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Background Malnutrition is a serious concern in older populations. Simple screening approaches are needed to identify signs of early nutritional risk in older people, to allow intervention before overt malnutrition develops, along with the poorer health outcomes associated with it, such as sarcopaenia and frailty. The main aim of this study was to compare nutrition risk scores, calculated from the DETERMINE Checklist (‘Determine Your Nutritional Health’, also known as the Nutrition Screening Initiative Checklist), with physical function variables in a group of community-dwelling older adults. Another aim was to assess the prevalence of nutrition risk using the DETERMINE and the MUST (Malnutrition Universal Screening Tool). Methods Participants of the Hertfordshire Cohort Study (HCS) were recruited and visited at home by a trained researcher. Self-reported physical function was assessed using the SF-36 PF (Short Form-36 Physical Function) scale. The Short Physical Performance Battery (SPPB) was performed, which included the assessment of gait speed, chair rise time and standing balance. Handgrip strength was measured using a Jamar dynamometer. Frailty was assessed according to the presence of at least three of the following Fried frailty criteria: unintentional weight loss, weakness, self-reported exhaustion, slow gait speed and low physical activity. Nutrition risk scores were calculated from the DETERMINE checklist (range 0–21). Nutritional risk was also assessed using the MUST. Analyses were adjusted for sex, age, age left education and number of comorbidities. Results In the study, 176 participants (94 men and 82 women), median age 83.3 (IQR 81.5–85.7) years, were assessed. Almost half (47%) scored either ‘moderate’ (score 3–5) or ‘high’ (score ≥ 6) nutritional risk (9% were at high risk), using the DETERMINE checklist, whereas 8% were at risk using the MUST. Higher nutrition risk scores, calculated from DETERMINE, were associated with poorer self-reported physical function (difference in SF-36 PF score: − 0.36, 95% CI (− 0.60, − 0.12) SD per unit increase in nutrition risk score, P = 0.004) and higher odds of being frail (odds ratio Fried frailty: 2.23, 95% CI (1.15, 4.33), P = 0.017). There were no significant associations between DETERMINE nutrition risk scores and the other variables examined. Conclusion Cross-sectional associations between higher nutrition risk scores, assessed from the DETERMINE checklist, and poorer self-reported physical function and greater likelihood of frailty suggest that this screening tool may have utility for screening older populations. Prospective studies are required to explore the ability of the tool to predict poor physical function and frailty, though these data suggest it has potential for early, simple detection of nutritional problems in community-living older adults.

We considered how weight-bearing physical activity (WBPA) through the lifecourse related to bone health in late adulthood in the Hertfordshire Cohort Study (HCS), a cohort of community dwelling adults born 1931–9, to identify sex-specific differences and periods critical for optimal bone health. Available questionnaire data from 258 participants (128 men and 130 women) included current reported lifestyle factors (including physical activity) and WBPA, coded as participation in WBPA aged once a week. Hip bone mineral density (BMD) was measured using a Lunar Prodigy DXA scanner. The mean age was 75.4 (SD 2.5) years in men and 75.7 (SD 2.6) years in women. Men reported significantly higher levels of past WBPA aged p = 0.006) and aged 18–29 years than women (p p = 0.02) and 30–49 years (p = 0.02) compared with those who reported no WBPA (p = 0.019), after adjustment for confounders including current activity levels. In this cohort of older adults, recalled regular WBPA around the time of peak bone mass acquisition was less common in women than men, but associated with higher hip BMD in women in late adulthood.

Self-perceived risk of fracture (SPR) is associated with fracture independent of FRAX calculated risk. To understand this better we considered whether lifestyle factors not included in the FRAX algorithm and psychosocial factors (social isolation, self-efficacy, or mental health status) explain the relationship between SPR and fracture.We studied 146 UK community-dwelling older adults from the Hertfordshire Cohort Study. SPR ranked as 'lower', 'similar' and 'higher' relative to others of the same age, was assessed by questionnaire. Social isolation was assessed using the six-item Lubben Social Network Scale; self-efficacy was assessed using a shortened General Self-Efficacy Scale (GSE); mental health status was assessed using the anxiety/depression item from the EuroQoL questionnaire. SPR in relation to previous self-reported fracture was examined using logistic regression.Among participants of median age 83.4 (IQR 81.5-85.5) years, SPR was lower for 54.1% of participants, similar for 30.8%, and higher for 15.1%; 74.7% reported no previous fractures. Greater SPR was associated with increased odds of previous fractures when adjusting for sex and age only (OR 1.72, 95% CI 1.03-2.87, per higher band of SPR). While further individual adjustment for social isolation (1.73, 1.04-2.89), self-efficacy (1.71, 1.02-2.85), or mental health (1.77, 1.06-2.97) did not attenuate the relationship, individual adjustment for diet quality and number of comorbidities did.Adjustment for social isolation, self-efficacy or mental health status did not attenuate the relationship between SPR and fracture. By contrast, lifestyle factors not included in FRAX, such as diet quality, did attenuate relationships, suggesting a possible future area of investigation.

Background/Aims Physical activity is known to be beneficial for musculoskeletal health across the lifecourse. We have previously demonstrated that regular participation in weight-bearing physical activity (WBPA) at the time of peak bone mass acquisition is associated with higher hip bone mineral density in late adulthood in women. Understanding how WBPA tracks across the lifecourse may help us develop interventions to promote WBPA for musculoskeletal benefit; we consider these relationships here. Methods The study population consisted of 128 men and 130 women from the Hertfordshire Cohort Study. Questionnaire data on participation in sports and leisure time exercise involving WBPA e.g. running, racquet sports, football, rugby, hockey and dancing, but not walking, cycling or swimming were collected for the following age bands: Results The mean age of participants was 75.4 (SD 2.5) years in men and 75.7 (SD 2.6) years in women. Men tended to report higher levels of past WBPA throughout the lifecourse, with significant differences in WBPA up to the age of 18 years (p = 0.006) and 18-29 years (p < 0.001). Table 1 shows kappa statistics of relationships between reported WBPA levels at different ages. These decreased over time, and while broadly similar, the tracking was generally stronger in women than men. For example, we observed that participants who were active at 30-49 years were more likely to remain active in late adulthood with kappa in men 0.393 (95%CI: 0.295-0.442) and kappa in women 0.492 (95% CI: 0.400-0.555). Conclusion WBPA decreased with advancing age in both sexes, though was generally higher in men than women in this retrospective cohort study. The correlation between WBPA at different stages of the lifecourse weakened as time between the measurements increased in both sexes. Our results highlight the need for further work to understand the drivers to encourage WBPA at different stages in the lifecourse and to facilitate development of appropriate interventions to promote WBPA for musculoskeletal benefit. Disclosure J. Zhang: None. K. Jameson: None. L. Westbury: None. N. Fuggle: None. K. Ward: None. C. Cooper: None. E. Dennison: None.

BackgroundPhysical activity, nutrition and other lifestyle factors play important roles in maintaining musculoskeletal health. The coronavirus disease (COVID-19) originated in late 2019, spread globally to be declared a pandemic by the World Health Organisation in March 2020, and led to widespread behaviour change. The aim of this study was to use two existing cohorts, the Hertfordshire Cohort Study (HCS) and Health and Employment After Fifty Study (HEAF), to understand how wave one of the COVID-19 pandemic impacted lifestyle factors associated with musculoskeletal health in the UK.Methods125 eligible participants, 65 males and 60 females (drawn from the HCS study, median (IQR) age 84.3 (82.4-86.6) years, all Caucasian, and community dwelling) were contacted by telephone and asked to complete a questionnaire administered by a trained researcher. Data collection occurred over the period July 2020 to February 2021. 2469 participants, 1086 men and 1383 women (drawn from the HEAF study, median age 65.7 (62.0-69.3) years, mostly Caucasian and community dwelling) completed an online questionnaire in March 2021.ResultsIn HCS, 47% respondents reported being less physically active than before the pandemic (and only 5% more so), 27% said they consumed less alcohol compared to pre-pandemic times (and only 3% more so), and 18% reported eating less than before, although quality of diet was generally unchanged over this timeframe surveyed. In HEAF, 44% participants said they were less active than before the pandemic, while 17% reported being more active. The majority of participants reported no changes in alcohol consumption and diet; however, 19% said they drank more than before (32% of which was above recommended levels), 16% said their diet was less healthy, and 19% reported eating more than before.ConclusionWe have reported the experience of the first wave of the COVID-19 pandemic among participants of two Caucasian community dwelling UK cohorts, highlighting the impact of the pandemic on lifestyle factors associated with musculoskeletal health. Changed physical activity levels were reported in a high proportion of respondents in both studies; an investigation of reversibility of these changes is required.

Purpose of review The field of osteoporosis research has been active for the past 20 years and has allowed significant advancement in the management of osteoporosis. This review will give an overview of the latest data from international cohorts that relate to current and recent osteoporosis research. Recent findings The clinical diagnosis of osteoporosis relies heavily on bone mineral density (BMD) measured at femoral neck or spine and although BMD has excellent predictive value for future fractures, fracture risk assessment has evolved over the years, resulting in the birth of fracture prediction tools. Fracture risk factors not currently featured in these tools are being considered for inclusion, including imminent risk fracture following a sentinel fracture, number of falls, and previous vertebral fractures. Data from groups with comorbidities such as chronic obstructive pulmonary disease are helping us understand how to best manage patients with multiple comorbidities. Finally, the prevalence of vertebral fracture in the older general population and other selected populations has been explored, alongside the global burden of osteoporosis and its consequences. Summary Our understanding of osteoporosis continues to expand, but knowledge gaps remain.

Background The COVID-19 pandemic has led to dramatic changes in people’s lives globally. Older adults have been especially vulnerable to adverse effects from the pandemic including higher mortality and more severe disease complications. At the same time, social isolation, malnutrition and physical inactivity are serious concerns among older adults. The pandemic and associated restrictions may serve to exacerbate these issues, presenting increased risks to physical and mental health. The aim of this qualitative study was to explore how community-living older people in the UK experienced the first wave of the COVID-19 pandemic and how it impacted their health and well-being, and associated behaviours. Methods Qualitative data were collected by conducting serial telephone interviews, with an interval of approximately three months. Participants were from the Hertfordshire Cohort Study, all aged over 80 years. Discussions were audio-recorded, information related to the COVID-19 pandemic was transcribed verbatim and transcripts analysed thematically. Interviews were conducted from March to October 2020. Results Twelve participants were included in the study (7 men and 5 women). Data from a total of 35 qualitative interviews were used, comprising two or three timepoints per participant. Preliminary analysis identified five overarching themes: 1) shopping strategies and food accessibility, 2) limitations on activities and going out, 3) disruption to healthcare, 4) social and psychological repercussions, and 5) coping strategies. Initial findings highlight challenges associated with accessing shops, healthcare, and usual activities due to restrictions. Findings emphasize the issue of loneliness and isolation for some of the participants, especially those living alone, as well as fear of the virus, with restrictions leading to a loss of purpose for some, along with related effects on mental health (e.g. worry, anxiety). For some, these issues appeared to link to a reprioritisation of their behaviours (for example, exercise and diet were deprioritised). Coping strategies used by participants included finding ways to keep busy and to do physical activity safely, maintaining social contact online or by telephone, and having an optimistic or positive outlook, a ‘do what you can’ attitude. Conclusion Analysis is ongoing and will further aim to explore how older people’s experiences and behaviours might have changed over the duration of the pandemic. The findings from this study could improve understanding of how community-living older adults could be supported to be more resilient in the face of a variety of changing circumstances that might impact their health and well-being.

Background Covid-19, a coronavirus that originated in China in late 2019, spread globally to be declared a pandemic by the World Health Organisation in March 2020. The aim of this study was to usean existing cohort of community-dwelling older adults, the Hertfordshire Cohort Study (HCS), to understand how wave one of the Covid-19 pandemic impacted UK older adults, a group particularly vulnerable to severe disease. Methods 71 eligible participants, 39 males and 32 females (drawn from the HCS study, mean age 83.6 (2.5) years, all Caucasian, and community dwelling) were contacted by telephone and asked to complete a questionnaire administered by a trained researcher. Data collection occurred over the period of July to October 2020. Results Over a third (37.1%) of respondents lived alone. Of the remainder, 86.4% lived with a spouse while the remaining 13.6% lived with family. Of concern, 19.7% of participants had felt they needed to go out despite not wanting to; 47.1% had heard of the NHS Volunteer Responders programme, although only 3 (4.2%) had made use of this or other support services. Almost a third (31%) of participants reported they had access to a smartphone, while 62% reported having unlimited internet access, usually using a tablet or computer. Over two thirds (69.0%) of participants rated their understanding of Covid-19 itself as good. Perhaps unsurprisingly, a large majority (88.7%) of participants said their life was different compared to before Covid-19; 80.3% had less social contact and more than half (52%) of respondents reported being less physically active than before the pandemic (and only 4% more so). However, levels of sleep, alcohol consumption and diet were reportedly generally unchanged over the timeframe surveyed. Conclusion We have reported the experience of the first wave of the Covid-19 pandemic among participants of an older Caucasian community-dwelling UK cohort, highlighting the need to consider this group when developing public health interventions to support health and wellbeing, including those employing smartphone technology. Further larger studies in groups of wider socioeconomic status and more diverse racial background are indicated.

Background The health benefits of physical activity (PA) participation in later life are widely recognised. Understanding factors that can influence the participation of community-dwelling older adults in PA is crucial in an ageing society. This will be paramount in aiding the design of future interventions to effectively promote PA in this population. The main aim of this qualitative study was to explore influences on PA among community-dwelling older people, and the secondary aim was to explore gender differences. Methods Qualitative data were collected in 2014 by conducting focus group discussions using a semi-structured discussion guide with older people resident in Hertfordshire, UK. Discussions were audio-recorded, transcribed verbatim and transcripts analysed thematically. Results Ninety-two participants were recruited to the study (47% women; 74–83 years) and a total of 11 focus groups were conducted. Findings indicated six themes that appeared to affect older adults’ participation in PA: past life experiences; significant life events; getting older; PA environment; psychological/personal factors; and social capital. Overall, the findings emphasised the role of modifiable factors, namely psychological factors (such as self-efficacy, motivation, outcome expectancy) and social factors (such as social support and social engagement). These factors exerted their own influence on physical activity participation, but also appeared to mediate the effect of other largely non-modifiable background and ageing-related factors on participants’ engagement with PA in later life. Conclusion In view of these findings, intervention designers could usefully work with behavioural scientists for insight as to how to enhance psychological and social factors in older adults. Our data suggest that interventions that aim to build self-efficacy, motivation and social networks have the potential to indirectly promote PA participation in older adults. This would be best achieved by developing physical activity interventions through working with participants in an empowering and engaging way.

Purpose Social isolation has been associated with both physical and psychological adverse outcomes and is prevalent in older adults. We investigated the impact of social isolation on bone mineral density (BMD) and physical capability in community-dwelling older adults. Methods Data were collected in 2011 and 2017 from the Hertfordshire Cohort Study. In 2011, we assessed social isolation using the six-item Lubben Social Network Scale (LSNS-6) and the Maastricht Social Participation Profile (MSSP) and depressive and anxiety symptoms using the Hospital Anxiety and Depression Scale (HADS). Physical capability was assessed by performing tests of gait speed, chair stands, timed up and go and balance at both time points. BMD was assessed using dual X-ray absorptiometry (DXA) at both time points. Results Data were available from 369 participants in 2011 and 184 in 2017. Forty percent of men and 42.4% of women were socially isolated. Isolated participants had higher odds of depressive disorder (OR 3.01, 95% CI 1.27–7.11, p p Conclusions Social isolation was associated with higher odds of having depressive symptoms and predicted the development of poor physical capability 6 years later. Further longitudinal studies that include loneliness as a covariate are warranted.

To date conventional osteoporosis therapy has been largely dominated by the use of anti-resorptive therapy but more recently anabolic agents have emerged as an important option for bone health management. Teriparatide is the most well-known anabolic agent. Its efficacy with regard to bone mineral density increase and fracture reduction have been demonstrated in numerous studies while abaloparatide has been licenced in the United States for osteoporosis management. In the last year, a new therapeutic target, romosozumab, an anti-sclerostin monoclonal antibody, achieved approval in both Europe and the United States, for management of osteoporosis. This provides an overview of current and emerging potential therapeutic targets.

Background In the context of an aging population, age-related decline in muscle strength is well recognised, and is associated with functional limitation and increased mortality. However, scarce epidemiological data are available regarding its prevalence, or lifestyle associations at a time when intervention is still possible to retard or prevent loss. We considered these issues in the Hertfordshire Cohort Study, a cohort of late-middle aged community dwelling adults. Methods 2,987 participants were seen in 1999-2004, 1,572 men and 1,415 women. A lifestyle questionnaire was administered that asked about social class, physical activity, diet, co-morbidities and cigarette and alcohol consumption. Grip strength was measured with a Jamar dynamometer, three times on each side with the highest value used. Age related muscle strength decline was defined, according to current convention, as a grip strength Results The mean age of participants was 65.8 (IQR 63.5-67.8) years for men and 66.5 (IQR 64.5-68.7) years for women. Muscle strength decline was more common in women (10.3%) than men (3%); the odds ratio (OR) for age-related muscle strength decline was 3.73 (95%CI 2.66-5.23) in women relative to men (p < 0.001). Factors that appeared protective included higher physical activity scores in men (OR 0.97, 95%CI 0.96-0.99, p = 0.003) and in women (OR 0.97, 95%CI 0.96-0.98, p < 0.001) and a higher prudent diet score in women (OR: 0.74, 95%CI 0.60-0.90 p = 0.003). Muscle strength decline was strongly associated with quality of life in women (p ≤ 0.001) as assessed by SF36 and EuroQoL EQ-5D for all domains, although EuroQOL anxiety/depression and SF36 role emotional were less strongly associated (p-value=0.042, p-value=0.006, respectively). Table 1 shows self-reported impaired ability to move, self-care, perform usual activities and increased pain were associated with higher risk of age-related muscle strength decline in women. Conclusion Age related muscle strength decline was more common in community dwelling women than men, and diet and physical activity were predictors of such decline. Research into effective preventative interventions is now warranted. Disclosures J. Zhang None. F. Laskou None. K. Jameson None. C. Cooper None. E.M. Dennison None.

Background In recent years denosumab therapy has been widely used in the treatment of osteoporosis. However, since its first introduction to clinical practice, evidence has demonstrated discontinuation leads to rebound bone loss and risk of vertebral fracture. In view of this, guidance has been updated recommending transition to an alternative osteoporosis therapy. Given that osteoporosis management is largely managed in primary care, we performed this audit to investigate whether this educational message was being effectively relayed to primary care clinicians. Methods In this study, we closed the audit loop of a previous study of the first 50 patients commenced on denosumab at University Hospital Southampton in 2013; we explored the percentage of patients remaining on denosumab 6 years later, using the hospital electronic system, which is linked to the general practice electronic system, to confirm prescriptions for osteoporosis therapy. In cases where it was unclear, letters were written, or telephone calls were made to general practices for clarification. Continuation of denosumab or use of an alternative agent was then recorded. Results Nineteen (38%) patients had died since the initial audit, reflecting the use of the agent in later life post hip fracture. Of 15 patients no longer on denosumab, 9 (60%) were found not to be on alternative bone protection without other information recorded, 1 (7%) had denosumab suspended by the GP (with the presumption it may be restarted at a later date), 1 (7%) had denosumab suspended due to recurrent cellulitis with the view to reassess in a year and 3 (20%) were on alternative therapy. One patient was recorded as being on a ‘drug holiday’. Of 16 patients remaining on denosumab, 13 (81%) had pre-injection calcium level checks, and 12 (75%) had a recorded pre-injection renal function check. Conclusion These data reflect inappropriate widespread discontinuation of denosumab without follow-on with an alternative osteoporosis therapy, suggesting that targeted education of primary care physicians is necessary. A high proportion of patients on denosumab are having the relevant blood tests in primary care as per clinical guidelines. Disclosures J. Zhang None. M.A. Clynes None. C. Cooper None. E.M. Dennison None.

Nature Communications 8: Article number: 16081 (2017); Published: 17 July 2017, Updated: 13 July 2018 The original version of this Article omitted the following from the Acknowledgements: ‘We thank Robert Kirkpatrick for implementing the high throughput protein design strategy that enabled screeningand triage of essential A.

α7 nicotinic acetylcholine receptor agonists are promising therapeutic candidates for the treatment of cognitive impairment. As a follow up of our internal medicinal chemistry program we investigated a novel series of α7 nAChR agonists. Starting from molecular docking studies on two series of molecules recently developed in our laboratories, an alternative scaffold was designed attempting to combine the optimal features of these previously identified urea and pyrazole compounds. Based on our previous SAR knowledge and on predicted drug-like properties, a small library was synthesized in parallel manner, affording compounds with excellent α7 nAChR activity, selectivity and preliminary ADME profile.

The identification and prioritization of chemically tractable therapeutic targets is a significant challenge in the discovery of new medicines. We have developed a novel method that rapidly screens multiple proteins in parallel using DNA-encoded library technology (ELT). Initial efforts were focused on the efficient discovery of antibacterial leads against 119 targets from Acinetobacter baumannii and Staphylococcus aureus. The success of this effort led to the hypothesis that the relative number of ELT binders alone could be used to assess the ligandability of large sets of proteins. This concept was further explored by screening 42 targets from Mycobacterium tuberculosis. Active chemical series for six targets from our initial effort as well as three chemotypes for DHFR from M. tuberculosis are reported. The findings demonstrate that parallel ELT selections can be used to assess ligandability and highlight opportunities for successful lead and tool discovery., Encoded Library Technology (ELT) has streamlined the identification of chemical ligands for protein targets in drug discovery. Here, the authors optimize the ELT approach to screen multiple proteins in parallel and identify promising targets and antibacterial compounds for S. aureus, A. baumannii and M. tuberculosis.

Summary: Clustering of factors linked with poor bone health is common in older adults and is associated with lower bone density and increased fracture risk in women.Purpose: Many factors are associated with bone mineral density, which in turn is strongly linked with risk of fragility fracture. We assessed how commonly clustering of risk factors occurs and related such clustering to bone mineral density in a population of older community-dwelling men and women.Method: This is a cross-sectional study with 498 men and 498 women aged 59 to 72 years, who were participants in the Hertfordshire Cohort Study, in whom incident fracture was recorded. Physical activity, diet quality, history of prior fracture, family history of fracture, cigarette and alcohol consumption and comorbidities were obtained through baseline questionnaire. Measurements of grip strength and bone mineral density of the lumbar spine and total femur were also taken.Results: Clustering of risk factors was common, with over 30 % having two or more. In women, a graded association between the number of risk factors and low bone density was seen, and strong relationships were also seen between the number of risk factors and incident fracture; women with three or more risk factors had an adjusted hazard ratio (HR) of incident fracture of 5.98 (1.67, 21.43; p?=?0.006) compared to women with no risk factors; women with two risk factors had an adjusted HR of 2.97 (1.14, 7.74; p?=?0.03) and those with one, 2.28 (0.90, 5.75; p?=?0.08).Conclusion: Clustering of risk factors for poor bone health is common in community-dwelling older adults and is associated with increased risk of fracture and adverse bone health in women.

DNA-encoded small-molecule library technology has recently emerged as a new paradigm for identifying ligands against drug targets. To date, this technology has been used with soluble protein targets that are produced and used in a purified state. Here, we describe a cell-based method for identifying small-molecule ligands from DNA-encoded libraries against integral membrane protein targets. We use this method to identify novel, potent, and specific inhibitors of NK3, a member of the tachykinin family of G-protein coupled receptors (GPCRs). The method is simple and broadly applicable to other GPCRs and integral membrane proteins. We have extended the application of DNA-encoded library technology to membrane-associated targets and demonstrate the feasibility of selecting DNA-tagged, small-molecule ligands from complex combinatorial libraries against targets in a heterogeneous milieu, such as the surface of a cell.

The 5-hydroxytryptamine 2C (5-HT 2C ) receptor subtype has received considerable attention as a target for drug discovery, having been implicated in a wide variety of disorders. Here, we describe the in vitro pharmacological profile of the novel 5-HT 2C receptor-selective agonist vabicaserin [(−)-4,5,6,7,9,9a,10,11,12,12a-decahydrocyclopenta[c] [1,4]diazepino[6,7,1-ij]quinoline hydrochloride] (SCA-136), including a comprehensive strategy to assess 5-HT 2B receptor selectivity using diverse preparations and assays of receptor activation. Vabicaserin displaced 125 I-(2,5-dimethoxy)phenylisopropylamine binding from human 5-HT 2C receptor sites in Chinese hamster ovary cell membranes with a K i value of 3 nM and was >50-fold selective over a number of serotonergic, noradrenergic, and dopaminergic receptors. Binding affinity determined for the human 5-HT 2B receptor subtype using [ 3 H]5HT was 14 nM. Vabicaserin was a potent and full agonist (EC 50 , 8 nM; E max , 100%) in stimulating 5-HT 2C receptor-coupled calcium mobilization and exhibited 5-HT 2A receptor antagonism and 5-HT 2B antagonist or partial agonist activity in transfected cells, depending on the level of receptor expression. In rat stomach fundus and human colonic longitudinal muscle endogenously expressing 5-HT 2B receptors, vabicaserin failed to induce a 5-HT 2B receptor-dependent contraction and produced a rightward shift of the 5-HT and α-methyl-5-HT concentration-response curves in these preparations, respectively, consistent with 5-HT 2B competitive antagonism. Likewise, vabicaserin failed to induce a 5-HT 2B receptor-mediated contraction in arteries from deoxycorticosterone acetate-salt-treated rats, a model of hypersensitized 5-HT 2B receptor function, and produced a rightward shift in the 5-HT-induced response that was consistent with 5-HT 2B receptor antagonism. In summary, vabicaserin is a novel, potent, and selective 5-HT 2C receptor agonist.

High-dose chemotherapy followed by autologous peripheral blood stem cell transplantation is a widely applied treatment for advanced non-Hodgkin lymphoma (NHL), but few studies have analyzed the tolerability and outcomes in older patients compared with younger patients treated in a homogeneous manner. We retrospectively reviewed 152 consecutive patients who underwent autologous stem cell transplantation (ASCT) following BEAM conditioning (carmustine, etoposide, cytarabine, and melphalan) for NHL from January 2000 through August 2004 at our institution. We compared 59 patients age ≥60 years and 93 patients age 20,000/mm3 were similar in younger and older patients, although days to platelet count >50,000/mm3 were longer in the older patients (median 30.0 days versus 22.5 days, P = .01). Patients over the age of 60 were more likely to develop grade III/IV mucositis than their younger counterparts (37.7% versus17.4%, P = .0063). Otherwise, the frequency of other grade III/IV toxicities were similar between younger and older patients. Treatment-related mortality (TRM) was similar between older and younger patients (8.5% versus 5.4%, P = .45). Although age was not associated with TRM, the Charlson Comorbidity Index Score was significantly correlated with TRM (P = .03). Median disease-free survival was similar between older and younger patients (21.8 months versus 29.9 months, P = .93), as was overall survival (OS) (47.7 months versus 62.5 months, P = .20). After controlling for age, the Charlson Comorbidity Index Score influenced OS [P = .013]. Overall, our cohort of patients with NHL over the age of 60 who underwent ASCT following BEAM conditioning experienced toxicities and survival similar to their younger counterparts. Comorbidities significantly influenced TRM and OS in this retrospective cohort. Future study should focus on improving tolerability of conditioning and careful prospective evaluation of comorbidities and their association with outcomes.

Glioblastoma (GBM) is an astrocytic brain tumor characterized by an aggressive clinical course and intense resistance to all therapeutic modalities. Here, we report the identification and functional characterization of Bcl2L12 (Bcl2-like-12) that is robustly expressed in nearly all human primary GBMs examined. Enforced Bcl2L12 expression confers marked apoptosis resistance in primary cortical astrocytes, and, conversely, its RNA interference (RNAi)-mediated knockdown sensitizes human glioma cell lines toward apoptosis in vitro and impairs tumor growth with increased intratumoral apoptosis in vivo. Mechanistically, Bcl2L12 expression does not affect cytochrome c release or apoptosome-driven caspase-9 activation, but instead inhibits post-mitochondrial apoptosis signaling at the level of effector caspase activation. One of Bcl2L12’s mechanisms of action stems from its ability to interact with and neutralize caspase-7. Notably, while enforced Bcl2L12 expression inhibits apoptosis, it also engenders a pronecrotic state, which mirrors the cellular phenotype elicited by genetic or pharmacologic inhibition of post-mitochondrial apoptosis molecules. Thus, Bcl2L12 contributes to the classical tumor biological features of GBM such as intense apoptosis resistance and florid necrosis, and may provide a target for enhanced therapeutic responsiveness of this lethal cancer.

Data from serial renal magnetic resonance imaging of the Consortium of Radiologic Imaging Study of PKD (CRISP) autosomal dominant polycystic kidney disease (PKD) population showed that cystic expansion occurs at a consistent rate per individual, although it is heterogeneous in the population, and that larger kidneys are associated with more rapid disease progression. The significance of gene type to disease progression is analyzed in this study of the CRISP cohort. Gene type was determined in 183 families (219 cases); 156 (85.2%) had PKD1, and 27 (14.8%) had PKD2. PKD1 kidneys were significantly larger, but the rate of cystic growth (PKD1 5.68%/yr; PKD2 4.82%/yr) was not different (P = 0.24). Cyst number increased with age, and more cysts were detected in PKD1 kidneys (P < 0.0001). PKD1 is more severe because more cysts develop earlier, not because they grow faster, implicating the disease gene in cyst initiation but not expansion. These insights will inform the development of targeted therapies in autosomal dominant PKD.

We present evidence that the 5-hydroxytryptamine1A (5-HT1A) receptor antagonist, N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethyl}-N-(2-pyridinyl)cyclohexanecarboxamide (WAY-100635), can induce receptor internalization in a human (h)5-HT1A receptor Chinese hamster ovary (CHO-K1) cell system. Exposure of h5-HT1A CHO cells to WAY-100635 decreased the cell-surface h5-HT1A receptor density in a way that was both time (24–72 h) and concentration (1–100 nm) dependent.[3H]WAY-100635 and [3H]8-hydroxy-dipropylaminotetralin ([3H]8-OH-DPAT) saturation analyses demonstrated a significant reduction (50–60%) in total h5-HT1A receptor number in the WAY-100635-treated (100 nm; 72 h) compared with control cells. In WAY-100635-treated cells, the 8-OH-DPAT-mediated inhibition of forskolin (FSK)-stimulated cAMP accumulation was right-shifted and the maximal inhibitory response of 8-OH-DPAT was impaired compared with control cells. Similar results were obtained for 8-OH-DPAT-mediated Ca2+ mobilization after WAY-100635 treatment. h5-HT1A receptors labeled with [3H]WAY-100635, as well as [3H]4-(2′-Methoxy)-phenyl-1-[2′-(N-2′′-pyridinyl)-p-fluorobenzamido]ethyl-piperazine (MPPF), exhibited a time-dependent rate of cellular internalization that was blocked by endocytotic suppressors and was pertussis-toxin insensitive. In contrast, quantitative autoradiographic studies demonstrated that chronic treatment of rats with WAY-100635 for two weeks produced a region-specific increase in the 5-HT1A receptor density. In conclusion, prolonged exposure of an h5-HT1A cell-based system to the 5-HT1A antagonist, WAY-100635, induced a paradoxical internalization of cell surface receptor resulting in depressed functional activity. This suggests that an antagonist can influence 5-HT1A receptor recycling in vitro differently to in vivo regulatory conditions.

The pharmacological profile of WAY-163909 [(7bR, 10aR)-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta-[b][1,4]diazepino[6,7,1hi]indole], a novel 5-hydroxytryptamine (HT)(2C) (serotonin) receptor-selective agonist is presented. WAY-163909 displaced [(125)I]2,5-dimethoxy-4-iodoamphetamine binding from human 5-HT(2C) receptor sites, in Chinese hamster ovary (CHO) cell membranes, with a K(i) value of 10.5 +/- 1.1 nM. Binding affinities determined for the human 5-HT(2A) and 5-HT(2B) receptor subtypes were 212 and 485 nM, respectively. In functional studies, WAY-163909 stimulated the mobilization of intracellular calcium in CHO cells stably expressing the human 5-HT(2C) receptor with an EC(50) value of 8 nM, and E(max) relative to 5-HT of 90%. WAY-163909 failed to stimulate calcium mobilization in cells expressing the human 5-HT(2A) receptor subtype (EC(50) >> 10muM) and was a 5-HT(2B) receptor partial agonist (EC(50) 185 nM, E(max) 40%). WAY-163909 exhibited negligible affinity (

This article presents models of human phalanges and small joints developed by tissue engineering. Biodegradable polymer scaffolds support growth of osteoblasts, chondrocytes, and tenocytes after implantation of the models in athymic mice. The cell-polymer constructs are vascularized by the host mice, form new bone, cartilage, and tendon with characteristic gene expression and protein synthesis and secretion, and maintain the shape of human phalanges with joints. The study demonstrates critical progress in the design and fabrication of bone, cartilage, and tendon by tissue engineering and the potential of this field for human clinical orthopedic applications.

Using a universal signaling assay employing G-protein chimeras comprising the C-terminal five amino acids of Gi1/2, Gi3, Go, and Gz fused to Gq, the calcium mobilizing G-protein, we explored the role of the C-terminus of Gi family G-proteins as a determinant for 5-HT(1A) receptor functional coupling. Co-expression of the 5-HT(1A) receptor with each of the Gq/Gi family chimeras resulted in a concentration-dependent increase in calcium upon addition of 5-HT, although the coupling efficiency differed dramatically. Gq/Gi3 resulted in the most efficient coupling based on both potency and relative maximum response to 5-HT. Gq/Go also produced efficient coupling in terms of relative 5-HT efficacy (76% of the Gq/Gi3 maximum response), although 5-HT exhibited 4-fold lower agonist potency, and Gq/Gz and Gq/Gi1/2 conferred poor functional coupling. Agonist potencies and relative efficacies determined for a number of 5-HT(1A) receptor agonists using Gq/Gi3 coupling were significantly weaker than those described previously for coupling through the native G-protein. These results indicate the C-terminus of Gi3 as an important determinant for coupling to the 5-HT(1A) receptor, while the reduced functional agonist activities suggest additional motifs participate in receptor/G-protein coupling.

Metabotropic glutamate receptor 7 (mGluR7) remains the most elusive of the eight known mGluRs primarily because of the limited availability of tool compounds to interrogate its potential therapeutic utility. The discovery of N,N'-dibenzhydrylethane-1,2-diamine dihydrochloride (AMN082) as the first orally active, brain-penetrable, mGluR7-selective allosteric agonist by Mitsukawa and colleagues (Proc Natl Acad Sci USA 102:18712-18717, 2005) provides a means to investigate this receptor system directly. AMN082 demonstrates mGluR7 agonist activity in vitro and interestingly has a behavioral profile that supports utility across a broad spectrum of psychiatric disorders including anxiety and depression. The present studies were conducted to extend the in vitro and in vivo characterization of AMN082 by evaluating its pharmacokinetic and metabolite profile. Profiling of AMN082 in rat liver microsomes revealed rapid metabolism (t(1/2) < 1 min) to a major metabolite, N-benzhydrylethane-1,2-diamine (Met-1). In vitro selectivity profiling of Met-1 demonstrated physiologically relevant transporter binding affinity at serotonin transporter (SERT), dopamine transporter (DAT), and norepinephrine transporter (NET) (323, 3020, and 3410 nM, respectively); whereas the parent compound AMN082 had appreciable affinity at NET (1385 nM). AMN082 produced antidepressant-like activity and receptor occupancy at SERT up to 4 h postdose, a time point at which AMN082 is significantly reduced in brain and plasma while the concentration of Met-1 continues to increase in brain. Acute Met-1 administration produced antidepressant-like activity as would be expected from its in vitro profile as a mixed SERT, NET, DAT inhibitor. Taken together, these data suggest that the reported in vivo actions of AMN082 should be interpreted with caution, because they may involve other mechanisms in addition to mGluR7.

The ECE Dept. at the University of Alberta uses Tablet PCs as a key resource in the Software Engineering capstone design course. We are currently developing a survey instrument (piloted in 2009) to measure the utility of these Tablets. The instrument is based on technology adoption theory, which posits that specific psychological states are antecedents to the usage of a new technology. We perform an exploratory factor analysis of the pilot survey, with an emphasis on our operationalization of the construct of Use of the Technology. However, small-sample-size effects prevent us from fully validating the model.

Novel 5-cyclic amine-3-arylsulfonylindazoles were prepared, and several analogues within this class have been identified as high-affinity 5-HT(6) receptor ligands with improved pharmacokinetic and pharmacological properties. One selected example, 18b, showed good brain penetrability and a generally favorable pharmacokinetic profile with procognitive efficacy in the rat novel object recognition assay. The synthesis and structure-activity relationship of this potent class are discussed.

A dihydroquinolinone moiety was found to be a potent serotonin reuptake inhibitor pharmacophore when combined with certain amines. This fragment was coupled with selected D2 ligands to prepare a series of dual acting compounds with attractive in vitro profiles as dopamine D2 partial agonists and serotonin reuptake inhibitors. Structure–activity studies revealed that the linker plays a key role in contributing to D2 affinity, function, and SRI activity.

Biogenic amines such as norepinephrine, dopamine, and serotonin play a well-described role in the treatment of mood disorders and some types of pain. As alpha2A-adrenoceptors regulate the release of these neurotransmitters, we examined the therapeutic potential of BRL 44408, a potent (Ki=8.5 nM) and selective (>50-fold) alpha2A-adrenoceptor antagonist (K(B)=7.9 nM). In rats, BRL 44408 penetrated the central nervous system resulting in peak brain and plasma concentrations of 586 ng/g and 1124 ng/ml, respectively. In a pharmacodynamic assay, pretreatment with BRL 44408 to rats responding under a fixed-ratio 30 operant response paradigm resulted in a rightward shift of the clonidine dose-response curve, an effect indicative of alpha2-adrenoceptor antagonism in vivo. Consistent with presynaptic autoreceptor antagonism and tonic regulation of neurotransmitter release, acute administration of BRL 44408 elevated extracellular concentrations of norepinephrine and dopamine, but not serotonin, in the medial prefrontal cortex. Additionally, BRL 44408, probably by inhibiting alpha2A heteroceptors, produced a significant increase in cortical levels of acetylcholine. In the forced swim test and schedule-induced polydipsia assay, BRL 44408 produced an antidepressant-like response by dose-dependently decreasing immobility time and adjunctive water intake, respectively, while in a model of visceral pain, BRL 44408 exhibited analgesic activity by decreasing para-phenylquinone (PPQ)-induced abdominal stretching. Finally, BRL 44408 did not produce deficits in overall motor coordination nor alter general locomotor activity. This preclinical characterization of the neurochemical and behavioural profile of BRL 44408 suggests that selective antagonism of alpha2A-adrenoceptors may represent an effective treatment strategy for mood disorders and visceral pain.

A 5-fluoro-tetrahydrocarbazole serotonin reuptake inhibitor (SRI) building block was combined with a variety of linkers and dopamine D2 receptor ligands in an attempt to identify potent D2 partial agonist/SRI molecules for treatment of schizophrenia. This approach has the potential to treat a broader range of symptoms compared to existing therapies. Selected compounds in this series demonstrate high affinity for both targets and D2 partial agonism in cell-based and in vivo assays.

Background The antimyeloma agent bortezomib functions as an inhibitor of nuclear factor (NF)–κB. Although NF-κB inhibition is predicted to affect osteoclast function, preclinical and clinical studies have primarily reported an effect on osteoblasts. Patients and Methods We examined parameters of bone turnover prospectively in patients with multiple myeloma treated with bortezomib before and after autologous transplantation. Thirty-nine patients received 2 cycles of bortezomib on days 1, 4, 8, and 11 of a 21-day cycle. After high-dose melphalan with autologous stem cell transplantation, bortezomib 1.3 mg/m 2 on days 1, 8, 15, and 22 of a 5-week cycle was administered as maintenance therapy. Results During posttransplantation bortezomib, decreases in the urinary excretion of collagen N-telopeptide indicated that bortezomib suppresses osteoclast function. Conclusion The effects on osteoclasts occurred in the absence of bisphosphonate treatment and independently of changes in monoclonal protein levels. Further studies exploring the role of bortezomib as a bone protective agent could be warranted.

We present evidence that the 5-hydroxytryptamine(1A) (5-HT(1A)) receptor antagonist, N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethyl}-N-(2-pyridinyl)cyclohexanecarboxamide (WAY-100635), can induce receptor internalization in a human (h)5-HT(1A) receptor Chinese hamster ovary (CHO-K1) cell system. Exposure of h5-HT(1A) CHO cells to WAY-100635 decreased the cell-surface h5-HT(1A) receptor density in a way that was both time (24-72 h) and concentration (1-100 nm) dependent.[(3)H]WAY-100635 and [(3)H]8-hydroxy-dipropylaminotetralin ([(3)H]8-OH-DPAT) saturation analyses demonstrated a significant reduction (50-60%) in total h5-HT(1A) receptor number in the WAY-100635-treated (100 nm; 72 h) compared with control cells. In WAY-100635-treated cells, the 8-OH-DPAT-mediated inhibition of forskolin (FSK)-stimulated cAMP accumulation was right-shifted and the maximal inhibitory response of 8-OH-DPAT was impaired compared with control cells. Similar results were obtained for 8-OH-DPAT-mediated Ca(2+) mobilization after WAY-100635 treatment. h5-HT(1A) receptors labeled with [(3)H]WAY-100635, as well as [(3)H]4-(2'-Methoxy)-phenyl-1-[2'-(N-2''-pyridinyl)-p-fluorobenzamido]ethyl-piperazine (MPPF), exhibited a time-dependent rate of cellular internalization that was blocked by endocytotic suppressors and was pertussis-toxin insensitive. In contrast, quantitative autoradiographic studies demonstrated that chronic treatment of rats with WAY-100635 for two weeks produced a region-specific increase in the 5-HT(1A) receptor density. In conclusion, prolonged exposure of an h5-HT(1A) cell-based system to the 5-HT(1A) antagonist, WAY-100635, induced a paradoxical internalization of cell surface receptor resulting in depressed functional activity. This suggests that an antagonist can influence 5-HT(1A) receptor recycling in vitro differently to in vivo regulatory conditions.

WAY-161503 ((4a R )-8,9-dichloro-2,3,4,4a-tetrahydro-1 H -pyrazino[1,2-a]quinoxalin-5(6 H )-one), a 5-HT 2B/C receptor agonist, was characterized in vitro using stable Chinese hamster ovary cell lines expressing each of the human 5-HT 2 receptors and in vivo in animal models of obesity. WAY-161503 displaced both agonist ([ 125 I]2,5-dimethoxy-4-iodoamphetamine (DOI)) and antagonist ([ 3 H]mesulergine) radioligand binding to the human 5-HT 2C receptor with derived Ki values of 3.3 ± 0.9 and 32 ± 6 nM, respectively. Relative to 5-HT 2C receptor binding, WAY-161503 was approximately 6-fold less potent at human 5-HT 2A receptors ([ 125 I]DOI) with a derived Ki value of 18 nM and 20-fold less potent at human 5-HT 2B receptors ([ 3 H]5-HT) with a derived Ki value of 60 nM. In functional studies, WAY-161503 was a full agonist in stimulating 5-HT 2C -receptor-coupled [ 3 H]inositol phosphate (IP) formation and calcium mobilization with EC 50 values of 8.5 nM and 0.8 nM, respectively. WAY-161503 was also a 5-HT 2B agonist (EC 50 s of 6.9 and 1.8 nM for IP and calcium, respectively). In IP studies, WAY-161503 was a weak 5-HT 2A partial agonist (EC 50 , 802 nM) yet potently stimulated calcium mobilization (EC 50 , 7 nM) in 5-HT 2A receptor-expressing cells. Functionally, WAY-161503 also stimulated the phospholipase A 2 -coupled arachidonic acid release in 5-HT 2C receptor expressing cells albeit with lower potency (EC 50 , 38 nM) and efficacy (Emax, 77%) compared with activation of the PLC pathway. In vivo, WAY-161503 produced dose-dependent decreases in 2-h food intake in 24 h fasted normal Sprague–Dawley rats, diet-induced obese mice, and obese Zuker rats with ED 50 values of 1.9 mg/kg, 6.8 mg/kg, and 0.73 mg/kg, respectively. The reduction in food intake in normal Sprague–Dawley rats was reversed by administration of the 5-HT 2C receptor antagonist SB-242084. Following chronic administration (10 days) in growing Sprague–Dawley rats, WAY-161503 decreased food intake and attenuated body weight gain. Finally, following chronic administration (15 days) of WAY-161503 to obese Zuker rats, the rats maintained a 30% decrease in food intake over the 15-day period combined with a 25 g decrease in body weight relative to vehicle-treated controls demonstrating a lack of tolerance to its anorectic effects.

The pancreatic adenocarcinoma genome harbors multiple amplifications and deletions, pointing to the existence of numerous oncogenes and tumor suppressor genes driving the genesis and progression of this lethal cancer. Here, array comparative genomic hybridization on a cDNA microarray platform and informatics tools have been used to define the copy number alterations in a panel of 24 pancreatic adenocarcinoma cell lines and 13 primary tumor specimens. This high-resolution genomic analysis has identified all known regional gains and losses as well as many previously uncharacterized highly recurrent copy number alterations. A systematic prioritization scheme has selected 64 focal minimal common regions (MCRs) of recurrent copy number change. These MCRs possess a median size of 2.7 megabases (Mb), with 21 (33%) MCRs spanning 1 Mb or less (median of 0.33 Mb) and possessing an average of 15 annotated genes. Furthermore, complementary expression profile analysis of a significant fraction of the genes residing within these 64 prioritized MCRs has enabled the identification of a subset of candidates with statistically significant association between gene dosage and mRNA expression. Thus, the integration of DNA and RNA profiles provides a highly productive entry point for the discovery of genes involved in the pathogenesis of pancreatic adenocarcinoma.

Gene expression of osteopontin (OPN) has been investigated in mice by application of laser capture microdissection (LCM) and reverse transcriptase-polymerase chain reaction (RT-PCR) analysis. LCM permits individual cells to be isolated ("captured") from tissue sections for molecular analyses. In this study, chondrocytes were captured from growth plate zones in frozen sections of tibiae from 1-11-day-old postnatal mice. RNA was extracted from cells, DNAse-treated, and reverse-transcribed. cDNA was amplified by PCR and OPN mRNA was revealed on agarose gels. Whole cartilage and brain (a positive control) from the same animals also were examined. Reactions containing no RT were negative controls, and 18S rRNA standardized expressed message from captured cells. RT-PCR analysis of laser-captured whole cartilage showed a general qualitative loss of OPN mRNA as animal age increased. Youngest mice gave equivalent OPN expression over all laser-microdissected cartilage zones. For 7-11 day-old mice, OPN expression was qualitatively greatest in resting and lowest in hypertrophic regions of cartilage. Expression of OPN correlated with mineral in the tissue suggests that OPN functionally may inhibit normal vertebrate growth plate mineralization, and its loss with increasing tissue maturation appears permissive to mineral development.

Growth of InAs epitaxial layers on GaAs (001 ) by migration-enhanced epitaxy (MEE) and molecular beam epitaxy (MBE) has been studied. Reflection high-energy-electron diffraction (RHEED) patterns were studied, and persistent RHEED intensity oscillations were observed during MEE growth of InAs. The dependence of RHEED oscillation on MEE growth parameters is discussed. InAs layers grown by MEE at low substrate temperature exhibit comparable quality as MBE layers grown at higher substrate temperature.

Multiple Myeloma (MM) is characterized by a clonal proliferation of abnormal plasma cells in the bone marrow and is among the most frequent and lethal hematological diseases. In spite of significant effort towards the identification of the molecular events leading to this malignancy, the genetic alterations responsible for the pathogenesis of this disease remain poorly understood. Regional copy number alterations (CNAs) in cancer genomes have been among the most informative structural changes in cancer and have led to the discovery of many oncogenes and tumor supressor genes. Using array comparative genomic hybridization (array-CGH) and expression microarray technologies we have analyzed a large collection of cell lines and clinically annotated primary tumors. This high-resolution genomic analysis has identified all previously reported regional gains and losses as well as many novel highly recurrent genetic loci with potential biological and clinical relevance. In particular, we have identified an amplification at chromosome 1q21 as one of the most recurrent genetic changes in cell lines and in a subgroup of primary tumors. This chromosomal change has been previously implicated with disease progression. Analysis across several cell lines has allowed the identification of a Minimal Common Region (MCRs) of amplification at 1q21. Correlation between DNA copy number changes and expression profiling data has identified a limited set of candidate genes within this MCR that are amplified and overexpressed. Using shRNAi technology we have identified BCL-9 as a candidate gene residing at the 1q21 MCR. In vitro and in vivo functional data about the role of BL-9 will be presented. These data will provide critical understanding on the diverse pathways leading to Multiple Myeloma progression.