In-home dementia caregiving is associated with greater psychological burden and poorer mental health than out-of-home caregiving: a cross-sectional study.

INTRODUCTION: Caregivers who live with a person with dementia who receives care, compared with those who live elsewhere, are often considered to experience greater levels of psychological and affective burden. The evidence for this is, however, only limited to studies employing small sample sizes and that failed to examine caregivers' psychological wellbeing. We address these issues in a large cohort of dementia caregivers. METHODS: We conducted a cross-sectional study comparing caregivers living with a dementia care recipient (n = 240) to caregivers living elsewhere (n = 255) on caregivers' burden, anxiety, and depression. RESULTS: We found that caregivers living with the care recipient relative to those living elsewhere showed significantly greater burden and depression, but we found no group difference in anxiety. CONCLUSIONS: Our study adds to the evidence by showing that cohabiting with a care recipient with dementia is associated with greater burden and poorer psychological wellbeing. Strategies aiming to improve caregivers' burden and psychological wellbeing should take account of caregivers' living arrangements.

The combined diabetes and renal control trial (C-DIRECT) - a feasibility randomised controlled trial to evaluate outcomes in multi-morbid patients with diabetes and on dialysis using a mixed methods approach.

BACKGROUND: This cluster randomised controlled trial set out to investigate the feasibility and acceptability of the "Combined Diabetes and Renal Control Trial" (C-DIRECT) intervention, a nurse-led intervention based on motivational interviewing and self-management in patients with coexisting end stage renal diseases and diabetes mellitus (DM ESRD). Its efficacy to improve glycaemic control, as well as psychosocial and self-care outcomes were also evaluated as secondary outcomes. METHODS: An assessor-blinded, clustered randomised-controlled trial was conducted with 44 haemodialysis patients with DM ESRD and ≥ 8% glycated haemoglobin (HbA1c), in dialysis centres across Singapore. Patients were randomised according to dialysis shifts. 20 patients were assigned to intervention and 24 were in usual care. The C-DIRECT intervention consisted of three weekly chair-side sessions delivered by diabetes specialist nurses. Data on recruitment, randomisation, and retention, and secondary outcomes such as clinical endpoints, emotional distress, adherence, and self-management skills measures were obtained at baseline and at 12 weeks follow-up. A qualitative evaluation using interviews was conducted at the end of the trial. RESULTS: Of the 44 recruited at baseline, 42 patients were evaluated at follow-up. One patient died, and one discontinued the study due to deteriorating health. Recruitment, retention, and acceptability rates of C-DIRECT were generally satisfactory HbA1c levels decreased in both groups, but C-DIRECT had more participants with HbA1c < 8% at follow up compared to usual care. Significant improvements in role limitations due to physical health were noted for C-DIRECT whereas levels remained stable in usual care. No statistically significant differences between groups were observed for other clinical markers and other patient-reported outcomes. There were no adverse effects. CONCLUSIONS: The trial demonstrated satisfactory feasibility. A brief intervention delivered on bedside as part of routine dialysis care showed some benefits in glycaemic control and on QOL domain compared with usual care, although no effect was observed in other secondary outcomes. Further research is needed to design and assess interventions to promote diabetes self-management in socially vulnerable patients. TRIAL REGISTRATION NUMBER: Trial registered with the International Standard Randomised Controlled Trial (ISRCTN10546597). Registered 12 September 2016 (Retrospectively registered).

Health-related quality of life of Asian patients with end-stage renal disease (ESRD) in Singapore.

BACKGROUND: This study aimed to identify factors associated with the health-related quality of life (HRQOL) of multiethnic Asian end-stage renal disease (ESRD) patients treated with dialysis. The role of dialysis modality was also explored. METHODS: Data used in this study were from two cross-sectional surveys of Singaporean ESRD patients on haemodialysis (HD) or peritoneal dialysis (PD). In both surveys, participants were assessed using the kidney disease quality of life (KDQOL) instrument and questions assessing socio-demographic characteristics. Clinical data including co-morbidity (measured by Charlson comorbidity index [CCI]), albumin level, haemoglobin level, and dialysis-related variables (e.g. dialysis vintage and dialysis adequacy) were retrieved from medical records. The 36-item KDQOL (KDQOL-36) was used to generate three summary scores (physical component summary [PCS], mental component summary [MCS] and kidney disease component summary [KDCS]) and two health utility scores (Short Form 6-dimension [SF-6D] and EuroQol 5-dimension [EQ-5D]). Linear regression analysis was performed to examine the association of factors with each of the HRQOL scale scores. RESULTS: Five hundred and two patients were included in the study (mean age 57.1 years; male 52.4 %; HD 236, PD 266). Mean [standard deviation (SD)] PCS, MCS and KDCS scores were 37.9 (9.7), 46.4 (10.8) and 57.6 (18.1), respectively. Mean (SD) health utility score was 0.66 (0.12) for SF-6D and 0.60 (0.21) for EQ-5D. In multivariate regression analysis, factors found to be significantly associated with better HRQOL included: young (<45 years) or old age (>60 years), low CCI (<5), high albumin (≥37 g/l) and high haemoglobin (≥11 g/dl) with PCS; long dialysis vintage (≥3.5 years) with MCS; old age, Malay ethnicity and PD modality with KDCS; low CCI, high albumin and high haemoglobin with EQ-5D and high albumin with SF-6D. CONCLUSIONS: Clinical characteristics are better predictors of HRQOL in ESRD patients than socio-demographics in Singapore. Dialysis modality has no impact on the health utility of those patients.

In vivo and in vitro properties of STX2484: a novel non-steroidal anti-cancer compound active in taxane-resistant breast cancer.

BACKGROUND: STX2484 is a novel non-steroidal compound with potent anti-proliferative activity. These studies aimed to identify STX2484's mechanism of action, in vivo efficacy and activity in taxane-resistant breast cancer models. METHODS: Effects of STX2484 and paclitaxel on proliferation, cell cycle and apoptosis were assessed in vitro in drug-resistant (MCF-7(DOX)) and non-resistant cells (MCF-7(WT)). STX2484 efficacy in ßIII tubulin overexpression in MCF-7 cells was also determined. Anti-angiogenic activity was quantified in vitro by a co-culture model and in vivo using a Matrigel plug assay. An MDA-MB-231 xenograft model was used to determine STX2484 efficacy in vivo. RESULTS: STX2484 is a tubulin disruptor, which induces p53 expression, Bcl2 phosphorylation, caspase-3 cleavage, cell cycle arrest and apoptosis. In addition, STX2484 is a potent anti-angiogenic agent in vitro and in vivo. In breast cancer xenografts, STX2484 (20 mg kg(-1) p.o.) suppressed tumour growth by 84% after 35 days of daily dosing, with limited toxicity. In contrast to paclitaxel, STX2484 efficacy was unchanged in two clinically relevant drug-resistant models. CONCLUSIONS: STX2484 is an orally bioavailable microtubule-disrupting agent with in vivo anti-angiogenic activity and excellent in vivo efficacy with no apparent toxicity. Crucially, STX2484 has superior efficacy to paclitaxel in models of clinical drug resistance.

Quality of life and emotional distress between patients on peritoneal dialysis versus community-based hemodialysis.

PURPOSE: Patient-reported outcomes are important endpoints to evaluate new models of renal delivery. This is the first study to compare Quality of Life (QOL) and emotional adjustment outcomes between patients on community-based hemodialysis (HD) and those on peritoneal dialysis (PD). METHODS: Data were collected between 2009 and 2011 from a cross-sectional sample of 232 HD patients and 201 PD patients recruited through community dialysis centers and outpatient PD clinics in Singapore. Participants completed the Hospital Anxiety and Depression Scale, World Health Organization Quality of Life Brief and the Short form for the Kidney Disease Quality of Life. Measures of ESRD severity, comorbidity and biochemistry were also collected. RESULTS: Physical and emotional QOL impairments were noted for both dialysis groups. Case-mix-adjusted comparisons indicated higher symptoms of depression (p = 0.027), and poorer physical health yet higher satisfaction with care (p = 0.001) in PD relative to community-based HD. CONCLUSIONS: Peritoneal dialysis regimes offer flexibility and autonomy under the support of PD teams. Although outcomes for most QOL domains measured were equivalent, PD patients are more satisfied with care but are at risk for emotional distress and provide poor ratings of physical health. Further research is needed to explore the expansion of standards of care to address psychosocial needs in PD populations.

What do we know about self-reported fatigue in systemic lupus erythematosus?

Fatigue is one of the most complex and ill understood symptoms of chronic illness often reported as the number one complaint by patients with systemic lupus erythematosus (SLE). This paper aims to provide a comprehensive review of the literature on fatigue in SLE. A pool of 55 relevant articles was retrieved via electronic searches of six databases including MEDLINE, EMBASE, CINAHL, AMED, PsychINFO and PubMed. Fatigue in the studies reviewed was assessed by a range of self-report instruments, the content of which is varied. The results displayed a consensus on the high prevalence of fatigue in SLE, which is significantly higher when compared with controls. The aetiology of fatigue appears to be multifactorial. Disease activity is not always significantly associated with fatigue, in comparison with other secondary features of SLE and psychological variables. The literature is limited by the cross-sectional nature of most of the studies, which does not permit for any firm conclusion regarding the direction of causal relationships to be made. The high prevalence of fatigue in SLE emphasizes the need for further detailed prospective research to inform the understanding of its aetiology, course and management.

Religious coping strategies in patients diagnosed with breast cancer in the UK.

OBJECTIVES: The use of religious/spiritual coping strategies may be particularly prevalent when dealing with the stress of a cancer diagnosis. There has, however, been very little research conducted on this topic outside the USA. Existing measures of coping largely ignore the complexity of religious/spiritual coping and its potential to be adaptive as well as maladaptive. The aim of this study was to examine the prevalence of various religious coping strategies in a UK cancer sample. METHOD: A longitudinal design assessed religious coping strategies in patients newly diagnosed with breast cancer at the time of surgery and at 3 and 12 months post surgery. We recruited 202 patients of which, at 12 months, 160 remained. A non-religious coping measure was included for comparison. RESULTS: The use of religious coping strategies was overall common; up to 73% of patients used positive religious coping to some degree at surgery and up to 53% experienced various religious/spiritual struggles. The use of some religious coping strategies showed differing patterns of change across time while others remained stable. CONCLUSION: Using religious/spiritual resources in the coping process during the early stages of breast cancer appears common in the UK. Patients may benefit from having their spiritual needs addressed as experiencing some form of religious/spiritual struggle may serve as a barrier to illness adjustment. Health-care professionals should also be aware that some religious coping strategies may be more prevalent at different times during the first year of illness.

The impact of a breast cancer diagnosis on religious/spiritual beliefs and practices in the UK.

The use of religious/spiritual resources may increase when dealing with the stress of a cancer diagnosis. However, there has been very little research conducted into changes in religious/spiritual beliefs and practices as a result of a cancer diagnosis outside the USA. The aim of this study was to examine the impact of a breast cancer diagnosis on patients' religious/spiritual beliefs and practices in the UK where religious practice is different. The study used two methods. One compared the religious/spiritual beliefs and practices of 202 patients newly diagnosed with breast cancer with those of a control group of healthy women (n = 110). The other examined patients' perceived change in religious/spiritual beliefs and practices at the time of surgery with those in the year prior to surgery. The aspects of religiousness/spirituality assessed were: levels of religiosity/spirituality, strength of faith, belief in God as well as private and public practices. Patient's perceived their belief in God, strength of faith and private religious/spiritual practices to have significantly increased shortly after surgery compared with the year prior to surgery. However, there were no significant differences in religious/spiritual beliefs and practices between patients and healthy participants. Change scores demonstrated both a reduction and an increase in religious/spiritual beliefs and practices. Although belief in God, strength of faith and private religious/spiritual practices were perceived by patients to be significantly higher after their cancer diagnosis, no significant differences in religious/spiritual beliefs and practices were found between the cancer group at the time of surgery and the control group. Different methodologies appear to produce different results and may explain contradictions in past US studies. Limitations of this study are discussed and suggestions for future research are made.

Offshore pelagic subsidies dominate carbon inputs to coral reef predators.

Coral reefs were traditionally perceived as productive hot spots in oligotrophic waters. While modern evidence indicates that many coral reef food webs are heavily subsidized by planktonic production, the pathways through which this occurs remain unresolved. We used the analytical power of carbon isotope analysis of essential amino acids to distinguish between alternative carbon pathways supporting four key reef predators across an oceanic atoll. This technique separates benthic versus planktonic inputs, further identifying two distinct planktonic pathways (nearshore reef-associated plankton and offshore pelagic plankton), and revealing that these reef predators are overwhelmingly sustained by offshore pelagic sources rather than by reef sources (including reef-associated plankton). Notably, pelagic reliance did not vary between species or reef habitats, emphasizing that allochthonous energetic subsidies may have system-wide importance. These results help explain how coral reefs maintain exceptional productivity in apparently nutrient-poor tropical settings, but also emphasize their susceptibility to future ocean productivity fluctuations.

Class III beta-tubulin expression and in vitro resistance to microtubule targeting agents.

BACKGROUND: Class III beta-tubulin overexpression is a marker of resistance to microtubule disruptors in vitro, in vivo and in the clinic for many cancers, including breast cancer. The aims of this study were to develop a new model of class III beta-tubulin expression, avoiding the toxicity associated with chronic overexpression of class III beta-tubulin, and study the efficacy of a panel of clinical and pre-clinical drugs in this model. METHODS: MCF-7 (ER+ve) and MDA-MB-231 (ER-ve) were either transfected with pALTER-TUBB3 or siRNA-tubb3 and 24 h later exposed to test compounds for a further 96 h for proliferation studies. RT-PCR and immunoblotting were used to monitor the changes in class III beta-tubulin mRNA and protein expression. RESULTS: The model allowed for subtle changes in class III beta-tubulin expression to be achieved, which had no direct effect on the viability of the cells. Class III beta-tubulin overexpression conferred resistance to paclitaxel and vinorelbine, whereas downregulation of class III beta-tubulin rendered cells more sensitive to these two drugs. The efficacy of the colchicine-site binding agents, 2-MeOE2, colchicine, STX140, ENMD1198 and STX243 was unaffected by the changes in class III beta-tubulin expression. CONCLUSION: These data indicate that the effect of class III beta-tubulin overexpression may depend on where the drug's binding site is located on the tubulin. Therefore, this study highlights for the first time the potential key role of targeting the colchicine-binding site, to develop new treatment modalities for taxane-refractory breast cancer.

Steroid sulfatase: molecular biology, regulation, and inhibition.

Steroid sulfatase (STS) is responsible for the hydrolysis of aryl and alkyl steroid sulfates and therefore has a pivotal role in regulating the formation of biologically active steroids. The enzyme is widely distributed throughout the body, and its action is implicated in physiological processes and pathological conditions. The crystal structure of the enzyme has been resolved, but relatively little is known about what regulates its expression or activity. Research into the control and inhibition of this enzyme has been stimulated by its important role in supporting the growth of hormone-dependent tumors of the breast and prostate. STS is responsible for the hydrolysis of estrone sulfate and dehydroepiandrosterone sulfate to estrone and dehydroepiandrosterone, respectively, both of which can be converted to steroids with estrogenic properties (i.e., estradiol and androstenediol) that can stimulate tumor growth. STS expression is increased in breast tumors and has prognostic significance. The role of STS in supporting tumor growth prompted the development of potent STS inhibitors. Several steroidal and nonsteroidal STS inhibitors are now available, with the irreversible type of inhibitor having a phenol sulfamate ester as its active pharmacophore. One such inhibitor, 667 COUMATE, has now entered a phase I trial in postmenopausal women with breast cancer. The skin is also an important site of STS activity, and deficiency of this enzyme is associated with X-linked ichthyosis. STS may also be involved in regulating part of the immune response and some aspects of cognitive function. The development of potent STS inhibitors will allow investigation of the role of this enzyme in physiological and pathological processes.

BCRP expression does not result in resistance to STX140 in vivo, despite the increased expression of BCRP in A2780 cells in vitro after long-term STX140 exposure.

The anti-proliferative and anti-angiogenic properties of the endogenous oestrogen metabolite, 2-methoxyoestradiol (2-MeOE2), are enhanced in a series of sulphamoylated derivatives of 2-MeOE2. To investigate possible mechanisms of resistance to these compounds, a cell line, A2780.140, eightfold less sensitive to the 3,17-O,O-bis-sulphamoylated derivative, STX140, was derived from the A2780 ovarian cancer cell line by dose escalation. Other cell lines tested did not develop STX140 resistance. RT-PCR and immunoblot analysis demonstrated that breast cancer resistance protein (BCRP) expression is dramatically increased in A2780.140 cells. The cells are cross-resistant to the most structurally similar bis-sulphamates, and to BCRP substrates, mitoxantrone and doxorubicin; but they remain sensitive to taxol, an MDR1 substrate, and to all other sulphamates tested. Sensitivity can be restored using a BCRP inhibitor, and this pattern of resistance is also seen in a BCRP-expressing MCF-7-derived cell line, MCF-7.MR. In mice bearing wild-type (wt) and BCRP-expressing tumours on either flank, both STX140 and mitoxantrone inhibited the growth of the MCF-7wt xenografts, but only STX140 inhibited growth of the MCF-7.MR tumours. In conclusion, STX140, a promising orally bioavailable anti-cancer agent in pre-clinical development, is highly efficacious in BCRP-expressing xenografts. This is despite an increase in BCRP expression in A2780 cells in vitro after chronic dosing with STX140.

Randomized controlled trial to assess the impact of continuous glucose monitoring on HbA(1c) in insulin-treated diabetes (MITRE Study).

AIMS: To determine whether continuous glucose information provided through use of either the GlucoWatch G2 Biographer or the MiniMed continuous glucose monitoring system (CGMS) results in improved glycated haemoglobin (HbA(1c)) for insulin-treated adults with diabetes mellitus, relative to an attention control and standard care group. METHODS: Four hundred and four adults taking at least two daily insulin injections and with two consecutive HbA(1c) values > or = 7.5% were recruited to this randomized controlled trial (RCT). All were trained at baseline to use the same monitor for traditional capillary glucose testing throughout the 18-month study. The CGMS group were asked to wear the device three times during the first 3 months of the trial and on another three occasions thereafter. The GlucoWatch group wore the device a minimum of four times per month and a maximum of four times per week during the first 3 months and as desired for the remainder of the trial. Trained diabetes research nurses used downloaded data to guide therapy adjustments. Proportional reduction in HbA(1c) from baseline to 18 months was the primary outcome measure. RESULTS: Neither an intention-to-treat nor per-protocol analysis showed improvement in HbA(1c) in the device groups compared with standard care. For the intention-to-treat analysis, when the standard care group was compared with each of the other groups, this equated to differences in mean relative HbA(1c) reduction (95% confidence interval) from baseline to 18 months of 3.5% (-1.3 to 8.3; GlucoWatch), 0.7% (-4.1 to 5.5; CGMS), and -0.1% (-4.6 to 4.3; attention control). CONCLUSIONS: The additional information provided by these devices did not result in improvements in HbA(1c) in this population.

Lung deposition of aclidinium bromide from Genuair, a multidose dry powder inhaler.

BACKGROUND: Aclidinium bromide is a novel, long-acting inhaled muscarinic antagonist currently in development for the treatment of chronic obstructive pulmonary disease (COPD). A next-generation multidose dry powder inhaler will be used for the delivery of aclidinium bromide. OBJECTIVES: To quantify whole lung deposition and regional lung deposition of aclidinium delivered by a multidose dry powder inhaler (Genuair) in healthy subjects. METHODS: A single dose (200 microg) of aclidinium bromide, radiolabelled with (99m)Tc, was administered from the multidose dry powder inhaler at a targeted peak inspiratory flow rate (PIFR) of 90 litres/min in 12 healthy males (18-63 years). Gamma scintigraphy was used to quantify drug deposition in the lungs and oropharynx, as well as amounts retained in the inhaler and exhaled. The quantities of drug deposited in 6 concentric regions within the lungs were also determined. RESULTS: The mean (+/- SD) PIFR was 79.0 +/- 9.4 litres/min. The mean (+/- SD) percentages of the metered dose deposited in the whole lung and oropharynx were 30.1 +/- 7.3 and 54.7 +/- 7.2%, respectively. Deposition of aclidinium occurred in all 6 lung zones, but was highest in the most central zone. CONCLUSIONS: These results demonstrated that the multidose dry powder inhaler delivered aclidinium efficiently to the lungs. The whole lung deposition seen in this study is an indication of the likely whole lung deposition in COPD patients who inhale with similar PIFRs; however, further studies in patients are required to confirm this.

Temporal effective size estimates of a managed walleye Sander vitreus population and implications for genetic-based management.

The goal of this research was to use the long-term fishery data set and DNA from archived scales of walleye Sander vitreus in Escanaba Lake, WI, U.S.A., to improve the understanding of the underlying mechanism(s) influencing genetic diversity in naturally recruiting populations. The introduced population of S. vitreus in Escanaba Lake has a low mean effective population size (N(E)) between 124.6 and 185.5 despite a mean census size (N(C)) of 4659 (N(E)/N(C)c. 0.04), suggesting an accelerated rate of genetic drift between 1952 and 2002. These values are smaller than the median N(E) range of several studies suggesting typical N(E)/N(C) ratios of 0.11-0.16 in a wide range of taxa. N(E) increased steadily during the past two sampled decades (1992 and 2002) and was consistent with a lowering of the variance in S. vitreus reproductive success, possibly linked to a large, sustained exploitation (mean 28%) rate. Variance in reproductive success is one of the most important factors influencing N(E) in species, like S. vitreus, which have a potential for large fecundities and large juvenile mortalities (type III survivorship). The N(B) estimates across six sequential cohorts (age classes of S. vitreus, assayed from 1994 to 1999) was consistent with estimates of N(E) reported for 1992-2002. These results, coupled with in-depth census and exploitation data, show that the genetic characteristics of Escanaba Lake S. vitreus have changed substantially and that management activities, such as supplemental stocking and harvest practices, have profoundly influenced the genetic dynamics of S. vitreus in this lake.

2-Methoxyoestradiol-3,17-O,O-bis-sulphamate and 2-deoxy-D-glucose in combination: a potential treatment for breast and prostate cancer.

Drug combination therapy is a key strategy to improve treatment efficacy and survival of cancer patients. In this study the effects of combining 2-methoxyoestradiol-3,17-O,O-bis-sulphamate (STX140), a microtubule disruptor, with 2-deoxy-D-glucose (2DG) were assessed in MCF-7 (breast) and LNCaP (prostate) xenograft models in vivo. In mice bearing MCF-7 xenografts, daily p.o. administration of STX140 (5 mg kg(-1)) resulted in a 46% (P<0.05) reduction of tumour volume. However, the combination of STX140 (5 mg kg(-1) p.o.) and 2DG (2 g kg(-1) i.p.) reduced tumour volume by 76% (P<0.001). 2-Methoxyoestradiol-3,17-O,O-bis-sulphamate also reduced tumour vessel density. 2-Deoxy-D-glucose alone had no significant effect on tumour volume or vessel density. A similar benefit of the combination treatment was observed in the LNCaP prostate xenograft model. In vitro the degree of inhibition of cell proliferation by STX140 was unaffected by oxygen concentrations. In contrast, the inhibition of proliferation by 2DG was enhanced under hypoxia by 20 and 25% in MCF-7 and LNCaP cells, respectively. The combination of STX140 and 2DG in LNCaP cells under normoxia or hypoxia inhibited proliferation to a greater extent than either compound alone. These results suggest that the antiangiogenic and microtubule disruption activities of STX140 may make tumours more susceptible to inhibition of glycolysis by 2DG. This is the first study to show the benefit of combining a microtubule disruptor with 2DG in the two most common solid tumours.

The in vivo properties of STX243: a potent angiogenesis inhibitor in breast cancer.

The steroidal-based drug 2-ethyloestradiol-3,17-O,O-bis-sulphamate (STX243) has been developed as a potent antiangiogenic and antitumour compound. The objective of this study was to ascertain whether STX243 is more active in vivo than the clinically relevant drug 2-methoxyoestradiol (2-MeOE2) and the structurally similar compound 2-MeOE2-3,17-O,O-bis-sulphamate (STX140). The tumour growth inhibition efficacy, antiangiogenic potential and pharmacokinetics of STX243 were examined using four in vivo models. Both STX243 and STX140 were capable of retarding the growth of MDA-MB-231 xenograft tumours (72 and 63%, respectively), whereas no inhibition was observed for animals treated with 2-MeOE2. Further tumour inhibition studies showed that STX243 was also active against MCF-7 paclitaxel-resistant tumours. Using a Matrigel plug-based model, in vivo angiogenesis was restricted with STX243 and STX140 (50 and 72%, respectively, using a 10 mg kg(-1) oral dose), thereby showing the antiangiogenic activity of both compounds. The pharmacokinetics of STX243 were examined at two different doses using adult female rats. The compound was orally bioavailable (31% after a single 10 mg kg(-1) dose) and resistant to metabolism. These results show that STX243 is a potent in vivo drug and could be clinically effective at treating a number of oncological conditions.

Development and piloting of an acceptability questionnaire for continuous glucose monitoring devices.

BACKGROUND: User acceptability of new health technologies is important in determining their widespread use and adoption. The aim of this current study was twofold: first, to investigate the acceptability of two continuous glucose monitoring devices for people with diabetes; and second, to develop a valid questionnaire measure to assess the acceptability of continuous glucose monitoring devices. METHODS: Semi-structured interviews were conducted with six people with diabetes who had previously used the GlucoWatchBiographer (Animas Corp., West Chester, PA) or the CGMS continuous glucose monitoring system (Medtronic MiniMed, Northridge, CA) in order to increase understanding of the issues relating to acceptability of, and satisfaction with, the devices. Interview transcripts were analyzed qualitatively using framework analysis. These analyses, together with consultation with researchers and health professionals in the field, provided the foundation for development of a questionnaire measure that was piloted with 19 individuals. RESULTS: Six broad themes were elicited from the framework analysis: interference with daily activities; reliability and accuracy of the devices; practicality and ease of use; improvements in glycemic control; side effects; and self-consciousness and disclosure. Piloting of the questionnaire arising from this analysis demonstrated face validity. Further psychometric testing of the questionnaire will be conducted as part of a randomized controlled trial evaluating the clinical efficacy and cost-effectiveness of the CGMS and GlucoWatch G2 Biographer. CONCLUSIONS: Ultimately it is the user's preferences and his or her assessment of acceptability that will determine uptake and use of continuous glucose monitoring devices. It is therefore essential to consider and evaluate this alongside clinical efficacy and cost-effectiveness.

The regulation and inhibition of 17beta-hydroxysteroid dehydrogenase in breast cancer.

17Beta-hydroxysteroid dehydrogenase Type 1 (17beta-HSD1) has a pivotal role in regulating the synthesis of oestradiol (E2) within breast tumours. In whole body studies in postmenopausal women with breast cancer the conversion of oestrone (E1) to E2 (4.4+/-1.1%) was much lower than the inactivation of E2 to E1 (17.3+/-5.0%). In contrast, an examination of in vivo oestrogen metabolism within breast tumours revealed that whereas little metabolism of E2 occurred, E1 was converted to E2 to a much greater extent in malignant (48+/-14%) than in normal (19+/-6%) breast tissue. Findings from these studies originally suggested that oestrogen metabolism within breast tumours may differ from the mainly oxidative direction found in most other body tissues and that the activity of 17beta-HSD1 might be regulated by tumour-derived factors. Several growth factors (e.g. IGF-I, IGF-II) and cytokines (e.g. IL-6, TNFalpha) have now been identified which can markedly stimulate the activity of 17beta-HSD1 and such a mechanism may account for the high concentrations of E2 found in most breast tumours. Cells of the immune system, which can infiltrate breast tumours, are thought to be a major source of the growth factors and cytokines which can modulate 17beta-HSD1 activity. Given the central role that 17beta-HSD1 has in regulating breast tumour E2 concentrations the development of potent inhibitors of this enzyme has recently attracted considerable attention. Our initial studies in this area explored the use of derivatives of E1 as inhibitors, with 2-ethyl- and 2-methoxy E1 being found to inhibit 17beta-HSD1 activity in T-47D breast cancer cells by 96+/-2 and 91+/-1% respectively at 10 microM, but with a lack of specificity. Using the E1 scaffold a number of potent, selective 17beta-HSD1 inhibitors have now been identified including E1- and 2-ethyl-E1 containing a side chain with a m-pyridylmethylamidomethyl functionality extending from the 16beta position of the steroid nucleus. At 10 microM these compounds both inhibited 17beta-HSD1 activity by >90%, however some inhibition of 17beta-HSD2 activity was exhibited by the E1 derivative (25%) but not the 2-ethyl analogue. It is now apparent that 17beta-HSD1 activity contributes to the high E2 concentrations found in most breast tumours. The identification of potent, selective novel 17beta-HSD1 inhibitors will allow their efficacy to be tested in in vitro and in vivo studies.