RESUMEN
Hematide is a synthetic PEGylated peptidic erythropoiesis stimulating agent (ESA) that is presently being developed for the correction of anemia in patients with chronic renal failure. Unlike currently marketed ESAs, Hematide does not possess any sequence homology to erythropoietin (EPO) and has not elicited moribund immune responses in animal safety studies thereby allowing the generation of a robust safety package. Animals administered marketed ESAs develop anti-EPO antibodies that null the effect of the administered ESA and neutralize endogenous EPO, resulting in severe anemia that precludes the interpretation of chronic safety studies. The primary objective of this study is to determine whether Hematide-specific antibodies are generated when male monkeys are exposed to high Hematide doses (10 mg/kg, intravenous [IV] and subcutaneous [SC]) administered at frequent dosing intervals (every two weeks) for a total of 9 doses; secondary objectives are to evaluate whether developed antibodies impact pharmacokinetics (PK) and pharmacology. In this study, no Hematide-specific antibodies were detected. Hematide exhibits a prolonged plasma half-life and slow clearance by either IV or SC administration. Hematide induced significant erythropoiesis with reticulocytosis and subsequent increases in red blood cells, hematocrit and hemoglobin (Hgb) levels. No erythropoietic differences were noted between the IV and the SC dosed groups with mean +/- SD Hgb levels of 20.9 +/- 2.5 and 20.3 +/- 2.1 g/dL, respectively, occurring on Day 48, corresponding to Hgb increases of 6.5 and 6.7 g/dL, respectively, over pre-dose levels. In conclusion, Hematide is a potent erythropoiesis stimulating agent that exhibits plasma persistence in monkeys. Similar erythropoietic responses were produced following IV and SC administration. The absence of antibody development suggests that Hematide, at the doses and regimen described, has a low immunogenic potential in cynomolgus monkeys.
Asunto(s)
Eritropoyesis/efectos de los fármacos , Péptidos/farmacología , Polietilenglicoles/farmacología , Animales , Eritropoyetina/farmacología , Hemoglobinas/análisis , Inyecciones Intravenosas , Inyecciones Subcutáneas , Macaca fascicularis , Masculino , Péptidos/administración & dosificación , Péptidos/inmunología , Péptidos/farmacocinética , Polietilenglicoles/administración & dosificación , Polietilenglicoles/farmacocinética , Proteínas Recombinantes , Reticulocitos/efectos de los fármacosRESUMEN
BACKGROUND: A multicentre randomised controlled trial to determine the effect of a rigid plaster dressing applied at the time of trans-tibial amputation on the number of days to casting for a prosthesis, and the incidence of post-operative stump infection. METHODS: Patients requiring trans-tibial amputation were randomised to one of 2 groups: In Group 1 (intervention) a rigid above-knee plaster dressing was applied at operation and patients were managed according to a standard protocol. Group 2 (control) had the individual surgeons' usual non-rigid dressing regime. Rehabilitation data were extracted from the national physiotherapy database. On completion of the trial a questionnaire was sent to all participants. RESULTS: 14 surgeons in 7 centres enrolled 154 patients, with 96 ultimately cast for a prosthesis. Patients who received a rigid dressing (n = 78) had reduced days to casting (median 36, confidence interval 30-47) when compared with other dressings (n = 76) (median 42, confidence interval 36-45), these differences did not reach statistical significance. There was no significant difference in post-operative infection rates in the two groups. 64% of surgeons, and all physiotherapists and vascular nurses responding to the post-trial questionnaire felt that the rigid dressing was an improvement on their normal regime and wished to continue with the technique. CONCLUSIONS: Despite a median reduction of 6 days in time to casting in patients treated with a rigid post-operative dressing this failed to reach statistical significance. The majority of participants who replied to the post-trial questionnaire expressed a wish to continue using the rigid dressing technique. To confirm that the trends shown in this trial are statistically valid a larger trial is needed.
Asunto(s)
Muñones de Amputación , Amputación Quirúrgica , Arteriopatías Oclusivas/cirugía , Vendajes , Pierna/cirugía , Sulfato de Calcio , Competencia Clínica , Femenino , Humanos , Masculino , TibiaRESUMEN
The effect of motexafin gadolinium (MGd), a redox mediator, on tumor response to doxorubicin (Dox) and bleomycin (Bleo) was investigated in vitro and in vivo. MES-SA human uterine sarcoma cells were studied in vitro using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide viability assay. Rif-1, a murine fibrosarcoma cell line, was studied using a clonogenic survival assay. Tumor growth delay assays were performed using the EMT-6 murine mammary sarcoma cell line in BALB/c mice. MGd (25-100 microM) produced dose-dependent enhancement of Bleo cytotoxicity to MES-SA cells. The IC(50) for Bleo was reduced by approximately 10-fold using 100 microM MGd. In clonogenic assays using Rif-1 cells, MGd enhanced the activity of Bleo approximately 1000-fold. This effect was shown to be mediated, in part, by MGd inhibition of potentially lethal damage repair. MGd enhanced the tumor response to bleomycin and Dox in vivo. MGd had no significant effect on the systemic exposure to Dox (expressed in terms of the plasma area under the curve, 0-24 h) and did not increase Dox myelosuppression. MGd enhanced the effectiveness of the redox active drugs, Bleo and Dox.
Asunto(s)
Metaloporfirinas/farmacología , Fármacos Fotosensibilizantes/farmacología , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Bleomicina/farmacología , Bleomicina/uso terapéutico , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Doxorrubicina/farmacocinética , Doxorrubicina/farmacología , Doxorrubicina/uso terapéutico , Sinergismo Farmacológico , Femenino , Humanos , Masculino , Metaloporfirinas/uso terapéutico , Ratones , Ratones Endogámicos BALB C , Trasplante de Neoplasias , Neoplasias Experimentales/patología , Neoplasias Experimentales/prevención & control , Fármacos Fotosensibilizantes/uso terapéutico , Ratas , Ratas Sprague-Dawley , Resultado del Tratamiento , Células Tumorales CultivadasRESUMEN
BACKGROUND: Motexafin lutetium (Lu-Tex) is a photodynamic therapy (PDT) agent that localizes in atheromatous plaque in which it can be activated by far-red light. Lu-Tex biolocalization was examined in graft coronary artery disease (GCAD) with a rodent allograft model. After photoactivation, the effect on intimal proliferation was assessed. METHODS: A PVG to ACI rat heterotopic heart transplantation model was used. Lu-Tex (10 mg/kg) was intravenously administered 90 days after transplantation. Photoactivation was performed 24 hr after Lu-Tex administration. A light-emitting diode, central wavelength of 742 nm, was used to illuminate the intraperitoneally placed allografts via a laparotomy (light fluence of 75 J/cm2 at a power density of 75 mW/cm2). Animals were divided into four groups according to postoperative treatments: PDT with Lu-Tex injection and light illumination (n=21), Lu-Tex injection and laparotomy (n=14), laparotomy with light only (n=14), and laparotomy only (n=16). GCAD was quantitatively assessed 14 days after treatments. RESULTS: Lu-Tex localized in atherosclerotic plaque in vessels with GCAD. PDT significantly reduced both the percent of affected vessels and intimal proliferation compared to all other control study groups. alpha-Smooth muscle cell actin and anti-rat macrophage antibody-positive areas were significantly reduced within the neointima in allografts treated with PDT compared to all other study groups. CONCLUSIONS: PDT significantly reduced atherosclerotic lesions of GCAD. Lu-Tex-mediated PDT may, therefore, be a potential method for treating accelerated atherosclerosis associated with transplantation.
Asunto(s)
Enfermedad de la Arteria Coronaria/prevención & control , Trasplante de Corazón/efectos adversos , Metaloporfirinas/uso terapéutico , Fotoquimioterapia , Fármacos Fotosensibilizantes/uso terapéutico , Actinas/metabolismo , Animales , Enfermedad de la Arteria Coronaria/patología , Vasos Coronarios/metabolismo , Vasos Coronarios/patología , Masculino , Metaloporfirinas/farmacocinética , Miocardio/metabolismo , Fármacos Fotosensibilizantes/farmacocinética , Ratas , Ratas Endogámicas ACI , Ratas Endogámicas , Distribución Tisular , Túnica Íntima/metabolismo , Túnica Íntima/patologíaRESUMEN
Motexafin lutetium is a photosensitizer that accumulates in atherosclerotic plaque and, after activation by far-red light, produces cytotoxic singlet oxygen. The combination of photosensitizer and illumination, known as photodynamic therapy (PDT), has been shown to reduce atheroma formation in animal models and is under clinical investigation. However, the effects of PDT with motexafin lutetium on isolated vascular cells are unknown. This study was designed to characterize the effects of PDT on vascular cell viability and to define the cell-death pathway for this agent. Fluorescence microscopy of RAW macrophages and human vascular smooth muscle cells revealed time-dependent uptake of motexafin lutetium. Illumination of motexafin lutetium-loaded cells with 732-nm light (2 J/cm(2)) impaired cellular viability and growth (IC(50) 5 to 20 micromol/L). Depletion of intracellular glutathione potentiated (P=0.035) and the addition of antioxidant N-acetylcysteine attenuated (P=0.002) cell death, suggesting that the intracellular redox state influences motexafin lutetium action. PDT was associated with the loss of mitochondrial membrane potential, mitochondrial release of cytochrome c, and caspase activation. PDT promoted phosphatidylserine externalization and induced apoptotic DNA fragmentation, with the number of apoptotic cells increasing from 7+/-2% to 34+/-3% of total cells. Reducing plaque cellularity by the induction of apoptosis may be one mechanism by which PDT reduces plaque burden, possibly modulates plaque vulnerability, and inhibits restenosis in vivo.
Asunto(s)
Apoptosis/efectos de los fármacos , Metaloporfirinas/farmacología , Músculo Liso Vascular/efectos de los fármacos , Fotoquimioterapia , Fármacos Fotosensibilizantes/farmacología , Animales , Arteriosclerosis/tratamiento farmacológico , División Celular/efectos de los fármacos , Línea Celular , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Grupo Citocromo c/metabolismo , Humanos , Macrófagos/citología , Macrófagos/efectos de los fármacos , Potenciales de la Membrana , Metaloporfirinas/farmacocinética , Ratones , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Músculo Liso Vascular/citología , Oxidación-Reducción , Fármacos Fotosensibilizantes/farmacocinéticaRESUMEN
Motexafin gadolinium (MGd) is a unique therapeutic agent that localizes in cancer cells and increases tumor response to ionizing radiation and certain chemotherapeutics. The in vitro intracellular localization, accumulation, and retention of MGd in murine EMT6 mammary sarcoma and Rif-1 fibrosarcoma cell lines were studied using interferometric Fourier fluorescence microscopy. MGd cellular uptake was semiquantified using its characteristic fluorescence emission band centered at 758 nm. Colocalization studies were performed using mitochondrial, endoplasmic reticulum, Golgi apparatus, nuclear, and lysosomal fluorescent organelle probes, and verified using interferometric Fourier spectroscopy. Cellular uptake was gradual and increased significantly with incubation time. MGd localized primarily within the lysosomes and endoplasmic reticulum, and to a lesser extent within the Golgi apparatus and mitochondria. Mitochondrial staining was increased in media without serum. No nuclear uptake was detected in the Rif-1 cells, but after 48 h nuclear uptake was observed in 15% of EMT6 cells. These results indicated that MGd accumulates within cytoplasmic compartments. The sustained intracellular localization of MGd may, in part, account for its unique radiation and chemotherapy enhancement properties. Interferometric Fourier fluorescence microscopy is a potentially powerful tool in delineating and verifying localization sites of therapeutic agents.
Asunto(s)
Metaloporfirinas/análisis , Microscopía de Interferencia , Neoplasias Experimentales/metabolismo , Fármacos Sensibilizantes a Radiaciones/análisis , Sarcoma/metabolismo , Animales , Transporte Biológico/efectos de los fármacos , Núcleo Celular/metabolismo , Supervivencia Celular/efectos de los fármacos , Medio de Cultivo Libre de Suero/farmacología , Retículo Endoplásmico/metabolismo , Colorantes Fluorescentes , Aparato de Golgi/metabolismo , Lisosomas/metabolismo , Metaloporfirinas/farmacocinética , Ratones , Microscopía Fluorescente/métodos , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Trasplante de Neoplasias , Fotoquímica/métodos , Fármacos Sensibilizantes a Radiaciones/farmacocinética , Espectrometría de Fluorescencia , Células Tumorales CultivadasRESUMEN
BACKGROUND: Tertiary referral centres report that up to 60 per cent of patients may be suitable for endovascular repair of abdominal aortic aneurysm (EVAR). The aim of this study was to determine the percentage of abdominal aortic aneurysms (AAAs) presenting to a county-wide vascular service that were suitable for EVAR, and to examine the outcome of subsequent AAA repair in relation to aneurysm morphology. PATIENTS AND METHODS: All patients being assessed for AAA repair between January 1998 and December 1999 underwent spiral computed tomography angiography to determine aneurysm morphology and suitability for EVAR. Subsequent outcome for all patients in the study was recorded in a prospective vascular database. RESULTS: A total of 115 patients was assessed. Sixty-three aneurysms (55 per cent) had one or more absolute contraindications to EVAR, a further 13 (11 per cent) had at least one relative contraindication, and 39 (34 per cent) had no contraindication. Of patients with no absolute contraindication to EVAR, ten underwent successful EVAR, five did not meet recognized criteria for surgery, one awaits EVAR, four remain under observation, one awaits open repair, and 31 underwent open repair without death. CONCLUSION: Only 30 per cent of unselected AAAs presenting to a vascular service are entirely suitable for EVAR; most of these patients can safely undergo open AAA repair. These data suggest that increased use of EVAR is only possible by deploying devices in suboptimal morphology, and in treating patients who would not normally be considered for open AAA repair.
Asunto(s)
Angioscopía/métodos , Aneurisma de la Aorta Abdominal/cirugía , Anciano , Anciano de 80 o más Años , Aneurisma de la Aorta Abdominal/patología , Protocolos Clínicos , Contraindicaciones , Femenino , Humanos , Masculino , Persona de Mediana Edad , Selección de Paciente , Resultado del TratamientoRESUMEN
BACKGROUND: Motexafin lutetium (Lu-Tex) is a photosensitizer that targets atheromatous plaque. Subsequent photoactivation (photodynamic therapy [PDT]) induces local cytotoxic effects. The aim of the present study was to investigate whether Lu-Tex targets vein graft intimal hyperplasia and whether subsequent photoactivation attenuates the disease process. METHODS AND RESULTS: The subcellular localization of Lu-Tex and postillumination viability were studied in cultured human vein graft smooth muscle cells. Inferior vena cava-grafted rats were injected with Lu-Tex (10 mg/kg) 4 or 12 weeks after grafting. Biodistribution was assessed in a subgroup 24 hours after administration. Light therapy (742 nm) was performed 24 hours after Lu-Tex injection by illuminating intraperitoneally placed isografts using a laparotomy. Animals were divided into the following 4 groups: PDT (n=15), Lu-Tex injection and laparotomy (n=13), light treatment (n=14), and laparotomy only (n=13). Grafts were harvested 14 days after treatment for histochemical analysis. Lu-Tex localized within subcellular organelles of smooth muscle cells, and subsequent photoactivation induced cell death via apoptosis. The Lu-Tex concentrations present in the vein grafts were 9.3 times higher than those in the normal inferior vena cava. Postoperative PDT at 4 weeks after surgery significantly reduced the intima/media ratio, whereas treatment at 12 weeks did not reduce the intima/media ratio. Activated macrophages were observed 4 weeks after grafting; however, a significant reduction occurred in these cells by 12 weeks. The mechanism by which PDT works may be related to the presence of activated macrophages. CONCLUSIONS: PDT significantly reduces the intima/media ratio in the early phase of vein graft disease. Lu-Tex-mediated PDT may be a viable method for the attenuation of atherosclerotic disease in vein grafts.
Asunto(s)
Oclusión de Injerto Vascular/prevención & control , Metaloporfirinas/uso terapéutico , Músculo Liso Vascular/efectos de los fármacos , Fotoquimioterapia/métodos , Fármacos Fotosensibilizantes/uso terapéutico , Animales , Antígenos de Diferenciación/metabolismo , Células Cultivadas , Oclusión de Injerto Vascular/patología , Humanos , Hiperplasia/patología , Hiperplasia/prevención & control , Laparotomía , Luz , Macrófagos/metabolismo , Macrófagos/patología , Metaloporfirinas/farmacocinética , Músculo Liso Vascular/ultraestructura , Fármacos Fotosensibilizantes/farmacocinética , Ratas , Distribución Tisular , Trasplante Isogénico , Túnica Íntima/efectos de los fármacos , Túnica Íntima/metabolismo , Túnica Íntima/patología , Vena Cava Inferior/efectos de los fármacos , Vena Cava Inferior/patología , Vena Cava Inferior/trasplanteRESUMEN
Photodynamic therapy (PDT) has been studied and applied to various disease processes. The potential of PDT for selective destruction of target tissues is especially appealing in cardiovascular disease, in which other existing interventional tools are somewhat nonselective and carry substantial risk of damage to the normal arterial wall. Enthusiasm for photoangioplasty (PDT of vascular de novo atherosclerotic and, potentially, restenotic lesions) is fueled by more effective second-generation photosensitizers and technological advances in endovascular light delivery. This excitement revolves around at least 4 significant attributes of light-activated therapy: the putative selectivity and safety of photoangioplasty, the potential for atraumatic and effective debulking of atheromatous plaque through a biological mechanism, the postulated capability to reduce or inhibit restenosis, and the potential to treat long segments of abnormal vessel by simply using fibers with longer light-emitting regions. The available nonclinical data, coupled with the observations of a new phase I trial in human peripheral atherosclerosis, suggest a promising future for photoangioplasty in the treatment of primary atherosclerosis and prevention of restenosis.
Asunto(s)
Arteriosclerosis/tratamiento farmacológico , Enfermedades Cardiovasculares/tratamiento farmacológico , Fotoquimioterapia , Fármacos Fotosensibilizantes/uso terapéutico , Animales , Oclusión de Injerto Vascular/tratamiento farmacológico , Hematoporfirinas/uso terapéutico , Humanos , Fotoquimioterapia/métodosRESUMEN
PURPOSE: To investigate the suitability of lutetium texaphyrin (lu-tex) as a fluorescence imaging agent in the delineation of retinal vascular and choroidal vascular diseases. The utilization of an efficient fluorescent molecule that is also a photosensitizer represents a unique opportunity to couple diagnosis and therapy. METHODS: Fundus fluorescence angiography comparing lu-tex (motexafin lutetium, Optrin, Pharmacyclics Inc, Sunnyvale, California) with the conventional angiographic dyes, sodium fluorescein, and indocynanine green (ICG), was performed on the eyes of normal and laser-injured New Zealand white rabbits. Plasma pharmacokinetic data and plasma protein binding were assessed in addition to light microscopy of the retina in both imaged and laser-injured eyes. RESULTS: Normal retinal and choroidal vasculature was well delineated by lu-tex angiography. Experimentally induced choroidal and retinal vascular lesions were enhanced by lu-tex and demonstrated different staining patterns than fluorescein or ICG, particularly at the margins of the lesions. Lu-tex cleared rapidly from the plasma, with 39.7% bound to the high-density lipoprotein (HDL) fraction while 15.8% was bound to the low-density lipoprotein (LDL) fraction. No evidence of retinal toxicity after dye administration was observed by either ophthalmoscopy and fundus photography or by light microscopy. CONCLUSION: Lu-tex angiography is a potentially valuable method for retinal vascular and choroidal vascular evaluation, and it has advantages over fluorescein and ICG angiography. The same agent could conceivably be used for both the identification of abnormal vasculature and subsequent photodynamic treatment.
Asunto(s)
Neovascularización Coroidal/diagnóstico , Angiografía con Fluoresceína , Fondo de Ojo , Lutecio , Metaloporfirinas , Fotoquimioterapia/métodos , Fármacos Fotosensibilizantes , Neovascularización Retiniana/diagnóstico , Animales , Coroides/irrigación sanguínea , Coroides/metabolismo , Coroides/patología , Neovascularización Coroidal/tratamiento farmacológico , Neovascularización Coroidal/metabolismo , Neovascularización Coroidal/patología , Modelos Animales de Enfermedad , Fluoresceína , Verde de Indocianina , Lutecio/farmacocinética , Lutecio/uso terapéutico , Masculino , Metaloporfirinas/farmacocinética , Metaloporfirinas/uso terapéutico , Fármacos Fotosensibilizantes/farmacocinética , Fármacos Fotosensibilizantes/uso terapéutico , Conejos , Neovascularización Retiniana/tratamiento farmacológico , Neovascularización Retiniana/metabolismo , Neovascularización Retiniana/patología , Vasos Retinianos/metabolismo , Vasos Retinianos/patologíaRESUMEN
PURPOSE: Gadolinium texaphyrin (Gd-Tex, PCI-0120) is an expanded porphyrin that has demonstrated radiation enhancement. In this study, we evaluated the radiation enhancement and biolocalization of Gd-Tex in three animal tumor models. METHODS AND MATERIALS: EMT6, SMT-F, and MCa tumors were established intramuscularly or subcutaneously. Gd-Tex and other metallotexaphyrins were administered prior to single or multiple fractions of radiation. 14C-labeled Gd-Tex was used for biolocalization studies. RESULTS: Gd-Tex, in combination with radiation, produced significant tumor growth delay compared to irradiated control groups in both single and multifraction radiation studies. Gd-Tex radiation enhancement was observed only when the drug was given before, but not after irradiation. Several metallotexaphyrins, identical except for the metal ion, were studied in the EMT6 tumor model including gadolinium (Gd), lutetium (Lu), europium (Eu), yttrium (Y), and cadmium (Cd) texaphyrin complexes. Only Gd-Tex produced radiation enhancement. Biodistribution studies using 14C-labeled Gd-Tex demonstrated drug selectivity and retention in tumors growing intramuscularly compared to uninvolved muscle and plasma. CONCLUSIONS: Gd-Tex produces reproducible radiation enhancement in a variety of in vivo tumor models. This drug's unique radiochemistry, tumor selectivity, and in vivo activity suggests possible mechanisms of action not addressed by in vitro assay methods.
Asunto(s)
Antineoplásicos/uso terapéutico , Metaloporfirinas/uso terapéutico , Fármacos Sensibilizantes a Radiaciones/uso terapéutico , Animales , Antineoplásicos/farmacocinética , Relación Dosis-Respuesta en la Radiación , Ensayos de Selección de Medicamentos Antitumorales , Metaloporfirinas/farmacocinética , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C3H , Neoplasias Experimentales/metabolismo , Neoplasias Experimentales/radioterapia , Fármacos Sensibilizantes a Radiaciones/farmacocinética , Radiobiología , Distribución TisularRESUMEN
OBJECTIVE: To seek differences in the pattern of decline between groups of patients with early-onset dementia of varying aetiologies (clinically defined) on the basis of the investigation of their different clinical profiles. DESIGN: A cohort of 126 live patients with dementia diagnosed before the age of 65, of various aetiologies, were identified using the Lothian Psychiatric Case Register. Each person was seen for two assessments approximately 1 year apart. SETTING: Patients were either in long-term care (NHS or other) or at home, usually in the care of relatives. PATIENTS: Of 126 cases (53 male, 73 female, mean age at referral 58 years), 114 met the diagnostic criteria for DSM-III-R dementia: 60 Alzheimer's type dementia; 13 multi-infarct dementia; 14 alcohol-related dementia; with 25 in a mixed group of overlapping categories and two in 'other' dementia types. By the second assessment, 18 cases had died and two cases refused reassessment. MEASURES: The data collected included: demographic; behavioural and psychopathological; neurocognitive; neurological; and genetic. Change was assessed. RESULTS: The alcohol group was distinguished from the other groups by its generally milder profile of impairment and a pattern of change indicating some areas of improvement in the follow-up period. CONCLUSIONS: There are limitations in the instruments used to measure change in this group of patients; at present, measures of change in dementing illnesses cater predominantly for an elderly population with Alzheimer's disease.
Asunto(s)
Demencia/clasificación , Pruebas Neuropsicológicas/normas , Adulto , Edad de Inicio , Distribución de Chi-Cuadrado , Estudios de Cohortes , Demencia/diagnóstico , Demencia/epidemiología , Diagnóstico Diferencial , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Psicosis Alcohólicas/diagnóstico , Análisis de Regresión , Inducción de Remisión , Escocia/epidemiologíaRESUMEN
OBJECTIVE: The aim of the case ascertainment for the study was to identify as near complete as possible a population of patients with presenile dementia who had been identified by hospital contact within a defined period of time, and who were currently alive, in the Lothian area. It did not aim to establish epidemiological figures. DESIGN: The Lothian Psychiatric Case Register was the main source of case identification. Case notes were inspected and cases identified for the study. SETTING: Patients were either in long-term care or at home. PATIENTS: As described in Paper I, Age range 30-65 years. MEASURES: Various diagnostic codings, including those of the ICD-9 were used to identify cases from the register. Feighner criteria were applied on case note inspection and DSM-III-R criteria after individuals had been seen. RESULTS: A potential of 557 cases were identified from the case register, etc. Of these, 431 were excluded and 126 seen for the study. CONCLUSIONS: The criteria used for inclusion and exclusion of cases in this study are thus directed towards achieving the aims of this study, and the findings would have to be modified to reach an estimate of all cases of early-onset dementia in the Lothian area.
Asunto(s)
Demencia/epidemiología , Adulto , Edad de Inicio , Demencia/clasificación , Demencia/diagnóstico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Prevalencia , Psicosis Alcohólicas/diagnóstico , Psicosis Alcohólicas/epidemiología , Sistema de Registros/estadística & datos numéricos , Escocia/epidemiologíaRESUMEN
OBJECTIVE: To clinically characterise and diagnostically classify a sample of patients with early-onset dementia and determine the disabilities and nature of decline of each group, during a one year follow up. DESIGN: The Lothian Postgraduate Case Register was used to identify a cohort of 126 live patients of various aetiologies with dementia diagnosed before the age of 65. Each had two assessments approximately one year apart. Demographic; behavioural and psychopathological; neurocognitive; neurological and genetic data were collected and compared. SETTING: Patients were either in long term care or at home. SUBJECTS: Of 126 cases (53 male, 73 female, mean age at referral 58 years), 114 met the diagnostic criteria for Diagnostic and Statistical Manual Third Edition dementia; 60 Alzheimer's type Dementia; 13 Multi-infarct Dementia; 14 Alcohol related Dementia; with 25 in a mixed group overlapping these categories; and two in 'other' dementia types. By the second assessment, 18 patients had died and two refused reassessment. RESULTS: Levels of morbidity were high. The Alcohol group had a distinct profile and in general the dementia appeared less severe with minimal deterioration. CONCLUSIONS: This study investigates and compares early onset dementia of various types and attempts to provide clear information on their outlook.
Asunto(s)
Demencia/fisiopatología , Adulto , Edad de Inicio , Anciano , Estudios de Cohortes , Demencia/clasificación , Demencia/diagnóstico , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , EscociaRESUMEN
BACKGROUND: The development of devices designed for the endoluminal repair of abdominal aortic aneurysm has led to the emergence of new endovascular techniques. METHODS: Articles and case reports obtained from a Medline search of the English language literature from 1989 to 1997 are reviewed. This search was carried out using the MeSH heading 'aortic aneurysm, abdominal' and the keywords 'endovascular' and 'endoluminal'. RESULTS: Reported mortality and complication rates for endoluminal aneurysm repair are similar to those following conventional repair, with the exception of continued perfusion of the aneurysm sac which remains a major problem following endoluminal repair. CONCLUSION: Successful endoluminal aneurysm exclusion is associated with reduced aneurysm diameter. However, longer term results of endoluminal repair, in particular of sealed endoleaks, are required before randomized controlled trials of endoluminal versus conventional repair can be undertaken.
Asunto(s)
Angioplastia/métodos , Aneurisma de la Aorta Abdominal/cirugía , Angioplastia/efectos adversos , Angioplastia/mortalidad , Prótesis Vascular , Predicción , Humanos , Radiografía Intervencional , Resultado del TratamientoRESUMEN
Photodynamic therapy (PDT) of pigmented melanoma has generally been unsuccessful because of insufficient light penetration in such tissues. In this study, the responsiveness of the heavily pigmented B16F10 murine melanoma to lutetium texaphyrin (PCI-0123), a water-soluble sensitizer with strong absorbance in the near infrared (700-760 nm), was examined. These studies were carried out in both normal and ApoE deficient C57BL/6 mice. The latter strain exhibits a lipoprotein profile more like humans (low density lipoprotein > high density lipoprotein) than rodents (high density lipoprotein >> low density lipoprotein). Under optimal conditions of drug dose, light dose, and interval between drug administration and irradiation--the median survival time of C57BL/6 tumor bearing mice was approximately doubled (29 d) compared with tumor bearing control animals (13 d). The life-span of the ApoE knockout mice was greater (33 d) than the C57BL/6 animals (23 d) when irradiation occurred 3 h after administration of a 10 micromol per kg drug dose. The greater efficacy of PDT in the ApoE deficient mice was associated with more rapid clearance of drug from the blood, greater accumulation of sensitizer in tumor tissue, and substantially greater drug binding to the very low density lipoprotein/low density lipoprotein plasma fraction. Confocal laser scanning microscopy showed that the predominant subcellular site of photosensitizer binding was to melanosomes; costaining was performed with Mel-5. Melanosomes are susceptible to oxidative stress. Photo-oxidation, mediated by PCI-0123 PDT, could potentially overload an already highly oxidized stressed state leading to cell death. The good tissue penetration depth achieved by PCI-0213 mediated PDT and the activation of melanosomes makes PDT of pigmented melanoma, for the first time, clinically relevant.
Asunto(s)
Melanoma/tratamiento farmacológico , Metaloporfirinas/uso terapéutico , Fotoquimioterapia , Fármacos Fotosensibilizantes/uso terapéutico , Animales , Apolipoproteínas E/deficiencia , Apoptosis/efectos de los fármacos , Proteínas Sanguíneas/metabolismo , Femenino , Longevidad/efectos de los fármacos , Melanoma/patología , Metaloporfirinas/farmacocinética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Trasplante de Neoplasias , Fármacos Fotosensibilizantes/farmacocinética , Distribución TisularRESUMEN
BACKGROUND: Occlusive arterial disease causes alterations in blood rheology and levels of potential thrombotic and fibrinolytic mediators. The aim of this study was to investigate the effect of graft materials on these parameters in patients undergoing successful infrainguinal revascularization. METHODS: Some 186 consecutive infrainguinal grafts were observed for 12 months. Venous blood was sampled before operation and at 3, 6, and 12 months after surgery. Samples were assayed for thrombotic and rheological parameters. An area under the curve analysis was used to compare the effects of vein and synthetic grafting on these parameters in 99 patients whose grafts remained patent and free from stenosis. RESULTS: Plasma levels of fibrin degradation products were significantly higher in patients with synthetic grafts (n = 46) than in those with autogenous vein grafts (n = 53) (median 274 versus 150 ng/ml; P < 0.001). There were no significant differences in plasma fibrinogen or any other parameters between the two groups. CONCLUSION: Patients with a synthetic infrainguinal graft have a higher fibrin turnover than those with a vein graft. Further studies are required to determine whether this increase in fibrin turnover is an essential requirement to maintain patency of a synthetic infrainguinal graft.
Asunto(s)
Arteriopatías Oclusivas/sangre , Arteriopatías Oclusivas/cirugía , Prótesis Vascular , Viscosidad Sanguínea/fisiología , Politetrafluoroetileno/uso terapéutico , Anciano , Femenino , Fibrina/metabolismo , Productos de Degradación de Fibrina-Fibrinógeno/metabolismo , Fibrinógeno/metabolismo , Supervivencia de Injerto , Humanos , Masculino , Persona de Mediana Edad , Grado de Desobstrucción VascularRESUMEN
OBJECTIVE: The objective of this study was to determine the diagnostic value of computed tomography (CT) in patients with suspected ruptured abdominal aortic aneurysm. STUDY DESIGN: The study was an interrogation of a prospectively gathered computerized database. SETTING: The study was performed at a regional vascular surgery unit. SUBJECTS: Six hundred fifty-two consecutive patients were admitted to this unit with suspected ruptured abdominal aortic aneurysm between January 1, 1989, and December 31, 1996. Seventy-four patients (11.3%) in whom the diagnosis was in doubt on clinical grounds alone underwent urgent CT. A total of 47 men and 27 women with a median age of 73 years (range, 52 to 86 years) were evaluated. MAIN OUTCOME MEASURES: CT and operative findings were compared. RESULTS: CT correctly diagnosed rupture in 22 of 28 patients who underwent operation and correctly excluded rupture in 30 of 39 patients who underwent operation. The sensitivity and specificity of CT when compared with operative findings were therefore 79% and 77%, respectively. CONCLUSIONS: These data indicate that CT has little additional diagnostic value. If in the opinion of an experienced vascular surgeon rupture cannot be excluded on clinical grounds alone, and the patient has no medical contraindications to abdominal aortic aneurysm repair, then the patient should be taken directly to the operating department.