RESUMO
OBJECTIVES: The Cancer Control Act requires the maintenance of regional cooperation pathways (RCP) for cancer treatment. In 2008, we started RCP for early detection of new gastric cancer after endoscopic submucosal dissection (ESD). In gastric cancer treatment, RCP after surgical resection had been widely used, but little is known about RCP after ESD. This study aimed to evaluate the effectiveness of RCP after ESD. METHODS: This study included 465 patients on whom our RCP was implemented from 2008 to 2018. A regional family physician performed surveillance endoscopy at 3 months and 1 year after ESD and annually thereafter. We retrospectively evaluated the cumulative incidence and treatment outcomes of new gastric cancer and compared them with previous reports. RESULTS: During a median follow-up period of 70.5 months (3-120 months), 58 patients developed new gastric cancers, and metachronous gastric cancer was detected in 55 patients more than 1 year after ESD. The 5-year cumulative incidence rate was 9.8%. Three patients did not want treatment. Among the remaining 55 patients, the initial treatment was ESD in 51 and surgical resection in 4. Eventually, 50 patients (48 in the ESD group and 2 in the surgical resection group) fulfilled the pathologic criteria for curative ESD. There were no deaths due to gastric cancer. CONCLUSION: Our study was the first to reveal the incidence of new gastric cancer after ESD using RCP. Most lesions were cured with ESD, and no patients died of gastric cancer. Therefore, we consider RCPs to be an option for surveillance after ESD.
Assuntos
Detecção Precoce de Câncer , Ressecção Endoscópica de Mucosa , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/cirurgia , Neoplasias Gástricas/patologia , Ressecção Endoscópica de Mucosa/métodos , Masculino , Feminino , Detecção Precoce de Câncer/métodos , Estudos Retrospectivos , Pessoa de Meia-Idade , Idoso , Incidência , Resultado do Tratamento , Idoso de 80 Anos ou mais , Seguimentos , Gastroscopia/métodosRESUMO
Phantom tooth pain (PTP) is a rare and specific neuropathic pain that occurs after pulpectomy and tooth extraction, but its cause is not understood. We hypothesized that there is a genetic contribution to PTP. The present study focused on the CACNA1C gene, which encodes the α1C subunit of the Cav1.2 L-type Ca2+ channel (LTCC) that has been reported to be associated with neuropathic pain in previous studies. We investigated genetic polymorphisms that contribute to PTP. We statistically examined the association between genetic polymorphisms and PTP vulnerability in 33 patients with PTP and 118 patients without PTP but with pain or dysesthesia in the orofacial region. From within and around the CACNA1C gene, 155 polymorphisms were selected and analyzed for associations with clinical data. We found that the rs216009 single-nucleotide polymorphism (SNP) of the CACNA1C gene in the recessive model was significantly associated with the vulnerability to PTP. Homozygote carriers of the minor C allele of rs216009 had a higher rate of PTP. Nociceptive transmission in neuropathic pain has been reported to involve Ca2+ influx from LTCCs, and the rs216009 polymorphism may be involved in CACNA1C expression, which regulates intracellular Ca2+ levels, leading to the vulnerability to PTP. Furthermore, psychological factors may lead to the development of PTP by modulating the descending pain inhibitory system. Altogether, homozygous C-allele carriers of the rs216009 SNP were more likely to be vulnerable to PTP, possibly through the regulation of intracellular Ca2+ levels and affective pain systems, such as those that mediate fear memory recall.
Assuntos
Neuralgia , Polimorfismo de Nucleotídeo Único , Humanos , Polimorfismo de Nucleotídeo Único/genética , Canais de Cálcio Tipo L/genética , Canais de Cálcio Tipo L/metabolismo , Neuralgia/genéticaRESUMO
Negative pressure pulmonary edema (NPPE) can occur rapidly after the release of an upper airway obstruction. In general anesthesia, NPPE can be caused by laryngospasm after extubation. This report describes a case in which NPPE was thought to have occurred after extubation during general anesthesia in a disabled person. The patient was a 28-yearold man, 160 cm in height and 56 kg in weight, who was scheduled for dental caries treatment under ambulatory general anesthesia due to intellectual disability. After induction of general anesthesia, nasal intubation was performed after sufficient oral suctioning to remove a large amount of serous secretion. After completion of dental treatment, pressurized extubation was performed after oral suctioning as sufficient spontaneous breathing and body movement were observed. Immediately after extubation, SpO2 dropped to 80%, subsequently recovering to 99% under oxygen administration at 5 liter/min with an oxygen mask. It dropped to approximately 85% again, however, when administration of oxygen was discontinued. Although communication with the patient was difficult, no expression of anguish or dyspnea was observed. A chest radiograph showed symmetric middle-lobe and lingular segment infiltrates, and the patient was transferred to the nearest general hospital. No obvious clinical findings other than a decrease in SpO2 were observed, suggesting NPPE as a result of airway narrowing due to secretions.
Assuntos
Cárie Dentária , Laringismo , Edema Pulmonar , Masculino , Humanos , Adulto , Edema Pulmonar/diagnóstico por imagem , Edema Pulmonar/etiologia , Edema Pulmonar/terapia , Cárie Dentária/complicações , Anestesia Geral/efeitos adversos , Laringismo/complicações , Intubação Intratraqueal/efeitos adversos , OxigênioRESUMO
Mitochondrial diseases (MDs) are occasionally difficult to diagnose. Growth differentiation factor 15 (GDF15) has been reported as a biomarker useful for not only diagnosing MDs, but also evaluating disease severity and therapeutic efficacy. To enable the measurement of serum GDF15 concentrations at medical institutions, we developed a new latex-enhanced turbidimetric immunoassay (LTIA) as an automated diagnostic indication test for MDs. We also examined the equivalency of specificity and sensitivity in measuring serum GDF15 concentrations between a commercially available enzyme-linked immunosorbent assay (ELISA) kit and a novel LTIA device in patients with MDs, disease controls, and healthy controls. A clinical performance study used a newly developed LTIA device and an existing ELISA kit to measure the concentrations of GDF15 in 35 MD patients, 111 disease controls, and 86 healthy controls. The median (first quartile-third quartile) of serum GDF15 concentrations measured with the LTIA device was significantly higher (P < .001) in MD patients (1389.0 U/mL [869.5-1776.0 U/mL]) than in healthy controls (380.5 U/mL [330.2-471.8 U/mL]); the interquartile ranges did not overlap between MD patients and healthy controls. The areas under the curve in disease and healthy controls were 0.812 (95% confidence interval [CI]: 0.734-0.886) and 0.951 (95% CI: 0.910-0.992), respectively. The automated, high-throughput technology-based LTIA device has definite advantages over the ELISA kit in shorter processing time and lower estimated cost per sample measurement. The LTIA device of GDF15 may be a sufficiently reliable, frontline, diagnostic indicator of individuals with suspected MDs in the general population.
Assuntos
Automação Laboratorial , Fator 15 de Diferenciação de Crescimento/sangue , Imunoturbidimetria/métodos , Doenças Mitocondriais/sangue , Doenças Mitocondriais/diagnóstico , Adolescente , Adulto , Biomarcadores/sangue , Estudos de Casos e Controles , Criança , Pré-Escolar , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Látex/química , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
IL-36α (gene symbol Il1f6), a member of the IL-36 family, is closely associated with inflammatory diseases, including colitis and psoriasis. In this study, we found that Il1f6-/- mice developed milder psoriasiform dermatitis upon treatment with imiquimod, a ligand for TLR ligand 7 (TLR7) and TLR8, whereas Il1f6-/- mice showed similar susceptibility to dextran sodium sulfate-induced colitis to wild-type mice. These effects were observed in both cohoused and separately housed conditions, and antibiotic treatment did not cancel the resistance of Il1f6-/- mice to imiquimod-induced dermatitis. Bone marrow (BM) cell transfer revealed that IL-36α expression in skin-resident cells is important for the pathogenesis of dermatitis in these mice. Following stimulation with IL-36α, the expression of Il1f6 and Il1f9 (IL-36γ), but not Il1f8 (IL-36ß), was enhanced in murine BM-derived Langerhans cells (BMLCs) and murine primary keratinocytes but not in fibroblasts from mice. Upon stimulation with agonistic ligands of TLRs and C-type lectin receptors (CLRs), Il1f6 expression was induced in BMLCs and BM-derived dendritic cells. Furthermore, IL-36α stimulation resulted in significantly increased gene expression of psoriasis-associated Th17-related cytokines and chemokines such as IL-1α, IL-1ß, IL-23, CXCL1, and CXCL2 in BMLCs and fibroblasts, and IL-1α, IL-1ß, IL-17C, and CXCL2 in keratinocytes. Collectively, these results suggest that TLR/CLR signaling-induced IL-36α plays an important role for the development of psoriasiform dermatitis by enhancing Th17-related cytokine/chemokine production in skin-resident cells via a local autoamplification loop.
Assuntos
Adjuvantes Imunológicos/toxicidade , Quimiocinas/biossíntese , Colite/patologia , Imiquimode/toxicidade , Interleucina-1/metabolismo , Queratinócitos/metabolismo , Psoríase/patologia , Pele/patologia , Células Th17/imunologia , Animais , Células da Medula Óssea/citologia , Transplante de Medula Óssea , Células Cultivadas , Colite/induzido quimicamente , Células Dendríticas/metabolismo , Sulfato de Dextrana/toxicidade , Fibroblastos/metabolismo , Interleucina-1/genética , Células de Langerhans/metabolismo , Glicoproteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Psoríase/tratamento farmacológico , Psoríase/genética , Pele/citologia , Receptor 7 Toll-Like/metabolismo , Receptor 8 Toll-Like/metabolismoRESUMO
We isolated the transmembrane and coiled-coil domains 5A (Tmco5A) gene using polymerase chain reaction-based subtraction technique and showed that Tmco5A was predominantly expressed in rat testes starting at 4 weeks of postnatal development. When expressed in COS7 cells, TMCO5A was found to be distributed in the endoplasmic reticulum-nuclear membrane (ER-NM) of cells as a membrane-associated protein, while TMCO5AΔC lacking the transmembrane region (TM) mislocalized and diffused throughout the cytoplasm. The result suggested that TM is responsible for the retention of TMCO5A at the ER-NM. Immunocytochemical and immunoblotting analyses indicated that TMCO5A was localized along the posterior part of the nuclei in both round and elongated rat spermatids but disappeared from epididymal spermatozoa. Double immunolabeling of isolated spermatids with the anti-TMCO5A and the anti-ß tubulin antibodies showed that TMCO5A was always found to be closely associated with developing manchette microtubules but did not completely colocalize with them. On the other hand, we found that almost all TMCO5A colocalized with SUN4, a linker of nucleoskeleton and cytoskeleton complex protein present at the posterior part of spermatid nuclei. These data suggested that TMCO5A is located closer to the nuclei than the manchette microtubules. It is likely that TMCO5A, in association with manchette microtubules, is involved in the process of spermiogenesis.
Assuntos
Proteínas de Membrana/metabolismo , Microtúbulos/metabolismo , Membrana Nuclear/metabolismo , Espermátides/crescimento & desenvolvimento , Espermatogênese/fisiologia , Sequência de Aminoácidos , Animais , Células COS , Chlorocebus aethiops , Retículo Endoplasmático/metabolismo , Imuno-Histoquímica , Masculino , Proteínas Nucleares/metabolismo , Domínios Proteicos/fisiologia , Ratos , Ratos Wistar , Musaranhos , Testículo/metabolismoRESUMO
Ulcerative colitis (UC) is an inflammatory disease of the colon. IL1R2, which encodes IL-1 receptor type 2 (IL-1R2), was reported as a risk gene for UC. To elucidate the roles of IL-1R2 in the development of colitis, we examined the development of dextran sodium sulfate-induced colitis, a mouse model for UC using Il1r2-/- mice. We found the severity score of colitis was milder in Il1r2-/- mice compared with wild-type (WT) mice when they were housed separately, however the severity score was similar when they were housed in a cage. In the separate housing condition, relative contents of Actinobacteria and Bacilli in feces of Il1r2-/- mice were lower than that of WT mice. Furthermore, IL-1ß induced the expression of antimicrobial peptides (AMPs) from colon. Thus, we show that IL-1R2 is harmful for the development of colitis, because IL-1R2 promotes the growth of proinflammatory intestinal microbiota by suppressing IL-1ß-induced AMP production.
Assuntos
Peptídeos Catiônicos Antimicrobianos/imunologia , Colite/imunologia , Microbioma Gastrointestinal/imunologia , Receptores de Interleucina-1/imunologia , Animais , Colite/induzido quimicamente , Colite/patologia , Sulfato de Dextrana , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Interleucina-1/genéticaRESUMO
The tumor suppressors Lats1 and Lats2 are mediators of the Hippo pathway that regulates tissue growth and proliferation. Their N-terminal non-kinase regions are distinct except for Lats conserved domains 1 and 2 (LCD1 and LCD2), which may be important for Lats1/2-specific functions. Lats1 knockout mice were generated by disrupting the N-terminal region containing LCD1 (Lats1(ΔN/ΔN)). Some Lats1(ΔN/ΔN) mice were born safely and grew normally. However, mouse embryonic fibroblasts (MEFs) from Lats1(ΔN/ΔN) mice displayed mitotic defects, centrosomal overduplication, chromosomal misalignment, multipolar spindle formation, chromosomal bridging and cytokinesis failure. They also showed anchorage-independent growth and continued cell cycles and cell growth, bypassing cell-cell contact inhibition similar to tumor cells. Lats1(ΔN/ΔN) MEFs produced tumors in nude mice after subcutaneous injection, although the tumor growth rate was much slower than that of ordinary cancer cells. Yap, a key transcriptional coactivator of the Hippo pathway, was overexpressed and stably retained in Lats1(ΔN/ΔN) MEFs in a cell density independent manner, and Lats2 mRNA expression was downregulated. In conclusion, N-terminally truncated Lats1 induced Lats2 downregulation and Yap protein accumulation, leading to chromosomal instability and tumorigenesis.
Assuntos
Instabilidade Cromossômica , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Carcinogênese/genética , Carcinogênese/metabolismo , Adesão Celular/fisiologia , Proteínas de Ciclo Celular , Processos de Crescimento Celular , Linhagem Celular Tumoral , Regulação para Baixo , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Camundongos Nus , Fosfoproteínas/metabolismo , Proteínas Serina-Treonina Quinases/deficiência , Transdução de Sinais , Transcrição Gênica , Proteínas de Sinalização YAPRESUMO
An association between postoperative analgesic requirements in subjects who underwent orthognathic surgery and the rs1465040 single-nucleotide polymorphism close to the transient receptor potential subfamily C member 3 (TRPC3) gene was suggested by our previous genome-wide association study. To verify this association, we analyzed the association between the rs1465040 SNP and analgesic requirements, including opioid requirements, after open abdominal surgery. The association between the rs1465040 SNP and postoperative analgesic requirements was confirmed in the open abdominal surgery group (P = 0.036), suggesting that the TRPC3 SNP may contribute to predicting postoperative analgesic requirements.
Assuntos
Analgésicos/administração & dosagem , Estudo de Associação Genômica Ampla , Dor Pós-Operatória/tratamento farmacológico , Dor Pós-Operatória/genética , Polimorfismo de Nucleotídeo Único/genética , Cuidados Pós-Operatórios , Canais de Cátion TRPC/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Analgésicos Opioides/administração & dosagem , Feminino , Previsões , Humanos , Masculino , Pessoa de Meia-Idade , Procedimentos Cirúrgicos Ortognáticos , Adulto JovemRESUMO
Hepcidin is a key regulator of mammalian iron metabolism and mainly produced by the liver. Hepcidin excess causes iron deficiency and anemia by inhibiting iron absorption from the intestine and iron release from macrophage stores. Anemia is frequently complicated with heart failure. In heart failure patients, the most frequent histologic appearance of liver is congestion. However, it remains unclear whether liver congestion associated with heart failure influences hepcidin production, thereby contributing to anemia and functional iron deficiency. In this study, we investigated this relationship in clinical and basic studies. In clinical studies of consecutive heart failure patients (n = 320), anemia was a common comorbidity (41%). In heart failure patients without active infection and ongoing cancer (n = 30), log-serum hepcidin concentration of patients with liver congestion was higher than those without liver congestion (p = 0.0316). Moreover, in heart failure patients with liver congestion (n = 19), the anemia was associated with the higher serum hepcidin concentrations, which is a type of anemia characterized by induction of hepcidin. Subsequently, we produced a rat model of heart failure with liver congestion by injecting monocrotaline that causes pulmonary hypertension. The monocrotaline-treated rats displayed liver congestion with increase of hepcidin expression at 4 weeks after monocrotaline injection, followed by anemia and functional iron deficiency observed at 5 weeks. We conclude that liver congestion induces hepcidin production, which may result in anemia and functional iron deficiency in some patients with heart failure.
Assuntos
Anemia/sangue , Anemia/complicações , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/complicações , Hepcidinas/sangue , Hepatopatias/sangue , Hepatopatias/complicações , Idoso , Anemia/epidemiologia , Animais , Biomarcadores/metabolismo , Feminino , Humanos , Ferro/sangue , Hepatopatias/patologia , Masculino , Pessoa de Meia-Idade , Monocrotalina , Tamanho do Órgão , Oxigênio/sangue , Prevalência , Ratos Endogâmicos LewRESUMO
In this study, we applied an electrospinning (ES) method, which is mainly employed in the textile industry, to the field of pharmaceuticals. We developed and modified an ES instrument and then utilized it to produce methacrylic acid copolymer S (MAC) nano-fibers to prepare tablets. By attaching a conductor rod made from stainless steel to the central part of the nano-fiber-collection plate of the ES apparatus, a MAC nano-fiber sheet could be produced effectively. In addition, we studied various operating conditions for this new ES method, including needle gauge, voltage between the electrodes, distance between the needle and nano-fiber-collection plate and the flow rate of MAC polymer solution, but these had no significant effect on the diameter of MAC nano-fibers. On the other hand, the viscosity (concentration) of MAC polymer solution and permittivity of solvent used to dilute MAC were closely related to the mean diameter of the nano-fibers. Tableting of MAC nano-fibers was performed using a tableting machine without lubricants, and addition of Tween 20 to the tablets enabled regulation of the release profile of a water-soluble drug. The modified ES method reported here is a useful technique for the controlled-release of drugs and has wide-ranging potential for pharmaceutical applications.
Assuntos
Química Farmacêutica/métodos , Metacrilatos/química , Nanofibras/química , Polímeros/química , Nanofibras/ultraestrutura , Solventes/química , Comprimidos/química , ViscosidadeRESUMO
BACKGROUND: Anemia and relative iron deficiency (RID) are prevalent in patients with heart failure (HF). The etiology of anemia and RID in HF patients is unclear. Hepcidin expression may be closely related to anemia and RID in HF patients. Although hepcidin is produced mainly by the liver, and the most frequent histologic appearance of liver in HF patients is congestion, the influence of liver congestion (LC) on hepcidin production has not yet been investigated. We investigated whether hepcidin contributed to anemia and RID in rats with LC. METHODS AND RESULTS: LC was induced in rats by ligating the inferior vena cava and compared with bleeding anemia (BA) model induced by phlebotomy and hemolytic anemia (HA) model induced by injection of phenylhydrazine. BA and HA strongly suppressed expression of hepcidin in liver and so did not cause decrease in serum iron and transferrin saturation. However, hepcidin expression did not decrease in LC rats, which resulted in anemia and lower transferrin saturation. In addition, many cells with hemosiderin deposits were observed in the liver and spleen and not in the bone marrow, and this appeared to be related to suppression of hepcidin expression. Iron accumulated in hepatocytes, and bone morphogenetic protein 6, which induces hepcidin, increased. Inflammation was observed in the congestive liver, and there was an increase in interleukin-6, which also induced hepcidin and was induced by free heme and hemoglobin via Toll-like receptor 4. CONCLUSIONS: We conclude that LC contributes to RID and anemia, and it does so via inappropriate expression of hepcidin.
Assuntos
Anemia Ferropriva/genética , Hepcidinas/genética , Deficiências de Ferro , Hepatopatias/genética , Fígado/ultraestrutura , RNA/genética , Anemia Ferropriva/metabolismo , Animais , Células Cultivadas , Modelos Animais de Doenças , Microanálise por Sonda Eletrônica , Hepcidinas/biossíntese , Imuno-Histoquímica , Ferro/sangue , Fígado/metabolismo , Hepatopatias/metabolismo , Hepatopatias/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microscopia Eletrônica de Varredura , Ratos , Ratos Endogâmicos Lew , Reação em Cadeia da Polimerase em Tempo RealRESUMO
We investigated whether correlations between mRNA levels of cytokines versus other proteins from patchy lesion could estimate cytokine paracrine signaling in vivo. Experiments with rat experimental autoimmune myocarditis (EAM), a patchy myocarditis model, indicated IL-1 and other protein levels were correlated, indicating paracrine signaling pathways in vivo.
Assuntos
Miocardite/metabolismo , Comunicação Parácrina/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Animais , Doenças Autoimunes/metabolismo , Doenças Autoimunes/patologia , Modelos Animais de Doenças , Interleucina-1/genética , Miocardite/genética , Miocardite/patologia , RNA Mensageiro/análise , RatosRESUMO
Translational regulation plays a critical role in the control of cell growth and proliferation. A key player in translational control is eIF4E, the mRNA 5' cap-binding protein. Aberrant expression of eIF4E promotes tumorigenesis and has been implicated in cancer development and progression. The activity of eIF4E is dysregulated in cancer. Regulation of eIF4E is partly achieved through phosphorylation. However, the physiological significance of eIF4E phosphorylation in mammals is not clear. Here, we show that knock-in mice expressing a nonphosphorylatable form of eIF4E are resistant to tumorigenesis in a prostate cancer model. By using a genome-wide analysis of translated mRNAs, we show that the phosphorylation of eIF4E is required for translational up-regulation of several proteins implicated in tumorigenesis. Accordingly, increased phospho-eIF4E levels correlate with disease progression in patients with prostate cancer. Our findings establish eIF4E phosphorylation as a critical event in tumorigenesis. These findings raise the possibility that chemical compounds that prevent the phosphorylation of eIF4E could act as anticancer drugs.
Assuntos
Fator de Iniciação 4E em Eucariotos/metabolismo , Neoplasias/etiologia , Neoplasias/patologia , Animais , Progressão da Doença , Fator de Iniciação 4E em Eucariotos/genética , Regulação da Expressão Gênica , Técnicas de Introdução de Genes , Humanos , Masculino , Camundongos , Proteínas de Neoplasias/genética , Neoplasias/genética , Fosforilação/fisiologia , Regulação para CimaRESUMO
Hypophosphatasia (HPP) is a congenital disorder caused by mutations in the tissue-nonspecific alkaline phosphatase (TNALP) gene. The pathogenesis of HPP varies, ranging from severe cases in which there is total absence of fetal bone calcification, which leads to stillbirth, to relatively mild cases in which the effects are confined to the teeth, such as early loss of the primary teeth. In recent years, the establishment of enzyme supplementation as a treatment method has prolonged survival in patients; however, this approach does not provide sufficient improvement for failed calcification. Furthermore, the effects of enzyme replacement therapy on the jawbone and periodontal tissues have not yet been studied in detail. Therefore, in this study, we investigated the therapeutic effects of enzyme replacement therapy on jawbone hypocalcification in mice. Recombinant TNALP was administered to mothers before birth and newborns immediately after birth, and the effect of treatment was evaluated at 20 days of age. The treated HPP mice had improved mandible (mandibular length and bone quality) and tooth quality (root length of mandibular first molar, formation of cementum), as well as improved periodontal tissue structure (structure of periodontal ligament). Furthermore, prenatal treatment had an additional therapeutic effect on the degree of mandible and enamel calcification. These results suggest that enzyme replacement therapy is effective for the treatment of HPP, specifically in the maxillofacial region (including the teeth and mandible), and that early initiation of treatment may have additional beneficial therapeutic effects.
Assuntos
Calcinose , Hipofosfatasia , Animais , Humanos , Camundongos , Fosfatase Alcalina/genética , Fosfatase Alcalina/uso terapêutico , Hipofosfatasia/tratamento farmacológico , Hipofosfatasia/genética , Terapia de Reposição de Enzimas/métodos , Proteínas Recombinantes de Fusão/uso terapêutico , Calcinose/tratamento farmacológico , Calcinose/genéticaRESUMO
Objectives: Weight loss improves the liver pathophysiological status of nonalcoholic fatty liver disease (NAFLD) patients. However, there are few studies that investigate the accurate relationships between nutritional intake and disease progression in NAFLD patients. Methods: A total of 37 biopsy-confirmed NAFLD patients were enrolled in this study. Clinical and nutritional control data of 5074 persons were obtained from the National Institute of Health and Nutrition. Each NAFLD subject recorded dietary intake for seven consecutive days using a dietary questionnaire and photographs of each meal. A dietitian analyzed and quantified the nutritional data in each patient. We further analyzed the nutritional intake of NAFLD patients in three groups according to the following criteria: (1) liver fibrosis degree (advanced, early), (2) gender (male, female), and (3) body mass index (BMI) (high, low). Results: Excesses or deficiencies of multiple nutrients were found in NAFLD patients compared with control subjects. In addition, there were variations in nutritional intake. (1) The intake of vitamins A, B6, and E, pantothenic acid, soluble dietary fiber, and salt was lower in the advanced fibrosis group than in the early fibrosis group. (2) Fat intake was higher in male patients, and dietary fiber intake was lower in both male and female patients compared with control subjects. (3) Saturated fatty acid intake was higher, and copper and vitamin E intakes were lower in patients with high BMI than with low BMI. Conclusions: Our study demonstrates that differences were found in some nutrient intake of NAFLD patients and controls and according to the severity of the conditions (liver fibrosis degree, BMI).
Assuntos
Hepatopatia Gordurosa não Alcoólica , Biópsia , Fibras na Dieta , Ingestão de Alimentos , Feminino , Fibrose , Humanos , Cirrose Hepática , Masculino , Redução de PesoRESUMO
INTRODUCTION: Interleukin (IL)-1 is a key orchestrator of inflammation and IL-1 inhibitors are expected to be promising pharmaceutical agents for such pathologies. IL-1 is bound to the complex of two receptor components with much higher affinity than with either receptor component alone. MATERIALS AND METHODS: We examined the effect of a heterodimer of IL-1 receptor accessory protein (Acp)-immunoglobulin (Ig) and IL-1R type II (IL1R2)-Ig named AcP-Ig/IL1R2-Ig heterodimer, and compared its effects with other IL-1 inhibitors reported previously. RESULTS AND DISCUSSION: Our results demonstrated that the rat AcP-Ig/IL1R2-Ig heterodimer (IC50=1.95 pM) inhibited IL-1 response to a greater extent than IL1RA (IC50=1,935 pM), Acp-IL1R type I (IL1R1)-Ig homodimer (IC50=73.7 pM) and Acp-IL1R2-Ig homodimer (IC50=72.8 pM). Moreover, human AcP-Ig/IL1R2-Ig heterodimer (IC50=0.14 pM) inhibited it to a greater extent than Acp-IL1R1-Ig homodimer (IC50=4.48 pM) and strongly inhibited responses of both IL-1α and IL-1ß. CONCLUSIONS: The AcP-Ig/IL1R2-Ig heterodimer, which is similar to the original extracellular structure of the Acp/IL1R1 complex, may inhibit the IL-1 response more vigorously than other IL-1 blocking biopharmaceutical agents.
Assuntos
Anti-Inflamatórios/farmacologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/imunologia , Imunoglobulinas/metabolismo , Proteína Acessória do Receptor de Interleucina-1/metabolismo , Interleucina-1alfa/metabolismo , Interleucina-1beta/metabolismo , Complexos Multiproteicos/farmacologia , Receptores de Interleucina-1/metabolismo , Proteínas Recombinantes/metabolismo , Animais , Anti-Inflamatórios/imunologia , Anti-Inflamatórios/metabolismo , Sequência de Bases , Células COS , Células Cultivadas , Chlorocebus aethiops , Fibroblastos/citologia , Fibroblastos/metabolismo , Humanos , Imunoglobulinas/genética , Imunoglobulinas/imunologia , Inflamação , Concentração Inibidora 50 , Proteína Acessória do Receptor de Interleucina-1/genética , Proteína Acessória do Receptor de Interleucina-1/imunologia , Interleucina-1alfa/genética , Interleucina-1alfa/imunologia , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Dados de Sequência Molecular , Complexos Multiproteicos/imunologia , Complexos Multiproteicos/metabolismo , Plasmídeos , Ligação Proteica , Engenharia de Proteínas , Multimerização Proteica , Ratos , Receptores de Interleucina-1/genética , Receptores de Interleucina-1/imunologia , Receptores Tipo II de Interleucina-1/metabolismo , Proteínas Recombinantes/genética , Proteínas Recombinantes/imunologia , TransfecçãoRESUMO
The neuroprotective agent edaravone is an intravenous treatment for amyotrophic lateral sclerosis. As intravenous administration burdens patients, orally administered treatments are needed. This phase 1, open-label, single-dose crossover study in 42 healthy adults evaluated bioequivalence of a 105-mg edaravone oral suspension and intravenous edaravone (60 mg/60 min). The evaluation was whether the 90% confidence intervals (CIs) for the ratio of the maximum plasma concentration (Cmax ) and area under the plasma concentration-time curve from time 0 to the last quantifiable time point and to infinity of unchanged edaravone were between the bioequivalence limit of 0.80 and 1.25. Metabolic profiles and elimination pathways were also compared between the 2 routes. Geometric mean ratios and 90%CIs of area under the plasma concentration-time curve from time 0 to the last quantifiable time point and to infinity for unchanged edaravone satisfied bioequivalence limits. The geometric mean ratio and its lower limit of 90%CI of Cmax of the 105-mg oral suspension compared with 60-mg intravenous formulations for unchanged edaravone fell within bioequivalence limits. Both formulations showed triphasic plasma concentration-time profiles of unchanged edaravone after reaching Cmax . Plasma concentrations of edaravone inactive metabolites after oral administration were higher than with intravenous administration. Edaravone in both routes underwent urinary excretion, mainly as the glucuronide conjugate and, to a lesser extent, as the sulfate conjugate. Urinary excretion of unchanged edaravone was low, and urinary relative composition ratios of unchanged edaravone and metabolites were similar for both formulations. These findings showed equivalent exposure of the 105-mg oral suspension of edaravone to the 60-mg intravenous formulation, supporting further investigation of the oral suspension for treating amyotrophic lateral sclerosis.
Assuntos
Composição de Medicamentos/métodos , Edaravone/administração & dosagem , Edaravone/metabolismo , Sequestradores de Radicais Livres/administração & dosagem , Sequestradores de Radicais Livres/metabolismo , Administração Oral , Adolescente , Adulto , Estudos Cross-Over , Feminino , Voluntários Saudáveis , Humanos , Infusões Intravenosas , Masculino , Suspensões , Equivalência Terapêutica , Adulto JovemRESUMO
This randomized, single-blind, 3-way crossover study assessed the effect of edaravone on QT interval, including an exposure-response analysis. Twenty-seven healthy Japanese male volunteers, aged 20 to 49 years, were randomly assigned to receive a single intravenous dose of each treatment in 1 of 3 sequences (n = 9 each): ACB, BAC, and CBA, where A was edaravone 60 mg (therapeutic dose), B was edaravone 300 mg (supratherapeutic dose), and C was normal saline (placebo). Electrocardiographs were collected to assess treatment effects. In an exposure-response analysis, a linear model was determined to be valid and indicated no statistically significant positive slope for the relationship between change from baseline in QTcF (ΔQTcF) and edaravone concentration (0.000155 ms/(ng/mL); P = .1478); upper bounds of 2-sided 90% confidence intervals after placebo adjustment (ΔΔQTcF) were <10 milliseconds at the geometric mean maximum concentration for each edaravone dose. Overall estimated values by time point of ΔΔQTcF ≤0.9 milliseconds, no outlier values, and no morphologic changes suggestive of repolarization abnormalities were observed. Analysis of heart rate, PR interval, and QRS duration also revealed no adverse findings. These data indicate that edaravone, even at supratherapeutic doses, does not produce clinically meaningful QT prolongation and has no clinically relevant cardiac effects.
Assuntos
Edaravone/administração & dosagem , Sequestradores de Radicais Livres/administração & dosagem , Frequência Cardíaca/efeitos dos fármacos , Fármacos Neuroprotetores/administração & dosagem , Adulto , Estudos Cross-Over , Edaravone/efeitos adversos , Edaravone/sangue , Edaravone/farmacocinética , Eletrocardiografia/efeitos dos fármacos , Sequestradores de Radicais Livres/efeitos adversos , Sequestradores de Radicais Livres/sangue , Sequestradores de Radicais Livres/farmacocinética , Voluntários Saudáveis , Humanos , Síndrome do QT Longo , Masculino , Pessoa de Meia-Idade , Fármacos Neuroprotetores/efeitos adversos , Fármacos Neuroprotetores/sangue , Fármacos Neuroprotetores/farmacocinética , Método Simples-Cego , Adulto JovemRESUMO
BACKGROUND: Lipocalin-2/neutrophil gelatinase-B associated lipocalin (Lcn2/NGAL) is involved in the transport of iron and seems to play an important role in inflammation. A recent study has reported that it is also expressed in the failing heart and may be a biomarker not only for renal failure but also for heart failure. Because Lcn2/NGAL is thought to be induced by interleukin-1, it might be strongly induced in the presence of myocarditis. METHODS AND RESULTS: This study investigated the expression of Lcn2/NGAL in rat experimental autoimmune myocarditis (EAM) and in human myocarditis. In EAM hearts, the expression of Lcn2/NGAL was markedly increased (>100-fold at an early stage), and in human myocarditis it was also highly expressed compared with non-inflammatory failing hearts. Lcn2/NGAL expressing cells in hearts with EAM and human myocarditis were identified as cardiomyocytes, vascular wall cells, fibroblasts and neutrophils. Lcn2/NGAL in EAM rats was also expressed in the liver. Plasma Lcn2/NGAL levels abruptly increased at an early stage of EAM, and high levels were initially sustained during the inflammatory stage, then decreased with recovery. In contrast, levels of B-type natriuretic peptide increased only slowly as the disease progressed. CONCLUSIONS: Cardiomyocytes, vascular wall cells and fibroblasts in myocarditis strongly express Lcn2/NGAL via proinflammatory cytokines.