Hasil untuk "Medicine (General)"

Deema O. Qasrawi, Adriano M. C. Pimenta, Evgeniy V. Petrotchenko et al.

<b>Background:</b> Quantifying urinary catecholamines and metanephrines is essential for the clinical screening and diagnosis of neuroendocrine tumours. HPLC with electrochemical detection (HPLC-ECD) is commonly used for this type of analysis but requires extensive sample cleanup. Simple and rapid dilute-and-shoot LC–multiple-reaction monitoring (MRM)-MS assays have been developed for quantitating these analytes in urine but have not yet been validated according to the Clinical and Laboratory Standards Institute (CLSI) guidelines. <b>Methods:</b> A simple dilute-and-shoot sample preparation without derivatization was used. C18 RP-UPLC-MRM-MS and positive-ion ESI were used, usually with two transitions per analyte being monitored. Certified deuterated internal standards were used for each analyte. <b>Results:</b> This assay was validated according to the CLSI C62-A guidelines, including accuracy/trueness, imprecision, sensitivity, specificity, carryover, stability, and linearity. The final MRM-MS method was compared to the established HPLC-ECD clinical chemistry reference method. The run time was reduced from 25 min to 5 min. <b>Conclusions:</b> A simple, robust, rapid, and cost-effective LC-MRM-MS assay for measuring urinary catecholamines and metanephrines was developed and validated according to the CLSI guidelines. This validated method requires minimal sample manipulation before analysis and provides sensitivity, specificity, and improved precision. The implementation of this assay in clinical laboratories will facilitate early and accurate diagnosis.

Rafeeq P. H. Ahmed, Onur Kanisicak, Perwez Alam

<b>Background</b>: The limited regenerative capacity of adult mammalian cardiomyocytes (CMs) poses a significant challenge for cardiac repair following myocardial infarction. In contrast to adult mammals, CMs in zebrafish and newt hearts retain a lifelong capacity for proliferation and cardiac regeneration. Likewise, neonatal mice exhibit a brief postnatal period, during which CMs retain the ability to proliferate and contribute to myocardial repair, which markedly diminishes within the first week of life. Emerging evidence indicates that adult CM cell cycle progression is critically influenced by oxidative stress. Adult mammalian CMs possess a high mitochondrial content to meet their substantial energy demands. However, this also leads to elevated reactive oxygen species (ROS) production, resulting in DNA damage and subsequent cell cycle arrest. We hypothesize that reducing the mitochondrial content in adult CMs will mitigate ROS production, thereby facilitating cell cycle progression. <b>Methods</b>: Adult CMs were isolated from adult rats (≥12 weeks old). To induce mitophagy, adult CMs were transfected with parkin-expressing plasmid and then treated with carbonyl cyanide 3-chlorophenylhydrazone (CCCP), a mitochondrial protonophore, for 7 days. Post-treatment assessments included the quantification of adult CM proliferation, mitochondrial content, and ROS levels. <b>Results</b>: CCCP-treated adult CMs exhibited a significant increase in proliferation markers, including EdU incorporation, KI67, phospho-histone H3, and Aurora B. Furthermore, CCCP treatment significantly reduced the mitochondrial content, as evidenced by decreased MitoTracker, TMRM, and Tom20 staining compared to controls. This was accompanied by electron microscopy analysis, which showed a significant reduction in the mitochondrial number in the adult CM after CCCP treatment. Moreover, our results also demonstrate a marked reduction in oxidative stress, demonstrated by lower 123-dihydro-rhodamine (123-DHR), CellROX signals, and VDAC. <b>Conclusions</b>: Our findings demonstrate that CCCP-mediated mitochondrial depletion reduces oxidative stress and promotes cell cycle re-entry in adult CM. This study provides direct experimental evidence and substantiates the role of elevated mitochondria and ROS levels in adult CM cell cycle exit.

Wentong Chen, Mengxiao Ge, Shuangyi Sun et al.

Abstract As critical precursors to colorectal cancer (CRC), high-risk colorectal adenomas (HR-CRAs) lack effective chemopreventive strategies beyond endoscopic resection. We previously established a standardized protocol for culturing patient-derived HR-CRA organoids (HR-CRA-PDOs), creating a robust platform for targeted drug discovery in colorectal premalignancy. Bioinformatics investigation was conducted to unveil the significant dysregulation of lipid metabolism in HR-CRAs. HR-CRA-PDOs were primarily cultured and exposed to gradient concentrations of atorvastatin, with drug responses evaluated with high-throughput and high-content imaging and ATP-based viability assays. Parallel in vivo validation utilized AOM/DSS-induced mouse model under either normal or high-fat diets. Histological and molecular analyses were conducted to evaluate adenoma dynamics, apoptosis, and lipid metabolism-related gene and protein expressions. Bioinformatics analysis of GEO database (GSE100179 and GSE161277) revealed that HR-CRAs are characterized by dysregulated lipid metabolism, particularly through the upregulation of fatty acid metabolism pathways. In vitro, atorvastatin significantly inhibited HR-CRA-PDO growth in a dose-dependent manner via apoptosis induction and proliferation arrest. Mechanistically, atorvastatin treatment led to significant alterations of gene expression in lipid metabolism pathways including ACOX1, ACOX2, FABP2, NRG1, PPAR-α and SREBF1, concomitant with stemness marker suppression in HR-CRA-PDOs. In vivo, atorvastatin markedly reduced CRA burden in AOM-DSS-induced mouse model, particularly demonstrating enhanced efficacy in high-fat diet contexts. This translational study establishes atorvastatin’s dual mechanism in metabolic reprogramming and stemness inhibition, suggesting its potential as a therapeutic strategy for CRA prevention and treatment.

Manuel Cuerno, Luis Guijarro, Rosa María Arnaldo Valdés et al.

Analyzing flight trajectory data sets poses challenges due to the intricate interconnections among various factors and the high dimensionality of the data. Topological Data Analysis (TDA) is a way of analyzing big data sets focusing on the topological features this data sets have as point clouds in some metric space. Techniques as the ones that TDA provides are suitable for dealing with high dimensionality and intricate interconnections. This paper introduces TDA and its tools and methods as a way to derive meaningful insights from ATM data. Our focus is on employing TDA to extract valuable information related to airports. Specifically, by utilizing persistence landscapes (a potent TDA tool) we generate footprints for each airport. These footprints, obtained by averaging over a specific time period, are based on the deviation of trajectories and delays. We apply this method to the set of Spanish' airports in the Summer Season of 2018. Remarkably, our results align with the established Spanish airport classification and raise intriguing questions for further exploration. This analysis serves as a proof of concept, showcasing the potential application of TDA in the ATM field. While previous works have outlined the general applicability of TDA in aviation, this paper marks the first comprehensive application of TDA to a substantial volume of ATM data. Finally, we present conclusions and guidelines to address future challenges in the ATM domain.

Anja Levis, Markus Huber, Déborah Mathis et al.

Ketone bodies (KBs) are energy-efficient substrates utilized by the heart depending on its metabolic demand and substrate availability. Levels of circulating KBs have been shown to be elevated in acute and chronic cardiovascular disease and are associated with severity of disease in patients with heart failure and functional outcome after myocardial infarction. To investigate whether this pattern similarly applies to patients undergoing cardiac surgery involving cardiopulmonary bypass (CPB), we analysed prospectively collected pre- and postoperative blood samples from 192 cardiac surgery patients and compared levels and perioperative changes in total KBs with Troponin T as a marker of myocardial cell injury. We explored the association of patient characteristics and comorbidities for each of the two biomarkers separately and comparatively. Median levels of KBs decreased significantly over the perioperative period and inversely correlated with changes observed for Troponin T. Associations of patient characteristics with ketone body perioperative course showed notable differences compared to Troponin T, possibly highlighting factors acting as a “driver” for the change in the respective biomarker. We found an inverse correlation between perioperative change in ketone body levels and changes in troponin, indicating a marked decrease in ketone body concentrations in patients exhibiting greater myocardial cell injury. Further investigations aimed at better understanding the role of KBs on perioperative changes are warranted.

Chunhong Dong, Bao-Zhong Wang

Indrajit Sen

Abstract Non-normalizable states are difficult to interpret in the orthodox quantum formalism but often occur as solutions to physical constraints in quantum gravity. We argue that pilot-wave theory gives a straightforward physical interpretation of non-normalizable quantum states, as the theory requires only a normalized density of configurations to generate statistical predictions. In order to better understand such states, we conduct the first study of non-normalizable solutions of the harmonic oscillator from a pilot-wave perspective. We show that, contrary to intuitions from orthodox quantum mechanics, the non-normalizable eigenstates and their superpositions are bound states in the sense that the velocity field $$v_y \rightarrow 0$$ v y → 0 at large $$\pm y$$ ± y . We argue that defining a physically meaningful equilibrium density for such states requires a new notion of equilibrium, named pilot-wave equilibrium, which is a generalisation of the notion of quantum equilibrium. We define a new H-function $$H_{pw}$$ H pw , and prove that a density in pilot-wave equilibrium minimises $$H_{pw}$$ H pw , is equivariant, and remains in equilibrium with time. We prove an H-theorem for the coarse-grained $$H_{pw}$$ H pw , under assumptions similar to those for relaxation to quantum equilibrium. We give an explanation of the emergence of quantization in pilot-wave theory in terms of instability of non-normalizable states due to perturbations and environmental interactions. Lastly, we discuss applications in quantum field theory and quantum gravity, and implications for pilot-wave theory and quantum foundations in general.

Yuwei Yin, Zhixian Tang, Huachun Weng

Abstract Deep Self-Attention Network (Transformer) is an encoder–decoder architectural model that excels in establishing long-distance dependencies and is first applied in natural language processing. Due to its complementary nature with the inductive bias of convolutional neural network (CNN), Transformer has been gradually applied to medical image processing, including kidney image processing. It has become a hot research topic in recent years. To further explore new ideas and directions in the field of renal image processing, this paper outlines the characteristics of the Transformer network model and summarizes the application of the Transformer-based model in renal image segmentation, classification, detection, electronic medical records, and decision-making systems, and compared with CNN-based renal image processing algorithm, analyzing the advantages and disadvantages of this technique in renal image processing. In addition, this paper gives an outlook on the development trend of Transformer in renal image processing, which provides a valuable reference for a lot of renal image analysis.

ReJoyce Green, Anna E. Kirkland, Brittney D. Browning et al.

OBJECTIVES/GOALS: Adolescence represents a critical period for substance use initiation. Various factors may contribute to trying a sip or single puff of a substance, that could lead to more frequent use. However, less is known about how predictors from multiple domains converge to impact risk for general substance use initiation. METHODS/STUDY POPULATION: The Adolescent Brain Cognitive Development (ABCD) study is a multi-site longitudinal study following youth into early adulthood. The present study included 7,644 ABCD children who reported no lifetime substance use (including any experimentation) at baseline (ages 9–10). Our primary aim was to use a random forest classification model to predict binary substance use initiation, defined as trying any non-prescribed substance (e.g., alcohol, tobacco, cannabis, non-prescribed medications), during a 2-year follow-up after baseline. A total of 402 variables from the following categories were examined as predictors: demographics, peer substance use and availability, mental and physical health, culture and environment, biospecimens, neurocognitive functioning, and structural neuroimaging variables. RESULTS/ANTICIPATED RESULTS: Over a two-year follow-up, 751 (9.8%) of substance-naïve children reported trying a substance by age 11. The most common substance was alcohol, followed by cannabis and tobacco. Mean Decrease Accuracy (MDA) values were used to assess the relative importance of each predictor. The overall accuracy of the model in accurately predicting group membership (no substance use initiation vs. substance use initiation) was 57.66%. Of the top 5 predictors, the most important predictor was intent to use alcohol (MDA = .002). The following top predictors were structural neuroimaging variables: volume and surface area of right lateral occipital lobe (MDA = .0009 and .0008, respectively), surface area of right inferior temporal lobe (MDA = .0007), and surface area of left superior frontal lobe (MDA = .0007). DISCUSSION/SIGNIFICANCE: A combination of intent to use alcohol and structural neuroimaging indices were among the top predictors of substance use initiation. Understanding predictors of early substance use experimentation is important for identifying at-risk youth that may require targeted intervention approaches.

Angelo Mottaran, Amelio Ercolino, Lorenzo Bianchi et al.

<i>Background and Objectives</i>: The aim of this article is to present a single-surgeon, open retroperitoneal lymph node dissection (RPLND) series for testicular cancer in a high-volume center. <i>Materials and Methods</i>: We reviewed data from patients who underwent RPLND performed by an experienced surgeon at our institution between 2000 and 2019. We evaluated surgical and perioperative outcomes, complications, Recurrence-Free Survival (RFS), Overall Survival (OS), and Cancer-Specific Survival (CSS). <i>Results</i>: RPLND was performed in primary and secondary settings in 21 (32%) and 44 (68%) patients, respectively. Median operative time was 180 min. Median hospital stay was 6 days. Complications occurred in 23 (35%) patients, with 9 (14%) events reported as Clavien grade ≥ 3. Patients in the primary RPLND group were significantly younger, more likely to have NSGCT, had higher clinical N0 and M0, and had higher nerve-sparing RPLND (all <i>p</i> ≤ 0.04) compared to those in the secondary RPLND group. In the median follow-up of 120 (56–180) months, 10 (15%) patients experienced recurrence. Finally, 20-year OS, CSS, and RFS were 89%, 92%, and 85%, respectively, with no significant difference in survival rates between primary vs. secondary RPLND subgroups (<i>p</i> = 0.64, <i>p</i> = 0.7, and <i>p</i> = 0.31, respectively). <i>Conclusions</i>: Open RPLND performed by an experienced high-volume surgeon achieves excellent oncological and functional outcomes supporting the centralization of these complex procedures.

Thi-Hong Nhung Nguyen, Thi-Tuyet Trinh Tran, Thi-Hoa Luong et al.

We have established the footprint-free Vietnamese human induced pluripotent stem cell (hiPSC) line, VRISGi002-A, from CD71 + CD235a + erythroid progenitor cells (EPCs) of a 27-year-old healthy donor. The EPCs were enriched from isolated peripheral blood and reprogrammed using Sendai viruses which carried the reprogramming factors c-MYC, SOX2, KLF4, and OCT4 under a feeder-free culture system. The established VRISGi002-A cell line expressed typical pluripotency markers, displayed a normal karyotype, and demonstrated the potential to differentiate into the three germ layers. This hiPSC line could serve as a Vietnamese healthy control model for physiological processes and drug screening.

Yingjie Wang, Lulu Wang, Fuli Hu et al.

High-mobility group box 1 (HMGB1), a member of damage-associated molecular patterns (DAMPs), is involved in the immune regulation of several infectious diseases. <i>Mycoplasma gallisepticum</i> (MG) infection is proved to cause an abnormal immune response, but the role of HMGB1 in MG-induced chronic respiratory disease (CRD) is unclear. In this study, we found that HMGB1 was released from the nucleus to the extracellular in macrophages upon infection with MG. Extracellular HMGB1 bound to TLR2 activating the NF-κB pathway triggering a severe inflammatory storm and promoting the progression of MG infection. More importantly, TLR4 could be activated by HMGB1 to trigger immune disorders after TLR2 was silenced. This disease process could be interrupted by ethyl pyruvate (EP) inhibition of HMGB1 release or glycyrrhizic acid (GA). Furthermore, treatment of MG-infected chickens with GA significantly alleviated immune organ damage. In conclusion, we demonstrate that HMGB1 is secreted extracellularly to form an inflammatory environment upon MG infection, triggering a further cellular inflammatory storm in a positive feedback approach. Blocking MG-induced HMGB1 release or suppression downstream of the HMGB1-TLR2/TLR4 axis may be a promising novel strategy for the treatment of CRD. Furthermore, this study may provide a theoretical reference for understanding non-LPS-activated TLR4 events.

Katja Niesel, Michael Schulz, Julian Anthes et al.

Abstract The tumor microenvironment in brain metastases is characterized by high myeloid cell content associated with immune suppressive and cancer‐permissive functions. Moreover, brain metastases induce the recruitment of lymphocytes. Despite their presence, T‐cell‐directed therapies fail to elicit effective anti‐tumor immune responses. Here, we seek to evaluate the applicability of radio‐immunotherapy to modulate tumor immunity and overcome inhibitory effects that diminish anti‐cancer activity. Radiotherapy‐induced immune modulation resulted in an increase in cytotoxic T‐cell numbers and prevented the induction of lymphocyte‐mediated immune suppression. Radio‐immunotherapy led to significantly improved tumor control with prolonged median survival in experimental breast‐to‐brain metastasis. However, long‐term efficacy was not observed. Recurrent brain metastases showed accumulation of blood‐borne PD‐L1+ myeloid cells after radio‐immunotherapy indicating the establishment of an immune suppressive environment to counteract re‐activated T‐cell responses. This finding was further supported by transcriptional analyses indicating a crucial role for monocyte‐derived macrophages in mediating immune suppression and regulating T‐cell function. Therefore, selective targeting of immune suppressive functions of myeloid cells is expected to be critical for improved therapeutic efficacy of radio‐immunotherapy in brain metastases.

Chih-Ping Chen, Hsiu-Ting Tsai, Schu-Rern Chern et al.

Objective: We present prenatal diagnosis of mosaicism for double aneuploidy of 47, XXY and trisomy 7 (48,XXY,+7) at amniocentesis in a pregnancy with a favorable outcome. Case report: A 33-year-old woman underwent amniocentesis at 17 weeks of gestation because of an increased risk for Down syndrome in maternal serum screening. Amniocentesis revealed a karyotype of 48,XXY,+7[8]/46,XY[16]. Simultaneous array comparative genomic hybridization (aCGH) analysis on uncultured amniocytes revealed the result of arr [GRCh37] (7) × 3 [0.54], (X) × 2 [0.52], (Y) × 1, compatible with trisomy 7 mosaicism and Klinefelter syndrome mosaicism. The parental karyotypes and prenatal ultrasound findings were normal. Repeat amniocentesis performed at 23 weeks of gestation revealed a karyotype of 48,XXY,+7[13]/46,XY[7]. Simultaneous molecular cytogenetic analyses on uncultured amniocytes revealed 30% mosaicism for 48,XXY,+7 by aCGH and 37% (37/100 cells) mosaicism for trisomy 7 and disomy X by interphase fluorescence in situ hybridization (FISH) analysis. Polymorphic DNA marker analysis excluded uniparental disomy (UPD) 7 and indicated a maternal origin of the chromosome aberration. The pregnancy was continued to 39 weeks of gestation, and a 3070-g healthy male baby was delivered. The cord blood had a karyotype of 46,XY, the umbilical cord had a karyotype of 48,XXY,+7[3]/46,XY[37], and the placenta had a karyotype of 48,XXY,+7. At age one month, the neonate was phenotypically normal, and interphase FISH analysis revealed 4.8% (5/105 cells) mosaicism on buccal mucosal cells and 8.9% (8/90 cells) mosaicism on urinary cells for trisomy 7 and disomy X, compared with 2% in normal control. Interphase FISH analysis on buccal mucosal cells at age two months revealed normal findings in 100/100 cells. Conclusion: Mosaic 48,XXY,+7 at amniocentesis without UPD 7 can be associated with a favorable fetal outcome. Cytogenetic discrepancy between cultured amniocytes and uncultured amniocytes may occur in mosaic 48,XXY,+7 at amniocentesis.

Juan Enrique Bender del Busto

<p>Coincidimos con usted en que estamos frente a una enfermedad, producida por un virus altamente patógeno y letal, que se describió por primera vez, en diciembre del pasado año, en Wuhan (China), siendo notificados pacientes con síntomas respiratorios y neumonía que tenían como agente causal un nuevo coronavirus (2019-nCoV), cuya designación taxonómica, el 11 de febrero de 2020, fue síndrome respiratorio agudo por coronavirus 2 (<em>SARS-CoV-2</em>). Posteriormente la enfermedad fue nombrada coronavirus disease 2019 (<em>COVID-19</em>) y considerada pandemia por la Organización Mundial de la Salud el 11 de marzo de 2020.^(1-3)</p>

Ian M. Hastings, Diggory Hardy, Katherine Kay et al.

Abstract Introduction Control strategies for human infections are often investigated using individual‐based models (IBMs) to quantify their impact in terms of mortality, morbidity and impact on transmission. Genetic selection can be incorporated into the IBMs to track the spread of mutations whose origin and spread are driven by the intervention and which subsequently undermine the control strategy; typical examples are mutations which encode drug resistance or diagnosis‐ or vaccine‐escape phenotypes. Methods and results We simulated the spread of malaria drug resistance using the IBM OpenMalaria to investigate how the finite sizes of IBMs require strategies to optimally incorporate genetic selection. We make four recommendations. Firstly, calculate and report the selection coefficients, s, of the advantageous allele as the key genetic parameter. Secondly, use these values of “s” to calculate the wait time until a mutation successfully establishes itself in the pathogen population. Thirdly, identify the inherent limits of the IBM to robustly estimate small selection coefficients. Fourthly, optimize computational efficacy: when “s” is small, fewer replicates of larger IBMs may be more efficient than a larger number of replicates of smaller size. Discussion The OpenMalaria IBM of malaria was an exemplar and the same principles apply to IBMs of other diseases.

Ravleen Nagi, Shashikant Sahu, Dharmendra Gahwai et al.

Introduction: Early recognition of decreased or limited mouth opening in many pathological conditions is necessary for prompt diagnosis and to plan the treatment options judiciously. Therefore, it is essential to establish what constitutes normal opening for the population. Aim: This study was designed with an aim to consider the applicability of this method as an index to measure the maximum mouth opening (MMO) among different age groups in an Indian population. Materials and Methods: Total 400 healthy participants were studied in the age range of 17 to 60 years and stratified into four groups according to their age ranges. The maximum interincisal distance and width of three fingers (index, middle, and ring fingers) at the first distal interphalangeal folds of both right and left hand were measured using Vernier caliper. Statistical analysis was done using SPSS version 21 software package. Results: Results suggested that mean value and range of MMO for males was 51.00 mm (33.0–68.0 mm) and for females it was 46.3 mm (39.0–58.0 mm). Mean values of MMO correlated significantly with the width of three fingers of left and right hand as shown by Pearson correlation test. Conclusion: The study suggested that three finger index is a convenient and reliable tool for assessing normal MMO and is a most appropriate method to normal from restricted mouth opening.

Sylvain Zorman, Aleksander A Rebane, Lu Ma et al.

Soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) are evolutionarily conserved machines that couple their folding/assembly to membrane fusion. However, it is unclear how these processes are regulated and function. To determine these mechanisms, we characterized the folding energy and kinetics of four representative SNARE complexes at a single-molecule level using high-resolution optical tweezers. We found that all SNARE complexes assemble by the same step-wise zippering mechanism: slow N-terminal domain (NTD) association, a pause in a force-dependent half-zippered intermediate, and fast C-terminal domain (CTD) zippering. The energy release from CTD zippering differs for yeast (13 kBT) and neuronal SNARE complexes (27 kBT), and is concentrated at the C-terminal part of CTD zippering. Thus, SNARE complexes share a conserved zippering pathway and polarized energy release to efficiently drive membrane fusion, but generate different amounts of zippering energy to regulate fusion kinetics.

Juan Miguel Chala Tandrón, Liset Jiménez Fernández, Arlette Linares Borges et al.

<span lang="ES-TRAD">Se realizó una revisión acerca de las particularidades que presenta la reanimación cardiopulmonar en el niño.<span> </span>La misma incluye la reanimación básica, y en ella se analizan las particularidades de la ventilación artificial y el masaje cardíaco externo en todos los períodos de la niñez; asimismo, se trata la reanimación avanzada, y se hace énfasis en los cambios recomendados a partir de las Guías del 2000 por la American Heart Association en el empleo de fármacos, vías y soluciones de infusión.</span>

Pemra C. Ünalan, Serap Çifçili