RESUMO
BACKGROUND.: Prolonged invasive mechanical ventilation (IMV) is a frequent challenge, and an increasing number of patients are transferred from intensive care units to long-term acute care hospitals or specialized weaning units. There are few published data for discharge home rates, use of noninvasive ventilation (NIV), or long-term survival. METHODS.: A case-note and database review was conducted of patients admitted to a UK national specialized weaning unit for weaning from IMV between 1992 and 2012. Patients were grouped into diagnostic categories according to the predominant cause of weaning failure. Weaning outcomes and long-term survival were assessed according to diagnostic group and mode of ventilation on discharge. RESULTS.: Four hundred and fifty-eight patients were transferred for weaning from IMV. Four hundred and seventeen (91%) survived to hospital discharge, of whom at least 343 (82%) were ultimately discharged to their own home. Three hundred and thirty (72%) weaned from IMV, of whom 142 weaned from all ventilation and 188 weaned to nocturnal NIV. Weaning success was highest for patients with chronic obstructive pulmonary disease and chest wall disorders. Median survival from unit discharge was 25 months (interquartile range 5-74), with the longest survival seen for patients discharged with nocturnal NIV [37 (12-81) months]. CONCLUSIONS.: These results confirm successful weaning outcomes for patients transferred to a specialized weaning and long-term ventilation service. In contrast to other service models, most patients achieved discharge to their own home.
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Unidades Hospitalares/organização & administração , Desmame do Respirador/métodos , Idoso , Bases de Dados Factuais , Feminino , Humanos , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Ventilação não Invasiva/efeitos adversos , Ventilação não Invasiva/mortalidade , Alta do Paciente , Encaminhamento e Consulta , Respiração Artificial/métodos , Análise de Sobrevida , Resultado do Tratamento , Desmame do Respirador/mortalidade , Desmame do Respirador/estatística & dados numéricosRESUMO
VM202, a plasmid DNA that expresses two isoforms of hepatocyte growth factor, may elicit angiogenic effects that could benefit patients with critical limb ischemia (CLI). In a phase 2, double-blind trial in 52 CLI patients, we examined the safety and potential efficacy of intramuscular injections of low-dose (n=21) or high-dose (n=20) VM202 or placebo (n=11) in the affected limb (days 0, 14, 28 and 42). Adverse events and serious adverse events were similar among the groups; no malignancy or proliferative retinopathy was seen. In exploratory efficacy analyses, we found no differences in ankle or toe-brachial index, VAS, VascuQuol or amputation rate among the groups. Complete ulcer healing was significantly better in high-dose (8/13 ulcers; P<0.01) versus placebo (1/9) patients. Clinically meaningful reductions (>50%) in ulcer area occurred in high-dose (9/13 ulcers) and low-dose (19/27) groups versus placebo (1/9; P<0.05 and P<0.005, respectively). At 12 months, significant differences were seen in TcPO2 between the high-dose and placebo groups (47.5 ± 17.8 versus 36.6 ± 24.0 mm Hg, respectively; P<0.05) and in the change from baseline among the groups (P<0.05). These data suggest that VM202 is safe and may provide therapeutic bioactivity in CLI patients.
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Extremidades/irrigação sanguínea , Extremidades/lesões , Vetores Genéticos/efeitos adversos , Fator de Crescimento de Hepatócito/efeitos adversos , Fator de Crescimento de Hepatócito/genética , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Plasmídeos/efeitos adversos , Isoformas de Proteínas/efeitos adversos , Isoformas de Proteínas/genéticaRESUMO
New innovations and novel approaches to peripheral arterial occlusive disease have brought enormous benefits to the vascular patient. Diseases that were once manageable only by surgical intervention are now easily and successfully treated by minimally invasive procedures. While the early days of percutaneous intervention were filled with inventions of new devices, today the focus centers on using modern technology and manufacturing to further improve upon these devices. Advances in guidewires and catheters have allowed us to visualize and treat lesions in nearly any vessel, and technology is guiding us towards specialized applications for specific lesions in specific vessels. However, one of the big hurdles remaining in treating arterial occlusive diseases is the rate of restenosis and the need for reinterventions. The location and architecture of these vessels make them uniquely difficult to treat, and call for new technology to address these challenges. Current developments of drug-eluting and bioabsorbable stents are at the forefront of new advancements specifically directed at improving current patency and restenosis rates; perhaps the next step in percutaneous intervention will rely on nanotechnology and the molecular surface engineering that may achieve a new era of devices that are able to target specific cell ligands or proteins to prevent the inflammatory and proliferative response from vessels. The present review will focus on the current literature regarding technological devices in peripheral percutaneous interventions and clinical applications. Future advancements in materials engineering and biotechnology will continue to improve the current standard of percutaneous intervention for peripheral arterial occlusive diseases.
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Arteriopatias Oclusivas/terapia , Procedimentos Endovasculares/instrumentação , Angioplastia com Balão/instrumentação , Aterectomia/instrumentação , Catéteres , Dispositivos de Proteção Embólica , Desenho de Equipamento , Humanos , StentsRESUMO
Vein bypass grafting is an integral component of cardiovascular surgical practice for both arterial and venous diseases. However, many of these grafts will eventually fail due to either intrinsic or extrinsic causes. This review examines the current understanding and knowledge of venous histology, vein graft pathology and the associated endothelial and smooth muscle cell physiology and pharmacology. In addition, the status of research on the therapeutic control of vein graft intimal hyperplasia and accelerated atherosclerosis is assessed.
RESUMO
OBJECTIVES: Outcome prediction in DeBakey Type III aortic dissections (ADs) remains challenging. Large variations in AD morphology, physiology and treatment exist. Here, we investigate if computational fluid dynamics (CFD) can provide an initial understanding of pressure changes in an AD computational model when covering entry and exit tears and removing the intra-arterial septum (IS). DESIGN: A computational mesh was constructed from magnetic resonance images from one patient (one entrance and one exit tear) and CFD simulations performed (scenario #1). Additional meshes were derived by virtually (1) covering the exit tear (false lumen (FL) thrombus progression) (scenario #2), (2) covering the entrance tear (thoracic endovascular treatment, TEVAR) (scenario #3) and (3) completely removing the IS (fenestration) (scenario #4). Changes in flow patterns and pressures were quantified relative to the initial mesh. RESULTS: Systolic pressures increased for #2 (300 Pa increase) with largest inter-luminal differences distally (2500 Pa). In #3, false lumen pressure decreased essentially to zero. In #4, systolic pressure in combined lumen reduced from 2400 to 800 Pa. CONCLUSIONS: CFD results from computational models of a DeBakey type III AD representing separate coverage of entrance and exit tears correlated with clinical experience. The reported results present a preliminary look at a complex clinical problem.
Assuntos
Aneurisma Aórtico/cirurgia , Dissecção Aórtica/cirurgia , Simulação por Computador , Procedimentos Endovasculares , Hemodinâmica , Hidrodinâmica , Modelos Cardiovasculares , Dissecção Aórtica/fisiopatologia , Aneurisma Aórtico/diagnóstico , Aneurisma Aórtico/fisiopatologia , Pressão Sanguínea , Procedimentos Endovasculares/efeitos adversos , Procedimentos Endovasculares/instrumentação , Humanos , Interpretação de Imagem Assistida por Computador , Imageamento Tridimensional , Imagem Cinética por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Fluxo Sanguíneo Regional , Telas Cirúrgicas , Resultado do TratamentoRESUMO
INTRODUCTION: Knowledge about variations of the venous arm anatomy is limited despite its importance for a successful arteriovenous fistula creation. REPORT: We describe a complication of a basilic vein transposition (BVT) resulting from failure to recognize aberrant anatomy. The brachial-basilic junction was located in an unusual position near the antecubital fossa leading to inadvertent distal brachial vein ligation and transposition of basilic and the proximal and unusually unpaired brachial vein. DISCUSSION: This case highlights the prevalence of anomalies of upper extremity veins and the need for thorough Duplex vein mapping before surgery for the preservation and planning of future access.
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Derivação Arteriovenosa Cirúrgica/efeitos adversos , Veias Braquiocefálicas/cirurgia , Diálise Renal , Extremidade Superior/irrigação sanguínea , Adulto , Veias Braquiocefálicas/anormalidades , Veias Braquiocefálicas/diagnóstico por imagem , Circulação Colateral , Feminino , Humanos , Ligadura , Flebografia , Resultado do Tratamento , Ultrassonografia Doppler DuplaRESUMO
G-proteins are membrane-bound signal transduction proteins which couple extracellular receptor signals to various effectors. This study examines the expression and the function of G-proteins (alpha i, alpha s, alpha q, and alpha o) in experimental intimal hyperplasia. Vein bypass grafts were placed in 30 New Zealand White rabbits and were harvested after 28 d. The contralateral jugular veins served as controls. Isometric tension studies were performed on rings from veins and vein grafts (n = 10), and Western blot and mRNA analyses were performed in another 20 vessels. There was a fivefold increase in alpha q, a 2.7-fold increase in the alpha i2, and a 3.3-fold increase in alpha s expressions in vein grafts compared with veins. Detectable expression of alpha i3 was observed in vein grafts but not in jugular veins. In addition, there was a 3.8-fold increase in beta subunits in the vein grafts compared with the veins. mRNA for alpha s, alpha i3, and alpha i2 were all elevated in the vein grafts. No detectable levels of the alpha i1 protein or its mRNA were present in either veins or vein grafts. Contractile responses in the veins were not inhibited by pertussis toxin. The contractile responses to norepinephrine were enhanced by twofold, and the responses to serotonin developed de novo in vein grafts compared with veins. The contractile responses to both norepinephrine and serotonin were only partially inhibited by pertussis toxin in the vein grafts even though there was 100% ADP ribosylation with pertussis toxin in both veins and vein grafts. These data suggest that intimal hyperplasia is associated with increased or novel expression of G-proteins in vivo which occur simultaneously with the development of pertussis toxin-sensitive contractile responses. Changes in G-proteins at a transcriptional level or at the level of RNA stability may be involved in the response of smooth muscle cells to injury and to intimal hyperplasia formation.
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Proteínas de Ligação ao GTP/biossíntese , Veias Jugulares/metabolismo , Túnica Íntima/metabolismo , Alumínio/farmacologia , Animais , Artéria Carótida Primitiva/metabolismo , Flúor/farmacologia , Proteínas de Ligação ao GTP/genética , Proteínas de Ligação ao GTP/fisiologia , Hiperplasia/metabolismo , Hiperplasia/patologia , Contração Isométrica/efeitos dos fármacos , Veias Jugulares/patologia , Veias Jugulares/fisiologia , Veias Jugulares/transplante , Masculino , Norepinefrina/farmacologia , Toxina Pertussis , RNA Mensageiro/biossíntese , Coelhos , Serotonina/farmacologia , Transcrição Gênica , Túnica Íntima/patologia , Grau de Desobstrução Vascular , Fatores de Virulência de Bordetella/farmacologiaRESUMO
The growth of neointima and neointimal smooth muscle cells in baboon polytetrafluoroethylene grafts is regulated by blood flow. Because neointimal smooth muscle cells express both platelet-derived growth factor receptor-alpha and -beta (PDGFR-alpha and -beta), we designed this study to test the hypothesis that inhibiting either PDGFR-alpha or PDGFR-beta with a specific mouse/human chimeric antibody will modulate flow-induced neointimal formation. Bilateral aortoiliac grafts and distal femoral arteriovenous fistulae were placed in 17 baboons. After 8 weeks, 1 arteriovenous fistulae was ligated, normalizing flow through the ipsilateral graft while maintaining high flow in the contralateral graft. The experimental groups received a blocking antibody to PDGFR-alpha (Ab-PDGFR-alpha; 10 mg/kg; n=5) or PDGFR-beta (Ab-PDGFR-beta; 10 mg/kg; n=6) by pulsed intravenous administration 30 minutes before ligation and at 4, 8, 15, and 22 days after ligation. Controls received carrier medium alone (n=8). Serum antibody concentrations were followed. Grafts were harvested after 28 days and analyzed by videomorphometry. Serum Ab-PDGFR-alpha concentrations fell rapidly after day 7 to 0, whereas serum Ab-PDGFR-beta concentrations were maintained at the target levels (>50 microg/mL). Compared with controls (3.7+/-0.3), the ratio of the intimal areas (normalized flow/high flow) was significantly reduced in Ab-PDGFR-beta (1.2+/-0.2, P<0.01) but not in Ab-PDGFR-alpha (2.2+/-0.4). Ab-PDGFR-alpha decreased significantly the overall smooth muscle cell nuclear density of the neointima (P<0.01) compared with either the control or Ab-PDGFR-beta treated groups. PDGFR-beta is necessary for flow-induced neointimal formation in prosthetic grafts. Targeting PDGFR-beta may be an effective pharmacological strategy for suppressing graft neointimal development.
Assuntos
Endotélio Vascular/fisiologia , Músculo Liso Vascular/fisiologia , Neovascularização Patológica , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/fisiologia , Receptor beta de Fator de Crescimento Derivado de Plaquetas/fisiologia , Túnica Íntima/fisiologia , Animais , Anticorpos/farmacologia , Aorta/cirurgia , Apoptose , Derivação Arteriovenosa Cirúrgica , Velocidade do Fluxo Sanguíneo , Divisão Celular , Células Cultivadas , Quimiotaxia/efeitos dos fármacos , Quimiotaxia/fisiologia , Endotélio Vascular/citologia , Endotélio Vascular/transplante , Artéria Femoral/cirurgia , Veia Femoral/cirurgia , Humanos , Hiperplasia , Artéria Ilíaca/cirurgia , Masculino , Camundongos , Músculo Liso Vascular/citologia , Músculo Liso Vascular/transplante , Papio , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Receptor beta de Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Proteínas Recombinantes de Fusão/farmacologia , Estresse Mecânico , Túnica Íntima/citologia , Túnica Íntima/patologiaRESUMO
The epidermal metabolic activity of a patient with a marked generalized ichthyosis associated with heredopathia atactica polyneuritiformis has been investigated. Both the in vivo labeling index and the in vitro rates of incorporation of radioactively labeled thymidine, proline, histidine and acetate were increased relative to normal indicating a high rate of epidermopoiesis. Thin-layer chromatographic analysis of 14C-acetate containing lipid extracts revealed qualitative changes compared with normal. In particular, altered proportions of radioactivities were incorporated into the triglyceride and phospholipid moieties. However, as abnormal patterns of lipogenesis are also seen in autosomal dominant ichthyosis, these changes are probably a reflection of disordered keratinization.
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Epiderme/metabolismo , Doença de Refsum/metabolismo , Acetatos/metabolismo , Adulto , Ésteres do Colesterol/metabolismo , Ácidos Graxos não Esterificados/metabolismo , Feminino , Histidina/metabolismo , Humanos , Fosfolipídeos/metabolismo , Prolina/metabolismo , Timidina/metabolismo , Triglicerídeos/metabolismoRESUMO
In baboon smooth muscle cells (SMCs), pervanadate has a biphasic dose-dependent effect on MEK-1 activity. After a 30 min incubation period, low concentrations (1-10 microM) activate, while higher doses (30-100 microM) fail to stimulate MEK-1. One possibility is that higher doses of pervanadate induce an additional signaling pathway that inhibits MEK-1. Three lines of investigations provide support for the conclusion that this inhibitory effect is mediated by p38MAPK. First, pervanadate induces p38MAPK activity at concentrations that fail to activate MEK-1. Second, pervanadate-stimulated p38MAPK activity is maximal after a 10 min incubation, at a time, when MEK-1 activity disappears. Third, addition of the specific p38MAPK inhibitor SB203580 preserves MEK-1 activation by 100 microM pervanadate. The inhibitory effect of p38MAPK is probably not due to a phosphorylation of MEK-1 although we can not rule out that other p38MAPK isoforms such as SAPK3 and SAPK4 may be involved, and may directly phosphorylate and inhibit MEK-1.
Assuntos
Proteínas Quinases Dependentes de Cálcio-Calmodulina/metabolismo , Quinases de Proteína Quinase Ativadas por Mitógeno , Proteínas Quinases Ativadas por Mitógeno , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/antagonistas & inibidores , Vanadatos/farmacologia , Fator 2 Ativador da Transcrição , Animais , Proteínas Quinases Dependentes de Cálcio-Calmodulina/antagonistas & inibidores , Células Cultivadas , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Ativação Enzimática , Inibidores Enzimáticos/farmacologia , Imidazóis/farmacologia , MAP Quinase Quinase 1 , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Músculo Liso Vascular/enzimologia , Papio , Fosforilação , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/metabolismo , Piridinas/farmacologia , Proteínas Recombinantes de Fusão/metabolismo , Fatores de Transcrição/metabolismo , Proteínas Quinases p38 Ativadas por MitógenoRESUMO
Fifteen consecutive patients with PG have been studied during the period 1971-78. Systemic disease was found in 13 of the patients and preceded the skin disease in 10 patients by 1-25 years. Only two patients had ulcerative colitis. One patient had paroxysmal nocturnal hemoglobinuria and three patients had an IgA myeloma. Eight patients had polyarthritis; this was classical seropositive rheumatoid arthritis in two patients, and a seronegative inflammatory polyarthritis in six patients. Four patients had an unusual progressive erosive seronegative polyarthritis without evidence of granulomatous bowel disease, psoriasis, genital, urinary tract or eye disease. In three of these four patients the arthritis preceded the PG. Synovial fluid analysis showed depressed complement levels and in one patient deposits of immunoglobulins and complement were demonstrated in the synovial membrane. The course of the arthritis was progressive with development of disabling joint deformities and erosive destruction of joints, despite treatment with penicillamine, corticosteroids and nonsteroidal anti-inflammatory drugs. One other patient had severe degenerative joint disease and chondrocalcinosis in association with a seronegative inflammatory polyarthritis, and another patient had ulcerative proctitis and severe degenerative joint disease secondary to chronic seronegative inflammatory polyarthritis. None of the patients had colitic arthritis, but in view of the association between PG and ulcerative colitis, some patients previously reported with PG and joint disease may have been suffering from the arthritis of ulcerative colitis. PG developed at the site of skin trauma in six patients. The natural history of the skin disease ran one of two courses: an acute, progressive course in which the ulcers rapidly enlarged until arrested by treatment; and a chronic course in which the lesions extended slowly and which after a period of weeks began to show signs of spontaneous healing. In only the patients with ulcerative colitis was there any correlation between the activity of the associated disease and the onset and progression of the skin disease. Serum complement levels were normal and no circulating cryoprecipitable immune complexes were found. Skin histology showed no evidence of vasculitis and direct immunofluorescence examination of involved skin was negative for IgG, IgM, IgA and C3. No consistent abnormality of cell-mediated immunity or neutrophil function was found and no significantly increased prevalence of any HLA antigen type was noted. Twelve patients have been treated with systemic corticosteroids. Six of these patients developed serious steroid complications and four patients have died, all from complications of steroid therapy.
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Artrite/diagnóstico , Pioderma/diagnóstico , Úlcera Cutânea/diagnóstico , Adolescente , Adulto , Idoso , Artrite/imunologia , Artrite Reumatoide/diagnóstico , Quimiotaxia de Leucócito , Colite Ulcerativa/diagnóstico , Feminino , Hemoglobinúria Paroxística/diagnóstico , Humanos , Imunidade Celular , Imunoglobulinas/análise , Masculino , Pessoa de Meia-Idade , Neutrófilos/imunologia , Paraproteinemias/diagnóstico , Pioderma/complicações , Pioderma/imunologia , Recidiva , Úlcera Cutânea/complicaçõesRESUMO
Molecular biology is now a routine tool in almost all biological research fields. With the exponential growth in the number of molecular biological techniques, there is a recognizable need for sensitive, accurate and precise quantitation of nucleic acids. We present here two complementary instruments designed for the quantitation of nucleic acids, the GeneQuant II and the DyNA Quant 200 Fluorometer. The GeneQuant II can rapidly determine the UV absorbance of a solution and display the calculated DNA, RNA or protein concentration. In addition, the GeneQuant can display calculated melting temperatures for a given DNA oligonucleotide base sequence, a useful feature for primer design. The DyNA Quant 200 quantitates DNA on the basis of the fluorescent Hoechst 33258 dye/double-stranded (ds)DNA assay. Upon binding to dsDNA, the spectral properties of the dye change such that it becomes highly fluorescent at 460 nm when excited at 365 nm. The assay has proven to be a specific and sensitive alternative method for DNA quantitation, particularly for unpurified DNA samples. Together, the GeneQuant II and the DyNA Quant 200 are a cost-effective and convenient solution to the routine protein and nucleic acid quantification needs of the molecular biologist.
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DNA/análise , RNA/análise , Espectrometria de Fluorescência , Espectrofotometria Ultravioleta , Bisbenzimidazol/metabolismo , Calibragem , DNA/metabolismo , DNA Complementar/análise , Corantes Fluorescentes/metabolismo , Reação em Cadeia da Polimerase , Proteínas/análise , Espectrometria de Fluorescência/instrumentação , Espectrofotometria/instrumentação , Espectrofotometria Ultravioleta/instrumentaçãoRESUMO
Hypercholesterolemia is an important contributor to the development of intimal hyperplasia and superimposed accelerated atherosclerosis in vein bypass grafts. This study examines the effect of dietary modification of serum cholesterol on the development of intimal hyperplasia and vasomotor function of vein grafts. Thirty male New Zealand White rabbits had a right carotid vein bypass graft and were put to death 28 days after the operation. Twenty animals received a 1% cholesterol diet for 4 weeks before the operation. In 10 animals this diet was continued until harvest (hypercholesterolemia group). In another 10 animals the diet was changed to standard rabbit chow on the day of the surgical procedure and continued until harvest (cholesterol reduction group). The last 10 animals were control subjects. Vein grafts were harvested either for histologic study or for in vitro isometric tension studies. Cumulative dose response curves to norepinephrine, serotonin, bradykinin, and endothelin-1 were determined. After in situ pressure fixation, intimal thicknesses of the vein grafts were measured by videomorphometry. The change in diet produced a 74% reduction in serum cholesterol concentration within 28 days. There was a 26% reduction in the intimal thickness of vein graft intimal hyperplasia and the macroscopic disappearance of atheromatous lesions from the graft wall, which are always observed in vein grafts from the hypercholesterolemia group. Cholesterol reduction did not change hypercholesterolemia-induced agonist supersensitivity. Therefore, cholesterol reduction slows the formation of intimal hyperplasia in vein grafts but does not prevent the persistence of the hypercholesterolemia-associated smooth muscle phenotype.
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Hipercolesterolemia/fisiopatologia , Músculo Liso Vascular/fisiologia , Túnica Íntima/patologia , Vasoconstrição , Veias/transplante , Animais , Colesterol/sangue , Colesterol na Dieta , Hiperplasia , Técnicas In Vitro , Masculino , Microscopia Eletrônica de Varredura , Músculo Liso Vascular/patologia , Coelhos , Túnica Íntima/fisiologia , Túnica Íntima/ultraestrutura , Vasoconstrição/efeitos dos fármacos , Vasoconstritores/farmacologia , Veias/patologia , Veias/fisiologiaRESUMO
A previous study in which vein grafts were removed from the arterial circulation and reimplanted into the venous circulation of the same animal demonstrated regression of vein graft intimal hyperplasia and medial thickening within 14 days. The present study was designed to characterize the kinetics of the morphological and ultrastructural changes over this 14-day period. Twenty-one male New Zealand White rabbits received a reversed vein interposition bypass graft of the right common carotid artery. Fourteen days after the procedure, 21 vein grafts were isolated, removed, and reimplanted into the contralateral external jugular venous system as veno-venous interposition bypass grafts (reversal grafts). The grafts were harvested at 60 minutes, 1 day, 3 days, 5 days, 7 days, and 14 days after reversal. Before insertion into the venous circulation, the vein graft had a confluent endothelial cell surface with multiple layers of smooth muscle cells representing intimal hyperplasia. After 1 hour, the reversal graft retained an intact endothelial cell layer with no evidence of tissue edema or cellular disruption. By 24 hours, there were a few blood cells on the endothelial cell surface. There was no inflammatory infiltrate seen in the subendothelium, and the smooth muscle cells were unaltered. At 3 days, the endothelial cell lining remained intact with no polymorphonucleocytes in the subendothelium or within the graft wall. Underlying smooth muscle cells at this time were noted to contain cytoplasmic vacuoles. At 5 days, there were no inflammatory cells seen on the surface or within the vein graft wall, but many of the underlying smooth muscle cells within the intimal hyperplasia were noted to be fragmented and to have clumping of chromatin. After 7 days, the endothelial cells remained intact and there was widespread evidence of apoptosis beneath the subendothelium with highly fragmented smooth muscle cells, some of which were histologically in the process of breaking up. At 14 days, the grafts retained uniform endothelial cell surfaces. Most of the smooth muscle cells that composed the intimal hyperplasia seen before implantation as a reversal graft were gone. Areas of newly laid down collagen could be observed. There were no acute inflammatory cells but for some mast cells seen in the graft wall. This study demonstrates that in this model, regression of intimal hyperplasia was associated with apoptosis of the smooth muscle cells and the deposition of collagen. There was no evidence that this process is mediated by an acute inflammatory response. Regression therefore appears to be due to induction of smooth muscle cell apoptosis by either a reduction in pressure or flow or a combination of both factors. The findings will enable a systematic cellular and molecular analysis of the biology of regression, which may afford clues to better understand the biology of the developing intimal hyperplasia.
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Artéria Carótida Primitiva/cirurgia , Veias Jugulares/patologia , Veias Jugulares/transplante , Reimplante , Túnica Íntima/patologia , Animais , Apoptose , Endotélio Vascular/ultraestrutura , Hiperplasia , Veias Jugulares/cirurgia , Masculino , Microscopia Eletrônica de Varredura , Músculo Liso Vascular/ultraestrutura , Coelhos , Fatores de TempoRESUMO
AIMS: To investigate whether increasing the daily baseline of gut calcium can cause a gradual downregulation of the active intestinal transport of calcium via reduced parathyroid hormone (PTH) mediated activation of vitamin D, and to discuss why such a mechanism might prevent calcium oxalate rich stones. To demonstrate the importance of seasonal effects upon the evaluation of such data. METHODS: Within an intensive 24 hour urine collection regimen, daily calcium supplementation (500 mg) was given to five stone formers for a 10 week period during a six month crossover study. In a further population of patients on follow up for previous renal stone disease, observations were made on 1066 24 hour urine samples collected over five years in respect of seasonal effects relevant to the interpretation of the study. RESULTS: In the group of patients on calcium supplements the following results were found. During calcium supplementation, the proportion of urine calcium to oxalate was higher (increased calcium to oxalate molar ratio), the 24 hour urine product of calcium and oxalate did not rise, and urine oxalate was lower during the first six weeks of supplementation. Twenty four hour urine calcium was 10.2% higher than baseline in the final four weeks of the 10 weeks of supplementation. Twenty four hour urine phosphate was 11.4% lower during the first six weeks of supplementation, but then rose while the patients were still on supplementation; renal tubular reabsorption of phosphate (TmP/GFR) mirrored the urine phosphate changes inversely. PTH was higher after stopping supplementation, but 1,25-(OH)2-cholecalciferol changes were not detected. In the 1066 urine samples collected over five years the following results were found. Calcium and oxalate excretion correlated positively and not inversely. Urine calcium and phosphate excretion were 5.5% and 2.5% higher, respectively, in "light" months of the year compared with "dark" months. A post summer decline in both urine calcium and urine phosphate was relevant to the interpretation of the study. CONCLUSIONS: Regular calcium supplementation does not raise the product of calcium and oxalate in urine and the proportion of oxalate to calcium is reduced. The underlying mechanisms of the changes seen in phosphate, calcium, and PTH and the observations on 1,25-(OH)2-cholecalciferol are not clear. Observed changes in phosphate could possibly be part of a calcium regulating feedback loop operating over a period of weeks. In evaluating these mechanisms background seasonal effects are important. It is possible that "programming" of the gut mucosa in terms of calcium transport is a major determinant of the relation between calcium and oxalate concentrations in urine and their relative abundance. Increased oral calcium, in association with a reduction of the relative proportion absorbed, may be pertinent to the prevention of calcium oxalate rich stones.
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Cálcio/uso terapêutico , Suplementos Nutricionais , Cálculos Renais/prevenção & controle , Administração Oral , Adulto , Análise de Variância , Cálcio/urina , Oxalato de Cálcio/urina , Estudos Cross-Over , Regulação para Baixo , Seguimentos , Humanos , Cálculos Renais/sangue , Cálculos Renais/urina , Masculino , Pessoa de Meia-Idade , Hormônio Paratireóideo/sangue , Fosfatos/urina , Projetos Piloto , Estações do AnoRESUMO
AIMS: To present experimental evidence in support of a proposed common cause for absorptive hypercalciuria, renal hypercalciuria, renal phosphate leak and enhancement of 1,25-(OH)2-vitamin D concentrations in patients presenting with renal stone disease; and to suggest further investigation with a view to new management. METHODS: An oral calcium loading test was administered to 15 patients with renal stones and 10 normal controls in the fasting state: urine and blood were collected hourly. After the second urine sample, 400 mg calcium dissolved in water was administered orally. Serum calcium, albumin, parathyroid hormone (PTH), and phosphate were measured together with urine calcium clearance and urinary phosphate from which the TmPO4/glomerular filtration rate (GFR) ratio was calculated. Serum 1,25-(OH)2-vitamin D was measured in the first serum sample. In addition, 24 hour urine calcium results were collected retrospectively from the patients' case notes over the previous 18 months. RESULTS: In the basal state, renal stone patients had an overall greater phosphaturia (lower TmPO4/GFR: median 1.72 compared with 2.10 in controls) and increased calcium clearance. Serum corrected calcium and PTH concentrations did not differ between the groups. After calcium loading, serum calcium and urine calcium clearance rose in both groups, with patients with renal stones experiencing a greater percentage fall in phosphaturia. In both groups TmPO4/GFR fell (greater phosphaturia) with increased serum corrected calcium, with the patients showing notably greater phosphaturia for any given calcium concentration. Patients also had notably greater phosphaturia compared with the serum calcium concentration for any given PTH value. Serum 1,25-(OH)2-vitamin D was higher in patients than controls and for any 1,25-(OH)2-vitamin D concentration phosphaturia measured against serum calcium was greater in patients than controls. 1,25-(OH)2-vitamin D did not correlate with phosphaturia relative to serum calcium concentrations within the patient and control groups. CONCLUSIONS: It is proposed that patients with idiopathic hypercalciuria have an "inappropriately' high phosphate excretion for any given serum calcium concentration. Loss of phosphate may induce increased activation of 1,25-(OH)2-vitamin D. Some of the commonly described causes of stone formation may be manifestations of a single mechanism.
Assuntos
Cálculos Renais/fisiopatologia , Fosfatos/metabolismo , Adulto , Idoso , Cálcio/sangue , Cálcio/metabolismo , Cálcio/urina , Ergocalciferóis/sangue , Feminino , Taxa de Filtração Glomerular , Humanos , Túbulos Renais/fisiopatologia , Masculino , Pessoa de Meia-Idade , Hormônio Paratireóideo/sangue , Fosfatos/sangue , Fosfatos/urina , Análise de Regressão , Albumina Sérica/análiseRESUMO
BACKGROUND: Previous studies in animals and human beings have shown that vein bypass grafts exhibit diminished endothelium-dependent relaxation and the development of intimal hyperplasia. This study examines the effect of L-arginine on experimental vein graft endothelial cell function and the development of intimal hyperplasia. METHODS: Common carotid vein bypass grafts were performed in 24 New Zealand White rabbits: 12 were controls and 12 received L-arginine (2.25%) orally 7 days before operation and thereafter until harvest 28 days after operation. Intimal and medial dimensions were determined by planimetry on pressure-fixed vessels. Relaxation to acetylcholine, serotonin, calcium ionophore (A23187), and sodium nitroprusside was performed on precontracted vessel rings. RESULTS: Arginine-treated vein grafts showed a 47% reduction in mean intimal thickness (p < 0.001) compared with controls. By scanning and transmission electron microscopy, all vein grafts showed a confluent endothelium. In contrast to control grafts, which do not relax to acetylcholine and serotonin, arginine-treated vein grafts relaxed in response to both agonists. There was a significant increase (p < 0.05) in the maximal relaxation to calcium ionophore (A23187) in arginine-treated vein grafts compared with control grafts. Non-endothelium-dependent responses to sodium nitroprusside were equivalent in all vein grafts. CONCLUSIONS: This study shows that oral L-arginine supplementation significantly reduces intimal hyperplasia and preserves nitric oxide-mediated relaxation in experimental vein grafts, suggesting a role for nitric oxide in the regulation of the cellular events that lead to intimal hyperplasia.
Assuntos
Arginina/uso terapêutico , Oclusão de Enxerto Vascular/prevenção & controle , Veias Jugulares/transplante , Túnica Íntima/patologia , Animais , Arginina/farmacologia , Artéria Carótida Primitiva/cirurgia , Relação Dose-Resposta a Droga , Oclusão de Enxerto Vascular/fisiopatologia , Hiperplasia/tratamento farmacológico , Veias Jugulares/efeitos dos fármacos , Veias Jugulares/fisiologia , Óxido Nítrico , Coelhos , Túnica Íntima/efeitos dos fármacos , Túnica Íntima/fisiologia , Vasoconstrição/efeitos dos fármacos , Vasodilatação/efeitos dos fármacosRESUMO
BACKGROUND: The reversibility of the morphologic and functional alterations that occur in veins transplanted into the arterial circulation was examined in this study. METHODS: Common carotid vein bypass grafts (VG) were performed in 20 male New Zealand White rabbits. Ten VG and jugular veins (CV) were harvested after 14 days, and ten VG were reimplanted as venovenous bypass grafts (REV) and harvested after an additional 14 days. Vessels were taken for structural or isometric tension studies to norepinephrine, serotonin, and bradykinin and to acetylcholine and sodium nitroprusside after precontraction. RESULTS: There was a decrease in the thickness of the intima (p = 0.02) and the media (p = 0.002) in REV compared with VG. In REV, sensitivity to norepinephrine decreased (p = 0.0007) with a reduced maximal tension to norepinephrine (p = 0.02) and to serotonin (p = 0.0001). Bradykinin sensitivity increased in REV (p = 0.003 vs VG) and was greater than in CV. Only the precontracted CV and REV relaxed to acetylcholine. All tissues relaxed to sodium nitroprusside. CONCLUSIONS: This study suggests that intimal hyperplasia can be reversed with restoration of endothelium-dependent relaxing factor-mediated relaxation but that only a partial regression of the contractile abnormalities can be achieved.
Assuntos
Óxido Nítrico/fisiologia , Vasodilatação , Veias/transplante , Animais , Bradicinina/farmacologia , Endotélio Vascular/patologia , Endotélio Vascular/ultraestrutura , Histamina/farmacologia , Hiperplasia , Técnicas In Vitro , Masculino , Norepinefrina/farmacologia , Coelhos , Serotonina/farmacologia , Vasodilatação/efeitos dos fármacos , Veias/patologiaRESUMO
BACKGROUND: This study examines the effect of the angiotensin II receptor (type 1) antagonist (L158,809) on the formation of vein graft intimal hyperplasia in vivo, by both localized and systemic administration. METHODS: Forty New Zealand White rabbits underwent carotid interposition bypass grafting with the external jugular vein and were killed on postoperative day 28. To determine the effect of L158,809 on the development of intimal hyperplasia, 10 animals received long-term oral therapy with L158,809 (10 mg/kg/day, begun 5 days before operation and continued until harvest), 10 animals underwent coating of the grafts with a pluronic gel containing L158,809 (10(-5) mol/L), and 20 animals were controls (10 with and 10 without pluronic gel). These grafts were harvested for either histologic analysis (n = 6 per group) or in vitro isometric tension studies to angiotensin II (n = 4 per group). RESULTS: Long-term oral treatment with L158,809 produced a 43% decrease in intimal thickness from 76 +/- 6 microns (mean +/- SEM) in the control animals to 43 +/- 7 microns in the treated vein grafts (p = 0.002). There was also a significant decrease (44%) in the medial thicknesses between the control (75 +/- 4 microns) and L158,809-treated (42 +/- 6 microns) vein grafts (p = 0.007). The contractile responses to angiotensin II were abolished in the vein grafts by long-term L158,809 therapy. Local application by gel of L158,809 produced a significant decrease (33%) in the intimal thickness (48 +/- 3 microns) but no change in medical thicknesses (76 +/- 6 microns) compared with control grafts. The contractile responses to angiotensin II were unchanged in the vein grafts by local L158,809 therapy. CONCLUSIONS: This study shows that a local single application of L158,809 will reduce the intimal response but not the medial response in vein grafts, whereas long-term treatment will reduce intimal hyperplasia and the medial response in experimental vein grafts. Therefore angiotensin II acting through AT1 receptors mediates a significant part of the intimal hyperplastic response in vein grafts that appears to involve two phases: an acute intimal response requiring short-term therapy and a long-term medial response that requires prolonged therapy.