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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.

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.

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.

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.

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.

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.

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 (

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.

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.

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.