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Studies the temperature dependence of the critical magnetic field in Vitrovac-type magnetic amorphous ribbons. Use of polycrystalline nickel ferrite; General behavior of the critical fields as a function of temperature; Effect of nucleation and crystallization phenomena on the high-temperature behavior of the critical field.

Maritime accidents, share some factors already considered by the International Maritime Organization (IMO) and the researchers of the maritime world. The accelerated technological's changes, has allowed significant improvement of human activities, in many cases, improving the effectiveness and efficiency in the majority of the fields, of which marine transport is not the exception. Unfortunately in some cases, new technologies have led to relaxation in safety, so the idea to establish some minimum parameters, it is essential to ensure the safety of human life at sea, for increase the prevention of accidents and protection maritime environment. [ABSTRACT FROM AUTHOR]

Introducción: la adolescencia se define como el período de crecimiento y desarrollo humano entre los 10 y 19 años. El embarazo precoz es aquel que se produce en este grupo etario, sin importar la madurez o dependencia de su núcleo familiar de origen. En República Dominicana, el 22% de las adolescentes han estado embarazadas. Objetivo: evaluar los factores de riesgo de embarazo en adolescentes en la comunidad de Las Tablas, municipio Matanzas, provincia Peravia, República Dominicana, durante el período noviembre 2017 – enero 2018. Metodología: estudio prospectivo, descriptivo, de corte transversal en el que se entrevistaron 45 adolescentes fértiles de la comunidad de Las Tablas. Resultados: se obtuvo que un 20% (29 casos) presentó disfunción familiar como riesgo para desencadenar un embarazo adolescente. De las jóvenes con vida sexual activa, un 100% (12 casos) indicaron haberla iniciado a los 14 años o más. Un 69% (31 casos) han recibido información sobre el uso de los métodos anticonceptivos. Cabe destacar que 15 adolescentes (33%) han sido víctima de violencia en la comunidad. Conclusiones: el embarazo adolescente es una problemática multifactorial, donde predominan la disfunción familiar, ser hija de madre con historia de embarazo adolescente, uso de alcohol y otras sustancias, entre otras.

Background: The adequacy of biomarkers of potential harm (BOPH) for assessing tobacco products was explored based on their ability to distinguish tobacco use from non-use, change with cessation, and to show biological gradient., Methods: The sample included individuals with biomarker data in wave 1 of the Population Assessment of Tobacco Health study who never used tobacco, currently smoke cigarettes exclusively, used to smoke cigarettes exclusively (quit in past 12 months), currently use smokeless tobacco exclusively, and currently use e-cigarettes exclusively. We compared BOPH levels between groups and assessed the relationships between log-transformed biomarkers of exposure [BOE; total nicotine equivalents including seven nicotine metabolites (TNE-7), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanonol (NNAL), N-acetyl-S-(2-cyanoethyl)-L-cysteine, 1-hydroxypyrene, cadmium, and serum cotinine (SCOT)], and BOPH [high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), fibrinogen, soluble intercellular adhesion molecule-1 (sICAM-1), and 8-isoprostane]., Results: Among people who smoke, both sICAM-1 and 8-isoprostane distinguished smoking from non-use and were associated with all six BOE. Among people who use smokeless tobacco, 8-isoprostane was associated with TNE-7 and NNAL whereas hs-CRP was associated with SCOT. Among people who use e-cigarettes, no associations between BOPH and BOE were observed., Conclusions: Both sICAM-1 and 8-isoprostane may be useful for assessing the use or changes in use of some tobacco products. Studies examining their predictive validity could further strengthen our understanding of these two biomarkers., Impact: We found that two biomarkers of potential harm, soluble intercellular adhesion molecule-1 and 8-isoprostane, may have utility in studies assessing the potential harm of tobacco use in absence of long-term epidemiological studies., (©2024 American Association for Cancer Research.)

Purpose: Bispecific antibodies (BsAb) directed against B-cell maturation antigen (teclistamab) or the orphan G protein-coupled receptor GPRC5D (talquetamab) induce deep and durable responses in heavily pretreated patients with multiple myeloma. However, mechanisms underlying primary and acquired resistance remain poorly understood., Experimental Design: The anti-multiple myeloma activity of teclistamab and talquetamab was evaluated in bone marrow (BM) samples from patients with multiple myeloma. T-cell phenotype and function were assessed in BM/peripheral blood samples obtained from patients with multiple myeloma who were treated with these BsAb., Results: In ex vivo killing assays with 41 BM samples from BsAb-naive patients with multiple myeloma, teclistamab- and talquetamab-mediated multiple myeloma lysis was strongly correlated (r = 0.73, P < 0.0001). Both BsAb exhibited poor activity in samples with high regulatory T-cell (Treg) numbers and a low T-cell/multiple myeloma cell ratio. Furthermore, comprehensive phenotyping of BM samples derived from patients treated with teclistamab or talquetamab revealed that high frequencies of PD-1+ CD4+ T cells, CTLA4+ CD4+ T cells, and CD38+ CD4+ T cells were associated with primary resistance. Although this lack of response was linked to a modest increase in the expression of inhibitory receptors, increasing T-cell/multiple myeloma cell ratios by adding extra T cells enhanced sensitivity to BsAb. Further, treatment with BsAb resulted in an increased proportion of T cells expressing exhaustion markers (PD-1, TIGIT, and TIM-3), which was accompanied by reduced T-cell proliferative potential and cytokine secretion, as well as impaired antitumor efficacy in ex vivo experiments., Conclusions: Primary resistance is characterized by a low T-cell/multiple myeloma cell ratio and Treg-driven immunosuppression, whereas reduced T-cell fitness due to continuous BsAb-mediated T-cell activation may contribute to the development of acquired resistance., (©2024 American Association for Cancer Research.)

Study Objective: We sought to initiate an emergency department (ED)-based ultrasound-guided regional anesthesia (UGRA) program in our community teaching hospital system. Here, we present our development process and protocol. We also sought to assess the types, indications, and associated adverse event rates for the UGRA procedures in this study., Methods: We conducted a retrospective analysis of prospectively collected quality assurance data from a case series of patients who underwent an UGRA procedure in the ED. In August 2020, we developed an UGRA program for our community teaching hospital and its 2 affiliated freestanding EDs. For quality assurance purposes, we tracked all UGRA procedures performed in the ED, and we specifically assessed adverse events using structured follow-up. We subsequently obtained approval from our institutional review board to perform chart reviews of the patients in our dataset to abstract additional data and formally perform a research study. We determined the frequency with which different UGRA procedures were performed, and we calculated the adverse event rate., Results: Between August 24, 2020, and July 15, 2022, a total of 18 different sonographers performed and documented 229 UGRA procedures on 206 unique patients. This included 28 different types of procedures. Follow-up after disposition was successful in 82.0% of patients. In 2 cases, the patient reported no pain relief at all from the procedure, but no patients reported complications related to the procedure., Conclusion: We successfully initiated a robust ED-based UGRA program in our community teaching hospital system. Among patients with successful follow-up, no adverse events were identified., (Copyright © 2023 American College of Emergency Physicians. Published by Elsevier Inc. All rights reserved.)

Introduction: Carpal tunnel syndrome (CTS) is a common complaint in the emergency department (ED) and accounts for approximately 90% of all peripheral neuropathies. 6 Pain control from injection with corticosteroids into the carpal tunnel space is associated with multiple possible complications including atrophy, iatrogenic median nerve injury, and skin changes. Ultrasound (US)-guided mid-forearm median nerve block is an ED procedure that can be used to avoid direct injection into the carpal tunnel space. Here we present a case report proposing the use of US-guided mid-forearm block as a safe and effective adjunct to the management of acute pain caused by CTS., Case Report: A previously healthy 44-year-old, right-hand dominant female presented to the ED with left wrist pain. Her clinical exam and US findings were consistent with CTS. Given her allergy to non-steroidal anti-inflammatory drugs, she was offered a median nerve block, which was performed in the ED. The patient reported continued pain relief 24 hours after discharge from the ED., Conclusion: There is limited data on the use of US-guided mid-forearm median nerve block as an acute pain management tool for CTS in the ED. The US-guided median nerve block done in the mid-forearm location can provide pain control for those with CTS while reducing the risk of complications associated with direct carpal tunnel injection., Competing Interests: Conflicts of Interest: By the CPC-EM article submission agreement, all authors are required to disclose all affiliations, funding sources and financial or management relationships that could be perceived as potential sources of bias. The authors disclosed none.

The difficulty in predicting fatal outcomes in patients with coronavirus disease 2019 (COVID-19) impacts the general morbidity and mortality due to severe acute respiratory syndrome-coronavirus 2 infection, as it wears out the hospital services that care for these patients. Unfortunately, in several of the candidates for prognostic biomarkers proposed, the predictive power is compromised when patients have pre-existing comorbidities. A cohort of 147 patients hospitalized for severe COVID-19 was included in a descriptive, observational, single-center, and prospective study. Patients were recruited during the first COVID-19 pandemic wave (April-November 2020). Data were collected from the clinical history whereas immunophenotyping by multiparameter flow cytometry analysis allowed us to assess the expression of surface markers on peripheral leucocyte. Patients were grouped according to the outcome in survivors or non-survivors. The prognostic value of leucocyte, cytokines or HLA-DR, CD39, and CD73 was calculated. Hypertension and chronic renal failure but not obesity and diabetes were conditions more frequent among the deceased patient group. Mixed hypercytokinemia, including inflammatory (IL-6) and anti-inflammatory (IL-10) cytokines, was more evident in deceased patients. In the deceased patient group, lymphopenia with a higher neutrophil-lymphocyte ratio (NLR) value was present. HLA-DR expression and the percentage of CD39+ cells were higher than non-COVID-19 patients but remained similar despite the outcome. Receiver operating characteristic analysis and cutoff value of NLR (69.6%, 9.4), percentage NLR (pNLR; 71.1%, 13.6), and IL-6 (79.7%, 135.2 pg/mL). The expression of HLA-DR, CD39, and CD73, as many serum cytokines (other than IL-6) and chemokines levels do not show prognostic potential, were compared to NLR and pNLR values., (© 2023 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

B-cell maturation antigen (BCMA) is an attractive therapeutic target highly expressed on differentiated plasma cells in multiple myeloma and other B-cell malignancies. GSK2857916 (belantamab mafodotin, BLENREP) is a BCMA-targeting antibody-drug conjugate approved for the treatment of relapsed/refractory multiple myeloma. We report that GSK2857916 induces immunogenic cell death in BCMA-expressing cancer cells and promotes dendritic cell activation in vitro and in vivo GSK2857916 treatment enhances intratumor immune cell infiltration and activation, delays tumor growth, and promotes durable complete regressions in immune-competent mice bearing EL4 lymphoma tumors expressing human BCMA (EL4-hBCMA). Responding mice are immune to rechallenge with EL4 parental and EL4-hBCMA cells, suggesting engagement of an adaptive immune response, immunologic memory, and tumor antigen spreading, which are abrogated upon depletion of endogenous CD8 + T cells. Combinations with OX40/OX86, an immune agonist antibody, significantly enhance antitumor activity and increase durable complete responses, providing a strong rationale for clinical evaluation of GSK2857916 combinations with immunotherapies targeting adaptive immune responses, including T-cell-directed checkpoint modulators., (©2021 The Authors; Published by the American Association for Cancer Research.)

The development of novel agents has transformed the treatment paradigm for multiple myeloma, with minimal residual disease (MRD) negativity now achievable across the entire disease spectrum. Bone marrow-based technologies to assess MRD, including approaches using next-generation flow and next-generation sequencing, have provided real-time clinical tools for the sensitive detection and monitoring of MRD in patients with multiple myeloma. Complementary liquid biopsy-based assays are now quickly progressing with some, such as mass spectrometry methods, being very close to clinical use, while others utilizing nucleic acid-based technologies are still developing and will prove important to further our understanding of the biology of MRD. On the regulatory front, multiple retrospective individual patient and clinical trial level meta-analyses have already shown and will continue to assess the potential of MRD as a surrogate for patient outcome. Given all this progress, it is not surprising that a number of clinicians are now considering using MRD to inform real-world clinical care of patients across the spectrum from smoldering myeloma to relapsed refractory multiple myeloma, with each disease setting presenting key challenges and questions that will need to be addressed through clinical trials. The pace of advances in targeted and immune therapies in multiple myeloma is unprecedented, and novel MRD-driven biomarker strategies are essential to accelerate innovative clinical trials leading to regulatory approval of novel treatments and continued improvement in patient outcomes., (©2021 The Authors; Published by the American Association for Cancer Research.)

Belantamab mafodotin (belamaf) is a BCMA-targeted antibody-drug conjugate recently approved as monotherapy for adults with relapsed/refractory multiple myeloma who have received ≥4 prior therapies. Belamaf binds to BCMA and eliminates myeloma cells by multimodal mechanisms of action. The cytotoxic and potential immunomodulatory properties of belamaf have led to novel combination studies with other anticancer therapies. Here, we describe the rationale and design of DREAMM-5, an ongoing Phase I/II platform study evaluating the safety and efficacy of belamaf combined with novel agents, including GSK3174998 (OX40 agonist), feladilimab (an ICOS; GSK3359609), nirogacestat (a gamma-secretase inhibitor; PF-03084014) and dostarlimab (a PD-1 blocker) versus belamaf monotherapy for patients with relapsed/refractory multiple myeloma. Clinical trial registration: NCT04126200 (ClinicalTrials.gov).

Background: SARS-CoV-2, the etiological agent causing COVID-19, has infected more than 27 million people with over 894000 deaths worldwide since its emergence in December 2019. Factors for severe diseases, such as diabetes, hypertension, and obesity have been identified however, the precise pathogenesis is poorly understood. To understand its pathophysiology and to develop effective therapeutic strategies, it is essential to define the prevailing immune cellular subsets., Methods: We performed whole circulating immune cells scRNAseq from five critically ill COVID-19 patients, trajectory and gene ontology analysis., Results: Immature myeloid populations, such as promyelocytes-myelocytes, metamyelocytes, band neutrophils, monocytoid precursors, and activated monocytes predominated. The trajectory with pseudotime analysis supported the finding of immature cell states. While the gene ontology showed myeloid cell activation in immune response, DNA and RNA processing, defense response to the virus, and response to type 1 interferon. Lymphoid lineage was scarce. Expression of genes such as C/EBPβ, IRF1and FOSL2 potentially suggests the induction of trained immunity., Conclusions: Our results uncover transcriptomic profiles related to immature myeloid lineages and suggest the potential induction of trained immunity., (Copyright © 2020 IMSS. Published by Elsevier Inc. All rights reserved.)

Arginine methylation has been recognized as a post-translational modification with pleiotropic effects that span from regulation of transcription to metabolic processes that contribute to aberrant cell proliferation and tumorigenesis. This has brought significant attention to the development of therapeutic strategies aimed at blocking the activity of protein arginine methyltransferases (PRMTs), which catalyze the formation of various methylated arginine products on a wide variety of cellular substrates. GSK3368715 is a small molecule inhibitor of type I PRMTs currently in clinical development. Here, we evaluate the effect of type I PRMT inhibition on arginine methylation in normal human peripheral blood mononuclear cells and utilize a broad proteomic approach to identify type I PRMT substrates. This work identified heterogenous nuclear ribonucleoprotein A1 (hnRNP-A1) as a pharmacodynamic biomarker of type I PRMT inhibition. Utilizing targeted mass spectrometry (MS), methods were developed to detect and quantitate changes in methylation of specific arginine residues on hnRNP-A1. This resulted in the development and validation of novel MS and immune assays useful for the assessment of GSK3368715 induced pharmacodynamic effects in blood and tumors that can be applied to GSK3368715 clinical trials.

Objective: Lung cancer is one the leading causes of mortality worldwide. Symptomatic manifestations of the disease generally occur in the advanced-stage setting, and therefore an important number of patients have advanced or metastatic disease by the time they are diagnosed. This situation contributes to a poor prognosis in the treatment of lung cancer. Evidencebased clinical recommendations are of great value to support decision-making for daily practice, and thus improving health care quality and patient outcomes., Materials and Methods: This document was an initiative of the Mexican Society of Oncology (SMEO) in collaboration with Mexican Center of Clinical Excellence (Cenetec) according to Interna- tional Standards. Such standards included those described by the IOM, NICE, SIGN and GI-N. An interdisciplinary Guideline Development Group (GDG) was put together which included medical oncologists, surgical oncologistsc, radiation therapists, and methodologists with expertise in critical appraisal, sys- tematic reviews and clinical practice guidelines development., Results: 62 clinical questions were agreed among members of the GDG. With the evidence identified from systematic reviews, the GDG developed clinical recommendations using a Modified Delphi Panel technique. Patients' representatives validated them., Conclusions: These Clinical Practice Guideline aims to support the shared decision-making process for patients with different stages of non-small cell lung cancer. Our goal is to improve health-care quality on these patients., Competing Interests: Declaration of conflict of interests. The authors declare that they have no conflict of interests.

Background: The effect of decantation time on viability and apoptosis in adipocytes has not been described. The objective of the study was to describe viability and apoptosis in adipocytes up to 2 h after harvesting., Methods: Twenty patients who underwent esthetic liposuction from the abdomen were included. The lipoaspirate was obtained from the infra-umbilical area with the tumescent technique. Liposuction was performed with a 60-ml syringe and a 3-ml cannula. Lipoaspirates were centrifuged at 50 g for 5 min at 0, 60 and 120 min after harvesting. One gram of fat was digested with 0.1% type 1 collagenase and incubated at 37 degrees for 30 min. Adipocytes were counted on 10 random microscopic fields. Apoptosis was determined by TUNEL assay. A fluorescence microscope was used to visualize the staining nuclei and cells., Results: Regarding viability, immediately after harvesting, 57.6 ± 18.9% of the cells were viable, whereas 60 min after liposuction the viability decreased to 51.62 ± 8.8% and 120 min after liposuction the percentage of viable cells was 46.8 ± 16.9%. The percentage of apoptotic cells at time 0 was 38.2 ± 8.0%, whereas it was 51.24 ± 8.1% at 60 min and 62.9 ± 16.1% at 120 min after collection., Conclusions: Apoptosis and mortality of adipocytes after liposuction increase directly proportional to the time of decantation. Lipoinjection should be performed as soon as possible after harvesting., No Level Assigned: This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews, and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies, and Experimental Studies. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Evasion of the potent tumour suppressor activity of p53 is one of the hurdles that must be overcome for cancer cells to escape normal regulation of cellular proliferation and survival. In addition to frequent loss of function mutations, p53 wild-type activity can also be suppressed post-translationally through several mechanisms, including the activity of PRMT5. Here we describe broad anti-proliferative activity of potent, selective, reversible inhibitors of protein arginine methyltransferase 5 (PRMT5) including GSK3326595 in human cancer cell lines representing both hematologic and solid malignancies. Interestingly, PRMT5 inhibition activates the p53 pathway via the induction of alternative splicing of MDM4. The MDM4 isoform switch and subsequent p53 activation are critical determinants of the response to PRMT5 inhibition suggesting that the integrity of the p53-MDM4 regulatory axis defines a subset of patients that could benefit from treatment with GSK3326595.

Background: Nowadays, the term "physical fitness" has evolved from sports performance to health status, and it has been considered a strong predictor of cardiovascular disease. In this sense, test batteries have been developed to evaluate physical fitness such as the ALPHA-FIT battery. On the other hand, the analysis of dietary patterns has emerged as an alternative method to study the relationship between diet and chronic noncommunicable diseases. However, the association between dietary patterns and the physical fitness level has not been evaluated in both adults and adolescents. This association is most important in adolescents due to the fact that establishing healthy dietary behaviors and a favorable nutritional profile in early stages of life prevents various chronic-degenerative diseases., Objective: To analyze the association between dietary patterns and the level of fitness in Mexican teenagers., Methods: We analyzed the relationship between dietary patterns and the fitness level of 42 teenage students in Toluca, Mexico. Students were weighed and measured, and their food intake was recorded for 2 weekdays and one weekend day. Dietary patterns were obtained by factorial analysis. The ALPHA-FIT battery was used to measure the fitness level., Results: Fifty percent of the students were found to have a low fitness level (62.1% men; 37.9% women). There was no association ( X 2 = 0.83) between the dietary patterns "high in fat and sugar," "high in protein", and "low in fat and protein" and the level of physical condition in teens., Conclusions: In this study, all of teenagers with a very low level of fitness obtained a high dietary pattern in protein; however, 40% with a high level of physical condition resulted in the same pattern; that is why we did not find a relationship between the fitness level and the patterns investigated in this study.

Material and Method: This is a prospective, cross-sectional, and correlational study with a probabilistic sampling in which 150 teenagers from three different high schools from the city of Toluca, Mexico, aged 15-17, were assessed., Objective: To determine if weight, age, and gender have an influence on physical fitness evaluated with the EUROFIT and ALPHA-FITNESS batteries., Results: Women have a higher overweight and obesity rate than men (3 : 1). Adolescents who have normal weight have regular physical fitness (74.9%). When comparing genders we found that men have a higher mean than women in the tests, except for skinfold thickness and waist circumference. Age was only correlated with the plate tapping test ( p = 0.001). There are significant differences in the standing broad jump test and the Course-Navette of the EUROFIT and ALPHA-FITNESS batteries ( p = 0.000)., Conclusions: It is likely that regular physical activity, and not normal weight, helps generate healthy physical fitness. Male subjects had a higher mean than women, reporting a better physical fitness and more frequent physical activity.

Diagnostic testing was performed between 2000 and 2012 to determine the distribution of infectious pancreatic necrosis virus (IPNV) in the main states of the Mexican Republic with freshwater Rainbow Trout Oncorhynchus mykiss (Walbaum) farms. This virus was positively identified from Rainbow Trout farms in seven of the eight states assessed. Due to nonnormal data distribution, a logistic regression model was applied for statistical analysis, the results of which indicated that virus prevalence was variable between states, with moderate but significant differences. Regarding the time periods evaluated, IPNV prevalence was higher during the first years of the study. The susceptible, infected, removed model was used to examine this phenomenon, which indicated that the decreased prevalence during the latter years of the study could be associated with a real elimination of the infection. The information of the cases analyzed also suggests a relationship with the irregularity in the submission of samples to the laboratory and emphasizes other factors that have contributed to the transmission of IPNV throughout the country. Received November 10, 2014; accepted December 5, 2015.

Background: Breast cancer is a heterogeneous disease with different molecular subtypes that have varying responses to therapy. An ongoing challenge in breast cancer research is to distinguish high-risk patients from good prognosis patients. This is particularly difficult in the low-grade, ER-positive luminal A tumors, where robust diagnostic tools to aid clinical treatment decisions are lacking. Recent data implicating chromatin regulators in cancer initiation and progression offers a promising avenue to develop new tools to help guide clinical decisions., Methods: Here we exploit a published transcriptome dataset and an independent validation cohort to correlate the mRNA expression of selected chromatin regulators with respect to the four intrinsic breast cancer molecular subtypes. We then perform univariate and multivariate analyses to compare the prognostic value of a panel of chromatin regulators to Ki67, a currently utilized proliferation marker., Results: Unsupervised hierarchical clustering revealed a gene cluster containing several histone chaperones and histone variants highly-expressed in the proliferative subtypes (basal-like, HER2-positive, luminal B) but not in the luminal A subtype. Several chromatin regulators, including the histone chaperones CAF-1 (subunits p150 and p60), ASF1b, and HJURP, and the centromeric histone variant CENP-A, associated with local and metastatic relapse and poor patient outcome. Importantly, we find that HJURP can discriminate favorable and unfavorable outcome within the luminal A subtype, outperforming the currently utilized proliferation marker Ki67, as an independent prognostic marker for luminal A patients., Conclusions: The integration of chromatin regulators as clinical biomarkers, in particular the histone chaperone HJURP, will help guide patient substratification and treatment options for low-risk luminal A breast carcinoma patients., (Copyright © 2014. Published by Elsevier B.V.)

Introduction: In recent years, several investigations have related -hydroxy--methylbutyrate (HMB) to a reduced muscle proteolysis and to an increase in muscle mass. Therefore, a number of studies focused on the cellular and molecular mechanisms regulating these effects have been carried out., Aims: The objectives of this review are: to know both HMB metabolism and toxicity, and to identify HMB cellular and molecular mechanisms of action when used as a dietary supplement., Methods: A search was performed in the Web of Science, Pubmed and SportDiscus data bases. RESULTS were divided into two parts; this article presents aspects referring to HMB mechanisms of action., Results: There is insufficient evidence that HMB intake increases muscle cholesterol synthesis. It probably has positive effects on muscle metabolism through both the mTOR and ubiquitin-proteasome pathways, although the mechanism of action is unknown. HMB may increase blood levels of -hydroxybutyrate and this could explain the main effects of HMB on muscle proteolysis., Conclusion: According to these results, the possibility of justifying the action of HMB through the beta-hydroxybutyrate pathway opens an interesting line of research for future studies., (Copyright AULA MEDICA EDICIONES 2014. Published by AULA MEDICA. All rights reserved.)

Introduction: -hydroxy--methylbutyrate (HMB) is a leucine metabolite produced from -ketoisocaproic acid. HMB supplementation has been used as a dietary supplement in sports since 1997, with the aim of decreasing muscle proteolysis. In recent years, positive effects have been reported in different pathologies, which suggests potential health benefits., Aims: The objectives of this review are: to know both HMB metabolism and toxicity, and to identify HMB cellular and molecular mechanisms of action when used as a dietary supplement., Methods: A search was performed in the Web of Science, Pubmed and SportDiscus data bases. RESULTS were divided into two parts; this article presents the results about both HMB metabolism and possible toxicity., Results: Studies show that HMB is related to cholesterol metabolism in skeletal muscle, which could reduce proteolysis, through hydroxy-methyl-glutaryl-coenzyme A and mevalonate as a precursor in the synthesis of cholesterol. However, HMB could also be transformed from acetoacetate to beta-hydroxybutyrate by beta-hydrozybutyrate dehydrogenase. The calcium salt of HMB is the most used chemical form in dietary supplements, being the most common dose 3 g of HMB/day. Studies in humans and animals provide evidence that there are no adverse effects associated with HMB supplementation., Conclusion: Metabolic effects and lack of toxicity of HMB make it an adequate compound to be used as a dietary supplement., (Copyright AULA MEDICA EDICIONES 2014. Published by AULA MEDICA. All rights reserved.)

Retinoblastoma is a non-hereditary as well as an inherited pediatric tumor of the developing retina resulting from the inactivation of both copies of the RB1 tumor suppressor gene. Familial retinoblastoma is a highly penetrant genetic disease that usually develops by carrying germline mutations that inactivate one allele of the RB1 gene, leading to multiple retinoblastomas. However, large and complete germline RB1 deletions are associated with low or no tumor risk for reasons that remain unknown. In this study, we define a minimal genomic region associated with this low penetrance. This region encompasses few genes including MED4 a subunit of the mediator complex. We further show that retinoblastoma RB1 -/- cells cannot survive in the absence of MED4, both in vitro and in orthotopic xenograft models in vivo, therefore identifying MED4 as a survival gene in retinoblastoma. We propose that the contiguous loss of the adjacent retinoblastoma gene, MED4, explains the low penetrance in patients with large deletions that include both RB1 and MED4. Our findings also point to another synthetic lethal target in tumors with inactivated RB1 and highlight the importance of collateral damage in carcinogenesis., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Centromeres, epigenetically defined by the presence of the histone H3 variant CenH3, are essential for ensuring proper chromosome segregation. In mammals, centromeric CenH3(CENP-A) deposition requires its dedicated chaperone HJURP and occurs during telophase/early G1. We find that the cell-cycle-dependent recruitment of HJURP to centromeres depends on its timely phosphorylation controlled via cyclin-dependent kinases. A nonphosphorylatable HJURP mutant localizes prematurely to centromeres in S and G2 phase. This unregulated targeting causes a premature loading of CenH3(CENP-A) at centromeres, and cell-cycle delays ensue. Once recruited to centromeres, HJURP functions to promote CenH3(CENP-A) deposition by a mechanism involving a unique DNA-binding domain. With our findings, we propose a model wherein (1) the phosphorylation state of HJURP controls its centromeric recruitment in a cell-cycle-dependent manner, and (2) HJURP binding to DNA is a mechanistic determinant in CenH3(CENP-A) loading., (Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Taekwondo (TKD) is a combat sport, which has also been proposed as a fitness program, with a strong anaerobic component. Creatine (Cr) supplementation is used to improve both anaerobic exercise performance and body composition. Therefore, Cr supplementation could be beneficial in TKD., Aims: To determine the effect of Cr supplementation (50 mg/kg body wt) on body composition, anaerobic power and blood chemistry in young male TKD practitioners., Methods: Ten male TKD practitioners (age [20 ± 2 yr], height [1.69 ± 0.06 m], and mass [67 ± 9.8 kg]) participated in a placebo-controlled, double blind, crossover study. Body composition (DEXA), anaerobic power (Wingate Test), blood lactate and blood chemistry were measured before and after supplementation. Differences between data before and after supplementation were calculated for each treatment (Cr and Placebo) and were compared using the Wilcoxon signed-rank test., Results: Fat mass (kg) decreased after placebo (Mdn [IqR] = -0.75 [-1.44 to 0.03]) and increased following Cr intake (0.17 [-0.77 to 1.13] kg) (Z = 2.191, p < 0.028, r = 0.49). Serum triglyceride concentration (mg/mL) increased after Cr (45.00 [-7.50 to 75.00]) and decrease with placebo (-7.00 [-10.75 to 12.00]) (Z = 2.090, p < 0.037, r = 0.47). No changes were found in others parameters., Conclusion: Cr supplementation may increase fat mass and serum triglycerides concentration in young male TKD practitioners without improvement in anaerobic power. Cr supplementation appears to be safe, but athletes should be careful when they want to loss fat., (Copyright © AULA MEDICA EDICIONES 2013. Published by AULA MEDICA. All rights reserved.)

Defects in the nuclear envelope or nuclear 'lamina' networks cause disease and can perturb histone posttranslational (epigenetic) regulation. Barrier-to-Autointegration Factor (BAF) is an essential but enigmatic lamina component that binds lamins, LEM-domain proteins, DNA and histone H3 directly. We report that BAF copurified with nuclease-digested mononucleosomes and associated with modified histones in vivo. BAF overexpression significantly reduced global histone H3 acetylation by 18%. In cells that stably overexpressed BAF 3-fold, silencing mark H3-K27-Me1/3 and active marks H4-K16-Ac and H4-Ac5 decreased significantly. Significant increases were also seen for silencing mark H3-K9-Me3, active marks H3-K4-Me2, H3-K9/K14-Ac and H4-K5-Ac and a mark (H3-K79-Me2) associated with both active and silent chromatin. Other increases (H3-S10-P, H3-S28-P and silencing mark H3-K9-Me2) did not reach statistical significance. BAF overexpression also significantly influenced cell cycle distribution. Moreover, BAF associated in vivo with SET/I2PP2A (protein phosphatase 2A inhibitor; blocks H3 dephosphorylation) and G9a (H3-K9 methyltransferase), but showed no detectable association with HDAC1 or HATs. These findings reveal BAF as a novel epigenetic regulator and are discussed in relation to BAF deficiency phenotypes, which include a hereditary progeria syndrome and loss of pluripotency in embryonic stem cells.

Classical heterochromatin chromosomal landmarks, such as centromeres and telomeres, are characterized by specific chromatin signatures. Among these, the incorporation of histone variants has recently emerged as an important feature. Using the centromere as a paradigm, we consider the role of histone variant dynamics in locus-specific chromatin organization. We describe the distinct location and dynamics of CenH3, H3.3, and H2AZ at the centromere during the cell cycle. This leads us to present the current view concerning modes of incorporation at this chromosomal landmark. Finally, we highlight the importance of histone variants in the crosstalk between centric and pericentric domains for maintaining centromere identity., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

HP1 enrichment at pericentric heterochromatin is considered important for centromere function. Although HP1 binding to H3K9me3 can explain its accumulation at pericentric heterochromatin, how it is initially targeted there remains unclear. Here, in mouse cells, we reveal the presence of long nuclear noncoding transcripts corresponding to major satellite repeats at the periphery of pericentric heterochromatin. Furthermore, we find that major transcripts in the forward orientation specifically associate with SUMO-modified HP1 proteins. We identified this modification as SUMO-1 and mapped it in the hinge domain of HP1α. Notably, the hinge domain and its SUMOylation proved critical to promote the initial targeting of HP1α to pericentric domains using de novo localization assays, whereas they are dispensable for maintenance of HP1 domains. We propose that SUMO-HP1, through a specific association with major forward transcript, is guided at the pericentric heterochromatin domain to seed further HP1 localization.

Background: Current data on bronchiectasis prevalence, trends, and risk factors are lacking; such data are needed to estimate the burden of disease and for improved medical care and public health resource allocation. The objective of the present study was to estimate the trends and burden of bronchiectasis-associated hospitalizations in the United States., Methods: We extracted hospital discharge records containing International Classification of Diseases, 9th Revision, Clinical Modification codes for bronchiectasis (494, 494.0, and 494.1) as any discharge diagnosis from the State Inpatient Databases from the Agency for Healthcare Research and Quality. Discharge records were extracted for 12 states with complete and continuous reporting from 1993 to 2006., Results: The average annual age-adjusted hospitalization rate from 1993 to 2006 was 16.5 hospitalizations per 100,000 population. From 1993 to 2006, the age-adjusted rate increased significantly, with an average annual percentage increase of 2.4% among men and 3.0% among women. Women and persons aged > 60 years had the highest rate of bronchiectasis-associated hospitalizations. The median cost for inpatient care was 7,827 US dollars (USD) (range, 13-543,914 USD)., Conclusions: The average annual age-adjusted rate of bronchiectasis-associated hospitalizations increased from 1993 to 2006. This study furthers the understanding of the impact of bronchiectasis and demonstrates the need for further research to identify risk factors and reasons for the increasing burden.

Rationale: Single-site clinic-based studies suggest an increasing prevalence of pulmonary nontuberculous mycobacteria (NTM) disease, but systematic data are lacking., Objectives: To describe prevalence and trends for NTM lung disease at four geographically diverse integrated heath care delivery systems in the United States., Methods: We abstracted mycobacterial culture results from electronic laboratory databases and linked to other datasets containing clinical and demographic information. Possible cases were defined as a single positive NTM pulmonary isolate, and definite cases were defined as two positive sputum cultures, or one positive culture from a bronchoalveolar lavage or lung biopsy. Annual prevalence was calculated using United States census data; average annual prevalence is presented for 2004-2006. Poisson regression models were used to estimate the annual percent change in prevalence., Measurements and Main Results: A total of 28,697 samples from 7,940 patients were included in the analysis. Of these, 3,988 (50%) were defined as possible cases, and 1,865 (47%) of these were defined as definite cases. Average annual (2004-2006) site-specific prevalence ranged from 1.4 to 6.6 per 100,000. Prevalence was 1.l- to 1.6-fold higher among women relative to men across sites. The prevalence of NTM lung disease was increasing significantly at the two sites where trends were studied, by 2.6% per year among women and 2.9% per year among men. Among persons aged greater than or equal to 60 years, annual prevalence increased from 19.6 per 100,000 during 1994-1996 to 26.7 per 100,000 during 2004-2006., Conclusions: The epidemiology of nontuberculous mycobacterial lung disease is changing, with a predominance of women and increasing prevalence at the sites studied.

Nuclear lamin filaments and associated proteins form a nucleoskeletal ("lamina") network required for transcription, replication, chromatin organization and epigenetic regulation in metazoans. Lamina defects cause human disease ("laminopathies") and are linked to aging. Barrier-to-autointegration factor (BAF) is a mobile and essential component of the nuclear lamina that binds directly to histones, lamins and LEM-domain proteins, including the inner nuclear membrane protein emerin, and has roles in chromatin structure, mitosis and gene regulation. To understand BAF's mechanisms of action, BAF associated proteins were affinity-purified from HeLa cell nuclear lysates using BAF-conjugated beads, and identified by tandem mass spectrometry or independently identified and quantified using the iTRAQ method. We recovered A- and B-type lamins and core histones, all known to bind BAF directly, plus four human transcription factors (Requiem, NonO, p15, LEDGF), disease-linked proteins (e.g., Huntingtin, Treacle) and several proteins and enzymes that regulate chromatin. Association with endogenous BAF was independently validated by co-immunoprecipitation from HeLa cells for seven candidates including Requiem, poly(ADP-ribose) polymerase 1 (PARP1), retinoblastoma binding protein 4 (RBBP4), damage-specific DNA binding protein 1 (DDB1) and DDB2. Interestingly, endogenous BAF and emerin each associated with DDB2 and CUL4A in a UV- and time-dependent manner, suggesting BAF and emerin have dynamic roles in genome integrity and might help couple DNA damage responses to the nuclear lamina network. We conclude this proteome is a rich source of candidate partners for BAF and potentially also A- and B-type lamins, which may reveal how chromatin regulation and genome integrity are linked to nuclear structure.

We study the effect of folding ridges on the scaling properties of randomly crumpled sheets of different kinds of paper in the folded and unfolded states. We found that the mean ridge length scales with the sheet size with the scaling exponent mu determined by the competition between bending and stretching deformations in the folded sheet. This scaling determines the mass fractal dimension of randomly folded balls D{M}=2/mu. We also found that surfaces of crumpled balls, as well as unfolded sheets, both display self-affine invariance with zeta=nu{ph}, if mu < or =nu{ph} , where nu{ph}=34 is the size exponent for crumpled phantom membrane, or both exhibit an intrinsically anomalous roughness characterized by the universal local roughness exponent zeta=0.72+/-0.04 and the material dependent global roughness exponent alpha=mu, when mu>nu{ph}. The physical implications of these findings are discussed.