Influence of sex on circulating endothelial microparticle number and microRNA expression in middle-aged adults

Abstract

The aims of this study were to determine: 1) if circulating concentrations of endothelial microparticles (EMPs) differ in middle-aged men compared with women; and 2) whether there are sex-related differences in microRNA expression in EMPs. Peripheral blood was collected from 30 sedentary adults: 15 men (52 ± 8 yr) and 15 women (52 ± 8 yr). EMPs were defined by markers of activation (CD62e⁺) or apoptosis (CD31⁺/CD42b⁻) by flow cytometry. MicroRNA (miR-34a, 92a, 125a, and 126) expression in activation- and apoptosis-derived EMPs was measured by RT-PCR. Circulating activation- (33 ± 31 vs. 39 ± 35 MP μL⁻¹) and apoptosis- (49 ± 54 vs. 42 ± 43 MP μL⁻¹) derived EMPs were not significantly different between men and women. miR-125a expression (2.23 ± 2.01 vs. 6.95 ± 3.99 AU) was lower (∼215%; P < 0.05) in activation-derived EMPs; whereas, expression of miR-34a (1.17 ± 1.43 vs. 0.38 ± 0.35 AU) was higher (∼210%; P < 0.05) in apoptosis-derived EMPs from men than women. microRNA expression in circulating EMPs may provide novel insight into sex-related differences in cardiovascular disease.

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Dexrazoxane added to doxorubicin-based adjuvant chemotherapy of breast cancer: a retrospective cohort study with a comparative analysis of toxicity and survival.

Dexrazoxane is indicated as a cardioprotective agent for patients receiving doxorubicin who are at increased risk for cardiotoxicity. Concerns have been raised on the use of dexrazoxane, particularly in adjuvant therapy, because of the risk of interference with the antitumor effect of doxorubicin. Two meta-analyses in metastatic breast cancer have rejected this hypothesis, but have shown an apparent increase in the severity of myelosuppression when dexrazoxane is used. Here, we analyzed retrospectively a cohort of our institute database to assess whether the addition of dexrazoxane causes more bone marrow suppression in breast cancer patients receiving doxorubicin-based adjuvant therapy. The secondary objectives were assessment of the incidence of febrile neutropenia, dose-schedule modifications, recorded cardiac events or cardiac test abnormalities, and overall survival. Eight hundred and twenty-two female patients who received adjuvant (or neoadjuvant) doxorubicin and cyclophosphamide for breast cancer between 2001 and 2013 were included. One hundred and four of these patients also received dexrazoxane concurrently with the adjuvant treatment. Hospital records and, when accessible, community clinic records were reviewed. The median follow-up duration was 7 years for patients receiving dexrazoxane and 7.5 years for patients not receiving dexrazoxane. 85.6% of patients were alive at data lock. Compared with the nondexrazoxane group, patients who received dexrazoxane were older (median age at diagnosis 59 vs. 52 years) and more likely to receive dose-dense AC therapy (73 vs. 59%) and adjuvant trastuzumab treatment (29 vs. 15%). Compared with the nondexrazoxane group, dexrazoxane treatment was associated with a higher rate of hematological side effects: leukopenia (48 vs. 39%), neutropenia (45 vs. 31%, P=0.003), anemia (86 vs. 73%, P=0.005), and thrombocytopenia (37 vs. 22%, P=0.001). There were more febrile neutropenia hospitalizations (20 vs. 10%, P=0.001) and dose reductions (22 vs. 8%, P

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Pharmacokinetics of venetoclax in patients with 17p deletion chronic lymphocytic leukemia.

Venetoclax is a first-in-class orally available, B-cell lymphoma (BCL)-2 inhibitor indicated for the treatment of patients with relapsed/refractory chronic lymphocytic leukemia (CLL) harboring the 17p deletion. We used a novel approach for evaluating venetoclax pharmacokinetics using only sparse sampling in 155 patients enrolled in a phase 2, multicenter, open-label study in CLL patients with the 17p deletion. Patients received venetoclax doses within 30 min after the completion of breakfast or the first meal of the day, with no specific recommendations for the fat content in the meal. Blood samples for venetoclax assay were collected during the ramp-up period and on day 1 of weeks 8, 12, 16, 24, and every 12 weeks thereafter. The mean postdose (8 h) plasma venetoclax concentrations increased with increasing weekly venetoclax dose during the ramp-up period to reach 1.89 [micro]g/ml on week 5 day 1 at the 400 mg dose. The mean predose concentration at the 400 mg dose ranged between 0.69 and 0.99 [micro]g/ml across visits between weeks 8 and 120. Repeated-measures analysis detected no statistical significance (P>=0.05) for the mean predose concentrations at any of the times tested from weeks 8 to 24. The study shows that the pharmacokinetic profile of venetoclax in CLL patients with the 17p deletion is comparable to the overall CLL as well as non-Hodgkin's lymphoma patient populations. Furthermore, no specific recommendation in terms of fat content in the meal is needed for the intake of venetoclax in patients with CLL. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Responsiveness of the functioning and disability parts of the International Classification of Functioning, Disability, and Health core sets in postacute stroke patients.

To study the responsiveness of the International Classification of Functioning, Disability, and Health (ICF) core set with respect to human functioning and disability in stroke patients. Postacute stroke patients who were admitted to the convalescent rehabilitation wards were included in this observational cohort study. The comprehensive ICF core set for neurological conditions for postacute care and the ICF rehabilitation set were evaluated at admission and discharge using five-grade qualifiers. Extension indexes were calculated for entire two ICF core sets. Responsiveness was measured as change in the extension indexes in the ICF core sets. The correlation between changes in ICF core sets and improvement in the Functional Independence Measure (FIM) was analyzed using Spearman's correlation coefficient. The study included 108 poststroke patients (49 women, mean age 70.8 years, mean FIM score improvement: 23.0). The mean percentage of categories that showed changes with at least one qualifier level was 19.5% in the comprehensive ICF core set for neurological conditions for postacute care and 35.9% in the ICF rehabilitation set. Effect sizes in each ICF core set were moderate to large (0.79-0.80). Improvement in the two ICF core sets correlated significantly with changes in the FIM score. Our results indicate that functioning and disability parts of these two ICF core sets can detect changes in functioning and disability in patients who receive an inpatient rehabilitation program for postacute stroke. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Transient ischemic attacks on turning the head to one side, with immediate remission of symptoms when the head returned to the neutral position.

http://medicine-greece.blogspot.com/2017/05/transient-ischemic-attacks-on-turning.html

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Intravital investigation of rat mesenteric small artery tone and blood flow

Abstract

Functional characteristics of rat mesenteric small arteries (internal diameter ∼150–200 μm) have been extensively studied in vitro using isometric and isobaric myographs. In vivo, precapillary arterioles (internal diameter< 50 μm) have been studied, but only few studies have investigated the function of mesenteric small arteries. We here present a novel approach for intravital studies of rat mesenteric small artery segments (∼5 mm long) isolated in a chamber. The agonist-induced changes in arterial diameter and blood flow were studied using video imaging and laser speckle analysis in rats anaesthetized by isoflurane, pentobarbital, ketamine/xylazine, or by a combination of fentanyl, fluanison and midazolam (rodent mixture). The arteries had spontaneous tone. Noradrenaline added to the chamber constricted the artery in the chamber but not the downstream arteries in the intestinal wall. The constriction was smaller when rats were anaesthetised by rodent mixture in comparison with other anaesthetics, where responses were qualitatively similar to those reported in vitro. The contraction was associated with reduction of blood flow, but no flow reduction was seen in the downstream arteries in the intestinal wall. The magnitude of different endothelium-dependent relaxation pathways was dependent on the anaesthesia. Vasomotion was present under all forms of anaesthesia with characteristics similar to in vitro. We have established an intravital method for studying the tone and flow in rat mesenteric arteries. The reactivity of the arteries was qualitatively similar to the responses previously obtained under in vitro conditions, but the choice of anaesthetic affects the magnitude of responses.

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Coupling of excitation to Ca2+ release is modulated by dysferlin

Abstract

Dysferlin concentrates in the transverse tubules of skeletal muscle and stabilizes Ca²⁺ transients when muscle fibres are subjected to osmotic shock injury (OSI). We show here that voltage-induced Ca²⁺ transients elicited in dysferlin-null A/J myofibers are smaller than control A/WySnJ fibres. Regional expression of Venus-dysferlin chimeras in A/J fibres restores the full amplitude of the Ca²⁺ transients and protects against OSI. We also show that drugs that target ryanodine receptors (RyR1: dantrolene, tetracaine, S107) and L-type Ca²⁺ channels (LTCC: nifedipine, verapamil, diltiazem) prevent the decrease in Ca²⁺ transients in A/J fibres following OSI. Diltiazem specifically increases transients by ∼20% in uninjured A/J fibres, restoring them to control values. The fact that both RyR1s and LTCCs are involved in OSI-induced damage suggests that damage is mediated by increased Ca²⁺ leak from the sarcoplasmic reticulum (SR) through the RyR1. Congruent with this, injured A/J fibres produced Ca²⁺ sparks and Ca²⁺ waves. S107 (stabilizer of RyR1-FKBP coupling that reduces Ca²⁺ leak) or local expression of Venus-dysferlin prevented OSI-induced Ca²⁺ waves. Our data suggest that dysferlin modulates SR Ca²⁺ release in skeletal muscle, and that in its absence OSI causes increased RyR1-mediated Ca²⁺ leak from the SR into the cytoplasm.

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