RESUMO
PURPOSE: The aim of this study was to describe a simple technique to insert a venous catheter as a stent for the treatment of acquired punctal and canalicular stenosis. METHODS: We performed this technique using a central venous catheter as a stent for the treatment of acquired punctal and canalicular stenosis. RESULTS: The results show the easy availability of the material used for the intervention, its easy execution, and the low costs of materials. The goal of this technique is to have a lacrimal dot dilated and canalicular duct easy to irrigate. CONCLUSION: The use of a venous catheter as a stent for treatment of acquired punctal and canalicular stenosis seems to be simple, safe, repeatable, and noninvasive.
Assuntos
Doenças Palpebrais/cirurgia , Stents , Cateterismo Periférico , Constrição Patológica/cirurgia , Dacriocistorinostomia/métodos , Humanos , Aparelho LacrimalRESUMO
PURPOSE: To describe the use of a double suture and conjunctival cuts in the lateral tarsal strip (LTS) and to evaluate postsurgical outcome in patients with severe involutional ectropion. METHODS: A prospective randomized study was conducted on 16 eyelids of 8 patients with symptomatic severe involutional ectropion. The 8 patients were between 62 and 79 years. They were distributed into 2 groups consisting of 4 patients each. The control group was treated with a conventional lateral tarsal strip (C-LTS), the second group underwent a modified lateral tarsal strip (M-LTS). The mean follow-up was 18 months. Success was defined as relief in lid laxity. The recurrence rate was also evaluated. RESULTS: Patients treated with M-LTS showed lower horizontal laxity (3.5â±â0.2) than patients treated with C-LTS (5.7â±â0.2). During the 18-month follow-up, a statistically significant difference was found between the 2 groups with P value <0.05. CONCLUSIONS: The use of a double suture and conjunctival cuts in the lateral tarsal strip proposed by Meduri showed a reduction of postsurgical ectropion's grade and postsurgical recurrences. This technique could be used for the treatment of patients with a severe ectropion.
Assuntos
Blefaroplastia/métodos , Túnica Conjuntiva/cirurgia , Ectrópio/cirurgia , Técnicas de Sutura , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , SuturasRESUMO
We present a unique case involving a 6-year-old female with a unilateral corneal endotheliitis-like finding, who was ultimately found to have a form of anterior diffuse infiltrating retinoblastoma with no evidence of retinal involvement. The patient's presumed endotheliitis was initially treated with topical dexamethasone and oral acyclovir without improvement. She then underwent multiple fine-needle aspirations of anterior chamber fluid, which were negative for abnormal findings of viral polymerase chain reaction, viral cultures, and flow cytometry. Months after initial presentation, an anterior chamber angle mass developed and a biopsy identified retinoblastoma cells. The patient underwent plaque radiotherapy of the cornea and systemic chemotherapy. The patient regained good vision and is tumor-free at 13 months. Anterior inflammation is a rare form of masquerade syndrome associated with retinoblastoma; however, it tends to be associated with diffuse posterior segment retinoblastoma when it does occur. Diffuse anterior retinoblastoma is a rare form of retinoblastoma with no apparent focus in the retina. Ultimately, our patient developed an anterior chamber angle lesion, which was biopsied and proven to be retinoblastoma. Unusual corneal endotheliitis-like findings in children that are not responsive to conventional treatment should raise the clinician's suspicion of malignancy, even when no retinal lesion is detected.
Assuntos
Infecções Oculares Virais/diagnóstico , Ceratite/diagnóstico , Neoplasias da Retina/diagnóstico , Retinoblastoma/diagnóstico , Câmara Anterior/patologia , Criança , Diagnóstico Diferencial , Feminino , HumanosRESUMO
OBJECTIVE: To review the published literature on safety and outcomes of the Boston type I keratoprosthesis (BI-KPro) for the surgical treatment of corneal opacification not amenable to human cadaveric corneal transplantation. METHODS: Searches of peer-reviewed literature were conducted in PubMed and the Cochrane Library in December 2012, July 2013, and January 2014 without date restrictions. The searches were limited to studies published in English and yielded 587 citations. The abstracts of these articles were reviewed, 48 articles were selected for possible clinical relevance, and 22 were determined to be relevant for the assessment objectives. Nine studies were rated as level II evidence and 13 studies were rated as level III evidence. Excluded were level III evidence, case reports, review articles, letters, editorials, and case series with fewer than 25 eyes. RESULTS: In 9 articles, a best-corrected Snellen visual acuity (BCSVA) of 20/200 or better occurred in 45% to 89% of eyes. Five articles described a BCSVA of 20/50 or better in 43% to 69% of eyes, and 4 articles found a BCSVA of 20/40 or better in 11% to 39% of eyes. Retention rates of the BI-KPro ranged from 65% to 100%. Reasons for loss of vision after BI-KPro implantation most commonly included corneal melts resulting from exposure keratopathy, endophthalmitis, and infectious keratitis or corneal ulceration. The 2 most common complications after surgery were retroprosthetic membrane formation (range, 1.0%-65.0%; mean ± standard deviation [SD], 30.0±19.0%) and elevated intraocular pressure (range, 2.4%-64.0%; mean ± SD, 27.5±18.1%). The 2 most common posterior segment complications were endophthalmitis (range, 0%-12.5%; mean ± SD, 4.6±4.6%) and vitritis (range, 0%-14.5%; mean ± SD, 5.6±4.7%). CONCLUSIONS: The reviewed articles on BI-KPro use suggest that the device improves vision in cases of severe corneal opacification that were not amenable to corneal transplantation using human cadaveric keratoplasty techniques. A number of severe anterior and posterior segment complications can develop as follow-up continues, making ongoing close observation paramount for patients undergoing this surgery. These complications include infection, device extrusion, and permanent vision loss.
Assuntos
Órgãos Artificiais , Córnea , Opacidade da Córnea/cirurgia , Avaliação de Processos e Resultados em Cuidados de Saúde , Próteses e Implantes , Avaliação da Tecnologia Biomédica , Transtornos da Visão/reabilitação , Academias e Institutos/organização & administração , Humanos , Complicações Intraoperatórias , Oftalmologia/organização & administração , Complicações Pós-Operatórias , Implantação de Prótese , Resultado do Tratamento , Estados Unidos , Acuidade VisualRESUMO
The dystrophin-glycoprotein complex connects myofibers with extracellular matrix laminin. In Duchenne muscular dystrophy, this linkage system is absent and the integrity of muscle fibers is compromised. One potential therapy for addressing muscular dystrophy is to augment the amount of α7ß1 integrin, the major laminin-binding integrin in skeletal muscle. Whereas transgenic over-expression of α7 chain may alleviate development of muscular dystrophy and extend the lifespan of severely dystrophic mdx/utrn(-/-) mice, further enhancing levels of α7 chain provided little additional membrane integrin and negligible additional improvement in mdx mice. We demonstrate here that normal levels of ß1 chain limit formation of integrin heterodimer and that increasing ß1D chain in mdx mice results in more functional integrin at the sarcolemma, more matrix laminin and decreased damage of muscle fibers. Moreover, increasing the amount of ß1D chain in vitro enhances transcription of α7 integrin and α2 laminin genes and the amounts of these proteins. Thus manipulation of ß1D integrin expression offers a novel approach to enhance integrin-mediated therapy for muscular dystrophy.
Assuntos
Integrina beta1/genética , Integrinas/metabolismo , Laminina/metabolismo , Distrofias Musculares/metabolismo , Sarcolema/metabolismo , Animais , Antígenos CD/biossíntese , Antígenos CD/genética , Antígenos CD/metabolismo , Linhagem Celular , Retículo Endoplasmático/metabolismo , Cadeias alfa de Integrinas/biossíntese , Cadeias alfa de Integrinas/genética , Cadeias alfa de Integrinas/metabolismo , Integrina beta1/metabolismo , Laminina/biossíntese , Laminina/genética , Camundongos , Camundongos Endogâmicos mdx , Camundongos Knockout , Camundongos Transgênicos , Fibras Musculares Esqueléticas/metabolismo , Distrofias Musculares/prevenção & controle , Sarcolema/ultraestruturaRESUMO
BACKGROUND: Previously, we identified three loci affecting HDL-cholesterol levels in a screen for ENU-induced mutations in mice and discovered two mutated genes. We sought to identify the third mutated gene and further characterize the mouse phenotype. METHODS: We engaged, DNA sequencing, gene expression profiling, western blotting, lipoprotein characterization, metabolomics assessment, histology and electron microscopy in mouse tissues. RESULTS: We identify the third gene as Ampd2, a liver isoform of AMP Deaminase (Ampd), a central component of energy and purine metabolism pathways. The causative mutation was a guanine-to-thymine transversion resulting in an A341S conversion in Ampd2. Ampd2 homozygous mutant mice exhibit a labile hypercholesterolemia phenotype, peaking around 9 weeks of age (251 mg/dL vs. wildtype control at 138 mg/dL), and was evidenced by marked increases in HDL, VLDL and LDL. In an attempt to determine the molecular connection between Ampd2 dysfunction and hypercholesterolemia, we analyzed hepatic gene expression and found the downregulation of Ldlr, Hmgcs and Insig1 and upregulation of Cyp7A1 genes. Metabolomic analysis confirmed an increase in hepatic AMP levels and a decrease in allantoin levels consistent with Ampd2 deficiency, and increases in campesterol and ß-sitosterol. Additionally, nephrotic syndrome was observed in the mutant mice, through proteinuria, kidney histology and effacement and blebbing of podocyte foot processes by electron microscopy. CONCLUSION: In summary we describe the discovery of a novel genetic mouse model of combined transient nephrotic syndrome and hypercholesterolemia, resembling the human disorder.
Assuntos
AMP Desaminase/genética , Hipercolesterolemia/genética , Síndrome Nefrótica/genética , Animais , HDL-Colesterol/sangue , Expressão Gênica , Estudos de Associação Genética , Hipercolesterolemia/sangue , Glomérulos Renais/patologia , Camundongos Endogâmicos C57BL , Mutação de Sentido Incorreto , Síndrome Nefrótica/sangue , Proteinúria/sangue , Proteinúria/genéticaRESUMO
OBJECTIVE: To assess the outcomes and safety of current surgical options and adjuvants in the treatment of primary and recurrent pterygium. METHODS: Literature searches of the PubMed and the Cochrane Library databases were last conducted in January 2011 using keywords and were restricted to randomized controlled trials reporting on surgical intervention for pterygium. The searches were limited to articles published in English and yielded 120 citations. Citation abstracts, and if necessary the full text, were reviewed to identify randomized controlled trials that reported recurrence as an outcome measure and had a mean follow-up of at least 6 months. Fifty-one studies comparing bare sclera excision, conjunctival or limbal autograft, intraoperative mitomycin C, postoperative mitomycin C, and amniotic membrane transplantation for primary and recurrent pterygia fit these inclusion criteria. RESULTS: Four studies demonstrated that the conjunctival or limbal autograft procedure is more efficacious than amniotic membrane placement. Use of conjunctival or limbal autografts or mitomycin C during or after pterygium excision reduced recurrence compared with bare sclera excision alone in most studies of primary or recurrent pterygium. The outcomes of conjunctival or limbal autograft were similar to outcomes for intraoperative mitomycin C in the few studies that directly compared the 2 techniques. There is evidence that increased concentration and duration of exposure to intraoperative mitomycin C is associated with increased efficacy. Of the adjuvants studied, only mitomycin C was associated with vision-threatening complications, including scleral thinning, ulceration, and delayed conjunctival epithelialization; there is some evidence of increasing complications with increased concentration and duration of exposure. There is conflicting evidence as to whether increasing age is protective against recurrence, but the morphologic features of the pterygium were shown to affect the recurrence rate. CONCLUSIONS: Evidence indicates that bare sclera excision of pterygium results in a significantly higher recurrence rate than excision accompanied by use of certain adjuvants. Conjunctival or limbal autograft was superior to amniotic membrane graft surgery in reducing the rate of pterygium recurrence. Among other adjuvants, there is evidence that mitomycin C and conjunctival or limbal autografts reduce the recurrence rate after surgical excision of a pterygium. Furthermore, the data indicate that using a combination of conjunctival or limbal autograft with mitomycin C further reduces the recurrence rate after pterygium excision compared with conjunctival or limbal autograft or mitomycin C alone. Additional studies are necessary to determine the long-term effects, optimal route of administration, and dose and duration of treatment for mitomycin C. Factors such as availability of resources, primary or recurrent status of pterygium, age of patient, and surgeon or patient preference may influence the surgeon's choice of adjuvant because there are insufficient data to recommend a specific adjuvant as superior. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.
Assuntos
Alquilantes/administração & dosagem , Âmnio/transplante , Túnica Conjuntiva/transplante , Mitomicina/administração & dosagem , Procedimentos Cirúrgicos Oftalmológicos , Pterígio/cirurgia , Academias e Institutos , Humanos , Oftalmologia/organização & administração , Avaliação de Resultados em Cuidados de Saúde , Recidiva , Transplante Autólogo , Estados UnidosRESUMO
Transgenic expression of the α7 integrin can ameliorate muscle pathology in a mouse model of Duchenne muscular dystrophy (mdx/utr(-/-)) and thus can compensate for the loss of dystrophin in diseased mice. In spite of the beneficial effects of the α7 integrin in protecting mice from dystrophy, identification of molecular signaling events responsible for these changes remains to be established. The purpose of this study was to determine a role for signaling in the amelioration of muscular dystrophy by α7 integrin. Activation of PI3K, ILK, AKT, mTOR, p70S6K, BAD, ERK, and p38 was measured in the muscle from wild type (WT), mdx/utr(-/-) and α7BX2-mdx/utr(-/-) mice using in vitro activity assays or phosphospecific antibodies and western blotting. Significant increases in PI3K activity (47%), ILK activity (2.0-fold), mTOR (Ser2448) (57%), p70S6K (Thr389) (11.7-fold), and ERK (Thr202/Tyr204) (66%) were demonstrated in dystrophic mdx/utr(-/-) muscle compared to WT. A significant decrease in p38 phosphorylation (2.9-fold) was also observed. Although most of these signaling events were similar in dystrophic mdx/utr(-/-) mice overexpressing the α7 integrin, the AKT (Ser473):AKT ratio (2-fold vs. WT) and p70S6K phosphorylation (18-fold vs. WT) were higher in α7BX2-mdx/utr(-/-) compared to mdx/utr(-/-) mice. In addition, increased phosphorylation of BAD Serine 112 may contribute to the significant reduction in TUNEL(+) cells observed in α7BX2-mdx/utr(-/-) mice. We conclude that the α7ß1 integrin confers a protective effect in dystrophic muscle through the activation of the ILK, AKT, p70S6K and BAD signaling to promote muscle cell survival.
Assuntos
Integrinas/metabolismo , Distrofia Muscular de Duchenne/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Apoptose , Regulação da Expressão Gênica , Integrinas/genética , Camundongos , Camundongos Endogâmicos mdx , Camundongos Transgênicos , Músculo Esquelético/metabolismo , Distrofia Muscular de Duchenne/genética , Fosforilação , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Transdução de Sinais , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
BACKGROUND: Non-small-cell lung cancer (NSCLC) is categorized into various histologic subtypes that play an important role in prognosis and treatment outcome. We investigated the antitumor activity of motesanib, a selective antagonist of vascular endothelial growth factor receptors (VEGFR) 1, 2, and 3, platelet-derived growth factor receptor, and Kit, alone and combined with chemotherapy in five human NSCLC xenograft models (A549, Calu-6, NCI-H358, NCI-H1299, and NCI-H1650) containing diverse genetic mutations. RESULTS: Motesanib as a single agent dose-dependently inhibited tumor xenograft growth compared with vehicle in all five of the models (P < 0.05). When combined with cisplatin, motesanib significantly inhibited the growth of Calu-6, NCI-H358, and NCI-H1650 tumor xenografts compared with either single agent alone (P < 0.05). Similarly, the combination of motesanib plus docetaxel significantly inhibited the growth of A549 and Calu-6 tumor xenografts compared with either single agent alone (P < 0.05). In NCI-H358 and NCI-H1650 xenografts, motesanib with and without cisplatin significantly decreased tumor blood vessel area (P < 0.05 vs vehicle) as assessed by anti-CD31 staining. Motesanib alone or in combination with chemotherapy had no effect on tumor cell proliferation in vitro. CONCLUSIONS: These data demonstrate that motesanib had antitumor activity against five different human NSCLC xenograft models containing diverse genetic mutations, and that it had enhanced activity when combined with cisplatin or docetaxel. These effects appeared to be mediated primarily by antiangiogenic mechanisms.
Assuntos
Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas , Indóis/farmacologia , Neoplasias Pulmonares , Niacinamida/análogos & derivados , Taxoides/farmacologia , Animais , Antineoplásicos/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cisplatino/administração & dosagem , Cisplatino/farmacologia , Docetaxel , Feminino , Expressão Gênica , Humanos , Indóis/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Nus , Mutação , Niacinamida/administração & dosagem , Niacinamida/farmacologia , Oligonucleotídeos , Taxoides/administração & dosagem , Carga Tumoral/efeitos dos fármacos , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Erythropoiesis stimulating agents (ESAs) have been reported to activate erythropoietin receptors (EpoR) on cell types, including endothelial, neuronal, renal tubule, and cardiac cells. ESAs have also been reported to promote angiogenesis. However, those findings are controversial and confounded by methodologic issues. We show that EpoR mRNA was detected in essentially all cell types examined, including primary human endothelial, renal, cardiac, and neuronal cells but 10- to 100-fold lower than Epo-responsive cells using quantitative reverse-transcribed polymerase chain reaction. Total endothelial EpoR protein examined using a new monoclonal antibody was low to undetectable. Surface EpoR on endothelial cells was not detected using [(125)I]-rHuEpo surface-binding studies. There was no evidence of ESA-induced intracellular signaling in endothelial cells. There was a similar lack of EpoR expression and signaling in other cell types examined. Experiments were performed examining ESA function on these cells. An in vivo rat corneal angiogenesis assay demonstrated neo-vessel formation in response to recombinant human vascular endothelial growth factor (rHuVEGF). However, recombinant mouse Epo did not induce vessel formation. Similarly, ESAs did not reproducibly provide cytoprotection to neuronal, renal, or cardiac cells. Taken together, our data challenge the notion of presence or function of EpoR on nonhematopoietic cells, and call into question the preclinical basis for clinical studies exploring direct, "pleiotropic" actions of ESAs.
Assuntos
Células Endoteliais/metabolismo , Túbulos Renais Proximais/metabolismo , Miócitos Cardíacos/metabolismo , Neurônios/metabolismo , Receptores da Eritropoetina/metabolismo , Animais , Sequência de Bases , Linhagem Celular , Células Cultivadas , Primers do DNA/genética , Células Endoteliais/efeitos dos fármacos , Eritropoetina/metabolismo , Eritropoetina/farmacologia , Hematínicos/farmacologia , Humanos , Túbulos Renais Proximais/citologia , Túbulos Renais Proximais/efeitos dos fármacos , Camundongos , Miócitos Cardíacos/efeitos dos fármacos , Neovascularização Fisiológica/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Células PC12 , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Receptores da Eritropoetina/genética , Proteínas Recombinantes/farmacologia , Transdução de Sinais/efeitos dos fármacos , Distribuição Tecidual , Fatores de Crescimento do Endotélio Vascular/farmacologiaRESUMO
Angiopoietin-2 (Ang2) exhibits broad expression in the remodeling vasculature of human tumors but very limited expression in normal tissues, making it an attractive candidate target for antiangiogenic cancer therapy. To investigate the functional consequences of blocking Ang2 activity, we generated antibodies and peptide-Fc fusion proteins that potently and selectively neutralize the interaction between Ang2 and its receptor, Tie2. Systemic treatment of tumor-bearing mice with these Ang2-blocking agents resulted in tumor stasis, followed by elimination of all measurable tumor in a subset of animals. These effects were accompanied by reduced endothelial cell proliferation, consistent with an antiangiogenic therapeutic mechanism. Anti-Ang2 therapy also prevented VEGF-stimulated neovascularization in a rat corneal model of angiogenesis. These results imply that specific Ang2 inhibition may represent an effective antiangiogenic strategy for treating patients with solid tumors.
Assuntos
Angiopoietina-2/antagonistas & inibidores , Angiopoietina-2/imunologia , Anticorpos/farmacologia , Neoplasias/irrigação sanguínea , Neovascularização Patológica/prevenção & controle , Animais , Proliferação de Células/efeitos dos fármacos , Córnea/irrigação sanguínea , Células Endoteliais/efeitos dos fármacos , Feminino , Camundongos , Camundongos Nus , Transplante de Neoplasias , Testes de Neutralização , Receptores Fc , Proteínas Recombinantes de Fusão/farmacologia , Células Tumorais CultivadasRESUMO
γ-Secretase modulators (GSMs) have received much attention as potential therapeutic agents for Alzheimer's disease (AD). GSMs increase the ratio between short and long forms of the amyloid-ß (Aß) polypeptides produced by γ-secretase and thereby decrease the amount of the toxic amyloid species. However, the mechanism of action of these agents is still poorly understood. One recent paper [Richter et al. (2010) Proc. Natl. Acad. Sci. U. S. A.107, 14597-14602] presented data that were interpreted to support direct binding of the GSM sulindac sulfide to Aß(42), supporting the notion that GSM action is linked to direct binding of these compounds to the Aß domain of its immediate precursor, the 99-residue C-terminal domain of the amyloid precursor protein (C99, also known as the ß-CTF). Here, contrasting results are presented that indicate there is no interaction between monomeric sulindac sulfide and monomeric forms of Aß42. Instead, it was observed that sulindac sulfide is itself prone to form aggregates that can bind nonspecifically to Aß42 and trigger its aggregation. This observation, combined with data from previous work [Beel et al. (2009) Biochemistry48, 11837-11839], suggests both that the poor behavior of some NSAID-based GSMs in solution may obscure results of binding assays and that NSAID-based GSMs do not function by directly targeting C99. It was also observed that another GSM, flurbiprofen, fails to bind to monomeric Aß42 or to C99 reconstituted into bilayered lipid vesicles. These results disfavor the hypothesis that these NSAID-based GSMs exert their modulatory effect by directly targeting a site located in the Aß42 domain of free C99.
Assuntos
Doença de Alzheimer/enzimologia , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Secretases da Proteína Precursora do Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Anti-Inflamatórios não Esteroides/farmacologia , Inibidores Enzimáticos/farmacologia , Doença de Alzheimer/genética , Secretases da Proteína Precursora do Amiloide/genética , Precursor de Proteína beta-Amiloide/química , Precursor de Proteína beta-Amiloide/genética , Humanos , Cinética , Peptídeos/química , Peptídeos/genética , Peptídeos/metabolismo , Ligação Proteica , Processamento de Proteína Pós-TraducionalRESUMO
OBJECTIVE: To review the published literature on deep anterior lamellar keratoplasty (DALK) to compare DALK with penetrating keratoplasty (PK) for the outcomes of best spectacle-corrected visual acuity (BSCVA), refractive error, immune graft rejection, and graft survival. METHODS: Searches of the peer-reviewed literature were conducted in the PubMed and the Cochrane Library databases. The searches were limited to citations starting in 1997, and the most recent search was in May 2009. The searches yielded 1024 citations in English-language journals. The abstracts of these articles were reviewed, and 162 articles were selected for possible clinical relevance, of which 55 were determined to be relevant to the assessment objective. RESULTS: Eleven DALK/PK comparative studies (level II and level III evidence) were identified that compared the results of DALK and PK procedures directly; they included 481 DALK eyes and 501 PK eyes. Of those studies reporting vision and refractive data, there was no significant difference in BSCVA between the 2 groups in 9 of the studies. There was no significant difference in spheroequivalent refraction in 6 of the studies, nor was there a significant difference in postoperative astigmatism in 9 of the studies, although the range of astigmatism was often large for both groups. Endothelial cell density (ECD) stabilized within 6 months after surgery in DALK eyes. Endothelial cell density values were higher in the DALK groups in all studies at study completion, and, in general, the ECD differences between DALK and PK groups were significant at all time points at 6 months or longer after surgery for all of the studies reporting data. CONCLUSIONS: On the basis of level II evidence in 1 study and level III evidence in 10 studies, DALK is equivalent to PK for the outcome measure of BSCVA, particularly if the surgical technique yields minimal residual host stromal thickness. There is no advantage to DALK for refractive error outcomes. Although improved graft survival in DALK has yet to be demonstrated, postoperative data indicate that DALK is superior to PK for preservation of ECD. Endothelial immune graft rejection cannot occur after DALK, which may simplify long-term management of DALK eyes compared with PK eyes. As an extraocular procedure, DALK has important theoretic safety advantages, and it is a good option for visual rehabilitation of corneal disease in patients whose endothelium is not compromised.
Assuntos
Transplante de Córnea , Rejeição de Enxerto/fisiopatologia , Sobrevivência de Enxerto/fisiologia , Ceratoplastia Penetrante , Erros de Refração/fisiopatologia , Acuidade Visual/fisiologia , Academias e Institutos/organização & administração , Contagem de Células , Doenças da Córnea/fisiopatologia , Doenças da Córnea/reabilitação , Bases de Dados Factuais , Endotélio Corneano/patologia , Humanos , Oftalmologia/organização & administração , Refração Ocular/fisiologia , Avaliação da Tecnologia Biomédica , Resultado do Tratamento , Estados UnidosRESUMO
Purpose: This work aims to determine whether previously defined genotype risk groups interact with Age-Related Eye Disease Study formulation (AREDS-F) use in progression to neovascular age-related macular degeneration (nvAMD). Methods: We conducted a case-only study of 265 nvAMD patients. Patients were anonymously genotyped at the complement factor H and age-related maculopathy susceptibility 2 loci and segregated into genotype groups (GTGs) defined by specific combinations of risk alleles. Physicians, who were blind to patients' GTGs, obtained patients' AREDS-F use history. The facility performing genetic analysis was blind to the AREDS-F use history. We used logistic analysis to estimate the interaction coefficient between AREDS-F use and GTG 2 vs GTG 3 in a general-population model. Results: The odds ratio of numbers of patients reporting prior AREDS-F use to nonuse for GTG 2 vs GTG 3 was 4.18 (P = .001). Logistic regression, correcting for nongenetic risk factors, gave an estimate of the ß for interaction of AREDS-F with genotype of 1.57 (P = .001). This estimates a corrected odds ratio associated with the effect of interaction of 4.81 between those in GTG 2 compared with those in GTG 3. Conclusions: Our data indicate an interaction between GTGs and AREDS-F use that is consistent in size and direction with previously published reports, which had found that using AREDS-F supplements significantly increases the risk of nvAMD for some users and significantly protects other users.
RESUMO
Duchenne muscular dystrophy is a lethal neuromuscular disease that currently has no effective therapy. Transgenic overexpression of the alpha7 integrin in mdx/utrn(-/-) mice, a model of Duchenne muscular dystrophy ameliorates the disease. We have isolated and used alpha7(+/-) muscle cells expressing beta-galactosidase, driven by the endogenous alpha7 promoter, to identify compounds that increase alpha7 integrin levels. Valproic acid (VPA) was found to enhance alpha7 integrin levels, induce muscle hypertrophy, and inhibit apoptosis in myotubes by activating the Akt/mTOR/p70S6K pathway. This activation of the Akt pathway occurs within 1 hour of treatment and is mediated by phosphatidylinositol 3-OH kinase. To evaluate the potential use of VPA to treat muscular dystrophy, mdx/utrn(-/-) mice were injected with the drug. Treatment with VPA lowered collagen content and fibrosis, and decreased hind limb contractures. VPA-treated mice also had increased sarcolemmal integrity and decreased damage, decreased CD8-positive inflammatory cells, and higher levels of activated Akt in their muscles. Thus, VPA has important biological effects that may be applicable for the treatment of muscular dystrophy.
Assuntos
Distrofia Muscular de Duchenne/enzimologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ácido Valproico/farmacologia , Animais , Proteínas de Transporte/metabolismo , Técnicas de Cultura de Células , Modelos Animais de Doenças , Ativação Enzimática/efeitos dos fármacos , Engenharia Genética , Hipertrofia , Camundongos , Camundongos Endogâmicos mdx , Fibras Musculares Esqueléticas/patologia , Músculo Esquelético/enzimologia , Músculo Esquelético/patologia , Distrofia Muscular de Duchenne/patologia , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Regiões Promotoras Genéticas , Serina-Treonina Quinases TOR , beta-Galactosidase/genéticaRESUMO
The dystrophin-glycoprotein complex is a large complex of membrane-associated proteins linking the cytoskeleton to the extracellular matrix in muscle. Transmembrane heterodimeric (alphabeta) integrins serve also as cellular adhesion molecules and mechanotransducers. In the animal model for Duchenne muscular dystrophy, the mdx mouse, loss of dystrophin causes more severe abnormalities in skeletal than in cardiac muscle. We hypothesized that ablation of cardiac myocyte integrins in the mdx background would lead to a severe cardiomyopathic phenotype. Mdx mice were crossed to ones with cardiac myocyte-specific deletion of beta1 integrin (beta1KO) to generate beta1KOmdx. Unstressed beta1KOmdx mice were viable and had normal cardiac function; however, high mortality was seen in peri- and postpartum females by 6 months of age, when severe myocardial necrosis and fibrosis and extensive dystrophic calcification was seen. Decreased ventricular function and blunted adrenergic responsiveness was found in the beta1KOmdx mice compared with control (Lox/Lox, no Cre), beta1KO, and mdx. Similarly, adult beta1KOmdx males were more prone to isoproterenol-induced heart failure and death compared with control groups. Given the extensive calcification, we analyzed transcript levels of genes linked to fibrosis and calcification and found matrix gamma-carboxyglutamic acid protein, decorin, periostin, and the osteoblast transcription factor Runx2/Cbfa1 significantly increased in beta1KOmdx cardiac muscle. Our data show that combined deficiency of dystrophin and integrins in murine cardiac myocytes results in more severe cardiomyopathic changes in the stressed myocardium than reduction of either dystrophin or integrins alone and predisposes to myocardial calcification.
Assuntos
Calcinose/metabolismo , Cardiomiopatias/metabolismo , Distrofina/metabolismo , Integrina beta1/metabolismo , Miócitos Cardíacos/metabolismo , Função Ventricular , Agonistas Adrenérgicos beta/administração & dosagem , Animais , Calcinose/genética , Calcinose/fisiopatologia , Proteínas de Ligação ao Cálcio/metabolismo , Cardiomiopatias/genética , Cardiomiopatias/patologia , Cardiomiopatias/fisiopatologia , Moléculas de Adesão Celular/metabolismo , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Decorina , Modelos Animais de Doenças , Dobutamina/administração & dosagem , Distrofina/deficiência , Distrofina/genética , Proteínas da Matriz Extracelular/metabolismo , Feminino , Fibrose , Insuficiência Cardíaca/induzido quimicamente , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/fisiopatologia , Integrina beta1/genética , Isoproterenol/administração & dosagem , Masculino , Camundongos , Camundongos Endogâmicos mdx , Camundongos Knockout , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , Necrose , Fenótipo , Gravidez , Proteoglicanas/metabolismo , RNA Mensageiro/metabolismo , Índice de Gravidade de Doença , Fatores de Tempo , Regulação para Cima , Função Ventricular/efeitos dos fármacos , Proteína de Matriz GlaRESUMO
PURPOSE: Angiogenesis plays a critical role in breast cancer development and progression. Vascular endothelial growth factor (VEGF) is a potent angiogenic factor that regulates endothelial cell proliferation and survival. We investigated the effects of motesanib, a novel, oral inhibitor of VEGF receptors 1, 2, and 3; platelet-derived growth factor receptor; and Kit receptor, on the growth of xenografts representing various human breast cancer subtypes. EXPERIMENTAL DESIGN: Athymic nude mice were implanted with MCF-7 (luminal) or MDA-MB-231 (mesenchymal) tumor fragments or Cal-51 (mixed/progenitor) tumor cells. Once tumors were established, animals were randomized to receive increasing doses of motesanib alone or motesanib plus cytotoxic chemotherapy (docetaxel, doxorubicin, or tamoxifen). RESULTS: Across all three xenograft models, motesanib treatment resulted in significant dose-dependent reductions in tumor growth, compared with vehicle-treated controls, and in marked reductions in viable tumor fraction and blood vessel density. No significant effect on body weight was observed with compound treatment compared with control-treated animals. Motesanib did not affect the proliferation of tumor cells in vitro. There was a significantly greater reduction in xenograft tumor growth when motesanib was combined with docetaxel (MDA-MB-231 tumors) or with the estrogen receptor modulator tamoxifen (MCF-7 tumors), compared with either treatment alone, but not when combined with doxorubicin (Cal-51 tumors). CONCLUSIONS: Treatment with motesanib alone or in combination with chemotherapy inhibits tumor growth in vivo in various models of human breast cancer. These data suggest that motesanib may have broad utility in the treatment of human breast cancer.
Assuntos
Inibidores da Angiogênese/uso terapêutico , Indóis/uso terapêutico , Neoplasias Mamárias Experimentais/tratamento farmacológico , Niacinamida/análogos & derivados , Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-kit/metabolismo , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Peso Corporal/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Humanos , Neoplasias Mamárias Experimentais/irrigação sanguínea , Camundongos , Camundongos Nus , Niacinamida/uso terapêutico , Oligonucleotídeos , Distribuição Aleatória , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
OBJECTIVE: To review the published literature on safety and outcomes of Descemet's stripping endothelial keratoplasty (DSEK) for the surgical treatment of endothelial diseases of the cornea. DESIGN: Peer-reviewed literature searches were conducted in PubMed and the Cochrane Library with the most recent search in February 2009. The searches yielded 2118 citations in English-language journals. The abstracts of these articles were reviewed and 131 articles were selected for possible clinical relevance, of which 34 were determined to be relevant to the assessment objectives. RESULTS: The most common complications from DSEK among reviewed reports included posterior graft dislocations (mean, 14%; range, 0%-82%), followed by endothelial graft rejection (mean, 10%; range, 0%-45%), primary graft failure (mean, 5%; range, 0%-29%), and iatrogenic glaucoma (mean, 3%; range, 0%-15%). Average endothelial cell loss as measured by specular microscopy ranged from 25% to 54%, with an average cell loss of 37% at 6 months, and from 24% to 61%, with an average cell loss of 42% at 12 months. The average best-corrected Snellen visual acuity (mean, 9 months; range, 3-21 months) ranged from 20/34 to 20/66. A review of postoperative refractive results found induced hyperopia ranging from 0.7 to 1.5 diopters (D; mean, 1.1 D), with minimal induced astigmatism ranging from -0.4 to 0.6 D and a mean refractive shift of 0.11 D. A review of graft survival found that clear grafts at 1 year ranged from 55% to 100% (mean, 94%). CONCLUSIONS: The evidence reviewed is supportive of DSEK being a safe and effective treatment for endothelial diseases of the cornea. In terms of surgical risks, complication rates, graft survival (clarity), visual acuity, and endothelial cell loss, DSEK appears similar to penetrating keratoplasty (PK). It seems to be superior to PK in terms of earlier visual recovery, refractive stability, postoperative refractive outcomes, wound and suture-related complications, and intraoperative and late suprachoroidal hemorrhage risk. The most common complications of DSEK do not appear to be detrimental to the ultimate vision recovery in most cases. Long-term endothelial cell survival and the risk of late endothelial rejection are beyond the scope of this assessment. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.
Assuntos
Doenças da Córnea/cirurgia , Transplante de Córnea , Lâmina Limitante Posterior/cirurgia , Endotélio Corneano/transplante , Avaliação da Tecnologia Biomédica , Academias e Institutos/organização & administração , Sobrevivência de Enxerto , Humanos , Complicações Intraoperatórias , Oftalmologia/organização & administração , Complicações Pós-Operatórias , Resultado do Tratamento , Acuidade VisualRESUMO
A 66-year-old man presented with decreased vision and corneal edema after 2 failed Descemet-stripping automated endothelial keratoplasty (DSAEK) graft procedures in the left eye. An uneventful third DSAEK procedure combined with anterior vitrectomy through the previous limbal wound was performed. Postoperative recovery was uneventful. Histopathology of the excised failed graft revealed conjunctival epithelium on the posterior surface of the tissue. At 1 year, the endothelial cell count was 1997 cells/mm(2) and the uncorrected visual acuity was 20/20(-2). At 18 months, the graft remained clear with no signs of epithelial downgrowth. Clinicians should be aware that epithelial downgrowth can occur following DSAEK surgery. Fortunately, excision of the prior DSAEK graft with removal of the active epithelial membrane appears to have been a successful treatment in this patient.