Effectiveness of transcutaneous electrical nerve stimulation improves pain intensity, disability and quality of life in patients with fibromyalgia syndrome: a systematic review with meta-analysis.

PURPOSE: The transcutaneous electrical nerve stimulation (TENS) is one of the most frequently electrophysical agents employed in reducing the impact of FMS. This meta-analysis intended to determine the effectiveness of TENS on pain, disability, and quality of life (QoL) in patients with FMS. METHODS: According to PRISMA, we performed a meta-analysis (CRD42023456439), searching in PubMed Medline, PEDro, CINAHL Complete, Web of Science, and Scopus, since inception up to October 2023. This review focused on controlled clinical trials evaluating the effect of TENS on pain, disability, and QoL in patients with FMS. The pooled effect was estimated using Cohen's standardized mean difference (SMD) and its 95% confidence interval (95%CI). RESULTS: Twelve studies, providing data from 944 patients, were included (PEDro score of 5.6 points). Meta-analyses showed that TENS interventions are effective in improving pain (SMD = -0.61; 95%CI -1 to -0.16); disability (SMD = -0.27; 95%CI -0.41 to -0.12); and physical dimension of QoL (SMD = 0.26; 95%CI 0.08 to 0.44). Additionally, when TENS is used as a unique therapy, it represents the best therapeutic option for improving pain, disability, and QoL. CONCLUSIONS: This meta-analysis, including the largest number of studies, showed that TENS intervention is an effective therapy to reduce pain and disability and increase QoL in FMS patients.

Transcutaneous Electrical Nerve Stimulation (TENS) intervention is effective in reducing pain and disability; and increasing physical quality of life (QoL) in patients with Fibromyalgia Syndrome (FMS).Compared to sham or no intervention, TENS is more effectiveness for improving pain, disability and QoL is major when it is applied as isolated therapy in patients with FMS.In comparison to therapeutic exercise, TENS did not show to be better in reducing pain and disability in patients with FMS, suggesting the importance of considering combined or alternative treatments.

Palazestrant (OP-1250), A Complete Estrogen Receptor Antagonist, Inhibits Wild-type and Mutant ER-positive Breast Cancer Models as Monotherapy and in Combination.

The estrogen receptor (ER) is a well-established target for the treatment of breast cancer, with the majority of patients presenting as ER-positive (ER+). Endocrine therapy is a mainstay of breast cancer treatment but the development of resistance mutations in response to aromatase inhibitors, poor pharmacokinetic properties of fulvestrant, agonist activity of tamoxifen, and limited benefit for elacestrant leave unmet needs for patients with or without resistance mutations in ESR1, the gene that encodes the ER protein. Here we describe palazestrant (OP-1250), a novel, orally bioavailable complete ER antagonist and selective ER degrader. OP-1250, like fulvestrant, has no agonist activity on the ER and completely blocks estrogen-induced transcriptional activity. In addition, OP-1250 demonstrates favorable biochemical binding affinity, ER degradation, and antiproliferative activity in ER+ breast cancer models that is comparable or superior to other agents of interest. OP-1250 has superior pharmacokinetic properties relative to fulvestrant, including oral bioavailability and brain penetrance, as well as superior performance in wild-type and ESR1-mutant breast cancer xenograft studies. OP-1250 combines well with cyclin-dependent kinase 4 and 6 inhibitors in xenograft studies of ER+ breast cancer models and effectively shrinks intracranially implanted tumors, resulting in prolonged animal survival. With demonstrated preclinical efficacy exceeding fulvestrant in wild-type models, elacestrant in ESR1-mutant models, and tamoxifen in intracranial xenografts, OP-1250 has the potential to benefit patients with ER+ breast cancer.

Analytical validation of a multi-cancer early detection test with cancer signal origin using a cell-free DNA-based targeted methylation assay.

The analytical validation is reported for a targeted methylation-based cell-free DNA multi-cancer early detection test designed to detect cancer and predict the cancer signal origin (tissue of origin). A machine-learning classifier was used to analyze the methylation patterns of >105 genomic targets covering >1 million methylation sites. Analytical sensitivity (limit of detection [95% probability]) was characterized with respect to tumor content by expected variant allele frequency and was determined to be 0.07%-0.17% across five tumor cases and 0.51% for the lymphoid neoplasm case. Test specificity was 99.3% (95% confidence interval, 98.6-99.7%). In the reproducibility and repeatability study, results were consistent in 31/34 (91.2%) pairs with cancer and 17/17 (100%) pairs without cancer; between runs, results were concordant for 129/133 (97.0%) cancer and 37/37 (100%) non-cancer sample pairs. Across 3- to 100-ng input levels of cell-free DNA, cancer was detected in 157/182 (86.3%) cancer samples but not in any of the 62 non-cancer samples. In input titration tests, cancer signal origin was correctly predicted in all tumor samples detected as cancer. No cross-contamination events were observed. No potential interferent (hemoglobin, bilirubin, triglycerides, genomic DNA) affected performance. The results of this analytical validation study support continued clinical development of a targeted methylation cell-free DNA multi-cancer early detection test.

Entropy-driven translocation of disordered proteins through the Gram-positive bacterial cell wall.

In Gram-positive bacteria, a thick cross-linked cell wall separates the membrane from the extracellular space. Some surface-exposed proteins, such as the Listeria monocytogenes actin nucleation-promoting factor ActA, remain associated with the bacterial membrane but somehow thread through tens of nanometres of cell wall to expose their amino terminus to the exterior. Here, we report that entropy enables the translocation of disordered transmembrane proteins through the Gram-positive cell wall. We build a physical model, which predicts that the entropic constraint imposed by a thin periplasm is sufficient to drive the translocation of an intrinsically disordered protein such as ActA across a porous barrier similar to a peptidoglycan cell wall. We experimentally validate our model and show that ActA translocation depends on the cell-envelope dimensions and disordered-protein length, and that translocation is reversible. We also show that disordered regions of eukaryotic proteins can translocate Gram-positive cell walls via entropy. We propose that entropic forces are sufficient to drive the translocation of specific proteins to the outer surface.

Actin cables and comet tails organize mitochondrial networks in mitosis.

Symmetric cell division requires the even partitioning of genetic information and cytoplasmic contents between daughter cells. Whereas the mechanisms coordinating the segregation of the genome are well known, the processes that ensure organelle segregation between daughter cells remain less well understood1. Here we identify multiple actin assemblies with distinct but complementary roles in mitochondrial organization and inheritance in mitosis. First, we find a dense meshwork of subcortical actin cables assembled throughout the mitotic cytoplasm. This network scaffolds the endoplasmic reticulum and organizes three-dimensional mitochondrial positioning to ensure the equal segregation of mitochondrial mass at cytokinesis. Second, we identify a dynamic wave of actin filaments reversibly assembling on the surface of mitochondria during mitosis. Mitochondria sampled by this wave are enveloped within actin clouds that can spontaneously break symmetry to form elongated comet tails. Mitochondrial comet tails promote randomly directed bursts of movement that shuffle mitochondrial position within the mother cell to randomize inheritance of healthy and damaged mitochondria between daughter cells. Thus, parallel mechanisms mediated by the actin cytoskeleton ensure both equal and random inheritance of mitochondria in symmetrically dividing cells.

Hiperglicemia y volumen plaquetario medio como predictores tempranos del síndrome coronario agudo tipo IAM SEST / Hyperglycemia and mean platelet volume as early predictors of acute coronary syndro-me type IAM SEST

Introducción: El objetivo del presente trabajo de investigación es determinar la validez diag-nóstica que tiene la hiperglucemia y el volumen plaquetario medio en el diagnóstico tempra-no de pacientes que acuden al Departamento de Emergencia con dolor torácico y sospecha de infarto agudo de miocardio sin elevación del ST. Materiales y métodos: se realizó un ensayo clínico no controlado para validación de pruebas diagnósticas de 6 meses de duración, en 133 pacientes admitidos en el Departamento de Emergencia del Hospital Carlos Andrade Marín por dolor torácico y sospecha de síndrome coronario agudo. Un punto de cohorte de hiperglu-cemia >140 mg/dl y volumen plaquetario medio ≥ 10,33 fl a la admisión fue considerado tomando en cuenta valores propuestos en la curva ROC (curva operante receptor); así como también, se determinó el rendimiento diagnóstico de las pruebas, regresión univariante y multivariante. Resultados: de los 133 pacientes incluidos en el trabajo, 32 (24,1%) tuvieron infarto agudo de miocardio sin elevación del ST. El rendimiento diagnóstico del volumen plaquetario medio ≥ 10,33 fl (AUC: 0,91; IC 95%: 0,841-0,979; p<0,05) tuvo una sensibili-dad del 81,2%, especificidad de 93,1%, valor predictivo positivo 78,8%, valor predictivo negativo 94%, razón de verosimilitud positivo 11,723 y razón de verosimilitud negativo 0,201. Para la hiperglucemia >140 mg/dl (AUC: 0,923; IC 95%: 0,879-0,967; p<0,05) la sensibilidad fue del 71,9%, especificidad de 90,1%, valor predictivo positivo 69,7%, valor predictivo negativo 91%, razón de verosimilitud positivo 7,259 y razón de verosimilitud negativo 0,312. Conclusiones: la hiperglucemia y el volumen plaquetario medio son biomar-cadores con buena capacidad predictiva para el diagnóstico temprano del infarto agudo de miocardio sin elevación del ST.

Introduction: The aim of this research is to determine the diagnostic validity of hyperglycemia and mean platelet volume in the early diagnosis of patients who come to the Emergency Department with chest pain and suspected acute myocardial infarction without ST elevation. Materials and methods: an uncontrolled clinical trial was conducted to validate diagnostic tests of 6 months in 133 patients admitted to the Emergency Department of the Carlos Andra-de Marín Hospital for chest pain and suspected acute coronary syndrome. A cohort point of hyperglycemia> 140 mg / dl and mean platelet volume ≥ 10.33 fl upon admission was consi-dered taking into account values proposed in the ROC curve (receiver operant curve); as well as, the diagnostic performance of the tests, univariate and multivariate regression was deter-mined. Results: of the 133 patients included in the study, 32 (24.1%) had acute myocardial infarction without ST elevation. The diagnostic yield of mean platelet volume ≥ 10.33 fl (AUC: 0.91, 95% CI: 0.841-0.979, p <0.05) had a sensitivity of 81.2%, specificity of 93.1%, value positive predictive 78.8%, negative predictive value 94%, positive likelihood ratio 11.723 and negative likelihood ratio 0.201. For hyperglycemia> 140 mg / dL (AUC: 0.923, 95% CI: 0.879-0.967, p <0.05) the sensitivity was 71.9%, specificity 90.1%, positive predic-tive value 69.7%, negative predictive value 91%, positive likelihood ratio 7,259 and negative likelihood ratio 0,312. Conclusion: hyperglycaemia and mean platelet volume are biomar-kers with good predictive capacity for the early diagnosis of acute myocardial infarction without ST elevation.

Listeria monocytogenes cell-to-cell spread in epithelia is heterogeneous and dominated by rare pioneer bacteria.

Listeria monocytogenes hijacks host actin to promote its intracellular motility and intercellular spread. While L. monocytogenes virulence hinges on cell-to-cell spread, little is known about the dynamics of bacterial spread in epithelia at a population level. Here, we use live microscopy and statistical modeling to demonstrate that L. monocytogenes cell-to-cell spread proceeds anisotropically in an epithelial monolayer in culture. We show that boundaries of infection foci are irregular and dominated by rare pioneer bacteria that spread farther than the rest. We extend our quantitative model for bacterial spread to show that heterogeneous spreading behavior can improve the chances of creating a persistent L. monocytogenes infection in an actively extruding epithelium. Thus, our results indicate that L. monocytogenes cell-to-cell spread is heterogeneous, and that rare pioneer bacteria determine the frontier of infection foci and may promote bacterial infection persistence in dynamic epithelia. Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter).

A Multi-well Format Polyacrylamide-based Assay for Studying the Effect of Extracellular Matrix Stiffness on the Bacterial Infection of Adherent Cells.

Extracellular matrix stiffness comprises one of the multiple environmental mechanical stimuli that are well known to influence cellular behavior, function, and fate in general. Although increasingly more adherent cell types' responses to matrix stiffness have been characterized, how adherent cells' susceptibility to bacterial infection depends on matrix stiffness is largely unknown, as is the effect of bacterial infection on the biomechanics of host cells. We hypothesize that the susceptibility of host endothelial cells to a bacterial infection depends on the stiffness of the matrix on which these cells reside, and that the infection of the host cells with bacteria will change their biomechanics. To test these two hypotheses, endothelial cells were used as model hosts and Listeria monocytogenes as a model pathogen. By developing a novel multi-well format assay, we show that the effect of matrix stiffness on infection of endothelial cells by L. monocytogenes can be quantitatively assessed through flow cytometry and immunostaining followed by microscopy. In addition, using traction force microscopy, the effect of L. monocytogenes infection on host endothelial cell biomechanics can be studied. The proposed method allows for the analysis of the effect of tissue-relevant mechanics on bacterial infection of adherent cells, which is a critical step towards understanding the biomechanical interactions between cells, their extracellular matrix, and pathogenic bacteria. This method is also applicable to a wide variety of other types of studies on cell biomechanics and response to substrate stiffness where it is important to be able to perform many replicates in parallel in each experiment.

Listeria monocytogenes InlP interacts with afadin and facilitates basement membrane crossing.

During pregnancy, the placenta protects the fetus against the maternal immune response, as well as bacterial and viral pathogens. Bacterial pathogens that have evolved specific mechanisms of breaching this barrier, such as Listeria monocytogenes, present a unique opportunity for learning how the placenta carries out its protective function. We previously identified the L. monocytogenes protein Internalin P (InlP) as a secreted virulence factor critical for placental infection. Here, we show that InlP, but not the highly similar L. monocytogenes internalin Lmo2027, binds to human afadin (encoded by AF-6), a protein associated with cell-cell junctions. A crystal structure of InlP reveals several unique features, including an extended leucine-rich repeat (LRR) domain with a distinctive Ca2+-binding site. Despite afadin's involvement in the formation of cell-cell junctions, MDCK epithelial cells expressing InlP displayed a decrease in the magnitude of the traction stresses they could exert on deformable substrates, similar to the decrease in traction exhibited by AF-6 knock-out MDCK cells. L. monocytogenes ΔinlP mutants were deficient in their ability to form actin-rich protrusions from the basal face of polarized epithelial monolayers, a necessary step in the crossing of such monolayers (transcytosis). A similar phenotype was observed for bacteria expressing an internal in-frame deletion in inlP (inlP ΔLRR5) that specifically disrupts its interaction with afadin. However, afadin deletion in the host cells did not rescue the transcytosis defect. We conclude that secreted InlP targets cytosolic afadin to specifically promote L. monocytogenes transcytosis across the basal face of epithelial monolayers, which may contribute to the crossing of the basement membrane during placental infection.

Adhesion to the host cell surface is sufficient to mediate Listeria monocytogenes entry into epithelial cells.

The intestinal epithelium is the first physiological barrier breached by the Gram-positive facultative pathogen Listeria monocytogenes during an in vivo infection. Listeria monocytogenes binds to the epithelial host cell receptor E-cadherin, which mediates a physical link between the bacterium and filamentous actin (F-actin). However, the importance of anchoring the bacterium to F-actin through E-cadherin for bacterial invasion has not been tested directly in epithelial cells. Here we demonstrate that depleting αE-catenin, which indirectly links E-cadherin to F-actin, did not decrease L. monocytogenes invasion of epithelial cells in tissue culture. Instead, invasion increased due to increased bacterial adhesion to epithelial monolayers with compromised cell-cell junctions. Furthermore, expression of a mutant E-cadherin lacking the intracellular domain was sufficient for efficient L. monocytogenes invasion of epithelial cells. Importantly, direct biotin-mediated binding of bacteria to surface lipids in the plasma membrane of host epithelial cells was sufficient for uptake. Our results indicate that the only requirement for L. monocytogenes invasion of epithelial cells is adhesion to the host cell surface, and that E-cadherin-mediated coupling of the bacterium to F-actin is not required.

Trinucleotide repeat containing 6c (TNRC6c) is essential for microvascular maturation during distal airspace sacculation in the developing lung.

GW182 (also known asTNRC6) family members are critically involved in the final effector phase of miRNA-mediated mRNA repression. The three mammalian paralogs, TNRC6a, b and c, are thought to be redundant based on Argonaute (Ago) binding, tethering assays, and RNAi silencing of individual members in cell lines. To test this idea, we generated TNRC6a, b and c knockout mice. TNRC6a mutants die at mid-gestation, while b- and c- deleted mice are born at a Mendelian ratio. However, the majority of TNRC6b and all TNRC6c mutants die within 24h after birth, the latter with respiratory failure. Necropsy of TNRC6c mutants revealed normal-appearing airways that give rise to abnormally thick-walled distal gas exchange sacs. Immunohistological analysis of mutant lungs demonstrated a normal distribution of bronchiolar and alveolar cells, indicating that loss of TNRC6c did not abrogate epithelial cell differentiation. The cellular kinetics and relative proportions of endothelial, epithelial, and mesenchymal cells were also not altered. However, the underlying capillary network was simplified and endothelial cells had failed to become tightly apposed to the surface epithelium in TNRC6c mutants, presumably causing the observed respiratory failure. TGFß family mutant mice exhibit a similar lung phenotype of thick-walled air sacs and neonatal lethality, and qRT-PCR confirmed dynamic downregulation of TGFß1 and TGFßR2 in TNRC6c mutant lungs during sacculation. VEGFR, but not VEGF-A ligand, was also lower, likely reflecting the overall reduced capillary density in TNRC6c mutants. Together, these results demonstrate that GW182 paralogs are not functionally redundant in vivo. Surprisingly, despite regulating a general cellular process, TNRC6c is selectively required only in the distal lung and not until late in gestation for proper expression of the TGFß family genes that drive sacculation. These results imply a complex and indirect mode of regulation of sacculation by TNRC6c, mediated in part by dynamic transcriptional repression of an inhibitor of TGFß family gene expression.

Oxygen regulation of breathing through an olfactory receptor activated by lactate.

Animals have evolved homeostatic responses to changes in oxygen availability that act on different timescales. Although the hypoxia-inducible factor (HIF) transcriptional pathway that controls long-term responses to low oxygen (hypoxia) has been established, the pathway that mediates acute responses to hypoxia in mammals is not well understood. Here we show that the olfactory receptor gene Olfr78 is highly and selectively expressed in oxygen-sensitive glomus cells of the carotid body, a chemosensory organ at the carotid artery bifurcation that monitors blood oxygen and stimulates breathing within seconds when oxygen declines. Olfr78 mutants fail to increase ventilation in hypoxia but respond normally to hypercapnia. Glomus cells are present in normal numbers and appear structurally intact, but hypoxia-induced carotid body activity is diminished. Lactate, a metabolite that rapidly accumulates in hypoxia and induces hyperventilation, activates Olfr78 in heterologous expression experiments, induces calcium transients in glomus cells, and stimulates carotid sinus nerve activity through Olfr78. We propose that, in addition to its role in olfaction, Olfr78 acts as a hypoxia sensor in the breathing circuit by sensing lactate produced when oxygen levels decline.

Cooperative recruitment of HMGB1 during V(D)J recombination through interactions with RAG1 and DNA.

During V(D)J recombination, recombination activating gene (RAG)1 and RAG2 bind and cleave recombination signal sequences (RSSs), aided by the ubiquitous DNA-binding/-bending proteins high-mobility group box protein (HMGB)1 or HMGB2. HMGB1/2 play a critical, although poorly understood, role in vitro in the assembly of functional RAG-RSS complexes, into which HMGB1/2 stably incorporate. The mechanism of HMGB1/2 recruitment is unknown, although an interaction with RAG1 has been suggested. Here, we report data demonstrating only a weak HMGB1-RAG1 interaction in the absence of DNA in several assays, including fluorescence anisotropy experiments using a novel Alexa488-labeled HMGB1 protein. Addition of DNA to RAG1 and HMGB1 in fluorescence anisotropy experiments, however, results in a substantial increase in complex formation, indicating a synergistic binding effect. Pulldown experiments confirmed these results, as HMGB1 was recruited to a RAG1-DNA complex in a RAG1 concentration-dependent manner and, interestingly, without strict RSS sequence specificity. Our finding that HMGB1 binds more tightly to a RAG1-DNA complex over RAG1 or DNA alone provides an explanation for the stable integration of this typically transient architectural protein in the V(D)J recombinase complex throughout recombination. These findings also have implications for the order of events during RAG-DNA complex assembly and for the stabilization of sequence-specific and non-specific RAG1-DNA interactions.

Pneumocystis carinii: presentación de caso clínico y revisión de la bibliografía principal / Pneumocystis carinii: presentation of clinical case and revision of the main bibliography

El Pneumocystis Carinii es un microorganismo patógeno, oportunista, causante de neumonía en los pacientes inmunodeprimidos, cuya presentación clínica es insidiosa, aparentando un cuadro respiratorio simple caracterizado por fiebre, rinorrea, aleteo nasal; no responde favorablemente al tratamiento convencional, deteriorando el estado general del paciente. Estos pacientes son ingresados para estudios complementarios, especialmente de tipo radiológico lo cual nos revela imágenes de infiltrados pulmonares parahiliares difusos, típicas de infección por pneumocystis carinii, aproximadamente en el 90 % de los casos, en pacientes inmunodeprimidos por HIV. Describimos el caso de un lactante menor que fue atendido en el servicio de neonatología del hospital “Roberto Gilbert Elizalde” con neumonía por Pneumocystis Carinii inmunocomprometido por HIV.

The Pneumocystis Carinii is a pathogenic, opportunistic microorganism, cause of neumonía in the inmunodeprimidos patients, whose clinical presentation are insidiosa, pretending a simple respiratory picture characterized by fever, rinorrea, nasal fluttering; it does not respond to the conventional treatment favorably, deteriorating the general state of the patient. These patients are entered for complementary studies, specially of radiological type which reveals images to us of infiltrated pulmonary diffuse parahiliares, typical of infection by Pneumocystis Carinii, approximately in 90 % of the cases, in patients inmunodeprimidos by HIV. We described the case of a suckling baby smaller than Robert was taken care of in the service of neonatología of the hospital Gilbert Elizalde with neumonía by Pneumocystis Carinii inmunocomprometido by HIV.