RESUMO
A 37-year-old man presented with symptoms of intermittent claudication. Investigations revealed atypical calf vessel disease but no obvious aetiology. Ten years later he re-presented with worsening symptoms. CT angiography confirmed the atypical pattern of lower limb arterial disease but also noted calcification of the renal parenchyma, myocardium and scrotum. A diagnosis of pseudo-xanthoma elasticum was confirmed by skin biopsy. Pseudo-xanthoma elasticum is a rare condition that presents infrequently to vascular surgeons. Early recognition should prompt aggressive risk factor management to slow accelerated atherosclerosis. Clinicians should be aware of the clinical features of this condition to allow early diagnosis.
Assuntos
Claudicação Intermitente/etiologia , Pseudoxantoma Elástico/complicações , Pseudoxantoma Elástico/diagnóstico , Adulto , Humanos , MasculinoRESUMO
BACKGROUND: Electronic medical records (EMR) provide a unique opportunity for efficient, large-scale clinical investigation in psychiatry. However, such studies will require development of tools to define treatment outcome. METHOD: Natural language processing (NLP) was applied to classify notes from 127 504 patients with a billing diagnosis of major depressive disorder, drawn from out-patient psychiatry practices affiliated with multiple, large New England hospitals. Classifications were compared with results using billing data (ICD-9 codes) alone and to a clinical gold standard based on chart review by a panel of senior clinicians. These cross-sectional classifications were then used to define longitudinal treatment outcomes, which were compared with a clinician-rated gold standard. RESULTS: Models incorporating NLP were superior to those relying on billing data alone for classifying current mood state (area under receiver operating characteristic curve of 0.85-0.88 v. 0.54-0.55). When these cross-sectional visits were integrated to define longitudinal outcomes and incorporate treatment data, 15% of the cohort remitted with a single antidepressant treatment, while 13% were identified as failing to remit despite at least two antidepressant trials. Non-remitting patients were more likely to be non-Caucasian (p<0.001). CONCLUSIONS: The application of bioinformatics tools such as NLP should enable accurate and efficient determination of longitudinal outcomes, enabling existing EMR data to be applied to clinical research, including biomarker investigations. Continued development will be required to better address moderators of outcome such as adherence and co-morbidity.
Assuntos
Pesquisa Biomédica/métodos , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Registros Eletrônicos de Saúde , Avaliação de Resultados em Cuidados de Saúde/estatística & dados numéricos , Psiquiatria , Adulto , Algoritmos , Assistência Ambulatorial , Estudos Transversais , Transtorno Depressivo Resistente a Tratamento/epidemiologia , Feminino , Humanos , Classificação Internacional de Doenças , Modelos Logísticos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Modelos Teóricos , Processamento de Linguagem Natural , New England , Avaliação de Resultados em Cuidados de Saúde/métodos , Curva ROCRESUMO
AIMS/HYPOTHESIS: Diminished cortical filamentous actin (F-actin) has been implicated in skeletal muscle insulin resistance, yet the mechanism(s) is unknown. Here we tested the hypothesis that changes in membrane cholesterol could be a causative factor, as organised F-actin structure emanates from cholesterol-enriched raft microdomains at the plasma membrane. METHODS: Skeletal muscle samples from high-fat-fed animals and insulin-sensitive and insulin-resistant human participants were evaluated. The study also used L6 myotubes to directly determine the impact of fatty acids (FAs) on membrane/cytoskeletal variables and insulin action. RESULTS: High-fat-fed insulin-resistant animals displayed elevated levels of membrane cholesterol and reduced F-actin structure compared with normal chow-fed animals. Moreover, human muscle biopsies revealed an inverse correlation between membrane cholesterol and whole-body glucose disposal. Palmitate-induced insulin-resistant myotubes displayed membrane cholesterol accrual and F-actin loss. Cholesterol lowering protected against the palmitate-induced defects, whereas characteristically measured defects in insulin signalling were not corrected. Conversely, cholesterol loading of L6 myotube membranes provoked a palmitate-like cytoskeletal/GLUT4 derangement. Mechanistically, we observed a palmitate-induced increase in O-linked glycosylation, an end-product of the hexosamine biosynthesis pathway (HBP). Consistent with HBP activity affecting the transcription of various genes, we observed an increase in Hmgcr, a gene that encodes 3-hydroxy-3-methyl-glutaryl coenzyme A reductase, the rate-limiting enzyme in cholesterol synthesis. In line with increased HBP activity transcriptionally provoking a membrane cholesterol-based insulin-resistant state, HBP inhibition attenuated Hmgcr expression and prevented membrane cholesterol accrual, F-actin loss and GLUT4/glucose transport dysfunction. CONCLUSIONS/INTERPRETATION: Our results suggest a novel cholesterolgenic-based mechanism of FA-induced membrane/cytoskeletal disorder and insulin resistance.
Assuntos
Actinas/metabolismo , Colesterol/metabolismo , Glucose/metabolismo , Adulto , Animais , Transporte Biológico , Biópsia por Agulha/métodos , Membrana Celular/metabolismo , Citoesqueleto/metabolismo , Ácidos Graxos/metabolismo , Feminino , Humanos , Insulina/metabolismo , Masculino , Microdomínios da Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Músculo Esquelético/metabolismo , Ácido Palmítico/metabolismo , RatosRESUMO
Therapeutic aerosol bioengineering (TAB) of Mycobacterium tuberculosis (MTb) therapies using inhalable microparticles offers a unique opportunity to target drugs to the site of infection in the alveolar macrophages, thereby increasing dosing in the lungs and limiting systemic exposure to often toxic drugs. Previous work by us used sophisticated, high content analysis to design the optimal poly(lactide-co-glycolic) acid (PLGA) microparticle for delivery of drugs to alveolar macrophages. Herein, we applied this technology to three different anti-MTb drugs. These formulations were then tested for encapsulation efficiency, drug-release, in vitro killing against MTb and aerosol performance. Methods for encapsulating each of the drugs in the PLGA microparticles were successfully developed and found to be capable of controlling the release of the drug for up to 4 days. The efficacy of each of the encapsulated anti-MTb drugs was maintained and in some cases enhanced post-encapsulation. A method of processing these drug-loaded microparticles for inhalation using standard dry powder inhaler devices was successfully developed that enabled a very high respirable dose of the drug to be delivered from a simple dry powder inhaler device. Overall, TAB offers unique opportunities to more effectively treat MTb with many potential clinical and economic benefits resulting.
Assuntos
Aerossóis , Antituberculosos/uso terapêutico , Ácido Láctico/administração & dosagem , Microesferas , Ácido Poliglicólico/administração & dosagem , Tuberculose Pulmonar/tratamento farmacológico , Antituberculosos/administração & dosagem , Linhagem Celular , Portadores de Fármacos , Desenho de Fármacos , Humanos , Microscopia Eletrônica de Varredura , Copolímero de Ácido Poliláctico e Ácido PoliglicólicoRESUMO
Targeted delivery of anti-tubercular therapeutics to alveolar macrophages via inhalation aims to achieve optimal concentration of the therapeutic in the mycobacteria's niche environment. However, several challenges need to be overcome when designing a system to achieve this targeted, intracellular delivery. The first objective is to design a system that is suitable for inhalation, i.e. it must be capable of deposition in the alveolar region of the lungs. The theme of this commentary will be on the biological barriers for intracellular targeting to alveolar macrophages once particles are deposited in the lungs with emphasis on the delivery of anti-tubercular therapy and implications for novel vaccine formulations. The commentary focuses on four key features: 1) How Mycobacterium tuberculosis enters and is trafficked through macrophages, 2) the mechanism by which current drug delivery systems (DDS) enter and are trafficked through cells and 3) How an ideal DDS for anti-tubercular therapy would be trafficked through the macrophage and 4) the potential for using DDS for novel anti-tubercular therapy and vaccine development. These four features of targeted DDS shall be discussed in relation to some new findings from our own research.
Assuntos
Antituberculosos/farmacologia , Sistemas de Liberação de Medicamentos , Macrófagos Alveolares/efeitos dos fármacos , Mycobacterium tuberculosis/efeitos dos fármacos , Fagocitose/efeitos dos fármacos , Tuberculose Pulmonar/tratamento farmacológico , Humanos , Tuberculose Pulmonar/imunologiaRESUMO
Although sudden cardiac death is one of the most important mode of death in Western Countries, pathologists and public health physicians have not given this problem the attention it deserves. New methods of preventing potentially fatal arrhythmias have been developed and the accurate diagnosis of the causes of sudden cardiac death is now of particular importance. Pathologists are responsible for determining the precise cause of sudden death but there is considerable variation in the way in which they approach this increasingly complex task. The Association for European Cardiovascular Pathology developed these Guidelines, which represent the minimum standard that is required in the routine autopsy practice for the adequate assessment of sudden cardiac death, including not only a protocol for heart examination and histological sampling, but also for toxicology and molecular investigation. Our recommendations apply to University Medical Centres, Regional and District Hospitals and all types of Forensic Medicine Institutes. If a uniform method of investigation is adopted throughout the European Union, this will lead to improvements in standards of practice, allow meaningful comparisons between different communities and regions and, most importantly, permit future trends in the patterns of disease causing sudden death to be monitored.
RESUMO
Atherosclerosis is no longer considered a disorder of lipid accumulation, but a disease process characterized by the dynamic interaction between endothelial dysfunction, subendothelial inflammation and the 'wound healing response' of the vascular smooth muscle cells. Prospective epidemiological studies have unequivocally demonstrated increased vascular risk in individuals with elevated levels of (i) cytokines such as interleukin-6 and tumour necrosis factor-alpha, (ii) cell adhesion molecules such as intercellular adhesion molecule-1 and P-selectin, and (iii) acute-phase proteins such as C-reactive protein, fibrinogen and serum amyloid A. Furthermore, evidence from clinical trials have demonstrated that risk reduction achieved with anti-inflammatory agents such as statins is significantly greater in patients with evidence of inflammation. A number of risk factors for atherogenesis, including infectious agents, have been shown to exert their influence via inflammatory mechanisms. However, despite compelling experimental evidence, clinical studies looking at the role of infection in atherogenesis have lacked consistency. The clinical product of this dynamic process is variable and unpredictable between individuals, even those with apparently similar risk profiles.
Assuntos
Aterosclerose/imunologia , Aterosclerose/microbiologia , Inflamação/imunologia , Endotélio Vascular/patologia , Humanos , Fatores de RiscoRESUMO
BACKGROUND: Atherosclerotic plaque at the carotid bifurcation is often associated with transient ischemic attack (TIA) and ischemic stroke, but the mechanisms are not completely understood. Previous histological studies have been too small or insufficiently detailed to reliably determine the temporal course of features of plaque instability or to stratify analyses by the nature of presenting symptoms. METHODS AND RESULTS: We performed the largest-ever histological study of symptomatic carotid plaques from consecutive patients (n=526) undergoing endarterectomy and related detailed reproducible histological assessments to the nature and timing of presenting symptoms. There was a high prevalence of many features of coronary-type plaque instability. Dense plaque inflammation (especially infiltration with macrophages) was the feature most strongly associated with both cap rupture (odds ratio 3.39, 95% confidence interval 2.31 to 4.98, P<0.001) and time since stroke (P=0.001). Strong negative associations with time since stroke were also seen for cap rupture (P=0.02), overall plaque inflammation (P=0.003), and "unstable plaque" (P=0.001). Although plaques removed < or =60 days after the most recent event were more unstable after a stroke than after a TIA, the instability persisted after a TIA, and plaques removed >180 days after most recent event were less unstable after a stroke than after a TIA (plaque inflammation: < or =60 days, odds ratio 2.33 [95% confidence interval 0.76 to 7.19]; >180 days, 0.36 [0.16 to 0.84]; P=0.008; unstable plaque: odds ratio 3.27 [95% confidence interval 0.93 to 11.50] versus 0.74 [0.33 to 1.69], P=0.05). CONCLUSIONS: Pathology of recently symptomatic carotid plaques is similar to that of culprit coronary plaques, with strong correlations between macrophage infiltration and plaque instability. The tendency for plaque inflammation and overall instability to persist with time after a TIA but to decrease with time after a stroke suggests that the nature of the underlying pathology may differ.
Assuntos
Isquemia Encefálica/patologia , Estenose das Carótidas/patologia , Ataque Isquêmico Transitório/patologia , Acidente Vascular Cerebral/patologia , Idoso , Isquemia Encefálica/etiologia , Isquemia Encefálica/fisiopatologia , Estenose das Carótidas/fisiopatologia , Endarterectomia das Carótidas , Feminino , Humanos , Inflamação , Ataque Isquêmico Transitório/etiologia , Ataque Isquêmico Transitório/fisiopatologia , Macrófagos/patologia , Masculino , Pessoa de Meia-Idade , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/fisiopatologia , Fatores de TempoAssuntos
Granuloma de Células Plasmáticas/diagnóstico por imagem , Hepatopatias/diagnóstico por imagem , Adolescente , Biópsia/métodos , Diagnóstico Diferencial , Feminino , Granuloma de Células Plasmáticas/patologia , Granuloma de Células Plasmáticas/cirurgia , Hepatectomia , Humanos , Laparoscopia , Hepatopatias/patologia , Hepatopatias/cirurgia , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND: Carotid angiographic plaque surface morphology is a powerful risk factor for stroke and systemic vascular risk. However, the underlying pathology is unclear, and a better understanding is required both to evaluate other forms of carotid imaging and to develop new treatments. Previous studies comparing angiographic plaque surface morphology with pathology have been small and unblinded, and the vast majority assessed only the crude macroscopic appearance of the plaque. We performed the first large study comparing angiographic surface morphology with detailed histology. METHODS AND RESULTS: Carotid plaque surface morphology was classified as ulcerated, irregular, or smooth on 128 conventional selective carotid artery angiograms from consecutive patients undergoing endarterectomy for severe symptomatic stenosis. Blinded angiographic assessments were compared with 10 histological features recorded on detailed microscopy of the plaque using reproducible semiquantitative scales. Angiographic ulceration was associated with plaque rupture (P=0.001), intraplaque hemorrhage (P=0.001), large lipid core (P=0.005), less fibrous tissue (P=0.003), and increased instability overall (P=0.001). For example, angiographically ulcerated plaques were much more likely than smooth plaques to be ruptured (OR=15.4, 95% CI=2.7 to 87.3, P<0.001), show a large lipid core (OR=26.7, 95% CI=2.6 to 270, P<0.001) or a large hemorrhage (OR=17.0, 95% CI=2.0 to 147, P=0.02). The equivalent odds ratios for angiographically irregular versus smooth plaque were 6.3 (1.3 to 31, P=0.02), 6.7 (1.5 to 30, P=0.008), and 9.2 (1.1 to 77, P=0.02), respectively. CONCLUSIONS: In contrast to previous studies based on macroscopic assessment, we found very strong associations between detailed histology and carotid angiographic plaque surface morphology. Plaque surface morphology on carotid angiography is a highly sensitive marker of plaque instability. Studies of the predictive value of MR- and CT-based lumen contrast plaque surface imaging are required.
Assuntos
Angiografia/métodos , Doenças das Artérias Carótidas/patologia , Radiografia Intervencionista , Idoso , Doenças das Artérias Carótidas/diagnóstico por imagem , Doenças das Artérias Carótidas/metabolismo , Doenças das Artérias Carótidas/cirurgia , Complicações do Diabetes/diagnóstico por imagem , Complicações do Diabetes/metabolismo , Complicações do Diabetes/patologia , Complicações do Diabetes/cirurgia , Endarterectomia das Carótidas , Feminino , Fibrose , Hemorragia/etiologia , Hemorragia/patologia , Humanos , Hiperlipidemias/complicações , Hipertensão/complicações , Lipídeos/análise , Masculino , Pessoa de Meia-Idade , Ruptura Espontânea , Método Simples-Cego , Fumar/epidemiologia , Propriedades de SuperfícieRESUMO
BACKGROUND: Thromboembolism from carotid plaque is an important cause of stroke. Identification of unstable plaque would therefore be clinically useful. Unfortunately, studies of carotid plaque imaging have shown poor agreement with histology. However, this may be due to inconsistent methods and the variability of assessments of carotid plaque histology, rather than inadequate imaging. METHODS: We assessed the reproducibility of histological assessment in 60 plaques, and section-to-section variability along the length of 26 plaques. RESULTS: Kappa values ranged from 0.35 to 0.89 and from 0.44 to 0.68, respectively, for intra- and inter-observer reproducibility. There was considerable section-to-section variability within plaques. CONCLUSIONS: The accuracy of imaging of carotid plaque morphology will be underestimated unless variability in the histology assessment is taken into account.
Assuntos
Artérias Carótidas/patologia , Doenças das Artérias Carótidas/patologia , Patologia Clínica/normas , Humanos , Variações Dependentes do Observador , Patologia Clínica/estatística & dados numéricos , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeAssuntos
Cardiomiopatia Dilatada/patologia , Colágeno/metabolismo , Fibrose Endomiocárdica/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Cardiomiopatia Dilatada/metabolismo , Fibrose Endomiocárdica/metabolismo , Feminino , Ventrículos do Coração , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
This report describes a case of venous dissecting aneurysm presenting as a popliteal mass, in a 33 year old woman. A 1 x 1 x 0.5 cm lump developed early in the course of a second pregnancy. Primary venous aneurysms are rare vascular abnormalities that can affect either the superficial or deep veins, and have been described throughout the venous system. Most commonly found in the neck and central thoracic veins, they have also been found in visceral veins and extremities. There is a tendency for vascular disturbances to occur during pregnancy. The haemodynamic changes and hormonal milieu may be the cause of vascular alterations, which can lead to new aneurysm formation, or weakening of pre-existing aneurysms. This is the first reported case of a dissecting venous aneurysm, and has the added interest that it occurred during pregnancy.
Assuntos
Dissecção Aórtica/cirurgia , Complicações Cardiovasculares na Gravidez/cirurgia , Veia Safena/cirurgia , Adulto , Dissecção Aórtica/patologia , Feminino , Humanos , Gravidez , Complicações Cardiovasculares na Gravidez/patologiaRESUMO
Senior house officer schools in histopathology have been established in Leeds, Leicester and Southampton, each training six new recruits each year. Nine hours of protected teaching time is provided each week giving a ratio of apprenticeship learning to formal teaching of 3:1. Evaluations have been very positive. Much of this success is attributed to careful planning and adequate funding. This may be a useful model for other specialties to follow.
Assuntos
Histologia/educação , Corpo Clínico Hospitalar/educação , Atitude do Pessoal de Saúde , Previsões , Humanos , Faculdades de Medicina , Reino UnidoRESUMO
BACKGROUND: Hepatic metastasis from colorectal cancer is a common problem. Hepatic resection offers the only chance of cure. Prognosis of patients following hepatic resection is currently based on clinicopathological factors (of both the primary cancer and the hepatic metastasis), which do not accurately predict the subsequent behaviour of the tumour. The aim of this study was to evaluate three molecular genetic markers - p53, DCC (deleted in colonic cancer) and thymidylate synthase - in both the primary colorectal tumour and the resected hepatic metastases, and to determine their correlation, if any, with survival in patients with resected hepatic metastases from colorectal cancer. METHODS: Sixty-three patients with hepatic metastases and 40 corresponding colorectal primary tumours were studied using immunohistochemical staining for p53, DCC and thymidylate synthase, as well as p53 gene mutations using polymerase chain reaction-single-stranded conformational polymorphism (PCR-SSCP) analysis. The results were correlated with survival. RESULTS: There was no correlation between p53, DCC or thymidylate synthase immunohistochemical staining, or between p53 PCR-SSCP analysis, and survival for either hepatic metastases or the colorectal primary tumour. CONCLUSION: Prediction of prognosis in patients having resection of hepatic metastases from colorectal cancer continues to be problematic. Other genetic markers or combination of markers need to be evaluated.
Assuntos
Neoplasias Colorretais , Genes p53 , Neoplasias Hepáticas/secundário , Timidilato Sintase/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais , Feminino , Marcadores Genéticos , Humanos , Imuno-Histoquímica/métodos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Masculino , Pessoa de Meia-Idade , Mutação/genética , Reação em Cadeia da Polimerase/métodos , Polimorfismo Conformacional de Fita Simples , Prognóstico , Análise de SobrevidaAssuntos
Doença da Artéria Coronariana/patologia , Trombose Coronária/patologia , Vasos Coronários/patologia , Morte Súbita Cardíaca/patologia , Doença Aguda , Adulto , Fatores Etários , Doença da Artéria Coronariana/complicações , Trombose Coronária/complicações , Morte Súbita Cardíaca/etiologia , Feminino , Humanos , Masculino , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
In this study, two alternatively spliced forms of the mouse death-associated protein kinase (DAPK) have been identified and their roles in apoptosis examined. The mouse DAPK-alpha sequence is 95% identical to the previously described human DAPK, and it has a kinase domain and calmodulin-binding region closely related to the 130-150 kDa myosin light chain kinases. A 12-residue extension of the carboxyl terminus of DAPK-beta distinguishes it from the human and mouse DAPK-alpha. DAPK phosphorylates at least one substrate in vitro and in vivo, the myosin II regulatory light chain. This phosphorylation occurs preferentially at Ser-19 and is stimulated by calcium and calmodulin. The mRNA encoding DAPK is widely distributed and detected in mouse embryos and most adult tissues, although the expression of the encoded 160-kDa DAPK protein is more restricted. Overexpression of DAPK-alpha, the mouse homolog of human DAPK has a negligible effect on tumor necrosis factor (TNF)-induced apoptosis. Overexpression of DAPK-beta has a strong cytoprotective effect on TNF-treated cells. Biochemical analysis of TNF-treated cell lines expressing mouse DAPK-beta suggests that the cytoprotective effect of DAPK is mediated through both intrinsic and extrinsic apoptotic signaling pathways and results in the inhibition of cytochrome c release from the mitochondria as well as inhibition of caspase-3 and caspase-9 activity. These results suggest that the mouse DAPK-beta is a negative regulator of TNF-induced apoptosis.
Assuntos
Processamento Alternativo , Apoptose/fisiologia , Proteínas Quinases Dependentes de Cálcio-Calmodulina/genética , Proteínas Quinases Dependentes de Cálcio-Calmodulina/metabolismo , Sequência de Aminoácidos , Animais , Proteínas Reguladoras de Apoptose , Proteínas Quinases Associadas com Morte Celular , Camundongos , Dados de Sequência Molecular , Cadeias Leves de Miosina/metabolismo , Miosina Tipo II/metabolismo , NF-kappa B/metabolismo , Fosforilação , Proteínas Recombinantes/metabolismo , Homologia de Sequência de Aminoácidos , Especificidade da Espécie , Distribuição Tecidual , Fator de Necrose Tumoral alfa/farmacologiaRESUMO
OBJECTIVE: To determine the localization of 3-nitrotyrosine (3-NT), a footprint marker of peroxynitrite (ONOO-) and other reactive nitrogen species, to the inflamed human synovium and to compare this with normal synovial and nonsynovial tissue of human and animal origin. METHODS: Monoclonal and polyclonal antibodies were used to investigate for 3-NT, inducible nitric oxide synthase (iNOS), macrophage marker CD68, and the vascular smooth muscle marker alpha-actin by avidin-biotin immunocytochemistry. RESULTS: In the inflamed synovium, 3-NT was found in the vascular smooth muscle and macrophages. In normal human synovium, 3-NT was present in the vascular smooth muscle and some lining cells and was not associated with immunoreactivity for iNOS. Similarly, 3-NT could be demonstrated in the vascular smooth muscle cells of normal rats and iNOS knockout mice. It was not present in the vascular smooth muscle of healthy, nonsynovial tissue. CONCLUSION: The synovial vasculature in histologically normal human and naive rodent synovium was alone among the normal tissues studied in exhibiting iNOS-independent immunoreactivity for 3-NT. These findings suggest a physiologic role for ONOO- in normal synovial vascular function.
Assuntos
Artrite Reumatoide/patologia , Membrana Sinovial/química , Membrana Sinovial/patologia , Tirosina/análogos & derivados , Tirosina/análise , Actinas/análise , Idoso , Idoso de 80 Anos ou mais , Animais , Antígenos CD/análise , Antígenos de Diferenciação Mielomonocítica/análise , Feminino , Humanos , Imuno-Histoquímica , Macrófagos/química , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Músculo Liso Vascular/química , Músculo Liso Vascular/patologia , Óxido Nítrico Sintase/análise , Óxido Nítrico Sintase/genética , Óxido Nítrico Sintase Tipo II , RatosRESUMO
PURPOSE: Long-term clinical studies have now shown that tight control of blood pressure in type 2 diabetes reduces the risk of diabetes-related death and common diabetic complications, including diabetic retinopathy. However, the mechanisms by which hypertension enhances diabetic microvascular disease, especially diabetic retinopathy, are poorly understood. We developed an experimental model of hypertension in diabetic rats and studied the early ultrastructural changes in retinal capillaries under these conditions. METHODS: Hypertension was induced in diabetic BioBreeding (BB) rats by unilateral nephrectomy, weekly subcutaneous mineralocorticoid and 0.9% oral saline. Serial blood pressures and ultrastructural features of retinal capillaries were recorded in four groups: normotensive Wistar rats, normotensive diabetic rats, hypertensive Wistar rats and hypertensive diabetic rats. RESULTS: A significant and sustained increase in systolic blood pressure occurred in both groups of nephrectomised rats. There was a significant increase in the number of caveolae (i) in both pericytes and endothelial cells in animals with hypertension and diabetes together compared with all other groups and (ii) in pericytes in animals with diabetes alone. The number of direct contacts between pericytes and endothelial cells was reduced in diabetic and hypertensive diabetic animals. Hypertension and diabetes had an interactive effect in producing retinal capillary basement membrane thickening. CONCLUSIONS: In the BB rat hypertension and diabetes have an interactive effect in increasing the number of caveolae in both endothelial cells and pericytes. We speculate that this may be a reflection of changes in calcium and nitric oxide metabolism in these animals.