RESUMO
INTRODUCTION: Health needs assessment (HNA) targets health resources to needs yet is rarely used in low-resource contexts such as the Indian villages. METHODS: The authors combined rapid participatory appraisal (RPA) and HNA tools into 4 steps: (a) define HNA parameters, objectives, and community; (b) describe community demographics, health status, felt needs, assets, and health services; (c) analysis; and (d) design interventions considering felt needs, assets, impact potential, and organizational resources. RESULTS: Community felt needs focused on lack of access to personal health services. Major morbidities included respiratory and diarrheal disease and maternal/child health problems. Formal anthropometry revealed high prevalence of underweight and stunting. Community assets included high land ownership, educated unmarried women, and operational government services. CONCLUSIONS: In low-resource developing country contexts with poor information systems, HNA is possible and useful. Including RPA and community participation to also assess assets resulted in programs responding to communities' needs using existing resources.
Assuntos
Avaliação das Necessidades/organização & administração , Serviços de Saúde Rural/organização & administração , Adulto , Feminino , Acessibilidade aos Serviços de Saúde/organização & administração , Humanos , Índia , Fatores SocioeconômicosRESUMO
OBJECTIVE: To compare the visual outcome of traumatic optic neuropathy treated with corticosteroids, treated with optic canal decompression surgery, or observed without treatment. DESIGN: Comparative nonrandomized interventional study with concurrent treatment groups. PARTICIPANTS: A total of 133 patients with traumatic optic neuropathy (127 unilateral and 6 bilateral) who had an initial visual assessment within 3 days of injury. At least 1 month of follow-up was required for inclusion in the primary analysis. INTERVENTIONS: On the basis of treatment received within 7 days of injury, patients with unilateral injuries were categorized as being in one of three treatment groups: untreated (n = 9), corticosteroid (n = 85), or optic canal decompression surgery (n = 33). MAIN OUTCOME MEASURE: Visual acuity. RESULTS: Visual acuity increased by > or = 3 lines in 32% of the surgery group, 57% of the untreated group, and 52% of the steroid group (P = 0.22). The surgery group had more patients whose initial vision was no light perception. After adjustment for the baseline visual acuity, there were no significant differences between any of the treatment groups. There was no indication that the dosage or timing of corticosteroid treatment or the timing of surgery was associated with an increased probability of visual improvement. CONCLUSIONS: No clear benefit was found for either corticosteroid therapy or optic canal decompression surgery. The number of patients studied was sufficient to rule out major effects in the treatment groups, although clinically relevant effects in specific subgroups could have been missed. These results and the existing literature provide sufficient evidence to conclude that neither corticosteroids nor optic canal surgery should be considered the standard of care for patients with traumatic optic neuropathy. It is therefore clinically reasonable to decide to treat or not treat on an individual patient basis.
Assuntos
Descompressão Cirúrgica/métodos , Traumatismos Oculares/terapia , Glucocorticoides/uso terapêutico , Metilprednisolona/uso terapêutico , Doenças do Nervo Óptico/terapia , Traumatismos do Nervo Óptico , Adulto , Traumatismos Oculares/etiologia , Traumatismos Oculares/fisiopatologia , Feminino , Seguimentos , Saúde Global , Glucocorticoides/administração & dosagem , Humanos , Masculino , Metilprednisolona/administração & dosagem , Doenças do Nervo Óptico/etiologia , Doenças do Nervo Óptico/fisiopatologia , Traumatismos do Nervo Óptico/fisiopatologia , Resultado do Tratamento , Acuidade Visual/fisiologiaRESUMO
The management of traumatic optic neuropathy remains controversial. In this report, we present the results of 45 patients treated with extracranial optic nerve decompression after at least 12 to 24 hours of corticosteroid therapy without improvement. Vision improved in 32 patients after surgery (71%), and the mean percentage of improvement from preoperative visual deficit was 40.7% +/- 6.9% (median improvement 41.2%). Worsening of vision occurred in none of the patients as a result of the surgery, and no intraoperative or postoperative complications were encountered. We present a treatment protocol for traumatic optic neuropathy with the use of megadose corticosteroids and optic nerve decompression.
Assuntos
Descompressão Cirúrgica , Doenças do Nervo Óptico/cirurgia , Adolescente , Adulto , Idoso , Dexametasona/uso terapêutico , Feminino , Glucocorticoides/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Doenças do Nervo Óptico/tratamento farmacológico , Doenças do Nervo Óptico/etiologia , Falha de Tratamento , Resultado do TratamentoRESUMO
Over a 10-year period the authors have performed 92 transethmoidal optic nerve decompressions for the treatment of visual loss due to various pathological processes, including 45 cases of trauma, 32 cases of neoplasm, 2 cases of bacterial pansinusitis, 5 cases of sphenoethmoidal mucocele, 4 cases of aspergillosis (all were immunocompetent patients), 2 cases of Wegener's granulomatosis, and 2 cases of sarcoidosis. Forty-eight patients (52%) had preoperative visual acuity of light perception or better, and in 44 patients (48%) the preoperative vision was no light perception. Sixty-five patients (71%) achieved improvement of vision postoperatively. Twenty-four patients (26%) had no change in vision and 3 patients (3%) had deterioration of vision after surgery. The mean percentage of improvement was 40.7% +/- 6.9% in the trauma group, 61.6% +/- 23.2% in the neoplasm group, 66.4% +/- 25.2% in the infectious/mucocele group, and only one patient in the inflammatory group had slight visual improvement from no light perception to counting fingers. Extracranial optic nerve decompression can result in the improvement of visual function in some patients with optic nerve injury from various causes.
Assuntos
Descompressão Cirúrgica/métodos , Osso Etmoide/cirurgia , Procedimentos Neurocirúrgicos/métodos , Traumatismos do Nervo Óptico/cirurgia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Granulomatose com Poliangiite/complicações , Granulomatose com Poliangiite/cirurgia , Neoplasias de Cabeça e Pescoço/complicações , Neoplasias de Cabeça e Pescoço/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Mucocele/complicações , Mucocele/cirurgia , Síndromes de Compressão Nervosa/complicações , Síndromes de Compressão Nervosa/etiologia , Síndromes de Compressão Nervosa/cirurgia , Traumatismos do Nervo Óptico/complicações , Traumatismos do Nervo Óptico/etiologia , Estudos Retrospectivos , Sinusite/complicações , Sinusite/cirurgia , Resultado do Tratamento , Transtornos da Visão/etiologia , Transtornos da Visão/cirurgia , Acuidade VisualRESUMO
OBJECTIVE: To discuss the multidisciplinary management of psammomatoid ossifying fibroma (POF) of the orbit and to clarify the clinicopathologic terminology. DESIGN: The authors present a cohort of cases of POF involving the frontal and ethmoid sinuses and the orbit and discuss the nomenclature and literature. PARTICIPANTS: Three patients with POF and their treatment are discussed. INTERVENTION: Patients were worked up and treated by a multidisciplinary team using imaging studies and histopathologic analysis. Reconstruction, if necessary, was carried out at the time of excision or in a second-stage procedure. MAIN OUTCOME MEASURES: In each case, the lesion was completely excised and has not recurred. RESULTS: The diagnosis of POF was made in each case, and the patient underwent successful resection of the tumor. CONCLUSION: The authors' experience suggests that a multidisciplinary approach, including a radiologist, pathologist, neurosurgeon, otolaryngologist, craniofacial surgeon, and orbital specialist, may be useful in the evaluation and management of these lesions.
Assuntos
Seio Etmoidal/cirurgia , Fibroma Ossificante/cirurgia , Seio Frontal/cirurgia , Neoplasias Orbitárias/cirurgia , Neoplasias dos Seios Paranasais/cirurgia , Adolescente , Adulto , Criança , Estudos de Coortes , Seio Etmoidal/diagnóstico por imagem , Seio Etmoidal/patologia , Feminino , Fibroma Ossificante/diagnóstico por imagem , Fibroma Ossificante/patologia , Seio Frontal/diagnóstico por imagem , Seio Frontal/patologia , Humanos , Masculino , Neoplasias Orbitárias/diagnóstico por imagem , Neoplasias Orbitárias/patologia , Neoplasias dos Seios Paranasais/diagnóstico por imagem , Neoplasias dos Seios Paranasais/patologia , Equipe de Assistência ao Paciente , Tomografia Computadorizada por Raios XAssuntos
Artéria Carótida Interna , Hemorragia Cerebral/etiologia , Fraturas Cranianas/complicações , Osso Temporal/lesões , Adulto , Artéria Carótida Interna/diagnóstico por imagem , Hemorragia Cerebral/diagnóstico por imagem , Hemorragia Cerebral/patologia , Evolução Fatal , Hematoma Subdural/etiologia , Humanos , Masculino , Fraturas Cranianas/diagnóstico por imagem , Osso Temporal/diagnóstico por imagem , Tomografia Computadorizada por Raios XAssuntos
Cegueira/cirurgia , Descompressão Cirúrgica , Traumatismos Maxilofaciais/complicações , Neuropatia Óptica Isquêmica/etiologia , Neuropatia Óptica Isquêmica/cirurgia , Adulto , Beisebol/lesões , Cegueira/etiologia , Síndromes Compartimentais/complicações , Síndromes Compartimentais/etiologia , Humanos , Masculino , Traumatismos Maxilofaciais/cirurgia , Neuropatia Óptica Isquêmica/complicações , Fraturas Orbitárias/complicações , Fraturas Orbitárias/cirurgia , Complicações Pós-Operatórias/cirurgia , Hemorragia Retrobulbar/complicações , Hemorragia Retrobulbar/etiologiaRESUMO
This prospective clinical descriptive study was designed to see whether patients who had endoscopic sinus surgery for sinusitis had relief of pain, and whether they had new pain postoperatively. The sample was 252 consecutive patients who underwent endoscopic sinus surgery after presenting with inflammatory sinus disorders meeting specific clinical definitions of sinusitis and criteria for surgically treatable sinus disorders developed by the treating surgeon. Of the 252 consecutive endoscopic sinus surgery patients, 106 (42%) had no preoperative pain and 146 (58%) patients had preoperative sinus pain. At 6- to 12-month postoperative evaluations, patients with no preoperative pain did not develop any new postoperative pain. Among the 146 patients with preoperative pain, 82 (56%) had no pain, residual symptoms, or further sequelae, and were considered cured; 42 (29%) reported a marked improvement of pain or discomfort; 9 (6%) had the same degree of pain or discomfort as before; 3 (2%) reported worse pain or discomfort; and 10 (7%) reported new pain or discomfort. These results suggest that the application of consistent definitions and clinical criteria for various forms of surgically treatable sinusitis will more likely predict improvement of pain and discomfort following surgical treatment. The risk of developing new pain and discomfort following endoscopic sinus surgery in individuals without preoperative pain or discomfort is negligible. The risk of worsening pain or new pain was less than 10% in patients with preoperative pain. Ongoing efforts such as the International Conference on Sinus Disease in the development of consistent terminology, staging, and therapy, and future modifications from additional clinical experience, should result in more predictable and effective care in the surgical treatment for pain of sinus disease.
Assuntos
Endoscopia , Dor Pós-Operatória/diagnóstico , Dor/diagnóstico , Sinusite/cirurgia , Humanos , Dor/etiologia , Medição da Dor , Estudos Prospectivos , Estudos Retrospectivos , Sinusite/complicaçõesRESUMO
OBJECTIVE: To evaluate the outcome of extracranial optic nerve decompression in patients with compressive optic neuropathy secondary to intracranial, paranasal sinus, or orbital neoplastic processes. DESIGN: A retrospective chart review and clinical follow-up of patients who underwent optic nerve decompression. SETTING: Tertiary care referral center. PATIENTS: During an 8-year period, 95 extracranial optic nerve decompressions were performed by one of us (M.P.J.) for optic neuropathy resulting from traumatic, inflammatory, infectious, iatrogenic, neoplastic, and idiopathic processes. Thirty patients with compressive optic neuropathy secondary to histopathologically confirmed tumors were identified. INTERVENTION: Optic nerve decompression via external ethmoidectomy approach. RESULTS: Twenty (67%) of 30 patients showed improvement in vision. Improvement in 17 of the 20 patients has been stable. Seven patients (23%) showed no improvement but there was no further worsening of vision after surgery. In 3 patients (10%) vision deteriorated following surgery. CONCLUSION: Extracranial optic nerve decompression may be considered for the preservation or improvement of vision in selected patients with compressive optic neuropathy from neoplasms.
Assuntos
Neoplasias de Cabeça e Pescoço/complicações , Síndromes de Compressão Nervosa/etiologia , Síndromes de Compressão Nervosa/cirurgia , Doenças do Nervo Óptico/cirurgia , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Síndromes de Compressão Nervosa/fisiopatologia , Estudos Retrospectivos , Acuidade VisualRESUMO
OBJECTIVE: To study the efficacy of a newly designed treatment strategy for esthesioneuroblastoma and neuroendocrine carcinoma of the paranasal sinuses. DESIGN AND SETTING: Nonrandomized prospective study of a case series in a tertiary referral center. PATIENTS: Nine consecutive patients with newly diagnosed esthesioneuroblastoma or neuroendocrine carcinoma of the paranasal sinuses from June 1992 to October 1995 underwent this treatment protocol. INTERVENTIONS: After histological diagnosis and detailed imaging, 2 cycles of cisplatin and etoposide chemotherapy were instituted. Chemotherapy responders were treated with combined photon and stereotaxic fractionated proton radiation therapy totaling approximately 68 Gy to the primary site, whereas poor responders were treated with surgical resection followed by postoperative radiation. In both cases, therapy was then concluded with 2 additional cycles of cisplatin and etoposide chemotherapy. MAIN OUTCOMES MEASURES: Response to therapy, survival, disease-free survival, and complications of therapy were examined. RESULTS: Nine patients with a median Dulguerov T stage of T3 (range, T2 to T4) completed the treatment protocol, with mean follow-up after diagnosis of 20.5 months. Eight of 9 patients exhibited a dramatic response to therapy with remission of their tumor, and resection was not required. One patient failed to respond to induction chemotherapy and received surgical therapy to be followed by postoperative radiotherapy. There have been no recurrences (mean disease-free interval of 14.0 months). Complications were limited and generally transient. CONCLUSIONS: The use of combined cisplatin and etoposide chemotherapy with proton radiation has demonstrated initial success in treatment of these tumors. Dramatic response from chemotherapy is possible even in bulky or unresectable disease. This protocol has an acceptable complication rate and conveys less morbidity than craniofacial resection and conventional radiotherapy. Further follow-up will be required to determine the long-term success rate of this therapeutic protocol.
Assuntos
Carcinoma Neuroendócrino/tratamento farmacológico , Carcinoma Neuroendócrino/radioterapia , Estesioneuroblastoma Olfatório/tratamento farmacológico , Estesioneuroblastoma Olfatório/radioterapia , Neoplasias dos Seios Paranasais/tratamento farmacológico , Neoplasias dos Seios Paranasais/radioterapia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Neuroendócrino/diagnóstico , Carcinoma Neuroendócrino/cirurgia , Cisplatino/administração & dosagem , Terapia Combinada , Estesioneuroblastoma Olfatório/diagnóstico , Estesioneuroblastoma Olfatório/cirurgia , Etoposídeo/administração & dosagem , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Neoplasias dos Seios Paranasais/diagnóstico , Neoplasias dos Seios Paranasais/cirurgia , Estudos Prospectivos , Dosagem Radioterapêutica , Análise de Sobrevida , Resultado do TratamentoRESUMO
Osseous craniofacial arteriovenous malformations are rare and challenging entities. A 20-year retrospective review at our institutions identified 47 cases of craniofacial arteriovenous malformations, 3 of which were in children with extensive osseous facial structure involvement. Diagnostic evaluation included computed tomography, magnetic resonance imaging, and angiography. A 3-stage treatment protocol employed both transarterial embolization and direct intralesional puncture embolization followed by complete surgical resection. Mean intraperative blood loss was limited to 1000 mL. There were no complications during therapy. All 3 patients are without recurrence at 2- to 4-year follow-up. Osseous craniofacial arteriovenous malformations should be approached with multimodality therapy, incorporating interventional neuroradiologic and surgical management. Using the outlined protocol, these lesions can be treated safely and effectively.
Assuntos
Malformações Arteriovenosas , Ossos Faciais , Adolescente , Malformações Arteriovenosas/diagnóstico , Malformações Arteriovenosas/terapia , Criança , Terapia Combinada , Embolização Terapêutica , Ossos Faciais/cirurgia , Feminino , Humanos , Masculino , Mandíbula , Maxila , Estudos RetrospectivosAssuntos
Doenças do Sistema Nervoso Central/complicações , Transtornos do Olfato/etiologia , Sarcoidose/complicações , Transtornos da Visão/etiologia , Doenças do Sistema Nervoso Central/diagnóstico , Doenças do Sistema Nervoso Central/patologia , Diagnóstico Diferencial , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Doenças dos Seios Paranasais/complicações , Sarcoidose/diagnóstico , Sarcoidose/patologiaRESUMO
Blindness can result from traumatic optic neuropathy following facial trauma and can complicate the management of concomitant facial fractures. Traumatic optic neuropathy can cause a substantial delay in the repair of facial fractures, leading to compromised surgical results. It can also result in postoperative visual loss following facial fracture repair. We present four cases of traumatic optic neuropathy that compromised the treatment of facial fractures. The management of facial fractures in patients with traumatic optic neuropathy must proceed cautiously. Delayed primary repair of midface fractures by postponing surgery for 10 to 14 days may be of benefit in avoiding further deterioration of vision. In addition, megadose corticosteroids and/or optic nerve decompression is useful in the management of these patients.
Assuntos
Ossos Faciais/lesões , Síndromes de Compressão Nervosa/etiologia , Traumatismos do Nervo Óptico , Fraturas Cranianas/complicações , Corticosteroides/uso terapêutico , Adulto , Cegueira/etiologia , Emergências , Ossos Faciais/diagnóstico por imagem , Ossos Faciais/cirurgia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Síndromes de Compressão Nervosa/diagnóstico por imagem , Síndromes de Compressão Nervosa/cirurgia , Nervo Óptico/cirurgia , Fraturas Cranianas/diagnóstico por imagem , Fraturas Cranianas/cirurgia , Tomografia Computadorizada por Raios XRESUMO
OBJECTIVE: To evaluate the use of an anterior, transfacial transclival approach to midline posterior circulation aneurysms in five patients. SURGICAL APPROACH: A skin incision is made on the right side of the nose with subsequent bony and cartilaginous disarticulation of the nasal complex. The nose remains attached along the left side and is reflected laterally. Removal of the nasal septum and bilateral ethmoidectomy, medial maxillectomy (usually bilateral), and opening of the sphenoid yield a large triangular exposure of the anterior clivus. After removal of the clivus with a drill, the vertebral and basilar arteries are exposed through a midline dural opening. RESULTS: The approach provided excellent exposure of basilar artery trunk aneurysms with room available for temporary clip placement in three patients. In a fourth patient, a midline posterior inferior cerebellar artery aneurysm was clipped using this technique. A basilar trunk dissection was treated by proximal basilar occlusion through this exposure in a fifth patient. Although three patients developed transient cerebrospinal fluid leaks with symptoms of meningitis, no permanent neurological morbidity resulted from the use of the approach. CONCLUSION: The transfacial transclival approach to midline aneurysms of the basilar trunk and its branches provided excellent exposure for surgical treatment in five patients. No patient had postoperative palatal dysfunction and cosmetic results were excellent. Cerebrospinal fluid leak and meningitis continue to be the major drawbacks to the use of this approach, although the availability of modern broad-spectrum antibiotics lessens the chance of permanent neurological sequelae.
Assuntos
Artéria Basilar/cirurgia , Cerebelo/irrigação sanguínea , Fossa Craniana Posterior/cirurgia , Craniotomia/métodos , Aneurisma Intracraniano/cirurgia , Artéria Vertebral/cirurgia , Adulto , Idoso , Dissecção Aórtica/cirurgia , Artérias/patologia , Artérias/cirurgia , Artéria Basilar/patologia , Angiografia Cerebral , Fossa Craniana Posterior/patologia , Feminino , Seguimentos , Humanos , Aneurisma Intracraniano/diagnóstico , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Seios Paranasais/patologia , Seios Paranasais/cirurgia , Complicações Pós-Operatórias/etiologia , Artéria Vertebral/patologiaRESUMO
Conventional strabismus surgery employs a conjunctival incision to gain access to Tenon's space where a wide variety of procedures are routinely performed on the tendon and anterior aspect of the extraocular muscles. Recently, transnasal endoscopic surgical techniques have gained acceptance as effective means of decompressing the medial wall and floor of the orbit in patients with thyroid-related orbitopathy. The orbital surface of the medial rectus and inferior rectus are exposed from the annulus of Zinn to a position close to where the muscles penetrate Tenon's capsule. In theory, this technique also provides the exposure necessary to locate and retrieve a "lost" medial rectus when the usual sub-Tenon's approach fails to recover the muscle. Cadaver studies demonstrate the feasibility of exposure and suture placement in the stump of a lost medial rectus with passage of the suture through Tenon's capsule to transmit the force of the muscle to the globe, provided that the lost muscle is retrieved before severe contracture develops.
Assuntos
Endoscopia/métodos , Cavidade Nasal/cirurgia , Músculos Oculomotores/cirurgia , Estrabismo/cirurgia , HumanosRESUMO
BACKGROUND: The management of traumatic optic neuropathy remains controversial. Reports of improvement have been published after observation alone, treatment with corticosteroids and surgical decompressions. OBJECTIVE: To systematically review the published literature about traumatic optic neuropathy using a meta-analysis. METHODS: We performed a retrospective literature review of case series and case reports of traumatic optic neuropathy. They include all English language cases and selected non-English language cases for which patient data were available. The cases were organized into four grades based on visual acuity and the locations and type of fracture. Grade 1 included patients with visual acuity greater than 20/200 in the affected eye and without a posterior orbit fracture; grade 2, patients with visual acuity between 20/200 and light perception; grade 3, patients without light perception or with a nondisplaced posterior orbital fracture and remaining vision; and grade 4, patients with no light perception and a displaced posterior orbital fracture. A meta-analysis was performed, analyzing for each case the recovery of visual acuity for treatment, fracture pattern, and grade. RESULTS: The recovery of vision in treated patients was significantly better than the recovery in patients receiving no treatment. No significant difference in improvement was found among patients treated with corticosteroids alone, with surgical decompression alone, or with corticosteroids and surgical decompression. Recovery was related to the severity of initial injury, as reflected in the grading system. A trend was noted for better improvement of visual acuity in patients without orbital fractures than those with orbital fractures, and also in patients with anterior orbital fractures than in patients with posterior fractures. CONCLUSIONS: Treatment with corticosteroids, extracranial decompression, or both, is better than no treatment of traumatic optic neuropathy. Because the data are insufficient to determine whether corticosteroids, surgery, or the use of both treatments is most effective, the findings of the ongoing International Optic Nerve Trauma Study should prove valuable. The standardized grading system we developed is a useful tool for comparing studies and treatment protocols.
Assuntos
Traumatismos Craniocerebrais/complicações , Doenças do Nervo Óptico/cirurgia , Traumatismos do Nervo Óptico , Corticosteroides/uso terapêutico , Terapia Combinada , Humanos , Doenças do Nervo Óptico/classificação , Doenças do Nervo Óptico/diagnóstico , Doenças do Nervo Óptico/etiologia , Fraturas Orbitárias/complicações , Estudos Retrospectivos , Índice de Gravidade de Doença , Resultado do Tratamento , Acuidade VisualRESUMO
Anterior midline approaches are safe and appropriate for extradural lesions of the central brain base. They are occasionally warranted for intradural lesions as well. Transnasal routes expose the clivus well. They are readily expanded superiorly, inferiorly, and laterally. Recent innovations are reductive; they expand exposure with less facial disassembly. Lateral and most intradural extensions of lesions warrant more lateral approaches.
Assuntos
Neurocirurgia/métodos , Base do Crânio/cirurgia , Neoplasias Encefálicas/cirurgia , Humanos , Neoplasias Hipofisárias/cirurgiaRESUMO
A conformational search using high-temperature molecular dynamics on angiotensin II(AII) and on two cyclic S-S bridged analogs, namely [Hcy3,5]AII and [Cys3,5]AII, in conjunction with a cluster analysis based on the similarities of the three-dimensional patterns of the binding and activation elements, had led to putative AII receptor-bound conformations. These conformations are characterized by a compact folded shape of the peptide backbone, and by particular relative positions of the four pharmacophore groups, namely the aromatic moieties of the Tyr4, His6 and Phe8 residues, and the C-terminal carboxyl group. This compact folded shape, arising from attractive electrostatic interactions between the desolvated N- and C-terminal groups, is similar to the crystallographically determined conformation of AII bound to the antibody Fab receptor.
Assuntos
Angiotensina II/química , Receptores de Angiotensina/química , Angiotensina II/análogos & derivados , Simulação por Computador , Modelos Moleculares , Conformação ProteicaRESUMO
The angiotensin II receptor of the AT1-type has been modeled starting from the experimentally determined three-dimensional structure of bacteriorhodopsin as the template. Intermediate 3D structures of rhodopsin and beta 2-adrenergic receptors were built because no direct sequence alignment is possible between the AT1 receptor and bacteriorhodopsin. Docking calculations were carried out on the complex of the modeled receptor with AII, and the results were used to analyze the binding possibilities of DuP753-type antagonistic non-peptide ligands. We confirm that the positively charged Lys199 on helix 5 is crucial for ligand binding, as in our model; the charged side chain of this amino acid interacts strongly with the C-terminal carboxyl group of peptide agonists or with the acidic group at the 2'-position of the biphenyl moiety of DuP753-type antagonists. Several other receptor residues which are implicated in the binding of ligands and the activation of receptor by agonists are identified, and their functional role is discussed. Therefore, a plausible mechanism of receptor activation is proposed. The three-dimensional docking model integrates most of the available experimental observations and helps to plan pertinent site-directed mutagenesis experiments which in turn may validate or modify the present model and the proposed mechanism of receptor activation.