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BACKGROUND: The extent of perfusion of a deep inferior epigastric artery perforator (DIEP) flap is a primary concern for surgeons. This study aimed to determine whether the flap area or volume can be estimated using perforator and flap characteristics. METHODS: Intraoperative flap perfusion was assessed using indocyanine green angiography in patients who underwent DIEP flap breast reconstruction between November 2018 and February 2023. The area perfused by a single dominant perforator was delineated on the surface of the flap and measured using the ImageJ software. Multiple linear regression analysis was conducted to estimate the 'perfusion ratio,' defined as the perfused area divided by the total flap area. Potential predictor variables included flap size (cm2), flap thickness (mm), perforator diameter (mm), perforator rows (medial/lateral), vertical location of perforator (at or above/below the umbilicus), and perforator eccentricity (vertical distance from upper flap margin to perforator, cm). RESULTS: In total, 101 patients were included in this analysis. The mean 'perfusion ratio' was 67.8% ± 11.5%, predicted by perforator diameter (p = 0.022) and vertical location below umbilicus (p < 0.001) with positive correlations and negatively correlated with flap thickness (p = 0.003) in the multivariable analysis. Both perfusion area and weight were predicted by perforator diameter, vertical location of perforator, flap size, and flap thickness (p < 0.001). The coefficient of determination (adjusted R2) for prediction of perfusion weight was higher than that for the perfusion area (75.5% vs. 69.4%). CONCLUSIONS: Flap volume, rather than area, is determined by a perforator of a given diameter and location.
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BACKGROUND: Concomitant iatrogenic proximal venous stenosis increases venous pressure and can be a risk factor for unfavorable outcomes of lymphaticovenular anastomosis (LVA) in extremities with secondary lymphedema. This study investigated the frequency and relevant factors of venous stenosis in patients diagnosed with secondary lymphedema who underwent LVA. METHODS: Patients who underwent preoperative computed tomographic venography (CTV) and LVA for secondary lymphedema of the extremities from October 2018 to March 2022 were included. The incidence of proximal venous stenosis in the affected limb on preoperative CTV and the rate of endovascular intervention were compared between upper and lower extremities. Factors affecting proximal venous stenosis were identified through multivariable analysis using independent variables, including patient age, body mass index, comorbidities, smoking history, radiation therapy, duration of lymphedema, and location of lymphedema. RESULTS: A total of 211 patients were analyzed, including 83 patients with upper extremity and 128 patients with lower extremity lymphedema. The incidence of proximal venous stenosis in the preoperative CTV was 32.5% and 7.8% in upper extremity, and lower extremity lymphedema, respectively (P < .001). The incidence of venous stenosis requiring endovascular intervention was significantly higher in the upper extremity compared with the lower extremity (16.9% vs 6.3%; P = .014). In multivariable analysis, risk factors affecting incidence of venous stenosis requiring endovascular intervention was the patient age (P = .007) and upper extremity (P = .009). CONCLUSIONS: Preoperative evaluation and treatment of venous stenosis in extremities with secondary lymphedema are necessary before LVA surgery, particularly in upper extremity lymphedema.
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Soft electronics have significantly enhanced user convenience and data accuracy in wearable devices, implantable devices, and human-machine interfaces. However, a persistent challenge in their development has been the disconnection between the rigid and soft components of devices due to the substantial difference in modulus and stretchability. To address this issue, establishing a durable and flexible connection that smoothly links components of varying stiffness to signal-capturing sections with a lower stiffness is essential. In this study, we developed a novel stretchable interconnect that strongly adheres to various materials, facilitating electrical connections effortlessly by applying minimal finger pressure. Capable of stretching up to 1000% while maintaining electrical integrity, this interconnect proves its applicability across multiple domains, including electrocardiogram (ECG), electromyography (EMG), and stretchable light-emitting diode (LED) circuits. Its versatility is further demonstrated through its compatibility with various manufacturing techniques such as 3D printing, painting, and spin coating, highlighting its adaptability in soft electronics.
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We aimed to develop an automated detector that determines laryngeal invasion during swallowing. Laryngeal invasion, which causes significant clinical problems, is defined as two or more points on the penetration-aspiration scale (PAS). We applied two three-dimensional (3D) stream networks for action recognition in videofluoroscopic swallowing study (VFSS) videos. To detect laryngeal invasion (PAS 2 or higher scores) in VFSS videos, we employed two 3D stream networks for action recognition. To establish the robustness of our model, we compared its performance with those of various current image classification-based architectures. The proposed model achieved an accuracy of 92.10%. Precision, recall, and F1 scores for detecting laryngeal invasion (≥PAS 2) in VFSS videos were 0.9470 each. The accuracy of our model in identifying laryngeal invasion surpassed that of other updated image classification models (60.58% for ResNet101, 60.19% for Swin-Transformer, 63.33% for EfficientNet-B2, and 31.17% for HRNet-W32). Our model is the first automated detector of laryngeal invasion in VFSS videos based on video action recognition networks. Considering its high and balanced performance, it may serve as an effective screening tool before clinicians review VFSS videos, ultimately reducing the burden on clinicians.
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Colorectal cancer (CRC) remains a global health burden, accounting for almost a million deaths annually. Deoxybouvardin (DB), a non-ribosomal peptide originally isolated from Bouvardia ternifolia, has been reported to possess antitumor activity; however, the detailed mechanisms underlying this anticancer activity have not been elucidated. We investigated the anticancer activity of the cyclic hexapeptide, DB, in human CRC HCT116 cells. Cell viability, evaluated by MTT assay, revealed that DB suppressed the growth of both oxaliplatin (Ox)-resistant HCT116 cells (HCT116-OxR) and Ox-sensitive cells in a concentration- and time-dependent manner. Increased reactive oxygen species (ROS) generation was observed in DB-treated CRC cells, and it induced cell cycle arrest at the G2/M phase by regulating p21, p27, cyclin B1, and cdc2 levels. In addition, Western blot analysis revealed that DB activated the phosphorylation of JNK and p38 MAPK in CRC. Furthermore, mitochondrial membrane potential (MMP) was dysregulated by DB, resulting in cytochrome c release and activation of caspases. Taken together, DB exhibited anticancer activity against both Ox-sensitive and Ox-resistant CRC cells by targeting JNK and p38 MAPK, increasing cellular ROS levels, and disrupting MMP. Thus, DB is a potential therapeutic agent for the treatment of Ox-resistant CRC.
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We evaluated modulation of the immunosuppressive tumor microenvironment in both local and liver metastatic colorectal cancer (LMCC), focusing on tumor-associated macrophages, which are the predominant immunosuppressive cells in LMCC. We developed an orally administered metronomic chemotherapy regimen, oral CAPOX. This regimen combines capecitabine and a nano-micelle encapsulated, lysine-linked deoxycholate and oxaliplatin complex (OPt/LDC-NM). The treatment effectively modulated immune cells within the tumor microenvironment by activating the cGAS-STING pathway and inducing immunogenic cell death. This therapy modulated immune cells more effectively than did capecitabine monotherapy, the current standard maintenance chemotherapy for colorectal cancer. The macrophage-modifying effect of oral CAPOX was mediated via the cGAS-STING pathway. This is a newly identified mode of immune cell activation induced by metronomic chemotherapy. Moreover, oral CAPOX synergized with anti-PD-1 antibody (αPD-1) to enhance the T-cell-mediated antitumor immune response. In the CT26. CL25 subcutaneous model, combination therapy achieved a 91 % complete response rate with a confirmed memory effect against the tumor. This combination also altered the immunosuppressive tumor microenvironment in LMCC, which αPD-1 monotherapy could not achieve. Oral CAPOX and αPD-1 combination therapy outperformed the maximum tolerated dose for treating LMCC, suggesting metronomic therapy as a promising strategy.
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Neoplasias Colorretais , Neoplasias Hepáticas , Proteínas de Membrana , Nucleotidiltransferases , Oxaliplatina , Microambiente Tumoral , Microambiente Tumoral/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Neoplasias Colorretais/imunologia , Animais , Proteínas de Membrana/metabolismo , Oxaliplatina/farmacologia , Oxaliplatina/uso terapêutico , Oxaliplatina/administração & dosagem , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/imunologia , Administração Oral , Linhagem Celular Tumoral , Nucleotidiltransferases/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Capecitabina/farmacologia , Capecitabina/uso terapêutico , Capecitabina/administração & dosagem , Humanos , Transdução de Sinais/efeitos dos fármacos , Feminino , Ácido Desoxicólico/química , Ácido Desoxicólico/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Macrófagos Associados a Tumor/efeitos dos fármacos , Macrófagos Associados a Tumor/imunologia , Macrófagos Associados a Tumor/metabolismoRESUMO
BACKGROUND AND OBJECTIVE: This study aimed to assess and compare the pharmacokinetics, safety, and tolerability of a fixed-dose combination product (FDCP) comprising four different drugs (two antihypertensive drugs, amlodipine and losartan, and two lipid-lowering agents, ezetimibe and rosuvastatin) with their separate tablets. METHODS: A total of 60 participants were enrolled in this open-label, randomized, single-dose crossover study. Each participant received a single dose of FDCP and individual tablets during each period, with a 14-day washout period between the periods. The pharmacokinetic parameters of amlodipine, losartan, EXP3174 (an active metabolite of losartan), rosuvastatin, free ezetimibe, and total ezetimibe were evaluated and compared. RESULTS: The pharmacokinetic profiles of amlodipine, losartan, rosuvastatin, and ezetimibe after administration of the individual products were similar to those of FDCP. The geometric mean ratios and 90% confidence intervals for maximum concentration (Cmax) and area under the curve (AUC) of FDCP to individual tablets were within 0.8-1.25 for all six analytes. No clinically relevant changes were observed in the vital signs or physical, biochemical, hematological, electrocardiographic, or urinalysis findings during the study, and no serious adverse events were reported. CONCLUSION: This study demonstrated that a newly developed FDCP containing amlodipine, losartan, ezetimibe, and rosuvastatin exhibited pharmacokinetic equivalence with the individual products and met the regulatory criteria. Both formulations were well tolerated. CLINICAL TRIAL REGISTRATION: This trial (NCT04322266) was retrospectively registered on 9 September 2019.
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Anlodipino , Estudos Cross-Over , Combinação de Medicamentos , Ezetimiba , Voluntários Saudáveis , Losartan , Rosuvastatina Cálcica , Humanos , Rosuvastatina Cálcica/farmacocinética , Rosuvastatina Cálcica/administração & dosagem , Anlodipino/farmacocinética , Anlodipino/administração & dosagem , Anlodipino/efeitos adversos , Masculino , Ezetimiba/farmacocinética , Ezetimiba/administração & dosagem , Losartan/farmacocinética , Losartan/administração & dosagem , Adulto , Feminino , Adulto Jovem , Pessoa de Meia-Idade , Anti-Hipertensivos/farmacocinética , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/efeitos adversos , Comprimidos , Anticolesterolemiantes/farmacocinética , Anticolesterolemiantes/administração & dosagem , Área Sob a CurvaRESUMO
Periodontitis is known to be affected by high-glucose conditions, which poses a challenge to periodontal tissue regeneration, particularly in bone formation. In this study, the potential effects of resveratrol (3,5,4'-trihydroxystilbene, RSV) in facilitating bone formation under high-glucose conditions after periodontitis has been investigated. We focused on the analysis of osteoblasts and periodontal ligament cells, which are essential for bone formation including cell proliferation and differentiation. And we aimed to investigate the impact of RSV on bone healing, employed diabetic mouse model induced by streptozotocin and confirmed through histological observation. High-glucose conditions adversely affected cell proliferation and ALP activity in both MC3T3-E1 and hPDLF in vitro, with more significant impact on MC3T3-E1 cells. RSV under high-glucose conditions had positive effects on both, showing early-stage effects for MC3T3-E1 cells and later-stage effects for hPDLF cells. RSV seemed to have a more pronounced rescuing role in MC3T3-E1 cells. Increased ALP activity was observed and the expression levels of significant genes, such as Col 1, TGF-ß1, ALP, and OC, in osteogenic differentiation were exhibited stage-specific expression patterns. Upregulated Col 1 and TGF-ß1 were detected in the early stage, and then ALP and OC expressions became more pronounced in the later stages. Similarly, stronger positive reactions against RUNX2 were detected in the RSV-treated group compared to the control. Furthermore, in in vivo experiment, RSV stimulates the growth and differentiation of osteoblasts, thereby promoting bone formation. High-glucose levels have the potential to impair cellular functions and the regenerative capacity to facilitate bone formation with MC3T3-E1 rather than hPDLF cells. Resveratrol appears to facilitate the inherent abilities of MC3T3-E1 cells compared with hPDLF cells, indicating its potential capacity to restore functionality during periodontal regeneration.
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PURPOSE: This study aimed to evaluate the effect of pretreatment of three different universal adhesives (Single Bond Universal [SBU], All-Bond Universal [ABU], and Prime&Bond universal [PBU]) on the bonding durability of an adhesive (Panavia F 2.0, PF) and a conventional (Duo-Link, DL) resin cements to air-abraded zirconia. MATERIALS AND METHODS: Rectangular-shaped zirconia specimens were prepared. The chemical composition and surface energy parameters of the materials were studied by Fourier transform infrared spectroscopy and contact angle measurement, respectively. To evaluate resin bonding to the zirconia, all the bonding specimens were immersed in water for 24 h and the specimens to be aged were additionally thermocycled 10000 times before the shear bond strength (SBS) test. RESULTS: The materials showed different surface energy parameters, including the degree of hydrophilicity/hydrophobicity. While the DL/CON (no pretreatment) showed the lowest SBS and a significant decrease in the value after thermocycling (P < .001), the PF/CON obtained a higher SBS value than the DL/CON (P < .001) and no decrease even after thermocycling (P = .839). When the universal adhesives were used with DL, their SBS values were higher than the CON (P < .05), but the trend was adhesive-specific. In conjunction with PF, the PF/SBU produced the highest SBS followed by the PF/ABU (P = .002), showing no significant decrease after thermocycling (P > .05). The initial SBS of the PF/PBU was similar to the PF/CON (P = .999), but the value decreased after thermocycling (P < .001). CONCLUSION: The universal adhesive pretreatment did not necessarily show a synergistic effect on the bonding performance of an adhesive resin cement, whereas the pretreatment was beneficial to bond strength and durability of a conventional resin cement.
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PURPOSE: The specific characteristics of autonomic involvement in patients with early Parkinson's disease (PD) are unclear. This study aimed to evaluate the characteristics of autonomic dysfunction in drug-naïve patients with early-stage PD without orthostatic hypotension (OH) by analyzing Valsalva maneuver (VM) parameters. METHODS: We retrospectively analyzed drug-naïve patients without orthostatic hypotension (n = 61) and controls (n = 20). The patients were subcategorized into early PD (n = 35) and mid-PD (n = 26) groups on the basis of the Hoehn and Yahr staging. VM parameters, including changes in systolic blood pressure at late phase 2 (∆SBPVM2), ∆HRVM3, Valsalva ratio (VR), pressure recovery time, adrenergic baroreflex sensitivity, and vagal baroreflex sensitivity, were assessed. RESULTS: In the early PD group, ∆SBPVM2, a marker of sympathetic function, was significantly lower compared with that in controls (risk ratio = 0.95, P = 0.027). Receiver operating characteristic (ROC) curve analysis showed an optimal cut-off value of -10 mmHg for ∆SBPVM2 [P = 0.002, area under the curve (AUC): 0.737]. VR exhibited an inverse relationship with Unified Parkinson's Disease Rating Scale Part 3 scores in the multivariable regression analysis (VR: P = 0.038, ß = -28.61), whereas age showed a positive relationship (age: P = 0.027, ß = 0.35). CONCLUSION: The ∆BPVM2 parameter of the VM may help detect autonomic nervous system involvement in early-PD without OH. Our results suggest that sympathetic dysfunction is an early manifestation of autonomic dysfunction in patients with PD.
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Doenças do Sistema Nervoso Autônomo , Barorreflexo , Doença de Parkinson , Manobra de Valsalva , Humanos , Doença de Parkinson/fisiopatologia , Doença de Parkinson/complicações , Doença de Parkinson/diagnóstico , Masculino , Feminino , Estudos Retrospectivos , Idoso , Pessoa de Meia-Idade , Doenças do Sistema Nervoso Autônomo/fisiopatologia , Doenças do Sistema Nervoso Autônomo/diagnóstico , Doenças do Sistema Nervoso Autônomo/etiologia , Manobra de Valsalva/fisiologia , Barorreflexo/fisiologia , Sistema Nervoso Simpático/fisiopatologia , Pressão Sanguínea/fisiologiaRESUMO
Continuous detection of sudden changes in blood glucose is essential for individuals with diabetes who have difficulty in maintaining optimal control of their blood glucose levels. Hypoglycemic shock or a hyperglycemic crisis are likely to occurs in patients with diabetes and poses a significant threat to their lives. Currently, commercial continuous glucose monitoring (CGM) has limits in the glucose concentration detection range, which is 40-500 mg/dL, making it difficult to prevent the risk of hyperglycemic shock. In addition, current CGMs are invasive, cause pain and irritation during usage, and expensive. In this research, we overcome these limitations by introducing a novel mechanism to detect glucose concentration using supercapacitors. The developed CGM, which is self-powered and minimally invasive due to the use of microneedles, can detect a wider range of glucose concentrations than commercial sensors. In addition, efficacy and stability were proven through in vitro and in vivo experiments. Thus, this self-powered, microneedle and supercapacitive-type CGM can potentially prevent both hypoglycemic and complications of hyperglycemia without pain and with less power consumption than current commercial sensors.
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Técnicas Biossensoriais , Glicemia , Monitoramento Contínuo da Glicose , Desenho de Equipamento , Agulhas , Animais , Técnicas Biossensoriais/instrumentação , Glicemia/análise , Monitoramento Contínuo da Glicose/instrumentação , CamundongosRESUMO
BACKGROUND: Viscosity is a common focus in the diet of patients with dysphagia. However, adhesiveness is an equally significant property that can affect swallowing function, even in semi-solid foods with similar levels of viscosity. The purpose of this study was to classify the adhesiveness of food into stages and determine whether these classifications are relevant to swallowing function. METHODS: This study included 30 healthy elderly adults aged 65 years. After categorizing adhesiveness into three levels based on the results of the sensory test, 30 participants were asked to swallow representative foods at each level. A videofluoroscopic swallowing study (VFSS) was performed to determine the presence or absence of pharyngeal residues based on the level of adhesiveness. The chi-square test was used to verify whether there was a difference in remnants according to the level of adhesiveness, and significance was judged with a p-value of less than 0.05. RESULTS: Adhesiveness was categorized into three distinct levels: level 1 (0-4 mJ), level 2 (4-18 mJ), and level 3 (>18 mJ). Upon examining the subjects presenting with residual material, we observed three cases of level 1 adhesiveness, 16 cases of level 2, and 25 cases of level 3. The chi-square test was used to assess the statistical significance between the levels, revealing a significant difference with a p-value < 0.0001. CONCLUSIONS: We presented the level of adhesiveness by dividing it into three stages and proved that it is meaningful in relation to the swallowing function. Selecting and recommending foods with an appropriate level of adhesiveness will help enhance swallowing safety in older adults.
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Panax ginseng fruit is known to have various biological effects owing to its large amount of saponins such as ginsenosides. In the present study, ginseng berry juice was confirmed to be effective against acute inflammation. Ginseng berry juice was used for analysis of active constituents, antioxidant efficacy, and in vivo inflammation. A high-performance liquid chromatography method was used for analysis of ginsenosides. In an HCl/ethanol-induced acute gastric injury model, microscopic, immunofluorescent, and immunohistochemical techniques were used for analysis of inhibition of gastric injury and mechanism study. In a mouse model of acute gastritis induced with HCl/ethanol, ginseng berry juice (GBJ, 250 mg/kg) showed similar gastric injury inhibitory effects as cabbage water extract (CB, 500 mg/kg, P.O). GBJ dose-dependently modulated the pro-inflammatory cytokines such as Tumor Necrosis Factor-α (TNF-α), Interleukin-6 (IL-6), and Interleukin-13 (IL-13). GBJ inhibited the activation of Nuclear Factor kappa bB (NF-κB) and suppressed the expressions of cyclooxigenase-2 (COX-2) and prostaglandin 2 (PGE2). The anti-inflammatory effect of GBJ is attributed to ginsenosides which have anti-inflammatory effects. Productivity as an effective food source for acute gastritis was analyzed and showed that GBJ was superior to CB. In addition, as a functional food for suppressing acute ulcerative symptoms, it was thought that the efficacy of gastric protection products would be higher if GBJ were produced in the form of juice rather than through various extraction methods.
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Gastrite , Ginsenosídeos , Panax , Animais , Camundongos , Frutas , Ginsenosídeos/farmacologia , Inflamação/tratamento farmacológico , Etanol , Anti-Inflamatórios/farmacologiaRESUMO
PURPOSE: Clinical implications of neoadjuvant immunotherapy in patients with locally advanced but resectable head and neck squamous cell carcinoma (HNSCC) remain largely unexplored. PATIENTS AND METHODS: Patients with resectable HNSCC were randomized to receive a single dose of preoperative durvalumab (D) with or without tremelimumab (T) before resection, followed by postoperative (chemo)radiotherapy based on multidisciplinary discretion and 1-year D treatment. Artificial intelligence (AI)-powered spatial distribution analysis of tumor-infiltrating lymphocytes and high-dimensional profiling of circulating immune cells tracked dynamic intratumoral and systemic immune responses. RESULTS: Of the 48 patients enrolled (D, 24 patients; D+T, 24 patients), 45 underwent surgical resection per protocol (D, 21 patients; D+T, 24 patients). D±T had a favorable safety profile and did not delay surgery. Distant recurrence-free survival (DRFS) was significantly better in patients treated with D+T than in those treated with D monotherapy. AI-powered whole-slide image analysis demonstrated that D+T significantly reshaped the tumor microenvironment toward immune-inflamed phenotypes, in contrast with the D monotherapy or cytotoxic chemotherapy. High-dimensional profiling of circulating immune cells revealed a significant expansion of T-cell subsets characterized by proliferation and activation in response to D+T therapy, which was rare following D monotherapy. Importantly, expansion of specific clusters in CD8+ T cells and non-regulatory CD4+ T cells with activation and exhaustion programs was associated with prolonged DRFS in patients treated with D+T. CONCLUSIONS: Preoperative D±T is feasible and may benefit patients with resectable HNSCC. Distinct changes in the tumor microenvironment and circulating immune cells were induced by each treatment regimen, warranting further investigation.
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Anticorpos Monoclonais Humanizados , Anticorpos Monoclonais , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias de Cabeça e Pescoço , Terapia Neoadjuvante , Carcinoma de Células Escamosas de Cabeça e Pescoço , Humanos , Masculino , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/terapia , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Pessoa de Meia-Idade , Feminino , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/uso terapêutico , Idoso , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/uso terapêutico , Neoplasias de Cabeça e Pescoço/terapia , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/patologia , Neoplasias de Cabeça e Pescoço/imunologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Terapia Neoadjuvante/métodos , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Adulto , Microambiente Tumoral/imunologia , Microambiente Tumoral/efeitos dos fármacosRESUMO
Background: For maintenance therapy in type 2 diabetes, glucagon-like peptide-1 agonist (GLP-1A), which exhibits low cardiovascular risk and high efficacy, is a promising peptide therapeutic. However, developing an oral GLP-1A presents challenges due to the analog's poor cellular permeability and gastrointestinal (GI) stability. Methods: To mitigate such limitations, an oral nanoformulation of liraglutide (LG) was designed and achieved by combining LG with bile acid derivatives using the nanoprecipitation method. This strategy allowed the bile acid moieties to localize at the nanoparticle surface, enhancing the binding affinity for apical sodium-dependent bile acid transporter (ASBT) and improving GI stability. The in vitro characteristics, cellular permeability, and absorption mechanisms of the LG nanoformulation (LG/TD-NF) were thoroughly investigated. Furthermore, the in vivo oral absorption in rats and the glucose-lowering effects in a diabetic (db/db) mouse model were evaluated. Results: The LG/TD-NF produced neutral nanoparticles with a diameter of 58.7 ± 4.3 nm and a zeta potential of 4.9 ± 0.4 mV. Notably, when exposed to simulated gastric fluid, 65.7 ± 3.6% of the LG/TD-NF remained stable over 120 min, while free LG was fully degraded. Relative to unformulated LG, the Caco-2 cellular permeability of the nanoformulation improved, measuring 10.9 ± 2.1 (× 10-6 cm/s). The absorption mechanism prominently featured endocytosis simultaneously mediated by both ASBT and epidermal growth factor receptor (EGFR). The oral bioavailability of the LG/TD-NF was determined to be 3.62% at a dosage of 10 mg/kg, which is 45.3 times greater than that of free LG. In a diabetes model, LG/TD-NF at 10 mg/kg/day exhibited commendable glucose sensitivity and reduced HbA1c levels by 4.13% within 28 days, similar to that of subcutaneously administered LG at a dosage of 0.1 mg/kg/day. Conclusion: The oral LG/TD-NF promotes ASBT/EGFR-mediated transcytosis and assures cellular permeability within the GI tract. This method holds promise for the development of oral GLP-1A peptides as an alternative to injections, potentially enhancing patient adherence to maintenance therapy.
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Diabetes Mellitus Tipo 2 , Liraglutida , Humanos , Camundongos , Ratos , Animais , Liraglutida/farmacologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Células CACO-2 , Peptídeo 1 Semelhante ao Glucagon/uso terapêutico , Trato Gastrointestinal/metabolismo , Ácidos e Sais Biliares , Glucose , Receptores ErbB , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêuticoRESUMO
BACKGROUND: Appropriate evaluation and management of dysphagia are essential in neurological disorders. However, there is currently a lack of a simple yet reliable method for dysphagia evaluation. AIM: This study aimed to investigate the usefulness of new dynamic M-mode ultrasonography (US) parameters of suprahyoid muscle (SHM) to evaluate dysphagia. DESIGN: Prospective observational, cross-sectional study. SETTING: Inpatient setting at neurology department of tertiary medical center. POPULATION: A total of 89 patients with dysphagia and 175 healthy volunteers were enrolled in the study. Patients were subdivided into mild and severe dysphagia groups depending on the need for dietary changes and disease classification, which included amyotrophic lateral sclerosis, peripheral neuromuscular diseases, and stroke. METHODS: Dynamic M-mode US was performed during swallowing to obtain the SHM thickness (the baseline thickness of the SHM), SHM displacement (peak-to-peak amplitude of SHM movement), SHM difference (SHM displacement - SHM thickness), SHM ratio (SHM displacement/SHM thickness), peak-to-peak time, and total duration. A videofluoroscopic swallowing study (VFSS) was performed. RESULTS: Significant differences were found in SHM displacement and SHM difference according to dysphagia severity (P<0.001). The SHM ratio, total duration (P<0.001), and peak-to-peak time (P=0.001) differed significantly according to the patients' underlying diseases. The pharyngeal delay time and penetration-aspiration scale from the VFSS demonstrated significant negative correlations with SHM displacement and difference (P<0.001). By combining SHM difference and total duration, patients with dysphagia could be distinguished from healthy controls, with the highest negative predictive value of 95.6%. CONCLUSIONS: Dynamic M-mode US of the SHM provided added value in evaluating the severity of dysphagia and differentiating swallowing mechanics of dysphagia related to underlying neurological disorders. CLINICAL REHABILITATION IMPACT: Dynamic M-mode US of the SHM can serve as a supportive tool for rapid screening and repetitive follow-up of patients with dysphagia, which would contribute to dysphagia rehabilitation in patients with various neurological disorders.
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Transtornos de Deglutição , Acidente Vascular Cerebral , Humanos , Transtornos de Deglutição/diagnóstico por imagem , Transtornos de Deglutição/etiologia , Estudos Transversais , Deglutição/fisiologia , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/diagnóstico por imagem , Ultrassonografia , MúsculosRESUMO
PURPOSE: Sentinel lymph node biopsy (SLNB) or axillary lymph node dissection (ALND) can be performed either with a separate axillary incision or through the mastectomy incision. The authors hypothesized that after SLNB or ALND through a single incision, connection of the axilla with mastectomy pocket could increase drainage. This study investigated whether a separate incision decreases drainage amount and duration in implant-based breast reconstruction. METHODS: Medical records of breast cancer patients who underwent nipple-sparing or skin-sparing mastectomy with immediate breast reconstruction with prosthesis from March 2018 to February 2021 in a single tertiary center were reviewed. Demographic data, intraoperative details, and postoperative complications were reviewed. Breast drains were removed if the drain amount was less than 30cc for two consecutive days. Total breast drain amount, duration until removal, and prolonged drainage were compared with multivariate analysis. RESULTS: A total of 206 patients were included in the study, with separate incisions placed in 145 breasts and a single breast incision placed in 70 breasts. Mean duration and amount until drain removal were 12.8 ± 4.9 days and 817 ± 520 cc in the single incision group, respectively, and 9.9 ± 3.1 days and 434 ± 228 cc in the separate incision group, respectively Separate incision placement (p < 0.001), lower mastectomy weight (p < 0.001), and prepectoral plane of insertion (p < 0.001) were significantly associated with less drain amount and duration. None-separate incision placement (p = 0.01) and preoperative radiation therapy (p = 0.023) were significant factors for prolonged drainage. CONCLUSION: Placing a separate incision for axillary surgery during mastectomy and immediate implant-based reconstruction can decrease both drain amount and duration and reduce the risk of prolonged drainage.
Assuntos
Neoplasias da Mama , Mamoplastia , Humanos , Feminino , Mastectomia , Neoplasias da Mama/cirurgia , Neoplasias da Mama/patologia , Axila/cirurgia , Linfonodos/cirurgia , Excisão de Linfonodo , Drenagem , Biópsia de Linfonodo Sentinela , Próteses e ImplantesRESUMO
Background and aim: Insulin resistance (IR) is a pathological condition in which cells fail to respond normally to insulin. Loss of insulin sensitivity disrupts glucose homeostasis and elevates the risk of developing the metabolic syndrome that includes Type 2 diabetes. This study assesses the effect on subcritical-water extract of Gracilaria chorda (GC) at 210 °C (GCSW210) in IR induction models of high glucose (HG)-induced zebrafish larvae and dexamethasone (DEX)-induced L6 myotubes. Experimental procedure: The dose of HG and DEX for IR induction in zebrafish larvae and L6 myotubes was 130 mM or 0.5 µM. The capacity of glucose uptake was quantified by fluorescence staining or intensity. In addition, the activation of protein and mRNA expressions for insulin signaling (insulin-dependent or independent pathways) was measured. Results and conclusion: Exposure of zebrafish larvae to HG significantly reduced the intracellular glucose uptake with dose-dependnet manner compared to control. However, the group treated with GCSW210 significantly averted HG levels like the insulin-treated group, and significantly up- or down-regulated the mRNA expressions related to insulin production (insα) and insulin signaling pathways. Moreover, the treatment with GCSW210 effectively regulated the protein expression of PI3K/AKT, AMPK, and GLUT4 involved in the action of insulin in IR models of L6 myotubes compared to DEX-treated control. Our data indicate that GCSW210 stimulates activation of PI3K/AKT and AMPK pathways to attenuate the development of IR induced by HG in zebrafish and DEX in L6 myotubes. In conclusion, GCSW210 is a potential agent for alleviating various diseases associated with the insulin resistance.
RESUMO
BACKGROUND: General anaesthesia can immobile patients during interventional neuroradiology to improve image quality. Remimazolam, an ultrashort-acting benzodiazepine, is advantageous for haemodynamic stability. This study compared remimazolam and propofol anaesthesia during neuroradiology procedures regarding intraoperative hypotensive events and rapid recovery. METHODS: This single-masked randomised-controlled study included 76 participants who underwent elective endovascular embolisation in a single centre. Patients were randomised between a continuous remimazolam infusion (n = 38) or a target-controlled propofol infusion group (n = 38). In the remimazolam group, flumazenil (0.2 mg) was administered at the end of the procedure. Phenylephrine was titrated to maintain the mean arterial pressure within ± 20% of the baseline value. The primary outcome was the total phenylephrine dose during the procedure. RESULTS: The total phenylephrine dose was 0.0 [0.0-30.0] µg in the remimazolam group and 30.0 [0.0-205.0] µg in the propofol group (p = 0.001). Hypotensive events were observed in 11 (28.9%) patients in the remimazolam group and 23 (60.5%) patients in the propofol group (p = 0.001). Recovery times to spontaneous breathing, eye-opening, extubation, and orientation were shorter in the remimazolam group than in the propofol group (all p < 0.001). CONCLUSIONS: Remimazolam anaesthesia showed superior haemodynamic stability compared with propofol anaesthesia during neuroradiology procedures. Systematic use of flumazenil enabled rapid recovery from remimazolam anaesthesia. REGISTRATION: University Hospital Medical Information Network Clinical Trials Registry; Registration number: UMIN000047384; URL: https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000054046.