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1.
Jpn J Ophthalmol ; 2021 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-33629268

RESUMO

PURPOSE: To investigate the regional differences in the genes and variants causing retinitis pigmentosa (RP) in Japan STUDY DESIGN: Retrospective multicenter study METHODS: In total, 1204 probands of each pedigree clinically diagnosed with nonsyndromic RP were enrolled from 5 Japanese facilities. The regions were divided into the Tohoku region, the Kanto and Chubu regions, and the Kyushu region according to the location of the hospitals where the participants were enrolled. We compared the proportions of the causative genes and the distributions of the pathogenic variants among these 3 regions. RESULTS: The proportions of genetically solved cases were 29.4% in the Tohoku region (n = 500), 29.6% in the Kanto and Chubu regions (n = 196), and 29.7% in the Kyushu region (n = 508), which did not differ statistically (P = .99). No significant regional differences in the proportions of each causative gene in genetically solved patients were observed after correction by multiple testing. Among the 29 pathogenic variants detected in all 3 regions, only p.(Pro347Leu) in RHO was an autosomal dominant variant; the remaining 28 variants were found in autosomal recessive genes. Conversely, 78.6% (275/350) of the pathogenic variants were detected only in a single region, and 6 pathogenic variants (p.[Asn3062fs] in EYS, p.[Ala315fs] in EYS, p.[Arg872fs] in RP1, p.[Ala126Val] in RDH12, p.[Arg41Trp] in CRX, and p.[Gly381fs] in PRPF31) were frequently found in ≥ 4 patients in the single region. CONCLUSION: We observed region-specific pathogenic variants in the Japanese population. Further investigations of causative genes in multiple regions in Japan will contribute to the expansion of the catalog of genetic variants causing RP.

2.
Commun Biol ; 4(1): 140, 2021 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-33514863

RESUMO

The genetic basis of Japanese autosomal recessive retinitis pigmentosa (ARRP) remains largely unknown. Herein, we applied a 2-step genome-wide association study (GWAS) in 640 Japanese patients. Meta-GWAS identified three independent peaks at P < 5.0 × 10-8, all within the major ARRP gene EYS. Two of the three were each in linkage disequilibrium with a different low frequency variant (allele frequency < 0.05); a known founder Mendelian mutation (c.4957dupA, p.S1653Kfs*2) and a non-synonymous variant (c.2528 G > A, p.G843E) of unknown significance. mRNA harboring c.2528 G > A failed to restore rhodopsin mislocalization induced by morpholino-mediated knockdown of eys in zebrafish, consistent with the variant being pathogenic. c.2528 G > A solved an additional 7.0% of Japanese ARRP cases. The third peak was in linkage disequilibrium with a common non-synonymous variant (c.7666 A > T, p.S2556C), possibly representing an unreported disease-susceptibility signal. GWAS successfully unraveled genetic causes of a rare monogenic disorder and identified a high frequency variant potentially linked to development of local genome therapeutics.

3.
CMAJ ; 192(49): E1784, 2020 Dec 07.
Artigo em Francês | MEDLINE | ID: mdl-33288518
4.
Artigo em Inglês | MEDLINE | ID: mdl-33253365

RESUMO

OBJECTIVES: We aimed to identify predictors of postoperative permanent neurological deficits (PNDs) and evaluate the early management of cerebral perfusion in patients undergoing surgical repair of acute type A aortic dissection with cerebral malperfusion. METHODS: Between October 2009 and September 2018, a total of 197 patients with acute type A aortic dissection underwent aortic replacement. Of these, 42 (21.3%) patients had an imaging cerebral malperfusion (ICM). ICM was assessed preoperatively, which also revealed whether dissected supra-aortic branch vessels were occluded or narrowed by a thrombosed false lumen. After September 2017, early reperfusion and extra-anatomic revascularization were performed in cases with ICM. RESULTS: Hospital mortality rates for cases with ICM were 4.8% (2/42). Before September 2017, PND were observed in 6 patients (54.5%) with preoperative neurological symptoms (n = 11), and 7 patients (33.3%) without neurological symptoms (n = 21) in patients with ICM. Occlusion or severe stenosis of supra-aortic branch vessels (odds ratio, 7.66; P < 0.001), regardless of preoperative clinical neurological symptoms, was a risk factor for PND. After September 2017, 7 of 10 patients with ICM underwent early reperfusion and extra-anatomic revascularization. PND did not occur in any of these 7 patients. CONCLUSIONS: Occlusion or severe stenosis of supra-aortic branch vessels is a predictor of PND risk in patients undergoing surgery for acute type A aortic dissection. Early reperfusion and extra-anatomic revascularization may reduce the risk of neurological complications in patients with ICM, with or without neurological symptoms.

5.
CMAJ ; 192(40): E1163, 2020 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-33020123
6.
Am J Hum Genet ; 107(1): 111-123, 2020 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-32533946

RESUMO

Partial or complete loss-of-function variants in SCN5A are the most common genetic cause of the arrhythmia disorder Brugada syndrome (BrS1). However, the pathogenicity of SCN5A variants is often unknown or disputed; 80% of the 1,390 SCN5A missense variants observed in at least one individual to date are variants of uncertain significance (VUSs). The designation of VUS is a barrier to the use of sequence data in clinical care. We selected 83 variants: 10 previously studied control variants, 10 suspected benign variants, and 63 suspected Brugada syndrome-associated variants, selected on the basis of their frequency in the general population and in individuals with Brugada syndrome. We used high-throughput automated patch clamping to study the function of the 83 variants, with the goal of reclassifying variants with functional data. The ten previously studied controls had functional properties concordant with published manual patch clamp data. All 10 suspected benign variants had wild-type-like function. 22 suspected BrS variants had loss of channel function (<10% normalized peak current) and 22 variants had partial loss of function (10%-50% normalized peak current). The previously unstudied variants were initially classified as likely benign (n = 2), likely pathogenic (n = 10), or VUSs (n = 61). After the patch clamp studies, 16 variants were benign/likely benign, 45 were pathogenic/likely pathogenic, and only 12 were still VUSs. Structural modeling identified likely mechanisms for loss of function including altered thermostability and disruptions to alpha helices, disulfide bonds, or the permeation pore. High-throughput patch clamping enabled reclassification of the majority of tested VUSs in SCN5A.


Assuntos
Canal de Sódio Disparado por Voltagem NAV1.5/genética , Arritmias Cardíacas/genética , Síndrome de Brugada/genética , Linhagem Celular , Feminino , Variação Genética , Genótipo , Células HEK293 , Ensaios de Triagem em Larga Escala/métodos , Humanos , Masculino , Fenótipo
7.
Elife ; 92020 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-32352381

RESUMO

Biophysical mechanisms underlying collective cell migration of eukaryotic cells have been studied extensively in recent years. One mechanism that induces cells to correlate their motions is contact inhibition of locomotion, by which cells migrating away from the contact site. Here, we report that tail-following behavior at the contact site, termed contact following locomotion (CFL), can induce a non-trivial collective behavior in migrating cells. We show the emergence of a traveling band showing polar order in a mutant Dictyostelium cell that lacks chemotactic activity. We find that CFL is the cell-cell interaction underlying this phenomenon, enabling a theoretical description of how this traveling band forms. We further show that the polar order phase consists of subpopulations that exhibit characteristic transversal motions with respect to the direction of band propagation. These findings describe a novel mechanism of collective cell migration involving cell-cell interactions capable of inducing traveling band with polar order.

8.
Open Vet J ; 10(1): 11-15, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32426251

RESUMO

Background: Atrial septal defect (ASD) is a rare congenital cardiac disease, and there have been no reports about the treatment of ASD in midget breed dogs. Case Description: A 7-month-old female toy poodle weighing 1.4 kg presented with cardiac enlargement. Echocardiography revealed a secundum-type ASD, right ventricular and atrial enlargement, and pulmonary hypertension. Blood flow through the ASD exhibited left-to-right shunting. The dog underwent ASD closure through a hybrid approach, in conjunction with catheter techniques and thoracotomy. Ten months after treatment, cardiac enlargement and pulmonary hypertension were improved. Conclusion: Even in midget dog breeds, ASD can be corrected through a hybrid approach.

9.
Clin Exp Ophthalmol ; 48(5): 644-657, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32112665

RESUMO

IMPORTANCE: A framework for understanding the phenotypic features of CRX retinopathy was established. BACKGROUND: To perform a phenotype-genotype correlation analysis in two groups of patients with heterozygous mutations in distinct locations of the CRX gene, encoding the cone-rod homeobox. DESIGN: Multicentre retrospective study. PARTICIPANTS: Twenty-one Japanese patients from 14 families with a heterozygous CRX mutation. METHODS: Retrospective data analysis. MAIN OUTCOME MEASURES: Clinical records on CRX mutation, symptoms, best-corrected visual acuity (BCVA), visual field, fundus photography, fundus auto-fluorescence, optical coherence tomography and electroretinograms (ERGs). RESULTS: Six different CRX heterozygous mutations were identified in the subjects. Twelve patients from 9 families shared the p.R41W mutation and 1 patient had the p.R43C mutation, both of which affect the homeobox domain of CRX. These patients often displayed adult-onset retinal dystrophy with macular degeneration. In contrast, five patients with downstream mutations (p.S204fs, p.S213fs, p.G243X and p.L299F) displayed retinal degeneration or macular degeneration with bone-spicule pigmentation. Three asymptomatic carriers with different mutations (p.R41W, p.S213fs and p.G243X) were present in both groups. Nearly all patients and carriers had an electronegative ERG in response to a bright flash under dark adaptation. There was no cross-sectional association between patients' age and BCVA, despite progressive decline in BCVA. CONCLUSIONS AND RELEVANCE: Heterozygous mutations within or downstream of the homeobox domain in CRX relate to the difference associated retinal phenotypes, which was confounded by variable expressivity and electronegative ERGs. CRX mutations should be considered in patients with an electronegative ERG with minimal or no macular changes.

10.
Drug Discov Ther ; 14(1): 14-20, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32147626

RESUMO

We compared the pharmaceutical properties, such as surface tension, drop volume, nozzle inner diameter, and force to push the drug product out of the container (squeeze force), of purified sodium hyaluronate eye drops preparations of one brand-name (Hyalein) and 11 generic drugs used for treatment of keratoconjunctiva epithelial disorders, and examined product selection based on the needs of the patient. The surface tension of Nissin (51.0 dyn/cm) and Nitten (52.3 dyn/cm) was significantly lower than that of Hyalein (62.8 dyn/cm), whereas Nitten PF (69.5 dyn/cm) was significantly higher than Hyalein. The drop volume of Tearbalance (42.4 mg), Nissin (43.7 mg), and Nitten (42.7 mg) was significantly lower than that of Hyalein (50.4 mg). We compared the squeeze force using a wearable touch sensor (Haptic Skill Logger: HapLog®) and digital force gauge (DF). The squeeze force of HapLog® showed values of about 1.7- to 3.5-fold higher than that of DF. Moreover, the squeeze force of Eyecare (34.0 N), Kyorin (35.4 N), and Nitten PF (44.3 N) by HapLog® was significantly higher than that of Hyalein (10.5 N). In contrast, the squeeze force of Kyorin (20.8 N) and Nitten PF (25.0 N) by DF was significantly higher than that of Hyalein (12.2 N). Two questionnaire surveys on the feeling of instillation of eye drops revealed a strong negative correlation between feeling of use and squeeze force.


Assuntos
Avaliação de Medicamentos , Soluções Oftálmicas , Avaliação de Medicamentos/normas , Medicamentos Genéricos/normas , Humanos , Soluções Oftálmicas/normas , Satisfação do Paciente , Dispositivos Eletrônicos Vestíveis
11.
Interact Cardiovasc Thorac Surg ; 30(5): 739-745, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32163575

RESUMO

OBJECTIVES: Although skeletal muscle quantity is linked to surgical outcomes, quality remains unexamined. In this study, we evaluated whether skeletal muscle quality and quantity could predict surgical outcomes in acute type A aortic dissection (ATAAD). METHODS: Skeletal muscle quality and quantity were evaluated using computed tomography (CT) values and the psoas muscle mass index, respectively. From May 2004 to December 2017, 324 ATAAD patients underwent aortic replacement after CT scans and psoas muscle mass index measurements. Patients were grouped into intramuscular fat (IMF; n = 55) and non-IMF (n = 269) deposition groups. RESULTS: The mean ages of the patients were 72.3 ± 9.7 and 66.8 ± 12.1 years (P = 0.002), and hospital mortality rates were 3.6% (2/55) and 7.4% (20/269; P = 0.393) for IMF and non-IMF deposition groups, respectively. IMF deposition was a risk factor for a deterioration in activities of daily living at discharge by multivariable analysis [odds ratio 0.33, 95% confidence interval (CI) 0.16-0.69; P = 0.003]. The mean follow-up was 43.9 ± 36.8 months. The 5-year survival was significantly worse for the IMF deposition group (IMF 73.8% vs non-IMF 88.2%; P = 0.010). The multivariable Cox proportional hazard analysis showed that IMF deposition significantly predicted poor survival (hazard ratio 3.26, 95% CI 1.47-7.24; P = 0.004), unlike psoas muscle mass index and age. CONCLUSIONS: Skeletal muscle quality, defined by IMF deposition, was an independent predictor of overall survival and postoperative activities of daily living dependence risk in patients undergoing surgery for ATAAD. Thus, IMF deposition may be an additional risk factor for estimating late outcomes of ATAAD surgery.


Assuntos
Aneurisma Dissecante/cirurgia , Aneurisma da Aorta Torácica/cirurgia , Músculo Esquelético/diagnóstico por imagem , Tomografia Computadorizada por Raios X/métodos , Procedimentos Cirúrgicos Vasculares/métodos , Atividades Cotidianas , Idoso , Aneurisma Dissecante/diagnóstico , Aneurisma da Aorta Torácica/diagnóstico , Feminino , Mortalidade Hospitalar/tendências , Humanos , Masculino , Período Pós-Operatório , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo
12.
Jpn J Ophthalmol ; 64(4): 346-350, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32193659

RESUMO

PURPOSE: To screen for the 328 bp Alu insertion (c.4052_4053ins328, p.Tyr1352Alafs) in RP1 in a group of retinitis pigmentosa (RP) patients who had been previously identified with a heterozygous deleterious mutation in the gene. STUDY DESIGN: Prospective, clinical and experimental study. METHODS: The Alu insertion in RP1 was screened with an optimized PCR-based method in 26 RP patients with a heterozygous deleterious mutation (nonsense or frameshift) in RP1 that had been identified in a preceding genetic study. The genetic location of the previously identified mutation and its inheritance pattern were assessed. RESULTS: Out of 26 RP patients with a heterozygous deleterious mutation in RP1, 5 (19.2%) were found to carry an additional heterozygous Alu insertion, presumably resulting in a compound heterozygous state. This included 3 patients who had been previously diagnosed as autosomal dominant RP based on genetic findings. They were re-diagnosed as having an autosomal recessive disease following our new findings. In all patients identified with the Alu insertion, the other mutations found in the preceding study were outside the defined region in exon 4 (encoding amino acids 677 to 917) in which truncation mutations have been suggested to exert a dominant negative effect. CONCLUSION: The founder Alu insertion in RP1 is an important cause of autosomal recessive RP in Japanese patients and can be missed in standard targeted resequencing. Screening optimized for this mutation is warranted, particularly in patients with a heterozygous deleterious mutation outside the defined region in exon 4 of RP1.

13.
Circ Arrhythm Electrophysiol ; 13(3): e007471, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32063070

RESUMO

BACKGROUND: Risk stratification in catecholaminergic polymorphic ventricular tachycardia remains ill defined. Heart rate recovery (HRR) immediately after exercise is regulated by autonomic reflexes, particularly vagal tone, and may be associated with symptoms and ventricular arrhythmias in patients with catecholaminergic polymorphic ventricular tachycardia. Our objective was to evaluate whether HRR after maximal exercise on the exercise stress test (EST) is associated with symptoms and ventricular arrhythmias. METHODS: In this retrospective observational study, we included patients ≤65 years of age with an EST without antiarrhythmic drugs who attained at least 80% of their age- and sex-predicted maximal HR. HRR in the recovery phase was calculated as the difference in heart rate (HR) at maximal exercise and at 1 minute in the recovery phase (ΔHRR1'). RESULTS: We included 187 patients (median age, 36 years; 68 [36%] symptomatic before diagnosis). Pre-EST HR and maximal HR were equal among symptomatic and asymptomatic patients. Patients who were symptomatic before diagnosis had a greater ΔHRR1' after maximal exercise (43 [interquartile range, 25-58] versus 25 [interquartile range, 19-34] beats/min; P<0.001). Corrected for age, sex, and relatedness, patients in the upper tertile for ΔHRR1' had an odds ratio of 3.4 (95% CI, 1.6-7.4) of being symptomatic before diagnosis (P<0.001). In addition, ΔHRR1' was higher in patients with complex ventricular arrhythmias at EST off antiarrhythmic drugs (33 [interquartile range, 22-48] versus 27 [interquartile range, 20-36] beats/min; P=0.01). After diagnosis, patients with a ΔHRR1' in the upper tertile of its distribution had significantly more arrhythmic events as compared with patients in the other tertiles (P=0.045). CONCLUSIONS: Catecholaminergic polymorphic ventricular tachycardia patients with a larger HRR following exercise are more likely to be symptomatic and have complex ventricular arrhythmias during the first EST off antiarrhythmic drug.


Assuntos
Exercício Físico/fisiologia , Frequência Cardíaca/fisiologia , Recuperação de Função Fisiológica/fisiologia , Taquicardia Ventricular/fisiopatologia , Adulto , Eletrocardiografia , Teste de Esforço , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Taquicardia Ventricular/diagnóstico , Nervo Vago/fisiopatologia , Adulto Jovem
14.
Circ Genom Precis Med ; 13(1): e002786, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31928070

RESUMO

BACKGROUND: Variants in ion channel genes have classically been studied in low throughput by patch clamping. Deep mutational scanning is a complementary approach that can simultaneously assess function of thousands of variants. METHODS: We have developed and validated a method to perform a deep mutational scan of variants in SCN5A, which encodes the major voltage-gated sodium channel in the heart. We created a library of nearly all possible variants in a 36 base region of SCN5A in the S4 voltage sensor of domain IV and stably integrated the library into HEK293T cells. RESULTS: In preliminary experiments, challenge with 3 drugs (veratridine, brevetoxin, and ouabain) could discriminate wild-type channels from gain- and loss-of-function pathogenic variants. High-throughput sequencing of the pre- and postdrug challenge pools was used to count the prevalence of each variant and identify variants with abnormal function. The deep mutational scan scores identified 40 putative gain-of-function and 33 putative loss-of-function variants. For 8 of 9 variants, patch clamping data were consistent with the scores. CONCLUSIONS: These experiments demonstrate the accuracy of a high-throughput in vitro scan of SCN5A variant function, which can be used to identify deleterious variants in SCN5A and other ion channel genes.

15.
Nat Plants ; 5(7): 731-741, 2019 07.
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.


Assuntos
Proteínas de Arabidopsis/genética , Arabidopsis/genética , Brassicaceae/genética , Flores/genética , Proteínas de Membrana/genética , Sequência de Aminoácidos , Arabidopsis/metabolismo , Proteínas de Arabidopsis/metabolismo , Evolução Biológica , Flores/metabolismo , Hibridização Genética , Proteínas de Membrana/metabolismo , Filogenia , Pólen/genética , Pólen/metabolismo
16.
Ophthalmology ; 126(11): 1557-1566, 2019 11.
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.


Assuntos
Arrestina/genética , Oftalmopatias Hereditárias/diagnóstico , Mutação , Cegueira Noturna/diagnóstico , Retinite Pigmentosa/diagnóstico , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Eletrorretinografia , Oftalmopatias Hereditárias/genética , Oftalmopatias Hereditárias/fisiopatologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Cegueira Noturna/genética , Cegueira Noturna/fisiopatologia , Fenótipo , Retina/fisiopatologia , Retinite Pigmentosa/genética , Retinite Pigmentosa/fisiopatologia , Estudos Retrospectivos , Tomografia de Coerência Óptica , Acuidade Visual/fisiologia , Testes de Campo Visual , Campos Visuais/fisiologia
17.
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.


Assuntos
Diclofenaco/química , Diclofenaco/farmacocinética , Medicamentos Genéricos/química , Medicamentos Genéricos/farmacocinética , Fenômenos Químicos , Humanos , Concentração de Íons de Hidrogênio , Preferência do Paciente , Permeabilidade , Farmacêuticos
18.
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 , Proteínas Associadas aos Microtúbulos , Mutação , Linhagem
19.
J Med Genet ; 56(10): 662-670, 2019 10.
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.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Retinite Pigmentosa/genética , Síndromes de Usher/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Feminino , Frequência do Gene , Variação Genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Mutação , Retinite Pigmentosa/diagnóstico , Análise de Sequência de DNA , Síndromes de Usher/diagnóstico , Adulto Jovem
20.
Heart Rhythm ; 16(11): 1698-1706, 2019 11.
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.

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