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Genetic loss-of-function mutations of Nav1.7 channel, abundantly expressed in peripheral nociceptive neurons, cause congenital insensitivity to pain (CIP) in humans, indicating that selective inhibition of the channel may lead to potential therapy of pain disorders. In this study, we investigated a novel compound, 5-chloro-N-(cyclopropylsulfonyl)-2-fluoro-4-(2-(8-(furan-2-ylmethyl)-8-azaspiro [4.5] decan-2-yl) ethoxy) benzamide (QLS-278) that inhibits Nav1.7 channel and exhibits anti-nociceptive activity. Compound QLS-278 exhibits inactivation- and concentration-dependent inhibition of macroscopic currents of Nav1.7 channels stably expressed in HEK293 cells with an IC50 of 1.2 {plus minus} 0.2 µM. QLS-278 causes a hyperpolarization shift of the channel inactivation and delays recovery from inactivation, without an obvious effect on voltage-dependent activation. In mouse DRG neurons, QLS-278 suppresses native TTX-sensitive Nav currents and also reduces neuronal firing. Moreover, QLS-278 dose-dependently relieves neuropathic pain induced by spared nerve injury and inflammatory pain induced by formalin without significant alteration of spontaneous locomotor activity in mice. Altogether, our identification of the novel compound QLS-278 may hold developmental potential for the treatment of chronic pain. Significance Statement QLS-278, a novel voltage-gated sodium Nav1.7 channel blocker, inhibits native TTX-S Na+ current and reduces action potential firings in DRG sensory neurons. QLS-278 also exhibits antinociceptive activity in mouse models of pain, thus demonstrating potential for the development of a treatment for chronic pain.
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OBJECTIVES: This study aims to investigate the short-term effects of transapical beating-heart septal myectomy (TA-BSM) on left atrial (LA) anatomy and function and its association with clinical indicators in patients with hypertrophic obstructive cardiomyopathy (HOCM). METHODS: A total of 105 HOCM patients who received TA-BSM were included. Clinical and comprehensive echocardiographic data were obtained before surgery, at discharge, and 3 months after myectomy. LA reverse remodelling was defined as LA maximum volume index (LAVI) ≤34 ml/m2 and a change of ≥10%. RESULTS: At 3 months after TA-BSM, New York Heart Association (NYHA) functional class and 6-min walking test were significantly improved, N-terminal pro-B-type natriuretic peptide (NT-proBNP) decreased, left ventricular outflow tract (LVOT) peak gradient and mitral regurgitation were significantly reduced. LAVI decreased in 76%, with a median change of 20%, and the criteria for LA reverse remodelling were met in 48%. LA strain parameters were improved at 3 months after TA-BSM. Moreover, left ventricular (LV) diastolic function was significantly improved, but LV global longitudinal strain was not significantly changed at 3 months after operation. Improvement in LVOT peak gradient, LAVI, LA reservoir strain (LASr) and conduit strain (LAScd) were associated with reduction in NT-proBNP. CONCLUSIONS: Along with effectively relieving the obstruction of the LVOT and mitral regurgitation, TA-BSM could significantly improve LA size and function during the short-term follow-up for HOCM patients. The indicators of LA reverse remodelling were associated with reduction in a biomarker of myocardial wall stress, indicating the early recovery of LV relaxation and clinical status for patients.
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Background: Aortic stenosis (AS) in combination with left ventricular outflow tract obstruction (LVOTO) has occasionally been reported. However, making a precise diagnosis and successfully treating this combination is challenging due to the hemodynamic interaction between the two conditions. Case summary: A 56-year-old male patient who had been diagnosed with severe AS and asymmetric left ventricular hypertrophy underwent aortic valve replacement (AVR) and a conventional septal myectomy. Immediately after the procedure, significant systolic anterior motion and mitral regurgitation developed, necessitating a surgical mitral edge-to-edge repair. Ten days after the procedure, the patient developed hematuria and LVOTO, which was confirmed by echocardiography. Because the LVOTO might have been the cause of the hematuria, the patient underwent alcohol septal ablation, but this had little effect. Three months later, a transapical beating-heart septal myectomy (TA-BSM) was performed in our hospital. Postoperatively, the LVOTO had been significantly ameliorated and the hematuria had resolved. Conclusion: For patients with AS and LVOTO due to a hypertrophic interventricular septum, inadequate amelioration of the LVOTO after AVR may lead to severe hemolytic hematuria. TA-BSM is a minimally invasive, safe, and effective surgical procedure for ameliorating LVOTO in patients with aortic valve prostheses.
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RATIONALE AND OBJECTIVES: This study aims to assess whether a radiomics-based nomogram correlates with a higher risk of future cerebro-cardiovascular events in patients with asymptomatic carotid plaques. Additionally, it investigates the nomogram's contribution to the revised Framingham Stroke Risk Profile (rFSRP) for predicting cerebro-cardiovascular risk. MATERIALS AND METHODS: Predictive models aimed at identifying an increased risk of future cerebro-cardiovascular events were developed and internally validated at one center, then externally validated at two other centers. Survival curves, constructed using the Kaplan-Meier method, were compared through the log-rank test. RESULTS: This study included a total of 2009 patients (3946 images). The final nomogram was generated using multivariate Cox regression variables, including dyslipidemia, lumen diameter, plaque echogenicity, and ultrasonography (US)-based radiomics risk. The Harrell's concordance index (C-index) for predicting events-free survival (EFS) was 0.708 in the training cohort, 0.574 in the external validation cohort 1, 0.632 in the internal validation cohort, and 0.639 in the external validation cohort 2. The final nomogram showed a significant increase in C-index compared to the clinical, conventional US, and US-based radiomics models (all P < 0.05). Furthermore, the final nomogram-assisted method significantly improved the sensitivity and accuracy of radiologists' visual qualitative score of plaque (both P < 0.001). Among 1058 patients with corresponding 1588 plaque US images classified as low-risk by the rFSRP, 75 (7.1%) patients with corresponding 93 (5.9%) carotid plaque images were appropriately reclassified to the high-risk category by the final nomogram. CONCLUSION: The radiomics-based nomogram demonstrated accurate prediction of cerebro-cardiovascular events in patients with asymptomatic carotid plaques. It also improved the sensitivity and accuracy of radiologists' visual qualitative score of carotid plaque and enhanced the risk stratification ability of rFSRP. SUMMARY: The radiomics-based nomogram allowed accurate prediction of cerebro-cardiovascular events, especially ipsilateral ischemic stroke in patients with asymptomatic carotid atherosclerotic plaques. KEY RESULTS: The radiomics-based nomogram allowed accurate prediction of cerebro-cardiovascular events, especially ipsilateral ischemic stroke in patients with asymptomatic carotid atherosclerotic plaques. The radiomics-based nomogram improved the sensitivity and accuracy of radiologists' visual qualitative score of carotid plaque. The radiomics-based nomogram improved the discrimination of high-risk populations from low-risk populations in asymptomatic patients with carotid atherosclerotic plaques and the risk stratification capability of the rFSRP.
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Introduction: The pattern of extraocular muscle involvement in ocular myasthenia gravis varies across different reports, diverging from our own observations. Thus, we employed two novel tools to discern this pattern. Methods: A retrospective analysis was conducted to collect and organize clinical data from 43 patients diagnosed with ocular myasthenia gravis. Each patient underwent both the computerized diplopia test and the Ocular Motor Nerve Palsy Scale assessment to evaluate the involvement of extraocular muscles. Results: Among the patients, there were 30 male and 13 female individuals, with a total of 113 affected extraocular muscles identified. Among all the affected extraocular muscles, the involvement of the levator palpebrae superioris muscle accounted for 35.40%, medial rectus muscle 7.7%, lateral rectus muscle 16.81%, superior rectus muscle 13.27%, inferior rectus muscle 12.39%, superior oblique muscle 1.77%, and inferior oblique muscle 2.65% of the total affected extraocular muscles. The positivity rates of the Neostigmine test were 89.19%, AChR antibody detection was 59.38%, and repetitive nerve stimulation was 34.38%. The AChR antibody positive rate among patients with only diplopia was 100%; among those with only ptosis, it was 80%; and among those with both diplopia and ptosis, it was 86.67%. Conclusion: The involvement of the extraocular muscles is not uniform. The levator palpebrae superioris exhibits the highest incidence rate, followed by the four rectus muscles and two oblique muscles. The inferior oblique involvement typically occurs when four or more EOMs are affected. Moreover, the levator palpebrae superioris and medial rectus show a higher tendency for bilateral involvement compared with other extraocular muscles.
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Two-dimensional materials with layered structures, appropriate band gaps, and high carrier mobility have attracted tremendous interest for their potential applications. Here we report the growth of monolayer SnP3 on Au(111) surfaces by molecular beam epitaxy. The kinetic processes for the growth and the crystalline properties are studied by scanning tunneling microscopy. The weak interaction between SnP3 and its Au(111) substrate is signified by the random crystal orientation distributions of SnP3 nanosheets. The electronic structures exhibit a band gap of â¼0.25 eV and high charge carrier mobility comparable to that of black phosphorus engineered by compressive strain. Additionally, domain boundary junctions with opposite chirality are observed, resulting from the strained film in the epitaxial growth process. Our work provides a method to fabricate high-quality monolayer SnP3 and suggests that the monolayer SnP3 is a promising candidate for applications in nanoelectronics and optoelectronics.
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The expression of metabotropic glutamate receptor 5 (mGluR5) is subject to developmental regulation and undergoes significant changes in neuropsychiatric disorders and diseases. Visualizing mGluR5 by fluorescence imaging is a highly desired innovative technology for biomedical applications. Nevertheless, there are substantial problems with the chemical probes that are presently accessible. In this study, we have successfully developed a two-photon fluorogenic probe, mGlu-5-TP, based on the structure of mGluR5 antagonist 6-methyl-2-(phenylethynyl)pyridine (MPEP). Due to this antagonist-based probe selectively recognizes mGluR5, high expression of mGluR5 on living SH-SY5Y human neuroblastoma cells has been detected during intracellular inflammation triggered by lipopolysaccharides (LPS). Of particular significance, the probe can be employed along with two-photon fluorescence microscopy to enable real-time visualization of the mGluR5 in Aß fiber-treated neuronal cells, thereby establishing a connection to the progression of Alzheimer's disease (AD). These results revealed that the probe can be a valuable imaging tool for studying mGluR5-related diseases in the nervous system.
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Colorantes Fluorescentes , Neuronas , Piridinas , Receptor del Glutamato Metabotropico 5 , Receptor del Glutamato Metabotropico 5/metabolismo , Receptor del Glutamato Metabotropico 5/antagonistas & inhibidores , Humanos , Colorantes Fluorescentes/química , Colorantes Fluorescentes/síntesis química , Neuronas/metabolismo , Piridinas/química , Piridinas/farmacología , Línea Celular Tumoral , Lipopolisacáridos/farmacología , Fotones , Imagen Óptica , Péptidos beta-Amiloides/metabolismo , Péptidos beta-Amiloides/análisisRESUMEN
Hydrogen sulfide (H2S), a critical gas signaling molecule, and N-acetyltransferase 2 (NAT2), a key enzyme in drug metabolism, are both known active biomarkers for liver function. However, the interactions and effects of H2S and NAT2 in living cells or lesion sites remain unknown due to the lack of imaging tools to achieve simultaneous detection of these two substances, making it challenging to implement real-time imaging and precise tracking. Herein, we report an activity-based two-photon fluorescent probe, TPSP-1, for the cascade detection of H2S and NAT2 in living liver cells. Continuous conversion from TPSP-1 to TPSP-3 was achieved in liver cells and tissues. Significantly, leveraging the outstanding optical properties of this two-photon fluorescent probe, TPSP-1, has been effectively used to identify pathological tissue samples directly from clinical liver cancer patients. This work provides us with this novel sensing and two-photon imaging probe, which can be used as a powerful tool to study the physiological functions of H2S and NAT2 and will help facilitate rapid and accurate diagnosis and therapeutic evaluation of hepatocellular carcinoma.
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Arilamina N-Acetiltransferasa , Carcinoma Hepatocelular , Colorantes Fluorescentes , Sulfuro de Hidrógeno , Neoplasias Hepáticas , Fotones , Sulfuro de Hidrógeno/análisis , Sulfuro de Hidrógeno/metabolismo , Colorantes Fluorescentes/química , Colorantes Fluorescentes/síntesis química , Humanos , Arilamina N-Acetiltransferasa/metabolismo , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/diagnóstico por imagen , Neoplasias Hepáticas/patología , Animales , Ratones , Células Hep G2 , Imagen ÓpticaRESUMEN
Cognitive dysfunction is a core symptom common in psychiatric disorders including depression that is primarily managed by antidepressants lacking efficacy in improving cognition. In this study, we report a novel dual serotonin transporter and voltage-gated potassium Kv7/KCNQ/M-channel inhibitor D01 (a 2-methyl-3-aryloxy-3-heteroarylpropylamines derivative) that exhibits both anti-depression effects and improvements in cognition. D01 inhibits serotonin transporters (Ki = 30.1 ± 6.9 nmol/L) and M channels (IC50 = 10.1 ± 2.4 µmol/L). D01 also reduces the immobility duration in the mouse FST and TST assays in a dose-dependent manner without a stimulatory effect on locomotion. Intragastric administrations of D01 (20 and 40 mg/kg) can significantly shorten the immobility time in a mouse model of chronic restraint stress (CRS)-induced depression-like behavior. Additionally, D01 dose-dependently improves the cognitive deficit induced by CRS in Morris water maze test and increases the exploration time with novel objects in normal or scopolamine-induced cognitive deficits in mice, but not fluoxetine. Furthermore, D01 reverses the long-term potentiation (LTP) inhibition induced by scopolamine. Taken together, our findings demonstrate that D01, a dual-target serotonin reuptake and M channel inhibitor, is highly effective in the treatment-resistant depression and cognitive deficits, thus holding potential for development as therapy of depression with cognitive deficits.
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AIMS/INTRODUCTION: To assess the effect of empagliflozin treatment on left ventricular (LV), right ventricular (RV) and left atrial (LA) functions in diabetes patients with normal ejection fraction. MATERIALS AND METHODS: The study included a total of 128 diabetes patients with multiple cardiovascular risk factors who were subjected to a 6-month follow up from the initiation of empagliflozin treatment. Before and after treatment with empagliflozin, LV, RV and LA strain, and noninvasive myocardial work parameters were evaluated by speckle tracking echocardiography. RESULTS: In 128 diabetes patients (mean age 56 ± 8 years, 85 men) with multiple cardiovascular risk factors, myocardial strain and work parameters were impaired, despite the absence of significant clinical symptoms of heart failure. After 6-month treatment with empagliflozin, the absolute value of LV strain in all directions increased, represented by LV global longitudinal strain (-18.0 ± 1.7% to -19.2 ± 1.7% [mean ± SD]). The same trend in LV global work efficiency (93 [91-94] % to 94 [93-95] % [median (IQR)]), RV free-wall longitudinal strain (-24.0 ± 2.7% to -25.0 ± 2.8%), LA reservoir (31 ± 5% to 34 ± 5%) and conduit strain (-14 ± 4% to -16 ± 4%) was also observed. LV mass index (106.9 ± 16.8-103.6 ± 16.4 g/m2) and LV global wasted work (143 [111-185] mmHg% to 108 [88-141] mmHg%) decreased after treatment (P < 0.05 for all). LV volume and LA volume index remained unchanged after treatment. In the multivariable analysis, the change in LA reservoir strain (ß = 0.050, P = 0.035) and baseline global longitudinal strain (ß = -0.488, P < 0.001) were independent predictors of improvement in LV global longitudinal strain. CONCLUSIONS: This study suggests that 6-month treatment with empagliflozin improved LV, RV and LA functions in diabetes patients with normal ejection fraction.
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Compuestos de Bencidrilo , Glucósidos , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Volumen Sistólico , Humanos , Glucósidos/uso terapéutico , Masculino , Compuestos de Bencidrilo/uso terapéutico , Persona de Mediana Edad , Femenino , Volumen Sistólico/efectos de los fármacos , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/fisiopatología , Ecocardiografía , Función Ventricular Izquierda/efectos de los fármacos , Anciano , Estudios de SeguimientoRESUMEN
Background: Distinguishing light-chain cardiac amyloidosis (AL CA) from left ventricular wall thickening (LVWT) resulted from other etiologies has proven to be challenging. This study aimed to determine the sensitivity and specificity of relative apical sparing in diagnosing AL CA and investigate the differences in clinical and echocardiographic characteristics between AL CA patients with apical sparing and those with non-apical sparing. Methods: A total of 63 consecutive patients with AL CA, 102 consecutive patients with LVWT (including 51 hypertrophic cardiomyopathy (HCM) and 51 hypertension) and 33 healthy individuals were recruited retrospectively at Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology. Conventional and speckle tracking echocardiography were performed on all subjects. Results: Although wall thickening was observed in all patients, almost all functional parameters were worse in AL CA, except for relative apical longitudinal strain (LS) (P=0.906). Of 63 patients with AL CA, only 17.5% (n=11) showed an apical sparing pattern. Patients with apical sparing had poorer cardiac performance than those with non-apical sparing. Relative apical sparing showed the lowest diagnostic accuracy with an area under the curve (AUC) of 0.58 [95% confidence interval (CI): 0.49-0.67, sensitivity: 17.5%, specificity: 98.0%, P=0.095] to detect AL CA, but right ventricular strain (RVS) (AUC: 0.86, P<0.001) showed the highest among all echocardiographic parameters. When diagnosing AL CA patients with non-apical sparing, RVS continued to maintain excellent diagnostic accuracy (AUC: 0.84, P<0.001), followed by left atrial reservoir strain (LASr) (AUC: 0.77, P<0.001). Conclusions: The diagnostic value of relative apical sparing for AL CA was limited with low sensitivity. In clinical practice, the diagnosis of early AL CA patients should not solely rely on relative apical sparing.
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Up to 40% of transplant recipients treated long-term with tacrolimus (TAC) develop post-transplant diabetes mellitus (PTDM). TAC is an important risk factor for PTDM, but is also essential for immunosuppression after transplantation. Long-term TAC treatment alters the gut microbiome, but the mechanisms of TAC-induced gut microbiota in the pathogenesis of PTDM are poorly characterized. Here, we showed that vancomycin, an inhibitor of bacterial beta-glucuronidase (GUS), prevents TAC-induced glucose disorder and insulin resistance in mice. Metagenomics shows that GUS-producing bacteria are predominant and flourish in the TAC-induced hyperglycemia mouse model, with upregulation of intestinal GUS activity. Targeted metabolomics analysis revealed that in the presence of high GUS activity, the hydrolysis of bile acid (BAs)-glucuronic conjugates is increased and most BAs are overproduced in the serum and liver, which, in turn, activates the ileal farnesoid X receptor (FXR) and suppresses GLP-1 secretion by L-cells. The GUS inhibitor vancomycin significantly eliminated GUS-producing bacteria and inhibited bacterial GUS activity and BAs levels, thereby enhancing L-cell GLP-1 secretion and preventing hyperglycemia. Our results propose a novel clinical strategy for inhibiting the bacterial GUS enzyme to prevent hyperglycemia without requiring withdrawal of TAC treatment. This strategy exerted its effect through the ileal bile acid-FXR-GLP-1 pathway.
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Diabetes Mellitus , Microbioma Gastrointestinal , Hiperglucemia , Ratones , Animales , Tacrolimus/farmacología , Tacrolimus/uso terapéutico , Vancomicina/farmacología , Inmunosupresores/uso terapéutico , Hiperglucemia/inducido químicamente , Hiperglucemia/tratamiento farmacológico , Bacterias/genética , Bacterias/metabolismo , Glucuronidasa/metabolismo , Glucuronidasa/farmacología , Ácidos y Sales Biliares/farmacología , Péptido 1 Similar al GlucagónRESUMEN
Enhancing α7 nAChR function serves as a therapeutic strategy for cognitive disorders. Here, we report the synthesis and evaluation of 2-arylamino-thiazole-5-carboxylic acid amide derivatives 6-9 that as positive allosteric modulators (PAMs) activate human α7 nAChR current expressed in Xenopus ooctyes. Among the 4-amino derivatives, a representative atypical type I PAM 6p exhibits potent activation of α7 current with an EC50 of 1.3 µM and the maximum activation effect on the current over 48-fold in the presence of acetylcholine (100 µM). The structure-activity relationship (SAR) analysis reveals that the 4-amino group is crucial for the allosteric activation of α7 currents by compound 6p as the substitution of 4-methyl group results in its conversion to compound 7b (EC50 = 2.1 µM; max effect: 58-fold) characterized as a typical type I PAM. Furthermore, both 6p and 7b are able to rescue auditory gating deficits in mouse schizophrenia-like model of acoustic startle prepulse inhibition.
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Tiazoles , Receptor Nicotínico de Acetilcolina alfa 7 , Animales , Receptor Nicotínico de Acetilcolina alfa 7/agonistas , Receptor Nicotínico de Acetilcolina alfa 7/metabolismo , Regulación Alostérica/efectos de los fármacos , Relación Estructura-Actividad , Humanos , Tiazoles/farmacología , Tiazoles/química , Tiazoles/síntesis química , Tiazoles/uso terapéutico , Ratones , Xenopus laevis , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacología , Ácidos Carboxílicos/síntesis química , Amidas/química , Amidas/farmacología , Amidas/síntesis química , Masculino , Disfunción Cognitiva/tratamiento farmacológico , Disfunción Cognitiva/metabolismoRESUMEN
OBJECTIVE: This study aimed to investigate the predictive value of left ventricular global longitudinal strain (GLS) and left atrial reservoir strain (LARS) on adverse events in chronic coronary artery disease (CAD) patients with reduced systolic function. METHODS: A total of 192 consecutive patients clinically diagnosed with chronic CAD and left ventricular ejection fraction (LVEF) ≤ 50% were finally included. Multiple strain parameters were analyzed with speckle tracking echocardiography. The composite endpoint included all-cause mortality, rehospitalization due to heart failure, myocardial infarction, and stroke. RESULTS: Patients experiencing the endpoint showed lower LVEF, lower absolute GLS and LARS than those without events. Both GLS (AUC = 0.82 [GLS] vs. 0.58 [LVEF], p < 0.001) and LARS (AUC = 0.71 [LARS] vs. 0.58 [LVEF], p = 0.033) were superior to LVEF in predicting adverse events. Multivariate cox regression analysis showed that both GLS (hazard ratio, 0.71; 95% CI, 0.63-0.79; p < 0.001) and LARS (hazard ratio, 0.96; 95% CI, 0.93-0.98; p < 0.001) were independent predictors for the endpoint. The addition of LARS (global chi-squared, 35.7 vs. 17.4; p < 0.05), GLS (global chi-squared, 58.6 vs. 17.4; p < 0.05) or both LARS and GLS (global chi-squared, 79.6 vs. 17.4; p < 0.05) to LVEF in the prediction model significantly improved its performance. The same significant improvement was also shown in the subgroups of mild (30% < LVEF ≤ 50%) and severe (LVEF ≤ 30%) reduced systolic function. CONCLUSIONS: Regarding CAD patients with reduced LVEF, both GLS and LARS are superior to LVEF in predicting adverse events, providing significant incremental value to LVEF.
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Enfermedad de la Arteria Coronaria , Disfunción Ventricular Izquierda , Humanos , Función Ventricular Izquierda , Volumen Sistólico , Pronóstico , Enfermedad de la Arteria Coronaria/complicaciones , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Disfunción Ventricular Izquierda/complicaciones , Disfunción Ventricular Izquierda/diagnóstico por imagenRESUMEN
The Kv4.3 channel features fast N-type inactivation and also undergoes a slow C-type inactivation. The gain-of-function mutations of Kv4.3 channels cause an inherited disease called Brugada syndrome (BrS), characterized by a shortened duration of cardiac action potential repolarization and ventricular arrhythmia. The sulfonylurea drug gliquidone, an ATP-dependent K+ channel antagonist, is widely used for the treatment of type 2 diabetes. Here, we report a novel role of gliquidone in inhibiting Kv4.3 and Kv4.3/KChIP2 channels that encode the cardiac transient outward K+ currents responsible for the initial phase of action potential repolarization. Gliquidone results in concentration-dependent inhibition of both Kv4.3 and Kv4.3/KChIP2 fast or steady-state inactivation currents with an IC50 of approximately 8 µM. Gliquidone also accelerates Kv4.3 channel inactivation and shifts the steady-state activation to a more depolarizing direction. Site-directed mutagenesis and molecular docking reveal that the residues S301 in the S4 and Y312A and L321A in the S4-S5 linker are critical for gliquidone-mediated inhibition of Kv4.3 currents, as mutating those residues to alanine significantly reduces the potency for gliquidone-mediated inhibition. Furthermore, gliquidone also inhibits a gain-of-function Kv4.3 V392I mutant identified in BrS patients in voltage- and concentration-dependent manner. Taken together, our findings demonstrate that gliquidone inhibits Kv4.3 channels by acting on the residues in the S4 and the S4-S5 linker. Therefore, gliquidone may hold repurposing potential for the therapy of Brugada syndrome. SIGNIFICANCE STATEMENT: We describe a novel role of gliquidone in inhibiting cardiac Kv4.3 currents and the channel gain-of-function mutation identified from patients with Brugada syndrome, suggesting its repurposing potential for therapy for the heart disease.
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Síndrome de Brugada , Diabetes Mellitus Tipo 2 , Compuestos de Sulfonilurea , Humanos , Síndrome de Brugada/genética , Simulación del Acoplamiento Molecular , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Potenciales de AcciónRESUMEN
OBJECTIVE: The relationship between gout and osteoporosis is poorly clarified, and the association between gout and fractures incidence remains controversial. Hence, in the present study, we aimed to comprehensively evaluate the available literature to elucidate whether gout is associated with an increased risk of both osteoporosis and fractures. MATERIALS AND METHODS: We conducted an exhaustive search of pertinent literature published until 20 March 2023, in well-recognized databases, namely Medline, Embase and Cochrane Library, focusing on examining the association between gout and the risk of osteoporosis or fracture. Meta-analysis was performed to aggregate the relative risks (RR) using random- or fixed-effects models. Sensitivity analyses were conducted iteratively, whereby each study was removed sequentially to gauge its impact on the overall outcome. Publication bias was assessed using Egger's and Begg's tests. This study was registered with PROSPERO (registry number: CRD42022376822). RESULTS: Herein, we included 10 observational studies comprising a total of 1,606,095 participants. An independent population sample of four studies validated the significant association between gout and osteoporosis (RRâ¯= 1.25, 95% confidence interval [CI] 1.05-1.48), with the results demonstrating robustness. However, our analysis did not detect any association between gout and fracture risk when compared with the control group (RRâ¯= 1.09, 95%CI 0.99-1.19), along with high heterogeneity (p for heterogeneityâ¯= 0.000; I2â¯= 79.7%). Further subgroup analysis revealed that gout is positively associated with fracture risk in the Chinese population (RRâ¯= 1.17, 95%CI 1.14-1.21), with no evidence of heterogeneity (p for heterogeneityâ¯= 0.420; I2â¯= 0.00%). CONCLUSION: Our meticulous evaluation of the available literature indicates that gout has no discernible impact on fracture incidence, although it is positively associated with an enhanced risk of osteoporosis. Therefore, it is imperative to prioritize preventive measures to prevent osteoporotic complications in individuals diagnosed with gout.
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Gota , Osteoporosis , Fracturas Osteoporóticas , Humanos , Fracturas Osteoporóticas/epidemiología , Osteoporosis/epidemiología , Gota/complicaciones , Gota/epidemiologíaRESUMEN
Since the first description of apical hypertrophic cardiomyopathy (ApHCM) in 1976, contrasting information from all over the world has emerged regarding the natural history of the disease. However, the recommended guidelines on hypertrophic cardiomyopathy (HCM) pay a cursory reference to ApHCM, without ApHCM-specific recommendations to guide the diagnosis and management. In addition, cardiologists may not be aware of certain aspects that are specific to this disease subtype, and a robust understanding of specific disease features can facilitate recognition and timely diagnosis. Therefore, the review covers the incidence, pathogenesis, and characteristics of ApHCM and imaging methods. Echocardiography and cardiovascular magnetic resonance imaging (CMR) are the most commonly used imaging methods. Moreover, this review presents the management strategies of this heterogeneous clinical entity. In this review, we introduce a novel transapical beating-heart septal myectomy procedure for ApHCM patients with a promising short-time result.
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Miocardiopatía Hipertrófica Apical , Cardiomiopatía Hipertrófica , Humanos , Cardiomiopatía Hipertrófica/diagnóstico , Ecocardiografía/métodosRESUMEN
BACKGROUNDS: Tacrolimus (TAC) concentration in peripheral blood mononuclear cells (PBMCs) is regarded as a better predictor of its immunosuppressive effect than the TAC concentration in whole blood. However, whether the exposure of TAC in PBMCs or WB was altered in post-transplant recipients with renal impairment remains unclear. METHODS: We investigated the relationship of trough TAC concentration in WB and PBMCs with renal functions in post-transplant recipients. The pharmacokinetic profiles of TAC in PBMCs and WB in the two chronic kidney disease (CKD) rat models were examined using UPLC-MS/MS. Western blotting and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) were used to analyze the expression of proteins and mRNAs related to TAC metabolism and transport, respectively. In addition, the effects of uremic toxins on human PBMCs were investigated using whole-transcriptome sequencing (RNA sequencing [RNA-seq]). RESULTS: We observed a decrease in the trough TAC concentration in PBMCs in the recipients with estimated glomerular filtration rate (eGFR) < 90 mL/min, compared with those of recipients with eGFR > 90 mL/min, but there was no difference in blood based on TAC concentrations (C0Blood). In a 150-patient post-transplant cohort, no significant relationship was observed between PBMCs and WB concentrations of TAC, and the eGFR value was correlated with TAC C0PBMCs but not with TAC C0Blood. In two CKD rat models, the TAC pharmacokinetic profile in the PBMCs was significantly lower than that in the control group; however, the blood TAC pharmacokinetic profiles in the two groups were similar. Transcriptome results showed that co-incubation of human PBMCs with uremic toxins upregulated the expression of AHR, ABCB1, and ABCC2. Compared to control rats, plasma IS increased by 1.93- and 2.26-fold and the expression of AHR, P-gp, and MRP2 in PBMCs was higher in AD and 5/6 nephrectomy (NX) rats, without modifying the expression of other proteins related to TAC exposure. CONCLUSION: The pharmacokinetics of TAC in PBMCs changed with a decline in renal function. Uremic toxins accumulate during renal insufficiency, which activates AHR, upregulates the expression of P-gp and MRP2, and affects their intracellular concentrations. Our findings suggest that monitoring TAC concentrations in PBMCs is more important than monitoring WB concentrations in post-transplant recipients with renal impairment.
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Insuficiencia Renal Crónica , Insuficiencia Renal , Humanos , Animales , Ratas , Tacrolimus/uso terapéutico , Inmunosupresores , Transportadoras de Casetes de Unión a ATP , Cromatografía Liquida , Leucocitos Mononucleares/metabolismo , Tóxinas Urémicas , Espectrometría de Masas en Tándem , Riñón/metabolismo , Insuficiencia Renal/metabolismo , Insuficiencia Renal Crónica/metabolismoRESUMEN
BACKGROUND: Laparoscopic anatomic resection of liver segment 4 is a technically challenging operation, which is rarely reported owing to the difficulty of defining the demarcation of a hepatic segment 4 on a monitor.1 The portal territory staining method is technically feasible to identify tumors and segment boundaries during hepatectomy.2 Herein, we describe the laparoscopic hepatectomy of segment 4 using the fluorescent-positive staining method. METHODS: A 72-year-old man recurred colorectal liver metastases after colectomy, positron emission tomography (PET)/computed tomography (CT) showed metastases located in segment 4 with involvement of the middle hepatic vein (MHV) and caudate lobe; no other organ metastasis or recurrence occurred. We performed an anatomical hepatectomy 4 with MHV and parenchymal resection of segment 1 (H1'/4-MHV).3 The key point of the procedure was dividing and clamping Glisson's branches for segment 2 and segment 3 using the hepatic round ligament approach; the G2 and G3 were dissected along the right side of round ligament via the extrahepatic Glissonian approach, then the left hepatic artery (LHA) was divided and injected with ICG in the left portal vein (LPV). Finally, transection was performed along the fluorescent stain location line and ischemic demarcation line. RESULTS: The operation time was 263 min; the Pringle lasted 110 min, and the estimated blood loss was 400 g. The patient was discharged on postoperative day 5 without complications. Sigmoid carcinoma and R0 margin were confirmed by histopathology. CONCLUSIONS: Laparoscopic anatomic hepatectomy 4 with middle hepatic vein invasion using indocyanine green (ICG) fluorescence staining is a feasible and effective technique.
Asunto(s)
Carcinoma Hepatocelular , Laparoscopía , Neoplasias Hepáticas , Masculino , Femenino , Humanos , Anciano , Verde de Indocianina , Carcinoma Hepatocelular/diagnóstico por imagen , Carcinoma Hepatocelular/cirugía , Carcinoma Hepatocelular/etiología , Venas Hepáticas/cirugía , Venas Hepáticas/patología , Neoplasias Hepáticas/diagnóstico por imagen , Neoplasias Hepáticas/cirugía , Neoplasias Hepáticas/patología , Hepatectomía/métodos , Laparoscopía/métodos , Coloración y EtiquetadoRESUMEN
OBJECTIVE: Pathogenesis of colorectal cancer (CRC) depends on multiple factors. Identifying risk factors for CRC may facilitate the early prevention of the disease. We aimed to assess whether existing evidence suggests that serum uric acid (SUA) levels and gout are associated with CRC incidence. METHODS: The study was registered on PROSPERO (CRD42022371591). Searches of PubMed, Embase, and Cochrane Library were conducted from the establishment to November 11, 2022. Pooled relative risk (RR) with 95â¯% confidence intervals (CI) was derived to evaluate the effect of SUA or gout on CRC incidence. Non-linear trend analysis was conducted to explore the relationship between SUA level and CRC incidence. RESULTS: Twelve eligible studies with 22 reports were included. A meta-analysis of the included studies showed that when the highest and lowest SUA level categories were compared, an association between SUA level and CRC incidence was revealed (RR, 1.35; 95â¯% CI: 1.27-1.43; P < 0.001). Non-linear relationship between SUA level and CRC incidence was found. Further meta-analysis indicated that gout was associated with CRC incidence (RR, 1.22; 95â¯% CI: 1.08-1.36; Pâ¯=â¯0.001). CONCLUSIONS: Both SUA level and gout were associated with an increased risk of CRC. Maintaining low SUA levels may be beneficial in reducing the incidence of CRC. Further studies evaluating the precise mechanisms underlying this association are needed to establish whether SUA/gout causes CRC.