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Managed Care Programs↗
Biomedical subjects
B D Wilson
Publications and source records attributed to B D Wilson.
An assay for O6-alkylguanine-DNA alkyltransferase based on restriction endonuclease inhibition and magnetic bead separation of products.
We describe an improved, rapid and cost effective assay for measuring O6-alkylguanine-DNA alkyltransferase (AGT) levels in large numbers of small biological samples. The assay is based on the use of a synthetic O6-methylguanine oligonucleotide bound to magnetic beads via a biotin-streptavidin linkage and bound to its complement. A 35S label is incorporated into the free end of the duplex. The basis of the assay lies in the observation that the restriction enzyme PvuII will not cleave the bead-bound duplex oligonucleotide having an O6-methylguanine within the restriction sequence. However, on removal of the methyl group by AGT present in cell extracts prior to incubation with PvuII, the 35S-labelled oligonucleotide is cleaved by the restriction enzyme, releasing a 35S-labelled 8 bp fragment. Due to the stoichiometric nature of the AGT reaction, quantitation of AGT is easily achieved by counting an aliquot of the supernatant after pelleting the unrestricted bead complexes with a magnet. AGT levels measured in certain cell lines and human lymphocytes by the reported assay are comparable to other methods. The assay can be performed in basic laboratories and allows for the rapid processing of many samples simultaneously, which could prove useful in clinical and epidemiological studies.
Base Sequence↗
Trampolines in New Zealand: a decade of injuries.
Despite international concern about the safety of trampolines, they have become increasingly popular in New Zealand. While internationally attention has centred on a relatively few cases of catastrophic cervical spine injury, little research effort has been directed at placing these incidents in a wider context. To redress this, a descriptive epidemiological study of trampoline-related injury in New Zealand was undertaken. National hospitalization and mortality data for a 10-year period revealed 2098 hospitalizations and two deaths. The incidence rate for hospitalizations increased from 3.1 per 100,000 population per year in 1979 to 9.3 in 1988. Of the hospitalized victims, 71% were injured on home trampolines and 80% fell from the trampoline to the surrounding surface. Fractures were the commonest type of injury (68%), and the body site most frequently involved was the upper limb (53%). There was no evidence of a high incidence of severe head and neck injuries. It was concluded that, although existing trampoline standards addressed many of the issues raised by this research, measures to reduce the impact of falls from trampolines to the ground and to prohibit the provision of trampolines as 'play equipment' are required.
Accidental Falls↗
Regulation of endothelial cell protein C activation and fibrinolysis by procoagulant albumin.
Endothelial cell regulation of protein C activation and fibrinolysis are important components of the hemostatic response to vascular injury or perturbation. Procoagulant albumin (P-A1), a constituent of normal human plasma has been purified and identified as an inducer of endothelial cell tissue factor activity. The purpose of the studies reported herein was to investigate the effects of P-A1 on human endothelial cell protein C activation and fibrinolysis. P-A1 suppressed protein C activation, enhanced release of plasminogen activator inhibitor-1, but had no effect on tissue-plasminogen activator release. Plasminogen activator inhibitor-1 released by P-A1 was functional as evidenced by the capacity to form a covalent complex with 125I-urokinase. Inactive albumin (isolated during the same purification procedure as P-A1, but without tissue factor-inducing activity) did not suppress protein C activation or increase plasminogen activator inhibitor-1 release. These results indicate that P-A1, a component of human plasma, can modulate multiple vascular hemostatic properties, and support the hypothesis that P-A1 is involved in normal or pathologic hemostasis.
Anions↗
Obesity and body fat distribution in New Zealanders: a pattern of coronary heart disease risk.
AIMS: To describe the prevalence of obesity and the body fat distribution of New Zealanders. To discuss this in the context of the coronary heart disease risk. METHODS: Body weight and height, body mass index (BMI), waist:hip ratio (WHR) and six skinfold measurements were determined for 3204 randomly selected New Zealanders who responded to an invitation to a health check (response rate 56%). RESULTS: In the study sample BMI generally increased with age. Fifty five percent of men and 38 per cent of women aged 18-64 had a BMI exceeding 25, and of these 13 per cent and 10 per cent were obese (BMI > 30). WHR was greater in men than in women of all ages, and a third of the men and a quarter of the women had values exceeding 0.9 and 0.8 respectively. Central skinfold measurements (subscapular, suprailiac and abdominal) were lowest in young men, but rose markedly with age and were similar to women above age 35. Limb skinfolds were lower in men. CONCLUSIONS: This survey indicates that a large percentage of New Zealanders are overweight or obese and their excess body fat tends to be centrally distributed, especially in men. Obesity is thus a significant health problem in New Zealand.
Adipose Tissue↗
Amiodarone causes decreased cell-mediated immune responses and inhibits the phospholipase C signaling pathway.
Amiodarone can cause pulmonary toxicity along with an increase in phospholipid in macrophages, lymphocytes, and other cell types. Phospholipid accumulates because amiodarone inhibits the lysosomal phospholipases A1 and A2. Since a wide array of cells are affected by amiodarone and because amiodarone might inhibit other phospholipases, we postulated that cellular functions might be affected. Therefore, the major focus of this study was to determine whether amiodarone inhibited cellular functions. We found that alveolar macrophages isolated from drug-fed rats were significantly less phagocytic, and that the rats had significantly depressed delayed-type hypersensitivity responses. Spleen cells isolated from the drug-fed rats also had severely depressed mitogen responses. Since the spleen cell proliferative response could be partially restored by stimulating the cells with ionomycin and phorbol myristate acetate, we postulated that amiodarone was inhibiting phospholipase C. To substantiate this hypothesis, we found that amiodarone could directly inhibit phospholipase C in vitro. We conclude that amiodarone affects both phagocytic responses and the development of cell-mediated immunity and that the lack of these normal responses could exacerbate amiodarone toxicity. One possible mechanism for decreased cellular functions may be the inhibition of phospholipase C. However, further studies are necessary to confirm this finding.
Amiodarone↗
Homocysteine, a risk factor for premature vascular disease and thrombosis, induces tissue factor activity in endothelial cells.
Elevated blood levels of homocysteine represent an independent risk factor for premature arterial vascular disease and thrombosis. We investigated whether homocysteine could induce tissue factor (TF) procoagulant activity in cultured human endothelial cells. Homocysteine increased cellular TF activity in a time- and concentration-dependent manner. Low concentrations of homocysteine (0.1 to 0.6 mmol/L), similar to those found in the blood of patients with homocystinuria, enhanced TF activity by 25% to 100%. Other sulfur-containing amino acids (cystine, homocystine, cysteine, and methionine) induced less TF activity than did homocysteine; however, beta-mercaptoethanol and dithiothreitol were more effective than homocysteine in increasing TF activity. Preincubation of homocysteine with a sulfhydryl inhibitor such as N-ethylmaleimide prevented homocysteine induction of TF activity. A quantitative polymerase chain reaction method indicated that homocysteine increased TF mRNA in endothelial cells. These results indicate that an atherogenic amino acid, homocysteine, can initiate coagulation by the TF pathway through a mechanism involving the free thiol group of the amino acid and by TF gene transcription. These data support the hypothesis that perturbation of vascular coagulant mechanisms may contribute to the thrombotic tendency seen in patients with homocystinuria.
Base Sequence↗
Amiodarone pulmonary toxicity in the rat is associated with increased lavage immunoglobulin and alveolar macrophages primed for increased interleukin-1 secretion.
To determine whether a hypersensitivity reaction played a role in amiodarone-induced pulmonary inflammation and affected humoral immunity, we examined pulmonary immunoglobulin (Ig) levels, alveolar macrophage release of interleukin-1 (IL-1)-like activity, and the ability to generate both systemic and pulmonary humoral immune responses after immunization. Levels of IgG, IgM, and albumin in lavage fluid were measured by enzyme-linked immunosorbent assay (ELISA) in control rats and rats fed drug for 3, 8, 11, and 30 wk. Control rats showed no change in lavage Ig levels at any time point. However, drug-fed rats had a significant increase in IgG/albumin at 11 and 30 wk and IgM/albumin at 30 wk. To determine whether alveolar macrophages were in an activated state, the amount of IL-1-like activity released by cells from control rats was compared with drug-fed rats, using the standard C3H/HeJ thymocyte proliferation assay. We found no difference in the spontaneous release of IL-1 activity, but lipopolysaccharide-stimulated macrophages from the drug-fed rats produced significantly more IL-1 than did control macrophages. Finally, to examine antibody responses, control and drug-fed rats were immunized and boosted with 1 mg/ml of ovalbumin (OA) in adjuvant followed by an intratracheal immunization of OA. There was no difference in antibody titers measured by ELISA. In conclusion, although there is some suggestion of an immune-mediated component in amiodarone-induced pulmonary inflammation, the increase in lymphocytes and lavage Ig appears too late to be the sole cause.
Amiodarone↗
Photodynamic therapy in the treatment of Bowen's disease.
BACKGROUND: The treatment of Bowen's disease in anatomically difficult areas or especially large lesions can challenge accepted modalities of treatment. OBJECTIVE: The purpose of this study was to illustrate the effectiveness of photodynamic therapy in the treatment of Bowen's disease. In addition, photodynamic therapy may be used as adjuvant therapy for difficult lesions. METHODS: Six patients with Bowen's disease in various anatomic sites were treated with photodynamic therapy. Four were in a difficult anatomic site, or were especially large, or both. Photofrin, 1.0 mg/kg, was administered intravenously and laser treatment was given approximately 48 hours later with the argon dye laser. Light was administered at a wavelength of 630 nm and the light dose ranged from 185 to 250 joules/cm2. Treatment was given by surface radiation only. RESULTS: Eight lesions were treated. All showed a complete response at 3 months (100%) and continue to show a complete response at 6 and 12 months. Morbidity was low; the most significant side effects were moderate pain and edema. Healing time varied depending on the size of the lesion. CONCLUSION: Photodynamic therapy is an effective and useful alternative for Bowen's disease, especially those lesions in anatomically difficult areas or those that are especially large.
Adult↗
Regulation of endothelial cell protein C activation by native and oxidized low density lipoprotein.
The effects of native LDL and Ox-LDL and HDL on endothelial cell protein C activation were examined. Ox-LDL, which is postulated to contribute to cardiovascular disease, markedly suppressed activation of protein C, an important vascular anticoagulant activity. This effect was seen with both human venous and arterial endothelial cells. Endothelial cells modified LDL to a form that reduced protein C activation, an effect prevented by the anti-oxidant, probucol. Endothelial cells are known to express the acetyl LDL (scavenger) receptor, which binds chemically modified and Ox-LDL. The effect of Ox-LDL on protein C activation does not appear to result from uptake via the acetyl LDL receptor, since a known scavenger receptor antagonist (fucoidin) did not inhibit the oxidized LDL effect. In contrast to the results with Ox-LDL, native LDL and both native and oxidized HDL increased protein C activation. These data indicate that native and modified lipoproteins regulate blood coagulation by affecting vascular anticoagulant activity and suggest mechanisms that may link modified lipoproteins with both vascular disease and thrombosis.
Cells, Cultured↗
Photodynamic therapy for the treatment of basal cell carcinoma.
BACKGROUND: Photodynamic therapy is an investigational method for the treatment of a variety of solid tumors. The purpose of this study was to determine the optimum factors and illustrate the effectiveness of photodynamic therapy in the treatment of basal cell carcinomas. This was a prospective study in which patients presenting with primary or recurrent basal cell tumors, particularly but not exclusively widespread tumors or large single tumors, were offered the option of photodynamic therapy in their treatment regimen. RESULTS: Patients were administered 1 mg/kg of a photosensitizer (Photofrin II). Light doses (630 nm) ranged from 72 to 288 J/cm2. A total of 37 patients with 151 sites were treated in this study. A complete response rate of 88% was achieved with one application. Morbidity was low; the most significant side effects were moderate pain and edema. CONCLUSIONS: Photodynamic therapy is a modality that offers localized treatment of primary or recurrent nonmelanoma skin cancer. By applying reciprocal doses of photosensitizer and light, the efficacy of photodynamic therapy in the treatment of skin lesions is demonstrated achieving significant light penetration into tissue with a high complete response rate of the lesions and acceptable normal tissue response.
Basal Cell Carcinoma↗
The cost benefit of rehabilitation of injured workers in New Zealand.
A multidisciplinary rehabilitation centre was established to address the needs of people with mild to moderate disability who had not worked for prolonged periods of time. A fitness based programme assisted 10 of the 20 who had been off work for more than six months to return to activity. Six and eighteen month follow up confirmed the durability of placement of most workers who had returned to work, and that projected benefits were achieved. Benefits were defined as savings in earnings related compensation (ERC), and compared to the costs of establishing and running the centre. Sensitivity analysis ascribing between 100% and 50% of benefit to the programme showed a positive benefit cost ratio, with benefits discounted at a rate of 10% over 10 years. With 75% ascribed, the project produced benefit cost ratio of about 1.5:1 in the first year, 2.8:1 in the second year, and rising to 6.2:1 in the fifth year and 10:1 by the tenth year. With only 50% ascribed, the benefit over the same times was 1.0:1, 1.9:1, 4.1:1 and 6.7:1 by the tenth year. These calculations probably underestimate true benefits.
Adult↗
Oxidized low-density lipoprotein increases cultured human endothelial cell tissue factor activity and reduces protein C activation.
Increasing evidence suggests that the formation of oxidized low-density lipoprotein (Ox-LDL) in vivo is associated with the development of atherosclerotic vascular disease. We investigated the effects of Ox-LDL on two vascular endothelial cell coagulant properties, tissue factor expression, and protein C activation. The Ox-LDL increased human arterial and venous endothelial cell tissue factor activity, with 100 micrograms/ml of Ox-LDL increasing factor activity fourfold. Native LDL modified by incubation with cultured human arterial and venous endothelial cells also induced endothelial cell tissue factor activity. This modification was blocked by coincubation with the antioxidants, probucol or ascorbic acid. It was determined, based on inhibition by known scavenger receptor antagonists (fucoidin, dextran sulfate), that binding of Ox-LDL via the acetyl LDL (scavenger) receptor was partially responsible for the increase in tissue factor expression. Whereas endothelial cell tissue factor expression was increased by incubation with Ox-LDL, protein C activation was reduced approximately 80% by incubating cultured endothelial cells with Ox-LDL. The effect of Ox-LDL on protein C activation was not inhibited by antagonists to the scavenger receptor. These data indicating that an atherogenic lipoprotein can regulate key vascular coagulant activities provide an additional link between vascular disease and thrombosis.
Anticoagulants↗
Localization of endogenous beta-galactoside-binding lectin as a means to distinguish malignant from benign skin tissue.
The immunolocalization of a 30-kd endogenous lectin, referred to as galaptin, was studied in various skin tumor types. Basal cell carcinomas expressed little or no galaptin, whereas nonmalignant basaloid cells, squamous cell carcinomas, melanoma, nevi, and stroma showed more prominent galaptin immunostaining. Therefore, the immunodetection of galaptin may aid the dermatopathologist in difficult histologic diagnosis.
Biomarkers, Tumor↗
Amiodarone-induced pulmonary inflammation. Correlation with drug dose and lung levels of drug, metabolite, and phospholipid.
To investigate the hypotheses that amiodarone-induced pulmonary inflammation may be related to direct drug toxicity, groups of 10 or more Wistar rats were fed amiodarone by gavage at concentrations of 175, 300, 400, and 500 mg/kg/day, or vehicle alone. After 6 wk of drug feeding, the rats were examined for histologic and cellular evidence of pulmonary inflammation. In addition, the amounts of amiodarone, the major metabolite of amiodarone N-desethylamiodarone (N-des), and phospholipid in the lungs were determined. We found that rats fed 175 mg/kg of amiodarone were essentially no different from control animals. The 175 mg/kg group had normal lung histologies, no change in lavage cell counts or differential counts, and very little amiodarone, N-des, or phospholipid in the lungs. In contrast, the three high-dose groups had abnormal lung histologies along with increases in lavage cell counts and change in differential counts. There were also significant increases in the amounts of amiodarone, N-des, and phospholipid in the lung. We conclude that the development of amiodarone-induced pulmonary inflammation is dose dependent, and that there is a direct correlation between the amount of amiodarone, N-des, and phospholipid in the lung with the development of inflammation. It therefore appears that the drug is directly toxic to lung tissue.
Amiodarone↗
The rehabilitation of injured workers in New Zealand: a pilot study.
At the request of the local office of the Accident Compensation Corporation (ACC) we established a centre which offered a multidisciplinary rehabilitation programme consisting of a full assessment and an eight week individually planned and monitored fitness programme. The clients progressed to occupational therapy, work trials, and later to paid work. The programme included education about back care and health maintenance, and relaxation techniques. Of the 48 injured people who attended the centre, 37 were assessed as suitable to enter the programme, and 32 people took part. Outcome, measured as return to work or change in assessed fitness to work, was not related to age, sex, marital status, length of time since accident, or work category. Only 25% of workers returned to jobs in medium or heavy manual work. Sickness impact profile total and physical scores improved over the programme, but did not correlate significantly with return to work or fitness for work. Client perception of benefit was not significantly related to outcome. We analysed data from the 20 clients with claims longer than 6 months separately because matched case controls could not be provided by the ACC. Six months after completion of the programme, four were in paid employment, four in prolonged work trials, one in a job partly paid by the ACC, and one setting up his own business. Their return to the work force demonstrated the effectiveness of the centre in restoring people to function after prolonged periods of inactivity.
Accidents, Occupational↗
Pulmonary accumulation of amiodarone and N-desethylamiodarone. Relationship to the development of pulmonary toxicity.
To investigate the relationship between the amount of amiodarone and the major metabolite N-desethylamiodarone found in the lung with the development of toxicity, Fischer 344 and Wistar rats were given 175 mg/kg/day of drug by gavage. After 1, 3, 6, and 12 wk of drug feeding, both stains were examined for histologic evidence of pulmonary inflammation and for changes in lavage cell counts and differentials. The amounts of amiodarone and N-desethylamiodarone in the lungs were determined using high performance liquid chromatography. We found that in drug-fed Wistar rats the lavage differentials were unchanged, lavage cell counts were decreased compared with those in control rats, and the lungs appeared normal except for some foamy macrophages. Wistar rats also had low levels of amiodarone and metabolite in both lung tissue and cells. In contrast, Fischer rats had an increase in lavage lymphocytes, neutrophils, and macrophages compared with that in control rats and abnormal lung histologies. Also, there was much more drug and metabolite in the lungs than the amounts found in Wistar rats. Because Fischer rats had more metabolite than amiodarone in the lung and the reverse was true in Wistar rats, the in vitro cytotoxicity of amiodarone and N-desethylamiodarone were compared. We found that N-desethylamiodarone was significantly more cytotoxic than amiodarone to both fibroblasts and endothelial cells. We conclude that there is a relationship between the amounts of drug and metabolite in the lung and the development of pulmonary inflammation, and that N-desethylamiodarone may be more cytotoxic than amiodarone.
Amiodarone↗
Experimental values of the ionization constants for L-3,5-di-iodotyrosine and a model for ionic interactions of thyroid hormone (T3) and its nuclear receptor.
Ionization characteristics of L-3,5-di-iodotyrosine have been measured under various conditions. These data, which correct an erroneous report of pK3 in the literature, have been used to estimate the ionization constants of the thyroid hormone L-3',3,5-tri-iodothyronine (T3). On this basis a reinterpretation has been made of the pH-dependent binding of the hormone to its solubilized rat liver nuclear receptor (Wilson BD and Gent WL, Biochem J 232: 663-667, 1985). The interaction may depend on the ionization of the phenolic group of T3 and an acidic group (pK'7.6) in the receptor site, leading to the formation of a hydrogen bond between the two groups. The changes of the number of binding sites with pH must then result independently from alterations in the conformation of the receptor protein.
Diiodothyronines↗