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1.
J Surg Res ; 301: 610-617, 2024 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-39094519

RESUMEN

INTRODUCTION: The geriatric nutritional risk index (GNRI) can easily identify malnutrition-associated morbidity and mortality. We investigated the association between preoperative GNRI and 30-d mortality in geriatric burn patients who underwent surgery. METHODS: The study involved geriatric burn patients (aged ≥ 65 y) who underwent burn surgery between 2012 and 2022. The GNRI was computed using the following formula: 1.489 × serum albumin concentration (mg/L) + 41.7 × patient body weight/ideal body weight. Patients were dichotomized into the high GNRI (≥ 82) and low GNRI (< 82) groups. GNRI was evaluated as an independent predictor of 30-d postoperative mortality. The study also evaluated the association between GNRI and sepsis, the need for continuous renal replacement therapy (CRRT), major adverse cardiac events (MACE), and pneumonia. RESULTS: Out of 270 patients, 128 (47.4%) had low GNRI (< 82). Multivariate Cox regression analysis revealed that low GNRI was significantly associated with 30-d postoperative mortality (hazard ratio: 1.874, 95% confidence interval [CI]: 1.146-3.066, P = 0.001). Kaplan-Meier analysis revealed that the 30-day mortality rate differed significantly between the low and high GNRI groups (log-rank test, P < 0.001). The 30-d postoperative mortality (hazard ratio: 2.677, 95% CI: 1.536-4.667, P < 0.001) and the incidence of sepsis (odds ratio [OR]: 2.137, 95% CI: 1.307-3.494, P = 0.004), need for CRRT (OR: 1.919, 95% CI: 1.101-3.344, P = 0.025), MACE (OR: 1.680, 95% CI: 1.018-2.773, P = 0.043), and pneumonia (OR: 1.678, 95% CI: 1.019-2.764, P = 0.044), were significantly higher in the low GNRI group than in the high GNRI group. CONCLUSIONS: Preoperative low GNRI was associated with increased 30-d postoperative mortality, sepsis, need for CRRT, MACE, and pneumonia in geriatric burn patients.

2.
Aquat Toxicol ; 274: 107027, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-39098124

RESUMEN

Plastics are one of the most pervasive materials on Earth, to which humans are exposed daily. Polystyrene (PS) is a common plastic packaging material. However, the impact of PS on human health remains poorly understood. Therefore, this study aimed to identify intestinal damage induced by PS nanoplastics (PS-NPs) in zebrafish larvae which have a high homology with humans. Four days post fertilization (dpf), zebrafish larvae were exposed to 0-, 10-, and 50-ppm PS-NPs for 48 h Initially, to ascertain if 100 nm PS-NPs could accumulate in the gastrointestinal (GI) tract of zebrafish larvae, the larvae were exposed to red fluorescence-labeled PS-NPs, and at 6 dpf, the larvae were examined using a fluorescence microscope. Analysis of the fluorescence intensity revealed that the GI tract of larvae exposed to 50-ppm exhibited a significantly stronger fluorescence intensity than the other groups. Nonfluorescent PS-NPs were then used in further studies. Scanning electron microscopy (SEM) confirmed the spherical shape of the PS-NPs. Fourier-transform infrared spectroscopy (FT-IR) analysis revealed chemical alterations in the PS-NPs before and after exposure to larvae. The polydispersity index (PDI) value derived using a Zetasizer indicated a stable dispersion of PS-NPs in egg water. Whole-mount apoptotic signal analysis via TUNEL assay showed increased apoptosis in zebrafish larval intestines exposed to 50-ppm PS-NPs. Damage to the intestinal tissue was assessed by Alcian blue (AB) and hematoxylin and eosin (H&E) staining. AB staining revealed increased mucin levels in the zebrafish larval intestines. Thin larval intestinal walls with a decrease in the density of intestinal epithelial cells were revealed by H&E staining. The differentially expressed genes (DEGs) induced by PS-NPs were identified and analyzed. In conclusion, exposure to PS-NPs may damage the intestinal barrier of zebrafish larvae due to increased intestinal permeability, and the in vivo gene network may change in larvae exposed to PS-NPs.


Asunto(s)
Apoptosis , Larva , Poliestirenos , Pez Cebra , Animales , Poliestirenos/toxicidad , Apoptosis/efectos de los fármacos , Larva/efectos de los fármacos , Contaminantes Químicos del Agua/toxicidad , Inflamación/inducido químicamente , Intestinos/efectos de los fármacos , Nanopartículas/toxicidad , Mucosa Intestinal/efectos de los fármacos
3.
Stud Health Technol Inform ; 316: 552-553, 2024 Aug 22.
Artículo en Inglés | MEDLINE | ID: mdl-39176801

RESUMEN

Previous studies have been limited to giving one or two tasks to Large Language Models (LLMs) and involved a small number of evaluators within a single domain to evaluate the LLM's answer. We assessed the proficiency of four LLMs by applying eight tasks and evaluating 32 results with 17 evaluators from diverse domains, demonstrating the significance of various tasks and evaluators on LLMs.


Asunto(s)
Simulación por Computador , Lenguaje
4.
Stud Health Technol Inform ; 316: 650-651, 2024 Aug 22.
Artículo en Inglés | MEDLINE | ID: mdl-39176825

RESUMEN

This study introduces a novel approach for generating machine-generated instruction datasets for fine-tuning medical-specialized language models using MIMIC-IV discharge records. The study created a large-scale text dataset comprising instructions, cropped discharge notes as inputs, and outputs in JSONL format. The dataset was generated through three main stages, generating instruction and output using seed tasks provided by medical experts, followed by invalid data filtering. The generated dataset consisted of 51,385 sets, with mean ROUGE between seed tasks of 0.185. Evaluation of the generated dataset were promising, with high validity rates determined by both GPT-3.5 and a human annotator (88.0% and 88.5% respectively). The study highlights the potential of automating dataset creation for NLP tasks in the medical domain.


Asunto(s)
Registros Electrónicos de Salud , Procesamiento de Lenguaje Natural , Humanos , Alta del Paciente , Resumen del Alta del Paciente
5.
Eur J Anaesthesiol ; 2024 Aug 14.
Artículo en Inglés | MEDLINE | ID: mdl-39138997

RESUMEN

BACKGROUND: Catheter-related bladder discomfort (CRBD) is problematic in patients with a urinary catheter. Transcutaneous electrical nerve stimulation (TENS) is a non-invasive analgesic modality used to relieve various types of pain. OBJECTIVES: We evaluated the effect of TENS on CRBD after transurethral resection of bladder tumours (TURBT). DESIGN: A randomised controlled trial. SETTING: A large university tertiary hospital, from October 2022 to March 2023. PATIENTS: Patients requiring urinary catheterisation after TURBT. INTERVENTION: In this randomised controlled trial, patients were randomly allocated to the TENS (n  = 56) or control (n  = 56) groups. CRBD manifests as a burning sensation with an urge to void or discomfort in the suprapubic area. Moderate to severe CRBD was defined as patients self-reporting CRBD symptoms with or without behavioural response, including attempts to remove the urinary catheter, intense verbal reactions, and flailing limbs. TENS was performed from the end of surgery to 1 h postoperatively. MAIN OUTCOME MEASURE: The primary endpoint was considered moderate to severe CRBD immediately postoperatively. Secondary endpoints included moderate to severe CRBD at 1, 2 and 6 h postoperatively. Additionally, postoperative pain, patient satisfaction, and TENS-related adverse effects were evaluated. RESULTS: Moderate to severe CRBD immediately postoperatively was significantly less frequent in the TENS group than in the control group: 10 (17.9%) vs. 34 (60.7%); P < 0.001; relative risk (95% CI) = 0.294 (0.161 to 0.536); absolute risk reduction = 0.43; number needed to treat = 2.3. Moderate to severe CRBD differed between the two groups at 1 h postoperatively: 1 (1.8%) vs. 16 (28.6%); P < 0.001; relative risk = 0.06 (95% CI 0.01 to 0.46); absolute risk reduction = 0.27; number needed to treat = 3.7. The TENS group exhibited a significantly lower score for postoperative pain at 1 h (1.8 ±â€Š0.6 vs. 2.2 ±â€Š0.4; P < 0.001, mean difference (95% CI) = 0.4 (0.2 to 0.6) and a higher score for patient satisfaction, 5.0 (4.0 to 6.0) vs. 3.0 (3.0 to 4.0); P < 0.001; median difference (95% CI) = 2.0 (1.0 to 2.0). CONCLUSIONS: TENS reduced moderate to severe CRBD, decreased postoperative pain, and increased patient satisfaction after TURBT. CLINICAL TRIAL REGISTRY: Clinical Research Information Service (KCT0007450). VISUAL ABSTRACT: http://links.lww.com/EJA/B12.

6.
Korean J Anesthesiol ; 2024 Aug 21.
Artículo en Inglés | MEDLINE | ID: mdl-39168453

RESUMEN

Background: The incidence of epistaxis during nasotracheal intubation via the left nostril is more frequent than that during intubation via the right nostril. This study evaluated the effect of the reverse bevel and tip direction of the nasotracheal tube on the incidence of epistaxis during nasotracheal intubation via the left nostril. Methods: Patients undergoing right-sided maxillofacial surgery requiring left nasotracheal intubation were randomly allocated to the control (tracheal tube in the conventional direction) or reverse (a 180˚ reverse direction, with the tube bevel facing the nasal septum and the leading edge (i.e., the tip) of the bevel pointing away from the nasal septum) groups (n = 37 for both). The primary outcome was the incidence of epistaxis evaluated using videolaryngoscopy. Results: The incidence of epistaxis in the reverse group was significantly lower than that in the control group (9 [24.3%] vs. 20 [54.1%], P = 0.009; relative risk = 0.45; 95% CI: 0.24, 0.85; absolute risk reduction = 29.8%; number needed to treat = 3.36). The severity of epistaxis was significantly lower in the reverse group (P = 0.002). The first attempt nasal passage (P = 0.027) was significantly higher in the reverse group. Postoperative nasal pain was lower (P < 0.001), and patient satisfaction was higher (P < 0.001) in the reverse group. Nasotracheal tube-related complications did not occur in either group. Conclusions: The reverse bevel and tip direction of the nasotracheal tube reduced the incidence and severity of epistaxis and increased patient satisfaction among patients undergoing left nasotracheal intubation.

7.
Cells ; 13(14)2024 Jul 21.
Artículo en Inglés | MEDLINE | ID: mdl-39056810

RESUMEN

Age-related ocular diseases such as age-related macular degeneration, glaucoma, and diabetic retinopathy are major causes of irreversible vision impairment in the elderly. Conventional treatments focus on symptom relief and disease slowdown, often involving surgery, but fall short of providing a cure, leading to substantial vision loss. Regenerative medicine, particularly mesenchymal stem cells (MSCs), holds promise for ocular disease treatment. This study investigates the synergistic potential of combining placenta-derived MSCs (PD-MSCs) with Achyranthis radix extract (ARE) from Achyranthes japonica to enhance therapeutic outcomes. In a 24-h treatment, ARE significantly increased the proliferative capacity of PD-MSCs and delayed their senescence (* p < 0.05). ARE also enhanced antioxidant capabilities and increased the expression of regeneration-associated genes in an in vitro injured model using chemical damages on human retinal pigment epithelial cell line (ARPE-19) (* p < 0.05). These results suggest that ARE-primed PD-MSC have the capability to enhance the activation of genes associated with regeneration in the injured eye via increasing antioxidant properties. Taken together, these findings support the conclusion that ARE-primed PD-MSC may serve as an enhanced source for stem cell-based therapy in ocular diseases.


Asunto(s)
Antioxidantes , Células Madre Mesenquimatosas , Placenta , Extractos Vegetales , Humanos , Células Madre Mesenquimatosas/efectos de los fármacos , Células Madre Mesenquimatosas/metabolismo , Antioxidantes/farmacología , Extractos Vegetales/farmacología , Femenino , Placenta/metabolismo , Placenta/efectos de los fármacos , Embarazo , Achyranthes/química , Epitelio Pigmentado de la Retina/efectos de los fármacos , Epitelio Pigmentado de la Retina/metabolismo , Epitelio Pigmentado de la Retina/citología , Proliferación Celular/efectos de los fármacos , Línea Celular
8.
Korean J Pain ; 37(3): 256-263, 2024 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-38946700

RESUMEN

Background: Cervical epidural block (CEB) is an effective intervention for managing cervical radicular pain. This study aimed to investigate the current status of performing CEB in South Korea. Methods: Pain physicians affiliated with the Korean Pain Society were asked to complete anonymous questionnaires regarding CEB between September and October 2022. The questionnaire consisted of 24 questions assessing the current status and methods of CEB in detail. Results: Of the 198 surveys collected, 171 physicians (86.4%) reported performing CEB. Among those, the majority (94.7%) used fluoroscopy during the procedure. The paramedian interlaminar (IL) approach was the most preferred method (50.3%). Respondents performing fluoroscopic-guided IL CEB were categorized into two groups based on clinical experience: those with ≤10 years of experience (≤10-year group, n = 91) and those with >10 years of experience (>10-year group, n = 71). The proportion of physicians obtaining informed consent in the ≤10-year group and >10-year group was 50.5% and 56.3%, respectively. When entering the epidural space during IL CEB, the contralateral oblique view was the second most frequently used in both groups (≤10-year group, 42.9%; >10-year group, 29.6%). In targeting the upper cervical lesions (C3-4), the proportion of respondents who used an IL space higher than C6-7 was 17.6% in the ≤10-year group and 29.5% in the >10-year experience group. Conclusions: This study demonstrated variability in the CEB technique used by pain physicians in South Korea. The findings highlight the need for education on informed consent and techniques to enhance safety.

9.
Medicina (Kaunas) ; 60(6)2024 May 24.
Artículo en Inglés | MEDLINE | ID: mdl-38929474

RESUMEN

Background: Increasing evidence supporting the clinical effectiveness of cooled radiofrequency ablation (RFA) therapy for genicular nerves in patients with chronic knee osteoarthritis (OA) exists. However, no study has been conducted to eliminate the potential influence of a placebo effect associated with this procedure. Therefore, we evaluated the efficacy of cooled RFA compared with a sham procedure in patients with painful knees due to OA. Methods: In this double-blind, randomized, controlled study, participants were randomly assigned to receive cooled RFA of the knee (cooled RFA group, n = 20) or a sham procedure (sham group, n = 20). The primary outcome was the proportion of successful responders at the three-month follow-up. The secondary outcomes were successful responders at one and six months; pain intensity of the knee; functional status; medication; and satisfaction at one, three, and six months after the procedures. Results: For the primary outcome, the successful responder rate was significantly higher in the cooled RFA group (76.5%) than in the sham group (33.3%) (p = 0.018). For the secondary outcome, more successful responders were observed in the cooled RFA group than in the sham group at one and six months after the procedure (p = 0.041 and 0.007, respectively). The decreased knee pain intensity was maintained throughout the six-month follow-up period in the cooled RFA group. No differences were observed in functional status, medication change, or satisfaction in both groups. Conclusions: The cooled RFA of genicular nerves offers significant pain relief and surpasses the effects attributable to a placebo.


Asunto(s)
Osteoartritis de la Rodilla , Ablación por Radiofrecuencia , Humanos , Método Doble Ciego , Osteoartritis de la Rodilla/terapia , Osteoartritis de la Rodilla/cirugía , Osteoartritis de la Rodilla/complicaciones , Femenino , Masculino , Ablación por Radiofrecuencia/métodos , Persona de Mediana Edad , Anciano , Resultado del Tratamiento , Dolor Crónico/terapia , Dolor Crónico/etiología , Dimensión del Dolor , Articulación de la Rodilla/inervación
10.
Nat Commun ; 15(1): 5117, 2024 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-38879551

RESUMEN

Hepatocellular carcinoma frequently recurs after surgery, necessitating personalized clinical approaches based on tumor avatar models. However, location-dependent oxygen concentrations resulting from the dual hepatic vascular supply drive the inherent heterogeneity of the tumor microenvironment, which presents challenges in developing an avatar model. In this study, tissue samples from 12 patients with hepatocellular carcinoma are cultured directly on a chip and separated based on preference of oxygen concentration. Establishing a dual gradient system with drug perfusion perpendicular to the oxygen gradient enables the simultaneous separation of cells and evaluation of drug responsiveness. The results are further cross-validated by implanting the chips into mice at various oxygen levels using a patient-derived xenograft model. Hepatocellular carcinoma cells exposed to hypoxia exhibit invasive and recurrent characteristics that mirror clinical outcomes. This chip provides valuable insights into treatment prognosis by identifying the dominant hepatocellular carcinoma type in each patient, potentially guiding personalized therapeutic interventions.


Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Oxígeno , Microambiente Tumoral , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/metabolismo , Humanos , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/metabolismo , Animales , Ratones , Oxígeno/metabolismo , Línea Celular Tumoral , Masculino , Femenino , Ensayos Antitumor por Modelo de Xenoinjerto , Persona de Mediana Edad , Dispositivos Laboratorio en un Chip
11.
Neuromodulation ; 2024 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-38752945

RESUMEN

OBJECTIVES: We hypothesized that the duration of pulsed radiofrequency (PRF) application may affect the effectiveness of PRF in patients with chronic lumbosacral radicular pain (LRP). MATERIALS AND METHODS: In this prospective, double-blind, randomized study, 68 patients were randomly allocated to two groups: a 6-minute group, in which PRF was applied at 42 °C for 2 minutes followed by a 2-minute pause, repeated three times; and a 12-minute group, with a continuous application at 42 °C for 12 minutes. The total application time in each group was equal. After PRF, 2 to 3 mL of 1% lidocaine with 5 mg of dexamethasone was injected. The primary outcome was the intensity of leg pain measured using a numerical rating scale (NRS) three months after the procedure. The secondary outcomes were intensities of leg and back pain, the Oswestry Disability Index (ODI), the Medication Quantification Scale III (MQS), the Global Perceived Effect of Satisfaction (GPES), and the incidence of adverse events during follow-up. Primary and secondary outcomes were analyzed using a linear mixed-effect model in the modified intention-to-treat population. RESULTS: Each group comprised 34 patients. Three patients in each group did not receive the allocated intervention owing to alleviation of pain. The estimated NRS mean of leg pain at three months was 4.0 (95% CI, 3.2-4.9) and 4.5 (95% CI, 3.6-5.4) in the 6- and 12-minute groups, respectively, with no significant difference between groups (estimated mean difference, -0.5; 95% CI, -1.8 to 0.8; p = 0.436). Regarding the intensities of leg and back pain, ODI, MQS, and GPES, there was no significant difference between the two groups except for GPES at six months. No adverse events were observed in the groups. CONCLUSIONS: Among patients with chronic LRP, a prolonged PRF application of 12 minutes, compared with 6 minutes, caused no significant difference in leg pain intensity. CLINICAL TRIAL REGISTRATION: The Clinicaltrials.gov registration number under the Clinical Trial Registry of Korea for the study is KCT0003850; https://cris.nih.go.kr.

13.
J Ethnopharmacol ; 321: 117501, 2024 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-38012970

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Psoralea corylifolia L. (PC) is widely used in traditional medicines to treat inflammatory and infectious diseases. Isobavachin (IBC) is a bioavailable prenylated flavonoid derived from PC that has various biological properties. However, little information is available on its anti-inflammatory effects and mechanisms of action. AIM OF THE STUDY: In this study, we aimed to determine the anti-inflammatory effects of IBC in vitro and in vivo by conducting a mechanistic study using murine macrophages. MATERIALS AND METHODS: We evaluated the modulatory effects of IBC on the production of pro-inflammatory cytokines and mediators in murine macrophages. In addition, we examined whether IBC inhibits lipopolysaccharide (LPS)-induced inflammatory responses in a zebrafish model. Alterations in inflammatory response-associated genes and proteins were determined using quantitative reverse transcriptional polymerase chain reaction (RT-qPCR) and Western blotting analysis. RESULTS: IBC markedly reduced the overproduction of inflammatory mediators, pro-inflammatory cytokines, inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), phosphorylation of mitogen-activated protein kinase (MAPK) and nuclear translocation of nuclear factor-kappa B (NF-κB) in macrophages induced by lipopolysaccharides (LPS). In addition, excessive NO, ROS, and neutrophil level induced by LPS, were suppressed by IBC treatment in a zebrafish inflammation model. CONCLUSIONS: Collectively, bioavailable IBC inhibited on the inflammatory responses by LPS via MAPK and NF-κB signaling pathways in vitro and in vivo, suggesting that it may be a potential modulatory agent against inflammatory disorders.


Asunto(s)
Proteínas Quinasas Activadas por Mitógenos , Psoralea , Animales , Ratones , Proteínas Quinasas Activadas por Mitógenos/metabolismo , FN-kappa B/metabolismo , Lipopolisacáridos/farmacología , Pez Cebra , Psoralea/metabolismo , Transducción de Señal , Flavonoides/farmacología , Citocinas/metabolismo , Macrófagos , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Antiinflamatorios/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Ciclooxigenasa 2/genética , Ciclooxigenasa 2/metabolismo
14.
Korean J Anesthesiol ; 77(2): 246-254, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-37956998

RESUMEN

BACKGROUND: Although elective surgery for unruptured intracranial aneurysms (UIA) has increased, few studies have evaluated the risk factors for transfusion during UIA surgery. We evaluated the association between the preoperative De Ritis ratio (aspartate transaminase/alanine transaminase) and the incidence of intraoperative transfusion in patients who had undergone surgical UIA clipping. METHODS: Patients who underwent surgical clipping of UIA were stratified into two groups according to the preoperative De Ritis ratio cutoff levels (< 1.54 and ≥ 1.54), and the propensity score (PS)-matching analysis was performed to compare the incidence of intraoperative transfusion. Logistic regression analyses were performed to determine the risk factors for intraoperative transfusion. Net reclassification improvement (NRI) and integrated discrimination improvement (IDI) analyses were performed to verify the improvement in the intraoperative transfusion predictive model upon addition of the De Ritis ratio. RESULTS: Intraoperative transfusion incidence was 15.4% (77/502). We observed significant differences in the incidence of intraoperative transfusion (16.2% vs. 39.7%, P = 0.004) between the groups after matching. In the logistic regression analyses, the De Ritis ratio ≥ 1.54 was an independent risk factor for transfusion (odds ratio [OR]: 3.04, 95% CI [1.53, 6.03], P = 0.002). Preoperative hemoglobin (Hb) value was a risk factor for transfusion (OR: 0.33, 95% CI [0.24, 0.47], P < 0.001). NRI and IDI analyses showed that the De Ritis ratio improved the intraoperative blood transfusion predictive models (P = 0.031 and P = 0.049, respectively). CONCLUSIONS: De Ritis ratio maybe a significant risk factor for intraoperative transfusion in UIA surgery.


Asunto(s)
Aneurisma Intracraneal , Humanos , Estudios Retrospectivos , Puntaje de Propensión , Aneurisma Intracraneal/cirugía , Transfusión Sanguínea
15.
Korean J Pain ; 37(1): 13-25, 2024 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-38155108

RESUMEN

Knee osteoarthritis (OA) is a prevalent and debilitating musculoskeletal condition that significantly affects the quality of life of millions of individuals worldwide. In recent years, cooled radiofrequency ablation (CRFA) has become a viable treatment option for knee OA. This review thoroughly evaluated the existing literature on CRFA therapy for knee OA. It delved into the mechanisms behind CRFA, evaluated its clinical efficacy, and investigated potential avenues for future research and application. The insights gained from this review are crucial for healthcare professionals, researchers, and policymakers, offering an updated perspective on CRFA's role as a viable therapeutic option for knee OA.

16.
Proc Natl Acad Sci U S A ; 120(34): e2304611120, 2023 08 22.
Artículo en Inglés | MEDLINE | ID: mdl-37590418

RESUMEN

Selective orthosteric inhibition of kinases has been challenging due to the conserved active site architecture of kinases and emergence of resistance mutants. Simultaneous inhibition of distant orthosteric and allosteric sites, which we refer to as "double-drugging", has recently been shown to be effective in overcoming drug resistance. However, detailed biophysical characterization of the cooperative nature between orthosteric and allosteric modulators has not been undertaken. Here, we provide a quantitative framework for double-drugging of kinases employing isothermal titration calorimetry, Förster resonance energy transfer, coupled-enzyme assays, and X-ray crystallography. We discern positive and negative cooperativity for Aurora A kinase (AurA) and Abelson kinase (Abl) with different combinations of orthosteric and allosteric modulators. We find that a conformational equilibrium shift is the main principle governing cooperativity. Notably, for both kinases, we find a synergistic decrease of the required orthosteric and allosteric drug dosages when used in combination to inhibit kinase activities to clinically relevant inhibition levels. X-ray crystal structures of the double-drugged kinase complexes reveal the molecular principles underlying the cooperative nature of double-drugging AurA and Abl with orthosteric and allosteric inhibitors. Finally, we observe a fully closed conformation of Abl when bound to a pair of positively cooperative orthosteric and allosteric modulators, shedding light on the puzzling abnormality of previously solved closed Abl structures. Collectively, our data provide mechanistic and structural insights into rational design and evaluation of double-drugging strategies.


Asunto(s)
Aurora Quinasa A , Mesilato de Imatinib , Niacinamida , Inhibidores de Proteínas Quinasas , Proteínas Proto-Oncogénicas c-abl , Humanos , Cristalografía por Rayos X , Mesilato de Imatinib/química , Mesilato de Imatinib/farmacología , Niacinamida/química , Niacinamida/farmacología , Proteínas Proto-Oncogénicas c-abl/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-abl/química , Aurora Quinasa A/antagonistas & inhibidores , Aurora Quinasa A/química , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología
17.
Reg Anesth Pain Med ; 2023 Jul 28.
Artículo en Inglés | MEDLINE | ID: mdl-37507223

RESUMEN

INTRODUCTION: Stenotic thoracic ligamentum flavum hypertrophy can cause leg and/or low back pain similar to that caused by lumbar spinal stenosis. However, the thoracic spine may occasionally be overlooked in patients with leg and/or low back pain. An accurate understanding of the prevalence of stenotic thoracic ligamentum flavum hypertrophy and its associated factors is necessary. METHODS: In this prevalence study, we reviewed whole-spine MRI scans of patients who visited the pain clinic complaining of leg and/or low back pain between 2010 and 2019. We analyzed the overall prevalence and prevalence according to the age group, sex, grade of lumbar disc degeneration, and thoracic level. In addition, we identified factors independently associated with stenotic thoracic ligamentum flavum hypertrophy occurrence. RESULTS: Among 1896 patients, the overall prevalence of stenotic thoracic ligamentum flavum hypertrophy was 9.8% (185/1896), with the highest prevalence observed in the ≥80-year-old age group among all age groups (15.9%, 14/88). The region with the highest prevalence was the T10/11 level (3.0%, 57/1896). Multivariable logistic regression analysis revealed that when compared with the <50-year-old age group, all other age groups were significantly associated with stenotic thoracic ligamentum flavum hypertrophy (p<0.01). In addition, grade 5 of lumbar disc degeneration was significantly associated with stenotic thoracic ligamentum flavum hypertrophy (p=0.03). CONCLUSIONS: Given the possibility for missed stenotic thoracic ligamentum flavum hypertrophy to potentially result in neurological complications, extending lumbar spine MRI covering the lower thoracic region may be considered for patients over 50 years of age with suspected severe lumbar disc degeneration.

18.
Medicine (Baltimore) ; 102(29): e34406, 2023 Jul 21.
Artículo en Inglés | MEDLINE | ID: mdl-37478213

RESUMEN

BACKGROUND: A high fresh gas flow of >5 L/minute is commonly used for emergence from inhalation anesthesia. In addition, a high fresh gas flow may have detrimental effects on climate change. However, no study has determined the optimal fresh gas flow for emergence from inhalation anesthesia. Therefore, we compared the effect of fresh gas flows of 5 L/minute and 10 L/minute on emergence time from sevoflurane anesthesia. METHODS: Patients who were scheduled for transurethral resection of bladder tumor were randomly assigned to receive fresh gas flows of 5 L/minute (group 5) or 10 L/minute (group 10) during emergence. Emergence time was defined as the time from discontinuation of sevoflurane to tracheal extubation. The primary outcome was the emergence time, and the secondary outcomes were the time to self-movement and the time to eye-opening. RESULTS: A total of 54 patients were included. In groups 5 and 10, emergence time (12.1 ± 2.9 minutes vs 11.1 ± 2.7 minutes, respectively; P = .232), time to self-movement (9.4 ± 3.8 minutes vs 8.5 ± 4.6 minutes, respectively; P = .435), and time to eye-opening (11.5 ± 3.1 minute vs 10.6 ± 3.0 minutes, respectively; P = .252) were not significantly different. CONCLUSIONS: Emergence time, time to self-movement, and time to eye opening were not significantly different between fresh gas flow rates of 5 L/minute and 10 L/minute in transurethral resection of bladder tumor, thus suggesting that fresh gas flow of 5 L/minute is sufficient for emergence from sevoflurane anesthesia. TRIAL REGISTRATION: ClinicalTrials.gov (NCT05376631).


Asunto(s)
Anestesiología , Anestésicos por Inhalación , Éteres Metílicos , Neoplasias , Humanos , Sevoflurano , Anestésicos por Inhalación/farmacología , Anestesia por Inhalación
19.
Korean J Pain ; 36(3): 358-368, 2023 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-37394275

RESUMEN

Background: Recent attention has been directed towards fatty infiltration in the cervical extensor muscles for predicting clinical outcomes in several cervical disorders. This study aimed to investigate the potential association between fatty infiltration in the cervical multifidus and treatment response following cervical interlaminar epidural steroid injection (CIESI) in patients with cervical radicular pain. Methods: The data of patients with cervical radicular pain who received CIESIs between March 2021 and June 2022 were reviewed. A responder was defined as a patient with a numerical rating scale decrease of ≥ 50% from the baseline to three months after the procedure. The presence of fatty infiltration in the cervical multifidus was assessed, along with patient characteristics, and cervical spine disease severity. To assess cervical sarcopenia, fatty infiltration in the bilateral multifidus muscles was evaluated at the C5-C6 level using the Goutallier classification. Results: Among 275 included patients, 113 (41.1%) and 162 (58.9%) were classified as non-responders and responders, respectively. The age, severity of disc degeneration, and grade of cervical multifidus fatty degeneration were significantly lower in responders. Multivariate logistic regression analysis revealed that pre-procedural symptoms (radicular pain with neck pain, odd ratio [OR] = 0.527, P = 0.024) and high-grade cervical multifidus fatty degeneration (Goutallier grade 2.5-4, OR = 0.320, P = 0.005) were significantly associated with an unsuccessful response to CIESI. Conclusions: These results suggest high-grade cervical multifidus fatty infiltration is an independent predictor of poor response to CIESI in patients with cervical radicular pain.

20.
J Clin Anesth ; 89: 111191, 2023 10.
Artículo en Inglés | MEDLINE | ID: mdl-37356194

RESUMEN

STUDY OBJECTIVE: We evaluated the effect of vitamin C administration on postoperative catheter-related bladder discomfort (CRBD). DESIGN: A double-blind, randomized controlled trial. SETTING: University tertiary hospital. PATIENTS: The participants were patients undergoing transurethral resection of bladder tumor. INTERVENTION: Patients were randomly assigned to either vitamin C (n = 59) or control (n = 59). The vitamin C group received 1 g of vitamin C intravenously and the control group received normal saline, administered after the induction of anesthesia. MEASUREMENTS: The primary endpoint was moderate or greater CRBD immediately postoperatively. Secondary outcomes included the incidence of moderate or greater CRBD at 1, 2, and 6 h postoperatively. The symptom of CRBD is either a burning sensation with an urge to void or discomfort in the suprapubic area. Moderate CRBD was defined as spontaneously reported by the patient without any behavioral responses, such as attempts to remove the urinary catheter, intense verbal reactions, and flailing limbs. Severe CRBD was spontaneously reported by the patient with behavioral responses. Patient satisfaction scores were also evaluated. MAIN RESULTS: The group that received vitamin C exhibited a significantly lower incidence of moderate or greater CRBD immediately postoperatively compared with the control group (17 [28.8%] vs. 40 [67.8%], p < 0.001, relative risk [95% confidence interval] = 0.426 [0.274-0.656]). The vitamin C group also showed a significantly lower incidence of moderate or greater CRBD at 1 and 2 h postoperatively compared with the control group (10 [16.9%] vs. 25 [42.4%], p = 0.003; and 5 [8.5%] vs. 16 [27.1%], p = 0.008, respectively). However, there was no significant difference in the incidence of moderate or greater CRBD 6 h postoperatively. Patient satisfaction scores were significantly higher in the vitamin C group than in the control group (5.0 ± 1.3 vs. 4.4 ± 1.4, p = 0.009). CONCLUSIONS: Patients who received vitamin C had decreased CRBD and improved patient satisfaction following transurethral resection of bladder tumor.


Asunto(s)
Neoplasias de la Vejiga Urinaria , Catéteres Urinarios , Humanos , Catéteres Urinarios/efectos adversos , Vejiga Urinaria/cirugía , Ácido Ascórbico/uso terapéutico , Resección Transuretral de la Vejiga , Dolor Postoperatorio/etiología , Neoplasias de la Vejiga Urinaria/cirugía , Método Doble Ciego
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