Effect of remote ischaemic preconditioning in cardiac dysfunction and end-organ injury following cardiac surgery with cardiopulmonary bypass in children: A translational approach investigating clinical outcome and myocardial molecular biology

Congenital heart disease (CHD) is the most common birth defect, causing an important rate of morbidity and mortality. Treatment of CHD requires surgical correction in a significant percentage of cases which exposes patients to cardiac and end organ injury. Cardiac surgical procedures often require the utilisation of cardiopulmonary bypass (CPB), a system that replaces heart and lungs function by diverting circulation into an external circuit. The use of CPB can initiate potent inflammatory responses, in addition a proportion of procedures require a period of aortic cross clamp during which the heart is rendered ischaemic and is exposed to injury. High O2 concentrations are used during cardiac procedures and when circulation is re-established to the heart which had adjusted metabolically to ischaemia, further injury is caused in a process known as ischaemic reperfusion injury (IRI). Several strategies are in place in order to protect the heart during surgery, however injury is still caused, having detrimental effects in patients at short and long term. Remote ischaemic preconditioning (RIPC) is a technique proposed as a potential cardioprotective measure. It consists of exposing a remote tissue bed to brief episodes of ischaemia prior to surgery in order to activate protective pathways that would act during CPB, ischaemia and reperfusion. This study aimed to assess RIPC in paediatric patients requiring CHD surgical correction with a translational approach, integrating clinical outcome, marker analysis, cardiac function parameters and molecular mechanisms within the cardiac tissue. A prospective, single blinded, randomized, controlled trial was conducted applying a RIPC protocol to randomised patients through episodes of limb ischaemia on the day before surgery which was repeated right before the surgery started, after anaesthesia induction. Blood samples were obtained before surgery and at three post-operative time points from venous lines, additional pre and post-bypass blood samples were obtained from the right atrium. Myocardial tissue was resected during the ischaemic period of surgery. Echocardiographic images were obtained before the surgery started after anaesthetic induction and the day after surgery, images were stored for later off line analysis. PICU surveillance data was collected including ventilation parameters, inotrope use, standard laboratory analysis and six hourly blood gas analysis. Pre and post-operative quantitation of markers in blood specimens included cardiac troponin I (cTnI) and B-type natriuretic peptide (BNP), inflammatory mediators including interleukins IL-6, IL-8, IL-10, tumour necrosis factor (TNF-α), and the adhesion molecules ICAM-1 and VCAM-1; the renal marker Cystatin C and the cardiovascular markers asymmetric dymethylarginine (ADMA) and symmetric dymethylarginine (SDMA). Nitric oxide (NO) metabolites and cyclic guanosine monophosphate (cGMP) were measured before and after bypass. Myocardial tissue was processed at baseline and after incubation at hyperoxic concentration during four hours in order to mimic surgical conditions. Expression of genes involved in IRI and RIPC pathways was analysed including heat shock proteins (HSPs), toll like receptors (TLRs), transcription factors nuclear factor κ-B (NF- κ-B) and hypoxia inducible factor 1 (HIF-1). The participation of hydrogen sulfide enzymatic genes, apelin and its receptor were explored. There was no significant difference according to group allocation in any of the echocardiographic parameters. There was a tendency for higher cTnI values and inotropic score in control patients post-operatively, however this was not statistically significant. BNP presented no significant difference according to group allocation. Inflammatory parameters tended to be higher in the control group, however only TNF- α was significantly higher. There was no difference in levels of Cystatin C, NO metabolites, cGMP, ADMA or SDMA. RIPC patients required shorter PICU stay, all other clinical and laboratory analysis presented no difference related to the intervention. Gene expression analysis revealed interesting patterns before and after incubation. HSP-60 presented a lower expression at baseline in tissue corresponding to RIPC patients, no other differences were found. This study provided with valuable descriptive information on previously known and newly explored parameters in the study population. Demographic characteristics and the presence of cyanosis before surgery influenced patterns of activity in several parameters, numerous indicators were linked to the degree of injury suffered by the myocardium. RIPC did not reduce markers of cardiac injury or improved echocardiographic parameters and it did not have an effect on end organ function; some effects were seen in inflammatory responses and gene expression analysis. Nevertheless, an important clinical outcome indicator, PICU length of stay was reduced suggesting benefit from the intervention. Larger studies with more statistical power could determine if the tendency of lower injury and inflammatory markers linked to RIPC is real. The present results mostly support findings of larger multicentre trials which have reported no cardiac benefit from RIPC in paediatric cardiac surgery.

Neuroradiological findings expand the phenotype of OPA1-related mitochondrial dysfunction

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Antioxidants attenuate hyperglycaemia-mediated brain endothelial cell dysfunction and blood–brain barrier hyperpermeability

Aims: Hyperglycaemia (HG), in stroke patients, is associated with worse neurological outcome by compromising endothelial cell function and the blood–brain barrier (BBB) integrity. We have studied the contribution of HG-mediated generation of oxidative stress to these pathologies and examined whether antioxidants as well as normalization of glucose levels following hyperglycaemic insult reverse these phenomena. Methods: Human brain microvascular endothelial cell (HBMEC) and human astrocyte co-cultures were used to simulate the human BBB. The integrity of the BBB was measured by transendothelial electrical resistance using STX electrodes and an EVOM resistance meter, while enzyme activities were measured by specific spectrophotometric assays. Results: After 5 days of hyperglycaemic insult, there was a significant increase in BBB permeability that was reversed by glucose normalization. Co-treatment of cells with HG and a number of antioxidants including vitamin C, free radical scavengers and antioxidant enzymes including catalase and superoxide dismutase mimetics attenuated the detrimental effects of HG. Inhibition of p38 mitogen-activated protein kinase (p38MAPK) and protein kinase C but not phosphoinositide 3 kinase (PI3 kinase) also reversed HG-induced BBB hyperpermeability. In HBMEC, HG enhanced pro-oxidant (NAD(P)H oxidase) enzyme activity and expression that were normalized by reverting to normoglycaemia. Conclusions: HG impairs brain microvascular endothelial function through involvements of oxidative stress and several signal transduction pathways.

Identification of telomere dysfunction in Friedreich ataxia.

Background: Friedreich ataxia (FRDA) is a progressive inherited neurodegenerative disorder caused by mutation of the FXN gene, resulting in decreased frataxin expression, mitochondrial dysfunction and oxidative stress. A recent study has identified shorter telomeres in FRDA patient leukocytes as a possible disease biomarker. Results: Here we aimed to investigate both telomere structure and function in FRDA cells. Our results confirmed telomere shortening in FRDA patient leukocytes and identified similar telomere shortening in FRDA patient autopsy cerebellar tissues. However, FRDA fibroblasts showed significantly longer telomeres at early passage, occurring in the absence of telomerase activity, but with activation of an alternative lengthening of telomeres (ALT)-like mechanism. These cells also showed accelerated telomere shortening as population doubling increases. Furthermore, telomere dysfunction-induced foci (TIF) analysis revealed that FRDA fibroblasts have dysfunctional telomeres. Conclusions: Our finding of dysfunctional telomeres in FRDA cells provides further insight into FRDA molecular disease mechanisms, which may have implications for future FRDA therapy.

Circuit resistance training improved endothelial dysfunction in obese aged women

Introduction: It is widely accepted that obesity is associated with endothelial dysfunction. In a recent paper, we have also found circuit resistance training may reduce visceral fat in obese aged women. Accordingly, the current study was conducted to ascertain the effects of circuit resistance training on markers of endothelial dysfunction in this population group. Methods: In the present interventional study, a total of 48 obese aged women were recruited from the community. Twenty-four of them were randomly assigned to perform a 12-week resistance circuit training programme, 3-days per week. This training was circularly performed in 6 stations: arm curl, leg extension, seated row, leg curl, triceps extension and leg press. The Jamar handgrip electronic dynamometer was used to assess maximal handgrip strength of the dominant hand. Lastly, serum samples were analysed using an immunoassay (ELISA) for endothelin-1, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). Results: When compared to baseline, resistance training significantly reduced serum levels of endothelin-1 (2.28 ± 0.7 vs. 1.98 ± 1.1 pg/ml; p = 0.019; d = 0.67) and ICAM-1 (290 ± 69 vs. 255 ± 76 ng/ml; p = 0.004; d = 0.92) in the experimental group. No significant changes in any of the tested outcomes were found in the control group. Conclusion: A short-term circuit resistance program improved endothelial dysfunction in aged obese women. Further studies on this topic are still required to consolidate this approach in clinical application.

Procalcitonin Biomarker Kinetics to Predict Multiorgan Dysfunction Syndrome in Children With Sepsis and Systemic Inflammatory Response Syndrome

Background: Procalcitonin (PCT) kinetics is a good prognosis marker in infectious diseases, but few studies of children sepsis have been performed. Objectives: The aim of our study was to examine kinetics of procalcitonin, to evaluate its relationship with severity and to analyze its usefulness in the prediction of multiorgan dysfunction syndrome (MODS). Patients and Methods: Prospective observational study in an 8-bed pediatric intensive care unit of a university hospital. Sixty-two children aged 0-19 years with systemic inflammatory response syndrome or septic states. The degree of severity was evaluated according pediatric logistic organ dysfunction (PELOD) score. Blood tests to determine levels of PCT were taken if the patients had the criteria of systemic inflammatory response syndrome or sepsis. The serum to determine levels of PCT in control group has been taken from patients undergoing elective surgery. Results: Higher values of PCT were identified in patients with PELOD score 12 and more compared to those with PELOD < 12 (P = 0.016). Similarly, higher PCT values were found in patients who developed MODS in contrast to those without MODS (P = 0.011). According to ROC analysis cut-off value of 4.05 ng/mL was found to best discriminate patients with PELOD < 12 and PELOD ≥ 12 with AUC = 0.675 (P = 0.035). Effect of procalcitonin levels on mortality was not demonstrated. Conclusions: Levels of procalcitonin from day 1 to day 5 are related to the severity and multiorgan dysfunction syndrome in children.

Olfactory dysfunction in young smokers J.

To establish the prevalence of olfactory dysfunction in smoking and non-smoking students of our Faculty who attend the Department of Otolaryngology (ENT) of our Hospital. Materials and method: Students (smokers and non-smokers) that do and do not suffer from olfactory dysfunction. We applied a questionnaire and a pocket smell test for screening all of the students. Results: We evaluated 207 students, between 18 and 30 years old; 50.7% (n=105) were women and 49.3% (n=102) were men. The smokers among them smoked up to 6 packs per year. One hundred twenty three students were non-smokers and 84 students were smokers. Of the 84 students who were smokers, 67 (79.7%) answered the Pocket Smell Test correctly (3/3) and 17 (20.2%) students had one or more errors. We had 123 non-smoker students and 103 (83.7%) students answered the Pocket Smell Test correctly and 20 (16.2%) answered with one or more errors. The prevalence of olfactory dysfunction in young smokers with a 95% conidence interval would be 32.8%. Conclusions: This study informed us about olfactory dysfunctions in our student population and their smoking habits. We corroborate that the Pocket Smell Test is reliable with the questionnaire; nevertheless it is a screening test. We have a population of young people who smoke one cigarette per day and who didn’t have a signiicant alteration in their ability of smell at the time of the study. This is consistent with medical literature. More studies should be conducted in order to expand this information.

Sexual dysfunction in breast cancer survivors: cross-cultural adaptation of the Sexual Activity Questionnaire for use in Portugal

"Introduction: The increasing survivor population of breast cancer has shifted research and practice interests into the impacts of the disease and treatment in quality of life aspects. The lack of tools available in Portuguese to objectively evaluate sexual function led to the development of this study, which aimed to cross-culturally adapt and validate the Sexual Activity Questionnaire for use in Portugal. Material and Methods: The questionnaire was translated and back-translated, refined following face-to-face interviews with seven breast cancer survivors, and then self-administered by a larger sample at baseline and a fortnight later to test validity and reliability. Results: Following cognitive debriefing (n = 7), minor changes were made and the Sexual Activity Questionnaire was then tested with 134 breast cancer survivors. A 3-factor structure explained 75.5% of the variance, comprising the Pleasure, Habit and Discomfort scales, all yielding good internal consistency (Cronbach’s α > 0.70). Concurrent validity with the FACt-An and the BCPT checklist was good (Spearman’s r > 0.65; p-value < 0.001) and reliability acceptable (Cohen’s k > 0.444). The Sexual Activity Questionnaire allowed the identification of 23.9% of sexually inactive women, for whom the main reasons were lack of interest or motivation and not having a partner. Discussion: Patient-reported outcomes led to a more comprehensive and improved approach to cancer, tackling areas previously abandoned. Future research should focus on the validation of this scale in samples with different characteristics and even in the overall population to enable generalizability of the findings. Conclusion: The adapted Sexual Activity Questionnaire is a valid tool for assessing sexual function in breast cancer survivors in Portugal."

Noninvasive Evaluation of Myocardial Systolic Dysfunction in the Early Stage of Kawasaki Disease: A Speckle-Tracking Echocardiography Study

Background: Evaluation of myocardial function by speckle-tracking echocardiography is a new method for the early diagnosis of systolic dysfunction. Objectives: We aimed to determine myocardial speckle-tracking echocardiography indices in Kawasaki Disease (KD) patients and compare them with the same indices in control subjects. Patients and Methods: Thirty-two patients (65.5% males) with KD and 19 control subjects with normal echocardiography participated in this study. After their demographic characteristics and clinical findings were recorded, all the participants underwent transthoracic echocardiography. Strain (S), Strain Rate (SR), Time to Peak Strain (TPS), and Strain Rate (TPSR), longitudinal velocity and view point velocity images in the two, three, and four-chamber views were semi-automatically obtained via speckle-tracking echocardiography. Results: Among the patients, Twenty-four cases (75%) were younger than 4 years. Mean global S and SR was significantly reduced in the KD patients compared to controls (17.03 ± 1.28 vs. 20.22 ± 2.14% and 1.66 ± 0.16 vs. 1.97 ± 0.25 1/second, respectively), while there were no significant differences regarding mean TPS, TPSR, longitudinal velocity and view point velocity. Using repeated measure of analysis of variances, we observed that S and SR decreased from base to apical level in both groups. The change in the pattern of age adjusted mean S and SR across levels was significantly different between the groups (P < 0.001 for both parameters). Conclusions: We showed changes in S and SR assessed in KD patients versus control subjects in the acute phase of KD. However, we suggest that further studies be undertaken to compare S and SR in the acute phase and thereafter in KD patients.

Erectile dysfunction: prevalence, risk factors and involvement of antihypertensive drugs intervention

Purpose: To explore the literature regarding prevalance, risk factors and the involvement of antihypertensive drugs in erectile dysfunction (ED). Methods: Original research articles, reviews, editorials and case reports published in English language on the prevalence of sexual/erectile dysfunction in hypertensive men taking antihypertensive drugs and risk factors were identified through a search of four bibliographic databases, namely, PubMed, EMBASE, CINAHL and EBSCO Health. Results: Recent analyses suggest that hypertensive men of almost all age groups suffer from ED but it is more prevalent in elderly male patients. The involvement of β-blockers was found to be controversial. Nevertheless, some evidence had been found regarding the use of propranolol in high doses. Conclusion: The present review indicates the need for research to unravel the role of β-blockers in the manifestation of ED in hypertensive males, whom there are no contributory factors such as sedentary lifestyle, aging, stress and anxiety, etc.

Theoretical investigation of intra- and inter-cellular spatiotemporal calcium patterns in microcirculation

Microcirculatory vessels are lined by endothelial cells (ECs) which are surrounded by a single or multiple layer of smooth muscle cells (SMCs). Spontaneous and agonist induced spatiotemporal calcium (Ca2+) events are generated in ECs and SMCs, and regulated by complex bi-directional signaling between the two layers which ultimately determines the vessel tone. The contractile state of microcirculatory vessels is an important factor in the determination of vascular resistance, blood flow and blood pressure. This dissertation presents theoretical insights into some of the important and currently unresolved phenomena in microvascular tone regulation. Compartmental and continuum models of isolated EC and SMC, coupled EC-SMC and a multi-cellular vessel segment with deterministic and stochastic descriptions of the cellular components were developed, and the intra- and inter-cellular spatiotemporal Ca2+ mobilization was examined.^ Coupled EC-SMC model simulations captured the experimentally observed localized subcellular EC Ca2+ events arising from the opening of EC transient receptor vanilloid 4 (TRPV4) channels and inositol triphosphate receptors (IP3Rs). These localized EC Ca2+ events result in endothelium-derived hyperpolarization (EDH) and Nitric Oxide (NO) production which transmit to the adjacent SMCs to ultimately result in vasodilation. The model examined the effect of heterogeneous distribution of cellular components and channel gating kinetics in determination of the amplitude and spread of the Ca2+ events. The simulations suggested the necessity of co-localization of certain cellular components for modulation of EDH and NO responses. Isolated EC and SMC models captured intracellular Ca2+ wave like activity and predicted the necessity of non-uniform distribution of cellular components for the generation of Ca2+ waves. The simulations also suggested the role of membrane potential dynamics in regulating Ca2+ wave velocity. The multi-cellular vessel segment model examined the underlying mechanisms for the intercellular synchronization of spontaneous oscillatory Ca2+ waves in individual SMC. ^ From local subcellular events to integrated macro-scale behavior at the vessel level, the developed multi-scale models captured basic features of vascular Ca2+ signaling and provide insights for their physiological relevance. The models provide a theoretical framework for assisting investigations on the regulation of vascular tone in health and disease.^

The Effects of Age, Ethnicity, Sexual Dysfunction, Urinary Incontinence, Masculinity, and Relationship with the Partner on the Quality of Life of Men with Prostate Cancer

Prostate cancer, the leading cause of cancer in men, has positive survival rates and constitutes a challenge to men with its side effects. Studies have addressed the bivaritate relationships between prostate cancer treatment side effects masculinity, partner relationship, and quality of life (QOL). However, few studies have highlighted the relationships among prostate cancer treatment side effects (i.e., sexual dysfunction, urinary incontinence), masculinity, and relationship with the partner together on QOL in men. Most studies were conducted with predominately Caucasian sample of men. Miami is a unique multiethnic setting that hosts Cuban, Columbian, Venezuelan, Haitian, other Latin American and Caribbean communities that were not represented in previous literature. The purpose of this study was to examine relative contributions of age, ethnicity, sexual dysfunction, urinary incontinence, masculinity, and perception of the relationship with the partner on the quality of life in men diagnosed with prostate cancer. Data were collected using self administered questionnaires measuring demographic variables, sexual and urinary functioning (UCLA PCI), masculinity (CMNI), partner relationship (DAS), and QOL (SF-36). A total of 117 partnered heterosexual men diagnosed with prostate cancer were recruited from four urology clinics in Miami, Florida. Men were 67.47 (SD = 8.42) years old and identified themselves to be of Hispanic origin (54.3 %, n = 63). Findings demonstrated that there was a significant moderate negative relationship between urinary and sexual functioning of men. There was a significant strong negative association between men’s perceived relationship with partner and masculinity. There was a weak negative relationship between the partner relationship and QOL. Hierarchal multiple regression showed that the partner relationship (β = -.25, t (91) = -2.28, p = .03) significantly contributed overall to QOL. These findings highlight the importance of the relationship satisfaction in the QOL of men with prostate cancer. Nursing interventions to enhance QOL for these men should consider strengthening the relationship and involving the female partner as an active participant.

Hypothermia protects brain mitochondrial function from hypoxemia in a murine model of sepsis

Sepsis is commonly associated with brain dysfunction, but the underlying mechanisms remain unclear, although mitochondrial dysfunction and microvascular abnormalities have been implicated. We therefore assessed whether cerebral mitochondrial dysfunction during systemic endotoxemia in mice increased mitochondrial sensitivity to a further bioenergetic insult (hyoxemia), and whether hypothermia could improve outcome. Mice (C57bl/6) were injected intraperitoneally with lipopolysaccharide (LPS) (5 mg/kg; n = 85) or saline (0.01 ml/g; n = 47). Six, 24 and 48 h later, we used confocal imaging in vivo to assess cerebral mitochondrial redox potential and cortical oxygenation in response to changes in inspired oxygen. The fraction of inspired oxygen (FiO2) at which the cortical redox potential changed was compared between groups. In a subset of animals, spontaneous hypothermia was maintained or controlled hypothermia induced during imaging. Decreasing FiO2 resulted in a more reduced cerebral redox state around veins, but preserved oxidation around arteries. This pattern appeared at a higher FiO2 in LPS-injected animals, suggesting an increased sensitivity of cortical mitochondria to hypoxemia. This increased sensitivity was accompanied by a decrease in cortical oxygenation, but was attenuated by hypothermia. These results suggest that systemic endotoxemia influences cortical oxygenation and mitochondrial function, and that therapeutic hypothermia can be protective.