MMSET deregulation affects cell cycle progression and adhesion regulons in t(4;14) myeloma plasma cells

BackgroundThe recurrent immunoglobulin translocation, t(4;14)(p16;q32) occurs in 15% of multiple myeloma patients and is associated with poor prognosis, through an unknown mechanism. The t(4;14) up-regulates fibroblast growth factor receptor 3 (FGFR3) and multiple myeloma SET domain (MMSET) genes. The involvement of MMSET in the pathogenesis of t(4;14) multiple myeloma and the mechanism or genes deregulated by MMSET upregulation are still unclear.Design and MethodsThe expression of MMSET was analyzed using a novel antibody. The involvement of MMSET in t(4;14) myelomagenesis was assessed by small interfering RNA mediated knockdown combined with several biological assays. In addition, the differential gene expression of MMSET-induced knockdown was analyzed with expression microarrays. MMSET gene targets in primary patient material was analyzed by expression microarrays.ResultsWe found that MMSET isoforms are expressed in multiple myeloma cell lines, being exclusively up-regulated in t(4;14)-positive cells. Suppression of MMSET expression affected cell proliferation by both decreasing cell viability and cell cycle progression of cells with the t(4;14) translocation. These findings were associated with reduced expression of genes involved in the regulation of cell cycle progression (e.g. CCND2, CCNG1, BRCA1, AURKA and CHEK1), apoptosis (CASP1, CASP4 and FOXO3A) and cell adhesion (ADAM9 and DSG2). Furthermore, we identified genes involved in the latter processes that were differentially expressed in t(4;14) multiple myeloma patient samples.ConclusionsIn conclusion, dysregulation of MMSET affects the expression of several genes involved in the regulation of cell cycle progression, cell adhesion and survival.

Genometa - A Fast and Accurate Classifier for Short Metagenomic Shotgun Reads

Metagenomic studies use high-throughput sequence data to investigate microbial communities in situ. However, considerable challenges remain in the analysis of these data, particularly with regard to speed and reliable analysis of microbial species as opposed to higher level taxa such as phyla. We here present Genometa, a computationally undemanding graphical user interface program that enables identification of bacterial species and gene content from datasets generated by inexpensive high-throughput short read sequencing technologies. Our approach was first verified on two simulated metagenomic short read datasets, detecting 100% and 94% of the bacterial species included with few false positives or false negatives. Subsequent comparative benchmarking analysis against three popular metagenomic algorithms on an Illumina human gut dataset revealed Genometa to attribute the most reads to bacteria at species level (i.e. including all strains of that species) and demonstrate similar or better accuracy than the other programs. Lastly, speed was demonstrated to be many times that of BLAST due to the use of modern short read aligners. Our method is highly accurate if bacteria in the sample are represented by genomes in the reference sequence but cannot find species absent from the reference. This method is one of the most user-friendly and resource efficient approaches and is thus feasible for rapidly analysing millions of short reads on a personal computer.

Mothers’ perception of recovery and satisfaction with patent medicine dealers’ treatment of childhood febrile conditions in rural communities

Background Infant mortality in rural areas of Nigeria can be minimized if childhood febrile conditions are treated by trained health personnel, deployed to primary healthcare centres (PHCs) rather than the observed preference of mothers for patent medicine dealers (PMDs). However, health service utilization/patronage is driven by consumer satisfaction and perception of services/product value. The objective of this study was to determine ‘mothers’ perception of recovery’ and ‘mothers’ satisfaction’ after PMD treatment of childhood febrile conditions, as likely drivers of mothers’ health-seeking behaviour, which must be targeted to reverse the trend. Methods Ugwuogo-Nike, in Enugu, Nigeria, has many PMDs/PHCs, and was selected based on high prevalence of childhood febrile conditions. In total, 385 consenting mothers (aged 15–45 years) were consecutively recruited at PMD shops, after purchasing drugs for childhood febrile conditions, in a cross-sectional observational study using a pre-tested instrument; 33 of them (aged 21–47 years) participated in focus group discussions (FGDs). Qualitative data were thematically analysed while a quantitative study was analysed with Z score and Chi square statistics, at p < 0.05. Results Most participants in FGDs perceived that their child had delayed recovery, but were satisfied with PMDs’ treatment of childhood febrile conditions, for reasons that included politeness, caring attitude, drug availability, easy accessibility, flexibility in pricing, shorter waiting time, their God-fearing nature, and disposition as good listeners. Mothers’ satisfaction with PMDs’ treatment is significantly (p < 0.05) associated with mothers’ perception of recovery of their child (χ2 = 192.94, df = 4; p < 0.0001; Cramer’s V = 0.7079). However, predicting mothers’ satisfaction with PMDs’ treatment from a knowledge of mothers’ perception of recovery shows a high accord (lambda[A from B] = 0.8727), unlike when predicting mothers’ perception of recovery based on knowledge of mothers’ satisfaction with PMDs’ treatment (lambda[A from B] = 0.4727). Conclusions Mothers’ satisfaction could be the key ‘driver’ of mothers’ health-seeking behaviour and is less likely to be influenced by mothers’ perception of recovery of their child. Therefore, mothers’ negative perception of their child’s recovery may not induce proportionate decline in mothers’ health-seeking behaviour (patronage of PMDs), which might be influenced mainly by mothers’ satisfaction with the positive attributes of PMDs’ personality/practice and sets an important agenda for PHC reforms.

N=4 supersymmetric AdS(5) vacua and their moduli spaces

We classify the N = 4 supersymmetric AdS(5) backgrounds that arise as solutions of five-dimensional N = 4 gauged supergravity. We express our results in terms of the allowed embedding tensor components and identify the structure of the associated gauge groups. We show that the moduli space of these AdS vacua is of the form SU(1, m)/ (U(1) x SU(m)) and discuss our results regarding holographically dual N = 2 SCFTs and their conformal manifolds.

Symmetry reduction due to gallium substitution in the garnet Li6.43(2)Ga0.52(3)La2.67(4)Zr2O12

Single-crystal structure refinements on lithium lanthanum zirconate (LLZO; Li7La3Zr2O12) substituted with gallium were successfully carried out in the cubic symmetry space group I [Formula: see text]3d. Gallium was found on two lithium sites as well as on the lanthanum position. Due to the structural distortion of the resulting Li6.43(2)Ga0.52(3)La2.67(4)Zr2O12 (Ga-LLZO) single crystals, a reduction of the LLZO cubic garnet symmetry from Ia[Formula: see text] d to I [Formula: see text]3d was necessary, which could hardly be analysed from X-ray powder diffraction data.

Síntese de novas 3,4-diidropirimidin-2(1H)-onas graxas e estudo da atividade antitumoral

Neste trabalho foi realizada a síntese de novas 3,4-diidropirimidinonas funcionalizadas com diferentes cadeias graxas. Para a síntese destes compostos os β-cetoésteres graxos foram obtidos a partir da transesterificação do acetoacetato de metila na presença dos álcoois palmítico (2a), esteárico (2b) e oleico (2c), utilizando como catalisador I2 e ácido sulfâmico (NH3SO3). Os compostos foram obtidos com rendimentos de 97%, 90% e 60%, respectivamente. Após, a reação multicomponente de Biginelli foi realizada na presença de InCl3 utilizando os β- cetoésteres graxos 3a-c, os aldeídos aromáticos, benzaldeído, 3-hidroxi benzaldeído e 4-dimetilaminobenzaldeído, na presença de uréia ou tiouréia, levando às 3,4- diidropirimidinonas graxas 5-substituídas 6-11a-c em rendimentos que variaram entre 60–94%. Todos os compostos, ainda inéditos na literatura, foram caracterizados por espectroscopia de infravermelho (IV) e ressonância magnética nuclear de hidrogênio (RMN ¹H) e carbono (RMN ¹³C). A análise do efeito das novas 3,4-diidropirimidin-2(1H)-onas graxas pelo método do MTT na linhagem de glioma C6 rato e UG-138 humana demonstrou uma maior diminuição da viabilidade celular para os compostos graxos contendo as cadeias palmítica e oleica derivados da tiouréia e do 3-hidroxi benzaldeído, respectivamente. Comportamento semelhante foi observado para os compostos contendo as cadeias palmítica e oleica, porém derivados da uréia. Uma diminuição significativa da viabilidade celular, porém em menor grau, foi observada para os compostos graxos contendo as cadeias palmítica e oleica derivados da uréia e do benzaldeído. Os resultados mostraram até o momento que os derivados graxos contendo a cadeia oleica na posição 5 do anel diidropirimídinico derivado do 3- hidroxi benzaldeído e da tiouréia apresentaram maior atividade na diminuição da viabilidade celular de linhagem de glioma.

Efectividad de la deslaminación mecánica con bisturí en la eliminación de helomas e hiperqueratosis

Introducción El motivo principal por el que acuden los pacientes a las consultas de podología es el dolor producido por los callos y callosidades plantares. El dolor producido por las callosidades y callos plantares provocan en el paciente cambios de presiones y alteraciones en el apoyo, dificultando la deambulación correcta. Existen numerosos estudios sobre la eliminación de callosidades en pacientes diabéticos, con AR, pero pocos en personas sanas. La eliminación de estos callos y callosidades se puede realizar mediante deslaminación mecánica con bisturí o mediante queratolíticos. Objetivos Objetivo principal Analizar el efecto de la deslaminación mecánica con bisturí de las callosidades y callos plantares sobre el dolor y la calidad de vida en sujetos sanos Objetivos secundarios Determinar la existencia de modificaciones en los parámetros de la marcha con la eliminación de callosidades y callos plantares Observar las diferencias y efectividad de tratamientos de la eliminación de callosidades plantares mediante la técnica de deslaminación mecánica con bisturí versus parches de ácido salicílico Comprobar los cambios producidos en los parámetros psíquicos y fiscos del paciente antes y después de las diferentes técnicas de eliminación de las callosidades empleadas Método Se realizan dos estudios: un estudio cuasi experimental aleatorizado no controlado, en el que a un grupo de 34 pacientes con callosidades plantares dolorosas se les mide el dolor con una escala visual analógica y para analizar los parámetros de la marcha, la paltaformaWin-Track, antes del tratamiento de deslaminación mecánica con bisturí y a las 24 horas. El segundo estudio es un ensayo clínico aleatorizado inscrito en Australian New ZelandClinicalstrials y aprobado por el Comité ético de la Universidad de Málaga, en el que 62 participantes con callosidades plantares dolorosas se dividieron en dos grupos de tratamiento. El grupo A recibió tratamiento con parche de ácido salicílico y el grupo B recibió tratmiento de deslaminación con bisturí. Se utilizó la escala visual analógica para la medida de dolor antes, inmediatamente después de la intervención, a las 2 semanas y a las 6 semanas. Para el dolor y la discapacidad funcional del pie se utilizó el cuestionario Manchester FootPain and Disability antes del tratamiento, a las 2 semanas y a las 6 semanas. Para medir la calidad de vida general se utilizó el cuestionario SF-12 Conclusiones La deslaminación mecánica con bisturí de los callos y callosidades plantares es efectiva para su eliminación a nivel de la sensación de dolor, aunque no tanto en lo que se refiere a la mejora de calidad de vida. No hay resultados significativos de que la eliminación mecánica con bisturí de callos y callosidades plantares modifican los parámetros de la marcha medido con la plataforma Win-track. Se observa como la deslaminación mecánica con bisturí para la eliminación de callos y callosidades plantares pueden ser más efectiva a corto plazo que la eliminación mediante parche con ácido salicílico. Se observa cómo se modifica los paramentos psíquicos en el grupo de tratamiento con parche con ácido salicílico, aunque con una significación baja. Bibliografía Balanowski, K. R., & Flynn, L. M. (2005). Effect of painful keratoses debridement on foot pain, balance and function in older adults. Gait & Posture, 22(4), 302-307. http://doi.org/10.1016/j.gaitpost.2004.10.006 Collins, S. L., Moore, R. A., &McQuay, H. J. (1997). The visual analogue pain intensity scale: what is moderate pain in millimetres? Pain, 72(1-2), 95-97. Coughlin, M. J. (2000).Common Causes of Pain in the Forefoot in Adults. Journal of Bone & Joint Surgery, British Volume, 82-B(6), 781-790. Farndon, L. J., Vernon, W., Walters, S. J., Dixon, S., Bradburn, M., Concannon, M., & Potter, J. (2013). The effectiveness of salicylic acid plasters compared with «usual» scalpel debridement of corns: a randomised controlled trial. Journal of Foot and Ankle Research, 6(1), 40. http://doi.org/10.1186/1757-1146-6-40 Freeman, D. B. (2002). Corns and calluses resulting from mechanical hyperkeratosis. American FamilyPhysician, 65(11), 2277-2280. Gijon-Nogueron, G., Ndosi, M., Luque-Suarez, A., Alcacer-Pitarch, B., Munuera, P. V., Garrow, A., & Redmond, A. C. (2014). Cross-cultural adaptation and validation of the Manchester Foot Pain and Disability Index into Spanish. Quality of Life Research: An International Journal of Quality of Life Aspects of Treatment, Care and Rehabilitation, 23(2), 571-579. http://doi.org/10.1007/s11136-013-0507-5 Grouios, G. (2005). Footedness as a potential factor that contributes to the causation of corn and callus formation in lower extremities of physically active individuals. The Foot, 15(3), 154-162. http://doi.org/10.1016/j.foot.2005.05.003 Landorf, K. B., Morrow, A., Spink, M. J., Nash, C. L., Novak, A., Potter, J., &Menz, H. B. (2013). Effectiveness of scalpel debridement for painful plantar calluses in older people: a randomized trial. Trials, 14, 243. http://doi.org/10.1186/1745-6215-14-243 Lang, L. M. G., Simmonite, N., West, S. G., & Day, S. (1994). Salicylic acid in the treatment of corns. The Foot, 4(3), 145-150. http://doi.org/10.1016/0958-2592(94)90019-1 Luo, X., Lynn George, M., Kakouras, I., Edwards, C. L., Pietrobon, R., Richardson, W., & Hey, L. (2003). Reliability, validity, and responsiveness of the short form 12-item survey (SF-12) in patients with back pain. Spine, 28(15), 1739-1745. http://doi.org/10.1097/01.BRS.0000083169.58671.96 Ramachandra, P., Maiya, A. G., & Kumar, P. (2012). Test-retest reliability of the Win-Track platform in analyzing the gait parameters and plantar pressures during barefoot walking in healthy adults. Foot & Ankle Specialist, 5(5), 306-312. http://doi.org/10.1177/1938640012457680 Siddle, H. J., Redmond, A. C., Waxman, R., Dagg, A. R., Alcacer-Pitarch, B., Wilkins, R. A., &Helliwell, P. S. (2013). Debridement of painful forefoot plantar callosities in rheumatoid arthritis: the CARROT randomised controlled trial. Clinical Rheumatology, 32(5), 567-574. http://doi.org/10.1007/s10067-012-2134-x

Preliminary structure-activity relationship studies on some novel s-substituted aliphatic analogues of 5-{1-[(4- chlorophenyl) sulfonyl]-3-piperidinyl}-1, 3, 4-oxadiazol-2-yl sulfide

Purpose: To study the structure-activity relationships of synthetic multifunctional sulfides through evaluation of lipoxygenase and anti-bacterial activities. Methods: S-substituted derivatives of the parent compound 5-(1-(4-chlorophenylsulfonyl) piperidin-3- yl)-1, 3, 4-oxadiazole-2-thiol were synthesized through reaction with different saturated and unsaturated alkyl halides in DMF medium, with NaH catalyst. Spectral characterization of each derivative was carried out with respect to IR, 1H - NMR, 13C - NMR and EI - MS. The lipoxygenase inhibitory and antibacterial activities of the derivatives were determined using standard procedures. Results: Compound 5e exhibited higher lipoxygenase inhibitory potential than the standard (Baicalein®), with % inhibition of 94.71 ± 0.45 and IC50 of 20.72 ± 0.34 μmoles/L. Compound 5b showed significant antibacterial potential against all the bacterial strains with % inhibition ranging from 62.04 ± 2.78, 69.49 ± 0.41, 63.38 ± 1.97 and 59.70 ± 3.70 to 78.32 ± 0.41, while MIC ranged from 8.18 ± 2.00, 10.60 ± 1.83, 10.84 ± 3.00, 9.81 ± 1.86 and 11.73 ± 5.00 μmoles/L for S. typhi, E. coli, P. aeruginosa, B. subtilis and S. aureus, respectively. Compounds 5d, 5e and 5g showed good antibacterial activity against S. typhi and B. subtilis bacterial strains. Conclusion: The results suggest that compound 5e bearing n-pentyl group is a potent lipoxygenase inhibitor, while compound 5b with n-propyl substitution is a strong antibacterial agent. In addition, compounds 5d, 5e and 5g bearing n-butyl, n-pentyl and n-octyl groups, respectively, are good antibacterial agents against S. typhi and B. subtilis.

Estado de las enfermedades raras que cursan con discapacidad intelectual en Colombia

Las enfermedades raras o huérfano son una problemática que ha tomado mucha importancia en el contexto mundial del presente siglo, estas se han definido como crónicas, de difícil tratamiento de sus síntomas y con baja prevalencia en la población; muchas de estas enfermedades cursan con varios tipos de discapacidad, siendo el objetivo del presente trabajo el enfocarse en aquellas enfermedades raras que cursan con discapacidad intelectual. Para poder profundizar en estas enfermedades se realizó una revisión teórica sobre las enfermedades raras, así como de la discapacidad psíquica y su importancia a nivel mundial y nacional. A partir de estas definiciones, se revisaron en profundidad 3 enfermedades raras que cursan con discapacidad intelectual en el contexto colombiano, como son: el síndrome de Rett, el síndrome de Prader-Willi y el síndrome de X frágil. En cada una de estas enfermedades además se explicaron los tipos de diagnóstico, intervención, prevención, grupos de apoyo y tipos de evaluación que más se usan en el contexto nacional

AAGL 2021 classification system and risk of surgical complications in women submitted to surgery for endometriosis

Introduction: Recently, the American Association of Gynecologic Laparoscopists proposed a new classification and scoring system with the specific aim to assess surgical complexity. This study sought to assess if a higher AAGL score correlates with an increased risk of peri-operative complications in women submitted to surgery for endometriosis. Methods: This is a retrospective cohort study conducted in a third level referral center. We collected data from women with endometriosis submitted to complete surgical removal of endometriosis from January 2019 to December 2021. ENZIAN, r-ASRM classifications and AAGL total score was calculated for each patient. Population was divided in two groups according to the occurrence or not of at least one peri-operative complication. Our primary outcome was to evaluate the correlation between AAGL score and occurrence of complications. Results: During the study period we analyzed data from 282 eligible patients. Among them, 80 (28.4%) experienced peri-operative complications. No statistically significant difference was found between the two groups in terms of baseline characteristics, except for pre-operative hemoglobin (Hb), which was lower in patients with complications (p=0.001). Surgical variables associated with the occurrence of complications were recto-sigmoid surgery (p=0.003), ileocecal resection (0.034), and longer operative time (p=0.007). Furthermore, a higher ENZIAN B score (p=0.006), AAGL score (p=0.045) and stage (p=0.022) were found in the group of patients with complications. The multivariate analysis only confirmed the significant association between the occurrence of peri-operative complications and lower pre-operative Hb level (OR 0.74; 95% CI, 0.59 - 0.94; p=0.014), longer operative time (OR 1.00; 95% CI, 1.00 – 1.01; p=0.013), recto-sigmoid surgery - especially discoid resection (OR 8.73; 95% CI, 2.18 – 35; p=0.016) and ENZIAN B3 (OR 3.62; 95% CI, 1.46 – 8.99; p= 0.006). Conclusion: According to our findings, high AAGL scores or stages do not seem to increase the risk of peri-operative complications.

Egfr Activating Mutations And Their Association With Response To Platinum-doublet Chemotherapy In Brazilian Non-small Cell Lung Cancer Patients.

The aim of the study was to analyze the frequency of epidermal growth factor receptor (EGFR) mutations in Brazilian non-small cell lung cancer patients and to correlate these mutations with response to benefit of platinum-based chemotherapy in non-small cell lung cancer (NSCLC). Our cohort consisted of prospective patients with NSCLCs who received chemotherapy (platinum derivates plus paclitaxel) at the [UNICAMP], Brazil. EGFR exons 18-21 were analyzed in tumor-derived DNA. Fifty patients were included in the study (25 with adenocarcinoma). EGFR mutations were identified in 6/50 (12 %) NSCLCs and in 6/25 (24 %) adenocarcinomas; representing the frequency of EGFR mutations in a mostly self-reported White (82.0 %) southeastern Brazilian population of NSCLCs. Patients with NSCLCs harboring EGFR exon 19 deletions or the exon 21 L858R mutation were found to have a higher chance of response to platinum-paclitaxel (OR 9.67 [95 % CI 1.03-90.41], p = 0.047). We report the frequency of EGFR activating mutations in a typical southeastern Brazilian population with NSCLC, which are similar to that of other countries with Western European ethnicity. EGFR mutations seem to be predictive of a response to platinum-paclitaxel, and additional studies are needed to confirm or refute this relationship.

Trypanosoma Cruzi Strains From Triatomine Collected In Bahia And Rio Grande Do Sul, Brazil.

Collection of triatomines in domestic, peridomestic and sylvatic environments in states of Bahia and Rio Grande do Sul, Northeastern and Southern Brazil respectively, and isolation of Trypanosoma cruzi strains. First, the captured triatomines were identified using insect identification keys, then their intestinal content was examined by abdominal compression, and the samples containing trypanosomatid forms were inoculated in LIT medium and Swiss mice. Six triatomine species were collected in cities in Bahia, namely Panstrongylus geniculatus (01), Triatoma melanocephala (11), T. lenti (94), T. pseudomaculata (02), T. sherlocki (26) and T. sordida (460), and two in cities in Rio Grande do Sul, namely T. circummaculata (11) and T. rubrovaria (115). Out of the specimens examined, T. cruzi was isolated from 28 triatomine divided into four different species: T. melanocephala (one), T. lenti (one), T. rubrovaria (16) and T. sordida (10). Their index of natural infection by T. cruzi was 6.4%. The isolation of T. cruzi strains from triatomines found in domestic and peridomestic areas shows the potential risk of transmission of Chagas disease in the studied cities. The maintenance of those T. cruzi strains in laboratory is intended to promote studies that facilitate the understanding of the parasite-vector-host relationship.

Genome Sequence Of Streptomyces Wadayamensis Strain A23, An Endophytic Actinobacterium From Citrus Reticulata.

The actinobacterium Streptomyces wadayamensis A23 is an endophyte of Citrus reticulata that produces the antimycin and mannopeptimycin antibiotics, among others. The strain has the capability to inhibit Xylella fastidiosa growth. The draft genome of S. wadayamensis A23 has ~7.0 Mb and 6,006 protein-coding sequences, with a 73.5% G+C content.

Urinary Tract Infection In Renal Transplant Recipients: Incidence, Risk Factors, And Impact On Graft Function.

Urinary tract infection (UTI) is the most common infection posttransplant. However, the risk factors for and the impact of UTIs remain controversial. The aim of this study was to identify the incidence of posttransplant UTIs in a series of renal transplant recipients from deceased donors. Secondary objectives were to identify: (1) the most frequent infectious agents; (2) risk factors related to donor; (3) risk factors related to recipients; and (4) impact of UTI on graft function. This was a retrospective analysis of medical records from renal transplant patients from January to December 2010. Local ethics committee approved the protocol. The incidence of UTI in this series was 34.2%. Risk factors for UTI were older age, (independent of gender), biopsy-proven acute rejection episodes, and kidneys from deceased donors (United Network for Organ Sharing criteria). For female patients, the number of pretransplant pregnancies was an additional risk factor. Recurrent UTI was observed in 44% of patients from the UTI group. The most common infectious agents were Escherichia coli and Klebsiella pneumoniae, for both isolated and recurrent UTI. No difference in renal graft function or immunosuppressive therapy was observed between groups after the 1-year follow-up. In this series, older age, previous pregnancy, kidneys from expanded criteria donors, and biopsy-proven acute rejection episodes were risk factors for posttransplant UTI. Recurrence of UTI was observed in 44%, with no negative impact on graft function or survival.

Toll-like Receptor 4 Activation Promotes Cardiac Arrhythmias By Decreasing The Transient Outward Potassium Current (ito) Through An Irf3-dependent And Myd88-independent Pathway.

Cardiac arrhythmias are one of the main causes of death worldwide. Several studies have shown that inflammation plays a key role in different cardiac diseases and Toll-like receptors (TLRs) seem to be involved in cardiac complications. In the present study, we investigated whether the activation of TLR4 induces cardiac electrical remodeling and arrhythmias, and the signaling pathway involved in these effects. Membrane potential was recorded in Wistar rat ventricle. Ca(2+) transients, as well as the L-type Ca(2+) current (ICaL) and the transient outward K(+) current (Ito), were recorded in isolated myocytes after 24 h exposure to the TLR4 agonist, lipopolysaccharide (LPS, 1 μg/ml). TLR4 stimulation in vitro promoted a cardiac electrical remodeling that leads to action potential prolongation associated with arrhythmic events, such as delayed afterdepolarization and triggered activity. After 24 h LPS incubation, Ito amplitude, as well as Kv4.3 and KChIP2 mRNA levels were reduced. The Ito decrease by LPS was prevented by inhibition of interferon regulatory factor 3 (IRF3), but not by inhibition of interleukin-1 receptor-associated kinase 4 (IRAK4) or nuclear factor kappa B (NF-κB). Extrasystolic activity was present in 25% of the cells, but apart from that, Ca(2+) transients and ICaL were not affected by LPS; however, Na(+)/Ca(2+) exchanger (NCX) activity was apparently increased. We conclude that TLR4 activation decreased Ito, which increased AP duration via a MyD88-independent, IRF3-dependent pathway. The longer action potential, associated with enhanced Ca(2+) efflux via NCX, could explain the presence of arrhythmias in the LPS group.