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1.
Ophthalmology ; 2019 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-31257036

RESUMO

PURPOSE: To present phenotypic features of 22 patients with S-antigen (SAG) mutations. DESIGN: Retrospective cohort study. PARTICIPANTS: Twenty-one Japanese patients from 16 families with a homozygous c.924delA mutation and 1 patient with a homozygous c.636delT mutation in the SAG gene. METHODS: Clinical records on symptoms; best-corrected visual acuity; and Goldmann perimetry, fundus photography, fundus autofluorescence (FAF), OCT, and electroretinography results were reviewed. MAIN OUTCOME MEASURES: Best-corrected visual acuity, Goldmann perimetry results, imaging findings, and electroretinography results. RESULTS: Ten patients had Oguchi disease and 12 had retinitis pigmentosa (RP) with mean follow-up periods of 13.8 and 10.2 years, respectively. Retinitis pigmentosa patients were older (mean age, 56.0 years) than those with Oguchi disease (mean age, 22.1 years; P < 0.001) at the initial visit. Night blindness noted in childhood was the most common initial symptom for both Oguchi disease (80.0%) and RP (91.7%) patients. Best-corrected visual acuity in the logarithm of the minimum angle of resolution (logMAR) was well preserved in Oguchi disease patients (mean, 0.02 logMAR in both eyes) but reduced in most RP patients (mean, 1.32 logMAR [right eye] and 1.35 logMAR [left eye]). Similarly, the visual field in the retinal area was preserved in Oguchi disease patients (mean, 677 mm2 right eye and 667 mm2 left eye) and reduced in RP patients (mean, 369 mm2 right eye and 294 mm2 left eye). Fundus images revealed a characteristic golden sheen with no retinal degeneration in Oguchi disease patients, excluding 2 with macular degeneration detected by FAF, OCT, or both and 1 with mild retinal degeneration confirmed by OCT and fluorescein angiography. Pigmentary retinal degeneration most evident posteriorly was observed in RP patients, accompanied by a characteristic golden sheen in 12 of 14 patients undergoing ultra-widefield fundus imaging. OCT showed disrupted macular structure, and FAF revealed variable hypofluorescence. Electroretinography identified absent rod responses in both diseases, along with relative preservation of cone responses in Oguchi disease patients. Three patients showed progressive loss of the golden sheen based on fundus images, including 1 who demonstrated RP 26 years after the initial diagnosis of Oguchi disease. CONCLUSIONS: Retinitis pigmentosa with SAG mutations often shows a characteristic golden sheen surrounding posterior pigmentary retinal degeneration. Oguchi disease can show progressive degeneration in adulthood, rarely resulting in RP.

2.
Drug Discov Ther ; 13(3): 150-156, 2019 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-31257355

RESUMO

With respect to diclofenac sodium-containing tape preparations of nonsteroidal antiphlogistic drug, we compared the pharmaceutical properties (pH, elongatedness, water-vapor permeability, adhesive force, and peeling-force) of 11 medicinal drugs (2 brand-name and 9 generic drugs) to obtain evidence for product selection in line with the needs of the patient. The elongatedness of the generic drugs Teikoku (1.39), Yutoku (1.40), and Nippon-zoki (1.43) were significantly higher than the brand-name drug Voltaren® (1.22). The adhesive force was measured using the probe tack test and the inclined ball tack test. The probe tack test results of Naboal® (6.8 N/cm2), Teikoku (6.1 N/cm2), Yutoku (5.9 N/cm2), Nippon-zoki (6.2 N/cm2), and Rakool (6.2 N/cm2) were higher than that of Voltaren (2.0 N/cm2). The inclined ball tack test results of Naboal (18.0), Teikoku (24.0), Yutoku (21.5), and Nippon-zoki (22.7) were also higher than that of Voltaren (7.2). Concerning peeling-force measurement, the 90° peeling-forces of Naboal (0.95 N), Teikoku (0.96 N), Yutoku (0.94 N), and Nippon-zoki (1.01 N) were higher than that of Voltaren (0.68 N). These results show that there were marked differences in the feeling of use of each product between the brand-name and generic drugs. The pharmacist indicates the basis for selection of a preparation according to the feeling of use desired by each patient. It has become possible to recommend products suitable for each patient, which will allow pharmacists to provide products according to the needs of each patient when a brand-name drug is changed to a generic one.

3.
Nat Plants ; 5(7): 731-741, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31263241

RESUMO

Pre-zygotic interspecies incompatibility in angiosperms is a male-female relationship that inhibits the formation of hybrids between two species. Here, we report on the identification of STIGMATIC PRIVACY 1 (SPRI1), an interspecies barrier gene in Arabidopsis thaliana. We show that the rejection activity of this stigma-specific plasma membrane protein is effective against distantly related Brassicaceae pollen tubes and is independent of self-incompatibility. Point-mutation experiments and functional tests of synthesized hypothetical ancestral forms of SPRI1 suggest evolutionary decay of SPRI1-controlled interspecies incompatibility in self-compatible A. thaliana. Hetero-pollination experiments indicate that SPRI1 ensures intraspecific fertilization in the pistil when pollen from other species are present. Our study supports the idea that SPRI1 functions as a barrier mechanism that permits entrance of pollen with an intrinsic signal from self species.

4.
Heart Rhythm ; 2019 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-31173922

RESUMO

BACKGROUND: Early repolarization syndrome (ERS) is characterized by J-point elevation on electrocardiograms and ventricular fibrillation (VF). Early repolarization arises from augmentation of the transmural electrical gradient in the cardiac action potential; therefore, the transient outward potassium current (Ito) has been regarded as a key candidate current for elucidating the mechanism of ERS. KCND3 encoding Kv4.3, an α-subunit of the Ito channel, is considered as one of target genes. OBJECTIVE: The purpose of this study was to search for novel KCND3 mutations associated with ERS and to clarify the pathogenesis. METHODS: We performed genetic screening for 11 unrelated probands with ERS and analyzed the electrophysiological properties of detected mutations by patch-clamp methods. RESULTS: A novel de novo KCND3 heterozygous mutation, Gly306Ala (c.917g>c), was found in 1 proband. The proband was a 12-year-old boy, who suffered VF storm and showed significant J-point elevation in multiple leads. Intravenous isoproterenol and subsequent administration of quinidine were effective in preventing VF recurrence and restored the J-point elevation. In electrophysiological analysis, cultured cells expressing mutant Kv4.3 showed significantly increased current densities, slow inactivation, and slow recovery from inactivation compared to wild type. Extracellular application of quinidine significantly restored the inactivation time course in mutant Kv4.3. A simulation study confirmed the relationship between the novel KCND3 mutation and early repolarization on electrocardiograms. CONCLUSION: A novel KCND3 heterozygous mutation was found to be associated with ERS. The pathogenesis can be explained by the increased Ito. Genetic screening for KCND3 could be useful for understanding the pathogenesis and selecting effective treatment.

5.
J Med Genet ; 2019 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-31213501

RESUMO

BACKGROUND: The genetic profile of retinitis pigmentosa (RP) in East Asian populations has not been well characterised. Therefore, we conducted a large-scale sequencing study to investigate the genes and variants causing RP in a Japanese population. METHODS: A total of 1209 Japanese patients diagnosed with typical RP were enrolled. We performed deep resequencing of 83 known causative genes of RP using next-generation sequencing. We defined pathogenic variants as those that were putatively deleterious or registered as pathogenic in the Human Gene Mutation Database or ClinVar database and had a minor allele frequency in any ethnic population of ≤0.5% for recessive genes or ≤0.01% for dominant genes as determined using population-based databases. RESULTS: We successfully sequenced 1204 patients with RP and determined 200 pathogenic variants in 38 genes as the cause of RP in 356 patients (29.6%). Variants in six genes (EYS, USH2A, RP1L1, RHO, RP1 and RPGR) caused RP in 65.4% (233/356) of those patients. Among autosomal recessive genes, two known founder variants in EYS [p.(Ser1653fs) and p.(Tyr2935*)] and four East Asian-specific variants [p.(Gly2752Arg) in USH2A, p.(Arg658*) in RP1L1, p.(Gly2186Glu) in EYS and p.(Ile535Asn) in PDE6B] and p.(Cys934Trp) in USH2A were found in ≥10 patients. Among autosomal dominant genes, four pathogenic variants [p.(Pro347Leu) in RHO, p.(Arg872fs) in RP1, p.(Arg41Trp) in CRX and p.(Gly381fs) in PRPF31] were found in ≥4 patients, while these variants were unreported or extremely rare in both East Asian and non-East Asian population-based databases. CONCLUSIONS: East Asian-specific variants in causative genes were the major causes of RP in the Japanese population.

6.
Nat Commun ; 10(1): 2884, 2019 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-31253780

RESUMO

Hereditary retinal degenerations (HRDs) are Mendelian diseases characterized by progressive blindness and caused by ultra-rare mutations. In a genomic screen of 331 unrelated Japanese patients, we identify a disruptive Alu insertion and a nonsense variant (p.Arg1933*) in the ciliary gene RP1, neither of which are rare alleles in Japan. p.Arg1933* is almost polymorphic (frequency = 0.6%, amongst 12,000 individuals), does not cause disease in homozygosis or heterozygosis, and yet is significantly enriched in HRD patients (frequency = 2.1%, i.e., a 3.5-fold enrichment; p-value = 9.2 × 10-5). Familial co-segregation and association analyses show that p.Arg1933* can act as a Mendelian mutation in trans with the Alu insertion, but might also associate with disease in combination with two alleles in the EYS gene in a non-Mendelian pattern of heredity. Our results suggest that rare conditions such as HRDs can be paradoxically determined by relatively common variants, following a quasi-Mendelian model linking monogenic and complex inheritance.


Assuntos
Ciliopatias/genética , Proteínas do Olho/genética , Predisposição Genética para Doença , Doenças Retinianas/genética , Elementos Alu/genética , Grupo com Ancestrais do Continente Asiático/genética , Genômica , Humanos , Japão , Mutação , Linhagem
7.
Eur Heart J ; 2019 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-31145795

RESUMO

AIMS: In patients with catecholaminergic polymorphic ventricular tachycardia (CPVT), implantable cardioverter-defibrillator (ICD) shocks are sometimes ineffective and may even trigger fatal electrical storms. We assessed the efficacy and complications of ICDs placed in patients with CPVT who presented with a sentinel event of sudden cardiac arrest (SCA) while undiagnosed and therefore untreated. METHODS AND RESULTS: We analysed 136 patients who presented with SCA and in whom CPVT was diagnosed subsequently, leading to the initiation of guideline-directed therapy, including ß-blockers, flecainide, and/or left cardiac sympathetic denervation. An ICD was implanted in 79 patients (58.1%). The primary outcome of the study was sudden cardiac death (SCD). The secondary outcomes were composite outcomes of SCD, SCA, appropriate ICD shocks, and syncope. After a median follow-up of 4.8 years, SCD had occurred in three patients (3.8%) with an ICD and none of the patients without an ICD (P = 0.1). SCD, SCA, or appropriate ICD shocks occurred in 37 patients (46.8%) with an ICD and 9 patients (15.8%) without an ICD (P < 0.0001). Inappropriate ICD shocks occurred in 19 patients (24.7%) and other device-related complications in 22 patients (28.9%). CONCLUSION: In previously undiagnosed patients with CPVT who presented with SCA, an ICD was not associated with improved survival. Instead, the ICD was associated with both a high rate of appropriate ICD shocks and inappropriate ICD shocks along with other device-related complications. Strict adherence to guideline-directed therapy without an ICD may provide adequate protection in these patients without all the potential disadvantages of an ICD.

8.
Invest Ophthalmol Vis Sci ; 60(4): 1192-1203, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30913292

RESUMO

Purpose: To describe the clinical and genetic spectrum of RP1-associated retinal dystrophies. Methods: In this multicenter case series, we included 22 patients with RP1-associated retinal dystrophies from 19 families from The Netherlands and Japan. Data on clinical characteristics, visual acuity, visual field, ERG, and retinal imaging were extracted from medical records over a mean follow-up of 8.1 years. Results: Eleven patients were diagnosed with autosomal recessive macular dystrophy (arMD) or autosomal recessive cone-rod dystrophy (arCRD), five with autosomal recessive retinitis pigmentosa (arRP), and six with autosomal dominant RP (adRP). The mean age of onset was 40.3 years (range 14-56) in the patients with arMD/arCRD, 26.2 years (range 18-40) in adRP, and 8.8 years (range 5-12) in arRP patients. All patients with arMD/arCRD carried either the hypomorphic p.Arg1933* variant positioned close to the C-terminus (8 of 11 patients) or a missense variant in exon 2 (3 of 11 patients), compound heterozygous with a likely deleterious frameshift or nonsense mutation, or the p.Gln1916* variant. In contrast, all mutations identified in adRP and arRP patients were frameshift and/or nonsense variants located far from the C-terminus. Conclusions: Mutations in the RP1 gene are associated with a broad spectrum of progressive retinal dystrophies. In addition to adRP and arRP, our study provides further evidence that arCRD and arMD are RP1-associated phenotypes as well. The macular involvement in patients with the hypomorphic RP1 variant suggests that macular function may remain compromised if expression levels of RP1 do not reach adequate levels after gene augmentation therapy.


Assuntos
Códon sem Sentido , Distrofias de Cones e Bastonetes/genética , Proteínas do Olho/genética , Mutação da Fase de Leitura , Degeneração Macular/genética , Retinite Pigmentosa/genética , Adolescente , Adulto , Idade de Início , Criança , Pré-Escolar , Distrofias de Cones e Bastonetes/diagnóstico , Distrofias de Cones e Bastonetes/fisiopatologia , Análise Mutacional de DNA , Eletrorretinografia , Éxons , Feminino , Humanos , Degeneração Macular/diagnóstico , Degeneração Macular/fisiopatologia , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Retinite Pigmentosa/diagnóstico , Retinite Pigmentosa/fisiopatologia , Acuidade Visual/fisiologia , Campos Visuais/fisiologia , Adulto Jovem
9.
BMC Cardiovasc Disord ; 19(1): 41, 2019 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-30782136

RESUMO

BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited myocardial disease characterized by fibrofatty replacement and ventricular arrhythmias. ARVC is believed to be a disease of the young, with most cases being diagnosed before the age of 40 years. We report here a case of newly diagnosed ARVC in an octogenarian associated with a pathogenic variant in the plakophilin 2 gene (PKP2). CASE PRESENTATION: An 80-year-old Japanese man was referred for sustained ventricular tachycardia. His baseline electrocardiogram showed negative T waves in V1-V4. Right ventriculography showed right ventricular aneurysm. Because this case met three major criteria, ARVC was diagnosed. He was successfully treated with radiofrequency ablation and oral amiodarone. Genetic analysis identified an insertion mutation in exon 8 of PKP2 (1725_1728dupGATG), which caused a frameshift and premature termination of translation (R577DfsX5). CONCLUSIONS: To the best of our knowledge, this is the first report of newly diagnosed ARVC in an octogenarian associated with a loss-of-function PKP2 pathogenic variant. Although the late clinical presentation of ARVC is rare, it should be included in the differential diagnosis when treating older patients with ventricular tachyarrhythmias.

10.
Drug Discov Ther ; 12(4): 248-253, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30224597

RESUMO

The physicochemical properties (pH, yield value, and squeeze force) of a drug for dermatomycosis, a terbinafine hydrochloride-containing cream (a brand-name product), and 12 over-the-counter drugs (OTCs) were measured and compared to ascertain the characteristics of each product. The pH of the brand-name product, Lamisil, was 4.1, and that of the OTC products ranged from 4.2 to 7.6; Lamisil Plus (7.6) had a significantly higher pH. Moreover, the yield value for Lamisil, as an index of cream ductility, was 128 dyn/cm2, and that for the OTC products ranged from 110 to 887 dyn/cm2. In particular, the OTC products Damalin (887 dyn/cm2), Barriact (512 dyn/cm2), and Exiv Deep (663 dyn/cm2) had a significantly higher yield value. In addition, the squeeze force was measured by attaching a HapLog® to the thumb and second finger. The squeeze force for Lamisil was 12.9 N, and that for the OTC products ranged from 1.8 to 14.6 N. The OTC product Bilumon (1.8 N) had a significantly lower squeeze force. These results indicated that there were marked differences in the pharmaceutical properties of brand-name and OTC products. External preparations are characterized by their feel during use. Based on the current results, the pharmaceutical characteristics of drugs resulted in differences in their feel during use, suggesting that products appropriate for individual patients can be recommended.

11.
Ann Thorac Surg ; 106(5): 1349-1355, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30086279

RESUMO

BACKGROUND: Although frailty is used to predict morbidity and mortality, its effect on the outcomes of acute type A aortic dissection has not been examined. Therefore, the objective of this study was to evaluate the role of frailty in predicting postoperative morbidity and mortality of patients with acute type A aortic dissection. METHODS: A retrospective analysis of a prospectively maintained database was undertaken for all patients (n = 310) undergoing aortic surgery between May 2004 and March 2017. Frailty was evaluated using an index consisting of age more than 70 years, body mass index less than 18.5 kg/m2, serum creatinine greater than 1.2 mg/dL, anemia, history of stroke, hypoalbuminemia, and the psoas muscle area index. One point was given for each criterion met, for a frailty score between 0 and 7. Frailty was defined as a score of 3 or more. RESULTS: Of all patients, 106 (34.2%) were defined as frail. Inhospital mortality rates of frail versus nonfrail patients were not significantly different (10.4% versus 8.3%, respectively; p = 0.54). Incidences of postoperative major morbidities without reexploration for bleeding were also not statistically different. Five-year survival rates were significantly worse for frail patients than for nonfrail patients (57.7% versus 85.1%, respectively; p = 0.0001). A frailty score of 3 or greater was associated with late mortality, and long-term outcomes were clearly stratified by frailty score. CONCLUSIONS: Frailty, as defined using a seven-component frailty index, can serve as an independent predictor of the risk of late mortality for patients undergoing surgery for acute type A aortic dissection. Such frailty markers, all of which are easily assessed preoperatively, may provide valuable information for patient counseling and risk stratification before aortic surgery.

12.
J Vet Med Sci ; 80(10): 1528-1533, 2018 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-30089738

RESUMO

The giraffe (Giraffa camelopardalis) is a difficult animal to keep in captivity as it has high mortality due to nutrition-related disorders, perhaps because the giraffe's condition is difficult to evaluate. Image analysis techniques have recently become popular and may be useful for evaluating the giraffe's somatotype. The present study aimed to evaluate the giraffe somatotype using a three-dimensional laser measurement device, and to examine the usefulness of this method. First, ten zoo staff members visually evaluated the somatotypes of three giraffes housed at Kanazawa Zoological Gardens, Japan. Next, three-dimensional point cloud datasets were obtained from these giraffes using the device. The point cloud datasets indicated that the cross-sectional area and width of the largest giraffe's body were large in the abdominal region in the transverse sections. However, by visual examination, the ten zoo staff members deemed a different giraffe to be the largest. These results indicated that the three-dimensional laser measurement device could be used to evaluate giraffe somatotype in detail, and that this method may be an alternative to visual evaluation.


Assuntos
Girafas/anatomia & histologia , Lasers , Animais , Feminino , Masculino , Somatotipos
13.
J Vet Med Sci ; 80(4): 648-652, 2018 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-29445072

RESUMO

To treat dental disorders and estimate age, it is important that veterinarians understand teeth eruption sequence for the animal in question. Few dental images of the eastern grey kangaroo have been published. In the present study, radiographic imagings of 29 kangaroos, ranging in age from 12 months to 10 years 9 months, was used to surveil the replacement of premolars and the eruption of molars. These images revealed eruption patterns in five stages, while the second and third deciduous premolars were shed non-systematically. Furthermore, the third premolars and fourth molars erupted in the mandible earlier than in the maxilla, which may contribute to the frequency of mandibular dental disorders.


Assuntos
Envelhecimento/fisiologia , Macropodidae/fisiologia , Dente Molar/fisiologia , Erupção Dentária/fisiologia , Animais , Feminino , Masculino
14.
Drug Discov Ther ; 12(1): 16-20, 2018 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-29479048

RESUMO

We measured and compared the physicochemical properties (pH, yield value, and squeeze force) of a drug for dermatomycosis, terbinafine hydrochloride-containing cream (brand-name product), and 12 generic products to clarify the characteristics of each product. On pH measurement, the pH value of the brand-name product, Lamisil, was 4.8, and those of the generic products ranged from 4.3 to 5.5, showing no marked difference. Furthermore, the yield value of Lamisil, as an index of cream ductility, was 122.2 dyn/cm2, and those of the generic products ranged from 42.1 to 1,621.5 dyn/cm2. In particular, the value of a generic product, Taiyo (42.1 dyn/cm2), was significantly lower, whereas that of another one, Viras (1,621.0 dyn/cm2), was significantly higher. In addition, the squeeze force was measured by attaching a HapLog® to the thumb and second finger. The value of Lamisil was 12.9 N, and those of the generic products ranged from 8.0 to 15.4 N. The values of generic products, Mylan (8.6 N), Tebinaceil (9.0 N), and Kelger (8.0 N), were significantly lower, whereas that of another one, Viras (15.4 N), was significantly higher. These results showed that there were marked differences in the pharmaceutical properties between the generic and brand-name products. The above pharmaceutical characteristics of drugs facilitated the presentation of reasons for differences in the sense of use, which characterizes external preparations, suggesting that products appropriate for individual patients can be recommended.

15.
Zoo Biol ; 37(2): 115-118, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29450906

RESUMO

Eastern grey kangaroos (Macropus giganteus) younger than 19 months at Kanazawa Zoological Gardens, Japan, frequently died of enteritis. The main cause of death was coccidiosis. This study aimed to reveal retrospectively the clinical features of enteritis and factors contributing to its high occurrence. In addition, haematological and serum biochemical parameters in kangaroos younger than 24 months were analyzed. The findings suggested that enteritis occurrence was higher in 10- to 12-month-old kangaroos than other ages and during seasons with high temperature and humidity than during seasons with low temperature and humidity. The haematological and serum biochemical analyses showed decreases in glucose, total cholesterol, calcium, and triglyceride levels at approximately 10 months of age. Joeys emerge from their mother's pouch at 8 months of age and permanently leave it at approximately 10 months of age. Subsequently, the joeys are exposed to the external environment and infectious agents. Although the joeys continue suckling until 13-19 months of age, the joeys start to eat the similar feed to the adult and their nutritional status may change at approximately 10 months of age. Seasonal influences, species behavior, and shifts in dietary composition are proposed to be contributory to the increased occurrence of enteritis between 10 and 12 months of age.


Assuntos
Coccidiose/veterinária , Enterite/veterinária , Macropodidae , Fatores Etários , Animais , Animais de Zoológico , Coccidiose/mortalidade , Dieta/veterinária , Enterite/mortalidade , Comportamento Alimentar , Umidade , Japão/epidemiologia , Estudos Retrospectivos , Fatores de Risco , Estações do Ano , Temperatura Ambiente
16.
Tohoku J Exp Med ; 244(1): 53-62, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29353823

RESUMO

Critical limb ischemia (CLI) is the most severe complication of peripheral arterial disease (PAD). Understanding the molecular mechanisms underlying tissue repair after CLI is necessary for preventing PAD progression. Y-box binding protein-1 (YB-1) regulates the expression of many genes in response to environmental stresses. We aimed to determine whether YB-1 is involved in ischemic muscle regeneration. A mouse ischemic hind-limb model was generated; namely, the femoral, saphenous, and popliteal arteries in the left hind limb were ligated. The right hind limb, with skin incisions alone, served as control. Hind limbs (n = 3-5 for each time point) were examined on day 0 (before the operation) and on postoperative days 1, 2, 7, 10, and 14, and the biceps femoris, adductor, rectus femoris, and gracilis muscles were subjected to histopathological and immunohistochemical analyses. In ischemic limbs, myogenesis, triggered by an increase in myotubes, began on day 7; thereafter, regenerated muscles gradually increased in volume. RT-PCR analysis showed that YB-1 mRNA levels were increased in the limbs after ischemic injury, peaked on day 2, and subsequently decreased. On day 7, expression levels of MyoD and alpha-smooth muscle actin (αSMA) mRNAs were significantly higher in ischemic muscles than in control muscles. Immunohistochemical analysis revealed increased YB-1 immunoreactivity in myoblasts and myotubes on day 7, which was decreased by day 14. The immunoreactive αSMA and smooth muscle myosin heavy chain were transiently increased in myotubes. This is the first report showing the increased expression of YB-1 during muscle regeneration after ischemic injury.


Assuntos
Membro Posterior/irrigação sanguínea , Membro Posterior/patologia , Isquemia/metabolismo , Isquemia/patologia , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Regeneração , Proteína 1 de Ligação a Y-Box/metabolismo , Actinas/genética , Actinas/metabolismo , Animais , Masculino , Camundongos Endogâmicos BALB C , Desenvolvimento Muscular , Fibras Musculares Esqueléticas/metabolismo , Proteína MyoD/genética , Proteína MyoD/metabolismo , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fatores de Tempo
17.
18.
J Cardiol ; 71(4): 401-408, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29146210

RESUMO

BACKGROUND: Missense mutations in KCNH2, a gene encoding the Kv11.1 channel, cause long QT syndrome (LQTS) type 2 primarily by disrupting the intracellular transport of Kv11.1 to the plasma membrane. The present study aimed to clarify the functional changes by two novel KCNH2 missense mutations. METHODS: We performed genetic screening of three unrelated symptomatic LQTS probands with family histories of cardiac symptoms. Chinese hamster ovary cells were transfected with wild-type (WT) and/or mutant KCNH2 plasmid and examined by patch-clamp technique. Immunostaining and confocal microscopy were performed to evaluate the intracellular localization of WT and homozygous mutant Kv11.1 in human embryonic kidney cells. For the study of trafficking rescue, we used low-temperature incubation (30°C). We also examined pharmacological rescue of homozygous mutant Kv11.1 current in cells treated with E-4031 or dofetilide. RESULTS: We identified two novel KCNH2 missense mutations, G785D and T826I. Electrophysiological study showed that both mutant channels were nonfunctional in homozygous condition and reduced current densities by half in heterozygous condition compared with WT Kv11.1. Heterozygous Kv11.1-G785D produced a significant positive shift in activation and a significant negative shift in inactivation, whereas heterozygous Kv11.1-T826I caused no kinetic changes. Immunostaining revealed that both were transport-refractory mutations. Incubation at 30°C rescued plasma membrane expression of Kv11.1-T826I but not G785D. We confirmed low-temperature-induced restoration of homozygous Kv11.1-T826I transport by functional current measurements. In contrast, incubation with E-4031 or dofetilide failed to produce measurable currents in both homozygous mutant channels. CONCLUSIONS: Two novel KCNH2 mutations disrupted the intracellular transport of Kv11.1. Low-temperature incubation rescued plasma membrane expression of Kv11.1-T826I but not G785D. Both mutations exerted loss-of-function effects on Kv11.1 and explained the phenotypes of the mutation carriers.

19.
Ann Vasc Surg ; 47: 279.e1-279.e5, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28647628

RESUMO

Aneurysm of the proximal ulnar artery is extremely rare. Ultrasonography, computed tomography, and magnetic resonance imaging generally provide accurate diagnosis of aneurysm. A 29-year-old woman who had undergone an excision biopsy of a mass in her right arm by an orthopedic surgeon was referred to our department. We resected the mass and interposed it with a reversed great saphenous vein. Histopathological examination suggested that the mass was a pseudoaneurysm consisting of organized thrombi with recanalization. Clinicians should be aware of the possibility of misdiagnosis of soft tissue tumor in cases of pseudoaneurysm, especially if imaging examination reveals a density consistent with organized thrombus with recanalization.


Assuntos
Falso Aneurisma/diagnóstico por imagem , Imagem Multimodal/métodos , Neoplasias de Tecidos Moles/diagnóstico por imagem , Artéria Ulnar/diagnóstico por imagem , Adulto , Falso Aneurisma/patologia , Falso Aneurisma/cirurgia , Biópsia , Angiografia por Tomografia Computadorizada , Diagnóstico Diferencial , Feminino , Humanos , Imagem por Ressonância Magnética , Valor Preditivo dos Testes , Veia Safena/transplante , Resultado do Tratamento , Artéria Ulnar/patologia , Artéria Ulnar/cirurgia , Ultrassonografia Doppler em Cores
20.
Mol Genet Genomic Med ; 5(6): 639-651, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-29178656

RESUMO

BACKGROUND: Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is an inherited cardiomyopathy mainly caused by desmosomal gene mutation. More than half of Caucasian probands have desmosomal mutations, which lead to earlier onset of ventricular arrhythmias. Among non-Caucasians, the genetic background of ARVD/C probands and its prognostic impact remain unclear. METHODS AND RESULTS: We genotyped 99 unrelated Japanese ARVD/C probands for plakophilin 2 (PKP2), desmoglein 2 (DSG2), desmoplakin (DSP), and desmocollin 2 (DSC2) between 2005 and 2014. Seventy-five probands who fulfilled "definite" category according to the 2010 Task Force Criteria (TFC) were enrolled and followed up for 6.4 years. Sixty-four percent of probands had desmosomal mutations; DSG2 was predominant (48% of mutations) followed by PKP2 (38%). DSG2 mutations were almost missense, whereas over 90% of PKP2 mutations were truncating mutations. Lethal ventricular arrhythmias (VAs, sustained ventricular tachycardia/fibrillation) occurred in 57% of probands as the first manifestation and 71% at the end of follow-up. Five died during follow-up. Truncating mutation carriers exhibited earlier lethal VAs onset compared to missense mutation carriers or mutation negatives (age at onset 35 ± 12, 49 ± 16, and 50 ± 19 years, respectively, P < 0.05 in each). Cox proportional hazard analysis revealed for the first time that, compared to mutation negatives, truncating mutation carriers had higher risk for lethal VAs, and especially for onset by their 40s, in an age-dependent manner (RR = 4.6, P < 0.01 by their 40s; RR = 2.9, P = 0.01 by their 50s). CONCLUSION: The genetic background of Japanese ARVD/C probands is distinct from that of Caucasian probands, leading to distinct prognosis. The most affected gene mutations in Japanese probands were missense mutations in DSG2 leading to modest outcome, whereas PKP2 truncating mutations were the second most and might be a strong marker for lethal VAs in non-Caucasian Japanese ARVD/C probands.


Assuntos
Displasia Arritmogênica Ventricular Direita/genética , Grupo com Ancestrais do Continente Asiático/genética , Adulto , Displasia Arritmogênica Ventricular Direita/diagnóstico , Displasia Arritmogênica Ventricular Direita/mortalidade , Estudos de Coortes , Desmocolinas/genética , Desmogleína 2/genética , Desmoplaquinas/genética , Feminino , Seguimentos , Mutação da Fase de Leitura , Estudos de Associação Genética , Patrimônio Genético , Genótipo , Heterozigoto , Humanos , Japão , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Razão de Chances , Fenótipo , Placofilinas/genética , Modelos de Riscos Proporcionais
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