RESUMO
Background and Objectives: Faricimab is a vascular endothelial growth factor A and angiopoietin-2 bispecific antibody. It is a novel therapeutic approach distinct from previous anti-vascular endothelial growth factor agents. This study aimed to evaluate the efficacy of switching from aflibercept to faricimab in the treatment of diabetic macular edema (DME) refractory to aflibercept, with a specific focus on the resolution of macular edema. Materials and Methods: The medical records of 29 eyes of 21 patients with DME that were refractory to intravitreal injections of aflibercept (IVAs) and who had completed the clinical follow-up of at least four intravitreal injections of faricimab (IVFs) were reviewed. The central retinal thickness (CRT), best-corrected visual acuity (BCVA), and the mean period (weeks) until the next injection were measured after the second-to-last IVA, first-to-last IVA, last IVA, and first to fourth IVFs following the transition to IVF. Results: The mean time from the first IVF to the assessment of effectiveness was significantly shorter than the time to the last IVA; however, no significant difference was found in the time from the second, third, and fourth IVFs to the assessment. The mean CRTs after the first and second IVFs were not significantly different from the CRT after the last IVA, but the mean CRT after the third and fourth IVFs was significantly thinner than that after the last IVA (p = 0.0025 and p = 0.0076, respectively). The mean BCVAs after the third and fourth IVFs significantly improved compared with that after the last IVA (p = 0.0050 and p = 0.0052, respectively). Conclusions: When switching the treatment to IVF for eyes with IVA-resistant DME, better treatment outcomes are achieved if IVF is performed three or more times.
Assuntos
Retinopatia Diabética , Injeções Intravítreas , Edema Macular , Receptores de Fatores de Crescimento do Endotélio Vascular , Proteínas Recombinantes de Fusão , Humanos , Edema Macular/tratamento farmacológico , Receptores de Fatores de Crescimento do Endotélio Vascular/administração & dosagem , Receptores de Fatores de Crescimento do Endotélio Vascular/uso terapêutico , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/uso terapêutico , Masculino , Feminino , Pessoa de Meia-Idade , Retinopatia Diabética/tratamento farmacológico , Idoso , Resultado do Tratamento , Injeções Intravítreas/métodos , Estudos Retrospectivos , Acuidade Visual/efeitos dos fármacos , Inibidores da Angiogênese/uso terapêutico , Inibidores da Angiogênese/administração & dosagem , Angiopoietina-2 , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidoresRESUMO
The mechanism underlying the development of tumors, particularly at early stages, still remains mostly elusive. Here, we report whole-genome long and short read sequencing analysis of 76 lung cancers, focusing on very early-stage lung adenocarcinomas such as adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma. The obtained data is further integrated with bulk and spatial transcriptomic data and epigenomic data. These analyses reveal key events in lung carcinogenesis. Minimal somatic mutations in pivotal driver mutations and essential proliferative factors are the only detectable somatic mutations in the very early-stage of AIS. These initial events are followed by copy number changes and global DNA hypomethylation. Particularly, drastic changes are initiated at the later AIS stage, i.e., in Noguchi type B tumors, wherein cancer cells are exposed to the surrounding microenvironment. This study sheds light on the pathogenesis of lung adenocarcinoma from integrated pathological and molecular viewpoints.
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Adenocarcinoma in Situ , Adenocarcinoma de Pulmão , Adenocarcinoma , Neoplasias Pulmonares , Humanos , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Neoplasias Pulmonares/patologia , Adenocarcinoma/genética , Adenocarcinoma/patologia , Pulmão/patologia , Adenocarcinoma in Situ/genética , Mutação , Microambiente TumoralRESUMO
Long-read sequencing technologies enable us to precisely identify structural variants (SVs), which would be occasionally associated with various types of diseases, including cancers. In this section, we introduce experimental and computational procedures for conducting long-read whole-genome sequencing (WGS) of cancer genomes from fresh frozen tissues/cells. We also demonstrate the analysis of SVs in cancer genomes using long-read WGS data from lung cancer cell lines by several representative computational tools, such as cuteSV and Sniffles2, as examples.
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Nanoporos , Neoplasias , Genoma , Sequenciamento Completo do Genoma/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Análise de Sequência de DNA/métodos , Neoplasias/genéticaRESUMO
The purpose of this study was to compare the efficacies of one initial intravitreal injection of aflibercept followed by a pro re nata (PRN; 1+PRN) regimen to those of three consecutive monthly injections followed by the PRN (3+PRN) regimen for diabetic macular edema (DME) with practical protocols. The medical records of 95 eyes of 71 cases that were diagnosed with DME and had received intravitreal aflibercept (IVA) injections were reviewed. Fifty-seven eyes had received IVA with the 1+PRN regimen, and 38 eyes had received IVA with the 3+PRN regimen. The best-corrected visual acuity (BCVA) and the central macular thickness (CMT) were measured at the baseline and at 1, 3, 6, and 12 months after the IVA. The mean number of injections of the 1+PRN group was 2.9 ± 1.7, which was significantly fewer than that of the 3+PRN group at 4.6 ± 1.4 (P < 0.001). The change of the mean BCVA before and after the IVA at 12 months of the 3+PRN group was -0.14 ± 0.17 logMAR units which was significantly better than that of the 1+PRN group of -0.045 ± 0.25 logMAR units (P = 0.02). The change of the CMT before and after the IVA at 6 months of the 3+PRN group was -141.3 ± 152.4 µm which was significantly more than that of the 1+PRN group at -86.1 ± 117.8 µm (P = 0.013). Although the mean number of injections was more than that in the 1+PRN regimen, the 3+PRN regimen had better visual outcomes at 12 months. In a practical protocol, we recommend the 3+PRN regimen for patients with DME (IRB#3541).
Assuntos
Inibidores da Angiogênese/administração & dosagem , Retinopatia Diabética/diagnóstico por imagem , Macula Lutea/efeitos dos fármacos , Edema Macular/tratamento farmacológico , Receptores de Fatores de Crescimento do Endotélio Vascular/administração & dosagem , Proteínas Recombinantes de Fusão/administração & dosagem , Idoso , Inibidores da Angiogênese/efeitos adversos , Retinopatia Diabética/diagnóstico , Retinopatia Diabética/fisiopatologia , Esquema de Medicação , Feminino , Humanos , Injeções Intravítreas , Macula Lutea/patologia , Macula Lutea/fisiopatologia , Edema Macular/diagnóstico , Edema Macular/fisiopatologia , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes de Fusão/efeitos adversos , Recuperação de Função Fisiológica , Estudos Retrospectivos , Fatores de Tempo , Resultado do Tratamento , Acuidade Visual/efeitos dos fármacosRESUMO
INTRODUCTION: Diabetic macular edema (DME) threatens daily life activities such as reading and driving and reduces the patients' quality-of-life. Recently, anti-vascular endothelial growth factor (VEGF) agents have become a first-line therapy in DME. However, therapy with anti-VEGF agents has several problems: repeated invasive injections are required; medical costs are high; and a certain proportion of patients with DME are resistant to treatment with anti-VEGF agents. While sodium-glucose co-transporter 2 (SGLT2) inhibitors have been widely used for the treatment of type 2 diabetes mellitus (T2DM), the effects of a combination therapy with anti-VEGF agent and SGLT2 inhibitor on DME are not yet known. METHODS: This study enrolls subjects with T2DM and DME, randomizes them into either a study agent treatment group (treated with ranibizumab as anti-VEGF agent and luseogliflozin as SGLT2 inhibitor) or a control group (treated with ranibizumab and glimepiride), and observes the subjects for 52 weeks after initiation of treatment. Planned outcomes: The primary endpoint is intergroup difference in the number of intravitreal anti-VEGF injections to the study eye from baseline to week 48. Secondary and exploratory endpoints include safety and ophthalmologic and internal medical clinical parameters. REGISTRATION: This study is registered at the University Hospital Medical Information Network Clinical Trial Registry (UMIN000033961) and Japan Registry of Clinical Trials (jRCTs031180210).
RESUMO
PURPOSE: We compared the efficacy of sub-Tenon triamcinolone acetonide (STTA) to intravitreal triamcinolone aceto-nide (IVTA) injections during cataract surgery (CS) for patients with diabetic macular edema (DME). METHODS: The medical records of 33 eyes (26 patients) with DME which had undergone CS with STTA were compared to those of 34 eyes (27 patients) with DME which had undergone CS with IVTA. Central foveal thickness and best-corrected visual acuity (BCVA) were measured at the baseline and 1, 3, and 6 months after the surgery. RESULTS: The BCVAs after STTA and IVTA were significantly improved at 3 and 6 months. Thirteen eyes in the IVTA group and 21 eyes in the STTA group required other therapies (p < 0.05). One case developed intraocular pressure elevation after IVTA and underwent selective la ser trabeculoplasty. CONCLUSIONS: Ophthalmologists should consider the merits and demerits of IVTA and STTA for DME treatment after CS.
Assuntos
Extração de Catarata , Catarata/complicações , Retinopatia Diabética/complicações , Edema Macular/tratamento farmacológico , Triancinolona Acetonida/administração & dosagem , Idoso , Retinopatia Diabética/diagnóstico , Retinopatia Diabética/tratamento farmacológico , Feminino , Seguimentos , Glucocorticoides/administração & dosagem , Humanos , Período Intraoperatório , Injeções Intravítreas , Edema Macular/diagnóstico , Edema Macular/etiologia , Masculino , Estudos Retrospectivos , Cápsula de Tenon , Tomografia de Coerência Óptica , Resultado do TratamentoRESUMO
Data on prasugrel use in Japanese patients are limited to phase II/III clinical trials. This early postmarketing observational study evaluated the safety and efficacy of short-term prasugrel use in patients with acute coronary syndrome (ACS) in real-world clinical settings in Japan. From May 2014 to January 2015, we enrolled consecutive patients with ACS requiring percutaneous coronary intervention in each institution. Each patient started prasugrel treatment ≥1 month before the end of the study period. Safety outcomes included incidence rates of adverse drug reactions (ADRs) and bleeding adverse events (AEs). Efficacy outcomes were incidence rates of cardiovascular events (including major adverse cardiovascular events [MACE]). Case report forms were collected from 749 patients, 732 of whom were eligible for the safety and efficacy analysis sets. Approximately 95% of patients had a prasugrel loading/maintenance dose of 20 mg/3.75 mg/day. The incidences of ADRs and bleeding AEs were 8.6 and 6.4%, respectively. Twelve patients experienced major bleeding AEs; approximately 60% (seven patients) of which were gastrointestinal disorders. The incidence of bleeding AEs was significantly higher primarily in patients of female sex, aged ≥75 years, with low body weight (≤50 kg), severe cardiovascular disease, or severe renal impairment. The incidence of MACE was 1.9% during prasugrel treatment, and 3.1% at the end of the study period. This short-term study indicated that prasugrel treatment at loading/maintenance doses of 20 mg/3.75 mg/day was safe and effective in Japanese ACS patients in an acute setting. CLINICAL TRIAL REGISTRATION: This study is registered at http://www.umin.ac.jp/ctr/ under the identifier UMIN000014699.
Assuntos
Síndrome Coronariana Aguda/tratamento farmacológico , Inibidores da Agregação Plaquetária/administração & dosagem , Cloridrato de Prasugrel/administração & dosagem , Síndrome Coronariana Aguda/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Intervenção Coronária Percutânea , Vigilância de Produtos Comercializados , Recidiva , Prevenção SecundáriaRESUMO
We compared the efficacy of intravitreal aflibercept (IVA) to intravitreal ranibizumab (IVR) injections in eyes with diabetic macular edema (DME). The medical records of 49 eyes of 36 patients who were diagnosed with DME and had received IVR and 46 eyes of 40 patients who had received IVA treatment were reviewed. The central macular thickness (CMT) and best-corrected visual acuity (BCVA) were measured at the baseline and at 1, 3, and 6 months after the IVR or IVA. The mean number of injections of IVR was 2.6 ± 1.1 and of IVA was 2.7 ± 1.4. At 6 months, the CMT was significantly thinner than the baseline after IVR and after IVA. The mean BCVA was significantly better than the baseline after IVR only at 1 and 3 months and after IVA at 1 and 6 months. The BCVA of eyes with serous retinal detachment (SRD) was significantly better at 1 month after the IVR and at 1 month and 6 months after the IVA. The BCVAs improved more significantly in the SRD+ group than in the SRD- group. The effects of IVA persist longer than that of IVR. The effectiveness of both IVR and IVA was not dependent on the presence of SRD (IRB#2107).
Assuntos
Retinopatia Diabética/tratamento farmacológico , Edema Macular/tratamento farmacológico , Ranibizumab/administração & dosagem , Receptores de Fatores de Crescimento do Endotélio Vascular/administração & dosagem , Proteínas Recombinantes de Fusão/administração & dosagem , Idoso , Retinopatia Diabética/patologia , Feminino , Humanos , Injeções Intravítreas , Edema Macular/patologia , Masculino , Pessoa de Meia-Idade , Fatores de TempoRESUMO
In an embryonic developmental stage of the peripheral nervous system (PNS), Schwann cell precursors migrate along neuronal axons to their final destinations. After birth, they eventually wrap around individual axons to form myelin sheaths, which insulate axons to increase the nerve conduction velocity. Some growth factors and adhesion molecules are known to control these developmental stages from in the fish to in the mammal. Neuregulin-1 (NRG1), which is composed of many alternative splicing variants, is such a growth factor. Among these variants, the type III isoform of NRG1, interacting with ErbB2 and ErbB3 receptors on Schwann cells, plays an essential role in myelination in the fish and the mammal. NRG1 type III is also known to promote migration of fish Schwann cell precursors; however, it still remains to be clarified whether mammalian type III isoform does it. We have therefore generated type III isoform-specific knockout mice in inbred strain. The mice result in delayed migration of the precursors from the dorsal to ventral root via a peripheral ganglion, comparing littermate controls. Similar results are observed in an in vitro migration assay using reaggregated Schwann cell precursors. Furthermore, the knockout mice exhibit reduced myelin thickness, consistent with the established role of NRG1 type III in myelination. These results indicate that in mice, NRG1 type III plays a key role not only in myelination but also in migration.
Assuntos
Bainha de Mielina/genética , Neuregulina-1/metabolismo , Receptor ErbB-2/metabolismo , Receptor ErbB-3/metabolismo , Células de Schwann/metabolismo , Medula Espinal/metabolismo , Animais , Diferenciação Celular , Movimento Celular , Expressão Gênica , Camundongos , Camundongos Knockout , Bainha de Mielina/metabolismo , Bainha de Mielina/patologia , Neuregulina-1/genética , Ratos , Ratos Sprague-Dawley , Receptor ErbB-2/genética , Receptor ErbB-3/genética , Células de Schwann/patologia , Transdução de Sinais , Medula Espinal/patologiaRESUMO
In Japanese black cattle, AI severely subfertile males have occasionally been found. In order to solve this problem, we previously asserted the need for exact examinations of acrosomal tyrosine-phosphorylated proteins and acrosome morphology in cryopreserved spermatozoa. In the present study, we further investigated acrosomal tyrosine-phosphorylated proteins in spermatozoa before cryopreservation and examined possible relationships between these phosphoproteins and acrosome stability. Ejaculated, epididymal and cryopreserved spermatozoa were subjected to examinations of general characteristics (motility, shape and acrosome morphology) and indirect immunofluorescence of acrosomal phosphoproteins. Unlike all general characteristic parameters, the distribution of acrosomal tyrosine-phosphorylated proteins in ejaculated and cauda epididymal spermatozoa varied considerably among bulls and was linked to the maintenance of morphologically normal acrosomes in cryopreserved spermatozoa or ejaculated spermatozoa after 270min incubation. Moreover, the distribution of these phosphoproteins was arranged in the spermatozoa of the proximal epididymides. These findings indicate that acrosomal tyrosine-phosphorylated proteins are distributionally arranged during early process of sperm maturation, that their distribution of cauda epididymal and ejaculated spermatozoa are largely different among bulls, and that varied states of acrosomal phosphoproteins may result in individual differences in acrosome stability among bulls.
Assuntos
Bovinos/metabolismo , Fosfoproteínas/metabolismo , Espermatozoides/metabolismo , Acrossomo/metabolismo , Animais , Doenças dos Bovinos/metabolismo , Criopreservação/veterinária , Ejaculação , Inibidores Enzimáticos/farmacologia , Epididimo/citologia , Epididimo/metabolismo , Infertilidade Masculina/metabolismo , Infertilidade Masculina/veterinária , Inseminação Artificial/veterinária , Masculino , Fosfoproteínas/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Fosfatases/antagonistas & inibidores , Preservação do Sêmen/veterinária , Espermatozoides/efeitos dos fármacos , Tirosina/químicaRESUMO
The purpose of this study was to determine the efficacy of one-year treatment of diabetic macular edema (DME) with intravitreal aflibercept (IVA) injections on a practical protocol. The medical records of 51 eyes of 43 patients who were diagnosed with DME and had received IVA treatments were reviewed. The best-corrected visual acuity (BCVA) and the central macular thickness (CMT) were measured at the baseline and at 1, 3, 6, and 12 months after the IVA. The mean number of IVA injections was 3.8 ± 2.4. The mean BCVA was significantly better and the CMT was thinner after the IVA at all follow-up times (P < 0.05). The BCVA was better in eyes with a serous retinal detachment (SRD) than without a SRD (P < 0.01). There was a significant correlation between the photoreceptor outer segment (PROS) length and BCVA at the baseline and at 12 months after the IVA (P < 0.05). A fewer number of IVA injections significantly improved the BCVA and the CMT in eyes with DME after one-year treatment. IVA was more effective in the SRD+ group than in the SRD- group. The PROS length may be a predictive marker for visual outcomes after one-year treatment with IVA for DME (IRB#2272).
Assuntos
Inibidores da Angiogênese/uso terapêutico , Retinopatia Diabética/tratamento farmacológico , Edema Macular/tratamento farmacológico , Receptores de Fatores de Crescimento do Endotélio Vascular/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Idoso , Inibidores da Angiogênese/administração & dosagem , Retinopatia Diabética/patologia , Feminino , Humanos , Injeções Intravítreas , Edema Macular/patologia , Masculino , Pessoa de Meia-Idade , Receptores de Fatores de Crescimento do Endotélio Vascular/administração & dosagem , Proteínas Recombinantes de Fusão/administração & dosagem , Epitélio Pigmentado da Retina/patologia , Estudos Retrospectivos , Acuidade VisualRESUMO
The CD98 heavy chain (CD98hc) regulates virus-induced cell fusion and monocyte fusion, and is involved in amino acid transportation. Here, we examined the role that CD98hc plays in the formation of osteoclasts using CD98hcflox/floxLysM-cre peritoneal macrophages (CD98hc-defect macrophages). Peritoneal macrophages were stimulated with co-cultured with osteoblasts in the presence of 1,25(OH)2 vitamin D3, and thereafter stained with tartrate-resistant acid phosphatase staining solution. The multinucleated osteoclast formation was severely impaired in the peritoneal macrophages isolated from the CD98hc-defect mice compared with those from wild-type mice. CD98hc mediates integrin signaling and amino acid transport through the CD98 light chain (CD98lc). In integrin signaling, suppression of the M-CSF-RANKL-induced phosphorylation of ERK, Akt, JNK and p130Cas were observed at the triggering phase in the CD98h-defect peritoneal macrophages. Moreover, we showed that the general control non-derepressible (GCN) pathway, which was activated by amino acid starvation, was induced by the CD98hc-defect peritoneal macrophages stimulated with RANKL. These results indicate that CD98 plays two important roles in osteoclast formation through integrin signaling and amino acid transport.
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PURPOSE: To compare the effects of sub-Tenon's capsule triamcinolone acetonide (STTA) injection to that of STTA injection combined with microaneurysm photocoagulation (MAPC; STTA + MAPC) on eyes with diabetic macular edema (DME). PATIENTS AND METHODS: The medical records of 138 eyes of 138 patients with DME treated by either STTA or STTA + MAPC were reviewed. The degree of DME was determined by the optical coherence tomographic features: patients with serous retinal detachment (SRD+; 38 eyes) and patients without SRD (non-SRD; 100 eyes). The central macular thickness (CMT) and the best-corrected visual acuity (BCVA) were measured periodically for 6 months after the treatments. RESULTS: The BCVA was significantly improved in the non-SRD group after STTA + MAPC. The CMT was significantly improved in all groups and improved considerably more in the non-SRD group than in the SRD+ group after STTA + MAPC. CONCLUSION: Our findings indicate that MAPC has an additive effect in the non-SRD type.
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The purpose of this study is to identify the risk factors for a recurrence or persistence of diabetic macular oedema (DME) after a sub-Tenon's capsule triamcinolone acetonide (STTA) injection. The medical records of 124 patients (124 eyes) treated by STTA were reviewed. The age, sex, HbA1c level, best-corrected visual acuity, central macular thickness, insulin use, pioglitazone use, systemic hypertension, serous retinal detachment, proteinuria, panretinal photocoagulation, microaneurysm photocoagulation (MAPC), subthreshold micropulse diode laser photocoagulation (SMDLP), cataract surgery, and history of vitrectomy were examined by logistic regression analysis. Procedures of MAPC and SMDLP were significantly associated with DME treated with STTA (P = 0.0315, P = 0.04, resp.). However, a history of vitrectomy was found to have significantly fewer recurrences or persistent DME after STTA (P = 0.0464). In conclusion, patients who required combined MAPC or SMDLP with a STTA injection had significantly higher refractoriness to STTA, but postvitrectomy may prevent the recurrence or persistence of DME after STTA injection.
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The purposes of this study were to examine the relationship between male artificial insemination (AI) fertility and sperm acrosomal conditions assessed by new and conventional staining techniques and to identify possible reproductive dysfunctions causing low conception rates in AI using frozen-thawed spermatozoa with poor acrosomal conditions in Japanese Black bulls. We investigated individual differences among bulls in the results concerning (1) acrosomal conditions of frozen-thawed spermatozoa as assessed by not merely peanut agglutinin-lectin staining (a conventional staining technique) but also immunostaining of acrosomal tyrosine-phosphorylated proteins (a new staining technique), (2) routine AI using frozen-thawed spermatozoa as assessed by pregnancy diagnosis, (3) in vivo fertilization of frozen-thawed spermatozoa and early development of fertilized eggs as assessed by superovulation/AI-embryo collection tests and (4) in vitro fertilization of frozen-thawed spermatozoa with oocytes. The percentages of frozen-thawed spermatozoa with normal acrosomal conditions assessed by the abovementioned staining techniques were significantly correlated with the conception rates of routine AI, rates of transferable embryos in superovulation/AI-embryo collection tests and in vitro fertilization rates. These results are consistent with new suggestions that the distribution of acrosomal tyrosine-phosphorylated proteins as well as the acrosomal morphology of frozen-thawed spermatozoa are AI fertility-associated markers that are valid for the prediction of AI results and that low conception rates in AI using frozen-thawed spermatozoa with poor acrosomal conditions result from reproductive dysfunctions in the processes between sperm insemination into females and early embryo development, probably failed fertilization of frozen-thawed spermatozoa with oocytes.
Assuntos
Acrossomo/fisiologia , Bovinos/fisiologia , Inseminação Artificial/veterinária , Espermatozoides/fisiologia , Acrossomo/química , Animais , Feminino , Fertilidade/fisiologia , Congelamento , Infertilidade/veterinária , Inseminação Artificial/métodos , Lectinas , Masculino , Organofosfatos , Aglutinina de Amendoim , Polímeros , Proteínas/análiseRESUMO
Livestock spermatozoa possess more tenacious suppressors of cAMP-triggered events-including capacitation-associated changes-than laboratory animal spermatozoa, leading to flagellar hyperactivation. In order to identify the suppressors, we examined effects of an inhibitor of serine/threonine protein phosphatases (calyculin A) on cAMP-triggered changes in the protein phosphorylation state, and subsequent occurrence of hyperactivation and acrosome reaction in ejaculated bull spermatozoa. Ejaculated spermatozoa were incubated in cAMP-supplemented medium, then assessed for motility, acrosome morphology, and phosphorylated protein localization. The addition of calyculin A greatly enhanced cAMP-triggered protein phosphorylation at serine/threonine and tyrosine residues in the connecting piece and induction of flagellar hyperactivation. Most hyperactivated spermatozoa exhibited extremely asymmetrical bends at the middle piece, which produced intensive twisting or figure-eight movements. In the sperm head, however, cAMP-triggered dephosphorylation of serine/threonine-phosphorylated proteins and subsequent acrosome reaction were abolished by the addition of calyculin A. Based on these results, we suggest that calyculin A-sensitive protein phosphatases in the connecting piece are suppressors of cAMP-triggered events leading to hyperactivation. By contrast, similar protein phosphatases in the sperm head accelerate cAMP-triggered events leading to the acrosome reaction. These findings are consistent with the indication that calyculin A-sensitive protein phosphatases have distinct functions in the regulation of cAMP-triggered events in different regions of ejaculated bull spermatozoa.
Assuntos
Reação Acrossômica/efeitos dos fármacos , AMP Cíclico/metabolismo , Flagelos/fisiologia , Oxazóis/farmacologia , Fosfoproteínas Fosfatases/metabolismo , Espermatozoides/metabolismo , Animais , Western Blotting , Bovinos , Movimento Celular/efeitos dos fármacos , Eletroforese em Gel de Poliacrilamida , Técnicas de Cultura Embrionária , Flagelos/efeitos dos fármacos , Técnica Indireta de Fluorescência para Anticorpo , Técnicas In Vitro , Masculino , Toxinas Marinhas , Oxazóis/antagonistas & inibidores , Fosforilação/efeitos dos fármacos , Espermatozoides/efeitos dos fármacosRESUMO
The myelin sheath insulates neuronal axons and markedly increases the nerve conduction velocity. In the peripheral nervous system (PNS), Schwann cell precursors migrate along embryonic neuronal axons to their final destinations, where they eventually wrap around individual axons to form the myelin sheath after birth. ErbB2 and ErbB3 tyrosine kinase receptors form a heterodimer and are extensively expressed in Schwann lineage cells. ErbB2/3 is thought to be one of the primary regulators controlling the entire Schwann cell development. ErbB3 is the bona fide Schwann cell receptor for the neuronal ligand neuregulin-1. Although ErbB2/3 is well known to regulate both Schwann cell precursor migration and myelination by Schwann cells in fishes, it still remains unclear whether in mammals, ErbB2/3 actually regulates Schwann cell precursor migration. Here, we show that knockdown of ErbB3 using a Schwann cell-specific promoter in mice causes delayed migration of Schwann cell precursors. In contrast, littermate control mice display normal migration. Similar results are seen in an in vitro migration assay using reaggregated Schwann cell precursors. Also, ErbB3 knockdown in mice reduces myelin thickness in sciatic nerves, consistent with the established role of ErbB3 in myelination. Thus, ErbB3 plays a key role in migration, as well as in myelination, in mouse Schwann lineage cells, presenting a genetically conservative role of ErbB3 in Schwann cell precursor migration.
Assuntos
Movimento Celular/genética , Regulação da Expressão Gênica no Desenvolvimento , Neurogênese/genética , Receptor ErbB-3/genética , Células de Schwann/metabolismo , Animais , Axônios/metabolismo , Axônios/ultraestrutura , Diferenciação Celular , Embrião de Mamíferos , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Bainha de Mielina/metabolismo , Bainha de Mielina/ultraestrutura , Neuregulina-1/genética , Neuregulina-1/metabolismo , Regiões Promotoras Genéticas , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Receptor ErbB-3/antagonistas & inibidores , Receptor ErbB-3/metabolismo , Células de Schwann/ultraestrutura , Nervo Isquiático/crescimento & desenvolvimento , Nervo Isquiático/metabolismo , Nervo Isquiático/ultraestrutura , Transdução de SinaisRESUMO
PURPOSE: To compare the effect of posterior sub-Tenon's capsule triamcinolone acetonide (STTA) injection to that of pars plana vitrectomy (PPV) for diabetic macular edema (DME). PATIENTS AND METHODS: The medical records of 50 patients (52 eyes) with DME were reviewed. Twenty-six eyes underwent STTA (20 mg) and the other 26 eyes underwent vitrectomy combined with cataract surgery. The central macular thickness (CMT), measured by optical coherence tomography, and best-corrected visual acuity (BCVA) were determined before and 1, 3, and 6 months after treatment. RESULTS: The differences in the BCVA and the CMT between the STTA group and the PPV group were not significant before or at any time after the treatment. In both the STTA and PPV groups, there were significant differences between the pre-treatment CMT and BCVA at any time after treatment. CONCLUSION: We recommend STTA injection for the treatment of DME.
RESUMO
PURPOSE: To compare the surgical outcomes during pars plana vitrectomy (PPV) for diffuse diabetic macular edema (DME) with pretreatment to those without pretreatment. METHODS: The medical charts of 43 eyes of 46 patients who underwent PPV for DME were reviewed. The previously treated (Prev. Tx) group included 19 eyes of 20 patients who were pretreated with intravitreal bevacizumab, sub-Tenon injection of triamcinolone acetonide, and/or subthreshold micropulse diode laser photocoagulation before the PPV. The treatment naïve (Tx.Naïve) group included 24 eyes of 26 patients who underwent PPV alone. The central macular thickness (CMT) and best-corrected visual acuity (BCVA) were measured before treatment and 1, 3, and 6 months after. RESULTS: In both groups, BCVA at 3 and 6 months and CMT at 1 month or later were significantly better than preoperative visual acuity. CMT at 1 month or later significantly decreased from the preoperative value (p<0.05). The differences in the BCVA and CMT between the Prev. Tx and Tx.Naïve group were not significant. CONCLUSIONS: PPV either with or without preoperative treatments can significantly improve the BCVA and reduce the CMT in patients with diffuse DME.
Assuntos
Complicações do Diabetes/cirurgia , Macula Lutea/patologia , Edema Macular/terapia , Cuidados Pré-Operatórios , Acuidade Visual , Vitrectomia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/administração & dosagem , Bevacizumab , Complicações do Diabetes/tratamento farmacológico , Complicações do Diabetes/patologia , Complicações do Diabetes/fisiopatologia , Feminino , Humanos , Injeções Intraoculares , Injeções Intravítreas , Lasers Semicondutores/uso terapêutico , Fotocoagulação , Edema Macular/patologia , Edema Macular/fisiopatologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento , Triancinolona Acetonida/administração & dosagemRESUMO
PURPOSE: To evaluate the microstructure of the inner and outer retina and the visual function after macular hole (MH) surgery using brilliant blue G (BBG) or indocyanine green (ICG) to make the internal limiting membrane (ILM) more visible. DESIGN: Comparative, retrospective, interventional case series. PARTICIPANTS: Sixty-three eyes of 63 consecutive cases with MH were studied. Thirty-five eyes of 35 cases were treated with BBG between January and August 2011. Twenty-eight eyes of 28 MH cases were treated with ICG from April 2009 through April 2010. METHODS: Vitrectomy was performed with a 23-gauge system and 0.25 mg/ml BBG or with 0.125% ICG. MAIN OUTCOME MEASURES: The best-corrected visual acuity (BCVA) and the microperimetry-determined retinal sensitivity were measured at baseline and at 3 and 6 months after surgery. The length of the defect of the photoreceptor inner segment/outer segment (IS/OS) junction and external limiting membrane (ELM), the central foveal thickness (CFT), and the thickness of the ganglion cell complex (GCC) were measured in the spectral-domain optical coherence tomographic images. RESULTS: The average BCVA was significantly better in the BBG group than in the ICG group at 3 months (P = 0.021) and 6 months (P = 0.045) after surgery. The mean retinal sensitivity in the BBG group was improved significantly in the central 2° at 3 and 6 months (P = 0.001 and P = 0.030, respectively), but was not significantly improved in the adjacent 10°. The length of IS/OS junction defect was significantly shorter in the BBG group at 3 months (P = 0.048), but was not significantly different at 6 months (P = 0.135). The length of ELM defect and the GCC thickness were not significantly different between the 2 groups at 3 and 6 months. The CFT was significantly thinner in the ICG group than in the BBG group at 3 and 6 months (P = 0.013 and P = 0.001, respectively). CONCLUSIONS: The postoperative BCVA and retinal sensitivity in the central 2° were better in eyes after BBG-assisted vitrectomy. The restoration of IS/OS junction was faster in the BBG group, and the CFT was significantly thinner in eyes after ICG. Brilliant blue G may be a better agent than ICG to make the ILM more visible. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.