RESUMO
Fibroblast growth factor (FGF) is a multifunctional protein that exhibits a wide range of biological effects. Most commonly, it acts as a mitogen, but it also has regulatory, morphological, and endocrine effects. The four receptor subtypes of FGF are activated by more than 20 different FGF ligands. FGF2, one of the FGF ligands, is an essential factor for cell culture in stem cells for regenerative medicine; however, recombinant FGF2 is extremely unstable. Here, we successfully generated homobivalent agonistic single-domain antibodies (variable domain of heavy chain of heavy chain antibodies referred to as VHHs) that bind to domain III and induce activation of the FGF receptor 1 and thus transduce intracellular signaling. This agonistic VHH has similar biological activity (EC50) as the natural FGF2 ligand. Furthermore, we determined that the agonistic VHH could support the proliferation of human-induced pluripotent stem cells (PSCs) and human mesenchymal stem cells, which are PSCs for regenerative medicine. In addition, the agonistic VHH could maintain the ability of mesenchymal stem cells to differentiate into adipocytes or osteocytes, indicating that it could maintain the properties of PSCs. These results suggest that the VHH agonist may function as an FGF2 mimetic in cell preparation of stem cells for regenerative medicine with better cost effectiveness.
Assuntos
Fator 2 de Crescimento de Fibroblastos , Domínios Proteicos , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos , Anticorpos de Domínio Único , Humanos , Adipócitos/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Fator 2 de Crescimento de Fibroblastos/metabolismo , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Ligantes , Mesoderma/citologia , Mesoderma/efeitos dos fármacos , Osteócitos/efeitos dos fármacos , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/agonistas , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/química , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Medicina Regenerativa , Transdução de Sinais/efeitos dos fármacos , Anticorpos de Domínio Único/metabolismo , Anticorpos de Domínio Único/farmacologiaRESUMO
PURPOSE: To investigate the characteristics of patients with over a 12-month remission after 3 monthly intravitreal aflibercept injections followed by a pro re nata regimen for exudative age-related macular degeneration (AMD). METHODS: One hundred forty-four eyes with exudative AMD were included. All patients received 3 monthly intravitreal aflibercept injections as a loading dose, followed by an as-needed regimen for 60 months. Patients were classified into the remission and recurrence groups depending on the presence or absence of a 12-month remission. ARMS2 A69S and CFH I62V were genotyped in all cases. RESULTS: During the study, 82 eyes (56.9%) showed 12 months or more remission at least once. The cumulative incidence rate of a 12-month remission showed a plateau pattern and converged to 60% (y = -166.26x-2.172 + 0.6, R2 = 0.8168). Patients in the remission group were younger than those in the recurrence group (P < 0.001) and had less risk allele frequency of the ARMS2 gene than the recurrence group (P < 0.001). The longer the remission interval was prolonged, the better visual acuity was achieved at the 60-month visit (P < 0.001). CONCLUSION: Fifty-seven percent of patients showed a 12-month remission or more at least once during a 60-month follow-up, suggesting that patients with no reactivation can prolong the treatment interval.
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Receptores de Fatores de Crescimento do Endotélio Vascular , Humanos , Lactente , Incidência , Protocolos Clínicos , Proteínas Recombinantes de FusãoRESUMO
PURPOSE: To compare the clinical and genetic characteristics of simple and complex central serous chorioretinopathy using central serous chorioretinopathy international group criteria. METHODS: Patients with idiopathic central serous chorioretinopathy were included. Depending on the presence or absence of retinal pigment alterations greater than 2-disc areas in either eye, patients were classified into complex or simple types. Demographic factors and clinical findings were compared between groups. CFH variants, including rs800292 and rs1329428, were genotyped using TaqMan technology. RESULTS: A total of 319 consecutive patients were evaluated at the initial presentation. Of them, 53 (16.6%) had the complex type. The complex type was exclusively seen in men (100% vs. 79.0%, P = 2.0 × 10 -4 ) and demonstrated a significantly higher proportion of bilateral involvement (75.5% vs. 17.7%, P = 6.2 × 10 -18 ) and descending tract(s) (83.0% vs. 0%, P = 1.2 × 10 -57 ) than the simple type. Increased choroidal thickness (425 ± 131 vs. 382 ± 110, P = 0.02) and decreased central retinal thickness (274 ± 151 vs. 337 ± 136, P = 2.9 × 10 -4 ) were observed for the complex versus simple type. The risk allele frequencies of both variants were significantly higher in the complex versus simple type (rs800292: 61.3% vs. 48.7%, P = 0.018; rs1329428: 65.1% vs. 54.3%, P = 0.04). CONCLUSION: In this new classification system, the complex type has distinct genetic and clinical characteristics compared with the simple type.
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Coriorretinopatia Serosa Central , Masculino , Humanos , Coriorretinopatia Serosa Central/genética , Retina , Corioide , Genótipo , Polimorfismo de Nucleotídeo Único , Tomografia de Coerência Óptica , Angiofluoresceinografia , Estudos RetrospectivosRESUMO
Astrocytes, a non-neuronal glial cell type in the nervous system, are essential for regulating physiological functions of the central nervous system. In various injuries and diseases of the central nervous system, astrocytes often change their phenotypes into neurotoxic ones that participate in pro-inflammatory responses (hereafter referred to as "immune functions"). Such astrocytic immune functions are not only limited to brain diseases but are also found in ocular neurodegenerative diseases such as glaucoma, a retinal neurodegenerative disease that is the leading cause of blindness worldwide. The eye has two astrocyte-lineage cells: astrocytes and Müller cells. They maintain the physiological environment of the retina and optic nerve, thereby controlling visual function. Dysfunction of astrocyte-lineage cells may be involved in the onset and progression of glaucoma. These cells become reactive in glaucoma patients, and animal studies have suggested that their immune responses may be linked to glaucoma-related events: tissue remodeling, neuronal death, and infiltration of peripheral immune cells. In this review, we discuss the role of the immune functions of astrocyte-lineage cells in the pathogenesis of glaucoma.
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Glaucoma , Doenças Neurodegenerativas , Animais , Astrócitos/metabolismo , Células Ganglionares da Retina/metabolismo , Doenças Neurodegenerativas/metabolismo , Glaucoma/metabolismo , ImunidadeRESUMO
Few studies report drusenoid pigment epithelial detachment (DPED) in Asians. In this multicenter study, we report the clinical and genetic characteristics of 76 patients with DPED, and, for comparison, 861 patients with exudative age-related macular degeneration (AMD) were included. On the initial presentation, the mean best-corrected visual acuity was 0.087 ± 0.17 (logMAR unit), and mean DPED height and width were 210 ± 132 and 1633 ± 1114 µm, respectively. Fifty-one (67%) patients showed macular neovascularization in the contralateral eye. The risk allele frequency of both ARMS2 A69S and CFH I62V was significantly higher in DPED than in typical AMD and polypoidal choroidal vasculopathy (PCV) (ARMS2 A69S risk allele frequency: DPED 77% vs. typical AMD 66% vs. PCV 57%, CFH I62V risk allele frequency: DPED 87% vs. typical AMD 73% vs. PCV 73%), although the risk allele frequency of both genes was similar between the DPED group and retinal angiomatous proliferation (RAP) group (ARMS2 A69S: p = 0.32, CFH I62V, p = 0.11). The prevalence of reticular pseudodrusen (RPD) was highest in RAP (60%), followed by DPED (22%), typical AMD (20%), and PCV (2%). Although the prevalence of RPD differs between DPED and RAP, these entities share a similar genetic background in terms of ARMS2 and CFH genes.
Assuntos
Descolamento Retiniano/genética , Descolamento Retiniano/patologia , Drusas Retinianas/genética , Drusas Retinianas/patologia , Epitélio Pigmentado da Retina/patologia , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Degeneração Macular/genética , Degeneração Macular/patologia , MasculinoRESUMO
Primary open-angle glaucoma (POAG) is the leading cause of irreversible blindness worldwide for which 15 disease-associated loci had been discovered. Among them, only 5 loci have been associated with POAG in Asians. We carried out a genome-wide association study and a replication study that included a total of 7378 POAG cases and 36 385 controls from a Japanese population. After combining the genome-wide association study and the two replication sets, we identified 11 POAG-associated loci, including 4 known (CDKN2B-AS1, ABCA1, SIX6 and AFAP1) and 7 novel loci (FNDC3B, ANKRD55-MAP3K1, LMX1B, LHPP, HMGA2, MEIS2 and LOXL1) at a genome-wide significance level (P < 5.0×10-8), bringing the total number of POAG-susceptibility loci to 22. The 7 novel variants were subsequently evaluated in a multiethnic population comprising non-Japanese East Asians (1008 cases, 591 controls), Europeans (5008 cases, 35 472 controls) and Africans (2341 cases, 2037 controls). The candidate genes located within the new loci were related to ocular development (LMX1B, HMGA2 and MAP3K1) and glaucoma-related phenotypes (FNDC3B, LMX1B and LOXL1). Pathway analysis suggested epidermal growth factor receptor signaling might be involved in POAG pathogenesis. Genetic correlation analysis revealed the relationships between POAG and systemic diseases, including type 2 diabetes and cardiovascular diseases. These results improve our understanding of the genetic factors that affect the risk of developing POAG and provide new insight into the genetic architecture of POAG in Asians.
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Doenças Cardiovasculares/genética , Diabetes Mellitus Tipo 2/genética , Proteínas do Olho/genética , Loci Gênicos , Predisposição Genética para Doença , Glaucoma de Ângulo Aberto/genética , Povo Asiático , População Negra , Doenças Cardiovasculares/complicações , Doenças Cardiovasculares/etnologia , Doenças Cardiovasculares/patologia , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/etnologia , Diabetes Mellitus Tipo 2/patologia , Receptores ErbB/genética , Receptores ErbB/metabolismo , Proteínas do Olho/metabolismo , Feminino , Expressão Gênica , Estudo de Associação Genômica Ampla , Glaucoma de Ângulo Aberto/complicações , Glaucoma de Ângulo Aberto/etnologia , Glaucoma de Ângulo Aberto/patologia , Humanos , Masculino , Mutação , Polimorfismo de Nucleotídeo Único , Transdução de Sinais , População BrancaRESUMO
BACKGROUND: Diabetic macular edema (DME) causes severe vision loss among patients with diabetes mellitus (DM). We aimed to investigate systemic and ocular diseases associated with the development of DME in a Japanese population. METHODS: A total of 3.11 million Japanese subjects who were registered in the database of the Japan Medical Data Center from 2005 to 2014 were analyzed. Subjects with DM were defined as individuals who had been prescribed any therapeutic medications for DM, and associated diseases were analyzed. The periods assessed were one year before the development of DME among patients with DME and one year before the last visit to an ophthalmic clinic among patients without DME. RESULTS: A total of 17,403 patients with DM satisfied the inclusion and exclusion criteria, and 420 patients developed DME. Univariate analysis revealed significant associations between 55 diseases, including 39 systemic and 16 ocular diseases, and DME development. Logistic analysis identified 21 systemic diseases and 10 ocular diseases as significant factors associated with DME development. CONCLUSION: Various types of systemic and ocular diseases are associated with DME development. Subjects with DM who present these risk factors must be carefully monitored to prevent visual impairment.
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Diabetes Mellitus , Retinopatia Diabética , Edema Macular , Diabetes Mellitus/epidemiologia , Retinopatia Diabética/complicações , Retinopatia Diabética/epidemiologia , Humanos , Japão/epidemiologia , Edema Macular/epidemiologia , Edema Macular/etiologia , Transtornos da Visão , Acuidade VisualRESUMO
BACKGROUND: Poor persistence with glaucoma therapy can lead to disease progression and subsequent blindness. Persistence with second-line glaucoma combination treatment in a Japanese real-world setting and whether it differed from fixed and unfixed combination drugs was investigated. METHODS: This was a retrospective, non-interventional, cohort study using data from a Japanese medical claims database. Patients with glaucoma aged ≥20 years with a first drug claim for glaucoma treatment between 01 July 2005 and 30 October 2014 and with data for > 6 months before and after this first prescription were included. The primary endpoint was duration of drug persistence among glaucoma patients with and without the use of fixed combination drugs in the year following initiation of second-line combination treatment. RESULTS: Of 1403 patients included in the analysis, 364 (25.94%) received fixed combination drugs and 1039 (74.06%) received unfixed combination drugs as second-line treatment. Baseline characteristics were generally comparable between the groups. A total of 39.01% of patients on fixed combination drugs, compared with 41.67% of patients on unfixed combination drugs, persisted on their glaucoma drugs 12 months post second-index date. Median persistence durations for the fixed combination drugs and unfixed combination drugs groups were 6 (95% confidence interval [CI]: 5-8) and 7 months (95% CI 6-9), respectively. Patients who received prostaglandin analogs (PGAs) were the most persistent with their treatment (n = 99, 12.84%). Patients diagnosed with primary open-angle glaucoma were less likely to experience treatment modification (hazard ratio [HR]: 0.800, 95% CI 0.649-0.986, P = 0.036), while those diagnosed with secondary glaucoma were more likely to experience treatment modification (HR: 1.678, 95% CI 1.231-2.288, P = 0.001) compared with glaucoma suspects. CONCLUSIONS: In this retrospective claims database study, the persistence rate of second-line glaucoma combination treatment was low, with no difference in persistence between glaucoma patients receiving unfixed combination drugs compared with fixed combination drugs. Patients on PGA showed greater persistence rates compared with other treatments.
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Anti-Hipertensivos/uso terapêutico , Glaucoma de Ângulo Aberto/tratamento farmacológico , Pressão Intraocular/efeitos dos fármacos , Adulto , Idoso , Inibidores da Anidrase Carbônica/uso terapêutico , Bases de Dados Factuais , Combinação de Medicamentos , Feminino , Glaucoma de Ângulo Aberto/fisiopatologia , Humanos , Reembolso de Seguro de Saúde , Japão , Masculino , Adesão à Medicação , Pessoa de Meia-Idade , Hipertensão Ocular/tratamento farmacológico , Prostaglandinas Sintéticas/uso terapêutico , Estudos Retrospectivos , Timolol/uso terapêutico , Cobertura Universal do Seguro de SaúdeRESUMO
PURPOSE: To investigate the epidemiological status of diabetes mellitus (DM)-related complications in Japan. METHODS: The subjects were 3.11 million Japanese individuals who were registered in the Japanese claim database between 2005 and 2014. Subjects with a diagnosis associated with codes related to DM and/or DM-related complications as classified by the International Classification of Diseases version 10 and those who were prescribed any therapeutic agents for DM were considered to have DM. The status of ocular, renal, and neural complications was investigated. RESULTS: A total of 66,923 patients with DM were included. The prevalence of subjects with DM was 3.8% in 2005 and 4.2% in 2014. The most frequent complication was diabetic retinopathy (23.6%, 95% CI: 21.7-25.5%), followed by diabetic nephropathy (14.8%, 95% CI: 14.0-15.6%) and diabetic neuropathy (4.9%, 95% CI: 4.5-5.3%). Among the subjects with ocular complications, 1.8% had proliferative diabetic retinopathy, 1.1% had diabetic macular edema (DME), 0.3% had neovascular glaucoma, and 1.5% had vitreous hemorrhage. Only DME significantly increased during the study period. The frequencies of the ocular and neural complications significantly decreased, while that of renal complications significantly increased during the study period. CONCLUSIONS: Ocular complications were the most common DM-related major complications in Japan. Notably, DME significantly increased in recent years.
Assuntos
Complicações do Diabetes , Diabetes Mellitus Tipo 2 , Retinopatia Diabética , Edema Macular , Olho , Humanos , JapãoRESUMO
PURPOSE: To investigate whether plasma high sensitivity C-reactive protein (hs-CRP) level is associated with exudative age-related macular degeneration (AMD) as well as variants of ARMS2 A69S and CFH I62V in patients with exudative AMD. METHODS: A case-control study was done comparing CRP among patients with exudative AMD including those with polypoidal choroidal vasculopathy, typical AMD and retinal angiomatous proliferation, and CRP were also compared between cases and controls. Plasma CRP was measured from peripheral blood using latex nepherometry for all participants. Genotyping of ARMS2 A69S and CFH I62V was performed for all patients with exudative AMD using TaqMan technology. RESULTS: Among 125 patients with exudative AMD, including 31 with typical neovascular AMD, 73 with PCV and 21 with RAP lesions and 150 controls, CRP levels were higher in exudative AMD than in controls. (P = 2.7 × 10-5) There was not a significant difference in hs-CRP levels among AMD subtypes. Neither variants of ARMS2 nor CFH was associated with hs-CRP level in patients with exudative AMD. A multiple regression analysis revealed that gender male, presence of exudative AMD and presence of cardiovascular diseases were associated with increased plasma hs-CRP. CONCLUSIONS: Plasma hs-CRP was elevated independent of variants of ARMS2 A69S and CFH I62V in patients with exudative AMD.
Assuntos
Inibidores da Angiogênese , Proteína C-Reativa , Estudos de Casos e Controles , Fator H do Complemento , Humanos , Degeneração Macular , Masculino , Proteínas , Fator A de Crescimento do Endotélio Vascular , Acuidade VisualRESUMO
BACKGROUND: Primary frozen shoulder has unknown etiology and significant restriction of active and passive motion. The distinction between frozen shoulder and stiff shoulder has been unclear. Therefore, the purposes of this study were to perform a survey regarding definition and classification of frozen shoulder proposed by the American Academy of Orthopedic Surgeons (AAOS) among the members of the Japan Shoulder Society (JSS) and to compare the results with those obtained among the members of the American Shoulder and Elbow Surgeons (ASES). METHODS: The Scientific Research Project Committee of the JSS prepared the questionnaire for frozen shoulder and stiff shoulder. Surveys were sent by e-mail on Jan 14, 2016 to JSS registered members and the response dead-line was set on March 13, 2016. RESULTS: The number of respondents was 230, including all directors, councilors, and senior doctors. Agreement with the definition of primary frozen shoulder was 67%, the classification of primary or secondary frozen shoulder was 53%, and the 3 divisions of secondary frozen shoulder was 53%. Diagnostic terms for the cases of shoulder stiffness with unknown etiology were as follows: frozen shoulder (31%), stiff shoulder (22%), periarthritis scapulohumeralis (16%), so called "Gojukata" in Japan, which means shoulder problems in their fifties (16%), idiopathic frozen shoulder (6%), primary frozen shoulder (4%), adhesive capsulitis (3%), others (2%). CONCLUSION: The survey shows lower rates of agreement among the JSS members than the ASES members for the definition of primary frozen shoulder, the classification of primary and secondary frozen shoulder, and the divisions of secondary frozen shoulder. To avoid confusion between stiff shoulder and frozen shoulder, the committee agrees to the ISAKOS recommendation that the term "frozen shoulder" should be used exclusively for primary idiopathic stiff shoulder.
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Bursite/diagnóstico , Adulto , Idoso , Bursite/classificação , Bursite/fisiopatologia , Feminino , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Amplitude de Movimento Articular , Inquéritos e Questionários , Terminologia como Assunto , Estados Unidos , Adulto JovemRESUMO
INTRODUCTION: Few reports have investigated the status of adherence in Japan on a large scale. We aimed to investigate the status of adherence to topical glaucoma treatment and its associated factors. METHODS: A nationwide survey was conducted as a prospective fashion. Participants in this survey were subjects with primary open-angle glaucoma, normal-tension glaucoma, or ocular hypertension or pseudoexfoliation glaucoma who had been prescribed anti-glaucoma ophthalmic eyedrops and whose ophthalmologist considered prescribing any fixed combination of ocular hypotensive eyedrops for the first time between 2011 and 2012. Subjects and their attending ophthalmologists independently completed a questionnaire by utilizing a fixed combination of ocular hypotensive eyedrops. RESULTS: A total of 1358 ophthalmologists from 1071 medical institutions participated in this survey. We registered 4430 subjects (2049 males and 2381 females). In total, data from 3853 subjects (87.6%) were analyzed after inclusion of subjects based on inclusion and exclusion criteria. Good adherence was defined as not forgetting instillation during the past week. Rates of good adherence reported by subjects and ophthalmologists were 72.4 and 78.5%, respectively (P < 0.0001). The consistency of adherence evaluation between subjects and ophthalmologists was moderate [kappa score 0.5025 (95% confidence interval 0.4740-0.5309)]. Significant factors associated with adherence were size of clinic, age, gender, number of types of ocular hypotensive eyedrops, ease of instillation, preferred number of eyedrops, preferred frequency of instillation of eyedrops, and knowledge of glaucoma. CONCLUSION: Adherence to ocular hypotensive eyedrops among Japanese subjects was relatively good. Concordance of adherence between subjects' reports and ophthalmologists' responses was moderate. Size of clinic, number of types of ocular hypotensive eyedrops, ease of instillation, preferred number of eyedrops, preferred frequency of instillation of eyedrops, and knowledge of glaucoma were associated with adherence among Japanese glaucoma subjects.
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Anti-Hipertensivos/administração & dosagem , Glaucoma/tratamento farmacológico , Pressão Intraocular/efeitos dos fármacos , Adesão à Medicação/estatística & dados numéricos , Hipertensão Ocular/tratamento farmacológico , Vigilância da População/métodos , Idoso , Feminino , Glaucoma/epidemiologia , Glaucoma/fisiopatologia , Humanos , Incidência , Japão/epidemiologia , Masculino , Hipertensão Ocular/epidemiologia , Hipertensão Ocular/fisiopatologia , Soluções Oftálmicas , Estudos Prospectivos , Tonometria OcularRESUMO
Excitotoxicity is well known in the neuronal death in the brain and is also linked to neuronal damages in the retina. Recent accumulating evidence show that microglia greatly affect excitotoxicity in the brain, but their roles in retina have received only limited attention. Here, we report that retinal excitotoxicity is mediated by microglia. To this end, we employed three discrete methods, that is, pharmacological inhibition of microglia by minocycline, pharmacological ablation by an antagonist for colony stimulating factor 1 receptor (PLX5622), and genetic ablation of microglia using Iba1-tTA::DTAtetO/tetO mice. Intravitreal injection of NMDA increased the number of apoptotic retinal ganglion cells (RGCs) followed by reduction in the number of RGCs. Although microglia did not respond to NMDA directly, they became reactive earlier than RGC damages. Inhibition or ablation of microglia protected RGCs against NMDA. We found up-regulation of proinflammatory cytokine genes including Il1b, Il6 and Tnfa, among which Tnfa was selectively blocked by minocycline. PLX5622 also suppressed Tnfa expression. Tumor necrosis factor α (TNFα) signals were restricted in microglia at very early followed by spreading into other cell types. TNFα up-regulation in microglia and other cells were significantly attenuated by minocycline and PLX5622, suggesting a central role of microglia for TNFα induction. Both inhibition of TNFα and knockdown of TNF receptor type 1 by siRNA protected RGCs against NMDA. Taken together, our data demonstrate that a phenotypic change of microglia into a neurotoxic one is a critical event for the NMDA-induced degeneration of RGCs, suggesting an importance of non-cell-autonomous mechanism in the retinal neuronal excitotoxicity.
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Morte Celular/fisiologia , Citocinas/metabolismo , Microglia/fisiologia , Células Ganglionares da Retina/fisiologia , Aminopiridinas/farmacologia , Animais , Animais Recém-Nascidos , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação ao Cálcio/metabolismo , Morte Celular/efeitos dos fármacos , Células Cultivadas , Citocinas/genética , Agonistas de Aminoácidos Excitatórios/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas dos Microfilamentos/genética , Proteínas dos Microfilamentos/metabolismo , Microglia/efeitos dos fármacos , Microglia/ultraestrutura , N-Metilaspartato/farmacologia , Degeneração Neural/induzido quimicamente , Traumatismos do Nervo Óptico/induzido quimicamente , Compostos Orgânicos/farmacologia , Pirróis/farmacologia , Células Ganglionares da Retina/efeitos dos fármacos , Células Ganglionares da Retina/ultraestrutura , Transdução de Sinais/efeitos dos fármacos , Fator de Transcrição Brn-3A/genética , Fator de Transcrição Brn-3A/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Müller cells, the primary macroglia of the retina, support various functions of retinal ganglion cells (RGCs). Here, we demonstrate a nucleotide-mediated communication between these two types of cells, by which Müller cells control neurite outgrowth of RGCs by activation of P2 receptors such as P2Y6 . Cultured mouse RGCs had significantly enhanced neurite outgrowth when cultured with either cultured mouse Müller cells or conditioned medium derived from Müller cells, and this was completely inhibited by the nucleotide-degrading enzyme, apyrase. This increase in outgrowth was mimicked by exogenously applied nucleotides such as ATP, uridine triphosphate, and uridine diphosphate. Pharmacological and genetic analysis revealed that P2Y6 receptor in RGCs was responsible for the increased neurite outgrowth. P2Y6 receptor was expressed in the ganglion cell layer of the retina and in RGC primary cultures. High performance liquid chromatography has revealed that Müller cells constitutively release uridine triphosphate, which is immediately metabolized into uridine diphosphate, an endogenous agonist for P2Y6 receptor. In the in vitro ocular hypertension model (i.e., glaucoma model), neurite outgrowth in RGCs was significantly reduced, which was associated with a decrease in P2Y6 receptors. Taken together, Müller cells control neurite outgrowth of RGCs by activating P2 receptors such as P2Y6 receptor, and the receptor expression level might be down-regulated in glaucoma. Müller cells support various functions of retina including those of retinal ganglion cells (RGCs). Here, we report an importance of nucleotide-mediated communication between these two types of cells. Müller cells were found to release uridine diphosphate (UTD), uridine triphosphate (UTP), and activate P2Y6 receptors in RGCs, which was essential for neurite outgrowth of RGCs. In addition, P2Y6 receptors in RGCs were reduced in a glaucoma model in vitro, suggesting an involvement of their dysfunction in the pathogenesis of glaucoma.
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PURPOSE: To investigate changes in the proportion of patients with age-related macular degeneration (AMD) visiting hospitals and to investigate factors associated with AMD, treatments, and medical expenses, as well as the outlook for AMD in Japan using a large health insurance database. DESIGN: Analysis of national insurance claims data. PARTICIPANTS: People 40 years of age or older who were registered in the Japan Medical Data Center database. METHODS: Patients with AMD were identified from 2005 through 2013 based on International Classification of Diseases, 10th revision, diagnosis codes. Changes in patient proportions, treatment procedures, and medical expenses were investigated during the study period. The data for each year were compared after adjustment based on the 2010 Japanese population annual census. The outlook for patients with AMD was predicted based on the combination of data in 2013 and an official future population prediction report. MAIN OUTCOME MEASURES: Changes in treatment patterns and health care costs in Japan. RESULTS: A total of 3â401â299 participants were included in the analysis, and 3058 AMD patients were identified over the 9-year period. The proportion of patients with AMD increased significantly from 0.084% (95% confidence interval, 0.050%-0.119%) in 2005 to 0.26% (95% confidence interval, 0.24%-0.29%) in 2013 (P = 0.0001, Pearson correlation coefficient test). There were significantly more men than women (odds ratio, 1.25; 95% confidence interval, 1.14-1.37), and the proportion of patients with AMD increased rapidly with age. Photodynamic therapy was replaced by anti-vascular endothelial growth factor (VEGF) therapy as the predominant therapy from 2009 onward. Medical expenses per 10â000 persons increased from $1530 to $137â000 over the 9-year period. The proportion of AMD patients is predicted to increase in the future and will reach a maximum of 223â000 in 2035. CONCLUSIONS: The proportion of AMD patients visiting hospitals, medical expenses, and the frequency of anti-VEGF therapy increased significantly over the 9-year period. These increasing trends are predicted to continue in Japan.
Assuntos
Custos de Cuidados de Saúde/tendências , Degeneração Macular/economia , Degeneração Macular/terapia , Programas Nacionais de Saúde/estatística & dados numéricos , Padrões de Prática Médica/tendências , Adulto , Idoso , Idoso de 80 Anos ou mais , Inibidores da Angiogênese/administração & dosagem , Bases de Dados Factuais , Feminino , Custos de Cuidados de Saúde/estatística & dados numéricos , Pesquisa sobre Serviços de Saúde , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Fotoquimioterapia/tendências , Padrões de Prática Médica/estatística & dados numéricos , Sistema de Registros , Distribuição por SexoRESUMO
PURPOSE: The influence of residual malalignment on biomechanical analysis after total knee arthroplasty (TKA) is currently uncertain. The hypothesis is that postoperative alignment would influence the in vivo kinematics after TKA, under weight-bearing conditions but not under non-weight-bearing condition. The purpose of the present study was to compare weight-bearing and non-weight-bearing conditions and to evaluate the effect of the postoperative alignment on the in vivo kinematics after posterior cruciate ligament-retaining TKA during midflexion using 2-dimensional/3-dimensional registration. METHODS: Thirty knees of 30 patients with pre-operative varus deformity were divided into 2 groups according to their postoperative alignment: the normal alignment group (N = 21) and the varus alignment group (N = 9). RESULTS: Under weight-bearing conditions, the varus alignment group showed a significant posterior displacement of the medial femoral condyle (flexion: 80°, 90° P < 0.05) and a significant anterior displacement of the lateral femoral condyle (flexion: 10° P < 0.01, 20° P < 0.05, and extension: 10°, 20° P < 0.01, 30°, 40° P < 0.05) as compared with the normal alignment group. In contrast, no significant difference in the medial and lateral femoral condyle positions under non-weight-bearing conditions was observed between the normal and varus alignment groups. CONCLUSION: The postoperative alignment influenced knee kinematics under weight-bearing conditions. The weight load influenced knee kinematics through posterior tibial slope and induced greater lateral femoral condyle mobility, which might explain the better clinical and functional outcome. These findings contribute to gaining a proper understanding of the in vivo kinematics of the postoperative varus alignment and might be useful for orthopaedic surgeons in the achievement of patient satisfaction. LEVEL OF EVIDENCE: III.
Assuntos
Artroplastia do Joelho , Articulação do Joelho/fisiopatologia , Suporte de Carga/fisiologia , Idoso , Fenômenos Biomecânicos/fisiologia , Feminino , Humanos , Articulação do Joelho/diagnóstico por imagem , Articulação do Joelho/cirurgia , Masculino , RadiografiaRESUMO
BACKGROUND: Glaucoma is one of the leading causes of blindness. Reduction of intraocular pressure is the only proven way to prevent progression of glaucomatous optic neuropathy. The majority of glaucoma patients need to use antiglaucoma ophthalmic solutions over the course of their life. Thus, good adherence and persistency of glaucoma treatment are important factors for better glaucoma care. OBJECTIVE: The purpose of this study was to investigate the impact of an Internet-based glaucoma care support system on glaucoma medication use. METHODS: Patients were randomly divided into two groups. The non-Internet access (NIA) group consisted of patients who had access to the Internet-based glaucoma care support system during the 4-year period only when they were examined by ophthalmologists. The Internet access (IA) group consisted of patients who had the same Internet-based glaucoma care support system access as the NIA group for the first 2 years following enrollment but who were also given free access to the glaucoma care support system for the remaining 2 years. Changes in glaucoma medication use were investigated. RESULTS: In total, 81 patients in the IA group and 90 patients in the NIA group satisfied the study protocol. The number of antiglaucoma ophthalmic solutions used during the study period significantly increased in the NIA group (P<.03) but not in the IA group. The percentages of patients with unchanged, increased, and decreased antiglaucoma ophthalmic solution use during the study period were 61.1% (55/90), 17.8% (16/90), and 3.3% (3/90), respectively, in the NIA group, and 56.8% (46/81), 8.6% (7/81), and 13.6% (11/81), respectively, in the IA group (P<.001). Internet access significantly shifted from an increasing intraocular pressure trend to a decreasing trend in the IA group (P=.002) among the patients who did not have any medication changes. CONCLUSIONS: Allowing patients to browse their medical data may reduce the use and improve the effectiveness of glaucoma medication. TRIAL REGISTRATION: UMIN-CTR Clinical Trial Number: UMIN000006982; https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function=brows&action=brows&type=summary&recptno=R000008238&language=E (Archived by WebCite at http://www.webcitation.org/6MRPQeEAv).
Assuntos
Acesso à Informação , Glaucoma/tratamento farmacológico , Internet , Humanos , Soluções Oftálmicas , Estudos Prospectivos , Método Simples-CegoRESUMO
We report the familial occurrence of a severe phenotype of central serous chorioretinopathy (CSC). A 62-year-old man was referred to our institute to treat a macular lesion in his right eye. Best-corrected visual acuity (BCVA) in his right eye was 0.05 (decimal format). On the initial visit, swept-source optical coherence tomography (SS-OCT) demonstrated subretinal hyperreflective material (SHRM) and subretinal fluid involving the central macula in the right eye and a descending tract on fundus autofluorescence (FAF) in the left eye, and fluorescein angiography revealed focal leakage corresponding to choroidal vascular hyperpermeability (CVH) on indocyanine green angiography (ICGA) of the right eye. He received photodynamic therapy (PDT) for the right eye and exudation disappeared. His 66-year-old elder brother had a medical history of CSC in both eyes and had received treatment at our hospital at 61 years old. On the initial presentation, ICGA showed multiple CVH in both eyes, and FAF showed hypofluorescence corresponding to retinal pigment epithelium (RPE) tears and RPE atrophy in both eyes. Bullous retinal detachment (RD) developed inferiorly in both eyes, and a vitrectomy was performed for the right eye to repair RD. The baseline BCVA was 0.3 in both eyes. Two years after the initial visit, recurrent serous RD developed in his left eye, and multiple PDT sessions were performed during the six-year follow-up. A severe phenotype of CSC may be associated with a genetic background.
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PURPOSE: To compare the genetic and clinical characteristics of central serous chorioretinopathy (CSC) in patients with and without steroid use. METHODS: A total of 407 consecutive patients with CSC were included. Demographic data and clinical factors, including subfoveal choroidal thickness, bilateral involvement, descending tracts, pachydrusen, fibrin, and dome-shaped pigment epithelial detachment, were obtained. Variants of complement factor H (CFH) I62V (rs800292) and rs1329428 were genotyped in all cases using TaqMan technology. RESULTS: Of the total patients, 48 (11.8%) were steroid users. The majority of males were non-steroid users (82.5%) than steroid users (58.3%) (p = 9.8 × 10-5). Demographic data and the prevalence of clinical factors were comparable between the two groups (all p-values > 0.10). Risk allele frequencies of CFH rs800292 and rs1329428 were also comparable between the two groups (p = 0.76, rs800292: steroid users = 52.1% vs. non-steroid users = 50.4%; p = 0.62, rs1329428: steroid users = 47.9% vs. non-steroid users = 45.3%). CONCLUSIONS: Except for the male/female ratio, there were no significant differences in the clinical presentation or genetic characteristics, including variants of the CFH gene, between the two groups.
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PURPOSE: We compared 12-month outcomes of eyes with polypoidal choroidal vasculopathy (PCV) with or without complete regression of polyps observed one month after three monthly intravitreal administrations (loading phase) of aflibercept (2.0 mg/0.05 mL) or brolucizumab (6.0 mg/0.05 mL). METHODS: All patients underwent indocyanine green angiography at both baseline and 3 months after initial injection and were followed up monthly with an as-needed regimen for up to 12 months. A total of 62 patients with PCV were included: 30 eyes were treated with brolucizumab, and 32 were treated with aflibercept. Eyes with complete regression of polyps (regression group) had significantly smaller maximum polyp diameter and were more frequently treated with brolucizumab than those without complete regression (non-regression) group. RESULTS: Best corrected visual acuity was comparable between the two groups at 12 months. Although the 12-month retreatment-free proportion was comparable between the two groups (33.0% versus 27.0%, p = 0.59), a retreatment-free period was significantly longer in the regression group than in the non-regression group (8.3 ± 3.3 versus 6.5 ± 3.6 months, p = 0.022), and the number of additional injections was significantly fewer in the regression group than in the non-regression group (1.2 ± 1.2 versus 3.0 ± 2.6, p = 0.007). CONCLUSIONS: Complete regression of polyps observed after the initial phase possibly prolongs the retreatment-free period and reduces the number of additional injections irrespective of aflibercept or brolucizumab.