Subject(s)
Lung Diseases , alpha 1-Antitrypsin Deficiency , Humans , Lung Diseases/diagnosis , Lung Diseases/etiology , Lung Diseases/therapy , alpha 1-Antitrypsin/therapeutic use , alpha 1-Antitrypsin Deficiency/complications , alpha 1-Antitrypsin Deficiency/diagnosis , alpha 1-Antitrypsin Deficiency/epidemiologyABSTRACT
INTRODUCTION: Telomeres are composed of a repeated sequence of double-stranded nucleotides TTAGGG and numerous proteins including the Shelterin complex. Their main role is to maintain the stability of the genome during cell replication through a mechanism of copying the repeted sequence by the telomerase complexe. All the diseases involving a deregulation of this complex are now grouped together under the term telomeropathies. They are difficult to diagnose and manage. Our objective was to describe the clinico-biological characteristics and treatments used, in patients affected by telomeropathies previously seen by an hematologist followed at the Lille University Hospital Center. METHODS: This is a retrospective, single-center study carried out within the department of internal medicine-clinical immunology, Reference center for rare autoimmune and systemic diseases at Lille University Hospital Center between 2005 and 2020 including all patients followed for telomeropathy. RESULTS: Probands and relatives were included. Fifteen patients were studied from 10 independant families. Sixty percent had an heterozygous TERC gene mutation. Sixty seven percent had haematological diseases including macrocytosis, anemia and/or thrombocytopenia, 20 % had a fibrotic hepatic disease, 27 % had a fibrotic pulmonary disease. Lymphocyte immunophenotyping showed a double negative T lymphocyte population with γδ TCR expression in 5 (33 %) patients. Forty-seven percent of the patients had not received any treatment. Twenty-seven percent were on androgen therapy. Twenty percent had received cyclosporine and 13 % anti-lymphocyte serum in the context of initial misdiagnosis. CONCLUSION: It is important to be aware of the complexity of telomeropathies, a differential diagnosis of immune aplastic anemia, in order to optimize management and avoid inappropriate treatments. Allografting of hematopoietic stem cells is the only potentially curative treatment. Our analysis found particularities in immunophenotyping lymphocyte not previously described to our knowledge, whose physiopathological imputability remains to be demonstrated.
Subject(s)
Anemia, Aplastic , Telomerase , Humans , Retrospective Studies , Shelterin Complex , Telomerase/genetics , Telomerase/metabolism , Telomere/metabolismABSTRACT
INTRODUCTION: Malignant pleural mesothelioma (MPM) is a quite rare cancer, but with increasing incidence, that is usually induced by previous asbestos exposure. Its prognosis is poor and there is no validated curative therapy to date. Surgery of MPM, done only by few expert teams within a multimodal treatment is of limited and still disputed value. The standard treatment of MPM, relying on first-line chemotherapy by combined cisplatin-pemetrexed is often poorly effective, even if combination with bevacizumab anti-VEGF antibodies has slightly improved the results. Moreover, no second line treatment is recommended in case of failure of this chemotherapy. Therefore, the search of new therapies or strategies is crucial and the recruitment of patients in clinical trials is highly encouraged. BACKGROUND: Among the treatments under investigation, various anti-tumour immunotherapies, in particular immune checkpoints inhibitors (ICI), currently exhibit the most promising preliminary results. First data from the phase II, randomized "IFCT MAPS-2", recently presented during the 2017 ASCO meeting, confirmed the value of ICI in MPM patients in cases of chemotherapy failure. OUTLOOK AND CONCLUSIONS: However, several exciting immunotherapies other than ICI are presently being evaluated in MPM and are reported in this article. Moreover, many questions still need to be answered about immunotherapy: what is its potential value as first line treatment? How to target the best candidates for these treatments? Which combinations between immunotherapy and standard chemotherapy, targeted therapies, surgery or radiotherapy? Finally, it is now essential that every clinician has sufficient knowledge about the possible toxicities of immunotherapy.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Immunotherapy/methods , Lung Neoplasms/drug therapy , Mesothelioma/drug therapy , Pleural Neoplasms/drug therapy , Bevacizumab/administration & dosage , Bevacizumab/adverse effects , Cisplatin/administration & dosage , Cisplatin/adverse effects , Combined Modality Therapy , Humans , Mesothelioma, Malignant , Pemetrexed/administration & dosage , Pemetrexed/adverse effectsABSTRACT
In vitro metabolism of permethrin, a pyrethroid insecticide, was assessed in primary human hepatocytes. In vitro kinetic experiments were performed to estimate the Michaelis-Menten parameters and the clearances or formation rates of the permethrin isomers (cis- and trans-) and three metabolites, cis- and trans-3-(2,2 dichlorovinyl)-2,2-dimethyl-(1-cyclopropane) carboxylic acid (cis- and trans-DCCA) and 3-phenoxybenzoic acid (3-PBA). Non-specific binding and the activity of the enzymes involved in permethrin's metabolism (cytochromes P450 and carboxylesterases) were quantified. Trans-permethrin was cleared more rapidly than cis-permethrin with a 2.6-factor (25.7±0.6 and 10.1±0.3 µL/min/10(6) cells respectively). A 3-factor was observed between the formation rates of DCCA and 3-PBA obtained from trans- and cis-permethrin. For both isomers, the rate of formation of DCCA was higher than the one of 3-PBA. The metabolism of the isomers in mixture was also quantified. The co-incubation of isomers at different ratios showed the low inhibitory potential of cis- and trans-permethrin on each other. The estimates of the clearances and the formation rates in the co-incubation condition did not differ from the estimates obtained with a separate incubation. These metabolic parameters may be integrated in physiologically based pharmacokinetic (PBPK) models to predict the fate of permethrin and metabolites in the human body.
Subject(s)
Hepatocytes/metabolism , Insecticides/metabolism , Permethrin/metabolism , Biotransformation , Cryopreservation , Cytochrome P-450 Enzyme System/metabolism , Esterases/metabolism , Female , Humans , Insecticides/chemistry , Isomerism , Male , Models, Statistical , Permethrin/chemistry , Primary Cell Culture , ToxicokineticsABSTRACT
An analytical method was developed to measure cis-permethrin and trans-permethrin in different biological rat matrices and fluids (whole blood, red blood cells, plasma, brain, liver, muscle, testes, kidneys, fat and faeces). The method was also suitable for the simultaneous quantification of their associated metabolites [cis-3-(2,2-dichlorovinyl)-2,2-dimethyl-(1-cyclopropane) carboxylic acid (cis-DCCA), trans-3-(2,2-dichlorovinyl)-2,2-dimethyl-(1-cyclopropane) carboxylic acid (trans-DCCA) and 3-phenoxybenzoic acid (3-PBA)] in blood (whole blood, red blood cells, plasma) and liver. The target analytes were derivatised in samples using a methanolic/hydrochloric acid solution and then extracted with toluene. The analysis was performed by gas chromatography, and detection using ion trap tandem mass spectrometry. The selectivity obtained for complex matrices such as rat organs allowed the use of a purification step to be avoided for most of the matrices investigated. In the case of fat, where permethrin is suspected to accumulate, a dedicated purification step was developed. In fluids, the limits of quantification were at the 50 ng/mL level for the parent compounds and 3-PBA and at 25 ng/mL for cis-DCCA and trans-DCCA. For solid matrices excluding fat, the limits of quantification ranged from 50 ng/g for muscle to 100 ng/g for brain and testes for both cis-permethrin and trans-permethrin. The extraction recoveries ranged primarily between 80 and 120% for the matrix tested. The stability of blood samples was tested through the addition of 1% v/v formic acid. The methods developed were applied in a toxicokinetic study in adult rats. cis-Permethrin and the metabolites were detected in all corresponding matrices, whereas trans-permethrin was detected only in blood, plasma and faeces.
Subject(s)
Gas Chromatography-Mass Spectrometry , Permethrin/blood , Permethrin/chemistry , Animals , Benzoates/chemistry , Brain/drug effects , Chemistry Techniques, Analytical , Environmental Exposure , Male , Pesticides/chemistry , Pyrethrins/chemistry , Quality Control , Rats , Rats, Sprague-Dawley , Testis/drug effects , Tissue Distribution , ToxicokineticsABSTRACT
INTRODUCTION: Obstructive Sleep Apnea (OSA) is a chronic, frequent pathology impacting patients' quality of life. Continuous positive airways pressure (CPAP) is the most effective treatment, but is often considered binding and thus poorly observed. The aim of this study was to assess the impact of an educational program in non-adherent patients with OSA, to identify the factors of inobservance and to determine risk groups. PATIENTS AND METHODS: We enrolled 21 patients presenting OSA in this monocentric, forward-looking study. Nineteen patients completed the study. The inclusion criterion was a daily observance less than 4 hours a night. Educational program was realized by a specialized, trained team, with the authorization of the Regional Agency of Health. RESULTS: Our population consisted of 15 male and six female, all of them obese, with a medium age of 57.7 ± 12.9 years, treated for 10,7 ± 15 months. All of our patients had few symptoms. After the educational program, two groups were individualized according to their observance. Fifty-two percent of patients became compliant to CPAP treatment. Demographic data and medical histories did not differ between these two groups: nine patients remained inobservant (medium daily treatment duration of 57 ± 49 minutes); ten patients became observant (medium daily treatment duration raising from 104 ± 70 minutes to 322 ± 65 minutes, P=0.0002). Among these ten patients, seven were considered as having accepted their disease at initial educational diagnosis. CONCLUSION: The educational program improved adherence to CPAP treatment in 52% of our patients. All included patients had few symptoms. This could raise the issue of a poorer perception of treatment efficacy in less symptomatic patients. Disease acceptance also appeared linked to CPAP treatment compliance.
Subject(s)
Continuous Positive Airway Pressure , Patient Compliance , Patient Education as Topic , Sleep Apnea, Obstructive/therapy , Adult , Aged , Continuous Positive Airway Pressure/psychology , Female , Follow-Up Studies , France , Home Care Services , Humans , Male , Middle Aged , Patient Compliance/psychology , Polysomnography , Prospective Studies , Quality of Life/psychology , Risk Factors , Sleep Apnea, Obstructive/psychologyABSTRACT
We report measurements of the oxygen-isotope effect (OIE) on the in-plane penetration depth lambda(ab)(0) in underdoped La2-xSrxCuO4 single crystals. A highly sensitive magnetic torque sensor with a resolution of Deltatau approximately 10(-12) N m was used for the magnetic measurements on microcrystals with a mass of approximately 10 &mgr;g. The OIE on lambda(-2)(ab)(0) is found to be -10(2)% for x = 0.080 and -8(1)% for x = 0.086. It arises mainly from the oxygen-mass dependence of the in-plane effective mass m(*)(ab). The present results suggest that lattice vibrations are important for the occurrence of high temperature superconductivity.
ABSTRACT
Ultrastructural and morphometric abnormalities of Syrian hamster cardiomyopathy were compared to those observed in two different models of cardiac hypertrophy produced by mechanical overload (abdominal aortic stenosis, 60-day duration) or by isoproterenol injection during 15 days in normal Syrian hamsters of the same strain. Aspects of increased protein synthesis were observed in all three groups of animals. This was the only abnormality observed in the aortic stenosis group. Cardiomyopathy was different from the two other types of overload by the existence of large calcium deposits inside of the myocytes, by the presence of thin filaments and amorphous material accumulation suggesting abnormal synthesis and by a significant reduction of myofibrils at the heart-failure phase. Nuclear abnormalities with nuclear constrictions suggesting a division process and an increased number of myocytes with two nuclei were present in both spontaneous cardiomyopathy and isoproterenol-induced cardiopathy. Therefore, Syrian hamster cardiomyopathy appears to be different from cardiopathy induced by hemodynamic overload but, in spite of specific aspects, resembles that induced by isoproterenol injections, strengthening the hypothesis of a pathogenic role of catecholamines in the Syrian hamster cardiomyopathy.
Subject(s)
Cardiomyopathies/pathology , Coronary Circulation , Coronary Disease/pathology , Myocardium/ultrastructure , Animals , Aortic Valve Stenosis/pathology , Cardiac Output, Low/pathology , Cardiomegaly/pathology , Cricetinae , Hemodynamics , Isoproterenol/pharmacology , Mesocricetus , Microscopy, Electron , Reference ValuesABSTRACT
The myocardial cell nucleus was studied in the rat during its normal growth and under different types of heart overloading. Under overloading of short duration, a disappearance of condensed chromatin and an increase in the nucleolus and nucleolonema were interpreted as representing cell overactivity. With isoproterenol overloading, a first stage of cell necrosis and of its consequences on chromatin and nucleolus was followed by the process of cell repair and overactivity. With overloading of long duration, several different nuclear aspects were encountered: (a) enlarged and distorted nuclei as possible supports of polyploidy; (b) a partial coupling between two adjacent nuclei, interpreted either as nuclear fusion or amitosis; (c) segregation of different proteins, probably due to cell damage. The number of nuclei per myocyte was high (90%) in the adult. It decreased (80%) two days after isoproterenol overloading, as well as in heart hypertrophy of 6-9-months duration. Nuclear size increased under isoproterenol overdosage of 48-h duration. The amount of nuclear DNA also increased two days after isoproterenol overdosage, particularly in mononucleated cells.