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1.
Cell ; 186(25): 5517-5535.e24, 2023 12 07.
Artículo en Inglés | MEDLINE | ID: mdl-37992713

RESUMEN

Transfer RNA (tRNA) modifications are critical for protein synthesis. Queuosine (Q), a 7-deaza-guanosine derivative, is present in tRNA anticodons. In vertebrate tRNAs for Tyr and Asp, Q is further glycosylated with galactose and mannose to generate galQ and manQ, respectively. However, biogenesis and physiological relevance of Q-glycosylation remain poorly understood. Here, we biochemically identified two RNA glycosylases, QTGAL and QTMAN, and successfully reconstituted Q-glycosylation of tRNAs using nucleotide diphosphate sugars. Ribosome profiling of knockout cells revealed that Q-glycosylation slowed down elongation at cognate codons, UAC and GAC (GAU), respectively. We also found that galactosylation of Q suppresses stop codon readthrough. Moreover, protein aggregates increased in cells lacking Q-glycosylation, indicating that Q-glycosylation contributes to proteostasis. Cryo-EM of human ribosome-tRNA complex revealed the molecular basis of codon recognition regulated by Q-glycosylations. Furthermore, zebrafish qtgal and qtman knockout lines displayed shortened body length, implying that Q-glycosylation is required for post-embryonic growth in vertebrates.


Asunto(s)
ARN de Transferencia , Animales , Humanos , Ratas , Anticodón , Línea Celular , Codón , Glicosilación , Nucleósido Q/química , Nucleósido Q/genética , Nucleósido Q/metabolismo , ARN de Transferencia/química , ARN de Transferencia/metabolismo , Porcinos , Pez Cebra/metabolismo , Conformación de Ácido Nucleico
2.
Mol Cell ; 74(6): 1205-1214.e8, 2019 06 20.
Artículo en Inglés | MEDLINE | ID: mdl-31080011

RESUMEN

Translation initiation of hepatitis C virus (HCV) genomic RNA is induced by an internal ribosome entry site (IRES). Our cryoelectron microscopy (cryo-EM) analysis revealed that the HCV IRES binds to the solvent side of the 40S platform of the cap-dependently translating 80S ribosome. Furthermore, we obtained the cryo-EM structures of the HCV IRES capturing the 40S subunit of the IRES-dependently translating 80S ribosome. In the elucidated structures, the HCV IRES "body," consisting of domain III except for subdomain IIIb, binds to the 40S subunit, while the "long arm," consisting of domain II, remains flexible and does not impede the ongoing translation. Biochemical experiments revealed that the cap-dependently translating ribosome becomes a better substrate for the HCV IRES than the free ribosome. Therefore, the HCV IRES is likely to efficiently induce the translation initiation of its downstream mRNA with the captured translating ribosome as soon as the ongoing translation terminates.


Asunto(s)
Factores Eucarióticos de Iniciación/química , Hepacivirus/genética , Iniciación de la Cadena Peptídica Traduccional , ARN Viral/química , Subunidades Ribosómicas Grandes de Eucariotas/ultraestructura , Subunidades Ribosómicas Pequeñas de Eucariotas/ultraestructura , Sitios de Unión , Microscopía por Crioelectrón , Factores Eucarióticos de Iniciación/genética , Factores Eucarióticos de Iniciación/metabolismo , Células HEK293 , Hepacivirus/metabolismo , Interacciones Huésped-Patógeno , Humanos , Sitios Internos de Entrada al Ribosoma , Modelos Moleculares , Conformación de Ácido Nucleico , ARN Viral/genética , ARN Viral/metabolismo , Subunidades Ribosómicas Grandes de Eucariotas/genética , Subunidades Ribosómicas Grandes de Eucariotas/metabolismo , Subunidades Ribosómicas Pequeñas de Eucariotas/genética , Subunidades Ribosómicas Pequeñas de Eucariotas/metabolismo
3.
Nat Chem Biol ; 20(5): 605-614, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38267667

RESUMEN

In response to environmental changes, cells flexibly and rapidly alter gene expression through translational controls. In plants, the translation of NIP5;1, a boric acid diffusion facilitator, is downregulated in response to an excess amount of boric acid in the environment through upstream open reading frames (uORFs) that consist of only AUG and stop codons. However, the molecular details of how this minimum uORF controls translation of the downstream main ORF in a boric acid-dependent manner have remained unclear. Here, by combining ribosome profiling, translation complex profile sequencing, structural analysis with cryo-electron microscopy and biochemical assays, we show that the 80S ribosome assembled at AUG-stop migrates into the subsequent RNA segment, followed by downstream translation initiation, and that boric acid impedes this process by the stable confinement of eukaryotic release factor 1 on the 80S ribosome on AUG-stop. Our results provide molecular insight into translation regulation by a minimum and environment-responsive uORF.


Asunto(s)
Ácidos Bóricos , Biosíntesis de Proteínas , Ribosomas , Ribosomas/metabolismo , Ácidos Bóricos/química , Factores de Terminación de Péptidos/metabolismo , Factores de Terminación de Péptidos/química , Factores de Terminación de Péptidos/genética , Microscopía por Crioelectrón , Sistemas de Lectura Abierta , Codón de Terminación , Arabidopsis/metabolismo , Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Proteínas de Arabidopsis/química , Proteínas de Arabidopsis/genética
4.
RNA ; 28(3): 290-302, 2022 03.
Artículo en Inglés | MEDLINE | ID: mdl-34906996

RESUMEN

Ribosome pauses are associated with various cotranslational events and determine the fate of mRNAs and proteins. Thus, the identification of precise pause sites across the transcriptome is desirable; however, the landscape of ribosome pauses in bacteria remains ambiguous. Here, we harness monosome and disome (or collided ribosome) profiling strategies to survey ribosome pause sites in Escherichia coli Compared to eukaryotes, ribosome collisions in bacteria showed remarkable differences: a low frequency of disomes at stop codons, collisions occurring immediately after 70S assembly on start codons, and shorter queues of ribosomes trailing upstream. The pause sites corresponded with the biochemical validation by integrated nascent chain profiling (iNP) to detect polypeptidyl-tRNA, an elongation intermediate. Moreover, the subset of those sites showed puromycin resistance, presenting slow peptidyl transfer. Among the identified sites, the ribosome pause at Asn586 of ycbZ was validated by biochemical reporter assay, tRNA sequencing (tRNA-seq), and cryo-electron microscopy (cryo-EM) experiments. Our results provide a useful resource for ribosome stalling sites in bacteria.


Asunto(s)
Extensión de la Cadena Peptídica de Translación , Terminación de la Cadena Péptídica Traduccional , Ribosomas/metabolismo , Codón de Terminación , Escherichia coli , Proteínas de Escherichia coli/genética , Proteínas de Escherichia coli/metabolismo , ARN de Transferencia/genética , ARN de Transferencia/metabolismo
5.
Nat Chem Biol ; 18(3): 321-331, 2022 03.
Artículo en Inglés | MEDLINE | ID: mdl-35177839

RESUMEN

Disaggregation of amyloid fibrils is a fundamental biological process required for amyloid propagation. However, due to the lack of experimental systems, the molecular mechanism of how amyloid is disaggregated by cellular factors remains poorly understood. Here, we established a robust in vitro reconstituted system of yeast prion propagation and found that heat-shock protein 104 (Hsp104), Ssa1 and Sis1 chaperones are essential for efficient disaggregation of Sup35 amyloid. Real-time imaging of single-molecule fluorescence coupled with the reconstitution system revealed that amyloid disaggregation is achieved by ordered, timely binding of the chaperones to amyloid. Remarkably, we uncovered two distinct prion strain conformation-dependent modes of disaggregation, fragmentation and dissolution. We characterized distinct chaperone dynamics in each mode and found that transient, repeated binding of Hsp104 to the same site of amyloid results in fragmentation. These findings provide a physical foundation for otherwise puzzling in vivo observations and for therapeutic development for amyloid-associated neurodegenerative diseases.


Asunto(s)
Priones , Proteínas de Saccharomyces cerevisiae , Amiloide/química , Proteínas de Choque Térmico/química , Proteínas de Choque Térmico/metabolismo , Chaperonas Moleculares/metabolismo , Factores de Terminación de Péptidos/metabolismo , Priones/química , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo
6.
Bioorg Med Chem ; 90: 117370, 2023 07 15.
Artículo en Inglés | MEDLINE | ID: mdl-37311373

RESUMEN

Transthyretin amyloidosis is a progressive systemic disorder that is caused by the amyloid deposition of transthyretin in various organs. Stabilization of the native transthyretin is an effective strategy for the treatment of transthyretin amyloidosis. In this study we demonstrate that the clinically used uricosuric agent benziodarone is highly effective to stabilize the tetrameric structure of transthyretin. An acid-induced aggregation assay showed that benziodarone had strong inhibitory activity similar to that of tafamidis, which is currently used as a therapeutic agent for transthyretin amyloidosis. Moreover, a possible metabolite, 6-hydroxybenziodarone, retained the strong amyloid inhibitory activity of benziodarone. An ex vivo competitive binding assay using a fluorogenic probe showed that benziodarone and 6-hydroxybenziodarone were highly potent for selective binding to transthyretin in human plasma. An X-ray crystal structure analysis revealed that the halogenated hydroxyphenyl ring was located at the entrance of the thyroxine binding channel of transthyretin and that the benzofuran ring was located in the inner channel. These studies suggest that benziodarone and 6-hydroxybenziodarone would potentially be effective against transthyretin amyloidosis.


Asunto(s)
Neuropatías Amiloides Familiares , Benzofuranos , Humanos , Prealbúmina/metabolismo , Neuropatías Amiloides Familiares/tratamiento farmacológico , Amiloide/metabolismo
7.
J Pharmacol Sci ; 151(1): 54-62, 2023 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-36522123

RESUMEN

Hereditary ATTR amyloidosis is caused by the point mutation in serum protein transthyretin (TTR) that destabilizes its tetrameric structure to dissociate into monomer. The monomers form amyloid fibrils, which are deposited in peripheral nerves and organs, resulting in dysfunction. Therefore, a drug that dissolves amyloid after it has formed, termed amyloid disruptor, is needed as a new therapeutic drug. Here, we first established a high throughput screening system to find TTR interactors from the LOPAC1280 compound library. Among the hit compounds, thioflavin T-based post-treatment assay determined lead compounds for TTR amyloid disruptors, NSC95397 and Gossypol, designated as B and R, respectively. Because these compounds have naphthoquinone-naphthalene structures, we tested 100 naphthoquinone derivatives, and found 10 candidate compounds that disrupted TTR amyloid. Furthermore, to determine whether these 10 compounds are selective for TTR amyloid, we evaluated them against beta-amyloid (Aß1-42). We found two compounds that were selective for TTR and did not disrupt Aß-derived amyloid. Therefore, we succeeded in identifying TTR-selective amyloid disruptors, and demonstrated that naphthoquinone compounds are useful structures as amyloid disruptors. These findings contribute to the on-going efforts to discover new therapeutic tools for TTR amyloidosis.


Asunto(s)
Neuropatías Amiloides Familiares , Amiloidosis , Naftoquinonas , Humanos , Prealbúmina/química , Prealbúmina/genética , Prealbúmina/metabolismo , Amiloide/metabolismo , Amiloide/uso terapéutico , Amiloidosis/metabolismo , Péptidos beta-Amiloides , Naftoquinonas/farmacología , Neuropatías Amiloides Familiares/tratamiento farmacológico , Neuropatías Amiloides Familiares/metabolismo
8.
BMC Anesthesiol ; 23(1): 272, 2023 08 11.
Artículo en Inglés | MEDLINE | ID: mdl-37568085

RESUMEN

BACKGROUND: Nasal intubation using a fiberoptic scope is a useful technique. In clinical practice, we have experienced difficulty in advancing the endotracheal tube (ETT) over the fiberoptic scope because of resistance to the passage of the ETT against rotation in the nasal cavity, when it gets hung up on structures of the laryngeal inlet. Several maneuvers have been proposed to overcome this difficulty. The gap between the tip of the ETT and the fiberoptic scope can be reduced using a thicker fiberoptic scope and a thinner ETT. Moreover, simultaneous rotation of the fiberoptic scope and ETT could lead to successful intubation by reducing impingement on the ETT. However, the discrepancy between these rotation angles is unclear. This observational prospective study aimed to investigate the discrepancy in the rotation angle between the ETT and fiberoptic scope during nasal intubation. METHODS: The patients (aged 20-80 years) who underwent nasal intubation for oral and maxillofacial surgery participated in three sizes of preformed nasal ETT and were intubated using a fiberoptic scope. They were divided into three groups; the ETT internal diameter (ID) 6.5 mm (6.5 group), ID 7.0 mm (7.0 group), and ID 7.5 mm (7.5 group). The ETT was then inserted through the nasal cavity into the pharynx. After the fiberoptic scope was advanced through the ETT above the glottis, simultaneous rotation by both the proximal end of the fiberoptic scope and ETT was performed in 90° and 180° in both right (clockwise) and left (counterclockwise) directions, and the rotation angle at the distal end of the ETT was monitored using a video laryngoscope (Pentax-AWS). RESULTS: A total of 39 patients were included in the study. When both the proximal end of the fiberscope and ETT were simultaneously rotated by 90°, in the 6.5 group (n = 13), the distal end of the ETT rotated by 47.8 ± 1.5°. In the 7.0 °group (n = 13), the distal end of the ETT rotated by 45.5 ± 1.0°. In the 7.5 group (n = 13), the distal end of the ETT rotated by 39.9 ± 1.0°. When the proximal end of the fiberscope and ETT were rotated by 180°, in the 6.5 group, the distal end of the ETT rotated by 166.2 ± 2.5°. In the 7.0 group, the distal end of the ETT rotated by 145.7 ± 2.2°. In the 7.5 group, the distal end of the ETT rotated by 115.1 ± 2.0°. All rotation angles in the distal end of the ETT were significantly lower than those in both the proximal end of the fiberscope and ETT (p < 0.05). Rotating right by 180° was significantly different among the three groups (p < 0.05), although rotating right by 90° was not significantly different. Similar results were obtained for the left rotation. CONCLUSION: Simultaneous rotation by the proximal end of the ETT and fiberscope above the glottis for the nasal approach induced significant differences in the distal end of the ETT. The larger tube lagged by the resistance of the nasal passages during rotation. Therefore, the ETT does not rotate as much as the rotation angle. TRIAL REGISTRATION: This prospective observational study was conducted after receiving approval from the Ethics Review Board of Kyushu University Hospital (Approval No. 30-447).


Asunto(s)
Intubación Intratraqueal , Laringe , Humanos , Intubación Intratraqueal/métodos , Cavidad Nasal , Estudios Prospectivos , Rotación , Adulto Joven , Adulto , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años
9.
J Anesth ; 37(5): 769-774, 2023 10.
Artículo en Inglés | MEDLINE | ID: mdl-37612435

RESUMEN

PURPOSE: Several studies indicate that assisted reproductive technology (ART) including in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) pregnancies carries increased risk of complications including postpartum hemorrhage (PPH). However, the association between IVF/ICSI and the bleeding risk particularly in cesarean delivery has not been systematically assessed. The aim of this study was to evaluate bleeding risk during and after cesarean delivery in parturients who conceived using IVF or ICSI. METHODS: This is a retrospective observational study analyzing data from 310 parturients who underwent cesarean delivery: 155 who had conceived using IVF or ICSI (IVF/ICSI group) and 155 age and year of delivery matched controls who had conceived spontaneously (control group). The primary outcome measure was the amount of blood lost during and within 24 h after cesarean delivery. Secondary outcome measure was the incidence of severe PPH. With 132 parturients in each group, we had 90% power to detect a 200 mL difference in the bleeding amount, at a 0.05 two-sided significance level. RESULTS: The amount of bleeding in the IVF/ICSI group was 1234 ± 669 mL, which was 124 mL (11.2%) greater than that in the control group (95% CI - 34 to 282; p = 0.12). The incidence of severe PPH in the IVF/ICSI group and in the control group was 23.9% and 16.8%, respectively (p = 0.16), and the unadjusted odds ratio was 1.6 (95% CI, 0.9-2.7; p = 0.12). No significant independent effect of IVF/ICSI on the bleeding amount and the incidence of severe PPH was observed in multivariable regression analyses (p = 0.22, p = 0.16). CONCLUSION: In this study, IVF and ICSI were not associated with increasing risk of bleeding in cesarean delivery.


Asunto(s)
Semen , Inyecciones de Esperma Intracitoplasmáticas , Embarazo , Femenino , Masculino , Humanos , Inyecciones de Esperma Intracitoplasmáticas/efectos adversos , Estudios Retrospectivos , Fertilización In Vitro/efectos adversos , Cesárea/efectos adversos , Resultado del Embarazo
10.
BMC Anesthesiol ; 22(1): 148, 2022 05 16.
Artículo en Inglés | MEDLINE | ID: mdl-35578184

RESUMEN

OBJECTIVE: The goal of this study was to compare the end-tidal sevoflurane concentration and time for intravenous cannulation at induction of anesthesia using sevoflurane with or without nitrous oxide in healthy children and in those with developmental disabilities. METHODS: Normal and developmentally disabled children were anesthetized by inhalation of sevoflurane with nitrous oxide or with nitrous oxide-free oxygen, and intravenous cannulae were introduced. Nitrous oxide was stopped after loss of consciousness. The following parameters were recorded for each patient: age, gender, height, weight, BMI, duration of intravenous cannulation, end-tidal concentration of sevoflurane at the completion of intravenous cannulation, and use of nitrous oxide. For each parameter except gender, p-value were calculated by one-way analysis of variance (ANOVA). For gender, p-value were calculated using the Fisher method. Two-way ANOVA was performed to evaluate the effect of patient health status and nitrous oxide use on the end-tidal concentrations of sevoflurane and the time required for intravenous cannulation. RESULTS: The end-tidal sevoflurane concentrations at the completion of the intravenous cannulation had received a significant main effect of the factor "the use of nitrous oxide" (F(1,166) = 25.8, p < 0.001, η2 = 0.13) and a small effect of the factor "the patient health status" (F(1,166) = 0.259, p = 0.611, η2 = 0.001). However, the time required for intravenous cannulation was not significantly affected by either of the two factors, "the use of nitrous oxide" (F(1,166) = 0.454, p = 0.501, η2 = 0.003) and "the patient health status" (F(1,166) = 0.308, p = 0.579, η2 = 0.002). CONCLUSIONS: Between the healthy children and the children with developmental disabilities, no significant differences in the time required for the intravenous cannulation from the beginning of anesthetic induction. However, the end-tidal sevoflurane concentrations at the completion of the intravenous cannulation was significantly different. Sevoflurane in alveoli might be diluted by nitrous oxide.


Asunto(s)
Anestésicos por Inhalación , Éteres Metílicos , Anestesia por Inhalación , Anestésicos por Inhalación/farmacología , Cateterismo , Niño , Discapacidades del Desarrollo , Humanos , Óxido Nitroso , Sevoflurano
11.
Sensors (Basel) ; 22(7)2022 Apr 02.
Artículo en Inglés | MEDLINE | ID: mdl-35408356

RESUMEN

The condition of arteriovenous fistula (AVF) blood flow is typically checked by using auscultation; however, auscultation should require a qualitative judgment dependent on the skills of doctors, and further attention to contact infection is required. For these reasons, this study developed a non-contact and non-invasive medical device to measure the pulse wave of AVFs by applying optical imaging technology. As a first step toward realization of the quantification judgment based on non-contact AVF measurement, we experimentally validated the developed system, whereby the hemodynamics of 168 subjects were visually and quantitatively evaluated based on clinical tests. Based on the evaluation results, the fundamental statistical characteristics of the non-contact measurement, including the average and median values, and distribution of measured signal-to-noise power ratio, were demonstrated. The clinical test results contributed to the future construction of quantified criteria for the AVF condition with the non-contact measurement.


Asunto(s)
Fístula Arteriovenosa , Derivación Arteriovenosa Quirúrgica , Fístula Arteriovenosa/diagnóstico por imagen , Derivación Arteriovenosa Quirúrgica/métodos , Frecuencia Cardíaca , Hemodinámica , Humanos , Diálisis Renal
12.
J Anesth ; 36(1): 144-151, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-34773505

RESUMEN

PURPOSE: Inflammation after stent graft surgery is known as postimplantation syndrome (PIS) and it causes leukocytosis. However, we have experienced leukopenia in the very early postoperative phase of endovascular surgery at our institution. We investigated leukopenia, an under-recognized phenomenon that occurred after transcatheter aortic valve implantation (TAVI), endovascular aortic repair (EVAR), and thoracic endovascular aortic repair (TEVAR). METHODS: Records of patients who underwent TAVI, EVAR, and TEVAR between March 2018 and February 2019 were retrospectively reviewed. Primary outcomes were the decline rate of white blood cell count (DR-WBC) in the immediate postoperative period and its differences among surgical procedures. The secondary endpoint was the relationship between DR-WBC and infectious complications. Furthermore, the incidence of PIS and its differences among the procedures and associations with DR-WBC were evaluated. RESULTS: A total of 108 patients (TAVI 41, EVAR 37, TEVAR 30) were included. DR-WBC immediately after surgery was higher in the TAVI group when compared with other groups (TAVI, 43.1 ± 22.6%; EVAR, 27.6 ± 17.3%; TEVAR, 25.4 ± 27.4%; P < 0.01). DR-WBC was not significantly different regardless of postoperative infection (P = 0.45) or PIS (P = 0.62). The incidence rate of PIS was higher in the EVAR group compared with the TAVI group, and was not associated with DR-WBC. CONCLUSIONS: Leukopenia was a common phenomenon immediately after endovascular surgery, especially TAVI. It resolved a day after surgery and was not associated with PIS or infectious complications. Therefore, it seems to be a transient abnormal hematological finding and a self-limiting condition.


Asunto(s)
Aneurisma de la Aorta Abdominal , Implantación de Prótesis Vascular , Procedimientos Endovasculares , Leucopenia , Aneurisma de la Aorta Abdominal/cirugía , Prótesis Vascular/efectos adversos , Implantación de Prótesis Vascular/efectos adversos , Procedimientos Endovasculares/efectos adversos , Humanos , Leucopenia/complicaciones , Leucopenia/etiología , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiología , Estudios Retrospectivos , Factores de Riesgo , Stents/efectos adversos , Resultado del Tratamiento
13.
J Neurochem ; 156(6): 957-966, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-32852783

RESUMEN

Patients with transthyretin (TTR)-type familial amyloid polyneuropathy (FAP) typically exhibit sensory dominant polyneuropathy and autonomic neuropathy. However, the molecular pathogenesis of the neuropathy remains unclear. In this study, we characterize the features of FAP TTR the substitution of lysine for glutamic acid at position 61 (E61K). This FAP was late-onset, with sensory dominant polyneuropathy, autonomic neuropathy, and cardiac amyloidosis. Interestingly, no amyloid deposits were found in the endoneurium of the four nerve specimens examined. Therefore, we examined the amyloidogenic properties of E61K TTR in vitro. Recombinant wild-type TTR, the substitution of methionine for valine at position 30 (V30M) TTR, and E61K TTR proteins were incubated at 37°C for 72 hr, and amyloid fibril formation was assessed using the thioflavin-T binding assay. Amyloid fibril formation by E61K TTR was less than that by V30M TTR, and similar to that by wild-type TTR. E61K TTR did not have an inhibitory effect on neurite outgrowth from adult rat dorsal root ganglion (DRG) neurons, but V30M TTR did. Furthermore, we studied the sural nerve of our patient by terminal deoxynucleotidyl transferase dUTP nick end labeling and electron microscopy. A number of apoptotic cells were observed in the endoneurium of the nerve by transferase dUTP nick end labeling. Chromatin condensation was confirmed in the nucleus of non-myelinating Schwann cells by electron microscopy. These findings suggest that E61K TTR is low amyloidogenic, in vitro and in vivo. However, TTR aggregates and amyloid fibrils in the DRG may cause sensory impairments in FAP because the DRG has no blood-nerve barrier. Moreover, Schwann cell apoptosis may contribute to the neurodegeneration.


Asunto(s)
Neuropatías Amiloides Familiares/genética , Amiloide/biosíntesis , Prealbúmina/genética , Sustitución de Aminoácidos , Amiloide/genética , Amiloidosis/patología , Animales , Apoptosis , Cristalografía por Rayos X , Humanos , Mutación , Nervios Periféricos/patología , Placa Amiloide/patología , Prealbúmina/química , Ratas , Ratas Wistar , Proteínas Recombinantes/farmacología , Células de Schwann/metabolismo , Nervio Sural/patología
14.
Bioorg Med Chem ; 44: 116292, 2021 08 15.
Artículo en Inglés | MEDLINE | ID: mdl-34225167

RESUMEN

Transthyretin is a tetrameric protein which functions as a transporter of thyroxine and retinol-binding protein. Misfolding and amyloid aggregation of transthyretin are known to cause wild-type and hereditary transthyretin amyloidosis. Stabilization of the transthyretin tetramer by low molecular weight compounds is an efficacious strategy to inhibit the aggregation pathway in the amyloidosis. Here, we investigated the inhibitory activities of anthraquinone and xanthone derivatives against amyloid aggregation, and found that xanthone-2-carboxylic acid with one chlorine or methyl group has strong inhibitory activity comparable with that of diflunisal, which is one of the best known stabilizers of transthyretin. X-ray crystallographic structures of transthyretin in complex with the compounds revealed that the introduction of chlorine, which is buried in a hydrophobic region, is important for the strong inhibitory effect of the stabilizer against amyloidogenesis. An in vitro absorption, distribution, metabolism and elimination (ADME) study and in vivo pharmacokinetic study demonstrated that the compounds have drug-like features, suggesting that they have potential as therapeutic agents to stabilize transthyretin.


Asunto(s)
Neuropatías Amiloides Familiares/tratamiento farmacológico , Antraquinonas/uso terapéutico , Xantonas/uso terapéutico , Antraquinonas/síntesis química , Antraquinonas/química , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Humanos , Modelos Moleculares , Estructura Molecular , Relación Estructura-Actividad , Xantonas/síntesis química , Xantonas/química
15.
Clin Oral Investig ; 25(4): 2077-2080, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-32804259

RESUMEN

OBJECTIVES: Developmental disability children have differences in growth. Therefore, tube size selection is important for nasotracheal intubation. In our previous study for healthy children undergoing dental surgery, height was the most suitable factor to predict nasotracheal tube size. The aim of this study was to find the most suitable formula for selection of nasotracheal tube size for them, retrospectively. MATERIAL AND METHODS: Developmental disability children aged 2 to 10 years were included in this study. They were intubated nasotracheally from April 2012 until May 2017. Their actually intubated tube sizes were checked. The predicted tube sizes were calculated according to the formulas by the backgrounds: the diameter of the trachea at the 6th cervical (C6), 7th cervical (C7), and 2nd thoracic vertebrae (T2) in X-ray. The actually intubated tube sizes were compared with predicted sizes. Data were analyzed using Spearman's regression analysis. RESULTS: The tube sizes with 5.0, 5.5, and 6.0 mm ID were intubated in 75 patients. The age-based formula was the most suitable; the correlation coefficients (r2) were 0.9027 (vs age), 0.5434 (vs height), 0.3779 (vs weight), 0.0785 (vs C6), 0.2279 (vs C7), and 0.3065 (Th2) (p < 0.01). However, 0.5-mm smaller size tubes were more frequently intubated actually. Their correspondence rate to the predicted size was 48% (5.0 mm), 52% (5.5 mm), and 39% (6.0 mm), respectively. CONCLUSION: The age-based formula could be the most suitable for predicting nasotracheal tube size in developmental disability children aged 2 to 10 years. One smaller size by the age formula was most suitable at first trial tube. CLINICAL RELEVANCE: The present data indicate that the selection of nasotracheal tube using one smaller size by the age formula (ID = 4 + age [years]/4) might be useful for developmental disability children.


Asunto(s)
Discapacidades del Desarrollo , Intubación Intratraqueal , Niño , Preescolar , Humanos , Lactante , Cuello , Estudios Retrospectivos , Tráquea
16.
Clin Exp Nephrol ; 24(12): 1140-1143, 2020 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-32772208

RESUMEN

BACKGROUND: Amelioration of hyperchloremic acidosis (Cl-Ac), a common complication in chronic kidney disease (CKD), could preserve renal function in chronic kidney disease (CKD). However, the development of Cl-Ac in CKD has not been clarified yet. METHODS: The degree of Cl-Ac, which is indicated as the bicarbonate concentration decrease with serum chloride concentration increase (∆[HCO3-]Cl), was compared with the estimated glomerular filtration rate (eGFR) by using CKD patient records. RESULTS: In 307 records with metabolic acidosis, a spline curve obtained from the plot comparing ∆[HCO3-]Cl with eGFR showed that ∆[HCO3-]Cl did not change, increased, and decreased during eGFR decrease until 27, from 27 to 17.5, and from 17.5 mL/min/1.73 m2, respectively. CONCLUSION: By CKD progression, Cl-Ac progressed and regressed at the CKD stages G4 and G5, respectively. The regression would have reflected the shift of Cl-Ac to high anion gap acidosis.


Asunto(s)
Equilibrio Ácido-Base , Acidosis/etiología , Cloruros/sangre , Tasa de Filtración Glomerular , Riñón/fisiopatología , Insuficiencia Renal Crónica/complicaciones , Acidosis/sangre , Acidosis/diagnóstico , Acidosis/fisiopatología , Adulto , Anciano , Anciano de 80 o más Años , Bicarbonatos/sangre , Biomarcadores/sangre , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Insuficiencia Renal Crónica/sangre , Insuficiencia Renal Crónica/diagnóstico , Insuficiencia Renal Crónica/fisiopatología , Estudios Retrospectivos
17.
BMC Anesthesiol ; 20(1): 81, 2020 04 07.
Artículo en Inglés | MEDLINE | ID: mdl-32264817

RESUMEN

BACKGROUND: Total hemoglobin (tHb) measurement is indispensable for determining the patient's condition (hemorrhagic vs. ischemic) and need for blood transfusion. Conductivity- and absorbance-based measurement methods are used for blood gas analysis of tHb. For conductivity-based measurement, tHb is calculated after converting blood conductivity into a hematocrit value, whereas absorbance measurement is based on light absorbance after red blood cell hemolysis. Due to changes in plasma electrolytes and hemolysis, there is a possibility that conductivity- and absorbance-based measurement methods may cause a difference in tHb. METHODS: In this study, test samples with controlled electrolyte changes and hemolysis were created by adding sodium chloride, distilled water or hemolytic blood to blood samples collected from healthy volunteers, and tHb values were compared between both methods. RESULTS: Conductivity-based measurement revealed reduced tHb value (from 15.49 to 13.05 g/dl) following the addition of 10% sodium chloride, which was also reduced by the addition of hemolysate. Conversely, the addition of distilled water significantly increased tHb value than the expected value. In the absorbance method, there was no significant change in tHb value due to electrolyte change or hemolysis. CONCLUSIONS: We have to recognize unexpected conductivity changes occur at all times when tHb is measured via conductivity- and absorbance-based measurement methods. The absorbance method should be used when measuring tHb in patients with expected blood conductivity changes. However, when using this method, the added contribution of hemoglobin from hemolytic erythrocytes lacking oxygen carrying capacity must be considered. We recognize that discrepancy can occur between conductivity- and absorbance-based measurement methods when tHb is measured.


Asunto(s)
Análisis de los Gases de la Sangre/métodos , Eritrocitos/citología , Hemoglobinas/análisis , Oxígeno/sangre , Adulto , Electrólitos/sangre , Hematócrito/métodos , Hemólisis/fisiología , Humanos , Masculino
18.
Aging Clin Exp Res ; 32(9): 1857-1864, 2020 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-31650503

RESUMEN

BACKGROUND: The characteristics of electroencephalogram (EEG) profiles under general anesthesia may depend on age and type of anesthetic. AIM: This study investigated age-related differences in EEG waveforms between three inhalational anesthetics used at the same minimum alveolar concentration (MAC), which indicates the level of analgesia. METHODS: Patients with American Society of Anesthesiologists physical status I-II were divided into three groups according to age: pediatric (≦ 15 years); adult (16-64 years); and elderly (≧ 65 years). Each group was divided into three subgroups according to the inhalational anesthetic used: sevoflurane, isoflurane, and desflurane. Anesthesia was maintained at 1 MAC, followed by assessment of 95% spectral edge frequency (SEF95) values and amplitude of EEG waveform. RESULTS: The 3 age groups comprised a total of 180 patients. The mean (± SD) EEG waveform amplitude and SEF95 values for sevoflurane in the pediatric, adult, and elderly age groups, respectively, were: 32.9 ± 2.9 µV and 16.7 ± 2.4 Hz; 16.4 ± 3.6 µV and 12.2 ± 1.3 Hz; and 11.0 ± 2.1 µV and 13.6 ± 1.6 Hz. EEG waveform amplitude and SEF95 values were significantly higher in the pediatric group than in the other groups. SEF95 value was higher in the elderly group than in the adult group. Similar results were obtained for isoflurane and desflurane. CONCLUSION: The amplitude of the EEG waveform and SEF95 values varied with age, even at the same analgesic state in patients under general anesthesia. This age-dependent change in EEG waveform was observed for all three inhalational anesthetics, and should be considered in procedures requiring general anesthesia.


Asunto(s)
Anestésicos por Inhalación , Adolescente , Adulto , Anciano , Anestesia General , Electroencefalografía , Humanos , Isoflurano , Éteres Metílicos , Persona de Mediana Edad , Sevoflurano , Adulto Joven
19.
J Oral Maxillofac Surg ; 77(12): 2465.e1-2465.e5, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31574262

RESUMEN

PURPOSE: Mask ventilation is a basic technique for induction of anesthesia. In head and neck surgery, we have encountered difficulty in ventilation owing to facial deformities. Recently, a new type of face mask without an air cushion, the QuadraLite face mask (Intersurgical, Berkshire, UK), was developed. The aim of this study was to compare the performance of cases with predicted difficult mask ventilation between the new type of face mask and a traditional face mask. PATIENTS AND METHODS: This study was a crossover prospective study. The participants were patients (aged > 18 years) who underwent oral-maxillofacial surgery under general anesthesia. The risk factors for a difficult airway were assessed. Patients were divided into 3 risk groups: low risk, 0 or 1 risk factor for predicted difficult mask ventilation; medium risk, 2 or 3 risk factors; and high risk, 4 or more risk factors. An air cushion face mask (Koo Medical, Shanghai, China) and the QuadraLite face mask were applied in turn under the setting of pressure-controlled ventilation. The expiratory tidal volumes were compared between these face masks. RESULTS: A total of 48 patients were included: 16 in the low-risk group, 16 in the medium-risk group, and 16 in the high-risk group. Higher expiratory tidal volumes were observed with the QuadraLite face mask than with the air cushion face mask, although the differences did not reach the statistically significant level: 574.3 ± 62.7 mL versus 553.1 ± 60.6 mL in the low-risk group (P = .44), 553.1 ± 112.9 mL versus 536.4 ± 114.2 mL in the medium-risk group (P = .38), and 560.0 ± 98.6 mL versus 548.2 ± 07.1 mL in the high-risk group (P = .22). In all cases, a sufficient ventilation volume was obtained by the QuadraLite face mask. CONCLUSIONS: The QuadraLite face mask is compact because there is no air cushion, and it can provide sufficient mask ventilation as well as a traditional face mask with an air cushion even in patients with a difficult airway.


Asunto(s)
Máscaras , Respiración Artificial , Adolescente , China , Humanos , Estudios Prospectivos , Volumen de Ventilación Pulmonar
20.
Clin Oral Investig ; 23(9): 3653-3656, 2019 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-31273527

RESUMEN

OBJECTIVE: The recovery after general anesthesia is influenced by the choice of inhalational agent. Stimulations might make patient's agitate. However, the recovery using no touch technique might be safer. In this study, we compared the recovery time, awakening end-tidal concentration, and respiratory complications among inhalational anesthetics in pediatric patients using no touch technique, retrospectively. MATERIAL AND METHODS: The subjects were pediatric patients aged 3 months to 11 years under general anesthesia using sevoflurane, isoflurane, or desflurane. Background, awakening end-tidal concentration, respiratory complications, the time of eye open, body movement, and extubation were recorded. RESULTS: A total of 170 patients were included in the study. There were no respiratory complications during emergence. Awakening end-tidal concentration in desflurane was 0.98%, sevoflurane (0.39%), and isoflurane (0.25%). In patients received desflurane, the time of body movement, eye open, and extubation were significantly shorter than patients who received other anesthetics (p < 0.05). CONCLUSIONS: The recovery from desflurane was significantly shorter among three inhalational anesthetics with no touch technique. In addition, no airway-related complication occurred. CLINICAL RELEVANCE: The recovery from desflurane might be useful to predict emergence by end-tidal inhalational concentration.


Asunto(s)
Periodo de Recuperación de la Anestesia , Anestésicos por Inhalación , Isoflurano , Anestesia Dental , Anestésicos por Inhalación/administración & dosificación , Niño , Preescolar , Desflurano/administración & dosificación , Humanos , Lactante , Isoflurano/administración & dosificación , Estudios Retrospectivos
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