BACKGROUND AND OBJECTIVES: Endovascular embolization of brain arteriovenous malformations (AVMs) is sometimes intentionally partial, in the case of staged treatment for instance. Residual AVMs may be prone to angioarchitectural modification during follow-up. The objective of this work is to evaluate the nature and extent of these modifications. METHODS: We performed a retrospective monocentric study on a cohort of adult patients treated by incomplete endovascular embolization for ruptured and unruptured AVMs with an available angiographic follow-up, without any intervening confounding event between the 2 angiographic examinations. AVM angioarchitectural modifications (arterial, nidal, and venous) were analyzed. Clinical and radiological data were tested in univariate analyses for association with the occurrence of AVM regression or progression. RESULTS: Eighty-two partial embolization sessions in 57 patients were included in the study. A 40% (33/82) rate of modification was found on follow-up, with 23/82 (28%) controls showing at least one angioarchitectural regression feature and 15/82 (18.3%) showing at least one angioarchitectural progression item. Nidal growth was the most frequent modification occurring after 12/82 (14.6%) embolizations. The only factor associated with nidal volume growth was a longer time interval between embolization and follow-up (median [IQR]: 190 [250] days vs 89.5[133] days in the subgroup without nidal growth; P = .02). Specific modifications of arterial supply, nidal anatomy, and venous drainage were identified and documented. CONCLUSION: Angioarchitectural modifications (both progression and regression) of brain AVMs are frequent findings after partial embolization. Nidal volume growth is associated with longer time intervals between embolization and follow-up.

Comparison of rescue intracranial stenting versus best medical treatment alone in acute refractory large vessel occlusion: study protocol for the PISTAR multicenter randomized trial.

BACKGROUND: Mechanical thrombectomy (MT) has become a standard treatment for acute ischemic strokes (AIS). However, MT failure occurs in approximately 10-30% of cases, leading to severe repercussions (with mortality rates up to 40% according to observational data). Among the available rescue techniques, rescue intracranial stenting (RIS) appears as a promising option. OBJECTIVE: This trial is poised to demonstrate the superiority of RIS in addition to the best medical treatment (BMT) in comparison with BMT alone, in improving the functional outcomes at 3 months for patients experiencing an AIS due to a large vessel occlusion refractory to MT (rLVO). METHODS: Permanent Intracranial STenting for Acute Refractory large vessel occlusions (PISTAR) is a multicenter prospective randomized open, blinded endpoint trial conducted across 11 French University hospitals. Adult patients (≥18 years) with an acute intracranial occlusion refractory to standard MT techniques will be randomized 1:1 during the procedure to receive either RIS+BMT (intervention arm) or BMT alone (control arm). RESULTS: The primary outcome is the rate of good clinical outcome at 3 months defined as a modified Rankin Scale score ≤2 and evaluated by an independent assessor blinded to the randomization arm. Secondary outcomes include hemorrhagic complications, all adverse events, and death. The number of patients to be included is 346. Two interim analyses are planned with predefined stopping rules. CONCLUSION: The PISTAR trial is the first randomized controlled trial focusing on the benefit of RIS in rLVOs. If positive, this study will open new insights into the management of AIS. TRIAL REGISTRATION NUMBER: NCT06071091.

Vaginal lubrication after cervicovaginal stimulation is facilitated by phosphodiesterase type 5 inhibition in ovariectomized mice.

INTRODUCTION: Nitric oxide synthases (NOSs) and estrogen receptors are expressed in the vagina. AIM: We aimed to assess the impact of sildenafil on vaginal lubrication according to the hormonal status and to determine the role of the neuronal isoform of NOS (nNOS). METHODS: Four-week-old C57/BL6 female mice were sham operated or ovariectomized. At 10 weeks of age, they were injected intraperitoneally by any combination of sildenafil, 7-nitroindazole (7-NI)--a potent selective nNOS inhibitor--or the corresponding vehicles. Vaginal lubrication was induced in a physiological manner by cervical vaginal probing and quantified depending on the hormonal and pharmacological conditions. The animals were then sacrificed for vaginal histomorphometry. MAIN OUTCOME MEASURES: The main outcome measure is the quantification of vaginal transudate after cervicovaginal stimulation and vaginal histomorphometry. RESULTS: Sildenafil increased cervicovaginal probing-induced vaginal lubrication in ovariectomized and sham-operated animals. Ovariectomized mice exhibited decreased vaginal lubrication as compared with sham-operated mice. When taking into account the presence of severe vaginal atrophy, a threefold increase in transudate per gram of vagina wet weight was revealed in ovariectomized animals. Castration markedly reduced the thickness of the vaginal wall. nNOS inhibition by 7-NI had no impact on vaginal lubrication. CONCLUSIONS: Irrespective of the hormonal status, sildenafil increased vaginal lubrication. The vaginal effect of sildenafil was independent of the nNOS pathway and more pronounced in ovariectomized animals.

The clinical status and survival in elderly dialysis: example of the oldest region of France.

BACKGROUND: The number of elderly (≥75 years) patients with end-stage renal disease (ESRD) has increased markedly, including in the Limousin region, which has the oldest population in France. We retrospectively compared outcomes in elderly and non-elderly ESRD patients who started dialysis during two time periods. METHODS: Baseline clinical characteristics, care, and survival rates were assessed in 557 ESRD patients aged ≥75 and <75 years who started dialysis in 2002-2004 and 2005-2007. Survival curves and Cox proportional hazards model were used to assess survival and factors associated with survival. RESULTS: Of the 557 patients, 343 and 214 were <75 years and ≥75 years, respectively. Dialysis was started in 2002-2004 and 2005-2007 by 197 and 146 patients <75 years, respectively, and by 96 and 118 patients ≥75 years, respectively. Median age (73.4 years [interquartile range [IQR] 61.7-79.5 years] vs 69.5 years [IQR 57.4-77.4 years] p = 0.001) and the proportion aged ≥75 years (44.7% vs 32.8%, p = 0.004) were significantly higher in 2005-2007 than in 2002-2004. Improved initial status during 2005-2007 was observed only in patients ≥75 years, with a decrease in some co-morbidities, improved walking and better preparation for dialysis. Mortality rates were significantly lower in 2005-2007 than in 2002-2004 (hazard ratio 0.81, 95% confidence interval 0.69-0.95; p = 0.008), with the difference due to factors associated with clinical status and care. CONCLUSIONS: Improved initial clinical status and better preparation for dialysis, accompanied by increased survival, were observed for patients ≥75 years who started dialysis more recently, perhaps because of early referral to a nephrologist.

Assessment of the inhibitory potential of anabolic steroids towards human AKR1D1 by computational methods and in vitro evaluation.

Exposure to xenobiotics can adversely affect biochemical reactions, including hepatic bile acid synthesis. Bile acids are essential for dissolving lipophilic compounds in the hydrophilic environment of the gastrointestinal tract. The critical micellar concentration of bile acids depends on the Δ4-reduction stereochemistry, with the 3-oxo-5ß-steroid-Δ4-dehydrogenase (AKR1D1) introducing the cis ring A/B conformation. Loss-of-function mutations in AKR1D1 cause hepatic cholestasis, which, if left untreated can progress into steatosis and liver cirrhosis. Furthermore, AKR1D1 is involved in clearing steroids with an A-ring Δ4-double bond. Here, we tested whether anabolic-androgenic steroids (AAS), often taken off-label at high doses, might inhibit AKR1D1, thereby potentially causing hepatotoxicity. A computational molecular model was established and used for virtual screening of the DrugBank database consisting of 2740 molecules, yielding mainly steroidal hits. Fourteen AAS were selected for in vitro evaluation, as such compounds can reach high hepatic concentrations in an abuse situation. Nandrolone, clostebol, methasterone, drostanolone, and methenolone inhibited to various extent the AKR1D1-mediated reduction of testosterone. Molecular modeling suggests that 9 out of 14 investigated AAS are competitive inhibitors. Moreover quantum mechanical calculations show that nadrolone and clostebol are substrates of AKR1D1 with different activation energy barriers for the hydrogen transfer from cofactor to the C5 position affecting their turnover. In this multidisciplinary approach, we established a molecular model of AKR1D1, identified several AAS as inhibitors, and described their binding mode. This approach may be applied to study other classes of inhibitors including non-steroidal compounds.