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Biomedical subjects

J R Williams

Publications and source records attributed to J R Williams.

At least 91 records · Page 5Linked to original sources
PubMed1996

Redefining comprehensiveness in the deficit era.

As health care systems undergo funding cutbacks, we cannot expect to receive all needed and wanted health care services at public expense. Instead, choices must be made about which services will be provided from public funds (and to whom), which will be available to individuals who wish to purchase them, and which will not be available at all. These are ethical questions, if only because the proposed answers will reflect different concepts of social justice. This article identifies and describes some of the major ethical considerations in redefining the principle of "comprehensiveness" in the Canada Health Act. The authors argue that the criterion of "medical necessity" may no longer be, if indeed it ever was, adequate for determining which health services should be publicly funded. They do not believe that any single criterion can fulfill this role. Instead, they propose that policy makers focus on developing a better process for making choices among health care priorities. Clearly defined roles in this process must be established for payers, the public and providers.

Canada↗
PubMed1995

Adrenocorticoid hormones and the development and expression of mammalian monogamy.

Based on research with prairie voles, we hypothesize that the unusual patterns of reproduction and social behavior associated with mammalian monogamy may arise as a consequence of normal developmental exposure to high levels of glucocorticoids and/or other hormones of the HPA axis. Increased HPA activity could functionally inhibit some of the masculinizing processes expected during the perinatal period. We hypothesize that the unique behavioral, physiological, and anatomical changes associated with monogamy may reflect the adaptive consequences of reduced exposure to the masculinizing actions of HPG hormones, such as testosterone. Reproductively naive, unpaired adult prairie voles also show unusual patterns of adrenal activity, including a marked decline in corticosterone levels within minutes following exposure to novel animals of the opposite sex. In females, this decline in corticosterone may contribute to pair bonding, since corticosterone injections inhibit, and adrenalectomy is associated with a facilitation of pair bond formation. In males, corticosterone injections facilitate pair bonding and adrenalectomy has the opposite effect. In animals from established social pairs corticosterone levels also fluctuate according to the social environment of the animal; the absence of a familiar partner is associated with increased corticosterone secretion, and in the presence of the familiar partner corticosterone levels tend to decline. Prairie voles may offer a valuable source of information regarding the behavioral, anatomical, and physiological consequences of long-term and short-term exposure to high levels of adrenal activity in the absence of pathology.

Adrenal Cortex Hormones↗
PubMed1995

Consensus finally achieved on resuscitative interventions.

A joint policy statement on the resuscitation of patients is published in this issue of CMAJ. Dr. John Williams, the CMA's director of ethics and legal affairs, discusses how it differs from the joint statement published last year.

Canada↗
PubMed1995

Prediction of tumor response to experimental radioimmunotherapy with 90Y in nude mice.

PURPOSE: To identify those factors that predict variability in tumor response to 90Y-radioimmunotherapy based on measurement of incorporated activity and physical dimensions of individual tumors and to apply the concept of effective dose to radioimmunotherapy. METHODS AND MATERIALS: Human colon carcinoma xenografts growing in nude mice were treated with anti-CEA antibodies labeled with 90Y directly or through a bispecific antibody/labeled hapten system. Tumor response was measured as the delay in growth to eight times the treatment volume. Noninvasive activity (based on bremsstrahlung radiation) and dimension measurements were made in these animals at several times after label injection. The following parameters were compared for their ability to predict individual tumor response: (a) injected activity, (b) injected activity times a factor based on average uptake as a function of volume, (c) in vivo activity per volume measured in each animal at a single time, (d) the integral over time of in vivo activity per volume in each animal, and (e) the minimum dose for each animal in a uniformly active ellipsoid whose total activity and dimensions varied over time the same as the tumor. RESULTS AND CONCLUSION: After correcting for differences in injected activity, two parameters account for much of the variability in tumor response. One of these is the general trend of larger tumors to take up less activity per volume. Additional variability can be accounted for by the in vivo activity per volume measurements. The minimum dose as introduced here is likely to be useful in estimating the biologically effective dose delivered by each treatment.

Animals↗
PubMed1995

Core and comprehensive health care services: 3. Ethical issues.

The CMA's Working Group on Core and Comprehensive Health Care Services recognizes ethics to be one of the three key factors in determining which services should be publicly funded. The role of ethics is to identify and make explicit the principles and values, at individual and societal levels, that lie behind judgements and positions. Two types of ethical issues are addressed: one deals with the criteria for these services and the other with the process to be followed. The five ethical criteria discussed are fairness, age, lifestyle, the identifiable versus the statistical patient, and futility. An ethical process incorporates appropriate roles for the public physicians and payers (government) and accountability of all participants. A provided checklist for determining a fair process asks such questions as Do potential users of a service, its providers and the public have an adequate say in the decision about whether the service should be publicly funded? Are the reasons for the decision communicated to those affected by it? and is the service being denied to potential users on the basis of unfair discrimination or lifestyle?

Age Factors↗
PubMed1995

Direct measurement of intratumor dose-rate distributions in experimental xenografts treated with 90Y-labeled radioimmunotherapy.

PURPOSE: To measure, quantify, and evaluate the planar dose-rate distribution for human tumor xenografts implanted into mice that are treated with 90Y-labeled monoclonal antibodies or bispecific antibodies and 90Y-labeled haptens. METHODS AND MATERIALS: Twenty-five LS174T human colon carcinoma tumors grown subcutaneously in nude mice were treated with 90Y by either directly labeled ZCE025 or bispecific ECA001-DBX antibody systems. A simple, quick technique using GAF radiochromic medium determined the dose-rate distribution in a plane passing through the tumor center. The dose-rate distribution is generated from exposure to activity situated in one-half of the tumor (0.045 to 0.83 g). RESULTS: Planar dose-rate distributions were obtained from the tumor xenografts. Planar dose-rate histograms were computed along with the coefficients of variance and skewness of the distributions. The observed dose-rate distributions were quantitatively compared to those calculated for a uniformly distributed activity in a half-ellipsoid of the same volume and approximate shape as the tumor half. The observed dose-rate distributions were usually broader with a more positive coefficient of skewness than the dose-rate distributions calculated from the uniformly active half-ellipsoids. For 90Y, tumor shape plays an important role in determining the minimum tumor dose. For these tumors, the tumor minimum dose-rate is always observed along the edge, usually where the edge curvature is most convex. Larger tumors tended to have broader dose-rate distributions and more positive coefficients of skewness. Exceptions to this trend were associated with dose-rate maxima displaced from the central regions due to activity heterogeneity or tumor size greatly exceeding the range of emission. Calculations for dose rate from the conventional Medical Internal Radiation Dose (MIRD) formulation exceeded the average and minimum dose rate derived from radiochromic media. The coefficient of skewness became more positive for increasing time between injection and tumor excision, consistent with the activity evolving into a more uniform activity distribution. CONCLUSION: Using radiochromic media to measure the spatial dose-rate distribution is a valuable method for comparing the dose-rate heterogeneity among experimental tumor xenografts in animals treated with radiolabeled antibodies. Tumor size (relative to the particle range) and changes in activity distribution radiolabeled antibodies. Tumor size (relative to the particle range) and changes in activity distribution affect the dose-rate distribution that are reflected by changes in the coefficients of skewness and variation of the dose-rate area histogram. The increase in coefficients of variation and skewness with tumor size and time results from the size of the 90Y beta particle penetration range that either exceeds or is comparable to the tumor dimensions. The minimum dose rate is more dependent, relative to the average and the maximum dose rates, on the curvature of the tumor surface.

Animals↗
PubMed1995

Disturbances in cell recognition molecules (N-CAM and L1 antigen) in the CSF of patients with schizophrenia.

Although the pathogenesis of schizophrenia is unknown, there are data which indicate that the disease may be due to neurodevelopmental disturbances. Cell recognition molecules such as N-CAM and L1 antigen are involved in cell-cell interactions during development and in plasticity of the nervous system and could therefore be altered in relation to ongoing or established pathological processes. Using the Western blot technique, we found significant increases in N-CAM immunoreactive proteins and decreases in L1 antigen in the CSF of schizophrenic patients as compared to normal controls. The decrease in L1 antigen was observed in the 140-kDa band, and N-CAM was increased only in the 120-kDa band. The 120-kDa band of N-CAM and the 140-kDa band of L1 antigen were prominent components of CSF, but in serum these bands were minor or not detectable. Neuroleptic treatment did not significantly change either N-CAM or L1 antigen concentrations in CSF. It is possible that these CSF proteins are derived from CNS cells as secreted soluble N-CAM isoforms and L1 peptides. Our results suggest the possibility of a specific pattern of abnormal cellular function in the CNS in schizophrenia.

Adult↗
PubMed1995

The syntheses of 3 beta-steroidal diacylglyceryl sulfides, sulfoxides, and sulfones.

The syntheses of the diacylglyceryl-sulfide 4a, sulfoxide 4b, and sulfone 4c of dehydroepiandrosterone (3 beta-hydroxyandrost-5-en-17-one, DHEA, 1a) are described. Nucleophilic substitution of 1,2-dipalmitoyl-3-iodo-rac-3-deoxyglycerol (2) with 3 beta-mercaptoandrost-5-en-17-one (3) afforded the diacylglyceryl-sulfide (4). Selective oxidation of 4 with m-chloroperbenzoic acid gave the diacylglyceryl-sulfoxide 4b and diacylglyceryl-sulfone 4c of DHEA. The sulfide 4a was a very weak inhibitor of glucose-6-phosphate dehydrogenase, whereas the sulfone 4c did not inhibit the enzyme.

Dehydroepiandrosterone↗
PubMed1995

Studies on the synthesis of dehydroepiandrosterone (DHEA) phosphatide.

Synthetic dehydroepiandrosterone (DHEA) phosphatide 1c, (R = C15H31), was prepared by three methods. The most efficient of these involved the coupling of the commercially available DHEA 1a and commercially available phosphatidic acid 2, via mesitylene sulfonyl chloride and pyridine. Alternatively, DHEA-3-phosphate 1b was coupled with dipalmitoyl glycerol 3 in the same way. The third synthesis gave 1c by coupling DHEA with the cyclic phosphotriester 4 followed by deblocking.

Dehydroepiandrosterone↗
PubMed1995

The synthesis and reactivity of 3 beta-(2-alkynylsulfonyl)- and 3 beta-(2-alkynylsulfonylmethyl) androst-5-en-17-ones as inhibitors of glucose-6-phosphate dehydrogenase.

3 beta-(Hexadec-2-ynylsulfonyl)androst-5-en-17-one, 2c, was designed as an analog of dehydroepiandrosterone sulfatide 1c, a potent, natural inhibitor of glucose-6-phosphate dehydrogenase (G6PDH). Nucleophilic substitution of 1-bromo hexadec-2-yne 11 with 3 beta-mercaptoandrost-5-en-17-one followed by oxidation afforded 2c. The propargylic sulfone 2c may tautomerize to the electrophilic allenic sulfone 3a and thus function as a masked affinity label of the steroidal binding site of G6PDH. Since 2c demonstrated low potency as an inhibitor of G6PDH, a sulfonylmethyl analog 4b was also designed and synthesized. Synthesis of 4b began by methylenation of androst-5-en-3,17-dione 17-ketal 6 with the Tebbe reagent, to yield the 3-methyleneandrost-5-ene 7. Hydroboration, followed by oxidation, gave a mixture of 3 alpha- and 3 beta-hydroxymethyl isomers 8a and 8b, respectively. The 3 beta alcohol 8b was converted to the thiol 10. Alkylation of 10 with 1-bromo-2-hexadecyne 11, followed by selective oxidation, gave the desired acetylenic sulfone 4b. Insertion of the methylene in 4a and 4b significantly increased their G6PDH inhibitory properties over the initial compounds, 2b and 2c.

Allosteric Site↗
PubMed1995

Towards eradication of measles virus: global progress and strategy evaluation.

Despite an increase in global measles vaccine coverage from under 20% in 1980 to around 80% in 1990, measles remains a major cause of morbidity and mortality world-wide. This paper addresses a number of issues relating to efforts to control measles, namely, (i) at the global level, how might we assess the impact of measles vaccination on the incidence of infection and associated disease, and, (ii), at the strategic level, how can we utilise an understanding of the transmission dynamics of childhood viral infections to aid the design of optimal immunisation programmes? Based on WHO vaccine coverage data, and organising countries according to similarities in demographic and epidemiological parameters, an age-structured model of measles transmission is used to capture the non-linear dynamics of infection and mass vaccination and to generate projections of the impact of measles immunization world-wide. The results provide a crude indication of the percentage reduction in measles cases by year 2000 (compared with no immunization) and suggest an approximately 70% reduction in cases over all ages, and 77% reduction in cases under 5 years (where there is the greatest risk of case fatality); these suggest that WHO targets for 1995 are unlikely to be achieved. In the second part of the paper, examples are given to illustrate the usefulness of a modelling approach in evaluating measles immunization policy. The introduction of MMR vaccine in the UK in 1988 has resulted in measles incidence falling to an all time low and attention has turned to the requirements of elimination. A realistic age structured model, validated using extensive serological data, is used to compare the merits of single or two dose strategies. Based upon recent estimates of vaccine efficacy (90%) and coverage (92% by end of second year of life) it is suggested that a two-dose policy with a pre-school second dose given irrespective of vaccine history is required to prevent the build up of susceptibles to epidemic proportions in the longer term. In a second example, prompted by the success of the campaign approach to polio and measles elimination in Central and South America, simple models are used to explore and quantify the process by which pulse vaccination programmes (i.e. repeated application across a wide age range) act to control transmission.

England↗
PubMed1995

Inhibition of breast and ovarian carcinoma cell growth by 1,25-dihydroxyvitamin D3 combined with retinoic acid or dexamethasone.

This study examined the growth inhibitory effects of combining 1,25-dihydroxyvitamin D3 (calcitriol) with retinoic acid or dexamethasone against cultured breast and ovarian carcinoma cells. Retinoic acid (12.5-50 nM) increased the effectiveness of calcitriol (12.5-50 nM) against MCF-7 and NIH:OVCAR3 cells, with synergistic interactions at two of the three ratios tested. Dexamethasone augmented calcitriol effects, with synergism at 0.05 and 0.1 nM dexamethasone in MCF-7 cells and 5 nM in Caov-4 ovarian cells. This study showed favorable interactions for calcitriol-retinoic acid and calcitriol-dexamethasone combinations in breast and ovarian cancer cell lines.

Antineoplastic Agents↗
PubMed1995

Failure of intraoperatively customized non-porous femoral components inserted without cement in total hip arthroplasty.

Seventy-four primary total hip arthroplasties were performed in sixty-eight patients between August 1990 and September 1991. Clinical assessments were made with use of the Harris hip score and, specifically, the pain component of that score. The preoperative radiographs were digitally quantified for calculation of the so-called canal-to-calcar ratio and the so-called cortical index. The postoperative radiographs were evaluated for the percentage of the cross-sectional area of the femoral canal that was occupied by the prosthesis; subsidence of the prosthesis; and adaptive osseous changes, including hypertrophic cortical remodeling, osteolysis, formation of sclerotic radiolucent lines around the prosthesis, and formation of a pedestal at the tip of the prosthesis. The indication for the arthroplasty was osteoarthrosis in fifty hips (68 per cent), avascular necrosis in fourteen (19 per cent), congenital dysplasia in six (8 per cent), and another diagnosis in four (5 per cent). The average duration of follow-up was thirty-one months (range, eleven to forty-six months). The average Harris hip score (and standard deviation) was 75 +/- 16.8 points (range, 29 to 100 points), and the average score for the pain component was 37 +/- 7.5 points (range, 0 to 44 points). The average canal-to-calcar ratio of the hips was 0.44 (range, 0.32 to 0.74), and the average cortical index was 0.54 (range, 0.33 to 0.66). The average subsidence of the component was 0.6 centimeter (range, 0.0 to 2.3 centimeters). The average fill of the canal was 100 per cent proximally, 97 per cent at the middle of the stem, and 92 per cent distally as measured on the anteroposterior radiographs made immediately postoperatively and 100, 95, and 90 per cent, respectively, as measured on the lateral radiographs. A failure occurred in twenty-one hips (28 per cent) in twenty-one patients, with an average time to failure of 21 +/- 13 months (range, one to forty-four months). The Kaplan-Meier survival estimate (and standard error) for this population was 0.45 +/- 0.11 (confidence interval, 0.67 to 0.23) at forty-four months. The average subsidence of the components that failed was 0.7 centimeter (range, 0.1 to 2.3 centimeters). There was no significant relationship between failure of the component and the age or sex of the patient, the diagnosis, or the side of the operation. Postoperative severity of pain (p = 0.09) or subsidence (p = 0.08) alone did not reach significance for predicting outcome. The Harris hip score alone (p = 0.05), the Harris hip score in combination with subsidence of the femoral component (p = 0.01), and the pain component of the Harris hip score in combination with subsidence of the femoral component (p = 0.01) were all significant for predicting outcome. No other measured radiographic variable was predictive of failure. Despite optimization of the fit of the component within the femoral canal and the percentage of the cross-sectional area of the femoral canal occupied by the component, the clinical results indicated a high rate of failure. Thus, these criteria are not the only requisites for stabilization of these femoral components without cement. On the basis of these data, we have discontinued the use of these intraoperatively customized, non-porous, smooth femoral prosthesis.

Activities of Daily Living↗
PubMed1995

Direct-to-consumer advertising of prescription drugs.

Starting consumers off on the "path to purchase" by encouraging them to seek more information is a major goal of direct-to-consumer (DTC) advertising for prescription medications. But the authors found that a consumer's attitude toward DTC advertising can determine which of several paths he or she is likely to take. The attitudes of older adults are especially significant for pharmaceutical marketers because these consumers are heavy users of the drugs being advertised.

Advertising↗
PubMed1994

The effect of polyamine depletion on the cytotoxic response to PUVA, gamma rays and UVC in V79 cells in vitro.

Difluoromethylornithine (DFMO) depletes cells of polyamines, sensitizing cells against the action of antineoplastic drugs and altering ability to repair radiation-induced DNA strand breaks. Others have hypothesized that the mechanism by which polyamine depletion sensitizes cells is through inhibition of DNA strand break repair or through altering the spectrum of initial DNA damage. We have compared the effect of polyamine depletion on cytotoxic effects in V79 cells for three agents that damage DNA: PUVA (8-methoxypsoralen and ultraviolet light, 365 nm), gamma-rays and UVC (ultraviolet light, 254 nm) in polyamine depleted V79 cells. DFMO pretreatment sensitizes cells to PUVA and gamma-ray toxicity but not to UVC. Unlike UVC photoinduction of DNA lesions, PUVA- and gamma-ray-induced DNA damage is modulated by chromatin structure. Our results suggest that polyamine depletion sensitizes cells to the action of PUVA and gamma-rays by mechanisms disparate from those for UVC, suggesting that the level or type of initial damage, rather than DNA repair, per se, may be the more important determinant of enhanced cytotoxicity.

Animals↗