Dose response relationships between physical activity, walking and health-related quality of life in mid-age and older women

Background Although physical activity is associated with health-related quality of life (HRQL), the nature of the dose-response relationship remains unclear. This study examined the concurrent and prospective dose-response relationships between total physical activity (TPA) and (only) walking with HRQL in two age cohorts of women. Methods Participants were 10,698 women born in 1946-1951 and 7,646 born in 1921-1926, who completed three mailed surveys for the Australian Longitudinal Study on Women's Health. They reported weekly TPA minutes (sum of walking, moderate, and vigorous minutes). HRQL was measured with the Medical Outcomes Study Short-Form 36 Health Status Survey (SF-36). Linear mixed models, adjusted for socio-demographic and health-related variables, were used to examine associations between TPA level (none, very low, low, intermediate, sufficient, high, and very high) and SF-36 scores. For women who reported walking as their only physical activity, associations between walking and SF-36 scores were also examined. Results Curvilinear trends were observed between TPA and walking with SF-36 scores. Concurrently, HRQL scores increased significantly with increasing TPA and walking, in both cohorts, with increases less marked above sufficient activity levels. Prospectively, associations were attenuated although significant and meaningful improvements in physical functioning and vitality were observed across most TPA and walking categories above the low category. Conclusion For women in their 50s-80s without clinical depression, greater amounts of TPA are associated with better current and future HRQL, particularly physical functioning and vitality. Even if walking is their only activity, women, particularly those in their 70s-80s, have better health-related quality of life.

A phase II study of the modulation of 5-fluorouracil and folinic acid with high-dose infusional hydroxyurea in metastatic colorectal carcinoma

Background: Hydroxyurea (HU), an inhibitor of ribonucleotide reductase, may potentiate the activity of 5-fluorouracil (5-FU) and folinic acid (FA) by reducing the deoxyribonucleotide pool available for DNA synthesis and repair. However as HU may inhibit the formation of 5-fluoro-2-deoxyuridine-5- monophosphate (FdUMP), one of the principal active metabolites of 5-FU, the scheduling of HU may be critical. In vitro experiments suggest that administration of HU following 5-FU, maintaining the concentration in the region of I mM for six or more hours, significantly enhances the efficacy of 5-FU. Patients and methods: 5-FU/FA was given as follows: days 1 and 2 - FA 250 mg/m 2 (max. 350 mg) over two hours followed by 5-FU 400 mg/m 2 by intravenous bolus (ivb) over 15 minutes and subsequently 5-FU 400 mg/m 2 infusion (ivi) over 22 hours. HU was administered on day 3 immediately after the 5-FU with 3 g ivb over 15 minutes followed by 12 g ivi over 12 hours. Results: Thirty patients were entered into the study. Median survival was nine months (range 1-51 + months). There were eight partial responses (28%, 95% CI: 13%-47%). The median duration of response was 6.5 (range 4-9 months). Grade 3-4 toxicities included neutropenia (grade 3 in eight patients and grade 4 in five), anaemia (grade 3 in one patient) and diarrhoea (grade 3 in two patients). Neutropenia was associated with pyrexia in two patients. Phlebitis at the infusion site occurred in five patients. The treatment was complicated by pulmonary embolism in one patient and deep venous thrombosis in another. Conclusion: HU administered in this schedule is well tolerated. Based on these results and those of other phase II studies, a randomised phase III study of 5-FU, FA and HU versus 5-FU and FA using the standard de Gramont schedule is recommended.

A phase I dose-escalating study of DaunoXome, liposomal daunorubicin, in metastatic breast cancer

The aims of this phase I study were to establish the maximum tolerated dose, safety profile and activity of liposomal daunorubicin, DaunoXome (NeXstar Pharmaceuticals), in the treatment of metastatic breast cancer. DaunoXome was administered intravenously over 2 h in 21 day cycles and doses were increased from 80 to 100, 120 and 150 mg m 2. Sixteen patients were enrolled. A total of 70 cycles of DaunoXome were administered. The maximum tolerated dose was 120 mg m 2, the dose-limiting toxicity being prolonged grade 4 neutropenia or neutropenic pyrexia necessitating dose reductions at 120 and 150 mg m 2. Asymptomatic cardiotoxicity was observed in three patients: grade 1 in one treated with a cumulative dose of 800 mg m 2 and grade 2 in two, one who received a cumulative dose of 960 mg m 2 and the other a cumulative dose of 600 mg m 2 with a previous neoadjuvant doxorubicin chemotherapy of 300 mg m 2. Tumour response was evaluable in 15 patients, of whom two had objective responses, six had stable disease and seven had progressive disease. In conclusion, DaunoXome is associated with mild, manageable toxicities and has anti-tumour activity in metastatic breast cancer. The findings support further phase II evaluation of DaunoXome alone and in combination with other standard non-anthracycline cytotoxic or novel targeted agents. Although the dose-limiting toxicity for DaunoXome was febrile neutropenia at 120 mg m 2, we would recommend this dose for further evaluation, as the febrile neutropenia occurred after four or more cycles in three of the four episodes seen, was short lived and uncomplicated. © 2002 Cancer Research UK.

Gemcitabine and paclitaxel associated pneumonitis in non-small cell lung cancer : report of a phase I/II dose-escalating study

The aim of this phase I/II dose escalating study was to establish the maximum tolerated dose (MTD) of gemcitabine and paclitaxel given in combination in non-small cell lung cancer (NSCLC). 12 patients with stage IIIB and IV NSCLC received paclitaxel administered intravenously over 1 h followed by gemcitabine given over 30 min on days 1, 8 and 15 every 28 days. Pneumonitis was the principal side-effect observed with 4 patients affected. Of these, 1 experienced grade 3 toxicity after one cycle of treatment and the others had grade 2 toxicity. All 4 cases responded to prednisolone. No other significant toxicities were observed. Of the 8 evaluable patients, 3 had a partial response and 2 had minor responses. The study was discontinued due to this dose-limiting toxicity. The combination of paclitaxel and gemcitabine shows promising antitumour activity in NSCLC, however, this treatment schedule may predispose to pneumonitis. (C) 2000 Elsevier Science Ltd.

Common variants near ATM are associated with glycemic response to metformin in type 2 diabetes

Metformin is the most commonly used pharmacological therapy for type 2 diabetes. We report a genome-wide association study for glycemic response to metformin in 1,024 Scottish individuals with type 2 diabetes with replication in two cohorts including 1,783 Scottish individuals and 1,113 individuals from the UK Prospective Diabetes Study. In a combined meta-analysis, we identified a SNP, rs11212617, associated with treatment success (n = 3,920, P = 2.9 P×-9, odds ratio = 1.35, 95% CI 1.22-1.49) at a locus containing ATM, the ataxia telangiectasia mutated gene. In a rat hepatoma cell line, inhibition of ATM with KU-55933 attenuated the phosphorylation and activation of AMP-activated protein kinase in response to metformin. We conclude that ATM, a gene known to be involved in DNA repair and cell cycle control, plays a role in the effect of metformin upstream of AMP-activated protein kinase, and variation in this gene alters glycemic response to metformin. © 2011 Nature America, Inc. All rights reserved.

Reducing the risk of posttraumatic stress disorder in children following natural disasters

A significant number of children suffer long term psychological disturbance following exposure to a natural disaster. Evidence suggests that a dose-response relationship exists, so that children and adolescents who experience the most intense or extensive exposure to the risk factors for PTSD are likely to develop the most serious and persistent symptoms. Risk factors include gender, age, personality, extent of exposure to the natural disaster, amount of damage to property and infrastructure, witnessing injury or death of others or perceiving a threat to their own life. Knowing these factors enables various strategies to be put in place to decrease the risk of psychological disturbance following the aftermath of traumatic events. Re-establishing a sense of safety, security and normality is important in the aftermath of a natural disaster, and promoting social connectedness, positive family functioning, and effective coping mechanisms can make children more resilient in the face of catastrophic events. This paper examines the risk and protective factors associated with the development of post traumatic stress disorder (PTSD), and considers how schools can use this knowledge to contribute to the recovery effort, and reduce the prevalence of PTSD amongst pupils in the wake of a natural disaster.

Elucidating the links between UV radiation and vitamin D synthesis : using an in vitro model

Ultraviolet radiation (UV) is the carcinogen that causes the most common malignancy in humans – skin cancer. However, moderate UV exposure is essential for producing vitaminDin our skin. VitaminDincreases the absorption of calcium from the diet, and adequate calcium is necessary for the building and maintenance of bones. Thus, low levels of vitamin D can cause osteomalacia and rickets and contribute to osteoporosis. Emerging evidence also suggests vitamin D may protect against falls, internal cancers, psychiatric conditions, autoimmune diseases and cardiovascular diseases. Since the dominant source of vitamin D is sunlight exposure, there is a need to understand what is a “balanced” level of sun exposure to maintain an adequate level of vitamin D but minimise the risks of eye damage, skin damage and skin cancer resulting from excessive UV exposure. There are many steps in the pathway from incoming solar UV to the eventual vitamin D status of humans (measured as 25-hydroxyvitamin D in the blood), and our knowledge about many of these steps is currently incomplete. This project begins by investigating the levels of UV available for synthesising vitamin D, and how these levels vary across seasons, latitudes and times of the day. The thesis then covers experiments conducted with an in vitro model, which was developed to study several aspects of vitamin D synthesis. Results from the model suggest the relationship between UV dose and vitamin D is not linear. This is an important input into public health messages regarding ‘safe’ UV exposure: larger doses of UV, beyond a certain limit, may not continue to produce vitamin D; however, they will increase the risk of skin cancers and eye damage. The model also showed that, when given identical doses of UV, the amount of vitamin D produced was impacted by temperature. In humans, a temperature-dependent reaction must occur in the top layers of human skin, prior to vitamin D entering the bloodstream. The hypothesis will be raised that cooler temperatures (occurring in winter and at high latitudes) may reduce vitamin D production in humans. Finally, the model has also been used to study the wavelengths of UV thought to be responsible for producing vitamin D. It appears that vitamin D production is limited to a small range of UV wavelengths, which may be narrower than previously thought. Together, these results suggest that further research is needed into the ability of humans to synthesise vitamin D from sunlight. In particular, more information is needed about the dose-response relationship in humans and to investigate the proposed impact of temperature. Having an accurate action spectrum will also be essential for measuring the available levels of vitamin D-effective UV. As this research continues, it will contribute to the scientific evidence-base needed for devising a public health message that will balance the risks of excessive UV exposure with maintaining adequate vitamin D.

Glycosaminoglycan and growth factor mediated murine calvarial cell proliferation

Understanding the complex mechanisms underlying bone remodeling is crucial to the development of novel therapeutics. Glycosaminoglycans (GAGs) localised to the extracellular matrix (ECM) of bone are thought to play a key role in mediating aspects of bone development. The influence of isolated GAGs was studied by utilising in vitro murine calvarial monolayer and organ culture model systems. Addition of GAG preparations extracted from the cell surface of human osteoblasts at high concentrations (5 microg/ml) resulted in decreased proliferation of cells and decreased suture width and number of bone lining cells in calvarial sections. When we investigated potential interactions between the growth factors fibroblast growth factor-2 (FGF2), bone morphogenic protein-2 (BMP2) and transforming growth factor-beta1 (TGFbeta1) and the isolated cell surface GAGs, differences between the two model systems emerged. The cell culture system demonstrated a potentiating role for the isolated GAGs in the inhibition of FGF2 and TGFbeta1 actions. In contrast, the organ culture system demonstrated an enhanced stimulation of TFGbeta1 effects. These results emphasise the role of the ECM in mediating the interactions between GAGs and growth factors during bone development and suggest the GAG preparations contain potent inhibitory or stimulatory components able to mediate growth factor activity.

p53-independent NOXA induction overcomes apoptotic resistance of malignant melanomas

Once melanoma metastasizes, no effective treatment modalities prolong survival in most patients. This notorious refractoriness to therapy challenges investigators to identify agents that overcome melanoma resistance to apoptosis. Whereas many survival pathways contribute to the death-defying phenotype in melanoma, a defect in apoptotic machinery previously highlighted inactivation of Apaf-1, an apoptosome component engaged after mitochondrial damage. During studies involving Notch signaling in melanoma, we observed a gamma-secretase tripeptide inhibitor (GSI; z-Leu-Leu-Nle-CHO), selected from a group of compounds originally used in Alzheimer's disease, induced apoptosis in nine of nine melanoma lines. GSI only induced G2-M growth arrest (but not killing) in five of five normal melanocyte cultures tested. Effective killing of melanoma cells by GSI involved new protein synthesis and a mitochondrial-based pathway mediated by up-regulation of BH3-only members (Bim and NOXA). p53 activation was not necessary for up-regulation of NOXA in melanoma cells. Blocking GSI-induced NOXA using an antisense (but not control) oligonucleotide significantly reduced the apoptotic response. GSI also killed melanoma cell lines with low Apaf-1 levels. We conclude that GSI is highly effective in killing melanoma cells while sparing normal melanocytes. Direct enhancement of BH3-only proteins executes an apoptotic program overcoming resistance of this lethal tumor. Identification of a p53-independent apoptotic pathway in melanoma cells, including cells with low Apaf-1, bypasses an impediment to current cytotoxic therapy and provides new targets for future therapeutic trials involving chemoresistant tumors.

Drinking and driving in Vietnam : perceptions and risk

Road traffic injuries are a major global public health problem but continue to receive inadequate attention. Alcohol influences both risk and consequence of road traffic injury but the scale of the problem is not well understood in many countries. In Vietnam, economic development has brought a substantial increase in the number of registered motorcycles as well as alcohol consumption. Traffic injury is among the leading causes of death in Vietnam but there is little local information regarding alcohol related traffic injuries. The primary goal of this study is to explore the drinking and driving patterns of males and their perceptions towards drink-driving and to determine the relationship between alcohol consumption and road traffic injuries. Furthermore, this thesis aims to present the situation analysis for choosing priority actions to reduce drinking and driving in Vietnam. The study is a combination of two cross-sectional surveys and a pilot study. The pilot study, involving 224 traffic injured patients, was conducted to test the tools and the feasibility of approach methods. In the first survey, male patrons (n=464) were randomly selected at seven restaurants. Face-to-face interviews were conducted when patrons just arrived and breath tests were collected when they were about to leave the restaurant. In the second survey, male patients admitted to hospital following a traffic injury (n=480, of which 414 were motorcycle or bicycle riders) were interviewed and their blood alcohol concentration (BAC) measured by breathalyzer. The results show broadly similar patterns of drinking and driving among male patrons and male traffic injured patients with a high frequency of drinking and drink-driving reported among the majority of the two groups. A high proportion of male patrons were leaving restaurants with a BAC over the legal limit. Factors that significantly associate with the number of drinks and BAC were age, hazardous drinking, frequency of drink-driving in the past year, self-estimated number of drinks consumed to drive legally, perceived family’s disapproval of drink-driving, and perceived legal risk and physical risk. The proportion of patrons and patients with BAC above the legal limit of 0.05 were 86.7% and 60.4% respectively, which was much higher than found in previous studies. In addition, both groups had a high prevalence of BAC over 0.15g/100ml (39.7% of patrons and 45.6% patients), a level that can seriously affect driving capacity. Results from the case-crossover analysis for patients indicate a dose-response relationship between alcohol consumption and the risk of traffic injury. The risk of traffic injury increased when alcohol was consumed before driving and there was a more than 13 fold increase when six or more drinks were consumed. Regarding perceptions towards drinking and driving, findings corroborate the low awareness among males in Vietnam, with a majority of respondents holding a low knowledge of safe and legally permissible alcohol use, and a low perceived risk of drinking and driving. The results also indicate a huge gap in prevention skills in terms of planning ahead or using alternative transport to avoid drink-driving and a perception by patrons and patients of a low rate of disapproval of drink-driving from peers and family. Findings in this study have considerable implications for national policy, injury prevention, clinical practice, reporting systems, and for further research. The low rate of compliance with existing laws and a generally low perceived legal risk toward drink-driving in this study call for the strengthening of enforcement along with mass media campaigns and news coverage in order to decrease the widespread perception of impunity and thereby, to reduce the level of drink-driving. In addition, no significant difference was found in this study on risk of traffic injuries between car drivers and motorcycle drivers. The current inconsistency between legal BAC for drivers of motorcycles, compared to cars, thus needs addressing. Furthermore, as drinking was found to be very common, rather than solely targeting drink-driving, it is important to call for a more strategic and comprehensive approach to alcohol policy in Viet Nam. This study also has considerable implications for clinical practice in terms of screening and brief interventions. Our study suggests that the short form of the AUDIT (AUDIT-C) screening tool is appropriate for use in busy emergency departments. The high proportion of traffic injured patients with evidence of alcohol abuse or hazardous drinking suggests that brief interventions by alcohol and drug counselors in emergency departments are a sensible option to addressing this important problem. The significance of this study is in the combination of the systematic collection of breath test and use of case-crossover design to estimate the risk of traffic injuries after alcohol consumption. The results provide convincing evidence to policy makers, health authorities and the media to help raise community awareness and policy advocacy toward the drinkdriving problem in Vietnam. The findings suggest an urgent need for a multi-sectoral approach to curtail drink-driving in Vietnam, especially programs to raise community awareness and effective legal enforcement. Furthermore, serving as a situation analysis, the thesis should inform the formulation of interventions designed to curtail drinking and driving in Vietnam and other developing countries.