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BACKGROUND: Although laser Doppler imaging (LDI) accurately delineates a hypoperfused area to help target hyaluronidase treatment, laser speckle contrast imaging (LSCI) is more appropriate for assessing microvascular hemodynamics and has greater reproducibility than LDI. This study investigated the use of LSCI in the evaluation and treatment of six patients who developed vascular complications after facial dermal filler injections. METHODS: The areas of vascular occlusion were accurately defined in real time by LSCI and were more precise than visual inspections or photographic evidence for guiding needling and hyaluronidase treatment. RESULTS: All patients had achieved satisfactory outcomes as early as Day 2 of treatment and no procedure-related complications were reported after a median follow-up of 9.5 (7-37) days. CONCLUSION: LSCI accurately and noninvasively delineated vascular occlusions in real time among patients experiencing complications of facial dermal filler injections. Moreover, LSCI was more accurate than visual and photographic evaluations. Clinicians can use LSCI to reliably follow-up therapeutic outcomes after salvage interventions for vascular occlusions. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .
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Técnicas Cosméticas , Preenchedores Dérmicos , Humanos , Preenchedores Dérmicos/efeitos adversos , Imagem de Contraste de Manchas a Laser , Hialuronoglucosaminidase , Reprodutibilidade dos Testes , Indução Percutânea de Colágeno , Técnicas Cosméticas/efeitos adversos , Ácido HialurônicoRESUMO
BACKGROUND AIMS: Mesenchymal stromal cells (MSCs) are recognized as a potential cell-based therapy for regenerative medicine. Short-term inflammatory cytokine pre-stimulation (cytokine priming) is a promising approach to enhance regenerative efficacy of MSCs. However, it is unclear whether their intrinsic heterogenic nature causes an unequal response to cytokine priming, which might blunt the accessibility of clinical applications. METHODS: In this study, by analyzing the single-cell transcriptomic landscape of human bone marrow MSCs from a naïve to cytokine-primed state, we elucidated the potential mechanism of superior therapeutic potential in cytokine-primed MSCs. RESULTS: We found that cytokine-primed MSCs had a distinct transcriptome landscape. Although substantial heterogeneity was identified within the population in both naïve and primed states, cytokine priming enhanced the several characteristics of MSCs associated with therapeutic efficacy irrespective of heterogeneity. After cytokine-priming, all sub-clusters of MSCs possessed high levels of immunoregulatory molecules, trophic factors, stemness-related genes, anti-apoptosis markers and low levels of multi-lineage and senescence signatures, which are critical for their therapeutic potency. CONCLUSIONS: In conclusion, our results provide new insights into MSC heterogeneity under cytokine stimulation and suggest that cytokine priming reprogrammed MSCs independent of heterogeneity.
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Citocinas , Células-Tronco Mesenquimais , Humanos , Análise da Expressão Gênica de Célula Única , Transcriptoma , Perfilação da Expressão GênicaRESUMO
ABSTRACT: Kimura disease (KD) is a rare, chronic inflammatory disorder presenting with solitary or multiple masses. Treatment options include surgical excision, corticosteroids, and radiotherapy; however, optimal therapy remains to be established. Moreover, efficacy of a humanized monoclonal antibody, dupilumab (Dupixent), requires to be demonstrated. Here, we present a 36-year-old male patient with an enlarging mass in the left medial thigh and chronic eczema over the abdomen and lower legs. Kimura disease was diagnosed after surgical excision. Postoperative treatment with dupilumab was applied with an initial dose of 600 mg followed by 300 mg every 2 weeks for 8 months. No recurrence of KD was observed in the 1-year follow-up. The eczematous lesions improved greatly. To our knowledge, this is the first report of using dupilumab for treating KD.
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Doença de Kimura , Coxa da Perna , Adulto , Anticorpos Monoclonais Humanizados/uso terapêutico , Humanos , Masculino , Coxa da Perna/cirurgia , Resultado do TratamentoRESUMO
Few studies have assessed the efficacy and safety of reconstruction of sternal infection using a pectoralis muscle flap combined with a rectus abdominis muscle (RAM) sheath fasciocutaneous flap. We report here our experience with this procedure to reconstruct the sternal defect in patients (n = 46) with a deep sternal wound infection (DSWI) after cardiac surgery. After wound reconstruction, the proportion of prolonged mechanical ventilation use and intensive care unit (ICU) stay were 17.4% (n = 8) and 21.7% (n = 10), respectively. The 30-day all-cause mortality was 15.2%; recurrence rate was 17.4%; postoperative complications were 15.2%; and median hospital stay was 31 (0-157) days. Multivariate logistic regression analysis revealed that hypertension (ß = 21.32, 95%CI 4.955-37.68, P = .014), drainage-tube use (ß = 0.944, 95%CI 0.273-1.614, P = .008), and prolonged intensive care unit stay (ß = 53.65, 95%CI 31.353-75.938, P < .001) were significantly correlated with hospital stay. In conclusion, a procedure including surgical debridement, sternal reconstruction with bilateral PM and RAM sheath flap, long-term antibiotics, and adequate drainage is a beneficial technique in the reconstruction of deep sternal wound infection after cardiac surgery. Duration of drainage tube use may be as an index for a hospital stay or wound healing.
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Músculos Peitorais , Reto do Abdome , Humanos , Músculos Peitorais/cirurgia , Reto do Abdome/cirurgia , Infecção da Ferida Cirúrgica/etiologia , Infecção da Ferida Cirúrgica/cirurgia , Desbridamento/métodos , Estudos Retrospectivos , Esterno/cirurgiaRESUMO
ABSTRACT: The Morel-Lavallée lesion (MLL) is a posttraumatic close degloving injury, which is often underdiagnosed at first. Patients with MLLs usually present with tender and enlarging soft tissue swelling with fluctuation, decreased skin sensation, ecchymosis, or even skin necrosis hours to days after the inciting injury. The lesion can lead to intractable morbidity if it remains untreated. There is no consensus regarding the treatment for MLL at present. Here, we report an MLL in the pretibial region of a 43-year-old woman who experienced a low-energy contusion in a motorbike accident. The pretibial lesion was diagnosed using sonography and fine-needle aspiration. We successfully treated the patient by performing percutaneous debridement via a small incision and injections of fibrin after conservative treatment failed. The method we herein propose achieved the goal of open surgical debridement, providing faster recovery and a high degree of patient comfort. We reviewed the available pertinent literature and propose our own treatment protocol with the aim to establish common therapies ofMLL.
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Adesivo Tecidual de Fibrina , Lesões dos Tecidos Moles , Adulto , Desbridamento , Drenagem , Feminino , Humanos , UltrassonografiaRESUMO
Injection of fillers has gained popularity over the past decades in aesthetic treatments. Calcium hydroxylapatite (CaHA; Radiesse) was introduced in the year 2003 and received approval from the Food and Drug Administration in 2006 for the treatment of moderate-to-severe wrinkles. The properties of CaHA include biostimulation, neocollagenesis, and stability over a long period. However, similar to other fillers, CaHA is associated with the risk of complications such as ecchymosis, inflammation, local infection, skin necrosis, and vascular occlusion. Iatrogenic vision loss remains the most devastating complication related to vascular occlusion. Development of vision impairment is associated with a relatively high risk of permanent damage to vision acuity and poor prognosis. The current report presents a case of a patient who suffered from skin necrosis, vision impairment, and ophthalmoplegia after the injection of CaHA into the nasal dorsum. Significant improvement in visual acuity was observed during hospitalization after the treatment. The patient recovered to near-normal visual acuity and completely recovered from ophthalmoplegia. We aimed to discuss the current treatment employed and review the literature on CaHA-related vision loss.
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Técnicas Cosméticas , Envelhecimento da Pele , Materiais Biocompatíveis , Cálcio , Técnicas Cosméticas/efeitos adversos , Durapatita/efeitos adversos , Humanos , Acuidade VisualRESUMO
Liver transplantation is the only effective therapy for patients with decompensated cirrhosis and fulminant liver failure. However, due to a shortage of donor livers and complications associated with immune suppression, there is an urgent need for new therapeutic strategies for patients with end-stage liver diseases. Given their unique function in self-renewal and differentiation potential, stem cells might be used to regenerate damaged liver tissue. Recent studies have shown that stem cell-based therapies can improve liver function in a mouse model of hepatic failure. Moreover, acellular liver scaffolds seeded with hepatocytes produced functional bioengineered livers for organ transplantation in preclinical studies. The therapeutic potential of stem cells or their differentiated progenies will depend on their capacity to differentiate into mature and functional cell types after transplantation. It will also be important to devise methods to overcome their genomic instability, immune reactivity, and tumorigenic potential. We review directions and advances in the use of mesenchymal stem cells and their derived hepatocytes for liver regeneration. We also discuss the potential applications of hepatocytes derived from human pluripotent stem cells and challenges to using these cells in treating end-stage liver disease.
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Doença Hepática Terminal/história , Transplante de Células-Tronco Mesenquimais/história , Medicina Regenerativa/história , Doença Hepática Terminal/terapia , Hepatócitos/transplante , História do Século XX , História do Século XXI , Humanos , Regeneração HepáticaRESUMO
Microbial drug resistance has become a serious problem of global concern, and the evolution and regulatory mechanisms of microbial drug resistance has become a hotspot of research in recent years. Recent studies showed that certain microbial resistance mechanisms are regulated by quorum sensing system. Quorum sensing is a ubiquitous cell-cell communication system in the microbial world, which associates with cell density. High-density microbial cells produce sufficient amount of small signal molecules, activating a range of downstream cellular processes including virulence and drug resistance mechanisms, which increases bacterial drug tolerance and causes infections on host organisms. In this review, the general mechanisms of microbial drug resistance and quorum-sensing systems are summarized with a focus on the association of quorum sensing and chemical signaling systems with microbial drug resistance mechanisms, including biofilm formation and drug efflux pump. The potential use of quorum quenching as a new strategy to control microbial resistance is also discussed.
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Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Infecções Bacterianas/microbiologia , Farmacorresistência Bacteriana , Percepção de Quorum , Animais , Bactérias/genética , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Humanos , Percepção de Quorum/efeitos dos fármacosRESUMO
Antibiotic resistance has become a serious concern in treatment of bacterial infections. Overexpression of efflux pump is one of the important mechanisms in antibiotic resistance. In Gram negative bacteria, RND (Resistance-nodulation-cell division) superfamily efflux pump plays a vital important role in antibiotics resistance. Recent research progress unveils an intriguing interrelationship between RND efflux pump and the bacterial quorum sensing system, whose regulation is dependent on small signal molecules. This article reviews the latest findings on the structure and transport mechanism of RND efflux pump, as well as the general features and regulatory mechanisms of quorum sensing, with a special focus on the role and mechanism of quorum sensing system in regulation of RND efflux pump, and the influence of efflux pump on quorum sensing signal transportation. Further investigation of the interrelationship between RND efflux pumps and the bacterial quorum sensing systems is critical for elucidation of the regulatory mechanisms that govern the expression of the RND efflux pumps genes, and may also provide useful clues to overcome the efflux pump mediated antibiotic resistance.
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Proteínas de Bactérias/metabolismo , Bactérias Gram-Negativas/fisiologia , Proteínas de Membrana Transportadoras/metabolismo , Percepção de Quorum , Antibacterianos/farmacologia , Proteínas de Bactérias/genética , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Negativas/genéticaRESUMO
The protein complex known as cohesin binds pericentric regions and other sites of eukaryotic genomes to mediate cohesion of sister chromatids. In budding yeast Saccharomyces cerevisiae, cohesin also binds silent chromatin, a repressive chromatin structure that functionally resembles heterochromatin of higher eukaryotes. We developed a protein-targeting assay to investigate the mechanistic basis for cohesion of silent chromatin domains. Individual silencing factors were tethered to sites where pairing of sister chromatids could be evaluated by fluorescence microscopy. We report that the evolutionarily conserved Sir2 histone deacetylase, an essential silent chromatin component, was both necessary and sufficient for cohesion. The cohesin genes were required, but the Sir2 deacetylase activity and other silencing factors were not. Binding of cohesin to silent chromatin was achieved with a small carboxyl terminal fragment of Sir2. Taken together, these data define a unique role for Sir2 in cohesion of silent chromatin that is distinct from the enzyme's role as a histone deacetylase.
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Proteínas de Ciclo Celular/genética , Cromátides/genética , Proteínas Cromossômicas não Histona/genética , Segregação de Cromossomos/genética , Saccharomyces cerevisiae/fisiologia , Proteínas Reguladoras de Informação Silenciosa de Saccharomyces cerevisiae/fisiologia , Sirtuína 2/fisiologia , Cromatina/genética , Microscopia de Fluorescência , Saccharomyces cerevisiae/genética , Proteínas Reguladoras de Informação Silenciosa de Saccharomyces cerevisiae/genética , Sirtuína 2/genética , CoesinasRESUMO
Macrophages play a crucial role in coordinating the skeletal muscle repair response, but their phenotypic diversity and the transition of specialized subsets to resolution-phase macrophages remain poorly understood. To address this issue, we induced injury and performed single-cell RNA sequencing on individual cells in skeletal muscle at different time points. Our analysis revealed a distinct macrophage subset that expressed high levels of Gpnmb and that coexpressed critical factors involved in macrophage-mediated muscle regeneration, including Igf1, Mertk, and Nr1h3. Gpnmb gene knockout inhibited macrophage-mediated efferocytosis and impaired skeletal muscle regeneration. Functional studies demonstrated that GPNMB acts directly on muscle cells in vitro and improves muscle regeneration in vivo. These findings provide a comprehensive transcriptomic atlas of macrophages during muscle injury, highlighting the key role of the GPNMB macrophage subset in regenerative processes. Targeting GPNMB signaling in macrophages could have therapeutic potential for restoring skeletal muscle integrity and homeostasis.
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Acute lung injury (ALI) is a life-threatening condition with limited treatment options. The pathogenesis of ALI involves macrophage-mediated disruption and subsequent repair of the alveolar barriers, which ultimately results in lung damage and regeneration, highlighting the pivotal role of macrophage polarization in ALI. Although exosomes derived from mesenchymal stromal cells have been established as influential modulators of macrophage polarization, the specific role of exosomal microRNAs (miRNAs) remains underexplored. This study aimed to elucidate the role of specific exosomal miRNAs in driving macrophage polarization, thereby providing a reference for developing novel therapeutic interventions for ALI. We found that miR-7704 is the most abundant and efficacious miRNA for promoting the switch to the M2 phenotype in macrophages. Mechanistically, we determined that miR-7704 stimulates M2 polarization by inhibiting the MyD88/STAT1 signaling pathway. Notably, intra-tracheal delivery of miR-7704 alone in a lipopolysaccharide-induced murine ALI model significantly drove M2 polarization in lung macrophages and remarkably restored pulmonary function, thus increasing survival. Our findings highlight miR-7704 as a valuable tool for treating ALI by driving the beneficial M2 polarization of macrophages. Our findings pave the way for deeper exploration into the therapeutic potential of exosomal miRNAs in inflammatory lung diseases.
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PURPOSE: To examine the unmet care needs (i.e., overall needs and need subdomains [physical and daily living needs, psychological and emotional needs, care and support needs, and health-system and informational needs]) of patients with cancer undergoing immunotherapy alone or in combination with other anticancer therapies, as well as related influencing factors. METHODS: A cross-sectional design was adopted. Cancer patients who received immunotherapy completed consent and questionnaires. Unmet care needs were evaluated with the Chinese version of the Supportive Care Needs Survey Screening Tool, symptom severity with the Symptom Severity Scale, distress severity with the Distress Thermometer Scale, and financial toxicity using the Financial Toxicity - Functional Assessment of Chronic Illness Therapy Questionnaire. RESULTS: In total, 105 patients were surveyed. The most frequently reported unmet needs were psychological and emotional needs (56.2%) followed by health-system and informational needs (36.2%). The major factors associated with unmet care needs and their subdomains were years of education, symptoms, distress, and financial toxicity. Years of education predicted overall unmet care needs, psychological and emotional needs, and care and support needs; symptoms predicted overall unmet care needs and all four subdomains; distress predicted psychological and emotional needs and health-system and informational needs; and financial toxicity predicted overall needs and psychological and emotional needs. CONCLUSIONS: Patients with higher education, severe symptoms, distress, and financial toxicity reported more unmet care needs. The findings of this study could be incorporated into immunotherapy-related clinical practice guidelines and future interventions to improve the quality of cancer care.
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Estresse Financeiro , Neoplasias , Humanos , Estudos Transversais , Estresse Psicológico/psicologia , Neoplasias/terapia , Neoplasias/psicologia , Inquéritos e Questionários , Necessidades e Demandas de Serviços de Saúde , Apoio SocialRESUMO
This research aimed to examine the diagnostic accuracy and clinical significance of endoscopic ultrasonography (EUS) in the context of small rectal neuroendocrine neoplasms (NENs). A total of 108 patients with rectal subepithelial lesions (SELs) with a diameter of < 20 mm were included in the analysis. The diagnosis and depth assessment of EUS was compared to the histology findings. The prevalence of NENs in rectal SELs was 78.7% (85/108). The sensitivity of EUS in detecting rectal NENs was 98.9% (84/85), while the specificity was 52.2% (12/23). Overall, the diagnostic accuracy of EUS in identifying rectal NENs was 88.9% (96/108). The overall accuracy rate for EUS in assessing the depth of invasion in rectal NENs was 92.9% (78/84). Therefore, EUS demonstrates reasonable diagnostic accuracy in detecting small rectal NENs, with good sensitivity but inferior specificity. EUS may also assist physicians in assessing the depth of invasion in small rectal NENs before endoscopic excision.
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Tumores Neuroendócrinos , Neoplasias Retais , Humanos , Endossonografia , Relevância Clínica , Tumores Neuroendócrinos/patologia , Neoplasias Retais/patologia , Reto/diagnóstico por imagem , Reto/patologiaRESUMO
Introduction: Forming a bridge made of functional axons to span the lesion is essential to reconstruct the motor circuitry following spinal cord injury (SCI). Dorsal root ganglion (DRG) axons are robust in axon growth and have been proved to facilitate the growth of cortical neurons in a process of axon-facilitated axon regeneration. However, whether DRG transplantation affects the axon outgrowth of spinal motor neurons (SMNs) that play crucial roles in motor circuitry remains unclear. Methods: We investigated the axonal growth patterns of co-cultured DRGs and SMN aggregates (SMNAs) taking advantage of a well-designed 3D-printed in vitro system. Chondroitin sulphate proteoglycans (CSPG) induced inhibitory matrix was introduced to imitate the inhibitory environment following SCI. Axonal lengths of DRG, SMNA or DRG & SMNA cultured on the permissive or CSPG induced inhibitory matrix were measured and compared. Results: Our results indicated that under the guidance of full axonal connection generated from two opposing populations of DRGs, SMNA axons were growth-enhanced and elongated along the DRG axon bridge to distances that they could not otherwise reach. Quantitatively, the co-culture increased the SMNA axonal length by 32.1 %. Moreover, the CSPG matrix reduced the axonal length of DRGs and SMNAs by 46.2 % and 17.7 %, respectively. This inhibitory effect was antagonized by the co-culture of DRGs and SMNAs. Especially for SMNAs, they extended the axons across the CSPG-coating matrix, reached the lengths close to those of SMNAs cultured on the permissive matrix alone. Conclusions: This study deepens our understanding of axon-facilitated reconstruction of the motor circuitry. Moreover, the results support SCI treatment utilizing the enhanced outgrowth of axons to restore functional connectivity in SCI patients.
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UNLABELLED: Liver transplantation is the only definitive treatment for end-stage cirrhosis and fulminant liver failure, but the lack of available donor livers is a major obstacle to liver transplantation. Recently, induced pluripotent stem cells (iPSCs) derived from the reprogramming of somatic fibroblasts, have been shown to resemble embryonic stem (ES) cells in that they have pluripotent properties and the potential to differentiate into all cell lineages in vitro, including hepatocytes. Thus, iPSCs could serve as a favorable cell source for a wide range of applications, including drug toxicity testing, cell transplantation, and patient-specific disease modeling. Here, we describe an efficient and rapid three-step protocol that is able to rapidly generate hepatocyte-like cells from human iPSCs. This occurs because the endodermal induction step allows for more efficient and definitive endoderm cell formation. We show that hepatocyte growth factor (HGF), which synergizes with activin A and Wnt3a, elevates the expression of the endodermal marker Foxa2 (forkhead box a2) by 39.3% compared to when HGF is absent (14.2%) during the endodermal induction step. In addition, iPSC-derived hepatocytes had a similar gene expression profile to mature hepatocytes. Importantly, the hepatocyte-like cells exhibited cytochrome P450 3A4 (CYP3A4) enzyme activity, secreted urea, uptake of low-density lipoprotein (LDL), and possessed the ability to store glycogen. Moreover, the hepatocyte-like cells rescued lethal fulminant hepatic failure in a nonobese diabetic severe combined immunodeficient mouse model. CONCLUSION: We have established a rapid and efficient differentiation protocol that is able to generate functional hepatocyte-like cells from human iPSCs. This may offer an alternative option for treatment of liver diseases.
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Diferenciação Celular/fisiologia , Linhagem da Célula , Transplante de Células/métodos , Hepatócitos/citologia , Células-Tronco Pluripotentes/citologia , Animais , Tetracloreto de Carbono/efeitos adversos , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Glutamina/farmacologia , Fator de Crescimento de Hepatócito/farmacologia , Hepatócitos/fisiologia , Hepatócitos/transplante , Humanos , Técnicas In Vitro , Falência Hepática/induzido quimicamente , Falência Hepática/terapia , Camundongos , Camundongos SCID , Oncostatina M/farmacologia , Células-Tronco Pluripotentes/fisiologia , Resultado do TratamentoRESUMO
Sarcopenia is an age-related progressive loss of skeletal muscle mass, quality, and strength disease. In addition, sarcopenia is tightly correlated with age-associated pathologies, such as sarcopenic obesity and osteoporosis. Further understanding of disease mechanisms and the therapeutic strategies in muscle regeneration requires a deeper knowledge of the interaction of skeletal muscle and other cells in the muscle tissue. Skeletal muscle regeneration is a complex process that requires a series of highly coordinated events involving communication between muscle stem cells and niche cells, such as muscle fibro/adipogenic progenitors and macrophages. Macrophages play a critical role in tissue regeneration and the maintenance of muscle homeostasis by producing growth factors and cytokines that regulate muscle stem cells and myofibroblast activation. Furthermore, the aging-related immune dysregulation associated with the release of trophic factors and the polarization in macrophages transiently affect the inflammatory phase and impair muscle regeneration. In this review, we focus on the role and regulation of macrophages in skeletal muscle regeneration and homeostasis. The aim of this review is to highlight the important roles of macrophages as a therapeutic target in age-related sarcopenia and the increasing understanding of how macrophages are regulated will help to advance skeletal muscle regeneration.
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Background: Reuse of cardiac implantable electronic devices (CIEDs) can reduce the cost of using these expensive devices. However, whether resterilized CIEDs will increase the risk of reinfection in patients with previous device infection remains unknown. The aim of the present study is to compare the reinfection rates in patients who had initial CIED infection and underwent reimplantation of resterilized CIEDs or new devices. Methods: Data from patients with initial CIED infection who received debridement of the infected pocket and underwent reimplantation of new or resterilized CIEDs at MacKay Memorial Hospital, Taipei, Taiwan, between January 2014 and June 2019 were retrospectively analyzed. Patient characteristics, relapse rates of infection, and potential contributing factors to the infection risk were examined. Results: Twenty-seven patients with initial CIED infection and reimplanted new CIEDs (nâ =â 11) or resterilized CIEDs (nâ =â 16) were included. During the 2-year follow-up, there were 1 (9.1%) and 2 (12.5%) infection relapses in the new and resterilized CIED groups, respectively. No relapse occurred for either group if the lead was completely removed or cut short. The median duration between debridement and device reimplantation in patients with infection relapse vs patients without relapse was 97 vs 4.5 days for all included patients, and 97 vs 2 days and 50.5 vs 5.5 days for the new and resterilized CIED groups, respectively. Conclusions: Subpectoral reimplanting of resterilized CIEDs in patients with previous device infection is safe and efficacious. With delicate debridement and complete extraction of the leads, the CIED pocket infection relapse risk can be greatly decreased.
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Cadmium is toxic to the kidney through mechanisms involving oxidative stress and inflammation. We studied reciprocal crosstalk among the oxidative stress, inflammation, and the nuclear Nrf2 pathway in cadmium-induced nephrotoxicity on HK-2 human renal proximal tubular epithelial cells. Cadmium chloride (CdCl2) caused cell viability loss, Reactive Oxygen Species (ROS) generation, glutathione reduction, and Interleukin-6 (IL-6) expression, accompanied by Nrf2 activation and Heme Oxygenase-1 (HO-1) expression. Pharmacological treatments demonstrated cytotprotective and anti-inflammatory effects of Nrf2 activation. Intriguingly, inhibition of HO-1 activity mitigated cell viability loss and IL-6 expression in CdCl2-treated cells. Parallel attenuation by HO-1 inhibitor was demonstrated in cadmium-induced ROS generation and glutathione reduction. CdCl2-treated cells also increased levels of ferrous iron, cGMP, Mitogen-Activated Protein Kinases phosphorylation, as well as NF-κB DNA-binding activity. These increments were mitigated by antioxidant N-Acetyl Cysteine, HO-1 inhibitor SnPP, and PKG inhibitor KT5823, and were mimicked by the Carbon Monoxide-releasing compound. In the kidney cortex of CdCl2-exposed Sprague-Dawley rats, we found similar renal injury, histological changes, ROS generation, IL-6 expression, and accompanied pro-oxidant and pro-inflammatory changes. These observations indicated that cadmium-induced nephrotoxicity was associated with oxidative stress and inflammation, and HO-1 likely acts as a linking molecule to induce nephrotoxicity-associated IL-6 expression upon cadmium exposure.
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Cloreto de Cádmio/toxicidade , Regulação da Expressão Gênica/efeitos dos fármacos , Heme Oxigenase (Desciclizante)/metabolismo , Heme Oxigenase-1/metabolismo , Interleucina-6/metabolismo , Acetilcisteína , Animais , Antioxidantes/farmacologia , Carbazóis , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Heme Oxigenase (Desciclizante)/genética , Humanos , Interleucina-6/genética , Nefropatias/induzido quimicamente , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
BACKGROUND: Spinocerebellar ataxia (SCA) refers to a disease entity in which polyglutamine aggregates are over-produced in Purkinje cells (PCs) of the cerebellum as well as other neurons in the central nervous system, and the formation of intracellular polyglutamine aggregates result in the loss of neurons as well as deterioration of motor functions. So far there is no effective neuroprotective treatment for this debilitating disease although numerous efforts have been made. Mesenchymal stem cells (MSCs) possess multi-lineage differentiation potentials as well as immuno-modulatory properties, and are theoretically good candidates for SCA treatment. The purpose of this study is to investigate whether transplantation of human MSCs (hMSCs) can rescue cerebellar PCs and ameliorate motor function deterioration in SCA in a pre-clinical animal model. METHOD: Transgenic mice bearing poly-glutamine mutation in ataxin-2 gene (C57BL/6J SCA2 transgenic mice) were serially transplanted with hMSCs intravenously or intracranially before and after the onset of motor function loss. Motor function of mice was evaluated by an accelerating protocol of rotarod test every 8 weeks. Immunohistochemical stain of whole brain sections was adopted to demonstrate the neuroprotective effect of hMSC transplantation on cerebellar PCs and engraftment of hMSCs into mice brain. RESULTS: Intravenous transplantation of hMSCs effectively improved rotarod performance of SCA2 transgenic mice and delayed the onset of motor function deterioration; while intracranial transplantation failed to achieve such neuroprotective effect. Immunohistochemistry revealed that intravenous transplantation was more effective in the preservation of the survival of cerebellar PCs and engraftment of hMSCs than intracranial injection, which was compatible to rotarod performance of transplanted mice. CONCLUSION: Intravenous transplantation of hMSCs can indeed delay the onset as well as improve the motor function of SCA2 transgenic mice. The results of this preclinical study strongly support further exploration of the feasibility to transplant hMSCs for SCA patients.