Mitochondrial transfer from MSCs to T cells induces Treg differentiation and restricts inflammatory response.

Mesenchymal stem cells (MSCs) have fueled ample translation for the treatment of immune-mediated diseases. They exert immunoregulatory and tissue-restoring effects. MSC-mediated transfer of mitochondria (MitoT) has been demonstrated to rescue target organs from tissue damage, yet the mechanism remains to be fully resolved. Therefore, we explored the effect of MitoT on lymphoid cells. Here, we describe dose-dependent MitoT from mitochondria-labeled MSCs mainly to CD4+ T cells, rather than CD8+ T cells or CD19+ B cells. Artificial transfer of isolated MSC-derived mitochondria increases the expression of mRNA transcripts involved in T-cell activation and T regulatory cell differentiation including FOXP3, IL2RA, CTLA4, and TGFß1, leading to an increase in a highly suppressive CD25+ FoxP3+ population. In a GVHD mouse model, transplantation of MitoT-induced human T cells leads to significant improvement in survival and reduction in tissue damage and organ T CD4+ , CD8+ , and IFN-γ+ expressing cell infiltration. These findings point to a unique CD4+ T-cell reprogramming mechanism with pre-clinical proof-of-concept data that pave the way for the exploration of organelle-based therapies in immune diseases.

Extinction risk assessment of a Patagonian ungulate using population dynamics models under climate change scenarios.

Climate change affects population cycles of several species, threatening biodiversity. However, there are few long-term studies on species with conservation issues and restricted distributions. Huemul is a deer endemic to the southern Andes in South America and it is considered endangered mostly due to a 50% reduction of its distribution over the last 500 years. To assess environmental variables potentially affecting huemul population viability and the impact of climate change, we developed population dynamics models. We used a 14-year survey data from Bernardo O'Higgins National Park, coastal Chilean Patagonia. We used Ricker models considering winter and spring temperatures and precipitation as variables influencing huemul population dynamics. We used the Bayesian information criterion (BIC) to select models with the greatest predictive power. The two best models (ΔBIC < 2) included winter temperature and density-dependence population growth drivers. The best model considered a lateral effect, where winter temperature influences carrying capacity and the second best a vertical effect with winter temperature influencing Rmax and carrying capacity. Population viability was evaluated using those models, projecting them over a 100-year period: (a) under current conditions and (b) under conditions estimated by Global Climate Models for 2050 and 2070. The extinction risk and quasi-extinction were estimated for this population considering two critical huemul abundance levels (15 and 30 individuals) for persistence. The population is currently in a quasi-extinction process, with extinction probabilities increasing with climate change. These results are crucial for conservation of species like huemul that have low densities and are threatened by climate change.

CO2 adsorption on gas-phase Cu4-xPtx (x = 0-4) clusters: a DFT study.

Transition and noble metal clusters have proven to be critical novel materials, potentially offering major advantages over conventional catalysts in a range of value-added catalytic processess such as carbon dioxide transformation to methanol. In this work, a systematic computational study of CO2 adsorption on gas-phase Cu4-xPtx (x = 0-4) clusters is performed. An exhaustive potential energy surface exploration is initially performed using our recent density functional theory basin-hopping global optimization implementation. Ground-state and low-lying energy isomers are identified for Cu4-xPtx clusters. Secondly, a CO2 molecule adsorption process is analyzed on the ground-state Cu4-xPtx configurations, as a function of cluster composition. Our results show that the gas-phase linear CO2 molecule is deformed upon adsorption, with its bend angle varying from about 132° to 139°. Cu4-xPtx cluster geometries remain unchanged after CO2 adsorption, with the exception of Cu3Pt1 and Pt4 clusters. For these particular cases, a structural conversion between the ground-state geometry and the corresponding first isomer configurations is found to be assisted by the CO2 adsorption. For all clusters, the energy barriers between the ground-state and first isomer structures are explored. Our calculated CO2 adsorption energies are found to be larger for Pt-rich clusters, exhibiting a volcano-type plot. The overall effect of a hybrid functional including dispersion forces is also discussed.

Resolution of lung injury after a single event of aspiration: a model of bilateral instillation of whole gastric fluid.

Gastric aspiration is a high-risk condition for lung injury. Consequences range from subclinical pneumonitis to respiratory failure, with fibrosis development in some patients. Little is known about how the lung repairs aspiration-induced injury. By using a rat model of single orotracheal instillation of whole gastric contents, we studied the time course of morphological and biochemical changes during injury and resolution, and evaluated whether repair involved long-term fibrosis. Anesthetized rats received one gastric fluid instillation. At 4, 12, and 24 hours and 4 and 7 days, we performed lung histological studies and biochemical measurements in bronchoalveolar lavage fluid and lung tissue. Physiological measurements were performed at 12 to 24 hours. Long-term outcome was studied histologically at day 60. During the first 24 hours, severe peribronchiolar injury involving edema, intra-alveolar proteinaceous debris, hemorrhage, increased neutrophils and cytokines, and physiological dysfunction were observed. At days 4 and 7, an organizing pneumonia (OP) pattern developed, with foreign-body giant cells and granulomas. Lung matrix metalloproteinase 9 and 2 activities increased, with metalloproteinase-9 linked to early inflammation and metalloproteinase-2 to OP. At day 60, lung architecture was normal. In conclusion, a continuum of alterations starting with severe injury, evolving toward OP and later resolving, characterizes the rat single aspiration event. In addition to identifying markers of staging and severity, this model reveals that OP participates in the repair of aspiration-induced injury.

The impact of graft-versus-host disease prophylaxis in reduced-intensity conditioning allogeneic stem cell transplant in acute myeloid leukemia: a study from the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation.

The impact of the intensity of graft-versus-host-disease immunoprophylaxis on transplantation outcomes in patients undergoing transplantation following reduced-intensity conditioning is unclear. This study addresses this issue in 228 adult patients above 50 years of age with acute myeloid leukemia in first complete remission given peripheral blood stem cells from HLA-identical siblings after fludarabine and 2 days of intravenous busulfan reduced-intensity conditioning. A total of 152 patients received anti-thymocyte globulin, either in combination with cyclosporine A in 86 patients (group 1), or with cyclosporine A and mycophenolate mofetil or short course methotrexate in 66 patients (group 2). The remaining 76 patients did not receive anti-thymocyte globulin but were given cyclosporine A and methotrexate or mycophenolate mofetil (group 3). Incidences of grade II-IV acute graft-versus-host-disease were comparable in the three groups (16.5%, 29.5% and 19.5% in groups 1, 2 and 3, respectively, P=0.15). In multivariate analysis, the absence of anti-thymocyte globulin was the only factor associated with a higher risk of chronic graft-versus-host-disease (P=0.005), while the use of triple immunosuppression (group 3) was associated with an increased risk of relapse (P=0.003). In comparison to anti-thymocyte globulin and cyclosporine A alone, the other two strategies of graft-versus-host-disease prophylaxis were associated with reduced leukemia-free survival and overall survival (P=0.001 for each parameter), independently of the dose of anti-thymocyte globulin. These data suggest that fine tuning of the intensity of this prophylaxis can affect the outcome of transplantation and that anti-thymocyte globulin and cyclosporine A alone should be the preferred combination with the fludarabine-busulfan reduced-intensity conditioning regimen and sibling donors.

Pneumomediastinum as a Complication of Cocaine Insufflation.

A 25-year-old man presents to the ED for unresponsiveness after consuming cocaine and other unknown substances. Chest imaging from the presentation was unremarkable, but after developing fever and leukocytosis, he underwent extensive work-up in search of infectious foci. A CT scan of the chest showed a small pneumomediastinum and the possibility of an esophageal tear. After recovering consciousness and the ability to recount events, the patient admitted to the concomitant use of cocaine and opiates via insufflation.

Cardiac Amyloidosis Disguised as Atrial Flutter: A Case Report.

Cardiac amyloidosis (CA) is a rare form of infiltrative cardiomyopathy (IC) that frequently leads to heart failure (HF). Its symptoms can range from minimal to significant shortness of breath, palpitations, leg swelling, and chest discomfort. Early diagnosis and treatment are crucial in preventing the further progression of the disease and improving outcomes. This case report describes a 63-year-old male with no prior medical history who presented with severe dyspnea, palpitations, and chest heaviness. Initially diagnosed with atrial flutter, he was later confirmed to have cardiac amyloidosis through a thorough workup with multimodality imaging. The patient was started on guideline-directed medical therapy (GDMT) and discharged home with a follow-up from a heart failure specialist. An outpatient workup confirmed the diagnosis of amyloidosis with a positive pyrophosphate scan. At a seven-month follow-up, the workup for extra-cardiac involvement was negative, and the ejection fraction (EF) had improved. This case highlights the importance of a high index of suspicion and a thorough workup in cases of suspected cardiac amyloidosis to achieve early diagnosis and prevent disease progression.

An Uncommon Case of Acute Coronary Stent Thrombosis.

Coronary stent thrombosis is an uncommon complication of percutaneous coronary intervention, which can result in myocardial infarction and often death. We present a case of acute stent thrombosis in a patient with newly diagnosed triple vessel coronary artery disease occurring within less than an hour of stent placement along with a review of the literature.

Atypical Presentation of a Right Atrial Myxoma.

Primary cardiac tumors are exceptionally rare and predominantly located in the left atrium with occasional involvement on the right side of the heart. We present the case of a 52-year-old man who presented with chest pain, leading to suspicion of acute coronary syndrome. However, further investigation revealed a right atrial tumor measuring 6.3 cm. After surgical removal, the pathology analysis of the mass confirmed the histology of myxoma. Differential diagnoses for atrial myxomas include thrombus and other tumors, such as rhabdomyomas. More than half of these tumors arise in the left atrium and may be complicated by neurologic symptoms secondary to embolization. Right atrial myxomas are rare and described in the literature with a myriad of symptoms (signs of right heart failure [i.e., fatigue, peripheral edema, hepatomegaly, ascites], a diastolic murmur, and symptoms of pulmonary emboli). In other cases, they may be asymptomatic. Due to the low incidence and variety in their clinical picture, careful documentation of these cases is suggested for early recognition and directed management.

Hemophagocytic Lymphohistiocytosis Following COVID-19 Infection.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been associated with multiple inflammatory symptoms involving several organ systems, including hematologic manifestations. Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening syndrome caused by excessive inflammation in the absence of immune regulation. We present the case of a patient with HLH secondary to dysregulated inflammatory response following COVID-19; we also describe the diagnostic and management challenges associated with the condition.

Tetrahelix conformations and transformation pathways in Pt1Pd12 clusters.

The threshold method is used to explore the potential energy surface of the Pt(1)Pd(12) bimetallic cluster, defined by the Gupta semiempirical potential. A set of helical structures, which follow a Bernal tetrahelix pattern, correspond to local minima for the Pt(1)Pd(12) cluster, characterizing the region of the energy landscape where these structures are present. Both right-handed and left-handed chiral forms were discovered in our searches. Energetic and structural details of each of the tetrahelices are reported as well as the corresponding transition probabilities between these structures and with respect to the icosahedron-shaped global minimum structure via a disconnectivity graph analysis.

[Molecular epidemiology of tuberculosis in Almeria (Spain). Factors associated with recent transmission]. / Epidemiología molecular de la tuberculosis en Almería. Factores asociados a transmisión reciente.

BACKGROUND: Molecular epidemiology is used in tuberculosis (TB) to identify clusters in which the cases are assumed to belong to the same recent transmission chain. An endogenous reactivation of latent TB is considered when the Mycobacterium tuberculosis isolates have a unique genotype. OBJECTIVE: To describe factors associated with recent transmission of TB in Almeria, from 2003-2007. METHODS: We conducted an observational prospective study that included patients with Mycobacterium tuberculosis positive culture. The strains were genotyped by Restriction Fragment Length Polymorphism and spoligotyping. Adjusted odds ratio and 95% confidence intervals were calculated to study factors associated with cluster groups, using a multivariate logistic regression model. RESULTS: We analysed 427 isolates, of which 71% were from males and 56.2% of them belonged to foreign residents. Furthermore, 44% were classified as a cluster. The resistance to isoniazid was 8.4%. The factors associated with clusters were age, principally the group under 10 years (adjusted OR=12.75; 95% CI, 2.52-64.58) and the group aged between 50-59 years (adjusted OR=13.85; 95% CI, 3.04-63.17), and born in Spain (adjusted OR=2.17; 95% CI, 1.41-3.36). CONCLUSIONS: In Almeria, native population, children under 10 years old and patients aged between 50-59 years have more probability to belong to the same recent transmission chain. The molecular epidemiology can be used to find out which population groups need more control and this information must be used in tuberculosis prevention programs.

PPARß/δ Is Required for Mesenchymal Stem Cell Cardioprotective Effects Independently of Their Anti-inflammatory Properties in Myocardial Ischemia-Reperfusion Injury.

Myocardial infarction ranks first for the mortality worldwide. Because the adult heart is unable to regenerate, fibrosis develops to compensate for the loss of contractile tissue after infarction, leading to cardiac remodeling and heart failure. Adult mesenchymal stem cells (MSC) regenerative properties, as well as their safety and efficacy, have been demonstrated in preclinical models. However, in clinical trials, their beneficial effects are controversial. In an experimental model of arthritis, we have previously shown that PPARß/δ deficiency enhanced the therapeutic effect of MSC. The aim of the present study was to compare the therapeutic effects of wild-type MSC (MSC) and MSC deficient for PPARß/δ (KO MSC) perfused in an ex vivo mouse model of ischemia-reperfusion (IR) injury. For this purpose, hearts from C57BL/6J mice were subjected ex vivo to 30 min ischemia followed by 1-h reperfusion. MSC and KO MSC were injected into the Langendorff system during reperfusion. After 1 h of reperfusion, the TTC method was used to assess infarct size. Coronary effluents collected in basal condition (before ischemia) and after ischemia at 1 h of reperfusion were analyzed for their cytokine profiles. The dose-response curve for the cardioprotection was established ex vivo using different doses of MSC (3.105, 6.105, and 24.105 cells/heart) and the dose of 6.105 MSC was found to be the optimal concentration. We showed that the cardioprotective effect of MSC was PPARß/δ-dependent since it was lost using KO MSC. Moreover, cytokine profiling of the coronary effluents collected in the eluates after 60 min of reperfusion revealed that MSC treatment decreases CXCL1 chemokine and interleukin-6 release compared with untreated hearts. This anti-inflammatory effect of MSC was also observed when hearts were treated with PPARß/δ-deficient MSC. In conclusion, our study revealed that the acute cardioprotective properties of MSC in an ex vivo model of IR injury, assessed by a decreased infarct size at 1 h of reperfusion, are PPARß/δ-dependent but not related to their anti-inflammatory effects.

COVID-19 Infection in Pregnancy: PCR Cycle Thresholds, Placental Pathology, and Perinatal Outcomes.

(1) This study aimed to evaluate characteristics, perinatal outcomes, and placental pathology of pregnant women with or without SARS-CoV-2 infection in the context of maternal PCR cycle threshold (CT) values. (2) This was a retrospective case-control study in a third-level health center in Mexico City with universal screening by RT-qPCR. The association of COVID-19 manifestations, preeclampsia, and preterm birth with maternal variables and CT values were assessed by logistic regression models and decision trees. (3) Accordingly, 828 and 298 women had a negative and positive test, respectively. Of those positive, only 2.6% of them presented mild to moderate symptoms. Clinical characteristics between both groups of women were similar. No associations between CT values were found for maternal features, such as pre-gestational BMI, age, and symptomatology. A significantly higher percentage of placental fibrinoid was seen with women with low CTs (<25; p < 0.01). Regarding perinatal outcomes, preeclampsia was found to be significantly associated with symptomatology but not with risk factors or CT values (p < 0.01, aOR = 14.72). Moreover, 88.9% of women diagnosed with COVID-19 at <35 gestational weeks and symptomatic developed preeclampsia. (4) The data support strong guidance for pregnancies with SARS-CoV-2 infection, in particular preeclampsia and placental pathology, which need further investigation.

Prevalence, clinical features, and outcomes of SARS-CoV-2 infection in pregnant women with or without mild/moderate symptoms: Results from universal screening in a tertiary care center in Mexico City, Mexico.

The perinatal consequences of SARS-CoV-2 infection are still largely unknown. This study aimed to describe the features and outcomes of pregnant women with or without SARS-CoV-2 infection after the universal screening was established in a large tertiary care center admitting only obstetric related conditions without severe COVID-19 in Mexico City. This retrospective case-control study integrates data between April 22 and May 25, 2020, during active community transmission in Mexico, with one of the highest COVID-19 test positivity percentages worldwide. Only pregnant women and neonates with a SARS-CoV-2 result by quantitative RT-PCR were included in this study. Among 240 pregnant women, the prevalence of COVID-19 was 29% (95% CI, 24% to 35%); 86% of the patients were asymptomatic (95% CI, 76%-92%), nine women presented mild symptoms, and one patient moderate disease. No pregnancy baseline features or risk factors associated with severity of infection, including maternal age > 35 years, Body Mass Index >30 kg/m2, and pre-existing diseases, differed between positive and negative women. The median gestational age at admission for both groups was 38 weeks. All women were discharged at home without complications, and no maternal death was reported. The proportion of preeclampsia was higher in positive women than negative women (18%, 95% CI, 10%-29% vs. 9%, 95% CI, 5%-14%, P<0.05). No differences were found for other perinatal outcomes. SARS-CoV-2 test result was positive for nine infants of positive mothers detected within 24h of birth. An increased number of infected neonates were admitted to the NICU, compared to negative neonates (44% vs. 22%, P<0.05) and had a longer length of hospitalization (2 [2-18] days vs. 2 [2-3] days, P<0.001); these are potential proxies for illness severity. This report highlights the importance of COVID-19 detection at delivery in pregnant women living in high transmission areas.

Single cell migration profiling on a microenvironmentally tunable hydrogel microstructure device that enables stem cell potency evaluation.

Cell migration is a key function in a myriad of physiological events and disease conditions. Efficient, quick and descriptive profiling of migration behaviour in response to different treatments or conditions is highly desirable in a series of applications, ranging from fundamental studies of the migration mechanism to drug discovery and cell therapy. This investigation applied the use of methacrylamide gelatin (GelMA) to microfabricate migration lanes based on GelMA hydrogel with encapsulated migration stimuli and structural stability under culture medium conditions, providing the possibility of tailoring the microenvironment during cell-based assays. The actual device provides 3D topography, cell localization and a few step protocol, allowing the quick evaluation and quantification of individual migrated distances of a cell sample by an ImageJ plugin for automated microscopy processing. The detailed profiling of migration behaviour given by the new device has demonstrated a broader assay sensitivity compared to other migration assays and higher versatility to study cell migration in different settings of applications. In this study, parametric information extracted from the migration profiling was successfully used to develop predictive models of immunosuppressive cell function that could be applied as a potency test for mesenchymal stem cells.

Altered behavior with an organic cause: a case report.

BACKGROUND: Insulinomas are pancreatic endocrine tumors of rare incidence worldwide, the vast majority are of single occurrence and benign. These may not always present with the clear symptoms described in the literature and may be overlooked because their neuroglycopenic characteristics present in a fashion similar to some psychiatric conditions. CASE REPORT: A 50-year-old Hispanic man referred severe psychomotor symptoms, described as anxiety, aggressiveness, agitation, weakness, diaphoresis, and decreased visual acuity. Laboratory testing performed during his last episode revealed increased insulin levels and C-peptide among other findings. Imaging, biopsy, and histopathologic analysis confirmed an insulinoma was the cause of the symptoms, proving the importance of ruling out organic causes of altered mental status prior to consideration of psychiatric disorders. CONCLUSION: It is of critical importance to rule out organic causes of altered mental status prior to consideration of psychiatric disorders, as unusual diseases may be overlooked by physicians and be detrimental to the patient's progress.

Differentiation of adipose-derived stem cells to functional CD105neg CD73low melanocyte precursors guided by defined culture condition.

BACKGROUND: The generation of functional human epidermal melanocytes (HEM) from stem cells provides an unprecedented source for cell-based therapy in vitiligo. Despite the important efforts exerted to obtain melanin-producing cells from stem cells, pre-clinical results still lack the safety and scalability characteristics essential for their translational application. METHODS: Here, we report a rapid and efficient protocol based on defined culture conditions capable of differentiating adult adipose-derived stem cells (ADSC) to scalable amounts of proliferative melanocyte precursors (PreMel) within 30 days. PreMel were characterized in vitro through qPCR, Western blot, flow cytometry, biochemical assays, and in vivo assays in immunocompromised mice (NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ, or NSG). RESULTS: After 30 days of differentiation, the stem cell-derived PreMel were defined as CD105neg CD73low according to immunophenotypic changes in comparison with parental stem cell markers. In addition, expression of microphthalmia-associated transcription factor (MITF), active tyrosinase (TYR), and the terminal differentiation-involved premelanosome protein (PMEL) were detected. Furthermore, PreMel had the potential to synthesize melanin and package it into melanosomes both in vitro and in vivo in NSG mice skin. CONCLUSIONS: This study proposes a rapid and scalable protocol for the generation of proliferative melanocyte precursors (PreMel) from ADSC. These PreMel display the essential functional characteristics of bona fide HEM, opening a new path for an autologous cellular therapy for vitiligo patients.

Current concepts on bibliometrics: a brief review about impact factor, Eigenfactor score, CiteScore, SCImago Journal Rank, Source-Normalised Impact per Paper, H-index, and alternative metrics.

BACKGROUND: Understanding the impact of a publication by using bibliometric indices becomes an essential activity not only for universities and research institutes but also for individual academicians. This paper aims to provide a brief review of the current bibliometric tools used by authors and editors and proposes an algorithm to assess the relevance of the most common bibliometric tools to help the researchers select the fittest journal and know the trends of published submissions by using self-evaluation. METHODS: We present a narrative review answering at least two related consecutive questions triggered by the topics mentioned above. How prestigious is a journal based on its most recent bibliometrics, so authors may choose it to submit their next manuscript? And, how can they self-evaluate/understand the impact of their whole publishing scientific life? RESULTS: We presented the main relevant definitions of each bibliometrics and grouped them in those oriented to evaluated journals or individuals. Also, we share with our readers our algorithm to assess journals before manuscript submission. CONCLUSIONS: Since there is a journal performance market and an article performance market, each one with its patterns, an integrative use of these metrics, rather than just the impact factor alone, might represent the fairest and most legitimate approach to assess the influence and importance of an acceptable research issue, and not only a sound journal in their respective disciplines.

Gilz-Activin A as a Novel Signaling Axis Orchestrating Mesenchymal Stem Cell and Th17 Cell Interplay.

Mesenchymal stem cells (MSC) are highly immunosuppressive cells able to reduce chronic inflammation through the active release of mediators. Recently, we showed that glucocorticoid-induced leucine zipper (Gilz) expression by MSC is involved in their therapeutic effect by promoting the generation of regulatory T cells. However, the mechanisms underlying this pivotal role of Gilz remain elusive. Methods and Results In this study, we have uncovered evidence that Gilz modulates the phenotype and function of Th1 and Th17 cells likely by upregulating the level of Activin A and NO2 secreted by MSC. Adoptive transfer experiments sustained this Gilz-dependent suppressive effect of MSC on Th1 and Th17 cell functions. In immunoregulatory MSC, obtained by priming with IFN-γ and TNF-α, Gilz was translocated to the nucleus and bound to the promoters of inos and Activin ßA to induce their expression. The increased expression of Activin A directly impacted on Th17 cells fate by repressing their differentiation program through the activation of Smad3/2 and enhancing IL-10 production. Conclusion Our results reveal how Gilz controls inos and Activin ßA gene expression to ultimately assign immunoregulatory status to MSC able to repress the pathogenic Th17 cell differentiation program and uncover Activin A as a novel mediator of MSC in this process.