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.

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.

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).

Does strabismus surgery improve quality and mood, and what factors influence this?

AimsTo establish the impact of adult strabismus surgery on clinical and psychosocial well-being and determine who experiences the greatest benefit from surgery and how one could intervene to improve quality of life post-surgery.MethodsA longitudinal study, with measurements taken pre-surgery and at 3 and 6 months post-surgery. All participants completed the AS-20 a disease specific quality of life scale, along with measures of mood, strabismus and appearance-related beliefs and cognitions and perceived social support. Participants also underwent a full orthoptic assessment at their preoperative visit and again 3 months postoperatively. Clinical outcomes of surgery were classified as success, partial success or failure, using the largest angle of deviation, diplopia and requirement for further therapy.Results210 participants took part in the study. Strabismus surgery led to statistically significant improvements in psychosocial and functional quality of life. Those whose surgery was deemed a partial success did however experience a deterioration in quality of life. A combination of clinical variables, high expectations, and negative beliefs about the illness and appearance pre-surgery were significant predictors of change in quality of life from pre- to post-surgery.ConclusionsStrabismus surgery leads to significant improvements in quality of life up to 6 months postoperatively. There are however a group of patients who do not experience these benefits. A series of clinical and psychosocial factors have now been identified, which will enable clinicians to identify patients who may be vulnerable to poorer outcomes post-surgery and allow for the development of interventions to improve quality of life after surgery.

Which factors are associated with quality of life in patients with Graves' orbitopathy presenting for orbital decompression surgery?

PURPOSE: Graves' orbitopathy (GO) is associated with changes in the appearance of the eyes and visual dysfunction. Patients report feeling socially isolated and unable to continue with day-to-day activities. This study aimed at investigating the demographic, clinical, and psychosocial factors associated with quality of life in patients presenting for orbital decompression surgery. METHODS: One-hundred and twenty-three adults with GO due for orbital decompression at Moorfields Eye Hospital London were recruited prospectively. Clinical measures including treatment history, exophthalmos, optic neuropathy, and diplopia were taken by an ophthalmologist. Participants completed psychosocial questionnaires, including the Graves' Ophthalmopathy Quality of Life Scale (GO-QOL), the Hospital Anxiety and Depression Scale, and the Derriford Appearance Scale. Hierarchical multiple regression analyses were used to identify predictors of quality of life. RESULTS: Higher levels of potential cases of clinical anxiety (37%) and depression (26%) were found in this study sample than in patients with other chronic diseases or facial disfigurements. A total of 55% of the variance in GO-QOL visual function scores was explained by the regression model; age, asymmetrical GO and depressed mood were significant unique contributors. In all, 75% of the variance in GO-QOL appearance scores was explained by the regression model; gender, appearance-related cognitions and depressed mood were significant unique contributors. CONCLUSION: Appearance-related quality of life and mood were particularly affected in this sample. Predominantly psychosocial characteristics were associated with quality of life. It is important when planning surgery for patients that clinicians be aware of factors that could potentially influence outcomes.

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.

Managing treatment for end-stage renal disease--a qualitative study exploring cultural perspectives on facilitators and barriers to treatment adherence.

Although adherence to hemodialysis (HD) regimes is important to maximise good clinical outcomes, it remains suboptimal and not well understood, particularly for those in non-Western settings and patients from Asian cultures. This qualitative study sought to explore cultural perspectives on facilitators and barriers to treatment adherence in HD patients. A descriptive exploratory design was used for the study, incorporating individual semi-structured interviews (n = 17) and three focus groups (n = 20). Each interview/focus group was audio-taped and transcribed verbatim, and coding was conducted by two coders using an iterative process. Study participants identified personal and social/contextual factors as major barriers or facilitators of treatment adherence. Barriers include time consumption, forgetfulness, concerns about safety, poor knowledge/understanding, poor communication and lack of control/social pressure. Participants also identified facilitators, both internal (self-initiated) and external (initiated by family, health care professional and peers) to ensure treatment adherence. These included support from family members and social obligation towards others, risk perception, establishment of routines and peer support. Internal and external factors can hinder or facilitate adherence to diet, fluid and medications in the context of dialysis. Several of these barriers/facilitators can be effectively addressed in the context of interventions and psycho-educational programmes.

What constitutes uncertainty in systemic lupus erythematosus and rheumatoid arthritis?

Patient uncertainty is associated with conditions with no known cause or cure, such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), and despite its potential role in chronic illness management, it is still a poorly understood concept. This study constitutes an in-depth investigation of patient uncertainty in SLE and RA. We conducted (i) structured interviews with a sample of rheumatology health care professionals (HCPs) (n = 8) and (ii) in-depth, semi-structured interviews with a sample of SLE (n = 17) and RA (n = 15) patients. Interviews were audio-taped, transcribed verbatim and analysed thematically using detailed line-by-line coding. Patient uncertainty was conceptualised in a framework of five domains: symptoms and prognosis, medical management, self-management, impact and social functioning. Even though these five domains were present in both the SLE and RA data, there were some differences at the sub-domain level. Several sources of uncertainty were put forward by the HCPs and subsequently confirmed in the patient interviews including the illness trajectory, age, gender and timing. Patients reported uncertainty relative to various aspects of their illness, its management and impact. Finally, HCPs discussed the behavioural and psychosocial impact of uncertainty, which further suggests its important role in patient management.

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.

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.

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.

A randomised controlled trial to compare minimally invasive glucose monitoring devices with conventional monitoring in the management of insulin-treated diabetes mellitus (MITRE).

OBJECTIVES: To evaluate whether the additional information provided by minimally invasive glucose monitors results in improved glycaemic control in people with poorly controlled insulin-requiring diabetes, and to assess the acceptability and health economic impact of the devices. DESIGN: A four-arm randomised controlled trial was undertaken. SETTING: Participants were recruited from secondary care diabetes clinics in four hospitals in England. PARTICIPANTS: 404 people aged over 18 years with insulin-treated diabetes mellitus (types 1 or 2) for at least 6 months who were receiving two or more injections of insulin daily were eligible. Participants had to have had two glycosylated haemoglobin (HbA1c) values > or = 7.5% in the last 15 months. INTERVENTIONS: Participants were randomised to one of four groups. Two groups received minimally invasive glucose monitoring devices [GlucoWatch Biographer or MiniMed Continuous Glucose Monitoring System (CGMS)]. These groups were compared with an attention control group (standard treatment with nurse feedback sessions at the same frequency as those in the device groups) and a standard control group (reflecting common practice in the clinical management of diabetes in the UK). MAIN OUTCOME MEASURES: Change in HbA1c from baseline to 3, 6, 12 and 18 months was the primary indicator of short- to long-term efficacy in this study. Perceived acceptability of the devices was assessed by use and a self-report questionnaire. A health economic analysis was also performed. RESULTS: At 18 months all groups demonstrated a decline in HbA1c levels from baseline. Mean percentage changes in HbA1c were -1.4 for the GlucoWatch group, -4.2 for the CGMS group, -5.1 for the attention control group and -4.9 for the standard care control group. At 18 months the relative percentage reduction in HbA1c in each of the intervention arms was less than that in the standard care control group. In the intention to treat analysis no significant differences were found between any of the groups at any of the assessment times. There was no evidence that the additional information provided by the devices resulted in any change in the number or nature of treatment recommendations offered by the nurses. The health economics analysis indicated no advantage in the groups who received the devices; a lower cost and higher benefit were found for the attention control arm. Assessment of device use and acceptability indicated a decline in use of both devices, which was most marked in the GlucoWatch group by 18 months (20% still using GlucoWatch versus 57% still using the CGMS). The GlucoWatch group reported more side effects, greater interference with daily activities and more difficulty in using the device than the CGMS group. CONCLUSIONS: Continuous glucose monitors do not lead to improved clinical outcomes and are not cost-effective for improving HbA1c in unselected individuals with poorly controlled insulin-requiring diabetes. On acceptability grounds the data suggest that the GlucoWatch will not be frequently used by individuals with diabetes because of the large number of side effects.

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.

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.

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.