Correlation between breast cancer subtypes determined by immunohistochemistry and n-COUNTER PAM50 assay: a real-world study.

PURPOSE: Molecular subtyping based on gene expression profiling (i.e., PAM50 assay) aids in determining the prognosis and treatment of breast cancer (BC), particularly in hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative tumors, where luminal A and B subtypes have different prognoses and treatments. Several surrogate classifications have been proposed for distinguishing between the luminal A and B subtypes. This study determines the accuracy of local immunohistochemistry (IHC) techniques for classifying HR-positive/HER2-negative (HR+/HER2-) tumors according to intrinsic subtypes using the nCOUNTER PAM50 assay as reference and the HR status definition according the ASCO/CAP recommendations. METHODS: Molecular subtypes resulting from nCOUNTER PAM50 performed in our laboratory between 2014 and 2020 were correlated with three different proxy surrogates proposed in the literature based on ER, PR, HER2, and Ki67 expression with different cut-off values. Concordance was measured using the level of agreement and kappa statistics. RESULTS: From 1049 samples with the nCOUNTER test, 679 and 350 were luminal A and B subtypes, respectively. Only a poor-to-fair correlation was observed between the three proxy surrogates and real genomic subtypes as determined by nCOUNTER PAM50. Moreover, 5-11% and 18-36% of the nCOUNTER PAM50 luminal B and A tumors were classified as luminal A and B, respectively, by these surrogates. CONCLUSION: The concordance between luminal subtypes determined by three different IHC-based classifiers and the nCOUNTER PAM50 assay was suboptimal. Thus, a significant proportion of luminal A and B tumors as determined by the surrogate classifiers could be undertreated or over-treated.

MYH10 activation rescues contractile defects in arrhythmogenic cardiomyopathy (ACM).

The most prevalent genetic form of inherited arrhythmogenic cardiomyopathy (ACM) is caused by mutations in desmosomal plakophilin-2 (PKP2). By studying pathogenic deletion mutations in the desmosomal protein PKP2, here we identify a general mechanism by which PKP2 delocalization restricts actomyosin network organization and cardiac sarcomeric contraction in this untreatable disease. Computational modeling of PKP2 variants reveals that the carboxy-terminal (CT) domain is required for N-terminal domain stabilization, which determines PKP2 cortical localization and function. In mutant PKP2 cells the expression of the interacting protein MYH10 rescues actomyosin disorganization. Conversely, dominant-negative MYH10 mutant expression mimics the pathogenic CT-deletion PKP2 mutant causing actin network abnormalities and right ventricle systolic dysfunction. A chemical activator of non-muscle myosins, 4-hydroxyacetophenone (4-HAP), also restores normal contractility. Our findings demonstrate that activation of MYH10 corrects the deleterious effect of PKP2 mutant over systolic cardiac contraction, with potential implications for ACM therapy.

Study of SARS-CoV-2 in semen from asymptomatic donors with the presence of virus in nasopharyngeal swabs.

RESEARCH QUESTION: Is severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) present in semen samples from asymptomatic donors who have positive virus results from nasopharyngeal swabs? DESIGN: Nasopharyngeal PCR was performed on 1943 sperm donors between January 2021 and March 2022. The result was positive for 140 donations, and the presence of SARS-CoV-2 could be studied in cryopreserved semen from 84 of these donors. This included 67 participants in whom the quality of fresh semen could be compared with the previous donation, the day of the PCR-positive nasopharyngeal sampling and the first subsequent donation. Semen donations were cryopreserved following total semen (n = 26) or ready-to-use (n = 58) protocols. The presence of SARS-CoV-2 in cryopreserved samples was determined by reverse transcription PCR. Semen quality (volume, concentration and progressive motility) was evaluated in accordance with World Health Organization 2010 recommendations. RESULTS: SARS-CoV-2 virus was not detected in any cryopreserved total semen or ready-to-use samples. No significant differences in semen volume, concentration or progressive motility were observed between the last previous donation, the day of the positive PCR nasopharyngeal sampling and the first subsequent donation. CONCLUSIONS: The lack of detection of SARS-CoV-2 in semen samples from asymptomatic individuals infected with SARS-CoV-2 supports the safety of assisted human reproduction treatments using this type of sample.

Assessment of a Genomic Assay in Patients With ERBB2-Positive Breast Cancer Following Neoadjuvant Trastuzumab-Based Chemotherapy With or Without Pertuzumab.

Importance: Biomarkers to guide the use of pertuzumab in the treatment of early-stage ERBB2 (formerly HER2)-positive breast cancer beyond simple ERBB2 status are needed. Objective: To determine if use of the HER2DX genomic assay (Reveal Genomics) in pretreatment baseline tissue samples of patients with ERBB2-positive breast cancer is associated with response to neoadjuvant trastuzumab-based chemotherapy with or without pertuzumab. Design, Setting, and Participants: This is a retrospective diagnostic/prognostic analysis of a multicenter academic observational study in Spain performed during 2018 to 2022 (GOM-HGUGM-2018-05). In addition, a combined analysis with 2 previously reported trials of neoadjuvant cohorts with results from the assay (DAPHNe and I-SPY2) was performed. All patients had stage I to III ERBB2-positive breast cancer, signed informed consent, and had available formalin-fixed paraffin-embedded tumor specimens obtained prior to starting therapy. Exposures: Patients received intravenous trastuzumab, 8 mg/kg, loading dose, followed by 6 mg/kg every 3 weeks in combination with intravenous docetaxel, 75 mg/m2, every 3 weeks and intravenous carboplatin area under the curve of 6 every 3 weeks for 6 cycles, or this regimen plus intravenous pertuzumab, 840 mg, loading dose, followed by an intravenous 420-mg dose every 3 weeks for 6 cycles. Main Outcome and Measures: Association of baseline assay-reported pathologic complete response (pCR) score with pCR in the breast and axilla, as well as association of baseline assay-reported pCR score with response to pertuzumab. Results: The assay was evaluated in 155 patients with ERBB2-positive breast cancer (mean [range] age, 50.3 [26-78] years). Clinical T1 to T2 and node-positive disease was present in 113 (72.9%) and 99 (63.9%) patients, respectively, and 105 (67.7%) tumors were hormone receptor positive. The overall pCR rate was 57.4% (95% CI, 49.2%-65.2%). The proportion of patients in the assay-reported pCR-low, pCR-medium, and pCR-high groups was 53 (34.2%), 54 (34.8%), and 48 (31.0%), respectively. In the multivariable analysis, the assay-reported pCR score (as a continuous variable from 0-100) showed a statistically significant association with pCR (odds ratio [OR] per 10-unit increase, 1.43; 95% CI, 1.22-1.70; P < .001). The pCR rates in the assay-reported pCR-high and pCR-low groups were 75.0% and 28.3%, respectively (OR, 7.85; 95% CI, 2.67-24.91; P < .001). In the combined analysis (n = 282), an increase in pCR rate due to pertuzumab was found in the assay-reported pCR-high tumors (OR, 5.36; 95% CI, 1.89-15.20; P < .001) but not in the assay-reported pCR-low tumors (OR, 0.86; 95% CI, 0.30-2.46; P = .77). A statistically significant interaction between the assay-reported pCR score and the effect of pertuzumab in pCR was observed. Conclusions and Relevance: This diagnostic/prognostic study demonstrated that the genomic assay predicted pCR following neoadjuvant trastuzumab-based chemotherapy with or without pertuzumab. This assay could guide therapeutic decisions regarding the use of neoadjuvant pertuzumab.

Design and Implementation of a Nationwide Population-Based Longitudinal Survey of SARS-CoV-2 Infection in Spain: The ENE-COVID Study.

Data System. The Spanish National Seroepidemiological Survey of SARS-CoV-2 (or ENE-COVID; SARS-CoV-2 [severe acute respiratory syndrome coronavirus 2] is the causative agent of COVID-19) was funded by the Spanish Ministry of Health, the Instituto de Salud Carlos III, and the Spanish National Health System. Data Collection/Processing. A stratified 2-stage probability sampling was used to select a representative cohort of the noninstitutionalized population of Spain. ENE-COVID collected longitudinal data from epidemiological questionnaires and 2 SARS-CoV-2 IgG antibody tests. From April 27 to June 22, 2020, 68 287 participants (77.0% of contacted persons) received a point-of-care test and 61 095 (68.9%) also underwent a laboratory immunoassay. A second follow-up phase was conducted between November 16 and 30, 2020. Data Analysis/Dissemination. Analyses use weights to adjust for oversampling and nonresponse and account for design effects of stratification and clustering. ENE-COVID data for research purposes will be available upon request from the official study Web page. Public Health Implications. ENE-COVID, a nationwide population-based study, allowed monitoring seroprevalence of antibodies against SARS-CoV-2 at the national and regional levels, providing accurate figures by gender, age (from babies to nonagenarians), and selected risk factors; characterizing symptomatic and asymptomatic infections; and estimating the infection fatality risk during the first pandemic wave. (Am J Public Health. 2023;113(5):525-532. https://doi.org/10.2105/AJPH.2022.307167).

Monkeypox and HIV in the Canary Islands: A Different Pattern in a Mobile Population.

BACKGROUND: The clinical and epidemiological data of the recent outbreak of monkeypox (MPX) differ from previous reports. One difference is the epidemiological profile; the disease mainly affects a subgroup of MSM (men who have sex with men) with high-risk sexual behaviors, frequently persons living with human immunodeficiency virus (PLHIV). METHODS: In this observational analysis, all patients with PCR (polymerase chain reaction)-confirmed MPX attending an Infectious Diseases and Tropical Medicine Unit in Gran Canaria (Spain) between May and July 2022 were considered. RESULTS: In total, 42 men were included; 88% were identified as MSM, with a median age of 40 years. Only 43% were born in Spain. All the patients had systemic symptoms and skin lesions. The distribution of lesions was more frequent in the genital/anal region, and the involvement of hands and feet was less common. Fever and lymphadenopathies were less frequent than in other series. Other unusual manifestations were proctitis, pharyngitis and penile-scrotal edema. Half of the patients had other associated infections (mainly STIs, sexually transmitted infections), and 60% of the monkeypox patients had PLHIV (People Living with HIV). When comparing the clinical characteristics between HIV-positive and -negative patients, we found three main differences: (i) a higher frequency of perioral lesions, (ii) a higher frequency of pharyngitis and (iii) a higher number of sexually transmitted infections in HIV-positive patients. CONCLUSIONS: The clinical findings in this outbreak of MPX had great variability in presentation. Several clinical differences were found in PLHIV-coinfected patients.

Role of Fibular Allograft in Proximal Humerus Fractures: A Systematic Review.

OBJECTIVES: To analyze the outcomes and complication rates of fibular allografts (FA) as an augmentation technique for proximal humeral fractures and determine their appropriate indications. DATA SOURCES: English- and Spanish-language articles in PubMed, MEDLINE, Embase, Web of Science (Core Collection), and Google Scholar databases were systematically reviewed with the Preferred Reporting Items for Systematic Reviews guidelines on April 10, 2020. STUDY SELECTION: Studies of patients with proximal humeral fractures treated primarily with FA and locking compression plates and with a minimum follow-up of 6 months were included, and presenting results with standardized clinical scales, radiological values, and operative complications. DATA EXTRACTION: Two authors independently extracted data from the selected studies with a standardized data collection form. Subsequently, each extracted data set was consolidated on the agreement of authors. DATA SYNTHESIS: From the initial screening of 361 articles, 5 case series and 6 retrospective cohort studies were included. A meta-analysis was not performed. CONCLUSIONS: FA improved the clinical and radiological results, thereby reducing complications. The optimal indication for this procedure may be a 4-part fracture with medial column disruption in younger adults. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

[COVID-19 impact on substance use and behaviors with addictive potential: Spanish Observatory on Drugs and Addictions survey.] / Impacto COVID-19 en el consumo de sustancias y comportamientos con potencial adictivo: encuesta del Observatorio Español de las Drogas y Adicciones.

The Covid-19 pandemic and the measures adopted for its control have had a significant impact, both in and at health, social and personal levels. The Spanish Observatory of Drugs and Addictions designed a survey to study the change in the pattern of consumption of psychoactive substances and other behaviors with addictive potential, such as the use of the Internet and gambling with money, in the Spanish population during the pandemic COVID-19. A random sample of 7,886 people aged 15 to 64 was interviewed by a telephone survey. The results show a decrease in the consumption of alcohol, tobacco and cannabis and non-internet gambling, along with an increase in the use of non-prescription hypnosedatives and the number of hours spent using the internet for recreational purposes, while online gambling remained unchanged. This overall decline in use occurs in a context of reduced access to illicit drugs, a consequence of the control measures adopted in the COVID-19 pandemic in Spain. The control measures also affected leisure environments, and this has possibly contributed to the changes observed, especially in heavy episodic alcohol consumption among young people, showing the impact of environmental prevention in tackling this problem.

La pandemia por Covid-19 y las medidas adoptadas para su control han supuesto un importante impacto, tanto sanitario como social y personal, a todos los niveles. El Observatorio Español de las Drogas y las Adicciones diseñó una encuesta para estudiar el cambio en el patrón de consumo de sustancias psicoactivas y otras conductas con potencial adictivo, como el uso de internet y el juego con dinero, en la población española durante la pandemia por Covid-19. Se realizó una encuesta telefónica sobre una muestra de 7.886 personas de 15 a 64 años representativa a nivel nacional. Los resultados muestran un descenso del consumo de alcohol, tabaco, cannabis y juego con dinero presencial, que contrasta con un aumento del consumo de hipnosedantes sin receta y del número de horas dedicado al uso de internet por diversión, mientras que el juego online permaneció sin cambios. El descenso generalizado de los consumos se ha producido en un contexto de diminución del acceso a las drogas ilegales, consecuencia de las medidas adoptadas para el control de la pandemia por COVID-19. Estas afectaron a los entornos de ocio lo que, posiblemente, ha contribuido a los cambios observados, en especial en los consumos intensivos de alcohol en jóvenes, sugiriendo la relevancia de las medidas de prevención ambiental en el abordaje de este problema.

Biochar ageing in polluted soils and trace elements immobilisation in a 2-year field experiment.

Biochar application to soils has become a focus of research during the last decade due to its high potential for C sequestration. Nevertheless, there is no exhaustive information on the long-term effects of biochar application in soils contaminated with trace elements. In this work, a 2-year field experiment was conducted comprising the application of different types of biochar to acidic and moderately acidic soils with high concentrations of As, Cu, Pb, Ba and Zn. In addition, representative samples of each biochar were buried in permeable bags that allowed the flow of water and microorganisms but not their physical interaction with soil aggregates. The biochars significantly adsorbed trace elements from polluted soils. However, given the high total concentration of these persistent trace elements in the soils, the application of biochars did not succeed in reducing the concentration of available metals (CaCl2 extractable fraction). After 2 years of ageing under field conditions, some degradation of the biochars from olive pit, rice husk and wood were observed. This study provides novel information concerning the biochar alterations during ageing in polluted soils, as the decrease of aryl C signal observed by 13C nuclear magnetic resonance (NMR) spectroscopy and the presence of O-containing groups shown by Fourier Transform mid-Infrared Spectroscopy (FT-IR) in aged biochar which enhanced trace elements adsorption. Scanning electron microscopy (SEM) revealed slight changes on surface morphology of aged biochar particles.

Sustained Elevated Blood Pressure Accelerates Atherosclerosis Development in a Preclinical Model of Disease.

The continuous relationship between blood pressure (BP) and cardiovascular events makes the distinction between elevated BP and hypertension based on arbitrary cut-off values for BP. Even mild BP elevations manifesting as high-normal BP have been associated with cardiovascular risk. We hypothesize that persistent elevated BP increases atherosclerotic plaque development. To evaluate this causal link, we developed a new mouse model of elevated BP based on adeno-associated virus (AAV) gene transfer. We constructed AAV vectors to support transfer of the hRenin and hAngiotensinogen genes. A single injection of AAV-Ren/Ang (1011 total viral particles) induced sustained systolic BP increase (130 ± 20 mmHg, vs. 110 ± 15 mmHg in controls; p = 0.05). In ApoE-/- mice, AAV-induced mild BP elevation caused larger atherosclerotic lesions evaluated by histology (10-fold increase vs. normotensive controls). In this preclinical model, atheroma plaques development was attenuated by BP control with a calcium channel blocker, indicating that a small increase in BP within a physiological range has a substantial impact on plaque development in a preclinical model of atherosclerosis. These data support that non-optimal BP represents a risk for atherosclerosis development. Earlier intervention in elevated BP may prevent or delay morbidity and mortality associated with atherosclerosis.

A Network of Macrophages Supports Mitochondrial Homeostasis in the Heart.

Cardiomyocytes are subjected to the intense mechanical stress and metabolic demands of the beating heart. It is unclear whether these cells, which are long-lived and rarely renew, manage to preserve homeostasis on their own. While analyzing macrophages lodged within the healthy myocardium, we discovered that they actively took up material, including mitochondria, derived from cardiomyocytes. Cardiomyocytes ejected dysfunctional mitochondria and other cargo in dedicated membranous particles reminiscent of neural exophers, through a process driven by the cardiomyocyte's autophagy machinery that was enhanced during cardiac stress. Depletion of cardiac macrophages or deficiency in the phagocytic receptor Mertk resulted in defective elimination of mitochondria from the myocardial tissue, activation of the inflammasome, impaired autophagy, accumulation of anomalous mitochondria in cardiomyocytes, metabolic alterations, and ventricular dysfunction. Thus, we identify an immune-parenchymal pair in the murine heart that enables transfer of unfit material to preserve metabolic stability and organ function. VIDEO ABSTRACT.

Carriers of cystic fibrosis among sperm donors: complete CFTR gene analysis versus CFTR genotyping.

OBJECTIVE: To determine the frequency of cystic fibrosis (CF) carriers among sperm donors in Spain studied through a complete analysis of the CFTR gene and to compare the results with those that would have been obtained by the 4 genotyping panels of the CFTR gene most commonly used as a carrier test in the context of assisted reproduction in our country. DESIGN: Descriptive observational study. SETTING: Private center. PATIENTS: Nine hundred thirty-five sperm donors, from January 2014 to June 2019. INTERVENTION: None. MAIN OUTCOME MEASURE: Presence of pathogenic variants in the CFTR gene. RESULTS: 17% of the donors were carriers of at least 1 pathogenic variant in CFTR, with 39 different pathogenic variants detected. Only 4 of these 39 variants (10.27%) would have been detected by the 4 genotyping tests considered, and 22 variants (56.41%) would not have been detected by any of the genotyping tests. The pathogenic variants of the CFTR gene included in the different genotyping tests analyzed vary widely, and <50% are common to all of them. CONCLUSIONS: Although the was not based in the general population, these results show that the use of genotyping tests is associated with a high reproductive risk, because the rate of detection of CF carriers was lower when these panels were applied, in comparison with the complete study of the CFTR gene. We recommend that complete sequencing of the CFTR gene by next-generation sequencing be performed as a screening method for CF in sperm donors.

Prevalence of SARS-CoV-2 in Spain (ENE-COVID): a nationwide, population-based seroepidemiological study.

BACKGROUND: Spain is one of the European countries most affected by the COVID-19 pandemic. Serological surveys are a valuable tool to assess the extent of the epidemic, given the existence of asymptomatic cases and little access to diagnostic tests. This nationwide population-based study aims to estimate the seroprevalence of SARS-CoV-2 infection in Spain at national and regional level. METHODS: 35 883 households were selected from municipal rolls using two-stage random sampling stratified by province and municipality size, with all residents invited to participate. From April 27 to May 11, 2020, 61 075 participants (75·1% of all contacted individuals within selected households) answered a questionnaire on history of symptoms compatible with COVID-19 and risk factors, received a point-of-care antibody test, and, if agreed, donated a blood sample for additional testing with a chemiluminescent microparticle immunoassay. Prevalences of IgG antibodies were adjusted using sampling weights and post-stratification to allow for differences in non-response rates based on age group, sex, and census-tract income. Using results for both tests, we calculated a seroprevalence range maximising either specificity (positive for both tests) or sensitivity (positive for either test). FINDINGS: Seroprevalence was 5·0% (95% CI 4·7-5·4) by the point-of-care test and 4·6% (4·3-5·0) by immunoassay, with a specificity-sensitivity range of 3·7% (3·3-4·0; both tests positive) to 6·2% (5·8-6·6; either test positive), with no differences by sex and lower seroprevalence in children younger than 10 years (<3·1% by the point-of-care test). There was substantial geographical variability, with higher prevalence around Madrid (>10%) and lower in coastal areas (<3%). Seroprevalence among 195 participants with positive PCR more than 14 days before the study visit ranged from 87·6% (81·1-92·1; both tests positive) to 91·8% (86·3-95·3; either test positive). In 7273 individuals with anosmia or at least three symptoms, seroprevalence ranged from 15·3% (13·8-16·8) to 19·3% (17·7-21·0). Around a third of seropositive participants were asymptomatic, ranging from 21·9% (19·1-24·9) to 35·8% (33·1-38·5). Only 19·5% (16·3-23·2) of symptomatic participants who were seropositive by both the point-of-care test and immunoassay reported a previous PCR test. INTERPRETATION: The majority of the Spanish population is seronegative to SARS-CoV-2 infection, even in hotspot areas. Most PCR-confirmed cases have detectable antibodies, but a substantial proportion of people with symptoms compatible with COVID-19 did not have a PCR test and at least a third of infections determined by serology were asymptomatic. These results emphasise the need for maintaining public health measures to avoid a new epidemic wave. FUNDING: Spanish Ministry of Health, Institute of Health Carlos III, and Spanish National Health System.

The pharmaceutical solvent N-methyl-2-pyrollidone (NMP) attenuates inflammation through Krüppel-like factor 2 activation to reduce atherogenesis.

N-methyl-2-pyrrolidone (NMP) is a versatile water-miscible polar aprotic solvent. It is used as a drug solubilizer and penetration enhancer in human and animal, yet its bioactivity properties remain elusive. Here, we report that NMP is a bioactive anti-inflammatory compound well tolerated in vivo, that shows efficacy in reducing disease in a mouse model of atherosclerosis. Mechanistically, NMP increases the expression of the transcription factor Kruppel-like factor 2 (KLF2). Monocytes and endothelial cells treated with NMP express increased levels of KLF2, produce less pro-inflammatory cytokines and adhesion molecules. We found that NMP attenuates monocyte adhesion to endothelial cells inflamed with tumor necrosis factor alpha (TNF-α) by reducing expression of adhesion molecules. We further show using KLF2 shRNA that the inhibitory effect of NMP on endothelial inflammation and subsequent monocyte adhesion is KLF2 dependent. Enhancing KLF2 expression and activity improves endothelial function, controls multiple genes critical for inflammation, and prevents atherosclerosis. Our findings demonstrate a consistent effect of NMP upon KLF2 activation and inflammation, biological processes central to atherogenesis. Our data suggest that inclusion of bioactive solvent NMP in pharmaceutical compositions to treat inflammatory disorders might be beneficial and safe, in particular to treat diseases of the vascular system, such as atherosclerosis.

Influence of inorganic additives on wheat straw composting: Characterization and structural composition of organic matter derived from the process.

Metallic oxides and clay minerals have gained increasing interest as additives of composting due to their influence in greenhouse gas emissions reduction and their effectivity in the stabilization of carbon both in compost and soils, leading to a cleaner compost production and potentially C sequestrant amendments. In this study, wheat straw (WS) was co-composted with iron oxide and allophanic soil and their influence on WS composting and composition of the end-products was evaluated. WS compost and their humic like-substances (HS) fraction were characterized by chemical and spectroscopic analyzes. After 126 days of process, the elemental composition showed slight differences of the N content for compost and HS, where the C/N atomic ratio tended to decrease relative to the initial material (WS; ~130). This trend was more pronounced in the HS from co-composted treatments (<30). The addition of inorganic materials increased the total acidity and phenolic-OH group contents (~15 and 14 mEq g-1 respectively, iron oxide treatment) relative to the treatment without inorganic additives. Nevertheless, the FTIR and solid-state 13CNMR spectroscopy barely support the wet chemical analysis and revealed a similar final composition between all the studied compost treatments. These results suggest that the incorporation of these materials as compost additives had no major effect on the spectroscopic features of the end-products, however, critical changes of the properties such as the extractability, functionality and composition of HS were revealed by traditional methods. In conclusion, the supply of metal oxides and clays could impact the aerobic composting of WS favorizing the stabilization of certain C pools and adsorptive properties of the end-products, that is of importance in production of amendments suitable for being used in degraded and contaminated soils. Nevertheless, under the experimental conditions of our research C stabilization apparently depends of other mechanisms that still need to be elucidate.

NF-kB signaling in cardiomyocytes is inhibited by sevoflurane and promoted by propofol.

Both inhalational and intravenous anesthetics affect myocardial remodeling, but the precise effect of each anesthetic on molecular signaling in myocardial remodeling is unknown. Here, we performed in silico analysis to investigate signaling alterations in cardiomyocytes induced by inhalational [sevoflurane (Sevo)] and intravenous [propofol (Prop)] anesthetics. Bioinformatics analysis revealed that nuclear factor-kappa B (NF-kB) signaling was inhibited by Sevo and promoted by Prop. Moreover, nuclear accumulation of p65 and transcription of NF-kB-regulated genes were suppressed in Sevo-administered mice, suggesting that Sevo inhibits the NF-kB signaling pathway. Our data demonstrate that NF-kB signaling is inhibited by Sevo and promoted by Prop. As NF-kB signaling plays an important role in myocardial remodeling, our results suggest that anesthetics may affect myocardial remodeling through NF-kB.

Feasibility and safety of pulmonary vein isolation by high-power short-duration radiofrequency application: short-term results of the POWER-FAST PILOT study.

PURPOSE: Pulmonary vein (PV) isolation (PVI) by point-by-point radiofrequency application (PPRF) results in longer procedures than that achieved by single-shot ablation techniques. In addition, it is associated with significant risk of oesophageal injury. The POWER-FAST pilot study evaluated the feasibility and safety of PVI by high-power short-duration (HPSD) PPRF. METHODS: HPSD PPRF around the PVs was done in 48 consecutive patients with atrial fibrillation. Fifty watts was delivered until a predefined lesion index value was reached (LSI ≥ 5 or Abl-I ≥ 350) and 60 W during 7-10 s in the first 18 and last 30 patients, respectively. A control group of 47 consecutive patients who had undergone PVI before the HPSD group with conventional PPRF (30 W for 30 s) was included for reference. Echocardiography and oesophageal endoscopy was performed shortly after ablation in all patients. RESULTS: PVI of all targeted veins was achieved in 98% and 100% of patients of the conventional and HPSD groups, respectively (p = 0.59). Total radiofrequency time was 34 ± 11, 24 ± 8, and 15 ± 5 min in groups 30 W, 50 W, and 60 W (p < 0.001). Audible steam pops occurred in 4 out of 48 (8%) patients in the HPSD group, accounting for 4 (0.08%) out of 5 269 HPSD radiofrequency applications. No patient in the HPSD group developed pericardial effusion. The incidence of oesophageal lesions was 28%, 22%, and 0% in groups 30 W, 50 W, and 60 W, respectively (p = 0.007) CONCLUSIONS: PVI can be achieved with HPSD PPRF in most patients. This approach appears safe and associated with low risk of esophageal damage.

p38γ is essential for cell cycle progression and liver tumorigenesis.

The cell cycle is a tightly regulated process that is controlled by the conserved cyclin-dependent kinase (CDK)-cyclin protein complex1. However, control of the G0-to-G1 transition is not completely understood. Here we demonstrate that p38 MAPK gamma (p38γ) acts as a CDK-like kinase and thus cooperates with CDKs, regulating entry into the cell cycle. p38γ shares high sequence homology, inhibition sensitivity and substrate specificity with CDK family members. In mouse hepatocytes, p38γ induces proliferation after partial hepatectomy by promoting the phosphorylation of retinoblastoma tumour suppressor protein at known CDK target residues. Lack of p38γ or treatment with the p38γ inhibitor pirfenidone protects against the chemically induced formation of liver tumours. Furthermore, biopsies of human hepatocellular carcinoma show high expression of p38γ, suggesting that p38γ could be a therapeutic target in the treatment of this disease.

Sudden cardiac arrest as first symptom of a benign cardiac tumor growth / Muerte súbita como primer síntoma de crecimiento de tumor cardíaco benigno

Abstract Primary cardiac tumors are rare, especially in the pediatric age. Most of them are benign in the sense they are not invasive. However, benign tumors maintain the potential for serious illness related to significant hemodynamic compromise or life-threatening dysrhythmias. We present the case of an infant with an initial diagnosis of cardiac rhabdomyoma who suffered ventricular arrhythmia and cardiac arrest. He suffered irreversible severe neurologic sequelae, due to his prolonged cardiopulmonary arrest and was finally diagnosed of cardiac fibroma. Good arrhythmia control was obtained after an extensive partial surgical resection of the tumor. This case highlights the importance of arrhythmia burden in this condition. A correct diagnosis based essentially in different imaging modalities and closer clinical and rhythm follow up could have avoided this ominous event.

Resumen Los tumores cardíacos primarios son raros, especialmente en la edad pediátrica. La mayoría de ellos son benignos, en el sentido de que no son invasivos. Sin embargo, los tumores benignos tienen el potencial para producir enfermedades graves que pueden causar compromiso hemodinámico significativo o arritmias potencialmente letales. Se presenta el caso de un niño con un diagnóstico inicial de rabdomioma cardíaco, quien sufrió una arritmia ventricular y una parada cardíaca. Tuvo secuelas neurológicas severas irreversibles debido al tiempo prolongado en parada cardiorrespiratoria y se le diagnosticó finalmente fibroma cardíaco. Se obtuvo un buen control de las arritmias después de una extensa resección parcial del tumor. Este caso pretende subrayar la importancia del riesgo de aparición de arritmias en esta situación. El diagnóstico correcto basado fundamentalmente en el uso de distintas modalidades de imagen y el seguimiento clínico y arritmológico, podrían haber evitado este desenlace fatal.

Layer-By-Layer Self-Assembly of Polyelectrolytic Block Copolymer Worms on a Planar Substrate.

Cationic and anionic block copolymer worms are prepared by polymerization-induced self-assembly via reversible addition-fragmentation chain transfer (RAFT) aqueous dispersion copolymerization of 2-hydroxypropyl methacrylate and glycidyl methacrylate (GlyMA), using a binary mixture of a nonionic poly(ethylene oxide) macromolecular RAFT agent and either a cationic poly([2-(methacryloyloxy)ethyl]trimethylammonium chloride) or an anionic poly(potassium 3-sulfopropyl methacrylate) macromolecular RAFT agent. In each case, covalent stabilization of the worm cores was achieved via reaction of the epoxide groups on the GlyMA repeat units with 3-mercaptopropyltriethoxysilane. Aqueous electrophoresis studies indicated a pH-independent mean zeta potential of +40 mV and -39 mV for the cationic and anionic copolymer worms, respectively. These worms are expected to mimic the rigid rod behavior of water-soluble polyelectrolyte chains in the absence of added salt. The kinetics of adsorption of the cationic worms onto a planar anionic silicon wafer was examined at pH 5 and was found to be extremely fast at 1.0 w/w % copolymer concentration in the absence of added salt. Scanning electron microscopy (SEM) analysis indicated that a relatively constant worm surface coverage of 16% was achieved at 20 °C for adsorption times ranging from just 2 s up to 2 min. Furthermore, the successive layer-by-layer deposition of cationic and anionic copolymer worms onto planar surfaces was investigated using SEM, ellipsometry, and surface zeta potential measurements. These techniques confirmed that the deposition of oppositely charged worms resulted in a monotonic increase in the mean layer thickness, with a concomitant surface charge reversal occurring on addition of each new worm layer. Unexpectedly, two distinct linear regimes were observed when plotting the mean layer thickness against the total number of adsorbed worm layers, with a steeper gradient (corresponding to thicker layers) being observed after the deposition of six worm layers.