Expression analysis of proteins involved in the non homologous end joining DNA repair mechanism, in the bone marrow of adult de novo myelodysplastic syndromes

Myelodysplastic syndromes (MDS) are characterized by genetic instability which is associated with abnormal DNA repair mechanisms. The most lethal type of DNA damage are double strand DNA breaks (DSBs), which are mainly repaired by Non Homologous End Joining Mechanism (NHEJ), whose core enzyme components include the Ku70/Ku80 heterodimer, DNA–PKcs, XRCC4 and DNA Ligase IV. The aim of the present study was the analysis of expression of proteins required for NHEJ in bone marrow cells of adult de novo MDS and their association with clinical characteristics and prognosis. Our analysis included 48 cases of MDS; 19 RA, 5 RARS, 19 RAEB, 3 RAEB-T, 1 CMML, 1 transformation to AML according to FAB classification. The expression of the enzymes Ku70, Ku80, XRCC4, DNA-PKcs and Ligase IV was determined by Western Blotting. The mean Ligase IV expression value was significantly lower in MDS patients compared to normal controls (0.53 vs. 0.78, p?=?0.03). A negative correlation was found between karyotype risk group and Ligase IV values. (p?=?0.05). Moreover, Ku70 expression levels were significantly lower in patients with a good prognosis karyotype (p?=?0.04). Furthermore, a negative correlation between Ku70 expression values and Hb levels was observed (p?=?0.04). Finally, a positive correlation was observed between enzyme Ku70 expression values and level of blasts (p?=?0.04). Our findings suppor-t a potential role of NHEJ enzyme Ligase IV in the pathogenesis of MDS. Larger numbers of cases need to be screened in order to draw definite conclusion.     

Soluble endothelial adhesion molecules and inflammation markers in patients with β-thalassemia intermedia

The term thalassemia intermedia, indicates a clinical condition of intermediate severity between thalassaemia minor, the asymptomatic carrier, and thalassaemia major, the transfusion-dependent, severe form. Thromboembolic events frequently complicate the outcome of thalassemia intermedia patients, reflecting a hypercoagulable state to which endothelial activation is believed to play an important role. The aim of this study was to evaluate the levels of soluble endothelial adhesion molecules that reflect endothelial activation and dysfunction and levels of chronic inflammation markers in the serum of β-thalassemia intermedia patients. Thirty-five Greek patients with β-thalassemia intermedia that have received different types of treatment (Hydroxyurea, splenectomy, untreated), aged 8–63 years, were included in the study. Twenty apparently healthy individuals matched for age and sex, formed the control group. Measurements of sVCAM-1, sICAM-1, sTM, P-selectin, E-selectin and CRP levels were performed using immunoassays. We found that all endothelial adhesion molecules and CRP were significantly increased in patients (p < 0.001) and not influenced by treatment. A negative correlation was observed between levels of sICAM-1 and sTM and this finding agrees with the results of studies, which propose this correlation as a predictive marker of increased risk for vascular damage. No correlation was observed between endothelial adhesion molecules and inflammation markers. These findings support the hypothesis that a serious degree of endothelial activation and damage along with a state of chronic inflammation underlie the pathophysiology of β-thalassemia intermedia. Furthermore, these findings are of particular importance in patients who can otherwise be characterized by a subtle clinical phenotype and may have an important role in their clinical care.     

Acute motor sensory polyneuropathy (AMSAN) complicating active ulcerative colitis with a patchy distribution

We report a case of acute motor and sensory neuropathy during a flare of ulcerative colitis. A 28-year-old male presented with a flare of distal ulcerative colitis despite treatment with mesalamine enemas and suppositories simultaneously with rapidly deteriorating weakness and needle sensation in both legs. Neurological assessment showed axonal sensorimotor polyneuropathy affecting mainly the lower limbs and to a lesser extent the upper limbs. Colonoscopy revealed moderately to severe active ulcerative colitis with a patchy distribution involving the rectum and the right colon. Vitamin and folic acid levels were normal. Virological, immunological and other laboratory tests were negative except for positive anti-ganglioside antibodies (anti-GM1). Ulcerative colitis and polyneuropathy improved when patient was treated with immunosuppressive therapy (corticosteroids, immunoglobulin and azathioprine). Peripheral polyneuropathy is a rare extraintestinal manifestation of ulcerative colitis and it is probably associated with an autoimmune pathogenetic mechanism.     

Contemporary Antithrombotic Treatment in Patients with Non-valvular Atrial Fibrillation Undergoing Percutaneous Coronary Intervention: Rationale and Design of the Greek AntiPlatElet Atrial Fibrillation (GRAPE-AF) Registry

Background

Approximately 5 to 7% of patients undergoing percutaneous coronary intervention (PCI) for the treatment of coronary artery disease require chronic oral anticoagulation (OAC) on top of aspirin and a P2Y₁₂ receptor antagonist, mainly due to non-valvular atrial fibrillation (AF). The advent of non-vitamin K antagonist oral anticoagulants (NOACs) increased treatment options, while there is cumulative evidence that dual combination of a NOAC and a P2Y₁₂ receptor antagonist attenuates risk of bleeding, compared to traditional triple therapy, consisting of a vitamin K antagonist (VKA), aspirin, and a P2Y₁₂ receptor antagonist, without significantly compromising efficacy.

Study Design

Greek AntiPlatElet Atrial Fibrillation (GRAPE-AF, NCT 03362788) is an observational, nationwide study of non-valvular AF patients undergoing PCI, planning to enroll over 1-year period >?500 participants in 25 tertiary and non-tertiary PCI centers in Greece. Key data to be collected pre-discharge include demographics, detailed past medical history, and antithrombotic and concomitant treatment. Patients will be followed up at 1, 6, and 12 months post hospital discharge. Αt each follow-up visit, data on antithrombotic treatment, ischemic, bleeding, and adverse events will be collected. Study’s primary endpoint is clinically significant bleeding (Bleeding Academic Research Consortium, BARC ≥?2) at 12 months, between VKAs and NOACs-treated patients, analyzed using Cox proportional hazards models, by an intention-to-treat principle. An independent endpoint committee will adjudicate all clinical events.

Conclusions

This study aims at providing “real-world” information on current antithrombotic treatment patterns and clinical outcome of patients with non-valvular AF undergoing PCI.

     

Transcatheter aortic valve replacement and stroke: a comprehensive review

Transcatheter aortic valve implantation (TAVR) has emerged as an alternative, rapidly evolving treatment option for patients with severe aortic stenosis and high surgical risk. Stroke is a devastating complication being confined mainly in the periprocedural and 30-day period following TAVR, with a lower and relatively constant frequency thereafter. Early stroke is mainly due to debris embolization during the procedure, whereas later events are associated with patient specific factors. Despite the fact that the rate of clinical stroke has been constantly decreasing compared to initial TAVR experience, modern neuro-imaging with MRI suggests that new ischemic lesions post-TAVR are almost universal. The impact of the latter is largely unknown. However, they seem to correlate with a reduction in neurocognitive function. Because TAVR is set to expand its indication to lower surgical-risk patients, stroke prophylaxis during and after TAVR becomes of paramount importance. Based on clinical and pathophysiological evidence, three lines of research are actively employed towards this direction: improvement in valve and delivery system technology with an aim to reduce manipulations and contact with the calcified aortic arch and native valve, antithrombotic therapy, and embolic protection devices. Careful patient selection, design of the procedure, and tailored antithrombotic strategies respecting the bleeding risks of this fragile population constitute the main defense against stroke following TAVR.     

The impact of atrial mechanical function on age‐dependent presentation of neurocardiogenic syncope

BackgroundThe contribution of atrial and ventricular function in neurocardiogenic syncope (NCS) pathophysiology is elusive.HypothesisWe assessed the influence of echocardiographic properties to the age of presentation and NCS recurrences.MethodsWe assigned 124 patients with symptoms suggesting NCS, to those with syncope initiation at age <35 (group A, n = 56) and >35 years (group B, n = 68). Echocardiographic indices were measured before head‐up tilt test (HUTT).ResultsA total of 55 had positive HUTT (44%) with a trend favoring group A (p = .08). Group A exhibited lower left atrial (LA) volume index (17 ± 6 vs. 22 ± 11 ml/m², p = .015), higher LA ejection fraction (69 ± 10 vs. 63 ± 11%, p = .008), LA peak strain (reservoir phase 41 ± 13 vs. 31 ± 14%, p = .001, contraction phase 27 ± 11 vs. 15 ± 10%, p < .001) and LA peak strain rate (reservoir phase 1.83 ± 1.04 vs. 1.36 ± 0.96 1/s, p = .012, conduit phase 2.36 ± 1.25 vs. 1.36 ± 0.78 1/s, p = .001). Group A showed smaller minimum right atrial (RA) volume, better RA systolic function, superior left ventricular diastolic indices, and lower filling pressures. Group A patients were more likely to have >3 recurrences (82.0% vs. 50.1%, p < .05).ConclusionsPatients with younger age of NCS onset and more syncopal recurrences manifest smaller LA and RA dimensions with distinct patterns of systolic and diastolic function and better LA reservoir and contraction properties. These findings may indicate an increased susceptibility to preload reduction, thereby triggering the NCS mechanism.     

How superhydrophobicity breaks down

A droplet deposited or impacting on a superhydrophobic surface rolls off easily, leaving the surface dry and clean. This remarkable property is due to a surface structure that favors the entrainment of air cushions beneath the drop, leading to the so-called Cassie state. The Cassie state competes with the Wenzel (impaled) state, in which the liquid fully wets the substrate. To use superhydrophobicity, impalement of the drop into the surface structure needs to be prevented. To understand the underlying processes, we image the impalement dynamics in three dimensions by confocal microscopy. While the drop evaporates from a pillar array, its rim recedes via stepwise depinning from the edge of the pillars. Before depinning, finger-like necks form due to adhesion of the drop at the pillar’s circumference. Once the pressure becomes too high, or the drop too small, the drop slowly impales the texture. The thickness of the air cushion decreases gradually. As soon as the water–air interface touches the substrate, complete wetting proceeds within milliseconds. This visualization of the impalement dynamics will facilitate the development and characterization of superhydrophobic surfaces.     

Saw-tooth cardiomyopathy

We report a rare case of a quinticuspid aortic valve associated with regurgitation and dilation of the ascending aorta, which was diagnosed and post-surgically followed up by cardiovascular magnetic resonance and dual source computed tomography.