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The increasing antibiotic resistance poses a significant global health challenge, threatening our ability to combat infectious diseases. The phenomenon of collateral sensitivity, whereby resistance to one antibiotic is accompanied by increased sensitivity to another, offers potential avenues for novel therapeutic interventions against infections unresponsive to classical treatments. In this study, we elucidate the emergence of tobramycin (TOB)-resistant small colony variants (SCVs) due to mutations in the hemL gene, which render S. Typhimurium more susceptible to nitrofurantoin (NIT). Mechanistic studies demonstrate that the collateral sensitivity in TOB-resistant S. Typhimurium SCVs primarily stems from disruptions in haem biosynthesis. This leads to dysfunction in the electron transport chain (ETC) and redox imbalance, ultimately inducing lethal accumulation of reactive oxygen species (ROS). Additionally, the upregulation of nfsA/B expressions facilitates the conversion of NIT prodrug into its active form, promoting ROS-mediated bacterial killing and contributing to this collateral sensitivity pattern. Importantly, alternative NIT therapy demonstrates a significant reduction of bacterial load by more than 2.24-log10 cfu/g in the murine thigh infection and colitis models. Our findings corroborate the collateral sensitivity of S. Typhimurium to nitrofurans as a consequence of evolving resistance to aminoglycosides. This provides a promising approach for treating infections due to aminoglycoside-resistant strains.
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Antibacterianos , Nitrofurantoína , Salmonella typhimurium , Tobramicina , Nitrofurantoína/farmacología , Animales , Salmonella typhimurium/efectos de los fármacos , Salmonella typhimurium/genética , Tobramicina/farmacología , Ratones , Antibacterianos/farmacología , Pruebas de Sensibilidad Microbiana , Farmacorresistencia Bacteriana/genética , Mutación , Femenino , Especies Reactivas de Oxígeno/metabolismo , Infecciones por Salmonella/microbiología , Infecciones por Salmonella/tratamiento farmacológico , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismoRESUMEN
As wireless communication devices gain popularity, concerns about the potential risks of environmental exposure to complex frequency electromagnetic radiation (EMR) on mental health have become a public health issue. Historically, EMR research has predominantly focused on single- frequency electromagnetic waves, neglecting the study of multi-frequency electromagnetic waves, which more accurately represent everyday life. To address these concerns, our study compared the emotional effects of single-frequency and dual-frequency EMR while exploring potential molecular mechanisms and intervention targets. Our results revealed that single-frequency EMR at 2.65 or 0.8 GHz did not induce anxiety-like behavior in mice. However, exposure to dual-frequency EMR at 2.65/0.8 GHz significantly led to anxiety-like behavior in mice. Further analysis of mouse sera revealed substantial increases in corticosterone and corticotrophin releasing hormone levels following exposure to 2.65/0.8 GHz EMR. Transcriptome sequencing indicated a significant decrease in the expression of Cnr1, encoding cannabinoid receptor 1 Type (CB1R), in the cerebral. This finding was consistently verified through western blot analysis, revealing a substantial reduction in CB1R content. Additionally, a significant decrease in the endocannabinoid 2-arachidonoylglycerol was observed in the cerebral cortex. Remarkably, administering the cannabinoid receptor agonist Win55-212-2 significantly alleviated the anxiety-like behavior, and the cannabinoid receptor antagonist AM251 effectively counteracted the anti-anxiety effects of Win55-212-2. In summary, our research confirmed that dual-frequency EMR is more likely to induce anxiety-like behavior in mice than single-frequency EMR, with implications for the hypothalamic-pituitary-adrenal axis and the endocannabinoid system. Furthermore, our findings suggest that Win55-212-2 may represent a novel avenue for researching and developing anti-EMR drugs.
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Ensuring adequate and equitable access to affordable HIV testing is a crucial step toward ending the HIV epidemic (EHE). Using the high-burden Baton Rouge Metropolitan Statistical Area (MSA) as an example, we measure spatial access to HIV testing facilities for vulnerable populations and assess whether their access would improve if eliminating a considerable barrier-costs. Locations and status (free, low-cost, and full cost) of HIV testing facilities are searched on the Internet and confirmed through a field survey. Vulnerable populations include the uninsured and people living with HIV (PLWH), disaggregated from county-level HIV prevalence data. Spatial access is computed by a normalized urban-rural two-step floating catchment area (NUR2SFCA) method. Our survey confirms that only 11% and 37% of the 103 Internet-searched HIV testing facilities are indeed free and low-cost. Making more facilities cheaper or free increases the average access of PLWH, the uninsured, and the entire population but their geographic patterns vary. Free testing facilities, clustered in Baton Rouge city, are highly accessible to 82.6%, 69.4%, and 70.2% of three population groups living in East and West Baton Rouge Parish. In comparison, making all low-cost facilities free increases access in most outlying parishes but at the cost of reducing access in East Baton Rouge Parish, leaving west Livingston, north Iberville, and east Pointe Coupee Parish with the poorest access. Making all full-cost facilities cheaper or free exhibits a similar pattern. The study has important policy implications for where and how to improve access to HIV testing for vulnerable populations.
RESUMEN: Medimos el acceso espacial a las instalaciones de pruebas de VIH para poblaciones vulnerables y evaluamos si su acceso mejoraría si se eliminaran las barreras de costos, utilizando como ejemplo el área estadística metropolitana de Baton Rouge, que tiene una alta carga. Nuestra encuesta confirma que el 11% y el 37% de los 103 centros de pruebas de VIH buscados en Internet son efectivamente gratuitos y de bajo costo. Hacer que más instalaciones sean más baratas o gratuitas aumenta el acceso promedio de las PLWH, las personas sin seguro y toda la población, pero sus patrones geográficos varían. Las instalaciones de pruebas gratuitas, agrupadas en la ciudad de Baton Rouge, son muy accesibles para el 82,6%, el 69,4% y el 70,2% de los tres grupos de población del este y oeste de Baton Rouge. En comparación, hacer que las instalaciones de bajo costo sean gratuitas aumenta el acceso en las parroquias periféricas, pero a costa de reducir el acceso en East Baton Rouge. Hacer que las instalaciones de costo total sean más baratas o gratuitas muestra un patrón similar. El estudio tiene importantes implicaciones políticas para mejorar el acceso a las pruebas del VIH para las poblaciones vulnerables.
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Infecciones por VIH , Prueba de VIH , Accesibilidad a los Servicios de Salud , Poblaciones Vulnerables , Humanos , Accesibilidad a los Servicios de Salud/estadística & datos numéricos , Infecciones por VIH/epidemiología , Infecciones por VIH/diagnóstico , Prueba de VIH/estadística & datos numéricos , Louisiana/epidemiología , Femenino , Masculino , Población Urbana/estadística & datos numéricos , Pacientes no Asegurados/estadística & datos numéricos , Prevalencia , Adulto , Tamizaje Masivo/estadística & datos numéricos , Análisis EspacialRESUMEN
With the rapid popularization of wireless electronic devices, there has been an increasing concern about the impacts of the electromagnetic environment on health. However, most research reports on the biological effects of microwaves have focused on a single frequency point. In reality, people are exposed to complex electromagnetic environments that consist of multiple frequency microwave signals in their daily lives. It is important to investigate whether multi-frequency combined microwave energies have different biological effects compared with single frequency microwave energy. Unfortunately, there are limited reports on this topic due to the lack of suitable platforms for research on multi-frequency microwave energy combined with biological exposure. To address this issue, this study presents a setup that has a very wide working frequency bandwidth and can be compatible with single frequency and multi-frequency microwave combined exposure. Moreover, it can achieve relatively equal exposure to multiple biological samples at any frequency point in the working frequency range, which is crucial for electromagnetic biology research. The experimental results are in good agreement with the simulation results, confirming its capability to facilitate the study of complex electromagnetic environment effects on organisms.
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MicroondasRESUMEN
PURPOSE: Oncology outreach is a common strategy for extending cancer care to rural patients. However, a nationwide characterization of the traveling workforce that enables this outreach is lacking, and the extent to which outreach reduces travel burden for rural patients is unknown. METHODS: This cross-sectional study analyzed a rural (nonurban) subset of a 100% fee-for-service sample of 355,139 Medicare beneficiaries with incident breast, colorectal, and lung cancers. Surgical, medical, and radiation oncologists were linked to patients using Part B claims, and traveling oncologists were identified by observing hospital service area (HSA) transition patterns. We defined oncology outreach as the provision of cancer care by a traveling oncologist outside of their primary HSA. We used hierarchical gamma regression models to examine the separate associations between patient receipt of oncology outreach and one-way patient travel times to chemotherapy, radiotherapy, and surgery. RESULTS: On average, 9,935 of 39,960 oncologists conducted annual outreach, where 57.8% traveled with low frequency (0-1 outreach visits/mo), 21.1% with medium frequency (1-3 outreach visits/mo), and 21.1% with high frequency (>3 outreach visits/mo). Oncologists provided surgery, radiotherapy, and chemotherapy to 51,715, 27,120, and 5,874 rural beneficiaries, respectively, of whom 2.5%, 6.9%, and 3.6% received oncology outreach. Rural patients who received oncology outreach traveled 16% (95% CI, 11 to 21) and 11% (95% CI, 9 to 13) less minutes to chemotherapy and radiotherapy than those who did not receive oncology outreach, corresponding to expected one-way savings of 15.9 (95% CI, 15.5 to 16.4) and 11.9 (95% CI, 11.7 to 12.2) minutes, respectively. CONCLUSION: Our study introduces a novel claims-based approach for tracking the nationwide traveling oncology workforce and supports oncology outreach as an effective means for improving rural access to cancer care.
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Viaje , Humanos , Estudios Transversales , Masculino , Femenino , Oncología Médica , Anciano , Neoplasias/terapia , Neoplasias/epidemiología , Población Rural , Estados Unidos/epidemiologíaRESUMEN
OBJECTIVES: Aquatic ecosystems serve as a dissemination pathway and a reservoir of both antibiotic resistant bacteria (ARB) and antibiotic resistance genes (ARGs). This study aimed to determine the prevalence of colistin-resistant mcr-like genes in Enterobacteriales in aquatic products, which may be contribute to the transfer of ARGs in water environments. METHODS: The mcr-1-positive Escherichia coli were recovered from 123 freshwater fish and 34 cultured crocodile cecum samples from 10 farmers' markets in Guangdong, China. Minimum inhibitory concentration (MIC) was determined using the agar dilution method. Genotyping was performed using pulsed-field gel electrophoresis (PFGE) and multi-locus sequence typing (MLST). Conjugation assay was carried out to investigate the transferability of mcr-1. Genomic information was obtained by whole genome sequencing (WGS) and bioinformatic analysis. RESULTS: Forty-four mcr-1 positive isolates showed co-resistance to tetracycline, trimethoprim/sulfamethoxazole, and gentamicin, while they were all sensitive to tigecycline, meropenem, and amikacin. They were typed into sixteen PFGE clusters. ST10 and ST117 were the most popular sequence types, followed by ST1114. S1-PFGE verified the presence of the mcr-1 gene on plasmids in sizes of â¼60 kb (n = 1) and â¼240 kb (n = 3). Whole genome sequencing-based analysis identified mcr-1 integrated in IncHI2 plasmid (n = 3), IncI2 plasmid (n = 2), and bacterial chromosome in two copies (n = 1). In addition to mcr-1, they carried several other antibiotic resistance genes, such as blaCTX-M-14, fosA3, and aac(6')-Ib-cr. CONCLUSION: These data suggest that aquatic products are an important antibiotic resistance reservoir and highlight possible risks regarding food safety.
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Proteínas de Escherichia coli , Escherichia coli , Animales , Tipificación de Secuencias Multilocus , Proteínas de Escherichia coli/genética , Antagonistas de Receptores de Angiotensina , Ecosistema , Inhibidores de la Enzima Convertidora de Angiotensina , Antibacterianos/farmacologíaRESUMEN
We studied the Ni-Cu-acid multifunctional synergism in NiCu-phyllosilicate catalysts toward 1,4-butynediol hydrogenation to 1,4-butanediol by varying the reduction temperature, which can activate different bimetal and support interactions. Compared with a monometallic Ni phyllosilicate (phy), which only showed one type of metal species when reduced at â¼750 °C, there are three types of metal species for the bimetallic Ni-Cu-phyllosilicate derived catalysts, namely Cuphy, differentiated Ni, and Niphy. Thorough structure-activity/selectivity correlation investigations showed that, although the Ni9Cu1-P catalyst matrix can produce tiny amounts of differentiated Ni0 species under the induction of reduced Cu0 at R250 condition, it could not form Ni-Cu bimetallic interactions for the collaborative hydrogenation of 1,4-butynediol, and the product stays in the semi hydrogenated state. When the reduction temperature is raised to 500 °C, stable Ni-Cu alloy active sites exist, accompanied by the strong metal support interaction and metal acid effect derived from the intimate contact between the extracted metal sites and the surviving functional phyllosilicate support; these functionalities yield a supreme hydrogenation performance of the R500 sample with a 1,4-butanediol yield larger than 91.2%.
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Streptococcus suis is a zoonotic pathogen that causes disease in humans after exposure to infected pigs or pig-derived food products. In this study, we examined the serotype distribution, antimicrobial resistance phenotypes and genotypes, integrative and conjugative elements (ICEs), and associated genomic environments of S. suis isolates from humans and pigs in China from 2008 to 2019. We identified isolates of 13 serotypes, predominated by serotype 2 (40/96; 41.7%), serotype 3 (10/96; 10.4%), and serotype 1 (6/96; 6.3%). Whole-genome sequencing analysis revealed that these isolates possessed 36 different sequence types (STs), and ST242 and ST117 were the most prevalent. Phylogenetic analysis revealed possible animal and human clonal transmission, while antimicrobial susceptibility testing indicated high-level resistance to macrolides, tetracyclines, and aminoglycosides. These isolates carried 24 antibiotic resistance genes (ARGs) that conferred resistance to 7 antibiotic classes. The antibiotic resistance genotypes were directly correlated with the observed phenotypes. We also identified ICEs in 10 isolates, which were present in 4 different genetic environments and possessed differing ARG combinations. We also predicted and confirmed by PCR analysis the existence of a translocatable unit (TU) in which the oxazolidinone resistance gene optrA was flanked by IS1216E elements. One-half (5/10) of the ICE-carrying strains could be mobilized by conjugation. A comparison of the parental recipient with an ICE-carrying transconjugant in a mouse in vivo thigh infection model indicated that the ICE strain could not be eliminated with tetracycline treatment. S. suis therefore poses a significant challenge to global public health and requires continuous monitoring, especially for the presence of ICEs and associated ARGs that can be transferred via conjugation. IMPORTANCE S. suis is a serious zoonotic pathogen. In this study, we investigated the epidemiological and molecular characteristics of 96 S. suis isolates from 10 different provinces of China from 2008 to 2019. A subset of these isolates (10) carried ICEs that were able to be horizontally transferred among isolates of different S. suis serotypes. A mouse thigh infection model revealed that ICE-facilitated ARG transfer promoted resistance development. S. suis requires continuous monitoring, especially for the presence of ICEs and associated ARGs that can be transferred via conjugation.
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Oxazolidinonas , Streptococcus suis , Humanos , Porcinos , Animales , Ratones , Streptococcus suis/genética , Filogenia , Farmacorresistencia Microbiana , Antibacterianos/farmacologíaRESUMEN
The purpose of delineating Cancer Service Areas (CSAs) is to define a reliable unit of analysis, more meaningful than geopolitical units such as states and counties, for examining geographic variations of the cancer care markets using geographic information systems (GIS). This study aims to provide a multiscale analysis of the U.S. cancer care markets based on the 2014-2015 Medicare claims of cancer-directed surgery, chemotherapy, and radiation. The CSAs are delineated by a scale-flexible network community detection algorithm automated in GIS so that the patient flows are maximized within CSAs and minimized between them. The multiscale CSAs include those comparable in size to those 4 census regions, 9 divisions, 50 states, and also 39 global optimal CSAs that generates the highest modularity value. The CSAs are more effective in capturing the U.S. cancer care markets because of its higher localization index, lower cross-border utilizations, and shorter travel time. The first two comparisons reveal that only a few regions or divisions are representative of the underlying cancer care markets. The last two comparisons find that among the 39 CSAs, 54% CSAs comprise multiple states anchored by cities near inner state borders, 28% are single-state CSAs, and 18% are sub-state CSAs. Their (in)consistencies across state borders or within each state shed new light on where the intervention of cancer care delivery or the adjustment of cancer care costs are needed to meet the challenges in the U.S. cancer care system. The findings could guide stakeholders to target public health policies for more effective coordination of cancer care in improving outcomes and reducing unnecessary costs.
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Medicare , Neoplasias , Anciano , Estados Unidos/epidemiología , Humanos , Neoplasias/epidemiología , Neoplasias/terapia , Sistemas de Información Geográfica , Algoritmos , CiudadesRESUMEN
Since the Dartmouth hospital service areas (HSAs) were proposed three decades ago, there has been a large body of work using the unit in examining the geographic variation in health care in the U.S. for evaluating health care system performance and informing health policy. However, many studies question the replicability and reliability of the Dartmouth HSAs in meeting the challenges of ever-changing and a diverse set of health care services. This research develops a reproducible, automated, and efficient GIS tool to implement Dartmouth method for defining HSAs. Moreover, the research adapts two popular network community detection methods to account for spatial constraints for defining HSAs that are scale flexible and optimize an important property such as maximum service flows within HSAs. A case study based on the state inpatient database in Florida from the Healthcare Cost and Utilization Project is used to evaluate the efficiency and effectiveness of the methods. The study represents a major step toward developing HSA delineation methods that are computationally efficient, adaptable for various scales (from a local region to as large as a national market), and automated without a steep learning curve for public health professionals.
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BACKGROUND: Traumatic brain injury (TBI) leads to cell and tissue impairment, as well as functional deficits. Stem cells promote structural and functional recovery and thus are considered as a promising therapy for various nerve injuries. Here, we aimed to investigate the role of ectoderm-derived frontal bone mesenchymal stem cells (FbMSCs) in promoting cerebral repair and functional recovery in a murine TBI model. METHODS: A murine TBI model was established by injuring C57BL/6 N mice with moderate-controlled cortical impact to evaluate the extent of brain damage and behavioral deficits. Ectoderm-derived FbMSCs were isolated from the frontal bone and their characteristics were assessed using multiple differentiation assays, flow cytometry and microarray analysis. Brain repairment and functional recovery were analyzed at different days post-injury with or without FbMSC application. Behavioral tests were performed to assess learning and memory improvements. RNA sequencing analysis, immunofluorescence staining, and quantitative reverse-transcription polymerase chain reaction (qRT-PCR) were used to examine inflammation reaction and neural regeneration. In vitro co-culture analysis and quantification of glutamate transportation were carried out to explore the possible mechanism of neurogenesis and functional recovery promoted by FbMSCs. RESULTS: Ectoderm-derived FbMSCs showed fibroblast like morphology and osteogenic differentiation capacity. FbMSCs were CD105, CD29 positive and CD45, CD31 negative. Different from mesoderm-derived MSCs, FbMSCs expressed the ectoderm-specific transcription factor Tfap2ß. TBI mice showed impaired learning and memory deficits. Microglia and astrocyte activation, as well as neural damage, were significantly increased post-injury. FbMSC application ameliorated the behavioral deficits of TBI mice and promoted neural regeneration. RNA sequencing analysis showed that signal pathways related to inflammation decreased, whereas those related to neural activation increased. Immunofluorescence staining and qRT-PCR data revealed that microglial activation and astrocyte polarization to the A1 phenotype were suppressed by FbMSC application. In addition, FGF1 secreted from FbMSCs enhanced glutamate transportation by astrocytes and alleviated the cytotoxic effect of excessive glutamate on neurons. CONCLUSIONS: Ectoderm-derived FbMSC application significantly alleviated neuroinflammation, brain injury, and excitatory toxicity to neurons, improved cognition and behavioral deficits in TBI mice. Therefore, ectoderm-derived FbMSCs could be ideal therapeutic candidates for TBI which mostly affect cells from the same embryonic origins as FbMSCs.
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Lesiones Traumáticas del Encéfalo , Lesiones Encefálicas , Células Madre Mesenquimatosas , Animales , Lesiones Encefálicas/metabolismo , Lesiones Traumáticas del Encéfalo/metabolismo , Ectodermo/metabolismo , Factor 1 de Crecimiento de Fibroblastos/metabolismo , Factor 1 de Crecimiento de Fibroblastos/farmacología , Factor 1 de Crecimiento de Fibroblastos/uso terapéutico , Hueso Frontal/metabolismo , Ácido Glutámico/metabolismo , Ácido Glutámico/farmacología , Ácido Glutámico/uso terapéutico , Inflamación/metabolismo , Inflamación/terapia , Células Madre Mesenquimatosas/metabolismo , Ratones , Ratones Endogámicos C57BL , Microglía/metabolismo , Enfermedades Neuroinflamatorias , OsteogénesisRESUMEN
BACKGROUND: Delays between breast cancer diagnosis and surgery are associated with worsened survival. Delays are more common in urban-residing patients, although factors specific to surgical delays among rural and urban patients are not well understood. METHODS: We used a 100% sample of fee-for-service Medicare claims during 2007-2014 to identify 238,491 women diagnosed with early-stage breast cancer undergoing initial surgery and assessed whether they experienced biopsy-to-surgery intervals > 90 days. We employed multilevel regression to identify associations between delays and patient, regional, and surgeon characteristics, both in combined analyses and stratified by rurality of patient residence. RESULTS: Delays were more prevalent among urban patients (2.5%) than rural patients (1.9%). Rural patients with medium- or high-volume surgeons had lower odds of delay than patients with low-volume surgeons (odds ratio [OR] = 0.71, 95% confidence interval [CI] = 0.58-0.88; OR = 0.74, 95% CI = 0.61-0.90). Rural patients whose surgeon operated at ≥ 3 hospitals were more likely to experience delays (OR = 1.29, 95% CI = 1.01-1.64, Ref: 1 hospital). Patient driving times ≥ 1 h were associated with delays among urban patients only. Age, black race, Hispanic ethnicity, multimorbidity, and academic/specialty hospital status were associated with delays. CONCLUSIONS: Sociodemographic, geographic, surgeon, and facility factors have distinct associations with > 90-day delays to initial breast cancer surgery. Interventions to improve timeliness of breast cancer surgery may have disparate impacts on vulnerable populations by rural-urban status.
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Neoplasias de la Mama , Medicare , Anciano , Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/cirugía , Femenino , Hispánicos o Latinos , Humanos , Oportunidad Relativa , Población Rural , Estados Unidos/epidemiologíaRESUMEN
A large number of studies on the biological effects of microwaves are carried out using rodents and cells, but the conditions are difficult to control, and the irradiation period is short; the results obtained have always been controversial and difficult to reproduce. In this study, we expose nematodes to an electromagnetic environment for a long-term and multigeneration period to explore the possible biological effects. Wild-type N2 strains of Caenorhabditis elegans are exposed to 9.4 GHz microwaves at a specific adsorption rate of 4 W/kg for 10 h per day from L1 larvae to adults. Then, adult worms are washed off, and the laid eggs are kept to hatch L1 larvae, which are continuously exposed to microwaves until passing through 20 generations. The worms of the 10th, 15th, and 20th generations are collected for index detection. Interestingly, we found that the fecundity of C. elegans decreased significantly in the exposed group from the 15th generation. At the same time, we found that the growth of C. elegans decreased, motility decreased, and oxidative stress occurred in the exposed group from the 10th generation, which may play roles in the decreased spawning in worms. We preliminarily believe that the microwave energy received by worms leads to oxidative stress, which causes a decrease in the spawning rate, and the underlying mechanism needs to be further studied. © 2022 Bioelectromagnetics Society.
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Caenorhabditis elegans , Microondas , Animales , Caenorhabditis elegans/efectos de la radiación , Fenómenos ElectromagnéticosRESUMEN
Stem-cell therapy provides a promising strategy for patients with ischemic heart disease. In recent years, numerous studies related to this therapeutic approach were performed; however, the results were often heterogeneous and contradictory. For this reason, we conducted a systematic review and meta-analysis of trials, reporting the use of stem-cell treatment against acute or chronic ischemic cardiomyopathies in large animal models with regard to Left Ventricular Ejection Fraction (LVEF). The defined research strategy was applied to the PubMed database to identify relevant studies published from January 2011 to July 2021. A random-effect meta-analysis was performed on LVEF mean data at follow-up between control and stem-cell-treated animals. In order to improve the definition of the effect measure and to analyze the factors that could influence the outcomes, a subgroup comparison was conducted. Sixty-six studies (n = 1183 animals) satisfied our inclusion criteria. Ischemia/reperfusion infarction was performed in 37 studies, and chronic occlusion in 29 studies; moreover, 58 studies were on a pig animal model. The meta-analysis showed that cell therapy increased LVEF by 7.41% (95% Confidence Interval 6.23−8.59%; p < 0.001) at follow-up, with significative heterogeneity and high inconsistency (I2 = 82%, p < 0.001). By subgroup comparison, the follow-up after 31−60 days (p = 0.025), the late cell injection (>7 days, p = 0.005) and the route of cellular delivery by surgical treatment (p < 0.001) were significant predictors of LVEF improvement. This meta-analysis showed that stem-cell therapy may improve heart function in large animal models and that the swine specie is confirmed as a relevant animal model in the cardiovascular field. Due to the significative heterogeneity and high inconsistency, future translational studies should be designed to take into account the evidenced predictors to allow for the reduction of the number of animals used.
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Compelling evidence has confirmed that inflammatory pathways involving TLR4-regulated cytokines and immune cells are vitallyimportant for the pathogenesis of posthemorrhagic hydrocephalus (PHH), hinting that pharmacological prevention of PHH is feasible. TAK-242, as a toll-like receptor 4 (TLR4) inhibitor, downregulates TLR4-induced inflammatory responses and becomes a potent and noveltherapeuticdrugcandidatefor PHH. In the present study, we investigate whether TAK-242 protects against hydrocephalus and improves the prognosis of intraventricular hemorrhage (IVH). We also explore the possible role of TAK-242 for the regulation of TLR4-NF-κB signaling pathway. A model of PHH was conducted in 6-week-old Male Sprague-Dawley (SD) rats. The rats were divided into four main groups, including the sham, IVH + vehicle, IVH + TAK-242 and IVH groups. Magnetic resonance imaging (MRI) was applied to measure the lateral ventricle volume. Western blot (WB) and immunofluorescence (IF) were applied to detect the expression of TLR4, NF-κB, fibronectin and laminin. A combined scoring system and Morris water maze were employed to evaluate neurological functions after IVH. We found that IVH induced heightened activation of TLR4-NF-κB signaling pathway. We observed the increased lateral ventricular volume, elevation of NF-κB in choroidplexus, as well as fibronectin and laminin in the subarachnoid space (SAS) and ventricular wall after IVH. Obviously, TAK-242 treatment effectively inhibited the up-regulation of NF-κB, fibronectin, laminin and significantly alleviated ventriculomegaly after IVH. Importantly, TAK-242 improved neurocognitive deficits after PHH. In conclusion, TAK-242 attenuated IVH-induced hydrocephalus and improved the prognosis of PHH. The underlying mechanism involved the TAK-242-mediated downregulation of TLR4-NF-κB signaling pathway.
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Hidrocefalia , Receptor Toll-Like 4 , Animales , Hemorragia Cerebral/tratamiento farmacológico , Hidrocefalia/tratamiento farmacológico , Hidrocefalia/etiología , Hidrocefalia/metabolismo , Masculino , FN-kappa B/metabolismo , Ratas , Ratas Sprague-Dawley , Transducción de Señal , Sulfonamidas , Receptor Toll-Like 4/metabolismoRESUMEN
BACKGROUND: The homeostasis of mesenchymal stem cells (MSCs) is modulated by both their own intracellular molecules and extracellular milieu signals. Hematopoiesis in the bone marrow is maintained by niche cells, including MSCs, and it is indispensable for life. The role of MSCs in maintaining hematopoietic homeostasis has been fully elucidated. However, little is known about the mechanism by which hematopoietic cells reciprocally regulate niche cells. The present study aimed to explore the close relationship between MSCs and hematopoietic cells, which may be exploited for the development of new therapeutic strategies for related diseases. METHODS: In this study, we isolated cells from the offspring of Tie2Cre + and Ptenflox/flox mice. After cell isolation and culture, we investigated the effect of hematopoietic cells on MSCs using various methods, including flow cytometry, adipogenic and osteogenic differentiation analyses, quantitative PCR, western bloting, and microCT analysis. RESULTS: Our results showed that when the phosphatase and tensin homolog deleted on chromosome 10 (Pten) gene was half-deleted in hematopoietic cells, hematopoiesis and osteogenesis were normal in young mice; the frequency of erythroid progenitor cells in the bone marrow gradually decreased and osteogenesis in the femoral epiphysis weakened as the mice grew. The heterozygous loss of Pten in hematopoietic cells leads to the attenuation of osteogenic differentiation and enhanced adipogenic differentiation of MSCs in vitro. Co-culture with normal hematopoietic cells rescued the abnormal differentiation of MSCs, and in contrast, MSCs co-cultured with heterozygous null Pten hematopoietic cells showed abnormal differentiation activity. Co-culture with erythroid progenitor cells also revealed them to play an important role in MSC differentiation. CONCLUSION: Our data suggest that hematopoietic cells function as niche cells of MSCs to balance the differentiation activity of MSCs and may ultimately affect bone development.
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Células Madre Mesenquimatosas , Osteogénesis , Animales , Células de la Médula Ósea , Diferenciación Celular/fisiología , Células Cultivadas , Hematopoyesis/genética , RatonesRESUMEN
Because of the extensive application of electromagnetic technology, its health impact on humans has attracted widespread attention. Due to the lack of a model organism with a stable response to electromagnetic waves, the research conclusions on the biological effects of electromagnetic waves have been vague. Therefore, the aim of this study was to investigate the effects of irradiation by pulsed 9.4 GHz high-power microwaves with a peak power density of 2126 W/cm2 using Caenorhabditis elegans. The development, movement, egg production, ROS, and lifespan of C. elegans were detected at different times after irradiation with different repetitive frequencies of 10, 20, and 50 Hz for 30 min. The results indicated that no obvious changes in basic life indices were induced compared with the sham radiation group, but the survival rate of positive control was significantly decreased compared with other groups, which is of interest for microwave protection research based on C. elegans and provides data for updating safety standards with respect to pulsed high-peak power microwave. © 2021 Bioelectromagnetics Society.
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Caenorhabditis elegans , Microondas , Animales , Fenómenos Electromagnéticos , HumanosRESUMEN
Defining a reliable geographic unit pertaining to cancer care is essential in its assessment, planning, and management. This study aims to delineate and characterize the cancer service areas (CSA) accounting for the presence of major cancer centers in the United States. We used the Medicare enrollment and claims from January 1, 2014 to September 30, 2015 to build a spatial network from patients with cancer to cancer care facilities that provided inpatient and outpatient care of cancer-directed surgery, chemotherapy, and radiation. After excluding those without clinical care or outside of the United States, we identified 94 NCI-designated and other academic cancer centers from the members of the Association of American Cancer Institutes. By explicitly incorporating existing specialized cancer referral centers, we refined the spatially constrained Leiden method that accounted for spatial adjacency and other constraints to delineate coherent CSAs within which the service volumes were maximal but minimal between them. The derived 110 CSAs had a high mean localization index (LI; 0.83) with a narrow variability (SD = 0.10). The variation of LI across the CSAs was positively associated with population, median household income, and area size, and negatively with travel time. Averagely, patients traveled less and were more likely to receive cancer care within the CSAs anchored by cancer centers than their counterparts without cancer centers. We concluded that CSAs are effective in capturing the local cancer care markets in the United States. They can be used as reliable units for studying cancer care and informing more evidence-based policy. Significance: Using the most refined network community detection method, we can delineate CSAs in a more robust, systematic, and empirical manner that incorporates existing specialized cancer referral centers. The CSAs can be used as a reliable unit for studying cancer care and informing more evidence-based policy in the United States. The cross-walk tabulation of ZIP code areas, CSAs, and related programs for CSAs delineation are disseminated for public access.
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Medicare , Neoplasias , Anciano , Humanos , Estados Unidos/epidemiología , Neoplasias/diagnóstico , RentaRESUMEN
Constructing service areas is an important task for evaluating geographic variation of health care markets. This study uses cancer care as an example to illustrate the methodology, with the nine-state Northeast Region of the U.S. as the study area. Two recent algorithms of network community detection are implemented to account for additional constraints such as spatial connectivity and threshold region size. The refined methods are termed "spatially-constrained Louvain (ScLouvain)" and "spatially-constrained Leiden (ScLeiden)" algorithms, corresponding to their predecessors Louvain and Leiden algorithms, respectively. Both are network optimization methods that maximize flows within delineated communities while minimizing inter-community flows. The service areas derived by the methods, termed "Cancer Service Areas (CSAs)", are more favorable than the commonly used comparable unit, Hospital Referral Regions (HRRs) for evaluating cancer-specific variation in care. Between the two, the ScLeiden performs better than ScLouvain in modularity, localization index and computational efficiency, and thus is recommended as an effective and efficient approach for defining functional regions.
RESUMEN
PURPOSE: Spatial behavior of patients in utilizing health care reflects their travel burden or mobility, accessibility for medical service, and subsequently outcomes from treatment. This paper derives the best-fitting distance decay function to capture the spatial behaviors of cancer patients in the Northeast region of the U.S., and examines and explains the spatial variability of such behaviors across sub-regions. PRINCIPAL RESULTS: (1) 46.8%, 85.5%, and 99.6% of cancer care received was within a driving time of 30, 60 and 180 minutes, respectively. (2) The exponential distance decay function is the best in capturing the travel behavior of cancer patients in the region and across most sub-regions. (3) The friction coefficient in the distance decay function is negatively correlated with the mean travel time. (4) The best-fitting function forms are associated with network structures. (5) The variation of the friction coefficient across sub-regions is related to factors such as urbanicity, economic development level, and market competition intensity. MAJOR CONCLUSIONS: The distance decay function offers an analytic metric to capture a full spectrum of travel behavior, and thus a more comprehensive measure than average travel time. Examining the geographic variation of travel behavior needs a reliable analysis unit such as organically defined "cancer service areas", which capture relevant health care market structure and thus are more meaningful than commonly-used geopolitical or census area units.