Heritability of fetal hemoglobin, white cell count, and other clinical traits from a sickle cell disease family cohort

Sickle cell disease (SCD) is the most common monogenic disorder in the world. Notably, there is extensive clinical heterogeneity in SCD that cannot be fully accounted for by known factors, and in particular, the extent to which the phenotypic diversity of SCD can be explained by genetic variation has not been reliably quantified. Here, in a family-based cohort of 449 patients with SCD and 755 relatives, we first show that 5 known modifiers affect 11 adverse outcomes in SCD to varying degrees. We then utilize a restricted maximum likelihood procedure to estimate the heritability of 20 hematologic traits, including fetal hemoglobin (HbF) and white blood cell count (WBC), in the clinically relevant context of inheritance from healthy carriers to SCD patients. We report novel estimations of heritability for HbF at 31.6% (±5.4%) and WBC at 41.2% (±6.8%) in our cohort. Finally, we demonstrate shared genetic bases between HbF, WBC, and other hematologic traits, but surprisingly little overlap between HbF and WBC themselves. In total, our analyses show that HbF and WBC have significant heritable components among individuals with SCD and their relatives, demonstrating the value of using family-based studies to better understand modifiers of SCD

Current Smoking and Prognosis After Acute ST-Segment Elevation Myocardial Infarction:New Pathophysiological Insights

Objectives: The aim of this study was to mechanistically investigate associations among cigarette smoking, microvascular pathology, and longer term health outcomes in patients with acute ST-segment elevation myocardial infarction (MI). Background: The pathophysiology of myocardial reperfusion injury and prognosis in smokers with acute ST-segment elevation MI is incompletely understood. Methods: Patients were prospectively enrolled during emergency percutaneous coronary intervention. Microvascular function in the culprit artery was measured invasively. Contrast-enhanced magnetic resonance imaging (1.5-T) was performed 2 days and 6 months post-MI. Infarct size and microvascular obstruction were assessed using late gadolinium enhancement imaging. Myocardial hemorrhage was assessed with T2* mapping. Pre-specified endpoints included: 1) all-cause death or first heart failure hospitalization; and 2) cardiac death, nonfatal MI, or urgent coronary revascularization (major adverse cardiovascular events). Binary logistic regression (odds ratio [OR] with 95% confidence interval [CI]) with smoking status was used. Results: In total, 324 patients with ST-segment elevation MI were enrolled (mean age 59 years, 73% men, 60% current smokers). Current smokers were younger (55 ± 11 years vs. 65 ± 10 years, p < 0.001), with fewer patients with hypertension (52 ± 27% vs. 53 ± 41%, p = 0.007). Smokers had better TIMI (Thrombolysis In Myocardial Infarction) flow grade (≥2 vs. ≤1, p = 0.024) and ST-segment resolution (none vs. partial vs. complete, p = 0.010) post–percutaneous coronary intervention. On day 1, smokers had higher circulating C-reactive protein, neutrophil, and monocyte levels. Two days post-MI, smoking independently predicted infarct zone hemorrhage (OR: 2.76; 95% CI: 1.42 to 5.37; p = 0.003). After a median follow-up period of 4 years, smoking independently predicted all-cause death or heart failure events (OR: 2.20; 95% CI: 1.07 to 4.54) and major adverse cardiovascular events (OR: 2.79; 95% CI: 2.30 to 5.99). Conclusions: Smoking is associated with enhanced inflammation acutely, infarct-zone hemorrhage subsequently, and longer term adverse cardiac outcomes. Inflammation and irreversible myocardial hemorrhage post-MI represent mechanistic drivers for adverse long-term prognosis in smokers. (Detection and Significance of Heart Injury in ST Elevation Myocardial Infarction. [BHF MR-MI]; NCT02072850)

Schizophrenia Bulletin Open

Treatment-resistant schizophrenia (TRS) affects around 30% of patients with schizophrenia (SZ) resulting in poor functioning, relapses, and reduced quality of life. Convergent findings show that inflammation could contribute to resistance. We thus search for immune signatures of patients with TRS/ultra TRS (UTRS) in a sample of community-dwelling outpatients with SZ. In total, 195 stabilized SZ patients (mean age = 31.2 years, 73% male gender) were consecutively included in the network of the FondaMental Expert Centers for Schizophrenia in France and received a thorough clinical assessment. At inclusion, psychotic symptomatology was evaluated by the Positive and Negative Syndrome Scale (PANSS) for schizophrenia. Circulating serum/plasma levels of a large panel of markers reflecting the main inflammatory pathways were evaluated. TRS was defined by current treatment by clozapine (CLZ) and UTRS by current CLZ treatment + PANSS total score ≥ 70. The frequency of TRS and UTRS patients was, respectively, 20% and 7.7% and was defined using multivariable analysis elevated by high levels of interleukin (IL)-12/IL-23p40, IL-17A, IL-10, and beta 2 microglobulin (B2M) and IL-12/IL-23p40, IL-17A, IL-6, IL-10, IFNγ, and B2M, respectively. These observations suggest that resistance and ultra resistance to CLZ treatment are underpinned by pro-inflammatory molecules mainly belonging to the T helper 17 pathway, a finding making sense given the interplay between inflammation and antipsychotic treatment responses. If confirmed, our findings may allow us to consider IL-23/IL-17 pathway as a therapeutic target for patients with resistance to antipsychotics.Sorbonne Universités à Paris pour l'Enseignement et la RechercheFondaMental-Cohorte

Genetic Characterization and Clinical Features of Helicobacter pylori Negative Gastric Mucosa-Associated Lymphoid Tissue Lymphoma

Background: In Western countries, the prevalence of gastric mucosa-associated lymphoid tissue (MALT) lymphoma has declined over the last three decades. Contemporaneously, H. pylori negative gastric MALT lymphoma is increasingly encountered, and their genetic basis and clinical features remain elusive. Methods: A total of 57 cases of H. pylori negative gastric MALT lymphoma were reviewed and investigated for chromosome translocation by fluorescence in-situ hybridization and for somatic mutations by the targeted sequencing of 93 genes. Results: MALT1 translocation, most likely t(11;18)(q21;q21)/BIRC3-MALT1, was detected in 39% (22/57) cases, and IGH translocation was further seen in 12 MALT1-negative cases, together accounting for 60% of the cohort. Targeted sequencing was successful in 35 cases, and showed frequent mutations in NF-κB signaling pathways (TNFAIP3 = 23%, CARD11 = 9%, MAP3K14 = 9%), together affecting 14 cases (40%). The NF-κB pathway mutations were mutually exclusive from MALT1, albeit not IGH translocation, altogether occurring in 86% of cases. There was no significant correlation between the genetic changes and clinicopathological parameters. The patients showed a median of progression-free survival (PFS) of 66.3 months, and a significant superior PFS when treated with systemic versus antibiotic therapy (p = 0.004). Conclusion: H. pylori negative gastric MALT lymphoma is characterized by highly frequent genetic changes in the NF-κB signaling pathways

Cognitive behaviour therapy plus aerobic exercise training to increase activity in patients with myotonic dystrophy type 1 (DM1) compared to usual care (OPTIMISTIC):Study protocol for randomised controlled trial

Peer reviewedPublisher PD

Factors involved in the pharmacokinetic variability in two glucuronidated drugs, mycophenolic acid and raltegravir

La variabilité pharmacocinétique liée à une élimination des médicaments par glucuronoconjugaison a été peu étudiée. Nous avons donc choisi d’étudier les caractéristiques pharmacocinétiques de deux médicaments glucuronoconjugués, l’acide mycophénolique (MPA, prodrogue, mycophénolate mofétil ou MMF) et le raltégravir, dans certaines situations cliniques spécifiques. Deux études cliniques ont été réalisées avec le MMF. En transplantation hépatique pédiatrique, des AUC0-12 de MPA supérieures à 30 mg.h/L ont été obtenues chez tous les enfants avec une dose de 600 mg/m² de MMF administrée par voie orale deux fois par jour. L’estimation de l’AUC0-12 par méthode non compartimentale étant particulièrement contraignante en pédiatrie, nous avons développé une stratégie de prélèvements limités permettant une estimation à partir de seulement trois prélèvements. Chez des patients adultes transplantés rénaux, nos travaux ont permis de caractériser le polymorphisme génétique des transporteurs ABCC2 et ABCB1 et l’albuminémie comme étant des facteurs de variabilité inter et intra-individuelle de la pharmacocinétique du MPA. Les concentrations intracellulaires moyennes de MPA dans les cellules mononuclées du sang périphérique étaient élevées et largement supérieures à la concentration de MPA inhibant 50% de l’activité de l’IMPDH. Nos premiers résultats concernant le raltégravir montrent que ses paramètres pharmacocinétiques sont caractérisés par une variabilité inter-individuelle importante chez des patients infectés par le VIH. Nous avons établi que le raltégravir ne se fixe pas du tout sur l’alpha-1-glycoprotéine acide mais se fixe à 60% sur l’albumine, cette fixation étant dépendante du pH plasmatique. Cependant, cette forte liaison du raltégravir à l’albumine n’empêche pas une bonne diffusion du médicament dans le compartiment séminal. En conclusion, les études de pharmacocinétique clinique que nous avons menées montrent que la variabilité de la pharmacocinétique de ces deux médicaments glucuronoconjugués est aussi importante que pour des médicaments métabolisés par le cytochrome P450 3A4. L’identification des facteurs de variabilité de ces médicaments contribue à l’optimisation des traitements.Pharmacokinetic variability was poorly studied for drugs eliminated by glucuronidation. We therefore chose to study the pharmacokinetic parameters of two glucuronidated drugs, mycophenolic acid (MPA, prodrug, mycophenolate mofetil or MMF) and raltegravir, in specific clinical situations. Two clinical studies were conducted with MMF. In pediatric liver transplantation, MPA AUC0-12 above the target AUC of 30 mg.h/L were obtained in all children with a MMF dosing regimen of 600 mg/m² administered orally twice a day. As extensive AUC monitoring is laborious, especially in children, we developed a limited sampling strategy to calculate MPA AUC0-12 with only three samples. In adult renal transplantation, our work allowed us to characterize genetic polymorphism of ABCC2 and ABCB1 genes and serum albumin as factors of inter and intraindividual variability in MPA pharmacokinetics. We demonstrated that MPA concentrations in peripheral blood mononuclear cells were high and well above the concentration of MPA responsible for a 50%-inhibition of the activity of IMPDH. Our first results show that the raltegravir pharmacokinetics is characterized by a wide interindividual variability in HIV-infected patients. Raltegravir does not bind to alpha-1-acid glycoprotein but binds to 60% to albumin and this binding is pH-dependent. Despite this high protein binding, a good penetration into the seminal compartment was evidenced. In conclusion, these clinical pharmacokinetic studies demonstrated that the variability in the pharmacokinetics of these glucuronidated drugs is as important as the one exhibited by drugs metabolized by cytochrome P450 3A4. Identifying factors of variability of these glucuronidated drugs contributes to optimizing patient care

Optimisation du suivi thérapeutique pharmacologique des immunosuppresseurs en transplantation d'organe

PARIS-BIUP (751062107) / SudocSudocFranceF

Population Pharmacokinetic Model of Plasma and Cellular Mycophenolic Acid in Kidney Transplant Patients from the CIMTRE Study

International audienceBackground and Objective Mycophenolate mofetil is widely used in kidney transplant recipients. Mycophenolate mofetil is hydrolysed by blood esterases to mycophenolic acid (MPA), the active drug. Although MPA therapeutic drug monitoring has been recommended to optimise the treatment efficacy by the area under the plasma concentration vs time curve, little is known regarding MPA concentrations in peripheral blood mononuclear cells, where MPA inhibits inosine monophosphate dehydrogenase. This study aimed to build a pharmacokinetic model using a population approach to describe MPA total and unbound concentrations in plasma and into peripheral blood mononuclear cells in 78 adult kidney transplant recipients receiving mycophenolate mofetil therapy combined with tacrolimus and prednisone. Methods Total and unbound plasma concentrations and peripheral blood mononuclear cell concentrations were assayed. A three-compartment model, two for plasma MPA and one for peripheral blood mononuclear cell MPA, with a zero-order absorption and a first-order elimination was used to describe the data. Results Mycophenolic acid average concentrations in peripheral blood mononuclear cells were well above half-maximal effective concentration for inosine monophosphate dehydrogenase and no relationship was found with the occurrence of graft rejection. Three covariates affected unbound and intracellular MPA pharmacokinetics: creatinine clearance, which has an effect on unbound MPA clearance, human serum albumin, which influences fraction unbound MPA and theABCB1 3435 C>T(rs1045642) genetic polymorphism, which has an effect on MPA efflux transport from peripheral blood mononuclear cells. Conclusion This population pharmacokinetic model demonstrated the intracellular accumulation of MPA, the efflux of MPA out of the cells being dependent on P-glycoprotein transporters. Nevertheless, further studies are warranted to investigate the relevance of MPA concentrations in peripheral blood mononuclear cells to dosing regimen optimisation

Cardioprotective Signaling Pathways in Obese Mice Submitted to Regular Exercise: Effect on Oxysterols

Exercise induces cardioprotection against myocardial infarction, despite obesity, by restoring pro-survival pathways and increasing resistance of mitochondrial permeability transition pore (mPTP) opening at reperfusion. Among the mechanisms involved in the inactivation of these pathways, oxysterols appear interesting. Thus, we investigated the influence of regular exercise on the reperfusion injury salvage kinase (RISK) pathway, oxysterols, and mitochondria, in the absence of ischemia-reperfusion. We also studied 7β-hydroxycholesterol (7βOH) concentration (mass spectrometry) in human lean and obese subjects. Wild-type (WT) and obese (ob/ob) mice were assigned to sedentary conditions or regular treadmill exercise. Exercise significantly increased Akt phosphorylation, whereas 7βOH concentration was reduced. Moreover, exercise induced the translocation of PKCε from the cytosol to mitochondria. However, exercise did not affect the calcium concentration required to open mPTP in the mitochondria, neither in WT nor in ob/ob animals. Finally, human plasma 7βOH concentration was consistent with observations made in mice. In conclusion, regular exercise enhanced the RISK pathway by increasing kinase phosphorylation and PKCε translocation and decreasing 7βOH concentration. This activation needs the combination with stress conditions, i.e., ischemia-reperfusion, in order to inhibit mPTP opening at the onset of reperfusion. The human findings suggest 7βOH as a candidate marker for evaluating cardiovascular risk factors in obesity