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C Robertson

Publications and source records attributed to C Robertson.

At least 73 records · Page 4Linked to original sources
PubMed2001

Type 2 diabetes. How new insights, new drugs are changing clinical practice.

In 1997, the American Diabetes Association recommended a normal fasting blood glucose of < 126 mg/dL as the criteria for diagnosis of type 2 diabetes. Since then, new data have suggested that post-prandial glucose may have a stronger correlation with cardiovascular disease than fasting blood glucose. Two trials, the DCCT and UKPDS, provided evidence of the relationship between hyperglycemia and long-term diabetic complications. Preventing short-term complications, such as cognitive decline, is a more immediate goal and less well-studied. Type 2 diabetes is understood to result most often from insulin resistance and insulin deficiency. New classes of drugs offer expanded therapeutic options for managing this dual metabolic defect. These drugs have invalidated the former therapeutic paradigm of diet, sulfonylureas, and then insulin therapy.

Acarbose↗
PubMed2001

Analytical and graphical methods to model the association between family history and disease from a case-control study.

Subjects within a family have a high probability of sharing environmental factors as well as genes. Without any previous hypothesis, familial aggregation cannot be attributed to genetic or environmental factors. In epidemiology a common measure of familial aggregation is the odds ratio (OR) evaluated from case-control studies which gives a measure of the increased risk associated with particular aspects of the family's history of disease. An analytical method is presented to model the OR of case-control studies in the presence of risk factors, genetic or environmental, that are correlated between relatives. A graphical approach that can be used to link the parameters of the model with the values of the OR is also described. The method is illustrated using the example of familial aggregation in colorectal cancer.

Case-Control Studies↗
PubMed2001

Correlation between tamoxifen elimination and biomarker recovery in a primary prevention trial.

We have shown previously that a reduction from the conventional dose of tamoxifen is associated with a comparable modulation of circulating biomarkers, including insulin-like growth factor-I and cholesterol. In the present study, we have correlated serum tamoxifen elimination with biomarker recovery in healthy subjects completing a 5-year intervention period. Tamoxifen, N-desmethyltamoxifen, and biomarker levels were measured at 0 (baseline), 2, 4, and 6 weeks after completion of treatment in 23 healthy postmenopausal women allocated to tamoxifen 20 mg/day and in 6 women allocated to placebo. Mean (+/-SD) serum tamoxifen and N-desmethyltamoxifen concentrations were, respectively, 141 +/- 50 and 226 +/- 77 ng/ml at baseline, 36 +/- 19 and 99 +/- 46 at 2 weeks, 20 +/- 15 and 61 +/- 37 at 4 weeks, and 12 +/- 9 and 36 +/- 26 at 6 weeks. Serum tamoxifen and N-desmethyltamoxifen half-lives were 9 and 13 days, respectively. Body mass index was associated positively with drug's serum half-life. Compared with baseline values, the percentage increase in total cholesterol, low-density lipoprotein cholesterol, and insulin-like growth factor-I 4 weeks after treatment completion was 5, 9, and 14%, respectively. No change during the 6-week period was observed in the placebo arm. Our findings indicate that the biomarker recovery is slower than serum tamoxifen elimination, suggesting that low tamoxifen concentrations may still exert a biological effect. In addition, the prolonged half-life of tamoxifen and metabolite provides the rationale for a weekly administration of the drug in a preventive context. However, the clinical implications of our findings remain to be defined.

Aged↗
PubMed2000

Closterovirus encoded HSP70 homolog and p61 in addition to both coat proteins function in efficient virion assembly.

Assembly of the viral genome into virions is a critical process of the virus life cycle often defining the ability of the virus to move within the plant and to be transmitted horizontally to other plants. Closteroviridae virions are polar helical rods assembled primarily by a major coat protein, but with a related minor coat protein at one end. The Closteroviridae is the only virus family that encodes a protein with similarity to cellular chaperones, a 70-kDa heat-shock protein homolog (HSP70h). We examined the involvement of gene products of Citrus tristeza virus (CTV) in virion formation and found that the chaperone-like protein plus the p61 and both coat proteins were required for efficient virion assembly. Competency of virion assembly of different CTV mutants was assayed by their ability to be serially passaged in Nicotiana benthamiana protoplasts using crude sap as inoculum, and complete and partial virus particles were analyzed by serologically specific electron microscopy. Deletion mutagenesis revealed that p33, p6, p18, p13, p20, and p23 genes were not needed for virion formation. However, deletion of either minor- or major-coat protein resulted in formation of short particles which failed to be serially transferred in protoplasts, suggesting that both coat proteins are required for efficient virion assembly. Deletion or mutation of HSP70h and/or p61 dramatically reduced passage and formation of full-length virions. Frameshift mutations suggested that the HSP70h and p61 proteins, not the RNA sequences, were needed for virion assembly. Substitution of the key amino acid residues in the ATPase domain of HSP70h, Asp(7) to Lys or Glu(180) to Arg, reduced assembly, suggesting that the chaperone-like ATPase activity is involved in assembly. Both HSP70h and p61 proteins appeared to contribute equally to assembly, consistent with coordinate functions of these proteins in closterovirus virion formation. The requirement of two accessory proteins in addition to both coat proteins for efficient assembly is uniquely complex for helical virions.

Amino Acid Substitution↗
PubMed2000

Depression and degree of acceptance of adjuvant cytotoxic drugs.

An interaction between psychological attitude and outcome in early-stage breast cancer has been postulated, with a possible explanation related to the presumed tendency of depressed patients to be less proactive in obtaining health care. We report on the degree of acceptance of adjuvant chemotherapy in patients with breast cancer who have concomitant depression. Only 20 (51.3%) of the study group accepted and received the proposed chemotherapy compared with 75 (92.2%) of the control group (p<0.0001). Treatment of depression might be essential for tailoring adjuvant treatments with chemotherapy.

Adult↗
PubMed2000

The fitness of citrus tristeza virus defective RNAs is affected by the lengths of their 5'- and 3'-termini and by the coding capacity.

Populations of the Closterovirus Citrus tristeza virus (CTV) generally contain defective RNAs (dRNAs) that vary in size, abundance, and sequence. The variation in abundance of the different dRNAs in a population suggests selection for those of higher fitness. To examine factors affecting fitness of dRNAs, we investigated a series of in vitro constructed dRNAs for their ability to be amplified in protoplasts by an efficiently replicated CTV deletion mutant. The minimal sequences required for accumulation of the dRNAs were within the genomic 5' proximal approximately 1 kb and the 3' 270 nucleotides. However, other factors were involved, because a dRNA with only the minimal sequences failed to be replicated. Rescue of a nonviable dRNA by insertion of nonviral sequences between the termini suggested that "spacing" between terminal cis-acting signals influenced fitness. A continuous open reading frame (ORF) through most of the sequences derived from the 5' of the genome was a requirement for dRNA amplification. In general, insertions, deletions, or nucleotide substitutions were tolerated in the dRNAs as long as an ORF was retained, whereas dRNAs with mutations that prematurely terminated the ORF were not viable. To discriminate between a requirement for an essential protein and ribosomal travel, perhaps to present replication signals to the replicase complex, mutations were made to modify the potential protein but still maintain an ORF. Deletions, insertions of nonviral sequences, or switching of reading frames that altered the amino acid sequence of the protein, except the N-terminal 161 amino acids, did not destroy the fitness of the dRNAs. Yet termination of the ORF in the middle of nonviral sequences did destroy the ability of the dRNAs to be amplified. These results suggest that even though a continuous ORF was needed for fitness, its protein product did not affect the amplification of the dRNAs.

Closterovirus↗
PubMed2000

Time course of fenretinide-induced modulation of circulating insulin-like growth factor (IGF)-i, IGF-II and IGFBP-3 in a bladder cancer chemoprevention trial.

The insulin-like growth factor (IGF) system is widely involved in human carcinogenesis. A significant association between high circulating IGF-I concentrations and an increased risk of lung, colon, prostate and pre-menopausal breast cancer has recently been reported. Lowering plasma IGF-I may thus represent an attractive strategy to be pursued for chemopreventive purposes. We have previously shown that the synthetic retinoid fenretinide (4-HPR) lowers plasma IGF-I in pre-menopausal breast cancer patients. We investigated the effect of fenretinide on circulating IGF-I, IGF-II and IGFBP-3 measured at yearly intervals during the 2-year treatment period and one year after treatment discontinuation in a predominantly male population of patients with superficial bladder cancer. Repeated measures analysis, after adjustment for age, body mass index (BMI) and year of study, showed a significant effect of fenretinide on IGF-I levels, which were further lowered after the second year of treatment and only partially recovered after drug discontinuation. Differently from breast cancer patients, the effect of fenretinide was not modified by age. No significant effect was evident on IGFBP-3, IGF-II and the IGF-I+IGF-II/IGFBP-3 molar ratio, expressing the tissue availability of the mitogenic peptides, although IGF-II and the molar ratio were lowered by treatment by an overall mean of 16% and 15%, respectively. Given the increasingly recognized importance of circulating IGFs in the pathogenesis of different solid tumors, our findings strengthen the rationale for studying fenretinide as a chemopreventive agent.

Age Factors↗
PubMed2000

Replication of heterologous combinations of helper and defective RNA of citrus tristeza virus.

Citrus tristeza virus (CTV) populations are among the more complex of plant RNA viruses with unusual mixtures of strains and defective RNAs (dRNAs). Citrus plants infected with different CTV isolates contain multiple dRNA molecules that differ in size and relative abundance within and between isolates. Additionally, we found mixtures of heterologous dRNAs in populations. To examine the replication of CTV dRNAs, the protoplast system had to be extended to support helper-assisted amplification of input dRNAs. The use of freshly extracted sap of CTV-infected tissue as inoculum increased the infection of Nicotiana benthamiana protoplasts sufficiently to result in accumulation of high levels of CTV RNAs as well as dRNAs within 2 or 3 days postinoculation. A series of dRNA-like molecules, each with a single large internal deletion, were created from an infectious cDNA clone of the CTV T36 isolate and examined for amplification in N. benthamiana protoplasts using a CTV deletion mutant as the helper virus. Of 12 synthetic dRNAs, only three with sizes of 3650, 3819, and 4460 nucleotides were efficiently replicated. CTV dRNA replication did not appreciably affect levels of accumulation of the genomic or the subgenomic RNAs of the helper virus. To investigate the maintenance of dRNAs in CTV populations, we examined heterologous interactions between dRNAs and helper viruses. Wild-type populations of heterologous strains T68 and T3, as well as the homologous T36, supported replication of synthetic T36 dRNAs. Replacement in the T36 dRNA of the 5' region, which is most variable among CTV strains, with the corresponding sequences from VT, T68, T3, or T30 resulted in chimeric dRNAs that failed to be replicated by the T36 helpers but were replicated to detectable levels by the T68 helper. The differential specificities of different CTV replicase complexes with dRNA replication signals is one possible factor that affects the maintenance of dRNA population structures.

Citrus↗
PubMed2000

Chemoprevention of breast cancer: the Italian experience.

The activity of our group is focused on the conduction of chemoprevention clinical trials of breast cancer in at-risk subjects, among which we include women on hormone replacement therapy (HRT). The role of the insulin-like growth factor (IGF) system and of mammographic breast density as surrogate biomarkers for breast cancer prevention is also being investigated. The IGF system is involved in human carcinogenesis of several solid tumors. IGF-I is a potent mitogen for breast cancer cells; elevated circulating IGF-I levels have been associated with a higher risk of premenopausal breast cancer, prostate and colorectal cancer in prospective studies. Both tamoxifen and the synthetic retinoid fenretinide (4-HPR) have been shown to decrease plasma IGF-I levels. A trial of their combination is ongoing in premenopausal women with increased risk for breast cancer. Mammographic breast density has also been associated with an increased risk of breast cancer in several prospective studies. In this article, we discuss the rationale for selection of appropriate cohorts, candidate agents, and putative surrogate biomarkers in our breast cancer prevention trials. Moreover, updated results of the secondary prevention trial of 4-H PR and of the primary prevention trial of tamoxifen are presented. Finally, the rationale for a reduction of tamoxifen dose in future prevention trials is provided.

Anticarcinogenic Agents↗
PubMed2000

Meta-analysis of clinical trials of permixon in the treatment of symptomatic benign prostatic hyperplasia.

OBJECTIVES: Permixon is a compound extracted from the fruit of the American dwarf palm tree, Serenoa repens. Controversy regarding the use of phytotherapeutic agents in men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia is significant. We analyzed all available clinical trial data of the Permixon preparation to determine its clinical efficacy compared with placebo. METHODS: All published clinical trial data on Permixon (11 randomized clinical trials and 2 open label trials), involving 2859 patients, were used. These trials were disparate in size (from 22 to 592 patients) and duration (from 21 to 180 days). Peak urinary flow rate and nocturia were the two common end points. The statistical analysis was based on a random effects meta-analysis. RESULTS: The average +/- SE placebo effect on the peak urinary flow rate was an increase of 0.51 +/- 0.51 mL/s. The estimated effect of Permixon was a further increase of 2.20 +/- 0.51 mL/s (P <0.001). Placebo was associated with a reduction in the mean number +/- SE of nocturnal urinations of 0.69 +/- 0.15. A further reduction of 0.50 +/- 0.01 episodes of urination (P <0.001) occurred that was attributable to Permixon. Some heterogeneity was found among the studies. Treatment duration did not appear to impact either of these effects. CONCLUSIONS: This meta-analysis of all available published trials of Permixon in the treatment of men with benign prostatic hyperplasia revealed a significant improvement in peak flow rate and reduction in nocturia greater than with placebo.

Androgen Antagonists↗
PubMed2000

Protective effect of pregnancy in women with lithium-responsive bipolar disorder.

BACKGROUND: Recent psychiatric literature, while indicating a high incidence of postpartum depression, contains a few clinical reports which support our observations that women with episodic bipolar disorder often remain well without treatment during pregnancy. Our retrospective study statistically examines the clinical course of 28 women with RDC typical bipolar disorder, type I, who became pregnant prior to receiving successful lithium prophylaxis. METHODS: We derived all data from the International Group for the Study of Lithium-treated Patients (IGSLI) database of excellent lithium responders. Data were compared both intraindividually, using data from three 9-month periods - immediately prior to pregnancy, pregnancy and postpartum - and interindividually, using never-pregnant women as controls. RESULTS: Intraindividual data show that women with typical bipolar disorder, type I, experience significantly fewer and shorter recurrences during pregnancy than either before or after. Interindividual comparisons indicate that the recurrence risk during pregnancy is markedly lower than the clinical course would predict. Moreover, the few recurrences observed during pregnancy all took place in the last 5 weeks. LIMITATIONS: Limiting cases to lithium responsive patients could have reduced heterogeneity and perhaps generalizability. CONCLUSIONS: The findings, nonetheless, indicate a marked improvement of the clinical course of typical bipolar disorder, type I, lithium-responsive, during pregnancy. Exploring the underlying protective mechanisms may lead to new understanding of the pathophysiology of mood disorders and to new approaches to treatment and prevention.

Adult↗
PubMed2000

Meta-analysis of studies on breast cancer risk and diet: the role of fruit and vegetable consumption and the intake of associated micronutrients.

A meta-analysis was carried out, in order to summarise published data on the relationship between breast cancer, fruit and vegetable consumption and/or the intake of beta-carotene and vitamin C. Relative risks were extracted from 26 published studies from 1982 to 1997. Random and fixed effects models were used. Between studies, heterogeneity was found for vegetables, fruit, vitamin C but not for beta-carotene. Summary relative risk (RR) estimates based upon a random effects model, except for beta-carotene, for 'high consumption' compared with 'low consumption', derived from the studies satisfying the inclusion criteria were as follows: vegetable consumption: RR=0.75 (95% CI (confidence interval) 0.66-0.85) from 17 studies; fruit consumption: RR=0.94 (95% CI 0.79-1.11) from 12 studies; vitamin C: RR=0.80 (95% CI 0.68-0.95) from 9 studies; beta-carotene: RR=0.82 (95% CI 0.76-0.91) from 11 studies. This analysis confirms the association between intake of vegetables and, to a lesser extent, fruits and breast cancer risk from published sources. Increasing vegetable consumption might reduce the risk of breast cancer.

Ascorbic Acid↗
PubMed2000

Colorectal cancer follow-up: perspectives for future studies.

This paper reviews some of the issues involved in the planning and execution of studies to assess the effect of different follow-up strategies for colorectal cancer patients. Mathematical models and many previous studies have failed to indicate strong support for the hypothesis that extensive follow-up leads to an increase in survival rates. In order to assess the best follow-up strategies, at present, within the different Dukes' stages, extremely large trials are required and none of the previous studies have satisfied this criterion, though recently planned studies will, if recruitment targets are met. The large number of patients required, the length of time the study must run, existing accepted follow-up practices in different countries, and the difficulty of managing patients on different follow-up strategies within the same centre all pose problems for the design of a randomized trial. These are not insurmountable, but do contribute to a possible downfall of a large multicentre randomized trial of follow-up strategies. Although such a trial will require considerable international cooperation it will have enormous benefits and implications if it is managed and completed successfully.

Colorectal Neoplasms↗
PubMed2000

Mortality from cutaneous melanoma: evidence for contrasting trends between populations.

In recent years several reports have been published concerning trends in melanoma mortality in different countries, some of which have indicated that rates are beginning to fall. Many of these reports, however, have been based on small populations and have used different forms of statistical analysis. Our objective was to analyse systematically to what degree the epidemic of melanoma mortality had evolved similarly in different populations and whether there were any divergent trends that might increase our understanding. Instead of using all available data, we focused on countries with a minimum time series of 30 years and a minimum of 100 deaths annually in at least one sex from melanoma. We first inspected sex-specific age-standardized mortality rates and then performed age-period-cohort modelling. We found that the increase in mortality observed after 1950 was more pronounced in the age group 60-79. Statistical modelling showed a general increase in mortality rates in generations born after the turn of the century. Downturns in mortality, essentially in women and starting with generations born just before World War II, were found in Australia (where the earliest decreases were noted), the Nordic countries and the USA. Small decreases in rates in more recent generations were found in the UK and Canada. However, in France, Italy and Czechoslovakia, mortality rates were seen to be still increasing in recent cohorts. Our analysis suggests that populations are at different places on the melanoma mortality epidemic curve. The three trend patterns we observed are in agreement with time differences between populations with respect to the promotion of sun protection and the surveillance of pigmented skin lesions.

Adult↗
PubMed2000

Breast cancer incidence rates in Slovenia 1971-1993.

BACKGROUND: Analyses of time trends in breast cancer incidence and mortality have generally revealed cohort-based changes in the rates. These have been linked to cohort-based changes in lifestyle factors. The effect of the changes in the reproductive risk factors on the changes in the rates, and the relative importance of the reproductive characteristics in Slovenia, a country which has not had much breast cancer screening, are investigated. METHODS: Data on breast cancer incidence for 1971-1993 were obtained from the Cancer Registry of Slovenia (Registry). The Registry covers the whole population of the Republic of Slovenia (1.99 million on 30 June 1993). The statistical analysis uses parametric age-period-cohort models. RESULTS: Breast cancer incidence has increased by 70% in Slovenia from 1971 to 1993, These changes are dominated by cohort effects and the cohorts born in 1907-1922 have the greatest increase in incidence. Period effects on changes in incidence were modest. The percentage of nulliparous women in the cohort and the average family size in the cohort explained 38% of the variation in the cohort effects. CONCLUSIONS: The percentage of nulliparous women in the cohort is the most important reproductive variable associated with the trends in the rates, with breast cancer risk predicted to be higher in cohorts with a larger percentage of nulliparous women. As the cohorts born 1932-1946 have a more favourable reproductive pattern as regards breast cancer risk, compared to the 1907-1922 cohorts, age-specific incidence rates in Slovenia would be predicted to decline in the future in the absence of changes in the other risk factors.

Adult↗