Electrical activity alterations induced by chronic absorption of lindane (gamma-hexachlorocyclohexane) trace concentrations in adult rat heart

International audienceThe heart of adult rat offspring, born to mothers treated with trace concentrations of lindane (0.5 to 2 ppb) through a beverage and to mothers chronically treated with lindane (CL-T) with the same trace concentration, also through a beverage, during lactation and growth has a round shape and accumulates lindane. The left ventricle (LV) presents a hypertrophied area, atrophied papillary muscles, and unorganized collagen bundles and layers. These observations led us to study the electrical activity of their left ventricle papillary muscles (LVPM) by recording action potential using intracellular microelectrodes. CL-T shortened LVPM action potential duration (APD): 1 ppb shortened the plateau; 2 ppb shortened the plateau and the slow repolarizing phase. In CL-T (2 ppb) and untreated groups, low temperature (22 degrees C) decreased the resting potential and prolonged APD. TEA (tetraethylammonium; 1-2 mmol/L) partially lengthened CL-T (2 ppb lindane) APD. Quinidine (0.2 mmol/L) and E-4031 (10 nmol/L) prolonged CL-T APD, suggesting that the rapid delayed outward K+ current (I-Kr) was increased. Our results indicate the silent effects of chronic exposure to trace concentrations of lindane on the morphological and electrical activity of heart muscle. They demonstrate that chronic lindane treatment of female rats alters the tissue integrity and electrical activity in the LV of their offspring

Action de la diphénylhydantoïne sur le métabolisme de l'acide ascorbique chez le Rat. Résultats préliminaires

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Toxicité du lindane sur la reproduction

Dans cette revue sont présentés les principaux effets du lindane (isomère γ de l’hexachlorocyclohexane) sur les fonctions endocriniennes et reproductrices des Mammifères. Le lindane est utilisé chez l’Homme, comme produit phytosanitaire contre les parasites (poux et gale). II a aussi été largement utilisé comme insecticide et désinfectant en agriculture, sylviculture et en élevage. Dans ces domaines, son usage a été, dès 1975, progressivement réduit aux USA et en Europe (où il est interdit depuis 2000) mais se poursuit dans le reste du monde. Absorbé par voie respiratoire, digestive ou transcutanée, le lindane s’accumule dans les tissus riches en lipides. Il provoque chez l’Homme des atteintes hépatiques, rénales, neurologiques, immunologiques et des cancers. L’absorption chronique de lindane perturbe sévèrement la reproduction des Oiseaux mais aussi celle des Mammifères. Pour des doses comprises entre 1 et 40 mg/kg, il perturbe la morphologie testiculaire, diminue la spermatogenèse, inhibe la stéroïdogenèse testiculaire et réduit les concentrations plasmatiques d’androgènes, menaçant ainsi les capacités reproductrices des mâles. Chez la femelle, il retarde la puberté, perturbe le cycle œstral, réduit les taux sériques d’œstrogènes et de progestérone et diminue la réceptivité sexuelle; chez les femelles gravides, il réduit la fertilité et la taille des portées. Ces effets se retrouvent chez un petit nombre d’animaux exposés à des doses résiduelles présentes dans l’environnement. Ces différentes atteintes sont d’autant plus marquées que l’exposition de l’individu se fait à des stades précoces de la vie, durant les phases critiques de différenciation et de développement sexuels. Les mécanismes impliqués font intervenir (i) des altérations des membranes cellulaires des gonades et des gamètes, (ii) des altérations du métabolisme cellulaire (atteinte des échanges calciques et potassiques, altération directe ou par l’intermédiaire de radicaux libres de la stéroïdogenèse, (iii) enfin des atteintes de l’axe hypothalamo-hypophyso-endocrinien qui retentissent sur les performances sexuelles des parents et, plus encore, sur celle de leurs petits exposés in utero ou pendant l’allaitement

Toxicité du lindane sur la reproduction [Different aspects of lindane toxicity: effect on reproduction]

International audienceDans cette revue sont présentés les principaux effets du lindane (isomère y de l'hexachlorocyclohexane) sur les fonctions endocriniennes et reproductrices des Mammifères. Le lindane est utilisé chez l'Homme, comme produit phytosanitaire contre les parasites (poux et gale). Il a aussi été largement utilisé comme insecticide et désinfectant en agriculture, sylviculture et en élevage. Dans ces domaines, son usage a été, dès 1975, progressivement réduit aux USA et en Europe (où il est interdit depuis 2000) mais se poursuit dans le reste du monde. Absorbé par voie respiratoire, digestive ou transcutanée, le lindane s'accumule dans les tissus riches en lipides. Il provoque chez l'Homme des atteintes hépatiques, rénales, neurologiques, immunologiques et des cancers. L'absorption chronique de lindane perturbe sévèrement la reproduction des Oiseaux mais aussi celle des Mammifères. Pour des doses comprises entre 1 et 40 mg/kg, il perturbe la morphologie testiculaire, diminue la spermatogenèse, inhibe la stéroïdogenèse testiculaire et réduit les concentrations plasmatiques d'androgènes, menaçant ainsi les capacités reproductrices des mâles. Chez la femelle, il retarde la puberté, perturbe le cycle oestral, réduit les taux sériques d'oestrogènes et de progestérone et diminue la réceptivité sexuelle; chez les femelles gravides, il réduit la fertilité et la taille des portées. Ces effets se retrouvent chez un petit nombre d'animaux exposés à des doses résiduelles présentes dans l'environnement. Ces différentes atteintes sont d'autant plus marquées que l'exposition de l'individu se fait à des stades précoces de la vie, durant les phases critiques de différenciation et de développement sexuels. Les mécanismes impliqués font intervenir (i) des altérations des membranes cellulaires des gonades et des gamètes, (ii) des altérations du métabolisme cellulaire (atteinte des échanges calciques et potassiques, altération directe ou par l'intermédiaire de radicaux libres de la stéroïdogenèse, (iii) enfin des atteintes de l'axe hypothalamo-hypophyso-endocrinien qui retentissent sur les performances sexuelles des parents et, plus encore, sur celle de leurs petits exposés in utero ou pendant l'allaitement

Tocilizumab for refractory dysthyroid myopathy (RDM): A monocenter observational study of 8 patients

International audienceBackground: Dysthyroïd myopathy (DM) refers to Graves’ ophthalmopathy (GO) in 90% of the cases but can also be observed with hypothyroidism, and is responsible for orbital fat and muscles inflammation. In those patients with euthyroidism and no thyroid receptor antibody, a strong argument for DM can be the aspect of the extra ocular muscles. In myositis of other causes, muscle insertions are increased in size. In DM, the insertions are respected and not increased in volume in magnetic resonance imaging. This was the case of our eight patients. Objectives: To describe the efficacy of Tocilizumab (TCZ) in RDM in 8 patients Methods: We conducted a monocenter study of 8 patients with RDM refractory to conventional treatment scheme All patients have been treated following the EUGOGO (European Group on Graves’ Orbitopathy) scheme, which consists in weekly infusions of 500 mg prednisolone (4 to 6) followed by weekly infusions of 250 g (4 to 6). One patient had received before oral prednisolone, which is known to be less effective and no other immunosuppressive therapy. The aim was to reduce the clinical activity score (CAS) of the disease to a score of 1 (score composed of 7 items) Results: We studied 8 female patients (16 eyes); mean age at diagnosis 64,37±9,37 years. All patients had normal thyroid function at diagnosis.Three patients had a previous history of hashimoto’s thyroiditis and the other 5 had no immunological abnormalities. The duration of orbitopathy between first supposed manifestations and therapy onset was 5,7 months +/- 2,3. TCZ was introduced at the end of the steroid pulses, or before, during steroid therapy, in 2 patients who did not improve at all their ocular status after 3 steroid infusions. TCZ was used intravenously as a monotherapy, at the classical dosage of 8 mg/kg per infusion, with no other immunosuppressives. According to the classification of severity of the EUGOGO group using the CAS 1, before TCZ, 1 had severe (n=2 eyes) or moderate (n= 14 eyes) disease. Moreover, patients presented exophthalmos (n=16 eyes), strabismus (n=16 eyes), muscle inflammation and volume increase at MRI and severe optic neuropathy (n=1). After a mean of 4 pulses (extremes 1 to 7), all patients experienced improvement with TCZ withdrawal in all due to complete remission in 3 and regression in ocular inflammation in 5. Unfortunately, one patient relapsed two months after the 6th TCZ infusion, despite of initial complete remission and was treated with 4 weekly infusions of rituximab at 375 mg/m 2 with a very good response three months later. Only one patient experienced a severe anal abcess after the first TCZ infusion leading to treatment interruption, but with a good improvement of DM. Improvement of ocular parameters with TCZ therapy. Data are expressed as mean±SD or median [IQR]. (VA : visual acuity; IOP : intra ocular pressure; CAS : clinical activity score) Before tocilizumab after tocilizumab VA 0,7 (0,3-1) 0,9 (0,7-1) IOP 26,5 +/-7,7 21,1+/-13 CAS 4,25 +/- 1,28 1 Conclusion: TCZ seems to be effective in RDM, as previously reported. In case of ineffectiveness or relapse, rituximab may be effective as well. This questions us about a new treatment scheme, which patients could benefit from biotherapies alone for a better and quicker efficiency? REFERENCES [1] - Dolman PJ. Grading Severity and Activity in Thyroid Eye Disease. Ophthalmic Plast Reconstr Surg. 2018;34(4S Suppl 1):S34-S4

Individual differences in socioemotional sensitivity are an index of salience network function

Connectivity in intrinsically connected networks (ICNs) may predict individual differences in cognition and behavior. The drastic alterations in socioemotional awareness of patients with behavioral variant frontotemporal dementia (bvFTD) are presumed to arise from changes in one such ICN, the salience network (SN). We examined how individual differences in SN connectivity are reflected in overt social behavior in healthy individuals and patients, both to provide neuroscientific insight into this key brain-behavior relationship, and to provide a practical tool to diagnose patients with early bvFTD. We measured SN functional connectivity and socioemotional sensitivity in 65 healthy older adults and 103 patients in the earliest stage [Clinical Dementia Rating (CDR) Scale score ≤1] of five neurodegenerative diseases [14 bvFTD, 29 Alzheimer's disease (AD), 20 progressive supranuclear palsy (PSP), 21 semantic variant primary progressive aphasia (svPPA), and 19 non-fluent variant primary progressive aphasia (nfvPPA)]. All participants underwent resting-state functional imaging and an informant described their responsiveness to subtle emotional expressions using the Revised Self-Monitoring Scale (RSMS). Higher functional connectivity in the SN, predominantly between the right anterior insula (AI) and both "hub" cortical and "interoceptive" subcortical nodes, predicted socioemotional sensitivity among healthy individuals, showing that socioemotional sensitivity is a behavioral marker of SN function, and particularly of right AI functional connectivity. The continuity of this relationship in both healthy and neurologically affected individuals highlights the role of socioemotional sensitivity as an early diagnostic marker of SN connectivity. Clinically, this is particularly important for identification of patients in the earliest stage of bvFTD, where the SN is selectively vulnerable

Neoadjuvant anthracycline-based (5-FEC) or anthracycline-free (docetaxel/carboplatin) chemotherapy plus trastuzumab and pertuzmab in HER2 + BC patients according to their TOP2A: a multicentre, open-label, non-randomized phase II trial

International audiencePurpose Previous studies have reported the benefit of dual HER2-targeting combined to neoadjuvant chemotherapy in HER2-amplified breast cancer (HER2 + BC). Moreover, besides the cardiac toxicity following their association to Trastuzumab, anthracyclines chemotherapy may not profit all patients. The NeoTOP study was designed to evaluate the complementary action of Trastuzumab and Pertuzumab, and the relevance of an anthracycline-based regimen according to TOP2A amplification status. Methods Open-label, multicentre, phase II study. Eligible patients were aged ≥ 18 with untreated, operable, histologically confirmed HER2 + BC. After centralized review of TOP2A status, TOP2A-amplified (TOP2A+) patients received FEC100 for 3 cycles then 3 cycles of Trastuzumab (8 mg/kg then 6 mg/kg), Pertuzumab (840 mg/kg then 420 mg/kg), and Docetaxel (75mg/m 2 then 100mg/m 2 ). TOP2A-not amplified (TOP2A-) patients received 6 cycles of Docetaxel (75mg/m 2 ) and Carboplatin (target AUC 6 mg/ml/min) plus Trastuzumab and Pertuzumab. Primary endpoint was pathological Complete Response (pCR) using Chevallier’s classification. Secondary endpoints included pCR (Sataloff), Progression-Free Survival (PFS), Overall Survival (OS), and toxicity. Results Out of 74 patients, 41 and 33 were allocated to the TOP2A + and TOP2A- groups respectively. pCR rates (Chevallier) were 74.4% (95%CI: 58.9–85.4) vs. 71.9% (95%CI: 54.6–84.4) in the TOP2A + vs. TOP2A- groups. pCR rates (Sataloff), 5-year PFS and OS were 70.6% (95%CI: 53.8–83.2) vs. 61.5% (95%CI: 42.5–77.6), 82.4% (95%CI: 62.2–93.6) vs. 100% (95%CI: 74.1–100), and 90% (95%CI: 69.8–98.3) vs. 100% (95%CI: 74.1–100). Toxicity profile was consistent with previous reports. Conclusion Our results showed high pCR rates with Trastuzumab and Pertuzumab associated to chemotherapy. They were similar in TOP2A + and TOP2A- groups and the current role of neoadjuvant anthracycline-based chemotherapy remains questioned. Trial registration number NCT02339532 (registered on 14/12/14)

Survival outcomes after neoadjuvant letrozole and palbociclib versus third generation chemotherapy for patients with high-risk oestrogen receptor-positive HER2-negative breast cancer.

Besides their development as additional adjuvant treatments, CDK4/6 inhibitors combined with endocrine therapy could represent less toxic alternatives to chemotherapy in postmenopausal women with high-risk oestrogen receptor-positive, HER2-negative breast cancer currently a candidate for chemotherapy. The multicentre, international, randomised phase 2 NEOPAL trial showed that the letrozole-palbociclib combination led to clinical and pathological responses equivalent to sequential anthracycline-taxanes chemotherapy. Secondary objectives included survival outcomes. Secondary end-points of NEOPAL included progression-free survival (PFS) and invasive-disease free survival (iDFS) in the intent-to-treat population. Exploratory end-points were overall survival (OS) and breast cancer specific survival (BCSS) in the intent-to-treat population, as well as iDFS, OS and BCSS according to the administration of chemotherapy. Hundred and six patients were randomised. Pathological complete response rates were 3.8% and 5.9%. Twenty-three of the 53 patients in the letrozole-palbociclib arm received postoperative adjuvant chemotherapy. At a median follow-up of 40.4 months [0-56.6], 11 progressions have been observed, of which three were in the letrozole-palbociclib and 8 in the control arm. PFS (HR = 1.01; [95%CI 0.36-2.90], p = 0.98) and iDFS (HR = 0.83; [95%CI 0.31-2.23], p = 0.71) did not differ between both arms. The 40 months PFS rate was 86.7% [95%CI 78.0-96.4] and 89.9% [95%CI 81.8-98.7] in letrozole-palbociclib and control arms, respectively. Outcomes of patients who did not receive chemotherapy were not statistically different from those who received it. NEOPAL suggests that a neoadjuvant letrozole-palbociclib strategy may allow sparing chemotherapy in some patients with luminal breast cancer while allowing good long-term outcomes. Larger confirmatory studies are needed