RESUMO
BACKGROUND: Pathological angiogenesis causes significant vision loss in neovascular age-related macular degeneration and other retinopathies with neovascularization (NV). Neuronal/glial-vascular interactions influence the release of angiogenic and neurotrophic factors. We hypothesized that botulinum neurotoxin serotype A (BoNT/A) modulates pathological endothelial cell proliferation through glial cell activation and growth factor release. METHODS: A laser-induced choroidal NV (CNV) was employed to investigate the anti-angiogenic effects of BoNT/A. Fundus fluorescence angiography, immunohistochemistry, and real-time PCR were used to assess BoNT/A efficacy in inhibiting CNV and the molecular mechanisms underlying this inhibition. Neuronal and glial suppressor of cytokine signaling 3 (SOCS3) deficient mice were used to investigate the molecular mechanisms of BoNT/A in inhibiting CNV via SOCS3. FINDINGS: In laser-induced CNV mice with intravitreal BoNT/A treatment, CNV lesions decreased > 30%; vascular leakage and retinal glial activation were suppressed; and Socs3 mRNA expression was induced while vascular endothelial growth factor A (Vegfa) mRNA expression was suppressed. The protective effects of BoNT/A on CNV development were diminished in mice lacking neuronal/glial SOCS3. CONCLUSION: BoNT/A suppressed laser-induced CNV and glial cell activation, in part through SOCS3 induction in neuronal/glial cells. BoNT/A treatment led to a decrease of pro-angiogenic factors, including VEGFA, highlighting the potential of BoNT/A as a therapeutic intervention for pathological angiogenesis in retinopathies.
RESUMO
Congenital fibrosis of the extraocular muscles (CFEOM) type 1 is associated with heterozygous missense variants in KIF21A, which encodes a kinesin-like motor protein. Individuals with CFEOM1 have severe paralysis of upgaze and ptosis, resulting in a pronounced chin-up head posture. There can also be limitations of horizontal eye movements. Loss of function of KIF26A, an unconventional kinesin motor protein that lacks ATP-dependent motor activity, has been recently reported to cause a spectrum of congenital brain malformations associated with defects in migration, localization, and growth of excitatory neurons. It has also been associated with megacolon resembling Hirschsprung's disease. We report the case of a boy with homozygous loss of function of KIF26A with restricted eye movements, specifically restricted upgaze and downgaze with variable nystagmus and dissociated vertical eye movements. This case represents a congenital cranial dysinnervation disorder, most similar to CFEOM, and is the first report of a congenital cranial dysinnervation disorder caused by a kinesin other than KIF21A.
Assuntos
Homozigoto , Cinesinas , Humanos , Masculino , Cinesinas/genética , Movimentos Oculares/fisiologia , Transtornos da Motilidade Ocular/genética , Transtornos da Motilidade Ocular/diagnóstico , Transtornos da Motilidade Ocular/fisiopatologia , Músculos Oculomotores/anormalidades , Músculos Oculomotores/fisiopatologia , Músculos Oculomotores/inervação , Transtornos Congênitos de Denervação Craniana , OftalmoplegiaRESUMO
Pathological retinal angiogenesis profoundly impacts visual function in vascular eye diseases, such as retinopathy of prematurity (ROP) in preterm infants and age-related macular degeneration in the elderly. While the involvement of photoreceptors in these diseases is recognized, the underlying mechanisms remain unclear. This study delved into the pivotal role of photoreceptors in regulating abnormal retinal blood vessel growth using an oxygen-induced retinopathy (OIR) mouse model through the c-Fos/A disintegrin and metalloprotease 17 (Adam17) axis. Our findings revealed a significant induction of c-Fos expression in rod photoreceptors, and c-Fos depletion in these cells inhibited pathological neovascularization and reduced blood vessel leakage in the OIR mouse model. Mechanistically, c-Fos directly regulated the transcription of Adam17 a shedding protease responsible for the production of bioactive molecules involved in inflammation, angiogenesis, and cell adhesion and migration. Furthermore, we demonstrated the therapeutic potential by using an adeno-associated virus carrying a rod photoreceptor-specific short hairpin RNA against c-fos which effectively mitigated abnormal retinal blood vessel overgrowth, restored retinal thickness, and improved electroretinographic (ERG) responses. In conclusion, this study highlights the significance of photoreceptor c-Fos in ROP pathology, offering a novel perspective for the treatment of this disease.
Assuntos
Proteína ADAM17 , Proteínas Proto-Oncogênicas c-fos , Neovascularização Retiniana , Animais , Neovascularização Retiniana/metabolismo , Neovascularização Retiniana/patologia , Neovascularização Retiniana/genética , Proteína ADAM17/metabolismo , Proteína ADAM17/genética , Proteínas Proto-Oncogênicas c-fos/metabolismo , Proteínas Proto-Oncogênicas c-fos/genética , Camundongos , Humanos , Retinopatia da Prematuridade/metabolismo , Retinopatia da Prematuridade/patologia , Retinopatia da Prematuridade/genética , Camundongos Endogâmicos C57BL , Transcrição Gênica , Regulação da Expressão Gênica , Vasos Retinianos/metabolismo , Vasos Retinianos/patologia , Células Fotorreceptoras Retinianas Bastonetes/metabolismo , Células Fotorreceptoras Retinianas Bastonetes/patologia , Modelos Animais de Doenças , AngiogêneseRESUMO
BACKGROUND: Alemtuzumab (AZ) is a monoclonal anti-CD52 antibody used as an induction agent in organ transplantation. Few studies have analyzed this agent in the context of simultaneous kidney-pancreas transplantation (SPKT). METHODS: We examined US registry data of SPKT recipient outcomes from January 2002 to October 2009 stratified by induction agent including AZ, other T-cell-depleting agents combined (T cell), IL2 receptor blockade (IL-2RAb), and no induction (none). RESULTS: Of 6860 SPKT recipients, induction therapy was AZ in 10%, T cell in 49%, IL-2RAb in 18%, and none in 22%. On multivariate analysis, there were no significant differences in overall patient survival, pancreas or renal allograft survival, or delayed renal graft function for the three induction groups compared with no induction. Rehospitalization within six months of transplantation occurred more often with AZ (51%) T cell (52%), and IL-2RAB (45%) compared with none (41%; p < 0.0001). On multivariate analysis, there was a significant higher odds of six-month rehospitalization with AZ (aOR 1.40, 95%CI 1.14-1.71), IL-2RAb (aOR 1.20, 95%CI 1.01-1.42-1.20), and other T-cell-depleting agents (aOR 1.50, 95%CI 1.31-1.73) compared with none. Median length of stay was significantly shorter in the AZ (8 d) compared with the IL-2RAb (9 d), T cell (10 d), and none (10 d) groups (p < 0.0001). CONCLUSIONS: There are no differences in patient, pancreas or renal allograft survival using AZ induction. AZ may confer an advantage in the perioperative period as evidenced by a decreased hospital length of stay. However, this benefit may be lost due to more frequent rehospitalizations.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/uso terapêutico , Rejeição de Enxerto/imunologia , Transplante de Rim , Transplante de Pâncreas , Receptores de Interleucina-2/imunologia , Linfócitos T/imunologia , Adulto , Alemtuzumab , Feminino , Seguimentos , Rejeição de Enxerto/mortalidade , Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto/efeitos dos fármacos , Sobrevivência de Enxerto/imunologia , Hospitalização , Humanos , Masculino , Prognóstico , Sistema de Registros , Indução de Remissão , Taxa de SobrevidaRESUMO
The effect of donor body mass index (BMI) and donor type on kidney transplant outcomes has not been well studied. Scientific Registry of Transplant Recipients data on recipients of deceased-donor kidneys between 1997 and 2010 were reviewed. Donors were categorized by DCD status (DCD, 6932; non-DCD, 90,158) and BMI groups at 5 kg/m(2) increments: 18.5-24.9, 25-29.9, 30-34.9, 35-39.9, 40-44.9, and ≥ 45 kg/m(2) . The primary outcome, death-censored graft survival (DCGS), was adjusted for donor, recipient, and transplant characteristics. Among recipients of non-DCD kidneys, donor BMI was not associated with DCGS. Among DCD recipients, donor BMI was not associated with DCGS for donor BMI categories < 45 kg/m(2) ; however, donor BMI ≥ 45 kg/m(2) was independently associated with DCGS compared to BMI of 20-24.9 kg/m(2) (adjusted hazard ratio, 1.84; 95% CI, 1.23, 2.74). The adjusted odds of delayed graft function (DGF) was greater for each level of BMI above reference for both DCD and non-DCD groups. There was no association of donor BMI with one-yr acute rejection for either type of donor. Although BMI is associated with DGF, long-term graft survival is not affected except in the combination of DCD with extreme donor BMI ≥ 45.
Assuntos
Morte Súbita Cardíaca , Rejeição de Enxerto/etiologia , Rejeição de Enxerto/mortalidade , Transplante de Rim/mortalidade , Obesidade/complicações , Doadores de Tecidos/estatística & dados numéricos , Adolescente , Adulto , Idoso , Índice de Massa Corporal , Cadáver , Função Retardada do Enxerto , Feminino , Seguimentos , Sobrevivência de Enxerto , Humanos , Transplante de Rim/efeitos adversos , Masculino , Pessoa de Meia-Idade , Obesidade/mortalidade , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida , Obtenção de Tecidos e Órgãos , Adulto JovemRESUMO
BACKGROUND: The influence of recipient body mass index (BMI) on pediatric-donor kidney transplant outcomes is unclear. We aimed to determine graft survival and functional outcomes of pediatric-donor kidneys compared with adult kidneys stratified by recipient BMI group. METHODS: Scientific Registry of Transplant Recipients data for recipients from 1996 to 2010 were reviewed. Donors were categorized by transplant type, pediatric single kidney transplant (SKT, n=3712), en bloc kidney transplant (EBK, n=1517), or adult standard criteria donor (SCD, n=66,741). Recipients were stratified by BMI tertiles (<24, 24-29, and >29 kg/m). RESULTS: SKT and EBK from donors ≤40 kg conferred similar risks of adjusted death-censored graft survival relative to SCDs regardless of recipient BMI except for EBK transplants in recipients with BMI <24 where the effect was protective (adjusted hazard ratio [aHR] 0.71, 95% confidence interval [CI] 0.56-0.94). SKT from donors ≤20 kg conferred worse death-censored graft survival in recipients with BMI <24 (aHR 1.3, 95% CI 1.0-1.6) and BMI >29 (aHR 1.5, 95% CI 1.1-2.0); however, most of the risk appeared early, and the effect was abrogated with reanalysis conditional on 1-year graft survival. Compared with SCDs, 1-year glomerular filtration rates of SKT from donors ≤20 kg were significantly higher when transplanted into recipients with BMI <24 (P<0.01) and similar in the other BMI groups. CONCLUSION: Increasing recipient BMI is not a clear risk factor for outcomes or graft function after transplantation with small pediatric-donor kidneys.