Soluble factors in COVID-19 mRNA vaccine-induced myocarditis causes cardiomyoblast hypertrophy and cell injury: a case report.

BACKGROUND: Inflammation affecting the heart and surrounding tissues is a clinical condition recently reported following COVID-19 mRNA vaccination. Assessing trends of these events related to immunization will improve vaccine safety surveillance and best practices for forthcoming vaccine campaigns. However, the causality is unknown, and the mechanisms associated with cardiac myocarditis are not understood. CASE PRESENTATION: After the first dose, we reported an mRNA vaccine-induced perimyocarditis in a young patient with a history of recurrent myocardial inflammation episodes and progressive loss of cardiac performance. We tested this possible inflammatory cytokine-mediated cardiotoxicity after vaccination in the acute phase (ten days), and we found a significant elevation of MCP-1, IL-18, and IL-8 inflammatory mediators. Still, these cytokines decreased considerably at the recovery phase (42 days later). We used the cardiomyoblasts cell line to test the effect of serum on cell viability, observing that serum from the acute phase reduced the cell viability to 75%. We did not detect this toxicity in cells when we tested serum from the patient in the recovery phase. We also tested serum-induced hypertrophy, a phenomenon in myocarditis and heart failure. We found that acute phase-serum has hypertrophy effects, increasing 25% of the treated cardiac cells' surface and significantly increasing B-type natriuretic peptide. However, we did not observe the hypertrophic effect in the recovery phase or sera from healthy controls. CONCLUSION: Our results opened the possibility of the inflammatory cytokines or serum soluble mediators as key factors for vaccine-associated myocarditis. In this regard, identifying anti-inflammatory molecules that reduce inflammatory cytokines could help avoid vaccine-induced myocardial inflammation.

A cross-sectional study evidences regulations of leukocytes in the colostrum of mothers with obesity.

BACKGROUND: Breastmilk is a dynamic fluid whose initial function is to provide the most adapted nutrition to the neonate. Additional attributes have been recently ascribed to breastmilk, with the evidence of a specific microbiota and the presence of various components of the immune system, such as cytokines and leukocytes. The composition of breastmilk varies through time, according to the health status of mother and child, and altogether contributes to the future health of the infant. Obesity is a rising condition worldwide that creates a state of systemic, chronic inflammation including leukocytosis. Here, we asked whether colostrum, the milk produced within the first 48 h post-partum, would contain a distinct leukocyte composition depending on the body mass index (BMI) of the mother. METHODS: We collected peripheral blood and colostrum paired samples from obese (BMI > 30) and lean (BMI < 25) mothers within 48 h post-partum and applied a panel of 6 antibodies plus a viability marker to characterize 10 major leukocyte subpopulations using flow cytometry. RESULTS: The size, internal complexity, and surface expression of CD45 and CD16 of multiple leukocyte subpopulations were selectively regulated between blood and colostrum irrespective of the study groups, suggesting a generalized cell-specific phenotype alteration. In obesity, the colostrum B lymphocyte compartment was significantly reduced, and CD16+ blood monocytes had an increased CD16 expression compared to the lean group. CONCLUSIONS: This is the first characterization of major leukocyte subsets in colostrum of mothers suffering from obesity and the first report of colostrum leukocyte subpopulations in Latin America. We evidence various significant alterations of most leukocyte populations between blood and colostrum and demonstrate a decreased colostrum B lymphocyte fraction in obesity. This pioneering study is a stepping stone to further investigate active immunity in human breastmilk.

Unexpected arterial thrombosis and acute limb ischemia in COVID-19 patients. Results from the Ibero-Latin American acute arterial thrombosis registry in COVID-19: (ARTICO-19).

OBJECTIVE: Few studies have focused on arterial thrombosis and acute limb ischemia in COVID-19. This international registry intended to study the spectrum of clinical characteristics, therapeutic trends, and outcomes in a cohort of Ibero-Latin American patients with arterial thrombosis or acute limb ischemia and COVID-19. METHODS: Data were retrospectively obtained from 21 centers in 9 countries. Patients with proven COVID-19 and asymptomatic or symptomatic arterial thrombosis were included. COVID-19 diagnosis was established by RT-PCR assay or IgM serology plus suggestive clinical/radiographical findings. We recorded and analyzed variables related to demography, clinical presentation, therapeutic trends, and outcomes. RESULTS: Eighty one patients were included in the registry. In 38.3%, acute limb ischemia symptoms were the first manifestation of COVID-19. Non-surgical management was more frequent in severe cases than surgical interventions, 11.1% vs. 88.9%, respectively (p = 0.004). Amputation rates were similar between all COVID severity groups (p = 0.807). Treatment was classified as non-surgical, open surgical, and endovascular treatment. Further analysis revealed an equal frequency of major leg amputation between treatment groups and increased mortality in patients with non-surgical management. However, multivariate regression analysis showed that treatment choices are associated with disease severity, with significant non-surgical treatment in critical patients; thus, mortality is related to the severity and confounds treatment analysis. CONCLUSION: Arterial thrombosis can be the initial symptom of a patient presenting with COVID-19. Physicians and health workers should potentially suspect COVID-19 in acute ischemia cases without a known risk factor or embolic cause. More experimental and clinical research is required to understand the complex phenomenon of arterial COVID-19 induced coagulopathy fully.

Differences between surviving and non-surviving venous thromboembolism COVID-19 patients: a systematic review.

BACKGROUND: To our knowledge, the treatment, outcome, clinical presentation, risk stratification of patients with venous thromboembolism and COVID-19 have not been well characterized. METHODS: We searched for systematic reviews, cohorts, case series, case reports, editor letters, and venous thromboembolism COVID-19 patients' abstracts following PRISMA and PROSPERO statements. We analyzed therapeutic approaches and clinical outcomes of venous thromboembolism COVID-19 patients. Inclusion: COVID-19 patients with venous thromboembolism confirmed by an imaging method (venous doppler ultrasound, ventilation-perfusion lung scan, computed tomography pulmonary angiogram, pulmonary angiography). We assessed and reported the original Pulmonary Embolism Severity Index for each pulmonary embolism patient. In addition, we defined major bleedings according to the International Society of Thrombosis and Haemostasis criteria. RESULTS: We performed a systematic review from August 9 to August 30, 2020. We collected 1,535 papers from PubMed, Scopus, Web of Science, Wiley, and Opengrey. We extracted data from 89 studies that describe 143 patients. Unfractionated and low-molecular-weight heparin was used as parenteral anticoagulation in 85/143 (59%) cases. The Food and Drug Administration-approved alteplase regimen guided the advanced treatment in 39/143 (27%) patients. The mortality was high (21.6%, CI 95% 15.2-29.3). The incidence of major bleeding complications was 1 (0.9%) in the survival group and 1 (3.2%) in the death group. Pulmonary Embolism Severity Index was class I in 11.6% and II in 22.3% in survivors compared to 0% and 6.5% in non-survivors, respectively. Patients who experienced venous thromboembolism events at home were more likely to live than in-hospital events. CONCLUSIONS: We determined a high mortality incidence of pulmonary embolism and a low rate of bleeding. Unfractionated and low-molecular-weight heparin drove parenteral anticoagulation and alteplase the advanced treatment in both groups. The original Pulmonary Embolism Severity Index could be helpful in the risk stratification.

Interventional pain training using phantom model during COVID-19 pandemic.

BACKGROUND: Fluoroscopic-guided lumbar procedures have increased in daily pain practice because the lumbar spine is one of the most common sources of pain. Interventional pain fellows must develop a minimum number of skills during their training in order to achieve the competences without neglecting radiological safety. However, medical training in fluoroscopic-guided interventions is being affected by the current coronavirus disease 2019 (COVID-19) situation. METHODS: The objective of this study was to evaluate the use of a phantom model for lumbar injection as a training strategy during the COVID-19 pandemic in fellows of interventional pain. The study was divided into theoretical and practical modules. The hands-on practice was performed in a lumbar model phantom where fellows were evaluated in four fluoroscopically guided approaches: intra-articular facet block (IAFB), medial branch block (MBB), transforaminal block (TFB), and interlaminar block (ILB) divided in 5 sessions. The aim was to make as many punctures as possible in every session. We measured total procedural performance (TPP), total needle hand time (TNH), and total radiation dose generated by the fluoroscopic machine (TRD) during each procedure. Additionally, a survey was applied to evaluate confidence and satisfaction before and after training. RESULTS: A total of 320 lumbar punctures were completed. The results were statistically significant in all approaches attempted (p < 0.01). The fellow's survey for satisfaction and confidence demonstrated a significant difference between pre and post-test (p < 0.01). CONCLUSIONS: The results of this study highlight the importance of adaptations and adoption of new educational models. The use of the phantom model for simulation could be a strategy for other emerging situations, like the COVID-19 pandemic. Including this practice in the interventional pain programs could lead to better results for the patient and operator radiology safety.

What Is the Role of the Inflammation in the Pathogenesis of Heart Failure?

PURPOSE OF REVIEW: In heart failure, whether it is associated with reduced or preserved ejection fraction, the immune system is activated and contributes to heart remodeling and impaired function. RECENT FINDINGS: Studies indicate that cells of the immune system not only play a role in the pathology but are also critical regulators of heart function. Knowledge about the role of the immune system driving heart failure will lead to the development of new targets to this system, particularly in those patients that, despite the apparent wellness, relapse and worsen. In this review, we will address the diverse mechanisms that trigger inflammation and their impact on heart failure progression.

Temporal Frame of Immune Cell Infiltration during Heart Failure Establishment: Lessons from Animal Models.

Heart failure (HF) is a cardiovascular syndrome characterized by maladaptive changes with an underlying inflammatory mediated pathogenesis. Nevertheless, current therapy is aimed at the heart workload and neurohormonal axis; thus, prognosis remains poor. To continue improving treatment, we rely on murine models for a better understanding of HF pathophysiology. Among them, pressure overload HF (PO-HF) animal models are a common strategy. Development of PO-HF is characterized by monocyte infiltration, which orchestrates a cascade of events leading to sustained inflammation and maladaptive changes. Here, we divide the PO-HF model progression into four phases and describe the inflammatory, structural, and gene expression profiles. This division is relevant due to its similarities with clinical hypertensive heart disease progression to HF. Evidence shows improvement in hemodynamic and other local parameters by altering the inflammatory response in a specific immune response at a specific point of time. Thus, it is relevant to focus on the time-dependent immune response interaction in order to provide more effective therapy. This review summarizes the pathogenesis of PO-HF murine models, highlighting the inflammatory events in a time frame view. By this approach, we expect to provide researchers with a better understanding of the intertwining time-dependent events that occur in PO-HF.

Venous thromboembolism: thrombosis, inflammation, and immunothrombosis for clinicians.

Venous thromboembolism (VTE) is a worldwide disease related with mortality, cardiovascular disability, impaired quality of life and, cause major long-term complications. Clinicians related to the acute and long-term patients care must be involved in the molecular mechanisms of thrombosis. The vessel wall and its inner lining of the endothelium are critical to the maintenance of a patent vasculature. After endothelial disruption, collagen (first line of endothelial defense) and intravascular tissue factor (second line of endothelial defense) are exposed to blood flow, starting the formation of a thrombus. Anticoagulant endovascular proteins and endogenous fibrinolysis have an active role in hemostasis. Currently, the process of coagulation is a cell surface-based model that includes three overlapping phases: initiation, amplification, and propagation. From a simple view, inflammation is one of the first responses of the immune system to infection; inflammation is driven by eicosanoids and cytokines, which are released by injured or infected cells. Common cytokines, which regulate inflammatory response, include interleukins (mainly interleukin-6) that are responsible for communication among white blood cells, chemokines that promote chemotaxis, and interferons that have anti-viral effects. Acute infections have been associated with a transient increase in the risk of myocardial infarction, stroke and recently with venous thrombosis, supporting the notion that systemic and respiratory infections increase the risk of thromboembolic events. Recently, immunothrombosis, another thrombosis mechanism that includes innate immune mechanisms, the neutrophil extracellular genetic traps, and the immunothrombosis dysregulation, could explain some cases of "unprovoked" VTE especially in elderly, a high-risk population for thrombosis.

Assessment of immune reconstitution status in recipients of a successful hematopoietic stem cell transplant from peripheral blood after reduced intensity conditioning.

OBJECTIVE: To document immune reconstitution status after hematopoietic stem cell transplantation (HSCT) for malignant hematologic diseases. METHODS: Hematology patients who received a reduced intensity conditioning (RIC) were followed after successful allogeneic or autologous HSCT. Patients had at least 100days post-transplant. T, B and NK cells in peripheral blood (PB), and CD34+, CD133+ progenitor cells in bone marrow (BM) and peripheral blood (PB) were determined by flow cytometry. RESULTS: Twenty-seven HSCT recipients, 19 allogeneic and 8 autologous, were studied at a median 155 (100-721) days post-transplant. In the whole group the median value of CD34+ cells was 1.03% in the bone marrow and 0.04% in PB, whereas values for CD133+ cells were 0.39% and 0.13%, respectively, without statistical differences between autologous and allogeneic recipients. Significantly more B cells (CD3-/CD56-/CD19+) were found in the autologous compared to the allogeneic group, 12.6 vs. 5.01, p=0.04. An increased number of CD8+ lymphocytes with a 0.63 CD4:CD8 relationship was documented in PB. CONCLUSION: In clinically recovered autologous and allogeneic HSCT recipients BM and PB CD34+/CD133+ hematoprogenitor homeostasis is maintained within normal ranges, with better B-cell reconstitution in the autologous group.

Increased bacterial infections after transfusion of leukoreduced non-irradiated blood products in recipients of allogeneic stem cell transplants after reduced-intensity conditioning.

Blood components transfused to hematopoietic stem cell transplant (HSCT) recipients are irradiated to prevent transfusion-associated graft-versus-host disease (TA-GVHD). The effect of transfusing non-irradiated blood products in HSCT outcome, including incidence of transplant complications, bacterial infections, acute and chronic GVHD presentation, and characteristics, has not been documented. Clinical records as well as blood bank and electronic databases of HSCT patients grafted after reduced-intensity conditioning who received irradiated versus non-irradiated blood products, after blood irradiation became unavailable at our center, were scrutinized for transplant outcome, clinical evolution, engraftment characteristics including days to neutrophil and platelet recovery, acute and chronic GVHD, rate and type of infections, and additional transplant-related comorbidities. All transfused blood products were leukoreduced. A total of 156 HSCT recipients was studied, 73 received irradiated and 83 non-irradiated blood components. Bacterial infections were significantly more frequent in patients transfused with non-irradiated blood products, P = .04. Clinically relevant increased rates of fever and neutropenia and mucositis were also documented in these patients. No cases of TA-GVHD occurred. Classical GVHD developed in 37 patients (50.7%) who received irradiated blood products and 36 (43.9%) who received non-irradiated blood products, P = .42. Acute GVHD developed in 28 patients (38.4%) in the blood-irradiated and 33 patients (39.8%) in the non-irradiation group, P = .87. The 2-year GVHD-free survival rate was 40% in the irradiated versus 40.6% in the non-irradiation group, P = .071. Increased bacterial infections were found in HSCT recipients transfused with non-irradiated blood products, which ideally must always be irradiated.

Mitochondrial Ca2+ Uniporter-Dependent Energetic Dysfunction Drives Hypertrophy in Heart Failure.

The role of the mitochondrial calcium uniporter (MCU) in energy dysfunction and hypertrophy in heart failure (HF) remains unknown. In angiotensin II (ANGII)-induced hypertrophic cardiac cells we have shown that hypertrophic cells overexpress MCU and present bioenergetic dysfunction. However, by silencing MCU, cell hypertrophy and mitochondrial dysfunction are prevented by blocking mitochondrial calcium overload, increase mitochondrial reactive oxygen species, and activation of nuclear factor kappa B-dependent hypertrophic and proinflammatory signaling. Moreover, we identified a calcium/calmodulin-independent protein kinase II/cyclic adenosine monophosphate response element-binding protein signaling modulating MCU upregulation by ANGII. Additionally, we found upregulation of MCU in ANGII-induced left ventricular HF in mice, and in the LV of HF patients, which was correlated with pathological remodeling. Following left ventricular assist device implantation, MCU expression decreased, suggesting tissue plasticity to modulate MCU expression.

Therapeutic Effects of WT1 Silencing via Respiratory Administration of Neutral DOPC Liposomal-siRNA in a Lung Metastasis Melanoma Murine Model.

The lungs represent a frequent target for metastatic melanoma as they offer a high-oxygen environment for tumor development. The overexpression of the WT1 protein has been associated with the occurrence of melanoma. In this study, we evaluated the effects of silencing the WT1 protein by siRNA in both in vitro in the B16F10 melanoma cell line and in vivo in a murine model of lung metastatic melanoma. We did this by implementing a novel respiratory delivery strategy of a neutral DOPC liposomal-siRNA system (L-siRNA). In vitro studies showed an effective silencing of the WT1 protein in the siRNAs' WT1-treated cells when compared with controls, resulting in a loss of the cell's viability and proliferation by inducing G1 arrest, the inhibition of the migration and invasion capacities of the cells, as well as the induction of apoptosis. In vivo, the respiratory administration of L-WT1 siRNA showed an efficient biodistribution on the lungs. After two weeks of treatment, the silencing of the WT1 protein resulted in an important antitumor activity that reduced the tumor weight. In the survival study, L-WT1 treatment could significantly delay the death of the animals. This work demonstrates the efficacy of the L-siRNA respiratory administration as a novel therapy to reduce pulmonary tumors and to increase survivability by silencing specific cancer oncogenes as WT1.

Synthesis and Characterization of Rutile TiO2 Nanoparticles for the Toxicological Effect on the H9c2 Cell Line from Rats.

The widespread use of titanium dioxide (TiO2) has raised concerns about potential health risks associated with its cytotoxicity in the cardiovascular system. To evaluate the cytotoxicity of TiO2 particles, the H9c2 rat cardiomyoblasts were used as a biological model, and their toxicological susceptibility to TiO2-anatase and TiO2-rutile particles was studied in vitro. The study examined dose and time exposure responses. The cell viability was evaluated based on metabolic inhibition and membrane integrity loss. The results revealed that both TiO2-anatase and TiO2-rutile particles induced similar levels of cytotoxicity at the inhibition concentrations IC25 (1.4-4.4 µg/cm2) and IC50 (7.2-9.3 µg/cm2). However, at more significant concentrations, TiO2-rutile appeared to be more cytotoxic than TiO2-anatase at 24 h. The study found that the TiO2 particles induced apoptosis events, but necrosis was not observed at any of the concentrations of particles used. The study considered the effects of microstructural properties, crystalline phase, and particle size in determining the capability of TiO2 particles to induce cytotoxicity in H9c2 cardiomyoblasts. The microstress in TiO2 particles was assessed using powder X-ray diffraction through Williamson-Hall and Warren-Averbach analysis. The analysis estimated the apparent crystallite domain and microstrain of TiO2-anatase to be 29 nm (ε = 1.03%) and TiO2-rutile to be 21 nm (ε = 0.53%), respectively. Raman spectroscopy, N2 adsorption isotherms, and dynamic light scattering were used to identify the presence of pure crystalline phases (>99.9%), comparative surface areas (10 m2/g), and ζ-potential values (-24 mV). The difference in the properties of TiO2 particles made it difficult to attribute the cytotoxicity solely to one variable.

Distinctions between survivors and non-survivors with SARS-CoV-2 vaccine-induced thrombotic thrombocytopenia: A systematic review and meta-analysis.

Vaccine-inducing immune thrombocytopenia, thrombosis, and bleeding emerge as infrequent and potential complications with mortality risk in healthy subjects. However, differences between survivors and non-survivors with SARS-CoV-2 vaccine-induced thrombotic thrombocytopenia (VITT) are unclear. Methods: According to the PRISMA statement, we conducted a systematic review and meta-analysis, and the protocol was registered in PROSPERO. The main objective is to identify differences among survivors and non-survivors of SARS-CoV-2 VITT patients. We systematically searched through PubMed, Scopus, and Web of Science. We included cohorts, case series, and case reports. We classified bleeding complications according to the ISTH definition. Statistics: unpaired Student's t-test or one-way ANOVA, Wilcoxon, and Kruskal-Wallis. Results: We systematically searched from January 2021 to June 2021 and identified 51 studies that included 191 patients. Non-survivors had the most severe thrombocytopenia (p 0.02) and lower fibrinogen measurements (p 0.01). Subjects vaccinated with mRNA vaccines (BNT162b2 and mRNA-1273) had an earlier onset of adverse events following immunization (p 0.001). We identified a higher trend of overall thrombotic events (p 0.001) in recipients of viral mechanism-dependent vaccines (Table 2). Non-survivors with cerebral venous sinus thrombosis (CVST) had more severe thrombocytopenia (p 0.01) than survivors with CVST. Finally, 61 % of survivors and 50 % with thrombosis received heparin. Conclusion: We identified more severe thrombocytopenia, lower fibrinogen measurements, and a higher trend of overall thrombotic events, including CVST and thrombotic storm, particularly with viral mechanisms-dependent vaccines in non-survivors VITT patients.

Risk Factors, Clinical Presentation, Therapeutic Trends, and Outcomes in Arterial Thrombosis Complicating Unvaccinated COVID-19 Patients: A Systematic Review.

Data on characteristics and outcomes of coronavirus (COVID)-19 patients complicated with arterial thrombosis (AT) are scarce. Therefore, we carried out a systematic review (PRISMA, PROSPERO statements; PubMed, Scopus, and Web of Science) to identify risk factors, clinical presentation, treatment, and outcomes. We included publications from December 2019 to October 2020. Groups: (a) ischemic stroke, (b) thrombotic storm, (c) peripheral vascular thrombosis, (d) myocardial infarction, and (e) left cardiac thrombus or in-transit thrombus (venous system thrombus floating or attaching to the right heart). We considered 131 studies. The most frequent cardiovascular risk factors were: hypertension, diabetes, and dyslipidemia. A high proportion presented with asymptomatic, mild, or moderate COVID-19 (n = 91, 41.4%). We identified a high percentage of isolated ischemic stroke and thrombotic storm. Groups with higher mortality rate: intracardiac thrombus (1/2, 50.0%), thrombotic storm (18/49, 36.7%), and ischemic stroke (48/131, 36.6%). A small number received thromboprophylaxis. Most patients received antithrombotic treatment. The most frequent bleeding complication was intracranial hemorrhage, primarily with isolated stroke. Overall mortality was 33.6% (74/220). Despite a wide range of COVID-19 severity, a high proportion had AT as a complication of non-severe disease. AT can affect different vascular territories; mortality is associated with stroke, intensive care unit stay, and severe COVID-19.

CAR-NK Cells for Cancer Therapy: Molecular Redesign of the Innate Antineoplastic Response.

The Chimeric Antigen Receptor (CAR) has arisen as a powerful synthetic biology-based technology with demonstrated versatility for implementation in T and NK cells. Despite CAR T cell successes in clinical trials, several challenges remain to be addressed regarding adverse events and long-term efficacy. NK cells present an attractive alternative with intrinsic advantages over T cells for treating solid and liquid tumors. Early preclinical and clinical trials suggest at least two major advantages: improved safety and an off-the-shelf application in patients due to its HLA independence. Due to the early stages of CAR NK translation to clinical trials, limited data is currently available. By analyzing these results, it seems that CAR NK cells could offer a reduced probability of Cytokine Release Syndrome (CRS) or Graft versus Host Disease (GvHD) in cancer patients, reducing safety concerns. Furthermore, NK cell therapy approaches may be boosted by combining it with immunological checkpoint inhibitors and by implementing genetic circuits to direct CAR-bearing cell behavior. This review provides a description of the CAR technology for modifying NK cells and the translation from preclinical studies to early clinical trials in this new field of immunotherapy.

Resveratrol Prevents Right Ventricle Dysfunction, Calcium Mishandling, and Energetic Failure via SIRT3 Stimulation in Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is characterized by pulmonary vessel remodeling; however, its severity and impact on survival depend on right ventricular (RV) failure. Resveratrol (RES), a polyphenol found in red wine, exhibits cardioprotective effects on RV dysfunction in PAH. However, most literature has focused on RES protective effect on lung vasculature; recent finding indicates that RES has a cardioprotective effect independent of pulmonary arterial pressure on RV dysfunction, although the underlying mechanism in RV has not been determined. Therefore, this study is aimed at evaluating sirtuin-3 (SIRT3) modulation by RES in RV using a monocrotaline- (MC-) induced PAH rat model. Myocyte function was evaluated by confocal microscopy as cell contractility, calcium signaling, and mitochondrial membrane potential (ΔΨm); cell energetics was assessed by high-resolution respirometry, and western blot and immunoprecipitation evaluated posttranslational modifications. PAH significantly affects mitochondrial function in RV; PAH is prone to mitochondrial permeability transition pore (mPTP) opening, thus decreasing the mitochondrial membrane potential. The compromised cellular energetics affects cardiomyocyte function by decreasing sarco-endoplasmic reticulum Ca2+-ATPase (SERCA) activity and delaying myofilament unbinding, disrupting cell relaxation. RES partially protects mitochondrial integrity by deacetylating cyclophilin-D, a critical component of the mPTP, increasing SIRT3 expression and activity and preventing mPTP opening. The preserved energetic capability rescues cell relaxation by maintaining SERCA activity. Avoiding Ca2+ transient and cell contractility mismatch by preserving mitochondrial function describes, for the first time, impairment in excitation-contraction-energetics coupling in RV failure. These results highlight the importance of mitochondrial energetics and mPTP in PAH.

Association of the Triglyceride/High-Density Lipoprotein Cholesterol Index with Insulin Resistance in a Pediatric Population in Northeast Mexico.

Background: The present study aimed to determine the association of the triglyceride/high-density lipoprotein cholesterol (TG/HDL-C) index with IR in pediatric patients with overweight (OW) and OB, to assess the ability of the TG/HDL-C index to predict IR, and to estimate the prevalence of IR and metabolic syndrome (MetS). Methods: A cross-sectional study comprised 628 Mexican children (2-16 years old) from the OB clinic. IR was estimated using the HOMA-IR index (‡2.5). The modified Adult Treatment Panel III criteria were used to define MetS. Correlation analyses and a receiver operating characteristic (ROC) curve were used to assess the association of the TG/HDL-C index with IR and to establish the best cutoff for the TG/HDL-C index. Results: About 79.3% of the children presented IR and 55.4% MetS. Common findings in patients with IR were acanthosis nigricans (94.8%) and a TG/HDL-C index ‡2.27 (70.5%). Considering all the patients with a high TG/HDL-C index, 78.4% presented MetS, and 88.0% IR. The area under the curve-ROC for the ability of the TG/HDL-C index to predict IR was 0.72 (P < 0.001), with a sensitivity of 70.5% and specificity of 63.1%. Conclusions: TG/HDL-C index is a feasible alternative to the HOMA-IR index to predict IR in Mexican children with OW or OB. It might be used to identify children with the greatest need for treatment interventions.

Resveratrol Prevents Right Ventricle Remodeling and Dysfunction in Monocrotaline-Induced Pulmonary Arterial Hypertension with a Limited Improvement in the Lung Vasculature.

Pulmonary arterial hypertension (PAH) is a life-threatening disease that is characterized by an increase in pulmonary vascular pressure, leading to ventricular failure and high morbidity and mortality. Resveratrol, a phenolic compound and a sirtuin 1 pathway activator, has known dietary benefits and is used as a treatment for anti-inflammatory and cardiovascular diseases. Its therapeutic effects have been published in the scientific literature; however, its benefits in PAH are yet to be precisely elucidated. Using a murine model of PAH induced by monocrotaline, the macroscopic and microscopic effects of a daily oral dose of resveratrol in rats with PAH were evaluated by determining its impact on the lungs and the right and left ventricular function. While most literature has focused on smooth muscle cell mechanisms and lung pathology, our results highlight the relevance of therapy-mediated improvement of right ventricle and isolated cardiomyocyte physiology in both ventricles. Although significant differences in the pulmonary architecture were not identified either micro- or macroscopically, the effects of resveratrol on right ventricular function and remodeling were observed to be beneficial. The values for the volume, diameter, and contractility of the right ventricular cardiomyocytes returned to those of the control group, suggesting that resveratrol has a protective effect against ventricular dysfunction and pathological remodeling changes in PAH. The effect of resveratrol in the right ventricle delayed the progression of findings associated with right heart failure and had a limited positive effect on the architecture of the lungs. The use of resveratrol could be considered a future potential adjunct therapy, especially when the challenges to making a diagnosis and the current therapy limitations for PAH are taken into consideration.

Mobilization kinetics of CD133+ hematoprogenitor cells for hematopoietic grafting.

BACKGROUND: Quantification of CD34+ mononuclear cells is the most important quality control measure for hematopoietic stem cell (HSC) transplantation. A fraction of CD34+ cells also express the CD133 antigen. These cells constitute a group of earlier, less-differentiated HSCs with a potentially higher capacity for engraftment. The correlation between total CD34+ peripheral HSCs and the fraction of these cells that coexpress CD133 was determined before and after automated collection by leukapheresis, as well as the effect of HSC CD133+ dose on hematopoiesis recovery. STUDY DESIGN AND METHODS: Granulocyte-colony-stimulating factor mobilization of HSCs from the marrow to the peripheral blood (PB) of allogeneic and autologous donors was followed by automated collection through leukapheresis on the fifth day. Quantification of CD34+ and CD133+ cells was performed on PB before collection and in the hematopoietic graft (HG) by flow cytometry. RESULTS: There was a significant correlation between CD133+ and CD34+ HSCs in the PB before collection and in the final product for grafting (r = 0.62 and 0.64; p < 0.01). CD34+ HSCs per microL in PB and the HG was the only variable that did not correlate (r = 0.18). CD34+/CD133+ correlation increased from 0.33 on PB to 0.94 on the leukapheresis product (p < 0.01). Time to recovery was not related to CD133+ HSCs infused. CONCLUSION: There was a significant correlation of both number per microL and percentage of CD34+/CD133+ HSCs before and after collection for transplantation; number of CD133+ cells had no apparent clinical impact on time to hematopoiesis regeneration.