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.

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.

Chronic sustained hypoxia-induced redox remodeling causes contractile dysfunction in mouse sternohyoid muscle

Chronic sustained hypoxia (CH) induces structural and functional adaptations in respiratory muscles of animal models, however the underlying molecular mechanisms are unclear. This study explores the putative role of CH-induced redox remodeling in a translational mouse model, with a focus on the sternohyoid—a representative upper airway dilator muscle involved in the control of pharyngeal airway caliber. We hypothesized that exposure to CH induces redox disturbance in mouse sternohyoid muscle in a time-dependent manner affecting metabolic capacity and contractile performance. C57Bl6/J mice were exposed to normoxia or normobaric CH (FiO2 = 0.1) for 1, 3, or 6 weeks. A second cohort of animals was exposed to CH for 6 weeks with and without antioxidant supplementation (tempol or N-acetyl cysteine in the drinking water). Following CH exposure, we performed 2D redox proteomics with mass spectrometry, metabolic enzyme activity assays, and cell-signaling assays. Additionally, we assessed isotonic contractile and endurance properties ex vivo. Temporal changes in protein oxidation and glycolytic enzyme activities were observed. Redox modulation of sternohyoid muscle proteins key to contraction, metabolism and cellular homeostasis was identified. There was no change in redox-sensitive proteasome activity or HIF-1α content, but CH decreased phospho-JNK content independent of antioxidant supplementation. CH was detrimental to sternohyoid force- and power-generating capacity and this was prevented by chronic antioxidant supplementation. We conclude that CH causes upper airway dilator muscle dysfunction due to redox modulation of proteins key to function and homeostasis. Such changes could serve to further disrupt respiratory homeostasis in diseases characterized by CH such as chronic obstructive pulmonary disease. Antioxidants may have potential use as an adjunctive therapy in hypoxic respiratory disease.

Impacto de los Niveles de Tacrolimus en el Rechazo al Injerto y la Tasa de Filtración Glomerular en Pacientes con Trasplante Hepático realizado en la FCI-IC entre 2009 y 2014

Introducción: El tacrolimus es el medicamento de elección para evitar el rechazo al injerto hepático. Su dosis se ajusta a partir de los niveles séricos que se toman periódicamente para asegurar rango terapéutico. Además, niveles elevados se asocian con disfunción renal postrasplante. Sin embargo, no hay consenso frente a los niveles adecuados para pacientes con trasplante hepático. Objetivo: Determinar la relación entre los niveles de tacrolimus y la presencia de rechazo agudo al injerto hepático en pacientes con trasplante hepático realizado en la Fundación Cardioinfantil – Instituto de Cardiología (FCI-IC). Determinar la relación entre los niveles de tacrolimus y la TFG en pacientes con trasplante hepático realizado en la FCI-IC. Métodos: Estudio observacional tipo cohorte histórica en pacientes adultos con trasplante hepático realizado en la FCI-IC entre 2009-2014. Resultados: No se encontró una asociación estadísticamente significativa entre los niveles de tacrolimus y la presencia de rechazo agudo, en sus diferentes definiciones (OR=1,02, p=0,14 y OR=1,01, p=0,29) incluso al ajustar por otras covariables (OR=1,03, p=0,10 y OR=1,02, p=0,25). No fue posible corroborar el diagnóstico con biopsia porque no todos la tenían. Si bien la relación entre los niveles de tacrolimus y la TFG fue estadísticamente significativa (p≤0,001), tiene bajo impacto clínico, pues la TFG disminuyó menos de un punto por cada incremento en 1 ng/ml en los niveles de tacrolimus. Conclusiones: Se necesitan más estudios para establecer la relación entre la exposición a tacrolimus y estos desenlaces para definir si es seguro disminuir su dosis con el fin de reducir los eventos adversos.

“Nanoglial interfaces: nanostructured materials, interfaces and devices to unveil the role of astrocytes in brain function and dysfunction”

The role of non-neuronal brain cells, called astrocytes, is emerging as crucial in brain function and dysfunction, encompassing the neurocentric concept that was envisioning glia as passive components. Ion and water channels and calcium signalling, expressed in functional micro and nano domains, underpin astrocytes’ homeostatic function, synaptic transmission, neurovascular coupling acting either locally and globally. In this respect, a major issue arises on the mechanism through which astrocytes can control processes across scales. Finally, astrocytes can sense and react to extracellular stimuli such as chemical, physical, mechanical, electrical, photonic ones at the nanoscale. Given their emerging importance and their sensing properties, my PhD research program had the general goal to validate nanomaterials, interfaces and devices approaches that were developed ad-hoc to study astrocytes. The results achieved are reported in the form of collection of papers. Specifically, we demonstrated that i) electrospun nanofibers made of polycaprolactone and polyaniline conductive composites can shape primary astrocytes’ morphology, without affecting their function ii) gold coated silicon nanowires devices enable extracellular recording of unprecedented slow wave in primary differentiated astrocytes iii) colloidal hydrotalcites films allow to get insight in cell volume regulation process in differentiated astrocytes and to describe novel cytoskeletal actin dynamics iv) gold nanoclusters represent nanoprobe to trigger astrocytes structure and function v) nanopillars of photoexcitable organic polymer are potential tool to achieve nanoscale photostimulation of astrocytes. The results were achieved by a multidisciplinary team working with national and international collaborators that are listed and acknowledged in the text. Collectively, the results showed that astrocytes represent a novel opportunity and target for Nanoscience, and that Nanoglial interface might help to unveil clues on brain function or represent novel therapeutic approach to treat brain dysfunctions.

Strategies to hijack MTs dysfunction in neurodegenerative tauopathies: Design and synthesis of novel CNS-disease-modifying tools

Neuronal microtubules assembly and dynamics are regulated by several proteins including (MT)-associated protein tau, whose aberrant hyperphosphorylation promotes its dissociation from MTs and its abnormal deposition into neurofibrillary tangles, a common neurotoxic hallmarks of neurodegenerative tauopathies. To date, no disease-modifying drugs have been approved to combat CNS tau-related diseases. The multifactorial etiology of these conditions represents one of the major limits in the discovery of effective therapeutic options. In addition, tau protein functions are orchestrated by diverse post-translational modifications among which phosphorylation mediated by PKs plays a leading role. In this context, conventional single-target therapies are often inadequate in restoring perturbed networks and fraught with adverse side-effects. This thesis reports two distinct approaches to hijack MT defects in neurons. The first is focused on the rational design and synthesis of first-in-class triple inhibitors of GSK-3β, FYN, and DYRK1A, three close-related PKs, which act as master regulators of aberrant tau hyperphosphorylation. A merged multi-target pharmacophore strategy was applied to simultaneously modulate all three targets and achieve a disease-modifying effect. Optimization of ARN25068 by a computationally and crystallographic driven SAR exploration, allowed to rationalize the key structural modifications to maintain a balanced potency against all three targets and develop a new generation of quite well-balanced analogs exhibiting improved physicochemical properties, a good in vitro ADME profile, and promising cell-based anti-tau phosphorylation activity. In Part II, MT-stabilizing compounds have been developed to compensate MT defects in tau-related pathologies. Intensive chemical effort has been devoted to scaling up BL-0884, identified as a promising MT-normalizing TPD, which exhibited favorable ADME-PK, including brain penetration, oral bioavailability, and brain pharmacodynamic activity. A suitable functionalization of the exposed hydroxyl moiety of BL-0884 was carried out to generate corresponding esters and amides possessing a wide range of applications as prodrugs and active targeting for cancer chemotherapy.