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1.
Mol Cell ; 80(6): 996-1012.e9, 2020 12 17.
Artículo en Inglés | MEDLINE | ID: mdl-33147438

RESUMEN

Reactive aldehydes arise as by-products of metabolism and are normally cleared by multiple families of enzymes. We find that mice lacking two aldehyde detoxifying enzymes, mitochondrial ALDH2 and cytoplasmic ADH5, have greatly shortened lifespans and develop leukemia. Hematopoiesis is disrupted profoundly, with a reduction of hematopoietic stem cells and common lymphoid progenitors causing a severely depleted acquired immune system. We show that formaldehyde is a common substrate of ALDH2 and ADH5 and establish methods to quantify elevated blood formaldehyde and formaldehyde-DNA adducts in tissues. Bone-marrow-derived progenitors actively engage DNA repair but also imprint a formaldehyde-driven mutation signature similar to aging-associated human cancer mutation signatures. Furthermore, we identify analogous genetic defects in children causing a previously uncharacterized inherited bone marrow failure and pre-leukemic syndrome. Endogenous formaldehyde clearance alone is therefore critical for hematopoiesis and in limiting mutagenesis in somatic tissues.


Asunto(s)
Alcohol Deshidrogenasa/genética , Aldehído Deshidrogenasa Mitocondrial/genética , Formaldehído/sangre , Leucemia/genética , Adolescente , Aldehídos/sangre , Animales , Niño , Preescolar , Aductos de ADN/genética , Daño del ADN/efectos de los fármacos , Reparación del ADN/efectos de los fármacos , Femenino , Formaldehído/toxicidad , Hematopoyesis/genética , Células Madre Hematopoyéticas/metabolismo , Humanos , Lactante , Leucemia/sangre , Leucemia/patología , Masculino , Ratones , Mutación/genética , Especificidad por Sustrato
2.
Jpn J Clin Oncol ; 2024 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-39354673

RESUMEN

OBJECTIVE: To evaluate the additive effect of naldemedine tosylate (naldemedine) on opioid-induced constipation in cancer patients insufficiently responding to magnesium oxide treatment. METHODS: We combined two randomized, double-blind, placebo-controlled, phase IIb and III trials of naldemedine and conducted a post hoc subgroup analysis. We evaluated the effect and safety of naldemedine in 116 patients who received naldemedine in addition to magnesium oxide (naldemedine group) and 117 patients who received placebo in addition to magnesium oxide (placebo group). Both groups included patients insufficiently responding to magnesium oxide for opioid-induced constipation. Effect was assessed using spontaneous bowel movement responder rate, complete spontaneous bowel movement responder rate, changes in spontaneous bowel movements and complete spontaneous bowel movements. Safety was also assessed. RESULTS: During the 2-week treatment period, the responder rates for spontaneous bowel movement and complete spontaneous bowel movement were 73.3 and 43.1% in naldemedine group, respectively, which were significantly higher (P < 0.0001) than 41.9 and 14.5% in placebo group, respectively. Median time to first spontaneous bowel movement and first complete spontaneous bowel movement was significantly shorter (P < 0.0001) in the naldemedine group (4.0 and 21.3 h, respectively) than in the placebo group (27.7 and 211.7 h, respectively). The incidence of adverse events and diarrhoea was significantly higher (P < 0.05) in the naldemedine group than in the placebo group, while the incidence of serious adverse events and severe diarrhoea was not significantly different between the naldemedine and placebo groups. CONCLUSION: The study suggested the addition of naldemedine as an effective treatment option for opioid-induced constipation in cancer patients insufficiently responding to magnesium oxide treatment.

3.
Artículo en Inglés | MEDLINE | ID: mdl-39146220

RESUMEN

OBJECTIVE: Epicardial adipose tissue (EAT) is an important imaging indicator of cardiovascular risk. EAT volume is usually measured using electrocardiogram (ECG) gating. However, there are concerns regarding the influence of motion artifacts when measuring EAT volume on non-ECG-gated plain chest computed tomography (CT) images. Few studies have evaluated the EAT volume using non-ECG gating. This study aimed to validate the accuracy of EAT quantification using non-ECG-gated chest CT imaging. METHODS: We included 100 patients (64 males, 36 females) who underwent simultaneous coronary artery calcification score imaging (ECG gated) and plain chest CT imaging (non-ECG gated). Images taken using non-ECG gating were reconstructed using the same field of view and slice thickness as those obtained with ECG gating. The EAT capacity of each image was measured and compared. An AZE Virtual Place (Canon) was used for the measurements. The Mann-Whitney U test and intraclass correlation coefficient were used for statistical analyses. P values <0.05 were considered statistically significant. Concordance was evaluated using Bland-Altman analysis. RESULTS: The mean EAT volume measured by ECG-gated imaging was 156.5 ± 66.9 mL and 155.4 ± 67.9 mL by non-ECG-gated imaging, with no significant difference between the two groups ( P = 0.86). Furthermore, the EAT volumes measured using ECG-gated and non-ECG-gated imaging showed a strong correlation ( r = 0.95, P < 0.05). Bland-Altman analysis revealed that the mean error of the EAT volume (non-ECG-gated imaging - ECG-gated imaging) was -1.02 ± 2.95 mL (95% confidence interval, -6.49 to 4.76). CONCLUSIONS: The EAT volume obtained using non-ECG-gated imaging was equivalent to that obtained using ECG-gated imaging.

4.
Chemotherapy ; : 1-6, 2024 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-38880094

RESUMEN

INTRODUCTION: Mucormycosis presents a diagnostic challenge characterized by high morbidity and mortality rates due to its swift and pervasive nature, which leads to extensive tissue destruction and dissemination. Immunocompromised individuals, notably those with hematological malignancies, are at a heightened risk. First-line antifungal agents include liposomal amphotericin B (L-AMB), posaconazole, and isavuconazole (IVZ), which offer advantages, such as minimal drug interactions and a favorable safety profile. However, the necessity and efficacy of therapeutic drug monitoring (TDM) of IVZ remain unclear. CASE PRESENTATION: We report a successful case of IVZ therapy in a patient who was intolerant of L-AMB, highlighting the efficacy and pharmacokinetics of IVZ in treating pulmonary mucormycosis. Pharmacokinetic analysis revealed steady plasma IVZ concentrations, emphasizing the importance of monitoring IVZ levels, particularly in patients undergoing renal replacement therapy. CONCLUSION: This case highlights the efficacy of IVZ therapy for mucormycosis and the potential utility of TDM in a specific patient population. Further research is needed to elucidate the optimal IVZ dosing and monitoring strategies to ensure safe and efficacious treatment.

5.
Cancer Sci ; 114(9): 3687-3697, 2023 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-37364599

RESUMEN

Langerhans cell histiocytosis (LCH) is a rare disease characterized by clonal expansion of CD1a+ CD207+ myeloid dendritic cells. The features of LCH are mainly described in children and remain poorly defined in adults; therefore, we conducted a nationwide survey to collect clinical data from 148 adult patients with LCH. The median age at diagnosis was 46.5 (range: 20-87) years with male predominance (60.8%). Among the 86 patients with detailed treatment information, 40 (46.5%) had single system LCH, whereas 46 (53.5%) had multisystem LCH. Moreover, 19 patients (22.1%) had an additional malignancy. BRAF V600E in plasma cell-free DNA was associated with a low overall survival (OS) rate and the risk of the pituitary gland and central nervous system involvement. At a median follow-up of 55 months from diagnosis, six patients (7.0%) had died, and the four patients with LCH-related death did not respond to initial chemotherapy. The OS probability at 5 years post-diagnosis was 90.6% (95% confidence interval: 79.8-95.8). Multivariate analysis showed that patients aged ≥60 years at diagnosis had a relatively poor prognosis. The probability of event-free survival at 5 years was 52.1% (95% confidence interval: 36.6-65.5), with 57 patients requiring chemotherapy. In this study, we first revealed the high rate of relapse after chemotherapy and mortality of poor responders in adults as well as children. Therefore, prospective therapeutic studies of adults with LCH using targeted therapies are needed to improve outcomes in adults with LCH.


Asunto(s)
Histiocitosis de Células de Langerhans , Neoplasias , Niño , Humanos , Masculino , Adulto , Adulto Joven , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Femenino , Pronóstico , Proteínas Proto-Oncogénicas B-raf/genética , Histiocitosis de Células de Langerhans/diagnóstico , Histiocitosis de Células de Langerhans/terapia , Supervivencia sin Progresión , Mutación
6.
Biochem Biophys Res Commun ; 657: 43-49, 2023 05 21.
Artículo en Inglés | MEDLINE | ID: mdl-36972660

RESUMEN

Adult T-cell leukemia (ATL) is a peripheral T-cell malignancy caused by human T-cell leukemia virus type 1 (HTLV-1). Microsatellite instability (MSI) has been observed in ATL cells. Although MSI results from impaired mismatch repair (MMR) pathway, no null mutations in the genes encoding MMR factors are detectable in ATL cells. Thus, it is unclear whether or not impairment of MMR causes the MSI in ATL cells. HTLV-1 bZIP factor (HBZ) protein interacts with numerous host transcription factors and significantly contributes to disease pathogenesis and progression. Here we investigated the effect of HBZ on MMR in normal cells. The ectopic expression of HBZ in MMR-proficient cells induced MSI, and also suppressed the expression of several MMR factors. We then hypothesized that the HBZ compromises MMR by interfering with a transcription factor, nuclear respiratory factor 1 (NRF-1), and identified the consensus NRF-1 binding site at the promoter of the gene encoding MutS homologue 2 (MSH2), an essential MMR factor. The luciferase reporter assay revealed that NRF-1 overexpression enhanced MSH2 promoter activity, while co-expression of HBZ reversed this enhancement. These results supported the idea that HBZ suppresses the transcription of MSH2 by inhibiting NRF-1. Our data demonstrate that HBZ causes impaired MMR, and may imply a novel oncogenesis driven by HTLV-1.


Asunto(s)
Virus Linfotrópico T Tipo 1 Humano , Leucemia-Linfoma de Células T del Adulto , Adulto , Humanos , Virus Linfotrópico T Tipo 1 Humano/genética , Reparación de la Incompatibilidad de ADN , Proteínas de los Retroviridae/genética , Proteínas de los Retroviridae/metabolismo , Proteína 2 Homóloga a MutS/genética , Proteína 2 Homóloga a MutS/metabolismo , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/genética , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/metabolismo , Leucemia-Linfoma de Células T del Adulto/patología
7.
Nature ; 545(7655): 500-504, 2017 05 25.
Artículo en Inglés | MEDLINE | ID: mdl-28514443

RESUMEN

Reprogrammed cellular metabolism is a common characteristic observed in various cancers. However, whether metabolic changes directly regulate cancer development and progression remains poorly understood. Here we show that BCAT1, a cytosolic aminotransferase for branched-chain amino acids (BCAAs), is aberrantly activated and functionally required for chronic myeloid leukaemia (CML) in humans and in mouse models of CML. BCAT1 is upregulated during progression of CML and promotes BCAA production in leukaemia cells by aminating the branched-chain keto acids. Blocking BCAT1 gene expression or enzymatic activity induces cellular differentiation and impairs the propagation of blast crisis CML both in vitro and in vivo. Stable-isotope tracer experiments combined with nuclear magnetic resonance-based metabolic analysis demonstrate the intracellular production of BCAAs by BCAT1. Direct supplementation with BCAAs ameliorates the defects caused by BCAT1 knockdown, indicating that BCAT1 exerts its oncogenic function through BCAA production in blast crisis CML cells. Importantly, BCAT1 expression not only is activated in human blast crisis CML and de novo acute myeloid leukaemia, but also predicts disease outcome in patients. As an upstream regulator of BCAT1 expression, we identified Musashi2 (MSI2), an oncogenic RNA binding protein that is required for blast crisis CML. MSI2 is physically associated with the BCAT1 transcript and positively regulates its protein expression in leukaemia. Taken together, this work reveals that altered BCAA metabolism activated through the MSI2-BCAT1 axis drives cancer progression in myeloid leukaemia.


Asunto(s)
Aminoácidos de Cadena Ramificada/metabolismo , Progresión de la Enfermedad , Leucemia Mielógena Crónica BCR-ABL Positiva/metabolismo , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Animales , Crisis Blástica , Diferenciación Celular , Proliferación Celular , Activación Enzimática , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Proteínas de Unión al ARN/metabolismo , Transaminasas/biosíntesis , Transaminasas/deficiencia , Transaminasas/genética , Transaminasas/metabolismo
8.
Nihon Shokakibyo Gakkai Zasshi ; 120(2): 183-189, 2023.
Artículo en Japonés | MEDLINE | ID: mdl-36775325

RESUMEN

A 48-year-old male patient with a history of alcoholic cirrhosis was admitted to our hospital due to hematemesis with a 7-day history of melena. Emergency esophagogastroduodenoscopy revealed esophageal variceal bleeding. We attempted hemostasis with endoscopic variceal ligation (EVL). The esophageal mucosa was not aspirated into the EVL device although the patient had no history of endoscopic injection sclerotherapy or EVL. Percutaneous transhepatic obliteration (PTO) was performed and esophageal variceal bleeding was successfully hemostasis. PTO is a viable option for refractory esophageal bleeding.


Asunto(s)
Várices Esofágicas y Gástricas , Hemorragia Gastrointestinal , Masculino , Humanos , Persona de Mediana Edad , Hemorragia Gastrointestinal/etiología , Hemorragia Gastrointestinal/cirugía , Várices Esofágicas y Gástricas/complicaciones , Várices Esofágicas y Gástricas/cirugía , Ligadura/efectos adversos , Endoscopía , Endoscopía del Sistema Digestivo , Resultado del Tratamiento
9.
Biochem Biophys Res Commun ; 622: 177-183, 2022 09 24.
Artículo en Inglés | MEDLINE | ID: mdl-35932529

RESUMEN

Severe congenital neutropenia (SCN) is characterized by severe neutropenia and recurrent critical infections. X-linked neutropenia (XLN) is caused by a gain-of-function mutation in the Wiskott-Aldrich syndrome gene (WAS), the product of which (WASp) is expressed only in blood cells, especially during neutrophil maturation. To investigate the mechanism of neutropenia, we established a novel knock-in mouse line expressing WASp-I292T. WASp-I292T neutrophils exhibited activated (dysregulated) actin polymerization. Although WASp-I292T mice did not recapitulate neutropenia, neutrophil levels were increased in the bone marrow, and extramedullary hematopoiesis was observed. Bone marrow neutrophils from WASp-I292T mice exhibited attenuated transmigration. These abnormalities were associated with downregulation of NFκB and TP53 and faulty activation of their downstream pathways.


Asunto(s)
Neutropenia , Avispas , Actinas/metabolismo , Animales , Síndromes Congénitos de Insuficiencia de la Médula Ósea/genética , Hematopoyesis/genética , Humanos , Ratones , Neutropenia/genética , Neutrófilos/metabolismo , Proteína del Síndrome de Wiskott-Aldrich/genética , Proteína del Síndrome de Wiskott-Aldrich/metabolismo
10.
Synapse ; 76(1-2): e22222, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-35034380

RESUMEN

In rodents, the representation of the body surface in the primary somatosensory cortex (S1) forms a mirror image along the ventral border of the S1 in the secondary somatosensory cortex (S2). Sensory information from the oral region is processed in the S1 and the border region between the S2 and insular oral region (IOR). We examined the relationship between somatosensory representations in the S1 and S2/IOR using optical imaging with a voltage-sensitive dye in urethane-anesthetized rats. In reference to the rhinal fissure and middle cerebral artery, we made a somatosensory map by applying electrical or air puff stimulation. The initial neural excitation in the S1 to facial structures, including the eyebrow, cornea, pinna, whisker pad, nasal tip, and nasal mucosa, spread toward the ventral area, putatively the S2. The initial cortical responses in the S1 to oral structures, including the lower lip, tongue, and teeth, were spatially separated from those in the S2/IOR. The representation of the tongue center, tongue tip, mandibular molar pulp, mandibular incisor pulp, and mandibular incisor periodontal ligament were almost linearly arranged from caudal to rostral in both S1 and S2/IOR. The lower lip was represented in the dorsal area from the representation of teeth and tongue in both S1 and S2/IOR. The representations of maxillary teeth were caudal and dorsal to the representations of mandibular teeth in the S1 and S2/IOR, respectively. These results suggest that the representation of oral structures in the S1 formed a non-mirror image, not a mirror image, in the S2/IOR.


Asunto(s)
Mapeo Encefálico , Corteza Somatosensorial , Animales , Mapeo Encefálico/métodos , Diente Molar , Imagen Óptica/métodos , Ratas , Ratas Sprague-Dawley , Corteza Somatosensorial/diagnóstico por imagen , Corteza Somatosensorial/fisiología
11.
Nihon Shokakibyo Gakkai Zasshi ; 119(12): 1081-1087, 2022.
Artículo en Japonés | MEDLINE | ID: mdl-36504100

RESUMEN

This is a case of a 61-year-old female who presented to our hospital with liver dysfunction without any symptoms. She was diagnosed with splenic arteriovenous fistula. About 8 months later, she visited the hospital again due to abdominal distention and diarrhea. Computerized tomography (CT) revealed splenic aneurysm, dilated splenic vein enhanced in the arterial phase, ascites, and intestinal edema. We considered that these findings were caused by portal hypertension due to splenic arteriovenous fistula. The splenic aneurysm was managed with coil embolization. Completion arteriography revealed the absence of flow into the splenic arteriovenous fistula. Surveillance CT scans at 2 months post-procedure confirmed complete occlusion of the aneurysm and arteriovenous fistula. There was no evidence of splenic infarction. The patient remained asymptomatic 1 year post-procedure. Asymptomatic splenic arteriovenous fistula is rare and needs immediate treatment due to the high probability of deterioration.


Asunto(s)
Fístula Arteriovenosa , Embolización Terapéutica , Hipertensión Portal , Infarto del Bazo , Femenino , Humanos , Persona de Mediana Edad , Fístula Arteriovenosa/complicaciones , Fístula Arteriovenosa/diagnóstico por imagen , Fístula Arteriovenosa/terapia , Ascitis/diagnóstico por imagen , Ascitis/etiología , Ascitis/terapia
12.
Pflugers Arch ; 473(12): 1911-1924, 2021 12.
Artículo en Inglés | MEDLINE | ID: mdl-34724104

RESUMEN

The nucleus accumbens (NAc) receives cortical projections principally from the insular cortex (IC) and medial prefrontal cortex (mPFC). Among NAc neurons, cholinergic interneurons (ChNs) regulate the activities of medium spiny neurons (MSNs), which make up ~ 95% of NAc neurons, by modulating their firing and synaptic properties. However, little is known about the synaptic mechanisms, including their cell-type-dependent corticoaccumbal projection properties and cholinergic effects on the NAc core. Here, we performed whole-cell patch-clamp recordings from NAc MSNs and ChNs in acute brain slice preparations obtained from rats that received an AAV5-hSyn-ChR2(H134R)-mCherry injection into the IC or mPFC. Light stimulation of IC or mPFC axons induced comparable phase-locked excitatory postsynaptic currents (EPSCs) in MSNs. On the other hand, ChNs showed consistent EPSCs evoked by light stimulation of mPFC axons, whereas light stimulation of IC axons evoked much smaller EPSCs, which often showed failure in ChNs. Light-evoked EPSCs were abolished by tetrodotoxin and were recovered by 4-aminopyridine, suggesting that corticoaccumbal projections monosynaptically induce EPSCs in MSNs and ChNs. Carbachol effectively suppressed the amplitude of EPSCs in MSNs and ChNs evoked by light stimulation of IC or mPFC axons and in ChNs evoked by stimulating mPFC axons. The carbachol-induced suppression was recovered by atropine or pirenzepine, while preapplication of gallamine, J104129, PD102807, or AF-DX384 did not block the carbachol-induced EPSC suppression. These results suggest that NAc MSNs and ChNs are differentially regulated by excitatory projections from the IC and mPFC and that these corticoaccumbal excitatory inputs are modulated by M1 receptor activation.


Asunto(s)
Neuronas Colinérgicas/metabolismo , Núcleo Accumbens/metabolismo , Corteza Prefrontal/metabolismo , Acetilcolina/farmacología , Animales , Animales Modificados Genéticamente/metabolismo , Carbacol/farmacología , Colinérgicos/metabolismo , Neuronas Colinérgicas/efectos de los fármacos , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Potenciales Postsinápticos Excitadores/fisiología , Femenino , Ácido Glutámico/metabolismo , Interneuronas/efectos de los fármacos , Interneuronas/metabolismo , Masculino , Núcleo Accumbens/efectos de los fármacos , Técnicas de Placa-Clamp/métodos , Corteza Prefrontal/efectos de los fármacos , Ratas , Transmisión Sináptica/efectos de los fármacos , Transmisión Sináptica/fisiología
13.
Am J Physiol Endocrinol Metab ; 320(1): E150-E159, 2021 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-33284091

RESUMEN

Sepsis remains a leading cause of mortality in critically ill patients. Muscle wasting is a major complication of sepsis and negatively affects clinical outcomes. Despite intense investigation for many years, the molecular mechanisms underlying sepsis-related muscle wasting are not fully understood. In addition, a potential role of muscle wasting in disease development of sepsis has not been studied. Myostatin is a myokine that downregulates skeletal muscle mass. We studied the effects of myostatin deficiency on muscle wasting and other clinically relevant outcomes, including mortality and bacterial clearance, in mice. Myostatin deficiency prevented muscle atrophy along with inhibition of increases in muscle-specific RING finger protein 1 (MuRF-1) and atrogin-1 expression and phosphorylation of signal transducer and activator of transcription protein 3 (STAT3; major players of muscle wasting) in septic mice. Moreover, myostatin deficiency improved survival and bacterial clearance of septic mice. Sepsis-induced liver dysfunction, acute kidney injury, and neutrophil infiltration into the liver and kidney were consistently mitigated by myostatin deficiency, as indicated by plasma concentrations of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and neutrophil gelatinase-associated lipocalin (NGAL) and myeloperoxidase activity in the organs. Myostatin deficiency also inhibited sepsis-induced increases in plasma high-mobility group protein B1 (HMGB1) and macrophage inhibitory cytokine (MIC)-1/growth differentiation factor (GDF)-15 concentrations. These results indicate that myostatin plays an important role not only in muscle wasting but also in other clinically relevant outcomes in septic mice. Furthermore, our data raise the possibility that muscle wasting may not be simply a complication, but myostatin-mediated muscle cachexia and related changes in muscle may actually drive the development of sepsis as well.NEW & NOTEWORTHY Muscle wasting is a major complication of sepsis, but its role in the disease development is not known. Myostatin deficiency improved bacterial clearance and survival and mitigated damage in the liver and kidney in septic mice, which paralleled prevention of muscle wasting. These results raise the possibility that muscle wasting may not simply be a complication of sepsis, but myostatin-mediated cachexic changes may have a role in impaired bacterial clearance and mortality in septic mice.


Asunto(s)
Atrofia Muscular/genética , Miostatina/deficiencia , Miostatina/genética , Sepsis/genética , Lesión Renal Aguda/genética , Animales , Caquexia/genética , Caquexia/prevención & control , Lipocalina 2/sangre , Hepatopatías/etiología , Hepatopatías/genética , Pruebas de Función Hepática , Masculino , Ratones , Proteínas Musculares/biosíntesis , Proteínas Musculares/genética , Atrofia Muscular/prevención & control , Infiltración Neutrófila/genética , Fosforilación , Factor de Transcripción STAT3/biosíntesis , Factor de Transcripción STAT3/genética , Sepsis/microbiología , Sepsis/mortalidad , Análisis de Supervivencia , Proteínas de Motivos Tripartitos/biosíntesis , Proteínas de Motivos Tripartitos/genética , Ubiquitina-Proteína Ligasas/biosíntesis , Ubiquitina-Proteína Ligasas/genética
14.
Anesthesiology ; 134(2): 219-233, 2021 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-33332534

RESUMEN

BACKGROUND: The general anesthetic propofol induces frontal alpha rhythm in the cerebral cortex at a dose sufficient to induce loss of consciousness. The authors hypothesized that propofol-induced facilitation of unitary inhibitory postsynaptic currents would result in firing synchrony among postsynaptic pyramidal neurons that receive inhibition from the same presynaptic inhibitory fast-spiking neurons. METHODS: Multiple whole cell patch clamp recordings were performed from one fast-spiking neuron and two or three pyramidal neurons with at least two inhibitory connections in rat insular cortical slices. The authors examined how inhibitory inputs from a presynaptic fast-spiking neuron modulate the timing of spontaneous repetitive spike firing among pyramidal neurons before and during 10 µM propofol application. RESULTS: Responding to activation of a fast-spiking neuron with 150-ms intervals, pyramidal cell pairs that received common inhibitory inputs from the presynaptic fast-spiking neuron showed propofol-dependent decreases in average distance from the line of identity, which evaluates the coefficient of variation in spike timing among pyramidal neurons: average distance from the line of identity just after the first activation of fast-spiking neuron was 29.2 ± 24.1 (mean ± SD, absolute value) in control and 19.7 ± 19.2 during propofol application (P < 0.001). Propofol did not change average distance from the line of identity without activating fast-spiking neurons and in pyramidal neuron pairs without common inhibitory inputs from presynaptic fast-spiking neurons. The synchronization index, which reflects the degree of spike synchronization among pyramidal neurons, was increased by propofol from 1.4 ± 0.5 to 2.3 ± 1.5 (absolute value, P = 0.004) and from 1.5 ± 0.5 to 2.2 ± 1.0 (P = 0.030) when a presynaptic fast-spiking neuron was activated at 6.7 and 10 Hz, respectively, but not at 1, 4, and 13.3 Hz. CONCLUSIONS: These results suggest that propofol facilitates pyramidal neuron firing synchrony by enhancing inhibitory inputs from fast-spiking neurons. This synchrony of pyramidal neurons may contribute to the alpha rhythm associated with propofol-induced loss of consciousness.


Asunto(s)
Corteza Cerebral/efectos de los fármacos , Hipnóticos y Sedantes/farmacología , Interneuronas/efectos de los fármacos , Propofol/farmacología , Células Piramidales/efectos de los fármacos , Transmisión Sináptica/efectos de los fármacos , Potenciales de Acción/efectos de los fármacos , Animales , Femenino , Masculino , Modelos Animales , Ratas , Ratas Transgénicas , Sinapsis/efectos de los fármacos
15.
Int J Clin Oncol ; 26(11): 2142-2150, 2021 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-34259983

RESUMEN

BACKGROUND: Multiple myeloma (MM) is an incurable hematological malignancy. Despite the introduction of several novel drugs, most patients relapse. Biomarkers to identify the early signs of relapse will make it possible to adjust the therapeutic strategy before the disease worsens. Although understanding genetic changes is important for the treatment of MM, currently known biomarkers of relapse, including serum free-light chains and monoclonal paraproteins, are not associated with genetic changes. METHODS: We therefore performed a multicenter study to examine the usefulness of circulating cell-free DNA (cfDNA) present in the peripheral blood (PB) plasma of patients as a biomarker for MM relapse. RESULTS: We identified several driver mutations by combined analysis of next-generation sequencing and existing databases of candidate oncogenes. Furthermore, relapse was detected more sensitively by monitoring the circulating cfDNA with these driver mutations than by conventional serum free-light chain examination. CONCLUSION: These results suggest the potential utility of cfDNA in the PB plasma of patients as a relevant early biomarker for MM relapse.


Asunto(s)
Ácidos Nucleicos Libres de Células , Mieloma Múltiple , Biomarcadores , Ácidos Nucleicos Libres de Células/genética , Humanos , Mieloma Múltiple/diagnóstico , Mieloma Múltiple/genética , Mutación , Recurrencia Local de Neoplasia/genética , Plasma
16.
Environ Health Prev Med ; 26(1): 117, 2021 Dec 21.
Artículo en Inglés | MEDLINE | ID: mdl-34933677

RESUMEN

BACKGROUND: The best approach to reduce congenital cytomegalovirus infection (cCMVi) is to practice behaviors that reduce cytomegalovirus (CMV) transmission during pregnancy. Expanding awareness and knowledge of CMV is expected to result in increased practice of preventative behaviors. To this end, it is necessary to understand current awareness and knowledge of CMV. METHODS: This web-based cross-sectional survey assessed the awareness and knowledge of cCMVi among pregnant women and the general public in Japan. Participants aged 20-45 years (pregnant and non-pregnant women, and men) were identified from a consumer panel. Study outcomes (all participants) included awareness of cCMVi and other congenital conditions. Among those aware of cCMVi, outcomes included knowledge of CMV transmission routes, long-term outcomes of cCMVi, and behaviors to prevent CMV transmission during pregnancy. Outcomes limited to pregnant women included the practice of preventative behaviors and opinion on how easy it is to implement these behaviors. The data of the pregnant group (pregnant at the time of the survey) were compared with those of the general group (non-pregnant women and men). RESULTS: There were 535 participants in the pregnant group and 571 in the general group. Awareness of cCMVi was generally low (pregnant, 16.1%; general, 10.2%). Pregnant participants were significantly more aware of most congenital conditions than those in the general group, including cCMVi (P = 0.004). Knowledge about CMV/cCMVi was limited; there were no significant differences between the two groups for 24 of the 26 knowledge questions. A small proportion (one third or less) of pregnant women practiced behaviors to prevent the transmission of CMV, though most (73.3-95.3%) pregnant women who were aware of cCMVi considered such behaviors easy to implement. CONCLUSIONS: Awareness and knowledge of CMV/cCMVi is low among pregnant women in Japan; the level of knowledge is similar to that among the general public. This needs to be improved. Most pregnant women considered behaviors to prevent CMV transmission easy to perform, which indicates that effectively educating pregnant women regarding the long-term outcomes of cCMVi, CMV transmission routes, and preventative behaviors will contribute to a reduced incidence of cCMVi. TRIAL REGISTRATION: UMIN Clinical Trials Registry, UMIN000041260 .


Asunto(s)
Infecciones por Citomegalovirus , Mujeres Embarazadas , Estudios Transversales , Infecciones por Citomegalovirus/epidemiología , Infecciones por Citomegalovirus/prevención & control , Femenino , Conocimientos, Actitudes y Práctica en Salud , Humanos , Internet , Japón/epidemiología , Masculino , Embarazo
17.
Pflugers Arch ; 472(6): 721-732, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-32458087

RESUMEN

Gustation and olfaction are integrated into flavor, which contribute to detection and identification of foods. We focused on the insular cortex (IC), as a possible center of flavor integration, because the IC has been reported to receive olfactory in addition to gustatory inputs. In the present report, we tested the hypothesis that these two chemosensory signals are integrated in the IC. We examined the spatiotemporal dynamics of cortical responses induced by stimulating the chorda tympani nerve (CT) and the main olfactory bulb (mOB) in male Sprague-Dawley rats by in vivo optical imaging with a voltage-sensitive dye (VSD). CT stimulation elicited responses in the rostral part of the dysgranular IC (DI), while responses to mOB stimulation were observed in the agranular IC (AI) as well as in the piriform cortex (PC). To characterize the temporal specificity of these responses, we performed combined mOB and CT stimulation with three different timings: simultaneous stimulation and the stimulation of the mOB 150 ms before or after CT stimulation. Simultaneous stimulation increased the signal amplitude in AI additively. These results indicate that the AI and DI contribute to the convergence of gustatory and olfactory information. Of them the DI predominantly processes the taste information, whereas the AI is more sensitive to the olfactory signal.


Asunto(s)
Corteza Cerebral/fisiología , Nervio de la Cuerda del Tímpano/fisiología , Bulbo Olfatorio/fisiología , Gusto/fisiología , Animales , Estimulación Eléctrica/métodos , Masculino , Neuronas/fisiología , Ratas , Ratas Sprague-Dawley , Olfato/fisiología , Percepción del Gusto/fisiología
18.
Anal Biochem ; 599: 113748, 2020 06 15.
Artículo en Inglés | MEDLINE | ID: mdl-32333903

RESUMEN

We applied an inducible gene expression system that utilizes the p-cmt operon, the cumate gene-switch, to generate mouse induced pluripotent stem (iPS) cells. Mouse embryonic fibroblast (MEF) E6E7-MEF cells were transfected with a single cumate gene-switch vector enabling concomitant expression of Oct4, Sox2, c-Myc, Klf4, and Gfp. Then, the cells were cultured with cumate, a monoterpene. An increase in colonies positive for alkaline phosphatase activity was observed dose-dependently with cumate. In the absence of cumate, the expression of GFP, a marker for transgene expression, was undetectable in tightly aggregated iPS cell-like colonies with endogenous expression of NANOG and OCT4. From primary MEFs using the cumate gene-switch, we also isolated iPS cells expressing endogenous NANOG, OCT4, SOX2, KLF4, and SSEA1 with hypo-methylated genomic promoter regions of endogenous Nanog and Oct4. In embryoid bodies with the progression of differentiation, expression of markers for all three germ layers was detected, and contracting cardiomyocytes were observed. Overall, we suggest that the cumate gene-switch is applicable for the generation of mouse iPS cells. The cumate gene-switch in combination with other inducible systems, such as the tet system, may provide useful approaches for analyzing the roles of transgenes underlying the establishment of iPS cells.


Asunto(s)
Benzoatos/farmacología , Vectores Genéticos , Células Madre Pluripotentes Inducidas , Transgenes , Animales , Diferenciación Celular , Línea Celular , Factor 4 Similar a Kruppel , Ratones
19.
J Pharmacol Sci ; 142(3): 83-92, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-31859144

RESUMEN

Little is known about how propofol modulates the spike firing correlation between excitatory and inhibitory cortical neurons in vivo. We performed extracellular unit recordings from rat insular cortical neurons, and classified neurons with high spontaneous firing frequency, bursting, and short spike width as high frequency with bursting neurons (HFB; pseudo fast-spiking GABAergic neurons) and other neurons with low spontaneous firing frequency and no bursting were classified as non-HFB. Intravenous administration of propofol (12 mg/kg) from the caudal vein reduced the firing frequency of HFB, whereas propofol initially increased (within 30 s) and then decreased the firing frequency of non-HFB. Both HFB and non-HFB spontaneous action potential discharge was depressed by propofol with a greater depression seen for HFB. Cross-correlograms and auto-correlograms demonstrated propofol-induced increases in the ratio of the peak, which were mostly observed around 0-10 ms divided to baseline amplitude. The analysis of interspike intervals showed a decrease in spike firing at 20-100 Hz and a relative increase at 8-15 Hz. These results suggest that propofol induces a larger suppression of firing frequency in HFB and an enhancement of synchronized neural activities in the α frequency band in the cerebral cortex (192 words).


Asunto(s)
Corteza Cerebral/fisiología , Electroencefalografía/efectos de los fármacos , Propofol/farmacología , Potenciales de Acción/efectos de los fármacos , Animales , Neuronas GABAérgicas/fisiología , Infusiones Intravenosas , Masculino , Propofol/administración & dosificación , Ratas Wistar , Estimulación Química
20.
Int J Clin Oncol ; 25(11): 1945-1950, 2020 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-32901339

RESUMEN

BACKGROUND: Langerhans cell histiocytosis (LCH) is a rare disease primarily occurring in children, and commonly involves the bone and skin; gastrointestinal tract involvement is notably rare. The incidence and significance of gastrointestinal lesions in adult LCH are unclear; thus, we aimed to investigate adult Japanese cases of LCH and clarify the features of gastrointestinal involvement. METHODS: We gathered clinical information on 43 Japanese cases of adult LCH and analyzed patient backgrounds, affected organs, features of the gastrointestinal lesions, and the clinical courses. RESULTS: Thirteen patients underwent endoscopic examinations: an upper gastrointestinal endoscopy alone in 5, lower gastrointestinal endoscopy alone in 3, and both in 5 patients. A gastric lesion (one case), colonic lesion (one case), and both gastric and rectal lesions (one case) were detected. The three cases of gastrointestinal involvement also exhibited nongastrointestinal multisystem LCH lesions and showed no gastrointestinal symptoms or increased uptake on positron emission tomography. Endoscopy revealed small erosions without specific features; histological examinations were required for diagnosis. These three cases were treated with chemotherapy, comprising vinblastine/prednisolone, methotrexate, and daily 6-mercaptopurine, for 36 weeks; in two cases, the clinical condition remained stable for several years post-treatment. One case showed recurrence 1 year 7 months after treatment, and chemotherapy was re-administered. No case with single-system disease exhibited gastrointestinal involvement. CONCLUSIONS: Although gastrointestinal LCH lesions are rare, they were more common than expected in our cases of multisystem LCH. However, these lesions were relatively small and did not affect the patients' clinical courses.


Asunto(s)
Enfermedades Gastrointestinales/patología , Histiocitosis de Células de Langerhans/patología , Adolescente , Adulto , Edad de Inicio , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Pueblo Asiatico , Colonoscopía , Endoscopía Gastrointestinal , Femenino , Enfermedades Gastrointestinales/diagnóstico por imagen , Enfermedades Gastrointestinales/tratamiento farmacológico , Histiocitosis de Células de Langerhans/diagnóstico por imagen , Histiocitosis de Células de Langerhans/tratamiento farmacológico , Humanos , Masculino , Metotrexato/administración & dosificación , Persona de Mediana Edad , Prednisolona/administración & dosificación , Recurrencia , Resultado del Tratamiento , Vinblastina/administración & dosificación , Adulto Joven
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