Acute Myocardial Infarction in a Young Bodybuilder: A Case Report and Review of the Literature.

BACKGROUND Misuse of androgenic anabolic steroids (AAS) is a current practice associated with vigorous bodybuilding for muscular hypertrophy, especially among gym practitioners and bodybuilders, influenced by the culture of body image. In addition to liver, psychiatric, genital, urinary, dermatological, and musculoskeletal complications, AAS misuse reportedly can lead to development of cardiovascular complications, such as hypertension, dyslipidemia, cardiac hypertrophy, and early coronary disease, and potentially acute myocardial infarction (AMI) and sudden death. CASE REPORT A 26-year-old male farmer who was also an amateur bodybuilder developed an extensive Killip Class I AMI in the anterior wall while using AAS. A few days before the acute event, his lipid and hormone levels were measured and found to be significantly elevated. The patient was asymptomatic after left anterior descending branch angioplasty, but he had significant electrocardiographic sequelae and ventricular dysfunction. CONCLUSIONS We describe the case of a young male bodybuilder using AAS who presented with AMI and was treated with primary angioplasty. Documentation of high levels of lipids and hormones 1 week before the acute event suggests some relationship between AAS and cardiovascular disease. The main effects of using these steroids on the cardiovascular system are reviewed. It is time for a new global warning about the risks of misusing AAS to obtain muscle hypertrophy. Based on current medical knowledge, these hormones should not be prescribed without a clear indication for their use.

TGF-beta/atRA-induced Tregs express a selected set of microRNAs involved in the repression of transcripts related to Th17 differentiation.

Regulatory T cells (Tregs) are essential regulators of immune tolerance. atRA and TGF-ß can inhibit the polarization of naïve T cells into inflammatory Th17 cells, favoring the generation of stable iTregs, however the regulatory mechanisms involved are not fully understood. In this context, the roles of individual microRNAs in Tregs are largely unexplored. Naïve T cells were immunomagnetically isolated from umbilical cord blood and activated with anti-human CD2/CD3/CD28 beads in the presence of IL-2 alone (CD4Med) or with the addition of TGF-ß and atRA (CD4TGF/atRA). As compared to CD4Med, the CD4TGF/atRA condition allowed the generation of highly suppressive CD4+CD25hiCD127-FOXP3hi iTregs. Microarray profiling allowed the identification of a set of microRNAs that are exclusively expressed upon TGF-ß/atRA treatment and that are predicted to target a set of transcripts concordantly downregulated. This set of predicted targets were enriched for central components of IL-6/JAK/STAT and AKT-mTOR signaling, whose inhibition is known to play important roles in the generation and function of regulatory lymphocytes. Finally, we show that mimics of exclusively expressed miRs (namely miR-1299 and miR-30a-5p) can reduce the levels of its target transcripts, IL6R and IL6ST (GP130), and increase the percentage of FoxP3+ cells among CD4+CD25+/hi cells.

MicroRNA-29 impairs the early phase of reprogramming process by targeting active DNA demethylation enzymes and Wnt signaling.

Somatic cell reprogramming by transcription factors and other modifiers such as microRNAs has opened broad avenues for the study of developmental processes, cell fate determination, and interplay of molecular mechanisms in signaling pathways. However, many of the mechanisms that drive nuclear reprogramming itself remain yet to be elucidated. Here, we analyzed the role of miR-29 during reprogramming in more detail. Therefore, we evaluated miR-29 expression during reprogramming of fibroblasts transduced with lentiviral OKS and OKSM vectors and we show that addition of c-MYC to the reprogramming factor cocktail decreases miR-29 expression levels. Moreover, we found that transfection of pre-miR-29a strongly decreased OKS-induced formation of GFP+-colonies in MEF-cells from Oct4-eGFP reporter mouse, whereas anti-miR-29a showed the opposite effect. Furthermore, we studied components of two pathways which are important for reprogramming and which involve miR-29 targets: active DNA-demethylation and Wnt-signaling. We show that inhibition of Tet1, Tet2 and Tet3 as well as activation of Wnt-signaling leads to decreased reprogramming efficiency. Moreover, transfection of pre-miR-29 resulted in elevated expression of ß-Catenin transcriptional target sFRP2 and increased TCF/LEF-promoter activity. Finally, we report that Gsk3-ß is a direct target of miR-29 in MEF-cells. Together, our findings contribute to the understanding of the molecular mechanisms by which miR-29 influences reprogramming.

The gene expression profile of non-cultured, highly purified human adipose tissue pericytes: Transcriptomic evidence that pericytes are stem cells in human adipose tissue.

Pericytes (PCs) are a subset of perivascular cells that can give rise to mesenchymal stromal cells (MSCs) when culture-expanded, and are postulated to give rise to MSC-like cells during tissue repair in vivo. PCs have been suggested to behave as stem cells (SCs) in situ in animal models, although evidence for this role in humans is lacking. Here, we analyzed the transcriptomes of highly purified, non-cultured adipose tissue (AT)-derived PCs (ATPCs) to detect gene expression changes that occur as they acquire MSC characteristics in vitro, and evaluated the hypothesis that human ATPCs exhibit a gene expression profile compatible with an AT SC phenotype. The results showed ATPCs are non-proliferative and express genes characteristic not only of PCs, but also of AT stem/progenitor cells. Additional analyses defined a gene expression signature for ATPCs, and revealed putative novel ATPC markers. Almost all AT stem/progenitor cell genes differentially expressed by ATPCs were not expressed by ATMSCs or culture-expanded ATPCs. Genes expressed by ATMSCs but not by ATPCs were also identified. These findings strengthen the hypothesis that PCs are SCs in vascularized tissues, highlight gene expression changes they undergo as they assume an MSC phenotype, and provide new insights into PC biology.

TNF-alpha and Notch signaling regulates the expression of HOXB4 and GATA3 during early T lymphopoiesis.

During the early thymus colonization, Notch signaling activation on hematopoietic progenitor cells (HPCs) drives proliferation and T cell commitment. Although these processes are driven by transcription factors such as HOXB4 and GATA3, there is no evidence that Notch directly regulates their transcription. To evaluate the role of NOTCH and TNF signaling in this process, human CD34+ HPCs were cocultured with OP9-DL1 cells, in the presence or absence of TNF. The use of a Notch signaling inhibitor and a protein synthesis inhibitor allowed us to distinguish primary effects, mediated by direct signaling downstream Notch and TNF, from secondary effects, mediated by de novo synthesized proteins. A low and physiologically relevant concentration of TNF promoted T lymphopoiesis in OP9-DL1 cocultures. TNF positively modulated the expression of both transcripts in a Notch-dependent manner; however, GATA3 induction was mediated by a direct mechanism, while HOXB4 induction was indirect. Induction of both transcripts was repressed by a GSK3ß inhibitor, indicating that activation of canonical Wnt signaling inhibits rather than induces their expression. Our study provides novel evidences of the mechanisms integrating Notch and TNF-alpha signaling in the transcriptional induction of GATA3 and HOXB4. This mechanism has direct implications in the control of self-renewal, proliferation, commitment, and T cell differentiation.

Effects of Light-Emitting Diode Therapy on Muscle Hypertrophy, Gene Expression, Performance, Damage, and Delayed-Onset Muscle Soreness: Case-control Study with a Pair of Identical Twins.

OBJECTIVE: The aim of this study was to verify how a pair of monozygotic twins would respond to light-emitting diode therapy (LEDT) or placebo combined with a strength-training program during 12 weeks. DESIGN: This case-control study enrolled a pair of male monozygotic twins, allocated randomly to LEDT or placebo therapies. Light-emitting diode therapy or placebo was applied from a flexible light-emitting diode array (λ = 850 nm, total energy = 75 J, t = 15 seconds) to both quadriceps femoris muscles of each twin immediately after each strength training session (3 times/wk for 12 weeks) consisting of leg press and leg extension exercises with load of 80% and 50% of the 1-repetition maximum test, respectively. Muscle biopsies, magnetic resonance imaging, maximal load, and fatigue resistance tests were conducted before and after the training program to assess gene expression, muscle hypertrophy and performance, respectively. Creatine kinase levels in blood and visual analog scale assessed muscle damage and delayed-onset muscle soreness, respectively, during the training program. RESULTS: Compared with placebo, LEDT increased the maximal load in exercise and reduced fatigue, creatine kinase, and visual analog scale. Gene expression analyses showed decreases in markers of inflammation (interleukin 1ß) and muscle atrophy (myostatin) with LEDT. Protein synthesis (mammalian target of rapamycin) and oxidative stress defense (SOD2 [mitochondrial superoxide dismutase]) were up-regulated with LEDT, together with increases in thigh muscle hypertrophy. CONCLUSIONS: Light-emitting diode therapy can be useful to reduce muscle damage, pain, and atrophy, as well as to increase muscle mass, recovery, and athletic performance in rehabilitation programs and sports medicine.

Somatosensory Psychophysical Losses in Inhabitants of Riverside Communities of the Tapajós River Basin, Amazon, Brazil: Exposure to Methylmercury Is Possibly Involved.

The purpose of this work was to evaluate the somatosensory system of methylmercury-exposed inhabitants living in the communities of the Tapajós river basin by using psychophysical tests and to compare with measurements performed in inhabitants of the Tocantins river basin. We studied 108 subjects from Barreiras and São Luiz do Tapajós, two communities of the Tapajós river basin, State of Pará, Amazon, Brazil, aged 13-53 years old. Mercury analysis was performed in head hair samples weighting 0.1-0.2 g by using atomic absorption spectrometry. Three somatosensory psychophysical tests were performed: tactile sensation threshold, vibration sensation duration, and two-point discrimination. Semmes-Weinstein 20 monofilaments with different diameters were used to test the tactile sensation in the lower lip, right and left breasts, right and left index fingers, and right and left hallux. The threshold was the thinner monofilament perceived by the subject. Vibration sensation was investigated using a 128 Hz diapason applied to the sternum, right and left radial sides of the wrist, and right and left outer malleoli. Two trials were performed at each place. A stopwatch recorded the vibration sensation duration. The two-point discrimination test was performed using a two-point discriminator. Head hair mercury concentration was significantly higher in mercury-exposed inhabitants of Tapajós than in non-exposed inhabitants of Tocantins (p < 0.01). When all subjects were divided in two groups independently of age-mercury-exposed and non-exposed-the following results were found: tactile sensation thresholds in mercury-exposed subjects were higher than in non-exposed subjects at all body parts, except at the left chest; vibration sensation durations were shorter in mercury-exposed than in non-exposed subjects, at all locations except in the upper sternum; two-point discrimination thresholds were higher in mercury-exposed than in non-exposed subjects at all body parts. There was a weak linear correlation between tactile sensation threshold and mercury concentration in the head hair samples. No correlation was found for the other two measurements. Mercury-exposed subjects had impaired somatosensory function compared with non-exposed control subjects. Long-term mercury exposure of riverside communities in the Tapajós river basin is a possible but not a definitely proven cause for psychophysical somatosensory losses observed in their population. Additionally, the relatively simple psychophysical measures used in this work should be followed by more rigorous measures of the same population.

Potential roles of microRNA-29a in the molecular pathophysiology of T-cell acute lymphoblastic leukemia.

Recent evidence has shown that deregulated expression of members of the microRNA-29 (miR-29) family may play a critical role in human cancer, including hematological malignancies. However, the roles of miR-29 in the molecular pathophysiology of T-cell acute lymphoblastic leukemia (T-ALL) has not been investigated. Here, we show that lower levels of miR-29a were significantly associated with higher blast counts in the bone marrow and with increased disease-free survival in T-ALL patients. Furthermore, miR-29a levels are extremely reduced in T-ALL cells compared to normal T cells. Microarray analysis following introduction of synthetic miR-29a mimics into Jurkat cells revealed the downregulation of several predicted targets (CDK6, PXDN, MCL1, PIK3R1, and CXXC6), including targets with roles in active and passive DNA demethylation (such as DNMT3a, DNMT3b, and members of the TET family and TDG). Restoring miR-29a levels in Jurkat and Molt-4 T-ALL cells led to the demethylation of many genes commonly methylated in T-ALL. Overall, our results suggest that reduced miR-29a levels may contribute to the altered epigenetic status of T-ALL, highlighting its relevance in the physiopathology of this disease.

Cultured Human Adipose Tissue Pericytes and Mesenchymal Stromal Cells Display a Very Similar Gene Expression Profile.

Mesenchymal stromal cells (MSCs) are cultured cells that can give rise to mature mesenchymal cells under appropriate conditions and secrete a number of biologically relevant molecules that may play an important role in regenerative medicine. Evidence indicates that pericytes (PCs) correspond to mesenchymal stem cells in vivo and can give rise to MSCs when cultured, but a comparison between the gene expression profiles of cultured PCs (cPCs) and MSCs is lacking. We have devised a novel methodology to isolate PCs from human adipose tissue and compared cPCs to MSCs obtained through traditional methods. Freshly isolated PCs expressed CD34, CD140b, and CD271 on their surface, but not CD146. Both MSCs and cPCs were able to differentiate along mesenchymal pathways in vitro, displayed an essentially identical surface immunophenotype, and exhibited the ability to suppress CD3(+) lymphocyte proliferation in vitro. Microarray expression data of cPCs and MSCs formed a single cluster among other cell types. Further analyses showed that the gene expression profiles of cPCs and MSCs are extremely similar, although MSCs differentially expressed endothelial cell (EC)-specific transcripts. These results confirm, using the power of transcriptomic analysis, that PCs give rise to MSCs and suggest that low levels of ECs may persist in MSC cultures established using traditional protocols.

Autologous haematopoietic stem cell transplantation reduces abnormalities in the expression of immune genes in multiple sclerosis.

Autologous haematopoietic stem-cell transplantation (AHSCT) has been experimented as a treatment in patients affected by severe forms of multiple sclerosis (MS) who failed to respond to standard immunotherapy. The rationale of AHSCT is to 'reboot' the immune system and reconstitute a new adaptive immunity. The aim of our study was to identify, through a robust and unbiased transcriptomic analysis, any changes of gene expression in T-cells potentially underlying the treatment effect in patients who underwent non-myeloablative AHSCT for treatment of MS. We evaluated by microarray DNA-chip technology the gene expression of peripheral CD4+ and CD8+ T-cell subsets sorted from patients with MS patients before AHSCT, at 6 months, 1 year and 2 years after AHSCT and from healthy control subjects. Hierarchical clustering analysis revealed that reconstituted CD8+ T-cells of MS patients at 2 years post-transplantation, aggregated together with healthy controls, suggesting a normalization of gene expression in CD8+ cells post-therapy. When we compared the gene expression in MS patients before and after therapy, we detected a large number of differentially expressed genes (DEG) in both CD8+ and CD4+ T-cell subsets at all time points after transplantation. We catalogued the biological function of DEG and we selected 27 genes known to be involved in immune function for accurate quantification of gene expression by real-time PCR. The analysis confirmed and extended with quantitative data, a number of significant changes in both the CD4+ and CD8+ T-cells subsets from MS post-transplant. Notably, CD8+ T-cells revealed more extensive changes in the expression of genes involved in effector immune responses.

Genome-wide gene expression profiling reveals unsuspected molecular alterations in pemphigus foliaceus.

Pemphigus foliaceus (PF) is a complex autoimmune disease characterized by bullous skin lesions and the presence of antibodies against desmoglein 1. In this study we sought to contribute to a better understanding of the molecular processes in endemic PF, as the identification of factors that participate in the pathogenesis is a prerequisite for understanding its biological basis and may lead to novel therapeutic interventions. CD4+ T lymphocytes are central to the development of the disease. Therefore, we compared genome-wide gene expression profiles of peripheral CD4+ T cells of various PF patient subgroups with each other and with that of healthy individuals. The patient sample was subdivided into three groups: untreated patients with the generalized form of the disease, patients submitted to immunosuppressive treatment, and patients with the localized form of the disease. Comparisons between different subgroups resulted in 135, 54 and 64 genes differentially expressed. These genes are mainly related to lymphocyte adhesion and migration, apoptosis, cellular proliferation, cytotoxicity and antigen presentation. Several of these genes were differentially expressed when comparing lesional and uninvolved skin from the same patient. The chromosomal regions 19q13 and 12p13 concentrate differentially expressed genes and are candidate regions for PF susceptibility genes and disease markers. Our results reveal genes involved in disease severity, potential therapeutic targets and previously unsuspected processes involved in the pathogenesis. Besides, this study adds original information that will contribute to the understanding of PF's pathogenesis and of the still poorly defined in vivo functions of most of these genes.

Monitoring mercury exposure in reproductive aged women inhabiting the Tapajós river basin, Amazon.

Among Amazonian communities, exposure to methylmercury is associated mainly with fish consumption that may affect fetal development in pregnant women. Therefore a temporal assessment was performed to assess the exposure of reproductive aged women to mercury who reside in the riparian communities of São Luís do Tapajós and Barreiras located in the Tapajós basin of the Brazilian Amazon from 1999 to 2012. The total mercury concentration in the 519 hair samples was assessed by cold vapor atomic absorption spectrometry. Data analysis showed that the average total mercury concentration decreased from 1.066 to 0.743 µg/g in those years. In 1999 the proportion of volunteers with mercury levels ≥ 10 µg/g was approximately 68 %. In general, exposure to mercury decreased among women of reproductive age, but the potential risks to reproduction and human health is still an issue as 22 % of the woman continued showing high mercury levels (≥ 10 µg/g) in 2012.

Hydroxycarbamide modulates components involved in the regulation of adenosine levels in blood cells from sickle-cell anemia patients.

Recent studies have demonstrated the role of adenosine (ADO) in sickle-cell anemia (SCA). ADO is produced by CD39 and CD73 and converted to inosine by adenosine deaminase (ADA). We evaluated the effects of hydroxycarbamide (HU) treatment on the modulation of adenosine levels in SCA patients. The expressions of CD39, CD73, and CD26 were evaluated by flow cytometry on blood cells in 15 HU-treated and 17 untreated patients and 10 healthy individuals. RNA was extracted from monocytes, and ADA gene expression was quantified by real-time PCR. ADA activity was also evaluated. We found that ADA transcripts were two times higher in monocytes of HU-treated patients, compared with untreated (P = 0.039). Monocytes of HU-treated patients expressed CD26, while monocytes of controls and untreated patients did not (P = 0.023). In treated patients, a lower percentage of T lymphocytes expressed CD39 compared with untreated (P = 0.003), and the percentage of T regulatory (Treg) cells was reduced in the treated group compared with untreated (P = 0.017) and controls (P = 0.0009). Besides, HU-treated patients displayed increased ADA activity, compared with untreated. Our results indicate a novel mechanism of action of HU mediated by the reduction of adenosine levels and its effects on pathophysiological processes in SCA.

[Neurological manifestations in riverine populations from areas exposed to mercury in the Brazilian Amazon]. / Manifestações neurológicas em ribeirinhos de áreas expostas ao mercúrio na Amazônia brasileira.

This study evaluated current levels of mercury exposure and sensory symptoms in adults from three riverine communities in Pará State, Brazil, two of which located in the Tapajós River basin and one in the Tocantins basin. Participants in this study included 78 residents in Barreiras (Tapajós), 30 in São Luiz do Tapajós (Tapajós), and 49 in Furo do Maracujá (Tocantins). Total hair mercury concentrations were quantified by atomic absorption spectrophotometry, and neurological evaluation was conducted by routine examination. Mercury concentrations in the Tapajós communities were higher than those in the Tocantins (p < 0.01). Evaluation of neurological changes showed no significant difference between the communities in exposed areas and control areas for the changes observed by conventional neurological examination, except for gait deviation (p < 0.05). The study concludes that despite the mercury exposure levels, there was a low frequency of sensory alterations according to conventional neurological testing.

Manifestações neurológicas em ribeirinhos de áreas expostas ao mercúrio na Amazônia brasileira / Neurological manifestations in riverine populations from areas exposed to mercury in the Brazilian Amazon / Manifestaciones neurológicas en las comunidades ribereñas expuestas al mercurio de la Amazonia brasileña

This study evaluated current levels of mercury exposure and sensory symptoms in adults from three riverine communities in Pará State, Brazil, two of which located in the Tapajós River basin and one in the Tocantins basin. Participants in this study included 78 residents in Barreiras (Tapajós), 30 in São Luiz do Tapajós (Tapajós), and 49 in Furo do Maracujá (Tocantins). Total hair mercury concentrations were quantified by atomic absorption spectrophotometry, and neurological evaluation was conducted by routine examination. Mercury concentrations in the Tapajós communities were higher than those in the Tocantins (p < 0.01). Evaluation of neurological changes showed no significant difference between the communities in exposed areas and control areas for the changes observed by conventional neurological examination, except for gait deviation (p < 0.05). The study concludes that despite the mercury exposure levels, there was a low frequency of sensory alterations according to conventional neurological testing.

No presente estudo, foram avaliados comparativamente os níveis atuais de exposição ao mercúrio e as manifestações neurológicas em ribeirinhos residentes em comunidades situadas no Estado do Pará, Brasil. Participaram do estudo 78 ribeirinhos de Barreiras (bacia do rio Tapajós), 30 de São Luiz do Tapajós (bacia do rio Tapajós) e 49 do Furo do Maracujá (bacia do rio Tocantins). As concentrações de mercúrio total foram quantificadas, em cabelo, pela espectrofotometria de absorção atômica, e a avaliação neurológica foi realizada por meio de testes de rotina. As concentrações de mercúrio nas comunidades do Tapajós foram maiores que as do Tocantins (p < 0,01). A avaliação das alterações neurológicas não mostrou diferença significativa entre as comunidades das áreas expostas e controle para os resultados observados pelo exame neurológico convencional, exceto para desvio da marcha (p < 0,05). Concluiu-se que, apesar dos níveis de exposição ao mercúrio, houve uma baixa frequência de alterações somatossensoriais encontradas por meio de exames neurológicos convencionais.

En el presente estudio se evaluó comparativamente los niveles actuales de exposición al mercurio y sus manifestaciones neurológicas en los residentes de las comunidades ribereñas en el Estado de Pará, Brasil. Los participantes fueron 78 de las riberas limítrofes (cuenca del Tapajós), 30 en São Luís do Tapajós (cuenca del Tapajós) y 49 en Pasiflora (cuenca del río Tocantins). Las concentraciones de mercurio total en el pelo se cuantificaron por espectrofotometría de absorción atómica y la evaluación neurológica se realizó mediante el análisis de rutina. Las concentraciones de mercurio en las comunidades Tapajós fueron más altas que en Tocantins (p < 0,01). La evaluación de los trastornos neurológicos no mostró diferencias significativas entre las comunidades de las zonas expuestas, ni en el control de los resultados observados durante el examen neurológico convencional, excepto por desviaciones de la marcha (p < 0,05). Se concluyó que, si bien existen niveles de exposición al mercurio, hubo una baja frecuencia de cambios, cuyo examen neurológico fue de tipo estándar somatosensorial.

Troca valvar aórtica minimamente invasiva: uma alternativa à técnica convencional / Minimally invasive aortic valve replacement: an alternative to the conventional technique

OBJETIVO: Demonstrar o uso da cirurgia minimamente invasiva para tratamento da valva aórtica e comparar seus resultados com o método tradicional. MÉTODOS: Entre 2006 e 2011, 60 pacientes foram submetidos à cirurgia na valva aórtica, após consentimento escrito, destes 40 pela técnica minimamente invasiva com acesso por minitoracotomia ântero-lateral direita (Grupo 1/G1)e 20 por esternotomia mediana (Grupo 2/G2). Comparamos os tempos operatórios e a evolução pós-operatória intra-hospitalar. RESULTADOS: Os tempos médios de circulação extracorpórea (CEC) e pinçamento aórtico no G1 foram, respectivamente, 142,7 ± 59,5 min e 88,6 ± 31,5 min e, no G2, 98,1 ± 39,1 min e 67,7 ± 26,2 min (P<0,05), uma diferença nas medianas de 39 minutos no tempo de CEC e 23 minutos no pinçamento aórtico foram observados a favor da técnica convencional. A perda sanguínea pelos drenos torácicos foi significativamente menor no grupo minimamente invasivo: 605,1 ± 679,5 ml (G1) versus 1617 ± 1390 ml (G2) (P<0,05). Os tempos médios de internamento em UTI e hospitalar foram menores em G1: 2,3 ± 1,8 dias e 5,5 ± 5,4 dias versus 5,1 ± 3,6 dias e 10 ± 5,1 dias em G2 (P<0,05), respectivamente. O uso de drogas vasoativas no pós-operatório também foi menor no grupo minimamente invasivo 12,8% em G1 versus 45% em G2. CONCLUSÃO: Troca valvar aórtica com o uso de técnicas minimamente invasivas, apesar de demonstrar maiores tempos intraoperatórios, não afeta os resultados pósoperatórios, que nesta casuística mostraram-se melhores quando comparado ao método tradicional.

OBJECTIVES: To demonstrate the use of minimally invasive surgery for aortic valve replacement and compare your results with the traditional method. METHODS: Between 2006 and 2011 sixty patients underwent surgery on aortic valve, after written consent, these 40 by minimally invasive technique with right anterior minithoracotomy access (Group 1/G1) and 20 by median sternotomy (Group 2/G2). Compare the operating times and postoperative evolution intra-hospital. RESULTS: The average times of bypass and aortic crossclamp in G1 were, respectively, 142.7 ± 59.5 min and 88.6 ± 31.5 min and, in G2, 98.1 ± 39.1 min and 67.7 ± 26.2 min (P < 0.05), a difference in medians of 39 minutes in bypass time and 23 minutes in aortic cross-clamp were observed in favour of conventional technique. The blood loss by the thoracic drains was significantly lower in the Group: minimally invasive 605.1 ± 679.5 ml (G1) versus 1617 ± 1390 ml (G2) (P < 0.05).The average time of ICU and hospital stay were shorter in G1: 2.3 ± 1.8 and 5.5 ± 5.4 days versus 5.1 ± 3.6 and 10 ± 5.1 in G2 (P < 0.05), respectively. Vasoactive drug use was also less post-operative at 12.8% in minimally invasive group G1 versus 45% in G2. CONCLUSION: Aortic valve replacement through minimally invasive techniques, although intraoperative times larger, not demonstrate affect postoperative results that this case proved best when compared to the traditional approach.

Mesenchymal stem cells promote the sustained expression of CD69 on activated T lymphocytes: roles of canonical and non-canonical NF-κB signalling.

Mesenchymal stem cells (MSCs) are known to induce the conversion of activated T cells into regulatory T cells in vitro. The marker CD69 is a target of canonical nuclear factor kappa-B (NF-κB) signalling and is transiently expressed upon activation; however, stable CD69 expression defines cells with immunoregulatory properties. Given its enormous therapeutic potential, we explored the molecular mechanisms underlying the induction of regulatory cells by MSCs. Peripheral blood CD3(+) T cells were activated and cultured in the presence or absence of MSCs. CD4(+) cell mRNA expression was then characterized by microarray analysis. The drug BAY11-7082 (BAY) and a siRNA against v-rel reticuloendotheliosis viral oncogene homolog B (RELB) were used to explore the differential roles of canonical and non-canonical NF-κB signalling, respectively. Flow cytometry and real-time PCR were used for analyses. Genes with immunoregulatory functions, CD69 and non-canonical NF-κB subunits (RELB and NFKB2) were all expressed at higher levels in lymphocytes co-cultured with MSCs. The frequency of CD69(+) cells among lymphocytes cultured alone progressively decreased after activation. In contrast, the frequency of CD69(+) cells increased significantly following activation in lymphocytes co-cultured with MSCs. Inhibition of canonical NF-κB signalling by BAY immediately following activation blocked the induction of CD69; however, inhibition of canonical NF-κB signalling on the third day further induced the expression of CD69. Furthermore, late expression of CD69 was inhibited by RELB siRNA. These results indicate that the canonical NF-κB pathway controls the early expression of CD69 after activation; however, in an immunoregulatory context, late and sustained CD69 expression is promoted by the non-canonical pathway and is inhibited by canonical NF-κB signalling.

Minimally invasive aortic valve replacement: an alternative to the conventional technique.

OBJECTIVES: To demonstrate the use of minimally invasive surgery for aortic valve replacement and compare your results with the traditional method. METHODS: Between 2006 and 2011 sixty patients underwent surgery on aortic valve, after written consent, these 40 by minimally invasive technique with right anterior minithoracotomy access (Group 1/G1) and 20 by median sternotomy (Group 2/G2). Compare the operating times and postoperative evolution intra-hospital. RESULTS: The average times of bypass and aortic crossclamp in G1 were, respectively, 142.7 ± 59.5 min and 88.6 ± 31.5 min and, in G2, 98.1 ± 39.1 min and 67.7 ± 26.2 min (P < 0.05), a difference in medians of 39 minutes in bypass time and 23 minutes in aortic cross-clamp were observed in favour of conventional technique. The blood loss by the thoracic drains was significantly lower in the Group: minimally invasive 605.1 ± 679.5 ml (G1) versus 1617 ± 1390 ml (G2) (P < 0.05).The average time of ICU and hospital stay were shorter in G1: 2.3 ± 1.8 and 5.5 ± 5.4 days versus 5.1 ± 3.6 and 10 ± 5.1 in G2 (P < 0.05), respectively. Vasoactive drug use was also less post-operative at 12.8% in minimally invasive group G1 versus 45% in G2. CONCLUSION: Aortic valve replacement through minimally invasive techniques, although intraoperative times larger, not demonstrate affect postoperative results that this case proved best when compared to the traditional approach.

Halofuginone has anti-proliferative effects in acute promyelocytic leukemia by modulating the transforming growth factor beta signaling pathway.

Promyelocytic leukemia-retinoic acid receptor alpha (PML-RARα) expression in acute promyelocytic leukemia (APL) impairs transforming growth factor beta (TGFß) signaling, leading to cell growth advantage. Halofuginone (HF), a low-molecular-weight alkaloid that modulates TGFß signaling, was used to treat APL cell lines and non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mice subjected to transplantation with leukemic cells from human chorionic gonadotrophin-PML-RARα transgenic mice (TG). Cell cycle analysis using incorporated bromodeoxyuridine and 7-amino-actinomycin D showed that, in NB4 and NB4-R2 APL cell lines, HF inhibited cellular proliferation (P<0.001) and induced apoptosis (P = 0.002) after a 24-hour incubation. Addition of TGFß revealed that NB4 cells were resistant to its growth-suppressive effects and that HF induced these effects in the presence or absence of the cytokine. Cell growth inhibition was associated with up-regulation of TGFß target genes involved in cell cycle regulation (TGFB, TGFBRI, SMAD3, p15, and p21) and down-regulation of MYC. Additionally, TGFß protein levels were decreased in leukemic TG animals and HF in vivo could restore TGFß values to normal. To test the in vivo anti-leukemic activity of HF, we transplanted NOD/SCID mice with TG leukemic cells and treated them with HF for 21 days. HF induced partial hematological remission in the peripheral blood, bone marrow, and spleen. Together, these results suggest that HF has anti-proliferative and anti-leukemic effects by reversing the TGFß blockade in APL. Since loss of the TGFß response in leukemic cells may be an important second oncogenic hit, modulation of TGFß signaling may be of therapeutic interest.