Biomedical subjects
Publications and source records attributed to F Shepherd.
As practices take on fund-holding status, GPs are thrown into a new management role/ According to Ross Hamilton and Fiona Shepherd, there is some doubt whether current medical training provides the skills for this.
In order to determine the most sensitive method for the early detection of HIV infection, polymerase chain reaction (PCR) and serology were compared using matched peripheral blood mononuclear cells (PBMC) and serum samples taken sequentially at 3-month intervals on 17 HIV seroconverters. All samples from the time of enrollment in the study to the time of seroconversion were studied. [There were only two of the 17 cases where PCR and antigen positivity preceded EIA detectable seroconversion.] Initially, one of these cases was found to be PCR positive 11 months prior to seroconversion, however DNA fingerprinting techniques indicated that the early positive specimen did not belong to the subject in question. In a single subject, PCR was negative at the time of serologic evidence of infection but was positive at the next sampling 3 months later. In the remaining 14 cases, PCR was positive at the same sample time as full or partial seroconversion as determined by three EIA screening tests and Western blot. EIA antibody screen tests showed variability in detection of early HIV antibodies. We found no evidence for prolonged HIV infection prior to seroconversion. PCR offers little if any advantage over serology in the early detection of HIV infection in adults.
Testing saliva for the detection of human immunodeficiency virus (HIV) antibodies has many potential advantages for epidemiologic surveillance. A commercial ELISA kit and a standardized in-house immunoblot (IB) system were slightly modified to enhance antibody detection in saliva. Frozen saliva specimens from Toronto Sexual Contact Study participants (including sequential saliva specimens collected during seroconversion) were tested as were fresh saliva samples collected from a population of street-based intravenous drug users (IVDUs). HIV antibody results on saliva were compared with HIV serostatus determined by ELISA and IB on serum or dried blood spots. The overall sensitivity was 98.3% (117/119) for the kit and 99.2% (118/119) for IB; the specificity was 100% (429/429). In the IVDU population, compliance in the voluntary submission of specimens increased from 69% agreeing to provide blood samples to 89% agreeing to provide blood, saliva, or both. Saliva specimens can be easily collected under difficult field conditions with minimal training and provide a valuable alternative to testing blood for HIV-seroprevalence studies.
Eight patients with AIDS (acquired immune deficiency syndrome) but free of life-threatening infection were treated with the immunosuppressive drug cyclosporine for a mean of 53.9 days. The serum cyclosporine levels were maintained in the desired therapeutic range. All eight patients experienced severe toxic symptoms, which necessitated discontinuation of cyclosporine therapy in six. The serum levels of creatinine, urea and potassium rose during treatment and fell after therapy was stopped. The total leukocyte count, hemoglobin level, platelet count, total T-cell count, and T4- and T8-cell counts all fell markedly during treatment. The total leukocyte count, platelet count, and T4- and T8-cell counts rose after therapy was stopped, but the hemoglobin level remained low. No patient experienced resolution of symptoms during therapy, and the condition of all patients improved after treatment was stopped. The results of this pilot study indicate that cyclosporine does not alleviate, and may worsen, the symptoms and laboratory findings in patients with AIDS.
In 1984 the General Practitioner Hypertension Study Group undertook a rescreening of their patient population, looking for patients who still had untreated mild to moderate essential hypertension. Suitable patients were entered into a clinical trial comparing the safety and efficacy of nicardipine (a calcium antagonist) and amiloride + hydrochlorothiazide (HCTZ) (moduretic). The study included one year of long-term follow-up. Both drugs significantly lowered BP in both the short and long term. Numbers and percentages of patients from each group reporting adverse experiences were similar in the short term, but in the long term the frequency of adverse event reporting was much lower with nicardipine treatment than with amiloride + HCTZ treatment (2/10 versus 9/17). Treatment with amiloride + HCTZ led to elevations in serum levels of cholesterol, uric acid and urea, which were maintained at one year, whilst no abnormalities in blood biochemistry were seen in patients treated with nicardipine. In conclusion we have found that nicardipine compares very favourably with amiloride + HCTZ in the treatment of mild to moderate hypertensive patients.
The effects of dietary fat on 7,12-dimethylbenzanthracene (DMBA)-induced mammary tumorigenesis were examined in BALB/c female mice. In the first experiment, BALB/c mice were treated with a total dose of 1, 3, or 6 mg DMBA to induce mammary tumors. One week after the last dose of DMBA, the mice were placed on a 5% (LF) or 20% (HF) corn oil semi-purified diet. The 20% corn oil diet resulted in a significantly decreased mean tumor latency period in each of the three groups of mice (p less than 0.05). However, the mammary tumor incidences at 11 months after DMBA treatment were the following: 6 mg DMBA (LF-14/32, HF-17/32); 3 mg DMBA (LF-13/50, HF-14/50); 1 mg (LF-2/50, HF-6/50). In the second experiment, prolonged hormonal stimulation by pituitary isografts, but not a HF diet, enhanced the incidence of mammary tumors in BALB/c mice given a threshold dose of DMBA (0.5 mg). In a further attempt to examine the mechanism of the enhancing effects of dietary fat, lipid peroxidation was measured in the microsomal-mitochondrial fractions of the mammary glands by two assays; measurements of conjugated dienes and TBA reactants (malonyldialdehyde). The high fat diet had no effect on the levels of conjugated dienes in mammary cell membrane preparations and decreased the levels of TBA reactants (malonyldialdehyde). The results indicated that a high fat diet did not lead to enhanced levels of lipid peroxidation in preparations of microsomal mitochondrial membranes from mouse mammary glands. The implications of these results are discussed with respect to the role of dietary fat as a promoter of mouse mammary tumorigenesis.
The effect of dietary selenium levels on 7,12-dimethylbenzanthracene (DMBA)-induced mammary tumors was examined in mice fed a semi-purified diet (20% casein, 50% sucrose, 5% corn oil). (C57BLxDBA/2f)F1 (BD2F1) female mice were fed diets containing 0.2, 0.5, 1.0 and 2.0 p.p.m. selenium starting at 7 weeks of age. The mammary tumor incidence was 56, 30, 25 and 16%, respectively, after the mice were on the diet for 9 months. In a second experiment, BALB/cV female mice were fed diets containing 0.2 and 2.0 p.p.m. selenium. After 9 months on the diet, the mammary tumor incidence was 39 and 7%, respectively. Both strains of mice grew equally well on the 0.2 and 2.0 p.p.m. selenium diets indicating that the highest dietary selenium level was compatible with normal growth. The selenium concentration and selenium dependent-glutathione peroxidase (GSH-Px) activity of mammary glands from control BD2F1 mice fed 0.2, 1.0 and 2.0 p.p.m. dietary selenium was examined at 8, 9 and 10 months of age. As in previous experiments in adult BALB/c mice, the concentration of mammary gland selenium, but not GSH-Px activity, increased with increasing levels of dietary selenium. These results document that nutritional levels of dietary selenium (0.5 p.p.m. Se) as well as non-toxic higher levels (2.0 p.p.m. Se) inhibit DMBA-induced mammary tumorigenesis.
The effect of supplemental selenium on 7,12-dimethylbenz[a] anthracene (DMBA)-induced mammary tumorigenesis was investigated in several mouse strains. Selenium, administered as SeO2 in the drinking water, inhibited mammary tumor formation in DMBA-treated (C57BL x DBA/2f)F1, C3H/StWi and BALB/c female mice. In addition, selenium inhibited the occurrence of DMBA-induced ductal hyperplasias in (C57BL x DBA/2f)F1 and BALB/c mice and mammary tumour virus-induced alveolar hyperplasias in BALB/cfC3H mice. Selenium did not alter the growth of established mammary tumors. These results demonstrate that supplemental selenium inhibits both chemical-and viral-induced mouse mammary tumorigenesis, and secondly, that the development of preneoplastic lesions, an early stage in mammary tumorigenesis, is very sensitive to selenium-mediated inhibition.
The effects of supplemental selenium on 7,12-dimethylbenz(a)anthracene (DMBA)-induced and murine mammary tumor virus (MuMTV)-induced mammary tumorigenesis were investigated in BALB/c mice. Selenium (4-10 ppm), administered in the drinking water, inhibited mammary tumor formation in DMBA-treated mice. The higher doses of selenium (7-10 ppm) were tolerated well by the DMBA-treated mice and blocked mammary tumor formation by 80-90%. In addition, selenium at the lowest dose (4 ppm) inhibited the tumor-producing capabilities of a MuMTV-positive preneoplastic nodule outgrowth line by greater than 75%. The inhibition of tumor formation could not be attributed to an alteration in virus expression because there was no qualitative difference in the expression of of MuMTV proteins between selenium-treated and -untreated mice. Additionally, selenium-dependent glutathione peroxidase activity was detectable in normal virgin and preneoplastic mammary tissues of mice raised on a commercial diet and was increased 2-fold by 4 ppm supplemental selenium in the drinking water. These results demonstrate that supplemental selenium is an effective inhibitor of both chemical- and viral-induced mouse mammary tumorigenesis, and secondly, that the neoplastic transformation in, as well as the development of, preneoplastic lesions is sensitive to selenium-mediated inhibition.
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The effects of selenium of mouse mammary tumorigenesis were examined in 2 systems. BALB/cfC3H (MuMTV-S positive) given 2 and 6 ppm selenium in the drinking water and maintained as breeding mice, had significantly lower incidences of mammary tumors (48% and 12%, respectively) than untreated control mice (82%). Selenium at 4 ppm inhibited the tumor-producing capabilities of only 1 of 4 preneoplastic outgrowth lines maintained in BALB/c (MuMTV-S negative) mice. Selenium at 2, 4 and 6 ppm had no effect on the growth rate of primary mammary tumors transplanted subcutaneously in BALB/c mice. Selenium inhibited mammary tumorigenesis without interference of normal reproductive function and weight gain.
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Preneoplastic mammary nodule lines D1, D2, and C4 were enzymatically dissociated with collagenase, hyaluronidase, and pronase or with only collagenase and hyaluronidase to produce high yields of viable single cells; 10(5) cells were injected into the cleared mammary fat pads of syngeneic BALB/cCrgl mice. In 11 experiments involving three different preneoplastic nodule lines with different tumor potentials, all dissociated nodule cell lines showed a marked increase in tumorigenicity as compared to the same tissues transplanted as 1-mm3 pieces. The results could not be explained on the basis of differences between the amounts of cells transplanted in the two procedures. In a second series of experiments, normal mammary cells from virgin, pregnant, or lactating mice were mixed in different ratios with 10(5) nodule cells and injected into the mammary fat pads. The presence of normal cells reversed the marked increase in the tumorigenicity of enzymatically dissociated nodule cells to a level equal to or less than the tumorigenicity of control transplants (1-mm3 pieces). The growth of 10(5) mammary tumor cells was not inhibited when tumor cells were mixed with 3 x 10(5) normal cells and transplanted into the mammary fat pads. These results showed that enzymatic dissociation can lead to an increase in tumor potential of preneoplastic mammary nodule lines, and they supported the hypothesis that nodule cells, but not neoplastic cells, are sensitive to the growth-inhibitory effects of normal mammary cells.
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