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Biomedical subjects

R A Smith

Publications and source records attributed to R A Smith.

At least 37 records · Page 2Linked to original sources
PubMed2003

Quantifying the potential problem of overdiagnosis of ductal carcinoma in situ in breast cancer screening.

The relevance of detection of ductal carcinoma in situ (DCIS) in a breast cancer screening programme, and the extent of overdiagnosis of non-progressive lesions, remains controversial. It was the purpose of this paper to estimate the incidence of non-progressive, 'overdiagnosed' DCIS. We defined non-progressive DCIS (DCIS(0)) as DCIS which could not have progressed to invasive disease if left untreated. Progressive DCIS (DCIS(1)) was defined as DCIS which has the propensity to progress to invasive disease. We fitted a Markov process model of the incidence of progressive and non-progressive DCIS, the transition of the former to preclinical invasive disease and the subsequent progression to clinical symptomatic cancer. We used data from the Swedish Two-County Trial and from service screening programmes in the UK, Netherlands, Australia and the USA to estimate the incidence of progressive and non-progressive DCIS, and the detection rates of each at the first and subsequent screening. Average incidence of non-progressive DCIS was 1.11 per 100000 per year. Average incidence of progressive DCIS was 2.1 per 1000 per year. At prevalence screen, 37% of DCIS cases were estimated to be non-progressive. A woman attending prevalence screen has a 19 times greater chance of having a progressive DCIS or an invasive tumour diagnosed than of having a non-progressive DCIS diagnosed. At incidence screen, only 4% of DCIS cases were estimated to be non-progressive. A woman attending an incidence screen has a 166 times higher probability of having a progressive DCIS or invasive lesion diagnosed than of having a non-progressive DCIS diagnosed. There is an element of overdiagnosis of DCIS in breast cancer screening, but the phenomenon is small in both relative and absolute terms.

Adult↗
PubMed2003

The hierarchical spatial distribution of chloroplast DNA polymorphism across the introduced range of Silene vulgaris.

Silene vulgaris was introduced into North America sometime prior to 1800. In order to document the population structure that has developed since that time, collections were made from 56 local populations distributed among 9 geographical regions in eastern North America. Individual plants were characterized for chloroplast DNA (cpDNA) haplotype by restriction fragment size analysis of four noncoding regions of cpDNA amplified by polymerase chain reaction. A total of 19 cpDNA haplotypes were detected using this method. The overall gene diversity of 0.85 is quite similar to the diversity detected in these same regions of cpDNA in a previously published sample of S. vulgaris taken from across much of Europe. The spatial distribution of the North American cpDNA diversity was quantified by hierarchical F-statistics that partitioned the genetic variance into variation among local populations within regions, and variation among regions. The average FST among populations within regions was 0.66 and the FST among regions was 0.09. The among-region variation was due to both differences among regions in the frequency of two most common haplotypes, and to the presence of a number of region-specific haplotypes. In order to test for isolation by distance at the regional level, FST values were calculated for all possible pairs of regions, and regressed against the geographical distance between those regions. There was no evidence for isolation by distance. It is suggested that the local population structure is generated by recent extinction/colonization dynamics, and that the among-region structure reflects demographic events associated with range expansion following introduction to North America.

DNA, Chloroplast↗
PubMed2003

The Swedish Two-County Trial of mammographic screening: cluster randomisation and end point evaluation.

BACKGROUND: The Swedish Two-County Trial has been criticised on the grounds of the cluster randomisation and alleged bias in classification of cause of death. PATIENTS AND METHODS: In the Two-County Trial, 77 080 women were randomised to regular invitation to screening (active study population, ASP) and 55 985 to no invitation (passive study population, PSP), in 45 geographical clusters. After approximately 7 years, the PSP was invited to screening and the trial closed. We analysed data using hierarchical statistical models to take account of cluster randomisation, and performed a conservative analysis assuming a systematic difference between ASP and PSP in baseline breast cancer mortality in one of the counties. We also analysed deaths from causes other than breast cancer and from all causes among breast cancer cases diagnosed in the ASP and PSP. RESULTS: Taking account of the cluster randomisation there was a significant 30% reduction in breast cancer mortality in the ASP. Conservatively, assuming a systematic difference between ASP and PSP clusters in baseline breast cancer mortality, there was a significant 27% reduction in mortality in the ASP. Ignoring classification of cause of death, there was a significant 13% reduction in all-cause mortality in breast cancer cases in the ASP. CONCLUSIONS: Breast cancer mortality is a valid end point and mammographic screening does indeed reduce mortality from breast cancer. The criticisms of the Swedish Two-County Trial are unfounded.

Adult↗
PubMed2002

Metabolic heat production as a measure of macrophage response to particles from orthopedic implant materials.

An in vitro method to gauge metabolic heat response of macrophages (MØ) to particulates is described. Whereas the majority of work cited relies on chemical analysis to assess MØ response to particles, we have used isothermal microcalorimetry (IMC) for direct continuous measurement of metabolic heat production to gauge the response. IMC is a screening method, in that it ensures that no energy-consuming phagocytic response goes undetected, and that the aggregate metabolic magnitude of the responses is determined. A four-well IMC was used in all microcalorimetric measurements. To accommodate "zero-time" monitoring of the interaction of particles and cells, a set of identical test chambers was constructed for use in the IMC. MØs were injected from outside the IMC onto particles contained in collagen or gelatin on glass coverslips at the bottom of each chamber. IMC runs were performed using MØs only, MØs and lipopolysaccharide (LPS) positive control, and MØs and clean or LPS-bound particles of either high-density polyethylene (HDPE) or cobalt-chrome alloy (CoCr). Total heat produced by the negative controls (MØs alone) was lower than for MØ exposure to LPS or particles. The trend was a higher response for LPS-bound HDPE compared with clean HDPE particles, though not significant. In conclusion, our results have shown that IMC can be used to detect the heat associated with the phagocytosis of particulate materials by MØs in vitro.

Bone Substitutes↗
PubMed2002

The relationships between intestinal damage and circulating endotoxins in experimental Trypanosoma brucei brucei infections.

The involvement of intestinal damage in experimental African trypanosomiasis was investigated in rats infected with Trypanosoma brucei brucei by measuring the urinary excretion of the previously administered non-metabolizable sugar probes, D-mannitol and lactulose, and the flux of FITC-dextran across isolated, everted gut segments. There was increased urinary recovery and flux of the sugar probes across the intestine which were significant (P < 0.05) and maximum at day 21 of the infection, but subsequently reduced, in the terminal stages of infection (day 33 p.i.). In the case of the everted sac studies the reductions were to less than 25% control values (P < 0.001). Levels of circulating endotoxin were increased approximately 3-fold at day 21 p.i., 4-fold at day 33 p.i., compared to controls. At day 21 there was a significant correlation (r = 0.63, P < 0.01) between the log endotoxin levels and the increased sugar excretion expressed as the lactulose/mannitol ratios. Histological studies showed damage to the villi, wall thinning and marked cellular infiltrations, which were very prominent in the proximal jejunum and duodenum. These results demonstrate that during trypanosome infections in rats, increased intestinal leakage and increased circulating endotoxins are significant pathological features.

Animals↗
PubMed2002

Targeting anticomplement agents.

Biological targeting is normally thought of as a process of specific direction of one molecule (the agent) to another (the target) in vivo. However, an addressive approach in which the agent is concentrated, first within the vasculature and then at a disease site containing one or more targets, may be more suitable for delivering therapeutic quantities of certain drugs. This approach has been applied to complement regulatory molecules expressed in recombinant soluble forms and attached post-translationally to highly soluble synthetic peptide derivatives comprising two addressin units, one with affinity for the membrane bilayer interior and the other for phospholipid headgroups. This combination conferred affinity for outer cell membranes in general, and areas of translocated acidic phospholipid in particular. Large increases in potency in cell-based antihaemolytic assays accompanied modification and were shown to be associated with membrane binding. Modified agents co-localized with glycosylphosphatidyl- inositol-anchored proteins in lipid rafts on cell membranes. One agent, a modified fragment of human complement receptor-1 (APT070), has been prepared on a large scale and has been shown to be an active anti-inflammatory agent when administered locally and systemically in animal models of vascular shock, rheumatoid arthritis and transplantation reperfusion injury. APT070 has been shown to be well tolerated in human subjects when given intravenously and is currently under study in rheumatoid arthritis patients to explore the therapeutic potential of localized complement inhibition in the synovial space.

Arthritis, Rheumatoid↗
PubMed2002

All-cause mortality among breast cancer patients in a screening trial: support for breast cancer mortality as an end point.

BACKGROUND: It has recently been suggested that all-cause mortality is a more appropriate end point than disease specific mortality in cancer screening trials, and that disease specific mortality is biased in favour of screening. This suggestion is based partly on supposed inconsistencies between all-cause mortality results and disease specific results in cancer screening trials, and alleged increases in deaths from causes other than breast cancer among breast cancer cases diagnosed among women invited to screening. METHODS: We used data from the Swedish Two-County Trial of mammographic screening for breast cancer, in which 77 080 women were randomised to an invitation to screening and 55 985 to no invitation. We estimated relative risks (RRs) (invited v control) of death from breast cancer, death from other causes within the breast cancer cases, and death from all causes within the breast cancer cases. RRs were adjusted for age and took account of the longer follow up of breast cancer cases in the invited group due to lead time. RESULTS: There was a significant 31% reduction in breast cancer mortality in the invited group (RR 0.69, 95% confidence interval (CI) 0.58-0.80; p<0.001). There was no significant increase in deaths from other causes among breast cancer cases in the invited group (RR 1.12, 95% CI 0.96-1.31; p=0.14). A significant 19% reduction in deaths from all causes was observed among breast cancer cases in the group invited to screening (RR 0.81, 95% CI 0.72-0.90; p<0.001). A more conservative estimation gave a significant 13% reduction (RR 0.87, 95% CI 0.78-0.97; p=0.01). These findings are consistent with the magnitude of the reduction in breast cancer mortality. CONCLUSIONS: Invitation to screening was associated with a reduction in deaths from all causes among breast cancer cases, consistent with high participation rates in screening. There is no significant evidence of bias in cause of death classification in the Two-County Trial, and as breast cancer mortality is the targeted clinical outcome in breast cancer screening, it is the appropriate end point in a breast cancer screening trial. All-cause mortality is a poor and inefficient surrogate for breast cancer mortality.

Adult↗
PubMed2002

Lung cancer. 2: screening and early diagnosis of lung cancer.

Technical developments in spiral CT scanning mean that considerably smaller lung cancers can now be identified than with previous methods of detection. Only time will tell whether this enhanced capability will result in a reduction in the number of deaths from lung cancer. The implications and problems of screening for lung cancer are discussed. Screening implies a careful refinement of a range of clinical activities that must be routinely delivered in a carefully coordinated fashion to allow for the possibility of improved outcome. Critical analyses of the nuances of this process are essential if the field is to move forward.

Decision Making↗
PubMed2001

Discovery and parallel synthesis of a new class of cathepsin K inhibitors.

Peptidomimetic aminomethyl ketones have been identified as a new class of cathepsin K inhibitors. Traditional and high-speed parallel synthesis techniques were applied to investigate this series. Structure-activity relationships were established, and certain analogues were characterized with IC(50) values in the range 200-500 nM.

Cathepsin K↗
PubMed2001

Discovery of heterocyclic ureas as a new class of raf kinase inhibitors: identification of a second generation lead by a combinatorial chemistry approach.

Heterocyclic ureas, such as N-3-thienyl N'-aryl ureas, have been identified as novel inhibitors of raf kinase, a key mediator in the ras signal transduction pathway. Structure-activity relationships were established, and the potency of the screening hit was improved 10-fold to IC(50)=1.7 microM. A combinatorial synthesis approach enabled the identification of a breakthrough lead (IC(50)=0.54 microM) for a second generation series of heterocyclic urea raf kinase inhibitors.

Proto-Oncogene Proteins c-raf↗
PubMed2001

Investigation of glutathione S-transferase zeta and the development of sporadic breast cancer.

BACKGROUND: Certain genes from the glutathione S-transferase superfamily have been associated with several cancer types. It was the objective of this study to determine whether alleles of the glutathione S-transferase zeta 1 (GSTZ1) gene are associated with the development of sporadic breast cancer. METHODS: DNA samples obtained from a Caucasian population affected by breast cancer and a control population, matched for age and ethnicity, were genotyped for a polymorphism of the GSTZ1 gene. After PCR, alleles were identified by restriction enzyme digestion and results analysed by chi-square and CLUMP analysis. RESULTS: Chi-squared analysis gave a chi2 value of 4.77 (three degrees of freedom) with P = 0.19, and CLUMP analysis gave a T1 value of 9.02 with P = 0.45 for genotype frequencies and a T1 value of 4.77 with P = 0.19 for allele frequencies. CONCLUSION: Statistical analysis indicates that there is no association of the GSTZ1 variant and hence the gene does not appear to play a significant role in the development of sporadic breast cancer.

Alleles↗
PubMed2001

Chromous hydrazine sulfate.

The title compound, catena-poly[dihydraziniochromium(II)-di-mu-sulfato-O:O'], [Cr(N2H5)2(SO4)2], was studied at 100 K and contains chains of chromium(II) ions linked by pairs of sulfate anions and coordinated to hydrazinium ions. The unique Cr atom lies on an inversion centre. All five H atoms were experimentally located and are involved in hydrogen bonding to O atoms of the sulfate groups.

Journal Article↗
PubMed2001

Beyond randomized controlled trials: organized mammographic screening substantially reduces breast carcinoma mortality.

BACKGROUND: The efficacy of mammographic screening in the reduction of breast carcinoma mortality has been demonstrated in randomized controlled trials. However, the evaluation of organized screening outside of research settings (so-called "service screening") faces unique methodologic and conceptual challenges. The current study describes the evaluation of organized mammography screening in a clinical setting and demonstrates the benefit obtained from service screening in two Swedish counties. METHODS: In the group of subjects ages 20--69 years, there were 6807 women diagnosed with breast carcinoma over a 29-year period in 2 counties in Sweden and 1863 breast carcinoma deaths. All patients were classified from patient charts based on their screening status (i.e., whether they had been invited to undergo screening and whether they actually had undergone screening). The number of women who lived in the 2 counties during the 29-year study period was provided by the Central Bureau of Statistics. Breast carcinoma-specific mortality was compared across three time periods: 1) 1968--1977, when no screening was taking place because mammography had not been introduced; 2) 1978--1987, the approximate period of the Two-County randomized controlled trial of screening in women ages 40--74 years; and 3) 1988--1996, when all women in the 2 counties ages 40--69 years were invited to undergo screening (service screening). When comparing breast carcinoma mortality in screened women with that in women diagnosed before screening was introduced, a correction for self-selection bias was incorporated to prevent overestimation of the benefit of screening. RESULTS: The mortality from incident breast carcinoma diagnosed in women ages 40-69 years who actually were screened during the service screening period (1988--1996) declined significantly by 63% (relative risk [RR] = 0.37; 95% CI, 0.30--0.46) compared with breast carcinoma mortality during the time period when no screening was available (1968--1977). The mortality decline was 50% (RR = 0.50; 95% CI, 0.41--0.60) when breast carcinoma mortality among all women who were invited to undergo screening (nonattendees included) was compared with breast cancer mortality during the time period when no screening was available (1968--1977). The reduction in mortality observed during the service screening period, adjusted for selection bias, was 48% (RR = 0.52; 95% CI, 0.43--0.63). No significant change in breast carcinoma mortality was observed over the three time periods in women who did not undergo screening. This group included women ages 20--39 years because these individuals were never invited to undergo screening, and women ages 40--69 years who did not undergo screening (not invited during the randomized trial or invited during the second and third time periods but declined). CONCLUSIONS: Regular mammographic screening resulted in a 63% reduction in breast carcinoma death among women who actually underwent screening. The policy of invitation to organized screening with mammography appears to have reduced breast carcinoma mortality by 50% in these 2 counties.

Adult↗