RESUMO
PURPOSE: To evaluate the tissue distribution and clinical significance of OX40 and OX40L in human non-small cell lung cancer (NSCLC). EXPERIMENTAL DESIGN: Using multiplexed quantitative immunofluorescence, we conducted simultaneous and localized measurements of OX40 and OX40L proteins, major T-cell subsets, and conventional type 1 dendritic cells (cDC1) in 614 primary NSCLCs from three independent cohorts represented in tissue microarrays. We also measured OX40L protein in samples from a phase I clinical trial of intratumor administration of a lipid nanoparticle encapsulated mRNA encoding OX40L (mRNA-2416) in human solid tumors. Finally, we studied the OX40 pathway in 212 uterine/ovarian serous carcinomas. RESULTS: OX40 protein was expressed in approximately 90% of NSCLCs, and OX40L was detected in approximately 10% of cases. Increased expression of OX40 was associated with higher CD4+ and CD8+ T lymphocytes, as well as cDC1s. Elevated expression of OX40L was consistently associated with increased CD4+ tumor-infiltrating lymphocytes and longer overall survival. No association was found between OX40 or OX40L levels and oncogenic driver mutations in EGFR and KRAS in lung adenocarcinomas. Delivering OX40L mRNA using intratumor mRNA-2416 injection mediated increased local OX40L protein levels that was most prominent in a patient with ovarian serous carcinoma. Detectable OX40L protein levels were observed in 15% of primary uterine/ovarian serous malignancies and associated with longer survival. CONCLUSIONS: The OX40 pathway is expressed in a fraction of NSCLCs and is associated with a favorable immune contexture. Although OX40L is uncommonly expressed in NSCLC and serous malignancies, it is associated with better prognosis and can be introduced using exogenous mRNA.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Carcinoma Pulmonar de Células não Pequenas/genética , Humanos , Lipossomos , Neoplasias Pulmonares/genética , Nanopartículas , Ligante OX40/genéticaRESUMO
Objective: To analyze the distribution characteristics of the anterior corneal astigmatism in 140 000 cataract patients from 18 hospitals in China. Methods: Retrospective study. A total of 143 889 patients (143 889 right eyes) over the age of 40 years with age-related catarac were admitted to 18 Aier eye hospitals in China from July 2015 to October 2018. The average values of the three measurements of the magnitude of anterior corneal astigmatism, the meridian of corneal astigmatism, anterior chamber depth, corneal refractive power, and axial length measured by IOLMaster 500 were obtained. The data acquisition method of each sub-center was to collect and analyze the electronic case data in accordance with the inclusion and exclusion criteria, and to provide them for the sponsor Wuhan Aier Eye Hospital. Non-normal distribution data are presented as M (P25, P75). Mann-Whitney test, Kruskal-Wallis test, Chi-square test were used to analyze the distribution differences of the magnitude of corneal astigmatism and the meridian of corneal astigmatism in gender, age, anterior chamber depth, corneal refractive power and axial length. Results: Among the 143 889 patients, 84 319 were females and 59 570 were males, the median age was 72 (65, 78) years old, the median corneal astigmatism was 0.84 (0.51, 1.33) D; the corneal astigmatism was ≥0.75 D in 80 895 patients (56.22%) and was ≥1.00 D in 57 304 patients (39.83%). The median corneal astigmatism was 0.87 (0.53, 1.37) D in women and 0.82 (0.50, 1.29) D in men; with statistical difference (U=-14.891; P<0.05). The proportion of with-the-rule (WTR) astigmatism was 33.26% (28 046/84 319) for women and 34.26% (20 408/59 570) for men; The proportion of against-the-rule (ATR) astigmatism was 49.08% (41 385/84 319) for women and 46.91% (27 945/59 570) for men, with statistical difference (χ²=70.913; P<0.05). With the increase of age, the magnitude of corneal astigmatism first decreased from 0.94 (0.57, 1.48) D to 0.75 (0.46, 1.18) D, and then increased to 1.19 (0.74, 1.79) D, with statistical difference (H=1 263.438; P<0.05), and the change was at 61 to 70 years old. With the increase of age, the proportion of WTR astigmatism decreased from 77.50% (396/511) to 12.50% (3/24), the proportion of ATR astigmatism increased from 11.15% (57/511) to 79.07% (34/43), and the proportion of oblique astigmatism changed little from 17.02% (16/94) to 19.92% (245/1 230), the distribution difference was significant (χ²=10 174.496; P<0.05). As the anterior chamber became shallow, the magnitude of corneal astigmatism significantly increased from 0.82 (0.51, 1.31) D to 1.05 (0.61, 1.56) D, and the proportion of ATR astigmatism increased from 47.32% (60 207/127 227) to 51.69% (184/356) (H=409.961, χ²=120.995, both P<0.05). With the corneal refractive power rising, the magnitude of corneal astigmatism increased from 0.80 (0.49, 1.33) D to 0.95 (0.58, 1.53) D, the proportion of ATR astigmatism decreased from 52.84% (4 963/9 392) to 39.97% (9 023/22 577); the difference was significant (H=808.562, χ²=752.147, both P<0.05). When the axial length was>25.00 mm, the magnitude of corneal astigmatism was highest [1.04 (0.62, 1.65) D], and the proportion of ATR astigmatism was also highest [49.00% (10 964/22 376)]; the difference was significant (H=2 071.198, χ²=131.130, all P<0.05). Conclusions: The meridian of corneal astigmatism in middle-aged and elderly cataract patients is mainly ATR astigmatism. With the increasing of age, the magnitude of corneal astigmatism decreases first and then increases. The turning point from the proportion of WTR astigmatism to the proportion of ATR astigmatism is 65 years old. The shallower the anterior chamber is, the more the magnitude of corneal astigmatism and the proportion of ATR astigmatism increase. When the axial length is>25.00 mm, both the magnitude of corneal astigmatism and the proportion of ATR astigmatism reach the peak. (Chin J Ophthalmol, 2021, 57: 56-62).
Assuntos
Astigmatismo , Catarata , Idoso , Astigmatismo/epidemiologia , Biometria , Catarata/epidemiologia , China/epidemiologia , Córnea , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
The success of targeted or immune therapies is often hampered by the emergence of resistance and/or clinical benefit in only a subset of patients. We hypothesized that combining targeted therapy with immune modulation would show enhanced antitumor responses. Here, we explored the combination potential of erdafitinib, a fibroblast growth factor receptor (FGFR) inhibitor under clinical development, with PD-1 blockade in an autochthonous FGFR2K660N/p53mut lung cancer mouse model. Erdafitinib monotherapy treatment resulted in substantial tumor control but no significant survival benefit. Although anti-PD-1 alone was ineffective, the erdafitinib and anti-PD-1 combination induced significant tumor regression and improved survival. For both erdafitinib monotherapy and combination treatments, tumor control was accompanied by tumor-intrinsic, FGFR pathway inhibition, increased T-cell infiltration, decreased regulatory T cells, and downregulation of PD-L1 expression on tumor cells. These effects were not observed in a KRASG12C-mutant genetically engineered mouse model, which is insensitive to FGFR inhibition, indicating that the immune changes mediated by erdafitinib may be initiated as a consequence of tumor cell killing. A decreased fraction of tumor-associated macrophages also occurred but only in combination-treated tumors. Treatment with erdafitinib decreased T-cell receptor (TCR) clonality, reflecting a broadening of the TCR repertoire induced by tumor cell death, whereas combination with anti-PD-1 led to increased TCR clonality, suggesting a more focused antitumor T-cell response. Our results showed that the combination of erdafitinib and anti-PD-1 drives expansion of T-cell clones and immunologic changes in the tumor microenvironment to support enhanced antitumor immunity and survival.
Assuntos
Antineoplásicos Imunológicos/farmacologia , Imunidade/efeitos dos fármacos , Neoplasias/imunologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptores de Fatores de Crescimento de Fibroblastos/antagonistas & inibidores , Animais , Biomarcadores , Linhagem Celular Tumoral , Modelos Animais de Doenças , Sinergismo Farmacológico , Humanos , Imunofenotipagem , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Camundongos , Camundongos Transgênicos , Mutação , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/metabolismo , Prognóstico , Receptor de Morte Celular Programada 1/genética , Pirazóis/farmacologia , Quinoxalinas/farmacologia , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Fatores de Crescimento de Fibroblastos/genética , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Resultado do Tratamento , Microambiente TumoralRESUMO
Many solid cancers contain dysfunctional immune microenvironments. Immune system modulators that initiate responses to foreign pathogens could be promising candidates for reigniting productive responses toward tumors. Interleukin-1 (IL-1) and IL-12 cytokine family members cooperate at barrier tissues after microbial invasion, in human inflammatory diseases, and in antitumoral immunity. IL-36γ, in classic alarmin fashion, acts in damaged tissues, whereas IL-23 centrally coordinates immune responses to danger signals. In this study, direct intratumoral delivery of messenger RNAs (mRNAs) encoding these cytokines produced robust anticancer responses in a broad range of tumor microenvironments. The addition of mRNA encoding the T cell costimulator OX40L increased complete response rates in treated and untreated distal tumors compared to the cytokine mRNAs alone. Mice exhibiting complete responses were subsequently protected from tumor rechallenge. Treatments with these mRNA mixtures induced downstream cytokine and chemokine expression, and also activated multiple dendritic cell (DC) and T cell types. Consistent with this, efficacy was dependent on Batf3-dependent cross-presenting DCs and cytotoxic CD8+ T cells. IL-23/IL-36γ/OX40L triplet mRNA mixture triggered substantial immune cell recruitment into tumors, enabling effective tumor destruction irrespective of previous tumoral immune infiltrates. Last, combining triplet mRNA with checkpoint blockade led to efficacy in models otherwise resistant to systemic immune checkpoint inhibition. Human cell studies showed similar cytokine responses to the individual components of this mRNA mixture, suggesting translatability of immunomodulatory activity to human patients.
Assuntos
Imunidade , Interleucina-1/genética , Interleucina-23/genética , Neoplasias/imunologia , Ligante OX40/genética , RNA Mensageiro/administração & dosagem , Animais , Proliferação de Células , Modelos Animais de Doenças , Humanos , Inflamação/patologia , Interleucina-1/metabolismo , Interleucina-23/metabolismo , Linfonodos/patologia , Ativação Linfocitária/imunologia , Camundongos , Ligante OX40/metabolismo , Distribuição Tecidual , Microambiente Tumoral/imunologiaRESUMO
Softwood bark is an important source for producing chemicals and materials as well as bioenergy. Extraction is regarded as a key technology for obtaining chemicals in general, and valorizing bark as a source of such chemicals in particular. In this paper, properties of 237 compounds identified in various studies dealing with extraction of softwood bark were described. Finally, some challenges and perspectives on the production of chemicals from bark are discussed.
Assuntos
Antioxidantes/química , Casca de Planta/química , Extratos Vegetais/química , Antioxidantes/isolamento & purificaçãoRESUMO
BMI1 is required for the self-renewal of stem cells in many tissues including the lung epithelial stem cells, Bronchioalveolar Stem Cells (BASCs). Imprinted genes, which exhibit expression from only the maternally or paternally inherited allele, are known to regulate developmental processes, but what their role is in adult cells remains a fundamental question. Many imprinted genes were derepressed in Bmi1 knockout mice, and knockdown of Cdkn1c (p57) and other imprinted genes partially rescued the self-renewal defect of Bmi1 mutant lung cells. Expression of p57 and other imprinted genes was required for lung cell self-renewal in culture and correlated with repair of lung epithelial cell injury in vivo. Our data suggest that BMI1-dependent regulation of expressed alleles at imprinted loci, distinct from imprinting per se, is required for control of lung stem cells. We anticipate that the regulation and function of imprinted genes is crucial for self-renewal in diverse adult tissue-specific stem cells.
Assuntos
Células-Tronco Adultas/metabolismo , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Proteínas Nucleares/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Repressoras/metabolismo , Proteínas Quinases Associadas a Fase S/metabolismo , Células-Tronco Adultas/patologia , Animais , Sobrevivência Celular/genética , Células Cultivadas , Inibidor p16 de Quinase Dependente de Ciclina/genética , Perfilação da Expressão Gênica , Genes p16/fisiologia , Loci Gênicos , Impressão Genômica/genética , Pulmão/patologia , Camundongos , Camundongos Mutantes , Proteínas Nucleares/genética , Complexo Repressor Polycomb 1 , Proteínas Proto-Oncogênicas/genética , RNA Interferente Pequeno/genética , Regeneração/genética , Proteínas Repressoras/genética , Proteínas Quinases Associadas a Fase S/genéticaRESUMO
DNA synthesis-coupled proteolysis of the prereplicative complex component Cdt1 by the CRL4(Cdt2) E3 ubiquitin ligase is thought to help prevent rereplication of the genome during S phase. To directly test whether CRL4(Cdt2)-triggered destruction of Cdt1 is required for normal cell cycle progression in vivo, we expressed a mutant version of Drosophila Cdt1 (Dup), which lacks the PCNA-binding PIP box (Dup(ΔPIP)) and which cannot be regulated by CRL4(Cdt2). Dup(ΔPIP) is inappropriately stabilized during S phase and causes developmental defects when ectopically expressed. Dup(ΔPIP) restores DNA synthesis to dup null mutant embryonic epidermal cells, but S phase is abnormal, and these cells do not progress into mitosis. In contrast, Dup(ΔPIP) accumulation during S phase did not adversely affect progression through follicle cell endocycles in the ovary. In this tissue the combination of Dup(ΔPIP) expression and a 50% reduction in Geminin gene dose resulted in egg chamber degeneration. We could not detect Dup hyperaccumulation using mutations in the CRL4(Cdt2) components Cul4 and Ddb1, likely because these cause pleiotropic effects that block cell proliferation. These data indicate that PIP box-mediated destruction of Dup is necessary for the cell division cycle and suggest that Geminin inhibition can restrain Dup(ΔPIP) activity in some endocycling cell types.
Assuntos
Proteínas de Ciclo Celular/genética , Proteínas de Ligação a DNA/genética , Proteínas de Drosophila/genética , Fase S/genética , Ubiquitina-Proteína Ligases/antagonistas & inibidores , Ubiquitina-Proteína Ligases/metabolismo , Sequência de Aminoácidos , Animais , Animais Geneticamente Modificados , Ciclo Celular/genética , Ciclo Celular/fisiologia , Proteínas de Ciclo Celular/metabolismo , Processos de Crescimento Celular/fisiologia , Proteínas Culina/genética , Proteínas Culina/metabolismo , Replicação do DNA , Proteínas de Ligação a DNA/metabolismo , Drosophila/citologia , Drosophila/enzimologia , Drosophila/genética , Drosophila/metabolismo , Proteínas de Drosophila/antagonistas & inibidores , Proteínas de Drosophila/metabolismo , Endodesoxirribonucleases/genética , Endodesoxirribonucleases/metabolismo , Feminino , Geminina , Regulação da Expressão Gênica , Masculino , Dados de Sequência Molecular , Mutação , Folículo Ovariano/metabolismo , Antígeno Nuclear de Célula em Proliferação/metabolismo , Domínios e Motivos de Interação entre Proteínas , Fase S/fisiologia , Complexos Ubiquitina-Proteína LigaseRESUMO
Expression of crassulacean acid metabolism (CAM) is characterized by extreme variability within and between taxa and its sensitivity to environmental variation. In this study, we determined seasonal fluctuations in CAM photosynthesis with measurements of nocturnal tissue acidification and carbon isotopic composition (δ(13)C) of bulk tissue and extracted sugars in three plant communities along a precipitation gradient (500, 700, and 1,000 mm year(-1)) on the Yucatan Peninsula. We also related the degree of CAM to light habitat and relative abundance of species in the three sites. For all species, the greatest tissue acid accumulation occurred during the rainy season. In the 500 mm site, tissue acidification was greater for the species growing at 30% of daily total photon flux density (PFD) than species growing at 80% PFD. Whereas in the two wetter sites, the species growing at 80% total PFD had greater tissue acidification. All species had values of bulk tissue δ(13)C less negative than -20, indicating strong CAM activity. The bulk tissue δ(13)C values in plants from the 500 mm site were 2 less negative than in plants from the wetter sites, and the only species growing in the three communities, Acanthocereus tetragonus (Cactaceae), showed a significant negative relationship between both bulk tissue and sugar δ(13)C values and annual rainfall, consistent with greater CO(2) assimilation through the CAM pathway with decreasing water availability. Overall, variation in the use of CAM photosynthesis was related to water and light availability and CAM appeared to be more ecologically important in the tropical dry forests than in the coastal dune.
Assuntos
Dióxido de Carbono/metabolismo , Crassulaceae/metabolismo , Crassulaceae/efeitos da radiação , Ecossistema , Luz , Ácidos/metabolismo , Ácidos/efeitos da radiação , Cactaceae/química , Cactaceae/metabolismo , Cactaceae/efeitos da radiação , Isótopos de Carbono/metabolismo , Crassulaceae/química , México , Chuva , Estações do AnoRESUMO
Understanding the pathways that control epithelial carcinogenesis is vital to the development of effective treatments. The Polycomb group family member Bmi1 is overexpressed in numerous epithelial tumors, but its role in their development has not been established. We now show a key role for Bmi1 in lung adenocarcinoma. Whereas lung development occurs normally in Bmi1-deficient mice, loss of Bmi1 decreases the number and progression of lung tumors at a very early point in an oncogenic K-ras-initiated mouse model of lung cancer. This correlates with a defect in the ability of Bmi1-deficient putative bronchiolalveolar stem cells (BASCs) to proliferate in response to the oncogenic stimulus. Notably, in the absence of oncogenic K-ras, Bmi1-deficient BASCs show impaired proliferation and self-renewal capacity in culture and after lung injury in vivo. Abrogated lung cancer development and BASC self-renewal occur partially in a p19(ARF)-dependent manner. Our data suggest that Bmi1 deficiency suppresses tumor development by limiting the expansion potential of BASCs, the apparent lung cancer cells of origin. Because Bmi1 is elevated in additional tumor types, this suggests that Bmi1 plays a key role in regulating proliferation of both stem cells and tumor cells in diverse adult epithelial tissues.
Assuntos
Brônquios/citologia , Transformação Celular Neoplásica/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Proteínas Nucleares/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Alvéolos Pulmonares/citologia , Proteínas Repressoras/metabolismo , Células-Tronco/metabolismo , Animais , Brônquios/metabolismo , Proliferação de Células , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , Células Cultivadas , Neoplasias Pulmonares/genética , Camundongos , Camundongos Knockout , Proteínas Nucleares/deficiência , Proteínas Nucleares/genética , Complexo Repressor Polycomb 1 , Proteínas Proto-Oncogênicas/deficiência , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas p21(ras)/deficiência , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Alvéolos Pulmonares/metabolismo , Proteínas Repressoras/genética , Células-Tronco/citologiaRESUMO
The metazoan cell cycle is driven by the timely and composite activities of cyclin-dependent kinases (CDKs). Among these, cyclin D- and cyclin E-dependent kinases phosphorylate the pRb family proteins during G(1) phase of the cell cycle and thereby advance cells beyond the restriction point. Increasing evidence suggests that cyclin D-dependent kinases might affect events other than Rb pathway-mediated entry into S phase, such as accumulation of cell mass. However, little is known about cyclin D activity toward Rb-independent pathway(s) or non-pRb substrates. In this article, we show that the tumor suppressor TSC2 is a cyclin D binding protein. Coexpression of cyclin D1-CDK4/6 in cultured cells leads to increased phosphorylation and decreased detection of both TSC2 and TSC1, and promotes the phosphorylation of the mTOR substrates, 4E-BP1 and S6K1, two key effectors of cell growth that are negatively regulated by the TSC1-TSC2 complex. At the cellular level, ectopic expression of cyclin D1 restores the cell size decrease caused by TSC1-TSC2 expression. Intriguingly, down-regulation of TSC proteins was also observed by the expression of a mutant cyclin D1 that is unable to bind to CDK4/6, or by the coexpression of cyclin D1 with either an INK4 inhibitor or with catalytically inactive CDK6, indicating that cyclin D may regulate TSC1-TSC2 independently of CDK4/6. Together, these observations suggest that mammalian D-type cyclins participate in cell growth control through negative regulation of TSC1-TSC2 function.
Assuntos
Ciclina D1/metabolismo , Fase G1 , Regulação da Expressão Gênica , Proteína do Retinoblastoma/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Proteínas Adaptadoras de Transdução de Sinal , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/patologia , Proteínas de Transporte/metabolismo , Proteínas de Ciclo Celular , Células Cultivadas , Quinase 4 Dependente de Ciclina/metabolismo , Quinase 6 Dependente de Ciclina/metabolismo , Inibidor p16 de Quinase Dependente de Ciclina , Humanos , Rim/metabolismo , Osteossarcoma/metabolismo , Osteossarcoma/patologia , Fosfoproteínas/metabolismo , Fosforilação , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Proteína 1 do Complexo Esclerose Tuberosa , Proteína 2 do Complexo Esclerose TuberosaRESUMO
PURPOSE: To evaluate the effectiveness of treating anterior corneal pathology by performing a superficial lamellar keratectomy with an automated microkeratome. METHODS: Retrospective chart review of 10 eyes (8 patients) seen in a subspecialty referral practice for anterior segment disease. With the use of an automated microkeratome, a lamellar flap was created, which was then surgically excised. RESULTS: Ten eyes of eight patients were followed for a mean of 5.4 months (range, 4 to 10 months). Subjective visual acuity and/or sensation of ocular irritation improved in 10 of 10 eyes. Mean improvement in Snellen best-corrected visual acuity was 1.8 lines (range, -1 to +3 lines). One patient lost 1 line of Snellen acuity due to progression of a posterior subcapsular cataract. Mean change in spherical equivalent was +0.5 diopters (range, -1.60 to +4.25 diopters), and mean improvement in corneal clarity (1 to 4 scale) was 1.8. Mean preoperative pachymetry was 589.0 microm (range, 507 to 741 microm). Mean postoperative pachymetry was 461.3 microm (range, 370 to 564 microm). Recurrence of pathology (band keratopathy and Salzmann's nodular degeneration) occurred in two patients. In one patient, immunohistochemical staining of corneal tissue from the lamellar dissection confirmed the diagnosis of herpes simplex virus type 1 stromal keratitis, improving the course of postoperative care. CONCLUSION: Lamellar keratectomy with the use of an automated microkeratome is a safe and effective method for removing superficial anterior corneal opacities. For selected cases, it offers specific advantages over other surgical modalities. In particular, this procedure may induce far less hyperopic shift than would the equivalent amount of tissue removal by performing excimer laser phototherapeutic keratectomy.
Assuntos
Opacidade da Córnea/cirurgia , Transplante de Córnea/métodos , Topografia da Córnea , Transplante de Córnea/instrumentação , Feminino , Humanos , Pessoa de Meia-Idade , Recidiva , Estudos Retrospectivos , Acuidade VisualRESUMO
PURPOSE: To present a case of Candida parapsilosis following laser in situ keratomileusis (LASIK). METHODS: Retrospective chart review. RESULTS: A case report of a 51-year-old woman who underwent bilateral LASIK is presented. Two weeks after the procedure, the patient presented with epithelial ingrowth OD. The ingrowth was treated with flap lifting and scraping, followed by postoperative antibiotics. Four weeks later, the patient presented with numerous interface infiltrates. Smears were positive for yeast forms and cultures grew Candida parapsilosis. Administration of topical and systemic antifungal therapy resulted in clearing of the infection with partial visual recovery. CONCLUSIONS: To our knowledge, this represents the first reported case of a post-LASIK Candida parapsilosis keratitis. A high degree of suspicion coupled with rapid and appropriate treatment can result in visual recovery.
Assuntos
Candidíase/microbiologia , Epitélio Corneano/patologia , Infecções Oculares Fúngicas/microbiologia , Ceratite/microbiologia , Ceratomileuse Assistida por Excimer Laser In Situ/efeitos adversos , Complicações Pós-Operatórias , Anfotericina B/uso terapêutico , Antifúngicos/uso terapêutico , Candidíase/diagnóstico , Candidíase/tratamento farmacológico , Desbridamento , Quimioterapia Combinada , Infecções Oculares Fúngicas/diagnóstico , Infecções Oculares Fúngicas/tratamento farmacológico , Feminino , Fluconazol/uso terapêutico , Humanos , Ceratite/diagnóstico , Ceratite/tratamento farmacológico , Pessoa de Meia-Idade , Ofloxacino/uso terapêutico , Estudos Retrospectivos , Retalhos Cirúrgicos/patologiaRESUMO
OBJECTIVE: To describe a case of keratomycosis caused by Arthrographis kalrae, mimicking Acanthamoeba keratitis. METHODS: Case report. RESULTS: A 23-year-old female contact lens wearer developed dendritic keratitis in her amblyopic eye (OD). Baseline vision was 20/50. Treatment with trifluridine 1% resulted in resolution of the dendrite, but an area of stromal haze developed, spreading to a discontinuous ring shape, and the vision dropped to 20/200. Photophobia was intense, and pain was out of proportion to the examination. Cultures were sent, and empiric treatment of Acanthamoeba was begun, without subsequent improvement. After 4 weeks, cultures were positive for a fungal species. Amphotericin 0.5% drops were begun, with moderately rapid resolution of the active keratitis. At last follow-up, best-corrected vision was 20/100. Review of the culture showed the organism to be Arthrographis kalrae. CONCLUSION: Arthrographis kalrae has been reported only once before as an ocular pathogen. As in the previously reported case of Arthrographis, our patient's presentation was strongly suggestive of Acanthamoeba keratitis.
Assuntos
Infecções Oculares Fúngicas/diagnóstico , Ceratite/diagnóstico , Fungos Mitospóricos/isolamento & purificação , Micoses/diagnóstico , Ceratite por Acanthamoeba/diagnóstico , Adulto , Anfotericina B/uso terapêutico , Antifúngicos/uso terapêutico , Diagnóstico Diferencial , Infecções Oculares Fúngicas/tratamento farmacológico , Infecções Oculares Fúngicas/microbiologia , Feminino , Humanos , Ceratite/tratamento farmacológico , Ceratite/microbiologia , Ceratite Dendrítica/complicações , Ceratite Dendrítica/tratamento farmacológico , Micoses/tratamento farmacológico , Micoses/microbiologia , Soluções OftálmicasRESUMO
PURPOSE: To investigate the effect of hyperthermia for the treatment of long-standing corneal flap striae after laser in situ keratomileusis (LASIK). SETTING: TLC Laser Eye Center, Garden City, New York, USA. METHODS: Patients with visually significant flap striae at least 3 weeks post-LASIK were offered hyperthermic treatment. The central 6.0 mm of epithelium was removed from affected corneas, and the flaps were elevated. A striae removal spatula was heated to 65 degrees C in sterile water, and both sides of the flaps were mechanically massaged with the spatula for 5 to 10 minutes until the striae were visually reduced. RESULTS: Thirty-six eyes of 34 patients were treated with hyperthermia to remove corneal striae. All patients had a clinical reduction in striae. The mean pretreatment best corrected visual acuity (BCVA) was 20/44, improving to 20/25 on follow-up (mean follow-up 16.4 months). Patients subjectively noted reduced haze and glare and no loss of BCVA. There were no serious flap complications. CONCLUSION: Hyperthermic treatment is a safe, effective treatment option for corneal striae after LASIK.
Assuntos
Doenças da Córnea/terapia , Substância Própria , Hipertermia Induzida , Ceratomileuse Assistida por Excimer Laser In Situ , Complicações Pós-Operatórias/terapia , Retalhos Cirúrgicos , Adulto , Doenças da Córnea/etiologia , Feminino , Humanos , Masculino , Segurança , Resultado do Tratamento , Acuidade VisualRESUMO
PURPOSE: To evaluate the effectiveness of lid hygiene and preservative-free artificial tears for the treatment of meibomian gland dysfunction (MGD) during a 6-week period. METHODS: Suitable patients with MGD were educated about their disease and instructed to begin a regimen of lid hygiene, which included the application of a heated saline solution and the use of nonpreserved artificial tears. Baseline measurements obtained at the time of enrollment included basic tear secretion test, tear breakup time, a questionnaire grading MGD symptoms (i.e., burning, irritation, itching, sharp pains, foreign body sensation, and hazy vision), and lid margin slitlamp photographs. All measurements except for basic tear secretion were repeated at the 6-week follow-up visit. Photographs were unlabeled, and two cornea specialists graded them in a masked fashion for the presence of lid erythema, irregularity, thickness, meibomian gland capping, and telangiectasis. RESULTS: Thirty-seven patients with a clinical diagnosis of MGD were enrolled, and 26 patients (70%) completed the study. Initial measurement of basic tear secretion averaged 17 mm and was more than 10 mm in 81% of eyes. The tear breakup time was prolonged by an average of 3.4 seconds; in 30% of cases, it was normalized to 10 seconds or more. Symptoms improved in 88% of cases; among those, symptoms were graded mild or less in 83%, and none in 39%. Photographs before and after treatment were not significantly different. CONCLUSIONS: In this noncontrolled case-cohort study of selected patients with MGD, lid hygiene and preservative-free artificial tears significantly improved tear breakup time and relieved symptoms of the condition.
Assuntos
Doenças Palpebrais/tratamento farmacológico , Glândulas Tarsais/efeitos dos fármacos , Soluções Oftálmicas/administração & dosagem , Cloreto de Sódio/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Doenças Palpebrais/metabolismo , Feminino , Humanos , Higiene , Masculino , Glândulas Tarsais/metabolismo , Pessoa de Meia-Idade , Estudos Prospectivos , Inquéritos e Questionários , Lágrimas/metabolismoRESUMO
AIMS/HYPOTHESIS: Retinal vascular leakage is an early pathological feature in diabetic retinopathy and can lead to macular oedema and loss of vision. Previously we have shown that plasminogen kringle 5 (K5), an angiogenic inhibitor, inhibits retinal neovascularisation in the rat model of oxygen-induced retinopathy (OIR). The purpose of this study was to examine the effect of K5 on vascular leakage in the retina. METHODS: Neonatal rats were exposed to hyperoxia to induce OIR. Diabetes was induced in adult rats by injecting streptozotocin. Vascular permeability was measured by Evans blue method. Expression of vascular endothelial growth factor (VEGF) was evaluated using immunohistochemistry and western blot analysis. RESULTS: Rats with OIR and diabetes showed abnormal vascular hyperpermeability in the retina and iris. Intravitreal injection of K5, reduced vascular permeability in both animal models, but did not affect permeability in normal rats. K5 reduced vascular permeability at doses substantially lower than that required for inhibition of retinal neovascularisation. The K5-induced reduction in vascular permeability correlated with its down-regulation of VEGF expression in the retina. Moreover, K5 inhibited IGF-1-induced hyperpermeability, which is known to arise through up-regulation of endogenous VEGF expression. However, K5 had no effect on the hyperpermeability induced by injection of exogenous VEGF. CONCLUSIONS/INTERPRETATION: Very low doses of K5 reduce pathological vascular leakage in the retina. K5 thus has therapeutic potential in the treatment of diabetic macular oedema. This effect can be ascribed, at least in part, to the down-regulation of endogenous VEGF expression.
Assuntos
Inibidores da Angiogênese/uso terapêutico , Diabetes Mellitus Experimental/fisiopatologia , Retinopatia Diabética/prevenção & controle , Fragmentos de Peptídeos/uso terapêutico , Plasminogênio/uso terapêutico , Animais , Diabetes Mellitus Experimental/patologia , Retinopatia Diabética/patologia , Imuno-Histoquímica , Fator de Crescimento Insulin-Like I/farmacologia , Ratos , Ratos Endogâmicos BN , Fator A de Crescimento do Endotélio Vascular/metabolismo , Fator A de Crescimento do Endotélio Vascular/farmacologiaRESUMO
PURPOSE: To investigate the effect of hinge position on corneal sensation and dry eye syndrome after laser in situ keratomileusis (LASIK). DESIGN: Prospective, randomized, self-controlled trial. PARTICIPANTS: Fifty-two patients >/=18 years of age undergoing bilateral LASIK. INTERVENTION: Patients underwent bilateral LASIK with the superior-hinge Hansatome microkeratome in one eye and the nasal-hinge Amadeus microkeratome in the other eye. In all eyes, the flaps were 160 micro m thick, with a diameter of 9.5 mm. MAIN OUTCOME MEASURES: Masked Cochet-Bonnet esthesiometry was performed centrally before surgery and at 1 week, 1 month, 3 months, and 6 months after surgery. Dry eye was evaluated at the same time intervals with lissamine green corneal and conjunctival staining, Schirmer testing with anesthesia, and tear-film breakup time. Subjective evaluation of dry eye sensation was performed at 3 and 6 months after surgery. RESULTS: Corneal sensation was reduced in eyes with either superior- or nasal-hinge corneal flaps at 1 week, 1 month, and 3 months after surgery (P < 0.001). Compared with preoperative values, a significant reduction in corneal sensation remained at 6 months in corneas with superior-hinge flaps (P < 0.001) but not in corneas with nasal-hinge flaps (P = 0.263). Mean corneal sensation was greater in corneas with a nasal-hinge flap compared with corneas with a superior-hinge flap at all postoperative visits (P < 0.001). The loss of sensation was greatest at 1 week and showed improvement at each subsequent time interval up to 6 months. Overall, dry eye signs and symptoms were greatest during the immediate postoperative period and improved at all subsequent time intervals. Dry eye signs and symptoms were generally greatest in the eyes with a superior-hinge flap and milder in eyes with a nasal-hinge flap. CONCLUSIONS: The long posterior corneal nerves, which innervate the cornea, enter the eye at 3- and 9-o'clock. A superior-hinge flap transects both arms of the neuroplexus, whereas a nasal hinge transects only the temporal arm. LASIK results in a significant reduction in corneal sensation. Corneal sensation and dry eye signs and symptoms decreased immediately after LASIK and improved at all time periods between 1 week and 6 months in eyes with both a nasal-hinge flap and a superior-hinge flap. However, the loss of corneal sensation and presence of dry eye syndrome were greater in eyes with a superior-hinge flap than in eyes with a nasal-hinge flap.
Assuntos
Córnea/fisiologia , Síndromes do Olho Seco/etiologia , Ceratomileuse Assistida por Excimer Laser In Situ/efeitos adversos , Transtornos de Sensação/etiologia , Sensação/fisiologia , Retalhos Cirúrgicos , Adulto , Substância Própria/cirurgia , Método Duplo-Cego , Síndromes do Olho Seco/fisiopatologia , Feminino , Humanos , Masculino , Estudos Prospectivos , Transtornos de Sensação/fisiopatologia , Fatores de TempoRESUMO
PURPOSE: To present a case of corneal perforation secondary to herpes simplex reactivation after laser in situ keratomileusis (LASIK) and its subsequent management. METHODSL A case report of a 69-year-old man who underwent LASIK after penetrating keratoplasty for herpes simplex keratitis (HSK) is presented. RESULTS: The patient is a 69-year-old man who had a penetrating keratoplasty of the right eye 6 years prior for corneal scarring secondary to HSK. A spectacle refraction of -13.25 + 6.00 x 45 yielded 20/60 visual acuity in his grafted eye. LASIK was performed, and the patient's visual acuity without correction on postoperative day 1 was 20/60. Ten days after LASIK, the patient developed thinning of the cornea at the temporal edge of the flap, which perforated the following day. The perforation site was glued with cyanoacrylate adhesive and covered with a soft contact lens. After 7 months, a 4-mm lamellar keratoplasty and conjunctivoplasty was performed. Nine months after surgery, the patient's visual acuity without correction is 20/50 and the graft remains intact. CONCLUSION: Herpes simplex keratitis may be a contraindication for LASIK in postkeratoplasty patients. Bandage contact lenses and cyanoacrylate adhesive can be used successfully to manage the rare complication of corneal perforation after LASIK.
Assuntos
Lesões da Córnea , Ceratite Herpética/complicações , Ceratomileuse Assistida por Excimer Laser In Situ/efeitos adversos , Simplexvirus/fisiologia , Ativação Viral , Ferimentos Penetrantes/virologia , Idoso , Túnica Conjuntiva/cirurgia , Lentes de Contato Hidrofílicas , Córnea/cirurgia , Transplante de Córnea , Cianoacrilatos/uso terapêutico , Humanos , Ceratoplastia Penetrante , Masculino , Prontuários Médicos , Período Pós-Operatório , Reoperação , Adesivos Teciduais/uso terapêutico , Acuidade Visual , Ferimentos Penetrantes/tratamento farmacológico , Ferimentos Penetrantes/cirurgiaRESUMO
PURPOSE: To investigate the efficacy of topical cyclosporine A 0.5% as a substitute for corticosteroids in the management of therapeutic keratoplasties for mycotic keratitis. METHODS: Prospective, nonrandomized interventional case series. Three patients with culture-proven mycotic keratitis underwent therapeutic keratoplasties. All were treated with topical cyclosporine A 0.5% postoperatively as a primary or an adjunctive therapy for prevention of allograft rejection. The patients were followed up from 15 to 42 months for maintenance of graft clarity and best-corrected visual acuity. RESULTS: Two of three patients maintained clear grafts while using topical cyclosporine A 0.5% twice daily with best-corrected visual acuity of 20/40 and 20/50. One patient developed an opacified graft secondary to preexisting ocular surface disease. CONCLUSIONS: Topical cyclosporine A 0.5% may be a useful adjunct in the management of therapeutic keratoplasties for mycotic keratitis.
Assuntos
Ciclosporina/uso terapêutico , Infecções Oculares Fúngicas/cirurgia , Rejeição de Enxerto/prevenção & controle , Imunossupressores/uso terapêutico , Ceratite/microbiologia , Ceratite/cirurgia , Ceratoplastia Penetrante , Micoses/cirurgia , Administração Tópica , Idoso , Candida albicans/isolamento & purificação , Cryptococcus/isolamento & purificação , Ciclosporina/administração & dosagem , Infecções Oculares Fúngicas/microbiologia , Feminino , Humanos , Imunossupressores/administração & dosagem , Masculino , Pessoa de Meia-Idade , Micoses/microbiologia , Estudos Prospectivos , Pseudallescheria/isolamento & purificação , Resultado do Tratamento , Acuidade VisualRESUMO
We investigate the computational properties of finite binary- and analog-state discrete-time symmetric Hopfield nets. For binary networks, we obtain a simulation of convergent asymmetric networks by symmetric networks with only a linear increase in network size and computation time. Then we analyze the convergence time of Hopfield nets in terms of the length of their bit representations. Here we construct an analog symmetric network whose convergence time exceeds the convergence time of any binary Hopfield net with the same representation length. Further, we prove that the MIN ENERGY problem for analog Hopfield nets is NP-hard and provide a polynomial time approximation algorithm for this problem in the case of binary nets. Finally, we show that symmetric analog nets with an external clock are computationally Turing universal.