The Gisborne Inquiry--what can we learn?
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Delivery of Health Care↗
Biomedical subjects
A Richardson
Publications and source records attributed to A Richardson.
A reliable assessment of 8-oxo-2-deoxyguanosine levels in nuclear and mitochondrial DNA using the sodium iodide method to isolate DNA.
A major controversy in the area of DNA biochemistry concerns the actual in vivo levels of oxidative damage in DNA. We show here that 8-oxo-2-deoxyguanosine (oxo8dG) generation during DNA isolation is eliminated using the sodium iodide (NaI) isolation method and that the level of oxo8dG in nuclear DNA (nDNA) is almost one-hundredth of the level obtained using the classical phenol method. We found using NaI that the ratio of oxo8dG/10(5 )deoxyguanosine (dG) in nDNA isolated from mouse tissues ranged from 0.032 +/- 0.002 for liver to 0.015 +/- 0.003 for brain. We observed a significant increase (10-fold) in oxo8dG in nDNA isolated from liver tissue after 2 Gy of gamma-irradiation when NaI was used to isolate DNA. The turnover of oxo8dG in nDNA was rapid, e.g. disappearance of oxo8dG in the mouse liver in vivo after gamma-irradiation had a half-life of 11 min. The levels of oxo8dG in mitochondrial DNA isolated from liver, heart and brain were 6-, 16- and 23-fold higher than nDNA from these tissues. Thus, our results showed that the steady-state levels of oxo8dG in mouse tissues range from 180 to 360 lesions in the nuclear genome and from one to two lesions in 100 mitochondrial genomes.
8-Hydroxy-2'-Deoxyguanosine↗
The anti-ageing action of dietary restriction.
Over 60 years ago, McCay's laboratory showed that dietary or calorie-restriction dramatically increased the lifespan of rats. Since then, numerous laboratories with a variety of strains of rats and mice have confirmed this initial observation and have shown that reducing calorie intake (without malnutrition) significantly increases both the mean and maximum survival of rodents. Currently, dietary restriction is the only experimental manipulation that has been shown to retard ageing of mammals. Although mechanism whereby dietary restriction retards ageing is currently unknown, much of the emerging data suggest that the calorie-restricted rodents live longer and age more slowly because they are more resistant to stress and have an enhanced ability to protect cells against damaging agents.
Aging↗
Efficacy and safety of a standardised 500 unit dose of Dysport (clostridium botulinum toxin type A haemaglutinin complex) in a heterogeneous cervical dystonia population: results of a prospective, multicentre, randomised, double-blind, placebo-controlled, parallel group study.
Results from a dose-ranging study in a selected group of de novo patients with rotational cervical dystonia (CD) suggest that 500 units of Dysport (Clostridium botulinum toxin type A haemaglutinin complex) is the optimal starting dose. The present study aimed to confirm the efficacy and safety profile of this dose in a population of CD patients more representative of those seen in a typical dystonia clinic. A total of 68 patients with moderate to severe CD (Tsui score > or = 9) were randomly assigned to receive placebo or Dysport 500 units. Treatment was administered according to the clinical pattern of head deviation, using a standardised injection protocol. A total of 21 patients (11 Dysport, 10 placebo) had not previously received botulinum toxin type A (BtxA) injections, and 47 patients (24 Dysport, 23 placebo) had received BtxA more than 12 weeks previously. Assessments were performed at baseline and weeks 4, 8 and 16. Patients defined as non-responders at week 4 were re-treated in an open phase with 500 units of Dysport at week 6, and were followed up at week 10. Significant between-group differences in Tsui scores were present at weeks 4 (p=0.001) and 8 (p=0.002). Similarly, there were significant between-group differences (p < 0.001) in patient and investigator assessments of response in favour of Dysport at weeks 4 and 8. Also, more Dysport (49%) than placebo (33%) patients were pain-free at week 4 (p=0.02). Overall, 30/35 (86 %) Dysport patients and 14/33 (42%) placebo patients were classified as responders at week 4. Adverse events were reported by 15/35 Dysport patients and 9/33 placebo patients. Open phase treatment produced improvements in Tsui (p < 0.001) and pain scores (p=0.011), and 23/24 patients were classified as responders. Although individual dose titration and muscle selection is desirable, this study demonstrated that a dose of 500 units of Dysport injected into clinically identified neck muscles without electromyographic guidance is safe and effective in the treatment of patients with the major clinical types of cervical dystonia.
Adolescent↗
The development of the Chemotherapy Symptom Assessment Scale (C-SAS): a scale for the routine clinical assessment of the symptom experiences of patients receiving cytotoxic chemotherapy.
The management of symptoms experienced by patients receiving cytotoxic chemotherapy influences quality of life during treatment. Symptom management may be improved through a structured approach to symptom assessment. This paper describes the development of the Chemotherapy Symptom Assessment Scale (C-SAS), a 24-item scale designed for the routine assessment of symptoms experienced by patients receiving cytotoxic chemotherapy. The scale development process focused both upon the psychometric properties and the clinical usefulness of the scale. Patients and health professionals played a significant role in item selection and scale design in order to maximise the clinical utility of the C-SAS.
Antineoplastic Agents↗
Effects of age and food restriction on oxidative DNA damage and antioxidant enzyme activities in the mouse aorta.
In this study, DNA damage in mouse aortic cells was measured using the comet assay. The tail moment of the comet assay in aortic cells obtained from 26-month-old mice fed ad libitum (O-AL) was significantly increased as compared to 6-month-old mice fed ad libitum (Y-AL) after the cells were incubated with formamidopyrimidine-DNA glycosylase (Fpg), which specifically recognizes oxidized purines, endonuclease III (Endo III), which specifically recognizes oxidized pyrimidines, or the combination of Endo III and Fpg. The tail moment in aortic cells obtained from 26-month-old mice fed a food-restricted diet (O-FR) was significantly reduced as compared to O-AL mice after the cells were incubated with the combination of Endo III and Fpg. These results indicate that oxidative DNA lesions, i.e. the Endo III- and Fpg-sensitive sites, increase with age in mouse aortic cells and that FR attenuates the age-related increase in oxidative DNA damage. To determine if the changes in oxidative DNA damage in mouse aortic cells are related to the antioxidant status in these cells, we measured the activities of Cu/Zn-superoxide dismutase (SOD), Mn-SOD, extracellular-SOD, catalase and glutathione peroxidase-1 in the mouse aorta. We observed that the activities of all antioxidant enzymes studied were significantly increased with age and that FR attenuated the age-related increase. These data indicate that the age-related increase and FR-induced decrease in oxidative DNA damage, i.e. the Endo III- and Fpg-sensitive sites, in mouse aortic cells is not due to alteration of the antioxidant defense system.
Aging↗
Oxidative damage to mitochondria and aging.
Oxidative damage has been implicated to be a major factor in the decline in physiologic function that occurs during the aging process. Because mitochondria are a primary site of generation of reactive oxygen species, they have become a major focus of research in this area. Increased oxidative damage to mitochondrial proteins, lipid and DNA has been reported to occur with age in several tissues in a variety of organisms. Decreased activity of electron transport chain complexes and increased release of reactive oxygen species from the mitochondria with age suggest that alterations in mitochondrial function occur with age as a consequence of increased oxidative damage. In addition, age-related alterations in the mitochondrial pathway of apoptosis, which could have profound affects on the physiological function of a tissue, could arise from oxidative damage to mitochondria. Alterations in mitochondrial turnover with age could also contribute to an increase in the number of dysfunctional mitochondria with age.
Aging↗
The focal adhesion targeting sequence is the major inhibitory moiety of Fak-related non-kinase.
Focal adhesion kinase (FAK) plays an important role in integrin-mediated signal transduction pathways and its C-terminal noncatalytic domain Fak-related non-kinase (FRNK), which is autonomously expressed, acts as an inhibitor of FAK. A model has been proposed where FAK and FRNK compete for an essential common binding protein. A FRNK variant in which the direct interaction with v-Crk-associated tyrosine kinase substrate (CAS) was disturbed by point mutations still functioned as an inhibitor of FAK, suggesting that FRNK is unlikely to inhibit FAK by sequestering CAS. Deletion variants of FRNK within the region N-terminal to the focal adhesion targeting (FAT) sequence were still able to inhibit FAK function, indicating that this region is dispensable for the inhibitory effect of FRNK. Overexpression of a green fluorescent protein (GFP) fusion protein containing the FAT sequence delayed cell spreading and reduced FAK tyrosine phosphorylation. This indicates that the FAT sequence is the major inhibitory moiety within FRNK.
Adaptor Proteins, Signal Transducing↗
Nucleotide diversity of the TNF gene region in an African village.
The wide variety of disease associations reported at the TNF locus raises the question of how much variation exists within a single population. To address this question, we sequenced the entire TNF gene in 72 chromosomes from healthy residents of a village in The Gambia, West Africa. We found 12 polymorphisms in 4393 nucleotides, of which five have not been previously described, giving an estimated nucleotide diversity (theta) of 5.6 x 10(-4). A significantly higher frequency of polymorphisms was found in the promoter region than in the coding region (8/1256 vs 0/882 nucleotides, P = 0.02). All polymorphisms with the exception of one rare allele were found to be present in Malawi, which is both geographically and genetically distant from The Gambia. Genotyping of 424 Gambian and 121 Malawian adults showed a significant frequency difference between the two populations for eight of the 12 polymorphisms, but the average fixation index across the variable sites was relatively low (F(ST) = 0.007). We conclude that, at the TNF locus, the nucleotide diversity found within a single African village is similar to the global value for human autosomal genes sampled across different continents.
Adolescent↗
Persons with insulin-dependent diabetes mellitus: acceptance and coping ability.
AIMS: The purposes of this study were to describe how persons with insulin-dependent diabetes mellitus (IDDM) accept their disease and what sense of coherence they have, in order to determine whether a person's acceptance of the disease is related to his or her sense of coherence. Whether acceptance of the disease and sense of coherence are related to the disease duration, complications of the disease, metabolic control and demographic data would also be determined. DESIGN: One hundred and seven, randomly selected, insulin-dependent, diabetic subjects (47 men and 60 women) participated in the study. The Acceptance of Disability Scale Modified (ADM scale), the Sense of Coherence Scale (SOC scale), a study-specific questionnaire and the patients records were used to collect the data. BACKGROUND: IDDM implies a major change in way of life. Ingrained procedures and patterns of behaviour must be adapted to the disease and its treatment. RESULTS: The results of the present study show that educational level seems to be an important factor for how well a person accepts the disease and the sense of coherence. Persons with higher scores on the ADM and the SOC scales had higher levels of education. Moreover, they also had a better metabolic control. Individuals with a poor metabolic control had more disease-related complications. A significant correlation between the ADM and the SOC scores was found, indicating that persons with a high degree of acceptance of the IDDM also had a high coping capability. CONCLUSIONS: It is important to individualize the care of subjects with IDDM and to identify the persons with low acceptance of their disease and a low sense of coherence.
Adaptation, Psychological↗
Nursing in Colorectal Cancer Initiative: the audit phase. Part 2. Content validity of the audit tool and implications of the standards set for clinical practice.
This paper gives an account of the process of refining the content validity of an audit tool, which defines and measures best practice in colorectal cancer nursing and identifies areas for development. The European Oncology Nursing Society (EONS) and AstraZeneca collaborated to develop the Nursing in Colorectal Cancer Initiative (NICCI). The initiative was funded through educational grants from AstraZeneca and led by EONS. It is a project with two components, education and audit. The education component culminated in a manual that provides a core set of materials concerning fundamental aspects of colorectal cancer, to foster a common understanding amongst nurses at national and international levels. An audit tool was developed to measure standards of nursing care in relation to the delivery of cytotoxic chemotherapy to patients with advanced colorectal cancer. The content validity of the audit tool was established in three stages by expert panel review with revisions made to the content and organisation of the audit measures at each stage. The standards set by the NICCI Audit Project have key implications for multi-professional practice in colorectal cancer care.
Journal Article↗
Nursing in Colorectal Cancer Initiative--the audit phase. Part 1. Development of the audit tool.
This paper describes the structure of an audit study together with the two-phase development of an audit tool and methodology. The purpose of the study was to develop a tool that defines and measures best practice in colorectal cancer nursing, and identifies areas for development. The European Oncology Nursing Society (EONS) and AstraZeneca collaborated to develop the Nursing in Colorectal Cancer Initiative (NICCI). The initiative was funded through educational grants from AstraZeneca and led by EONS. It is a project with two components, education and audit. The purpose of the project is to provide a sound educational basis for nurses in the elements of colorectal cancer care, together with the tools to evaluate and develop practice. The education phase culminated in an educational manual that provides a core set of materials concerning the fundamental aspects of colorectal cancer, to foster a common understanding amongst nurses nationally and internationally. The education manual provided the referenced rationale for the definition of a set of hallmarks and standards of clinical practice. The audit tool was developed from the hallmarks and standards and is focused on the care of patients receiving cytotoxic chemotherapy for colorectal cancer. The audit methodology is based on the structure, process outcome triad, together with the TELER system of audit.
Journal Article↗
The arts in cancer care: learning from experience.
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Editorial↗
Serine phosphorylation of focal adhesion kinase in interphase and mitosis: a possible role in modulating binding to p130(Cas).
Focal adhesion kinase (FAK) is an important regulator of integrin signaling in adherent cells and accordingly its activity is significantly modulated during mitosis when cells detach from the extracellular matrix. During mitosis, FAK becomes heavily phosphorylated on serine residues concomitant with its inactivation and dephosphorylation on tyrosine. Little is known about the regulation of FAK activity by serine phosphorylation. In this report, we characterize two novel sites of serine phosphorylation within the C-terminal domain of FAK. Phosphorylation-specific antibodies directed to these sites and against two previously characterized sites of serine phosphorylation were used to study the regulated phosphorylation of FAK in unsynchronized and mitotic cells. Among the four major phosphorylation sites, designated pS1-pS4, phosphorylation of pS1 (Ser722) is unchanged in unsynchronized and mitotic cells. In contrast, pS3 and pS4 (Ser843 and Ser910) exhibit increased phosphorylation during mitosis. In vitro peptide binding experiments provide evidence that phosphorylation of pS1 (Ser722) may play a role in modulating FAK binding to the SH3 domain of the adapter protein p130(Cas).
Animals↗
Caloric restriction mimetics: metabolic interventions.
Caloric restriction (CR) retards diseases and aging in laboratory rodents and is now being tested in nonhuman primates. One way to apply these findings to human health is to identify and test agents that may mimic critical actions of CR. Panel 2 focused on two outcomes of CR, reduction of oxidative stress and improved glucoregulation, for which candidate metabolic mimics exist. It was recommended that studies on oxidative stress should emphasize mitochondrial function and to test the efficacy of nitrone and other antioxidants in mimicking CR's effects. Studies should also focus on the long-term effects of compounds known to lower circulating glucose and insulin concentrations or to increase insulin sensitivity. Also, four other developing areas were identified: intermediary metabolism, response to infection, stress responses, and source of dietary fat. These areas are important because either they hold promise for the discovery of new mimetics or they need to be explored prior to initiation of CR trials in humans. Other recommendations were that transgenic approaches and adult-onset CR should be emphasized in future studies.
Animals↗
Screening and the number needed to treat.
OBJECTIVE: To develop a measure analogous to the "number needed to treat" (NNT), which would be appropriate for population based screening programmes. METHODS: A previous measure analogous to the NNT, the "number needed to screen" (NNS), calculated as the reciprocal of the absolute risk reduction, does not account for participation and selection effects in screening trials. A new measure is proposed; the NNBS (number needed to be screened) derived from the NNT adjusted for participation in screening and for selection effects associated with participation in screening. The NNBS for breast cancer screening and colorectal cancer screening are calculated, based on the results of randomised controlled trials. RESULTS: In the first 8 years from the start of each screening programme, the NNS to prevent one death from breast cancer was 781 women (95% confidence interval (95% CI) 550 to 1560). The NNS to prevent one death from colorectal cancer was 1250 people (95% CI 690 to 9090). The NNBS was 23% lower than the NNS for breast cancer screening (NNBS=601), and 45% lower than the NNS for colorectal cancer (NNBS=688). CONCLUSIONS: The NNT calculations may make population based screening programmes seem expensive and inefficient compared with other interventions. A new measure, the number needed to be screened (NNBS), which takes into account the participation rate adjusted for selection, may be more appropriate, especially when comparing screening programmes with disparate participation rates, or when comparing screening with other interventions.
Breast Neoplasms↗
Knockout mice heterozygous for Sod2 show alterations in cardiac mitochondrial function and apoptosis.
Heart mitochondria from heterozygous (Sod2(-/+)) knockout mice have a 50% reduction in manganese superoxide dismutase (MnSOD) activity. The decrease in MnSOD activity was associated with increased mitochondrial oxidative damage as demonstrated by a decrease in the activities of iron sulfhydryl proteins sensitive to oxygen stress (aconitase and reduced nicotinamide adenine dinucleotide-oxidoreductase). Mitochondrial function was altered in the Sod2(-/+) mice, as shown by decreased respiration by complex I and an increase in the sensitivity of the permeability transition to induction by calcium and t-butylhydroperoxide. The increased induction of the permeability transition in heart mitochondria from Sod2(-/+.)mice was associated with increased release of cytochrome c and an increase in DNA fragmentation. Cardiomyocytes isolated from neonatal Sod2(-/+) and Sod2(-/-) mice were more sensitive to cell death than cardiomyocytes from Sod2(+/+) mice after t-butylhydroperoxide treatment, and this increased sensitivity was prevented by inhibiting the permeability transition with cyclosporin A. These experiments demonstrate that MnSOD may play an important role in the induction of the mitochondrial pathway of apoptosis in the heart, and this appears to occur primarily through the permeability transition.
Aconitate Hydratase↗
Changes in expression of antioxidant enzymes affect cell-mediated LDL oxidation and oxidized LDL-induced apoptosis in mouse aortic cells.
Transgenic mice overexpressing Cu/Zn superoxide dismutase (hSod1Tg(+/0)) or catalase (hCatTg(+/0)) and knockout mice underexpressing manganese superoxide dismutase (Sod2(+/)(-)) or glutathione peroxidase-1 (Gpx1(-/-)) were used to study the effect of antioxidant enzymes on cell-mediated low density lipoprotein (LDL) oxidation and oxidized LDL (oxLDL)-induced apoptosis. Incubation of LDL with mouse aortic segments or smooth muscle cells (SMCs) resulted in a significant increase in LDL oxidation. However, LDL oxidation was significantly reduced when LDL was incubated with aortic segments and SMCs obtained from hSod1Tg(+/0) and hCatTg(+/0) mice compared with those obtained from wild-type mice. In contrast, LDL oxidation was significantly increased when LDL was incubated with aortic segments and SMCs obtained from Sod2(+/)(-) and Gpx1(-/-) mice. CuSO(4)-oxidized LDL increased DNA fragmentation and caspase activities in the primary cultures of mouse aortic SMCs. However, oxLDL-induced DNA fragmentation and caspase activities were reduced 50% in SMCs obtained from hSod1Tg(+/0) and hCatTg(+/0) mice compared with wild-type control mice. In contrast, oxLDL-induced DNA fragmentation and caspase activities were significantly increased in SMCs obtained from Sod2(+/)(-) and Gpx1(-/-) mice. These findings suggest that overexpression of Cu/Zn superoxide dismutase or catalase reduces cell-mediated LDL oxidation and oxLDL-induced apoptosis, whereas underexpression of manganese superoxide dismutase or glutathione peroxidase-1 increases cell-mediated LDL oxidation and oxLDL-induced apoptosis.
Animals↗