Impaired fibrinolysis in patients with isolated aortic stenosis is associated with enhanced oxidative stress

Aortic stenosis (AS) has been associated with impaired fibrinolysis and increased oxidative stress. This study aimed to investigate whether oxidative stress could alter fibrin clot properties in AS. We studied 173 non-diabetic patients, aged 51–79 years, with isolated AS. We measured plasma protein carbonylation (PC) and thiobarbituric acid reactive substances (TBARS), along with plasma clot permeability (Ks), thrombin generation, and fibrinolytic efficiency, which were evaluated by two assays: clot lysis time (CLT) and lysis time (Lys50). Coagulation factors and fibrinolytic proteins were also determined. Plasma PC showed an association with AS severity, reflected by the aortic valve area and the mean and maximum aortic gradients. Plasma PC was positively correlated with CLT, Lys50, plasminogen activator inhibitor-1 (PAI-1), and tissue factor (TF) antigens. TBARS were positively correlated with maximum aortic gradient, Lys50, and TF antigen. Regression analysis showed that PC predicted prolonged CLT (>104 min; odds ratio (OR) 6.41, 95% confidence interval (CI) 2.58–17.83, p < 0.001) and Lys50 (>565 s; OR 5.83, 95% CI 2.23–15.21, p < 0.001). Multivariate regression analysis showed that mean aortic gradient, PC, α2-antiplasmin, PAI-1, and triglycerides were predictors of prolonged CLT, while PC, α2-antiplasmin, and fibrinogen were predictors of Lys50. Our findings suggest that elevated oxidative stress contributes to impaired fibrinolysis in AS and is associated with AS severity

The effect of chronic tianeptine administration on the brain mitochondria : direct links with an animal model of depression

A growing body of evidence has focused on the impact of mitochondrial disturbances in the development of depression, but little data exist regarding the effects of chronic administration of antidepressant drugs on the brain’s mitochondrial protein profile. The aim of this study was to investigate the impact of chronic treatment with an atypical antidepressant drug—tianeptine—on the mitochondria-enriched subproteome profile in the hippocampus and the frontal cortex of 3-month-old male rats following a prenatal stress procedure. Rats that were exposed to a prenatal stress procedure displayed depressive- and anxiety-like disturbances based on the elevated plus-maze and Porsolt tests. Moreover, two-dimensional electrophoresis coupled with mass spectrometry showed structure-dependent mitoproteome changes in brains of prenatally stressed rats after chronic tianeptine administration. A component of 2-oxoglutarate and succinate flavoprotein subunit dehydrogenases, isocitrate subunit alpha, was upregulated in the hippocampus. In the frontal cortex, there was a striking increase in the expression of glutamate dehydrogenase and cytochrome bc1 complex subunit 2. These findings suggest that mitochondria are underappreciated targets for therapeutic interventions, and mitochondrial function may be crucial for the effective treatment of stress-related diseases

The course of pregnancy in patients with type 2 diabetes mellitus as compared with type 1 diabetes

WSTĘP. Wzrost częstości cukrzycy typu 2 w coraz młodszych grupach wiekowych dotyczy także kobiet w wieku rozrodczym. Zjawisko to prowadzi do zwiększenia liczby kobiet ciężarnych chorych na cukrzycę typu 2. Celem badania była analiza porównawcza wyrównania metabolicznego cukrzycy, ocena przebiegu ciąży i porodu u chorych na cukrzycę typu 2 i 1. MATERIAŁ I METODY. Przeprowadzono analizę retrospektywną danych 24 chorych z przedciążową cukrzycą typu 2 i dla porównania 110 chorych z cukrzycą typu 1 leczonych w Klinice Chorób Metabolicznych oraz w Klinice Ginekologii i Położnictwa Uniwersytetu Jagiellońskiego Collegium Medicum w Krakowie. Uwzględniono dane kliniczne, wyrównanie cukrzycy, ciśnienie tętnicze i zwiększenie masy ciała w każdym trymestrze ciąży oraz dane dotyczące noworodka. WYNIKI. Pacjentki z cukrzycą typu 2 w porównaniu z chorymi na cukrzycę typu 1 zgłaszały się do ośrodka specjalistycznego w ciąży bardziej zaawansowanej (18,9 &#177; 8,0 vs. 10,3 &#177; 5,5, p < 0,001), cechowały się starszym wiekiem (30-48 lat w cukrzycy typu 2 i 19-45 lat w cukrzycy typu 1, p < 0,001), wyższym wskaźnikiem masy ciała (33,8 &#177; 5,3 vs. 26,2 &#177; 3,1, p < 0,001), większą liczbą przebytych ciąż (2,8 &#177; 1,2 vs. 1,9 &#177; 1,3, p < 0,01). U kobiet z cukrzycą typu 2 stężenia cholesterolu i triglicerydów były istotnie wyższe niż u kobiet z cukrzycą typu 1 (5,1 &#177; 1,7 vs. 3,9 &#177; 0,6 mmol/l, p < 0,001 oraz 2,6 &#177; 2,2 vs. 0,9 &#177; 0,5 mmol/l, p < 0,001). Chore na cukrzycę typu 2 cechowały się wyższym ciśnieniem skurczowym przy zgłoszeniu się do ośrodka oraz w II trymestrze ciąży (130 &#177; 16 vs. 117 &#177; 10 mm Hg, p < 0,05 oraz 123 &#177; 12 vs. 109 &#177; 10 mm Hg, p < 0,01). Nie stwierdzono istotnych różnic w wyrównaniu cukrzycy między cukrzycą typu 1 a cukrzycą typu 2 przy zgłoszeniu się do ośrodka oraz w II i III trymestrze. Natomiast zarówno w cukrzycy typu 2, jak i w cukrzycy typu 1 stężenie HbA1c przy zgłoszeniu do ośrodka było istotnie statystycznie wyższe niż w trymestrze II i III (6,4 &#177; 1,3 vs. 5,9 &#177; 0,6 i 5,7 &#177; 0,6%, p < 0,05 oraz 7,2 &#177; 1,5 vs. 5,9 &#177; 0,9 i 5,9 &#177; 0,8%, p < 0,05). Aż u 25,0% noworodków matek chorych na cukrzycę typu 2 masa urodzeniowa przekroczyła 4000 g. Po uwzględnieniu zależności masy urodzeniowej i wieku ciążowego w cukrzycy typu 2 stwierdzono 33,3% noworodków o masie urodzeniowej powyżej 90. percentyla i 16,6% o masie urodzeniowej poniżej 10. percentyla. U kobiet z cukrzycą typu 2 występowała około 4,6-krotnie wyższa śmiertelność okołoporodowa noworodków, a także 4-krotnie częściej letalne wady wrodzone.WNIOSKI. Specjalistyczna opieka diabetologiczna i położnicza nad kobietami z cukrzycą typu 1 i 2 pozwala uzyskać dobre wyrównanie cukrzycy. Wyniki wskazują jednak na wyższą śmiertelność okołoporodową i częstsze występowanie wad wrodzonych u dzieci kobiet z cukrzycą typu 2, co może wynikać z późnego zgłaszania się do ośrodków specjalistycznych i z braku planowania ciąży przez kobiety z cukrzycą typu 2, a także z obecności innych czynników ryzyka, takich jak wiek i otyłość.INTRODUCTION. The increasing prevalence of type 2 diabetes mellitus in the increasingly younger age groups is observed also in women in the reproductive age. Consequently, the number of pregnant women with type 2 diabetes is also increased. Aim of the study was to compare diabetes normalization, course of pregnancy and delivery in patients with type 2 (DM2) and type 1 diabetes mellitus (DM1). MATERIAL AND METHODS: 24 patients with prepregnancy DM2 and for comparison 110 women with DM1 treated in the Department of Metabolic Diseases and the Department of Pathological Pregnancy were analyzed retrospectively with respect to clinical data, diabetes normalization, blood pressure, weight gain in each trimester, and data on delivery and neonates. RESULTS. Patients with DM2 as compared with DM1 patients referred for specialized care in the later stages of pregnancy (18.9 &#177; 8.0 vs. 10.3 &#177; 5.5, p < 0.001), were older (30-48 years in DM2 and 19-45 years in DM1, p < 0,001), had higher body mass index (33.8 &#177; 5.3 vs. 26.2 &#177; 3.1, p < 0.001), and a larger number of pregnancies (2.8 &#177; 1.2 vs. 1.9 &#177; 1.3, p < 0.01). In women with DM2 cholesterol and triglyceride levels were significantly higher than in women with DM1 (5.1 &#177; 1.7 vs. 3.9 &#177; 0.6 mmol/l, p < 0.001 and 2.6 &#177; 2.2 vs. 0.9 &#177; 0.5 mmol/l, p < 0.001). Women with DM2 had higher systolic blood pressure on admission and in the second trimester (130 &#177; 16 vs. 117 &#177; 10 mm Hg, p < 0.05 and 123 &#177; 12 vs. 109 &#177; 10 mm Hg, p < 0.01). There were no significant differences in diabetes normalization between DM2 and DM1 on admission and in trimester 2 and 3. However, both in DM2 and DM1 HbA1c levels on admission were significantly higher than in trimester 2 and 3 (6.4 &#177; 1.3 vs. 5.9 &#177; 0.6 and 5.7 &#177; 0,6%, p < 0.05 and 7,2 &#177; 1.5 vs. 5.9 &#177; 0.9 and 5.9 &#177; 0.8%, p < 0.05). In DM2 patients as many as 25% of neonates had birth weight exceeding 4000 g. After adjustment for birth weight and maternal age in DM2 there were 33.3% of neonates with birth weight > 90th percentile and 16.6% with birth weight < 10th percentile. In DM2 women perinatal mortality was 4.5-fold higher and lethal congenital defect rate was also 4-fold higher. CONCLUSIONS. Specialized diabetological and obstetrical care in women with DM1 and DM2 affects normalization of diabetes. The present findings indicate also higher perinatal mortality and congenital defect rates in DM2. This may be a result of late referral for specialist care and no planning for pregnancy by DM2 women, and the presence of other risk factors such as age and obesity

Direct left ventricular wire pacing during transcatheter aortic valve implantation

Background: Rapid ventricular pacing is used during balloon aortic valvuloplasty, balloon‑expandable transcatheter aortic valve implantation (TAVI), and for postdilatation. Right ventricular (RV) lead pacing has been regarded as a gold standard. Direct left ventricular (LV) wire pacing has recently been considered safe and effective in TAVI interventions. Aims: This study aimed to analyze procedural outcomes of direct LV pacing compared with RV stimulation in unselected patients undergoing TAVI. Methods: Direct LV wire pacing was provided via available preshaped guidewires and used only when no predictors of atrioventricular block were present. The primary study objective was the assessment of the efficacy of direct LV wire pacing. The secondary objectives included the evaluation of procedure duration and safety in comparison with the conventional method. A combined endpoint (major adverse cardiovascular event) was defined as the occurrence of death, stroke, venous puncture–related complications, and cardiac tamponade. Results: In 2017 and 2018, 143 patients underwent transfemoral TAVI. Of these, 114 (79.7%) had self‑ ‑expandable valves implanted. Direct LV wire pacing was the dominant method of pacing (82 patients [57.3%]), and its efficacy reached 97.6%. The median (interquartile range) procedure time was shorter in the direct LV wire pacing group (80 [70–90] min vs 85 [70–95] min; P = 0.02). Major adverse cardiovascular events were more frequent in the RV lead pacing group (11.5% vs 4.9%), but no statistical significance was achieved (P = 0.13). Conclusions: Direct LV wire pacing during TAVI is a simple, reproducible, and safe technique, which provides reliable, sustained stimulation with a low complication rate and potential reduction of procedural time

Prenatal stress enhances excitatory synaptic transmission and impairs long-term potentiation in the frontal cortex of adult offspring rats.

The effects of prenatal stress procedure were investigated in 3 months old male rats. Prenatally stressed rats showed depressive-like behavior in the forced swim test, including increased immobility, decreased mobility and decreased climbing. In ex vivo frontal cortex slices originating from prenatally stressed animals, the amplitude of extracellular field potentials (FPs) recorded in cortical layer II/III was larger, and the mean amplitude ratio of pharmacologically-isolated NMDA to the AMPA/kainate component of the field potential--smaller than in control preparations. Prenatal stress also resulted in a reduced magnitude of long-term potentiation (LTP). These effects were accompanied by an increase in the mean frequency, but not the mean amplitude, of spontaneous excitatory postsynaptic currents (sEPSCs) in layer II/III pyramidal neurons. These data demonstrate that stress during pregnancy may lead not only to behavioral disturbances, but also impairs the glutamatergic transmission and long-term synaptic plasticity in the frontal cortex of the adult offspring

The adjuvant double mutant Escherichia coli heat labile toxin enhances IL-17A production in human T cells specific for bacterial vaccine antigens.

The strong adjuvant activity and low enterotoxicity of the novel mucosal adjuvant double mutant Escherichia coli heat labile toxin, LT(R192G/L211A) or dmLT, demonstrated in mice, makes this molecule a promising adjuvant candidate. However, little is known about the mechanisms responsible for the adjuvant effect of dmLT or whether dmLT also has an adjuvant function in humans. We investigated the effect of DMLT on human T Cell responses to different bacterial vaccine antigens: the mycobacterial purified protein derivative (PPD) antigen, tested in individuals previously vaccinated with Bacillus Calmette-Guérin, the LT binding subunit (LTB), evaluated in subjects immunised with oral inactivated whole cell vaccines against enterotoxigenic Escherichia coli, and Streptococcus pneumoniae whole cell vaccine antigens, tested in subjects naturally exposed to pneumococci. We found that dmLT enhanced the production of IL-17A by peripheral blood mononuclear cells in response to all antigens tested. dmLT had comparable effects on IL-17A responses to PPD as the single mutant LT(R192G) adjuvant, which has demonstrated clinical adjuvant activity in humans. Neutralisation of IL-1β and IL-23, but not IL-6, suppressed the IL-17A-enhancing effect of dmLT. Furthermore, CD4+ T cells produced higher levels of IL-17A when stimulated with monocytes pulsed with PPD and dmLT compared to PPD alone, supporting an important role of antigen presenting cells in enhancing IL-17A responses. dmLT also potentiated mitogen-induced IL-17A and IL-13 production. However, dmLT had variable influences on IFN-γ responses to the different stimuli tested.Our demonstration of a potent ability of dmLT to enhance human Th17 type T cell responses to bacterial vaccine antigens encourages further evaluation of the adjuvant function of dmLT in humans

A (2012) The adjuvant double mutant Escherichia coli heat labile toxin enhances IL-17A production in human T cells specific for bacterial vaccine antigens. PLoS One 7: e51718

The strong adjuvant activity and low enterotoxicity of the novel mucosal adjuvant double mutant Escherichia coli heat labile toxin, LT(R192G/L211A) or dmLT, demonstrated in mice, makes this molecule a promising adjuvant candidate. However, little is known about the mechanisms responsible for the adjuvant effect of dmLT or whether dmLT also has an adjuvant function in humans. We investigated the effect of dmLT on human T cell responses to different bacterial vaccine antigens: the mycobacterial purified protein derivative (PPD) antigen, tested in individuals previously vaccinated with Bacillus Calmette-Guérin, the LT binding subunit (LTB), evaluated in subjects immunised with oral inactivated whole cell vaccines against enterotoxigenic Escherichia coli, and Streptococcus pneumoniae whole cell vaccine antigens, tested in subjects naturally exposed to pneumococci. We found that dmLT enhanced the production of IL-17A by peripheral blood mononuclear cells in response to all antigens tested. dmLT had comparable effects on IL-17A responses to PPD as the single mutant LT(R192G) adjuvant, which has demonstrated clinical adjuvant activity in humans. Neutralisation of IL-1b and IL-23, but not IL-6, suppressed the IL-17A-enhancing effect of dmLT. Furthermore, CD4+ T cells produced higher levels of IL-17A when stimulated with monocytes pulsed with PPD and dmLT compared to PPD alone, supporting an important role of antigen presenting cells in enhancing IL-17A responses. dmLT also potentiated mitogen-induced IL-17A and IL-13 production. However, dmLT had variable influences on IFN-c responses to the different stimuli tested. Our demonstratio