Survival does not differ by annual center transplant volume-A Pediatric Heart Transplant Society Registry study.

BACKGROUND: There are conflicting data regarding the relationship between center volume and outcomes in pediatric heart transplantation. Previous studies have not fully accounted for differences in case mix, particularly in high-risk congenital heart disease (CHD) groups. We aimed to evaluate the relationship between center volume and outcomes using the Pediatric Heart Transplant Society (PHTS) Registry and explore how case mix may affect outcomes. METHODS: A retrospective cohort study of all pediatric patients in the PHTS Registry who received a heart transplant from 2009 to 2018 was performed. Centers were divided into 5 groups based on average yearly transplant volume. The primary outcome was time to death or graft loss and outcomes were compared using Kaplan-Meier analysis. RESULTS: There were 4583 cases among 55 centers included. There was no difference in time to death or graft loss by center volume in the entire cohort (p = .75), in patients with CHD (p = .79) or in patients with cardiomyopathy (p = .23). There was also no difference in time to death or graft loss by center size in patients undergoing transplant after Norwood, Glenn or Fontan (log rank p = .17, p = .31, and p = .10 respectively). There was a statistically significant difference in outcomes by center size in the positive crossmatch group (p < .0001), though no discernible pattern related to high or low center volume. CONCLUSIONS: Outcomes are similar among transplant centers of all sizes, including for high-risk patient groups with CHD. Future work is needed to understand how patient-specific risk factors may vary among centers of various sizes and whether this influences patient outcomes.

Successful implementation of telehealth visits in the paediatric heart failure and heart transplant population.

The Advanced Cardiac Therapies Improving Outcomes Network (ACTION) and Pediatric Heart Transplant Society (PHTS) convened a working group at the beginning of 2020 during the COVID-19 pandemic, with the aim of using telehealth as an alternative medium to provide quality care to a high-acuity paediatric population receiving advanced cardiac therapies. An algorithm was developed to determine appropriateness, educational handouts were developed for both patients and providers, and post-visit surveys were collected. Telehealth was found to be a viable modality for health care delivery in the paediatric heart failure and transplant population and has promising application in the continuity of follow-up, medication titration, and patient education/counselling domains.

Reducing donor acceptance practice variation - Learnings from a discussion forum.

PURPOSE: Although waitlist mortality is unacceptably high, nearly half of donor heart offers are rejected by pediatric heart transplant centers. The Advanced Cardiac Therapy Improving Outcome Network (ACTION) and Pediatric Heart Transplant Society (PHTS) convened a multi-institutional donor decision discussion forum (DDDF) aimed at assessing donor acceptance practices and reducing practice variation. METHODS: A 1-h-long virtual DDDF for providers across North America, the United Kingdom, and Brazil was held monthly. Each session typically included two case presentations posing a real-world donor decision challenge. Attendees were polled before the presenting center's decision was revealed. Group discussion followed, including a review of relevant literature and PHTS data. Metrics of participation, participant agreement with presenting center decisions, and impact on future decision-making were collected and analyzed. RESULTS: Over 2 years, 41 cases were discussed. Approximately 50 clinicians attended each call. Risk factors influencing decision-making included donor quality (10), size discrepancy (8), and COVID-19 (8). Donor characteristics influenced 63% of decisions, recipient factors 35%. Participants agreed with the decision made by the presenting center only 49% of the time. Post-presentation discussion resulted in 25% of participants changing their original decision. Survey conducted reported that 50% respondents changed their donor acceptance practices. CONCLUSION: DDDF identified significant variation in pediatric donor decision-making among centers. DDDF may be an effective format to reduce practice variation, provide education to decision-makers, and ultimately increase donor utilization.

Cardiovascular remodelling in response to exercise training in patients after the Fontan procedure: a pilot study.

BACKGROUND: The cardiovascular adaptations associated with structured exercise training in Fontan patients remain unknown. We hypothesised that short-term training causes cardiac remodelling and parallel improvement in maximal exercise capacity (VO2 max) in these patients. METHODS AND RESULTS: Five patients, median age 19.5 (17.6-21.3) years, with a history of Fontan operation meeting inclusion/exclusion criteria, participated in a 3-month training programme designed to improve endurance. Magnetic resonance images for assessment of cardiac function, fibrosis, cardiac output, and liver elastography to assess stiffness were obtained at baseline and after training. Maximal exercise capacity (VO2 max) and cardiac output Qc (effective pulmonary blood flow) at rest and during exercise were measured (C2H2 rebreathing) at the same interval. VO2 max increased from median (IQR) 27.2 (26-28.7) to 29.6 (28.5-32.2) ml/min/kg (p = 0.04). There was an improvement in cardiac output (Qc) during maximal exercise testing from median (IQR) 10.3 (10.1-12.3) to 12.3 (10.9-14.9) l/min, but this change was variable (p = 0.14). Improvement in VO2 max correlated with an increase in ventricular mass (r = 0.95, p = 0.01), and improvement in Quality-of-life inventory (PedsQL) Cardiac scale scores for patient-reported symptoms (r = 0.90, p = 0.03) and cognitive problems (r = 0.89, p = 0.04). The correlation between VO2 max and Qc showed a positive trend but was not significant (r = 0.8, p = 0.08). No adverse cardiac or liver adaptations were noted. CONCLUSION: Short-term training improved exercise capacity in this Fontan pilot without any adverse cardiac or liver adaptations. These results warrant further study in a larger population and over a longer duration of time. TRIAL REGISTRATION NUMBER: NCT03263312, Unique Protocol ID: STU 122016-037; Registration Date: 18 January, 2017.

Analysis of combined non-invasive respiratory support in the first six waves of the COVID-19 pandemic. Outcome according to the first respiratory support.

Introduction: COVID-19 can lead to acute respiratory failure (ARF) requiring admission to intensive care unit (ICU). This study analyzes COVID-19 patients admitted to the ICU, according to the initial respiratory support. Its main aim is to determine if the use of combination therapy: high-flow oxygen system with nasal cannula (HFNC) and non-invasive ventilation (NIV), is effective and safe in the treatment of these patients. Methods: Retrospective observational study with a prospective database. All COVID-19 patients, admitted to the ICU, between March 11, 2020, and February 12, 2022, and who required HFNC, NIV, or endotracheal intubation with invasive mechanical ventilation (ETI-IMV) were analyzed. HFNC failure was defined as therapeutic escalation to NIV, and NIV failure as the need for ETI-IMV or death in the ICU. The management of patients with non-invasive respiratory support included the use of combined therapy with different devices. The study period included the first six waves of the pandemic in Spain. Results: 424 patients were analyzed, of whom 12 (2.8%) received HFNC, 397 (93.7%) NIV and 15 (3.5%) ETI-IMV as first respiratory support. PaO2/FiO2 was 145 ± 30, 119 ± 26 and 117 ± 29 mmHg, respectively (p = 0.003). HFNC failed in 11 patients (91.7%), who then received NIV. Of the 408 patients treated with NIV, 353 (86.5%) received combination therapy with HFNC. In patients treated with NIV, there were 114 failures (27.9%). Only the value of SAPS II index (p = 0.001) and PaO2/FiO2 (p < 0.001) differed between the six analyzed waves, being the most altered values in the 3rd and 6th waves. Hospital mortality was 18.7%, not differing between the different waves (p = 0.713). Conclusions: Severe COVID-19 ARF can be effectively and safely treated with NIV combined with HFNC. The clinical characteristics of the patients did not change between the different waves, only showing a slight increase in severity in the 3rd and 6th waves, with no difference in the outcome.

Psicología De Emergencias En España: Análisis Actual, Normativa Y Proposición Reguladora / Psychology Of Emergencies In Spain: Current Analysis, Norms And Regulatory Proposal

La psicología de emergencias en España ha tenido desde finales de los años noventa hasta la actualidad un desarrollo exponencial como nueva disciplina profesional del psicólogo. La demanda de psicólogos por parte de la sociedad en incidentes con múltiples víctimas, desastres, atentados terroristas, accidentes de tráfico, suicidios, etc., ha sido una constante en estos años. Por ello, se ha desarrollado numerosa normativa en la que se contempla la importancia de prestar esta asistencia a las personas afectadas por situaciones que, por su alto impacto, pueden resultar potencialmente traumáticas. En el presente trabajo, se realiza una revisión histórica de la evolución de la psicología de emergencias, la sintomatología más común presentada como consecuencia de estas vivencias, el impacto que ha supuesto a nuestra sociedad estos acontecimientos en cuanto a personas afectadas y la necesidad de prestar asistencia psicológica tanto en situaciones de emergencia cotidiana como en grandes catástrofes. Todo ello, nos lleva a la conclusión de la importancia de trabajar hacia una regulación de la psicología de emergencias que garantice la cualificación formativa de los profesionales de la psicología que van a ejercer esta actividad, así como su incorporación e integración en el sistema público asistencial. (AU)

Emergency psychology in Spain has experienced exponential development as a new professional discipline of the psychologist in the last decades. Society has shown a permanent demand for psychologists in mass casualty incidents, disasters, terrorist attacks, traffic accidents, suicides, etc. Consequently, numerous regulations have been developed regarding assistance in these situations which, due to their high impact, could be potentially traumatic. In the present work we present a historical review of the evolution of emergency psychology, the most common symptoms presented as a consequence of these experiences, the impact that these events have had on society, the people affected, and the necessity to provide psychological assistance, both in everyday emergency situations and in major catastrophes. We highlight the importance of emergency psychology regulation to guarantee the training qualification of the psychology professionals who will carry out this activity, as well as their incorporation and integration in the public healthcare system. (AU)

Psicología De Emergencias En España: Delimitación Conceptual, Ámbitos De Actuación Y Propuesta De Un Sistema Asistencial / Psychology Of Emergencies In Spain: Conceptual Delimitation, Action Areas And Healthcare System Proposal

La psicología de emergencias es un ámbito de aplicación de la psicología bastante reciente, lo que implica que no haya en laactualidad un consenso unificado sobre esta disciplina, su delimitación conceptual o campo de actuación. Tampoco queda reflejada su incursión en los itinerarios curriculares elaborados en nuestro país a partir del Espacio Europeo de Educación Superior,ni en la estructura sanitaria o de protección civil de cara a que los psicólogos de emergencias puedan intervenir en las situaciones de crisis, emergencias o desastres que se producen. Partimos en este trabajo de esta dificultad en la vertebración de este ámbito disciplinar para realizar una propuesta de sistema de asistencia psicológica que contribuya a clarificar la labor ycompetencias de los distintos servicios psicológicos implicados en estas situaciones de manera que facilite un sistema coordinadode actuación. Pretendemos generar un debate profesional y académico que nos lleve a encontrar el consenso necesario que impulse la consolidación de este específico perfil profesional, así como el reconocimiento y regulación de la Psicología de Emergencias que contribuya a afianzarla como disciplina dentro de la Psicología que permita ofrecer a la sociedad una actuaciónprofesional de calidad y adaptada a los retos actuales y futuros. (AU)

Emergency psychology is a recent area of application for psychology, which means that there is currently no unified consensus onthis discipline, its conceptual delimitation, or its field of action. Also not delimited are the curricular itineraries adapted to the European Higher Education Area, in either the health or civil protection structure, in order for emergency psychologists to be able tointervene in crisis situations, emergencies, and disasters. In the present work, we offer a proposal for a system of psychologicalassistance that contributes to clarifying the work and competences of the different psychological services involved in these situations, in a way that facilitates a coordinated system of action. We intend to generate a professional and academic debate to leadus to reach the necessary consensus to make it possible to consolidate this specific professional profile, as well as to recognizeand regulate emergency psychology in order to strengthen it as a discipline of psychology that allows us to offer a professionalperformance of quality, adapted to current and future challenges. (AU)

Center Donor Refusal Rate Is Associated With Worse Outcomes After Listing in Pediatric Heart Transplantation.

BACKGROUND: Pediatric donor heart acceptability differs among transplant centers. However, the impact of center donor acceptance on waitlist and posttransplant outcomes has not been investigated. The aim of our study was to investigate associations between transplant center refusal rate (RR) and outcomes after listing. METHODS: Retrospective analysis was performed using United Network for Organ Sharing/Organ Procurement and Transplant Network pediatric (<18 y) heart transplant data from 2007 to 2017. Center RR was defined as the median number of refusals per listed patient. Associations between RR center quartile and waitlist time, waitlist removal for death or clinical deterioration, posttransplant survival, and survival after listing were investigated. RESULTS: There were 5552 listed patients in 59 centers who met inclusion criteria. The lowest quartile RR centers had a median RR of ≤1 per listed patient, and highest RR centers percentile had a median RR of ≥4. Highest RR centers had shorter time to first offer (19 versus 38 d; P < 0.001), with longer waitlist times (203 versus 145 d; P < 0.001), were more likely to remove patients from the waitlist due to death or deterioration (24.1% versus 14.6%; P < 0.001), less likely to transplant listed patients (63.1% versus 77.6%; P < 0.001), and had a lower likelihood of survival 1 year after listing (79.2% versus 91.6%; odds ratio, 1.6; 95% confidence interval, 1.2-2.0; P < 0.001) compared with low RR centers. CONCLUSIONS: Patients listed at high RR centers had worse survival from listing despite having shorter times to first offer.

A comprehensive strategy in donor acceptance: Impact on pediatric waitlist and heart transplant outcomes.

Significant inter- and intra-center practice variability is present in pediatric donor heart acceptability. This may contribute to variation in the donor refusal rate and may impact waitlist time, morbidity, mortality, and transplant rates. In order to reduce practice variability, our center developed and implemented a comprehensive strategy regarding donor acceptance in September 2017. The aim of this study was to assess the impact of this strategy on waitlist time and outcomes as well as early post-transplant outcomes. We performed a single-center, retrospective analysis of all pediatric (<18 years) patients listed for single-organ heart transplant at our center from September 2015 to September 2018. Patients were divided into those listed before (Group 1) and after implementation of the comprehensive strategy (Group 2). The primary end-point was waitlist time. Secondary end-points included waitlist removal due to death or clinical deterioration, donor refusals per listed patient, early post-transplant outcomes (graft failure, mechanical ventilation time, inotropic support, length of hospital stay) and 1-year post-transplant survival. Of 78 listed patients, 54 were transplanted (29 in Group 1), 9 were removed due to death or clinical deterioration (7 in Group 1) and 15 were removed due to clinical improvement (12 in Group 1). The waitlist time was significantly shorter in Group 2 (17 days, IQR 7-53) vs Group 1 (90 days, IQR 14-162); P = .006. The number of donor refusals was lower in Group 2 (1, IQR 0-2.2) vs Group 1 (4, IQR 2-19); P < .001. The percentage of refused donors with normal function (Left ventricular ejection fraction > 50%) was lower in Group 2 vs Group 1 (53% vs 84%; P < .001). Difference in removal from the waitlist for death or deterioration in Group 2 vs Group 1 (n = 2, 7% vs n = 7, 20%, P = .18) did not reach statistical significance. There was no difference in post-transplant outcomes between groups. The waitlist time and donor refusals significantly decreased after implementation of a comprehensive donor acceptance strategy without impacting transplant outcomes. This analysis supports the need for a comprehensive approach to donor organ acceptance within a pediatric transplant center.

Mitochondrial Toxicogenomics for Antiretroviral Management: HIV Post-exposure Prophylaxis in Uninfected Patients.

Background: Mitochondrial genome has been used across multiple fields in research, diagnosis, and toxicogenomics. Several compounds damage mitochondrial DNA (mtDNA), including biological and therapeutic agents like the human immunodeficiency virus (HIV) but also its antiretroviral treatment, leading to adverse clinical manifestations. HIV-infected and treated patients may show impaired mitochondrial and metabolic profile, but specific contribution of viral or treatment toxicity remains elusive. The evaluation of HIV consequences without treatment interference has been performed in naïve (non-treated) patients, but assessment of treatment toxicity without viral interference is usually restricted to in vitro assays. Objective: The objective of the present study is to determine whether antiretroviral treatment without HIV interference can lead to mtDNA disturbances. We studied clinical, mitochondrial, and metabolic toxicity in non-infected healthy patients who received HIV post-exposure prophylaxis (PEP) to prevent further infection. We assessed two different PEP regimens according to their composition to ascertain if they were the cause of tolerability issues and derived toxicity. Methods: We analyzed reasons for PEP discontinuation and main secondary effects of treatment withdrawal, mtDNA content from peripheral blood mononuclear cells and metabolic profile, before and after 28 days of PEP, in 23 patients classified depending on PEP composition: one protease inhibitor (PI) plus Zidovudine/Lamivudine (PI plus AZT + 3TC; n = 9) or PI plus Tenofovir/Emtricitabine (PI plus TDF + FTC; n = 14). Results: Zidovudine-containing-regimens showed an increased risk for drug discontinuation (RR = 9.33; 95% CI = 1.34-65.23) due to adverse effects of medication related to gastrointestinal complications. In the absence of metabolic disturbances, 4-week PEP containing PI plus AZT + 3TC led to higher mitochondrial toxicity (-17.9 ± 25.8 decrease in mtDNA/nDNA levels) than PI plus TDF + FTC (which increased by 43.2 ± 24.3 units mtDNA/nDNA; p < 0.05 between groups). MtDNA changes showed a significant and negative correlation with baseline alanine transaminase levels (p < 0.05), suggesting that a proper hepatic function may protect from antiretroviral toxicity. Conclusions: In absence of HIV infection, preventive short antiretroviral treatment can cause secondary effects responsible for treatment discontinuation and subclinical mitochondrial damage, especially pyrimidine analogs such as AZT, which still rank as the alternative option and first choice in certain cohorts for PEP. Forthcoming efforts should be focused on launching new strategies with safer clinical and mitotoxic profile.

Heart transplantation in an infant with Williams-Beuren syndrome and rapidly progressive ischemic cardiomyopathy.

Ischemic cardiomyopathy with resultant refractory HF may occur in patients with WBS, often as the result of coronary involvement with SVAS. The rapid development of arteriopathy at a young age raises concerns regarding transplant candidacy due to progressive stenoses at other arterial sites with potential detrimental impact on long-term heart graft function. We report a 2-month-old male infant diagnosed with mild aortic stenosis during the neonatal period, but subsequently developed rapidly progressive supravalvar and coronary artery stenoses leading to cardiogenic shock due to myocardial ischemia. The presentation led to the diagnosis of WBS. He required prolonged CPR including ECMO therapy. He subsequently underwent LVAD implantation as bridge to transplant and 4 days later heart transplantation. His post-operative course was complicated by prolonged mechanical ventilation and extended intensive care unit and hospital stays. However, at follow-up 18 months post-transplant he continues to have normal graft function with mild, non-progressive residual coarctation of aorta and non-progressive moderately hypoplastic pulmonary arteries.

Donor organ turn-downs and outcomes after listing for pediatric heart transplant.

BACKGROUND: Pediatric heart transplant waitlist mortality remains significant but allograft offer refusals are common and allografts continue to be discarded. Our aim in this study was to assess the impact of donor organ refusals on mortality after listing using a multi-institutional data set. METHODS: In this study we conducted a retrospective review of donor offers made to pediatric (<18 years) recipients in the United States in the period from 2007 to 2017. Candidates were stratified by whether they refused an acceptable donor offer (ADO). Acceptance was defined as an offer from a donor <40 years old and within 1,000 miles that was ultimately accepted by a waitlist candidate. Candidate survival after an offer was assessed. RESULTS: There were 12,447 hearts offered at least once to a pediatric candidate. Most candidates (n = 4,282, 84.4%) refused the first offer, and 677 (15.4%) of these subsequently died or were removed from the list for deterioration. Refusal of an ADO was associated with higher mortality after listing, independent of transplant, in both univariate (1 year: 92% vs 87%, p = 0.002) and multivariate (hazard ratio 1.5, 95% CI 1.2 to 1.7, p < 0.0001) Cox regression analyses. ADO refusals were not correlated with improved post-transplant survival and >8 ADO refusals was associated with higher risk-adjusted post-transplant mortality (odds ratio 1.7, 95% confidence interval 1.0 to 2.9, p = 0.04). CONCLUSIONS: Refusal of ADOs is associated with higher risk-adjusted mortality after listing (independent of transplantation), without improvement in post-transplant outcomes. So, although a "perfect" organ would be ideal, acceptance of one that is "good enough" has the potential to improve survival among pediatric candidates for heart transplantation.

Exhaustion of mitochondrial and autophagic reserve may contribute to the development of LRRK2 G2019S -Parkinson's disease.

BACKGROUND: Mutations in leucine rich repeat kinase 2 (LRRK2) are the most common cause of familial Parkinson's disease (PD). Mitochondrial and autophagic dysfunction has been described as etiologic factors in different experimental models of PD. We aimed to study the role of mitochondria and autophagy in LRRK2 G2019S -mutation, and its relationship with the presence of PD-symptoms. METHODS: Fibroblasts from six non-manifesting LRRK2 G2019S -carriers (NM-LRRK2 G2019S ) and seven patients with LRRK2 G2019S -associated PD (PD-LRRK2 G2019S ) were compared to eight healthy controls (C). An exhaustive assessment of mitochondrial performance and autophagy was performed after 24-h exposure to standard (glucose) or mitochondrial-challenging environment (galactose), where mitochondrial and autophagy impairment may be heightened. RESULTS: A similar mitochondrial phenotype of NM-LRRK2 G2019S and controls, except for an early mitochondrial depolarization (54.14% increased, p = 0.04), was shown in glucose. In response to galactose, mitochondrial dynamics of NM-LRRK2 G2019S improved (- 17.54% circularity, p = 0.002 and + 42.53% form factor, p = 0.051), probably to maintain ATP levels over controls. A compromised bioenergetic function was suggested in PD-LRRK2 G2019S when compared to controls in glucose media. An inefficient response to galactose and worsened mitochondrial dynamics (- 37.7% mitochondrial elongation, p = 0.053) was shown, leading to increased oxidative stress. Autophagy initiation (SQTSM/P62) was upregulated in NM-LRRK2 G2019S when compared to controls (glucose + 118.4%, p = 0.014; galactose + 114.44%, p = 0.009,) and autophagosome formation increased in glucose media. Despite of elevated SQSTM1/P62 levels of PD-NM G2019S when compared to controls (glucose + 226.14%, p = 0.04; galactose + 78.5%, p = 0.02), autophagosome formation was deficient in PD-LRRK2 G2019S when compared to NM-LRRK2 G2019S (- 71.26%, p = 0.022). CONCLUSIONS: Enhanced mitochondrial performance of NM-LRRK2 G2019S in mitochondrial-challenging conditions and upregulation of autophagy suggests that an exhaustion of mitochondrial bioenergetic and autophagic reserve, may contribute to the development of PD in LRRK2 G2019S mutation carriers.

Comparison of basiliximab vs antithymocyte globulin for induction in pediatric heart transplant recipients: An analysis of the International Society for Heart and Lung Transplantation database.

This study aims to compare 2 common induction strategies, basiliximab and ATG. Analysis of the ISHLT transplant registry was performed. The database was queried for pediatric heart transplants from January 1, 2000, to June 30, 2015, who had received induction with basiliximab or ATG. Primary end-point was graft survival. Secondary end-points included 1-year survival and 1-year conditional survival. There were 3158 heart transplants who received induction with basiliximab or ATG. The ATG cohort was younger, more likely to have congenital heart disease or be a retransplant, have a higher PRA, longer ischemic time, and been transplanted earlier in the study period (all P<.01). There was no difference in graft loss in the basiliximab cohort compared to the ATG cohort (HR 1.18 P=.06). On conditional 1-year survival analysis, basiliximab induction was associated with graft loss (HR=1.35 95% CI 1.1-1.7, P<.01), and in the propensity-matched cohort, the basiliximab cohort was more likely to experience rejection prior to discharge (P=.04). Infection prior to discharge was more common in the antithymocyte cohort. Induction with ATG is associated with improved late graft survival compared to basiliximab.

HIV-1 promonocytic and lymphoid cell lines: an in vitro model of in vivo mitochondrial and apoptotic lesion.

To characterize mitochondrial/apoptotic parameters in chronically human immunodeficiency virus (HIV-1)-infected promonocytic and lymphoid cells which could be further used as therapeutic targets to test pro-mitochondrial or anti-apoptotic strategies as in vitro cell platforms to deal with HIV-infection. Mitochondrial/apoptotic parameters of U1 promonocytic and ACH2 lymphoid cell lines were compared to those of their uninfected U937 and CEM counterparts. Mitochondrial DNA (mtDNA) was quantified by rt-PCR while mitochondrial complex IV (CIV) function was measured by spectrophotometry. Mitochondrial-nuclear encoded subunits II-IV of cytochrome-c-oxidase (COXII-COXIV), respectively, as well as mitochondrial apoptotic events [voltage-dependent-anion-channel-1(VDAC-1)-content and caspase-9 levels] were quantified by western blot, with mitochondrial mass being assessed by spectrophotometry (citrate synthase) and flow cytometry (mitotracker green assay). Mitochondrial membrane potential (JC1-assay) and advanced apoptotic/necrotic events (AnexinV/propidium iodide) were measured by flow cytometry. Significant mtDNA depletion spanning 57.67% (P < 0.01) was found in the U1 promonocytic cells further reflected by a significant 77.43% decrease of mitochondrial CIV activity (P < 0.01). These changes were not significant for the ACH2 lymphoid cell line. COXII and COXIV subunits as well as VDAC-1 and caspase-9 content were sharply decreased in both chronic HIV-1-infected promonocytic and lymphoid cell lines (<0.005 in most cases). In addition, U1 and ACH2 cells showed a trend (moderate in case of ACH2), albeit not significant, to lower levels of depolarized mitochondrial membranes. The present in vitro lymphoid and especially promonocytic HIV model show marked mitochondrial lesion but apoptotic resistance phenotype that has been only partially demonstrated in patients. This model may provide a platform for the characterization of HIV-chronicity, to test novel therapeutic options or to study HIV reservoirs.

Mitochondrial DNA disturbances and deregulated expression of oxidative phosphorylation and mitochondrial fusion proteins in sporadic inclusion body myositis.

Sporadic inclusion body myositis (sIBM) is one of the most common myopathies in elderly people. Mitochondrial abnormalities at the histological level are present in these patients. We hypothesize that mitochondrial dysfunction may play a role in disease aetiology. We took the following measurements of muscle and peripheral blood mononuclear cells (PBMCs) from 30 sIBM patients and 38 age- and gender-paired controls: mitochondrial DNA (mtDNA) deletions, amount of mtDNA and mtRNA, mitochondrial protein synthesis, mitochondrial respiratory chain (MRC) complex I and IV enzymatic activity, mitochondrial mass, oxidative stress and mitochondrial dynamics (mitofusin 2 and optic atrophy 1 levels). Depletion of mtDNA was present in muscle from sIBM patients and PBMCs showed deregulated expression of mitochondrial proteins in oxidative phosphorylation. MRC complex IV/citrate synthase activity was significantly decreased in both tissues and mitochondrial dynamics were affected in muscle. Depletion of mtDNA was significantly more severe in patients with mtDNA deletions, which also presented deregulation of mitochondrial fusion proteins. Imbalance in mitochondrial dynamics in muscle was associated with increased mitochondrial genetic disturbances (both depletion and deletions), demonstrating that proper mitochondrial turnover is essential for mitochondrial homoeostasis and muscle function in these patients.

Mitochondrial disturbances in HIV pregnancies.

BACKGROUND: Mitochondrial consequences from foetal exposure to HIV infection and antiretrovirals could be further investigated. OBJECTIVE: The main objective of this study was to evaluate maternofoetal mitochondrial disturbances in HIV infection and antiretroviral administration in human pregnancies as the aetiopathogenic basis of suboptimal perinatal-clinical features. DESIGN: Cross-sectional, prospective, observational, exploratory and controlled study. METHODS: Clinical/epidemiological data of 35 HIV-infected pregnant women and 17 controls were collected. Mitochondrial DNA (mtDNA) and RNA (mtRNA) content (real time-PCR), enzymatic activities and content (spectrophotometry) were measured in leucocytes. Genetic-functional, maternofoetal and molecular-clinical correlations were assessed. RESULTS: Birth weight was lower in infants from HIV-infected mothers compared with controls. MtDNA values were slightly decreased in HIV cases, although not reaching statistical significance. MtRNA values were lower in HIV-infected mothers. Similarly, binary complex II+III enzymatic activity decreased to 50% in both HIV-infected mothers (44.45 ±â€Š3.77%) and their infants (48.79 ±â€Š3.41%) (P = 0.001 and P < 0.001). Global CI+III+IV enzymatic activity was lower in HIV-infected mothers and infants (90.43 ±â€Š2.39% and 51.16 ±â€Š9.30%) (P < 0.005 and P < 0.05). MtDNA content correlated with function in mothers and infants. Maternofoetal parameters correlated at genetic and functional levels. CONCLUSION: HAART toxicity caused mitochondrial damage in HIV-infected pregnant women and their newborns, being present at a genetic and functional level with a maternofoetal correlation.

Improvement in Tricuspid Annular Plane Systolic Excursion with Pulmonary Hypertension Therapy in Pediatric Patients.

BACKGROUND: Tricuspid annular plane systolic excursion (TAPSE) has emerged as a novel and reliable measure of right ventricular (RV) function. The purpose of this study was to determine the effect of pulmonary hypertension (PH) therapy on TAPSE in pediatric patients and compare TAPSE to other quantitative measures of RV function. METHODS: A retrospective review of medical records and echocardiograms of patients in the PH clinic from January 2011 to August 2013 was done. Echocardiograms were analyzed prior to initiation or addition of a PH drug and at least 8 weeks later. Following quantitative measures of RV function were compared: TAPSE, TAPSE age-based z-score, RV fractional area change (RVFAC), tricuspid annular S', tricuspid inflow E/tricuspid annular E' velocity (TV E/E'), and RV myocardial performance index (RVMPI). RESULTS: Of the 37 patients included in this study (median age 0.6 years), 23 (62.2%) were treatment naive and others had a new PH drug added to their regimen at the time of the baseline echocardiogram. The median duration between the baseline and follow-up echocardiogram was 8 (2-25) months. There was a significant improvement in TAPSE and TAPSE age-based z-score on the follow-up echocardiogram. RVFAC, tricuspid S', TV E/E', and RVMPI did not show a statistically significant change. CONCLUSION: In contrast to the other echocardiographic markers of RV function, TAPSE, and TAPSE age-based z-score significantly improve after initiation or addition of PH therapy and can be used for serial noninvasive monitoring of RV function in pediatric PH patients.