Parental mutations influence wild-type offspring via transcriptional adaptation.

Transgenerational epigenetic inheritance (TEI) is mostly discussed in the context of physiological or environmental factors. Here, we show intergenerational and transgenerational inheritance of transcriptional adaptation (TA), a process whereby mutant messenger RNA (mRNA) degradation affects gene expression, in nematodes and zebrafish. Wild-type offspring of animals heterozygous for mRNA-destabilizing alleles display increased expression of adapting genes. Notably, offspring of animals heterozygous for nontranscribing alleles do not display this response. Germline-specific mutations are sufficient to induce TA in wild-type offspring, indicating that, at least for some genes, mutations in somatic tissues are not necessary for this process. Microinjecting total RNA from germ cells of TA-displaying heterozygous zebrafish can trigger TA in wild-type embryos and in their progeny, suggesting a model whereby mutant mRNAs in the germline trigger a TA response that can be epigenetically inherited. In sum, this previously unidentified mode of TEI reveals a means by which parental mutations can modulate the offspring's transcriptome.

Genotype-Phenotype Relationships in the Context of Transcriptional Adaptation and Genetic Robustness.

Genetic manipulations with a robust and predictable outcome are critical to investigate gene function, as well as for therapeutic genome engineering. For many years, knockdown approaches and reagents including RNA interference and antisense oligonucleotides dominated functional studies; however, with the advent of precise genome editing technologies, CRISPR-based knockout systems have become the state-of-the-art tools for such studies. These technologies have helped decipher the role of thousands of genes in development and disease. Their use has also revealed how limited our understanding of genotype-phenotype relationships is. The recent discovery that certain mutations can trigger the transcriptional modulation of other genes, a phenomenon called transcriptional adaptation, has provided an additional explanation for the contradicting phenotypes observed in knockdown versus knockout models and increased awareness about the use of each of these approaches. In this review, we first cover the strengths and limitations of different gene perturbation strategies. Then we highlight the diverse ways in which the genotype-phenotype relationship can be discordant between these different strategies. Finally, we review the genetic robustness mechanisms that can lead to such discrepancies, paying special attention to the recently discovered phenomenon of transcriptional adaptation.

Residual Pulmonary Hypertension more than 20 Years after Repair of Shunt Lesions.

Background and Objectives: After successful surgical repair of a congenital shunt lesion, pulmonary hypertension (PH) often disappears. However, PH can persist long-term after the closure. This study aimed to assess the prevalence of PH long-term after surgical repair of congenital heart disease (CHD), and to evaluate the outcomes and preoperative factors related to residual PH. Materials and Methods: In this retrospective cohort study, we reviewed patients who underwent right heart catheterisation in Vilnius University Hospital Santaros Klinikos during the period of 1985-2007. Among 4118 right heart catheterisations performed, 160 patients underwent congenital systemic-to-pulmonary shunt repair at a young age (<18 years) and had pre-operative PH. Half of the patients were foreigners whose follow-up data were unavailable. Eventually, 88 patients with available follow-up data were included in this study. Results: The median age at diagnosis of CHD with PH was 0.8 (0.6-3.0) and 1.1 (0.6-3.9) years at surgery (50% females). Residual PH was assessed 9.5 years after surgery and observed in 30.7% (n = 27) of the patients. It was associated with having more than one shunt (44.4% (n = 12), p = 0.016) and higher median pulmonary vascular resistance (3.4 (2.5-6.5) vs. 2.2 (1.0-3.7), p = 0.035) at baseline. After a median follow-up of 21 (15-24) years, 9.1% of the patients were deceased. Kaplan-Meier survival analysis revealed significantly higher mortality in the residual PH group (p = 0.035). Conclusions: Residual PH affects a significant proportion of patients after surgical repair of a shunt lesion and is associated with worse long-term outcome.

The effect of cardiac shock wave therapy on myocardial function and perfusion in the randomized, triple-blind, sham-procedure controlled study.

BACKGROUND: Recent triple-blind sham procedure-controlled study revealed neutral effects of the cardiac shock wave therapy (CSWT) on exercise tolerance and symptoms in patients with stable angina. Current data about the effects of CSWT on global and regional myocardial contractility and perfusion is limited. Hereby we report the results of an imaging sub-study that evaluated the capacity of CSWT to ameliorate myocardial ischemia induced during dobutamine stress echocardiography (DSE) and cardiac single photon emission computed tomography (SPECT). METHODS: Prospective, randomized, triple-blind, sham procedure-controlled study enrolled 72 adult subjects who complied with defined inclusion criteria. The subjects were assigned to the OMT + CSWT and the OMT + sham procedure study groups with 1:1 ratio. Application of the CSWT covered all segments of the left ventricle. Imaging ischemia tests were performed in 59 study patients: DSE and SPECT before the CSWT treatment and after 6 months, with DSE carried out additionally at 3 months after randomization. Co-primary endpoints of the study were: change in wall motion score index (WMSI), representing the stress-induced impairment of regional myocardial function, and change in summed difference score (SDS), representing the amount of perfusion defect. RESULTS: OMT + CSWT and OMT + sham procedure study groups included 30 and 29 patients, respectively. Regional myocardial contractility during DSE significantly improved at 3 months follow-up in OMT + CSWT group compared to baseline as shown by WMSI at stress (1.4 ± 0.4 vs 1.6 ± 0.4, p = 0.001), but not in OMT + sham procedure group (1.5 ± 0.3 vs 1.6 ± 0.4, p = 0.136). The difference in stress DSE results between both study groups disappeared after 6 months. SPECT results demonstrated a significant reduction of inducible ischemia in OMT + CSWT group compared to OMT + sham procedure group at 6 months follow-up (SDS dropped from 5.4 ± 3.7 to 3.6 ± 3.8 vs 6.4 ± 5.9 to 6.2 ± 5 respectively, p = 0.034). CONCLUSIONS: Cardiac shock wave treatment showed the ability to reduce stress-induced myocardial ischemia, as assessed by wall motion abnormalities and perfusion defects, compared to sham procedure. TRIAL REGISTRATION: Clinicaltrials.gov ( NCT02339454 ). The trial was registered retrospectively on 12 January 2015.

A randomized, triple-blind trial of cardiac shock-wave therapy on exercise tolerance and symptoms in patients with stable angina pectoris.

BACKGROUND: Despite major advances in managing coronary artery disease and continuous research on alternative techniques to enhance myocardial perfusion and reduce symptoms, coronary artery disease is still one of the leading causes of adult disability worldwide. Cardiac shock-wave therapy (CSWT) has shown promising results in the amelioration of myocardial ischemia in experimental studies; however, clinical results are limited to single-center, mostly uncontrolled and underpowered trials. The current study aimed to evaluate whether CSWT can improve exercise tolerance and relieve angina symptoms in addition to optimal medical treatment in patients with stable angina. PARTICIPANTS AND METHODS: A prospective, randomized, triple blind, sham-procedure-controlled study was carried out. The primary endpoint was total exercise duration in the modified Bruce treadmill test at the 6-month follow-up. The secondary endpoints were changes in ST-segment depression during the treadmill test, angina symptoms during the treadmill test, number of angina attacks per week, number of sublingual nitroglycerin consumption per week, Canadian Cardiovascular Society angina functional class, and the Seattle Angina Questionnaire score at the 6-month follow-up. Patients were randomized at a 1 : 1 ratio to optimal medical plus cardiac shock-wave therapy (OMT+CSWT) and optimal medical therapy with sham procedure (OMT+placebo) groups. RESULTS: The mean exercise time improved in both study arms - CSWT and placebo treatment - at the 3- and 6-month follow-up, without a significant difference between groups. The magnitude and frequency of peak exercise ST-segment depression reduced significantly in the CSWT+OMT group compared with the OMT+placebo group at the 6-month follow-up (51.4 vs. 90.6%, P=0.001). Percentage of angina-free patients increased progressively in both groups throughout the study. The Seattle Angina Questionnaire scores improved significantly in both arms for four of five domains at the 3- and the 6-month follow-up. Numerically, although insignificant, the decrease in the number of angina episodes was more prominent in the OMT+CSWT group compared with the OMT+placebo group. CONCLUSION: The total exercise duration in the modified Bruce treadmill test at the 6-month follow-up did not differ significantly in patients treated with CSWT compared with optimal medical therapy alone. In addition, CSWT exerted a neutral effect on the quality of life and level of angina.

A rare case of REM sleep-related bradyarrhythmia syndrome with concomitant severe hypertension: a case report and a review of literature.

INTRODUCTION: Rapid eye movement (REM) sleep-related bradyarrhythmia syndrome is characterized by pathological asystoles during the REM sleep phase. It is a rare rhythm disorder, being reported only few times in the literature. Due to non-specific symptoms, REM sleep-related bradyarrhythmia might be often underdiagnosed. Other cardiac diseases associated with pathological sinus arrests must be excluded to establish the correct diagnosis of and appropriate therapy for REM sleep-related bradyarrhythmia. We report a case of this syndrome followed by hypertension and diastolic heart failure. THE CASE: A 49-year-old male with severe hypertension presented for a cardiologist's consultation. His main complaints were palpitations, fatigue, dyspnoea, and snoring. Polysomnography test revealed a normal sleep structure with episodes of bradycardia and increased parasympathetic activity during phasic events of REM sleep. Heart rate variability Poincare plot analysis demonstrated similar results. REM sleep-related bradyarrhythmia syndrome was diagnosed and patient was treated with dual chamber heart pacemaker implantation. DISCUSSION: Various components of the autonomic nervous system influence the development of REM sleep-related bradyarrhythmia syndrome. The main factor is likely an increased vagal tone during the phasic REM sleep with the absence of normal compensatory sympathetic activity. Concomitant hypertension in REM sleep-related bradyarrhythmia syndrome is caused by a paradoxically abnormal control of the autonomic nervous system and can be explained through the acetylcholine metabolism pathway. Best suited diagnostic and treatment options for REM sleep-related bradyarrhythmia syndrome are discussed. CONCLUSIONS: Patients with REM sleep-related bradyarrhythmia syndrome often present with indistinct symptoms. Polysomnography is an essential diagnostic test for the differential diagnosis of various nocturnal arrhythmias and sleep disorders. Severe hypertension is a common complication of sleep disorders and requires appropriate treatment of the underlying condition. An implantation of a heart pacemaker is the first-choice treatment for patients with REM sleep-related bradyarrhythmia syndrome.

Severity of hyperoxia as a risk factor in patients undergoing on-pump cardiac surgery.

BACKGROUND: Hyperoxia has long been perceived as a desirable or at least an inevitable part of cardiopulmonary bypass. Recent evidence suggest that it might have multiple detrimental effects on patient homeostasis. The aim of the study was to identify the determinants of supra-physiological values of partial oxygen pressure during on-pump cardiac surgery and to assess the impact of hyperoxia on clinical outcomes. MATERIALS AND METHODS: Retrospective data analysis of the institutional research database was performed to evaluate the effects of hyperoxia in patients undergoing elective cardiac surgery with cardiopulmonary bypass, 246 patients were included in the final analysis. Patients were divided in three groups: mild hyperoxia (MHO, PaO2 100-199 mmHg), moderate hyperoxia (MdHO, PaO2 200-299 mmHg), and severe hyperoxia (SHO, PaO2 >300 mmHg). Postoperative complications and outcomes were defined according to standardised criteria of the Society of Thoracic Surgeons. RESULTS: The extent of hyperoxia was more immense in patients with a lower body mass index (p = 0.001) and of female sex (p = 0.005). A significant link between severe hyperoxia and a higher incidence of infectious complications (p - 0.044), an increased length of hospital stay (p - 0.044) and extended duration of mechanical ventilation (p < 0.001) was confirmed. CONCLUSIONS: Severe hyperoxia is associated with an increased incidence of postoperative infectious complications, prolonged mechanical ventilation, and increased hospital stay.

Survival of children treated for Ewing sarcoma in Lithuania: a single centre experience.

INTRODUCTION: Ewing sarcoma (ES) is a rare and aggressive malignant neoplasm that mostly affects children and adolescents. Recent studies reported a gap of 20% in childhood cancer survival rates between the Northern/Western and the Eastern European countries. We aimed to analyse the survival of patients treated for ES at our institution, to evaluate its correspondence to current survival rates in the expert centres, and to assess changes in treatment outcomes over time. MATERIALS AND METHODS: A retrospective single-centre study was performed. Children under 18 years of age, diagnosed and treated for Ewing sarcoma/PNET at our institution from 2000 to 2014 were included. To assess the hypothesized improvement of treatment outcomes over time, a comparative analysis of two time periods - 2000-2007 and 2008-2014 - was carried out. Five-year overall survival (OS5y) and disease-free survival (DFS5y) were chosen as primary study end-points. Clinical and laboratory data were retrieved from patient records. RESULTS: In total, 40 patients were included in the study: 24 (60%) males and 16 (40%) females. Twenty-eight children (70%) presented with local and 12 (30%) with primary metastatic disease. Over the analysed time frame, improvement in treatment outcomes was observed: DFS5y improved from 46% in 2000-2007 to 61% in 2008-2014 (p = 0.27), whereas OS5y changed minimally from 62% in 2000-2007 to 65% in 2008-2014. Increase in DFS5y was more prominent for localized disease -from 50% in 2000-2007 to 74% in 2008-2014 (p = 0.14). Prognosis of initial metastatic disease remained poor with DFS5y: 25% in 2000-2007 and 38% in 2008-2014. Patients' median follow-up was 12.3 years (the range from 8.1 to 15.6) and 3.9 years (the range from 1.1 to 8.0) in the first and second study groups, respectively. CONCLUSIONS: OS5y of the entire patient cohort did not change considerably over time and remained slightly inferior compared to the best reported survival rates. There was an evident trend for improvement of DFS5y in localized disease. Survival of children with primary metastases remained poor despite slight increase in DFS5y. Implementation of international clinical trials, consolidation of multidisciplinary approach, patients' concentration and widening of research activities could be beneficial for the treatment of children in the future.