The newcastle 85+ study

Background: Low vitamin D status is common in very old adults which may have adverse consequences for muscle function, a major predictor of disability. Aims: To explore the association between 25-hydroxyvitamin D [25(OH)D] concentrations and disability trajectories in very old adults and to determine whether there is an ‘adequate’ 25(OH)D concentration which might protect against a faster disability trajectory. Methodology: A total of 775 participants from the Newcastle 85+ Study for who 25(OH)D concentration at baseline was available. Serum 25(OH)D concentrations of 50 nmol/L were used as cut-offs to define low, moderate and high vitamin D status, respectively. Disability was defined as difficulty in performing 17 activities of daily living, at baseline, after 18, 36 and 60 months. Results: A three-trajectory model was derived (low-to-mild, mild-to-moderate and moderate-to-severe). In partially adjusted models, participants with 25(OH)D concentrations <25 nmol/L were more likely to have moderate and severe disability trajectories, even after adjusting for sex, living in an institution, season, cognitive status, BMI and vitamin D supplement use. However, this association disappeared after further adjustment for physical activity. Conclusions: Vitamin D status does not appear to influence the trajectories of disability in very old adults.publishersversionpublishe

Capability and dependency in the Newcastle 85+ cohort study. Projections of future care needs

<p>Abstract</p> <p>Background</p> <p>Little is known of the capabilities of the oldest old, the fastest growing age group in the population. We aimed to estimate capability and dependency in a cohort of 85 year olds and to project future demand for care.</p> <p>Methods</p> <p>Structured interviews at age 85 with 841 people born in 1921 and living in Newcastle and North Tyneside, UK who were permanently registered with participating general practices. Measures of capability included were self-reported activities of daily living (ADL), timed up and go test (TUG), standardised mini-mental state examination (SMMSE), and assessment of urinary continence in order to classify interval-need dependency. To project future demand for care the proportion needing 24-hour care was applied to the 2008 England and Wales population projections of those aged 80 years and over by gender.</p> <p>Results</p> <p>Of participants, 62% (522/841) were women, 77% (651/841) lived in standard housing, 13% (106/841) in sheltered housing and 10% (84/841) in a care home. Overall, 20% (165/841) reported no difficulty with any of the ADLs. Men were more capable in performing ADLs and more independent than women. TUG validated self-reported ADLs. When classified by 'interval of need' 41% (332/810) were independent, 39% (317/810) required help less often than daily, 12% (94/810) required help at regular times of the day and 8% (67/810) required 24-hour care. Of care-home residents, 94% (77/82) required daily help or 24-hour care. Future need for 24-hour care for people aged 80 years or over in England and Wales is projected to increase by 82% from 2010 to 2030 with a demand for 630,000 care-home places by 2030.</p> <p>Conclusions</p> <p>This analysis highlights the diversity of capability and levels of dependency in this cohort. A remarkably high proportion remain independent, particularly men. However a significant proportion of this population require 24-hour care at home or in care homes. Projections for the next 20 years suggest substantial increases in the number requiring 24-hour care due to population ageing and a proportionate increase in demand for care-home places unless innovative health and social care interventions are found.</p

Clinical validation of the EndoPredict test in node-positive, chemotherapy-treated ER+/HER2− breast cancer patients: results from the GEICAM 9906 trial

INTRODUCTION: EndoPredict (EP) is an RNA-based multigene test that predicts the likelihood of distant recurrence in patients with estrogen receptor-positive (ER+), human epidermal growth factor receptor 2–negative (HER2−) breast cancer (BC) who are being treated with adjuvant endocrine therapy. Herein we report the prospective-retrospective clinical validation of EP in the node-positive, chemotherapy-treated, ER+/HER2− BC patients in the GEICAM 9906 trial. METHODS: The patients (N = 1,246) were treated either with six cycles of fluorouracil, epirubicin and cyclophosphamide (FEC) or with four cycles of FEC followed by eight weekly courses of paclitaxel (FEC-P), as well as with endocrine therapy if they had hormone receptor–positive disease. The patients were assigned to EP risk categories (low or high) according to prespecified cutoff levels. The primary endpoint in the clinical validation of EP was distant metastasis-free survival (MFS). Metastasis rates were estimated using the Kaplan-Meier method, and multivariate analysis was performed using Cox regression. RESULTS: The molecular EP score and the combined molecular and clinical EPclin score were successfully determined in 555 ER+/HER2− tumors from the 800 available samples in the GEICAM 9906 trial. On the basis of the EP, 25% of patients (n = 141) were classified as low risk. MFS was 93% in the low-risk group and 70% in the high-risk group (absolute risk reduction = 23%, hazard ratio (HR) = 4.8, 95% confidence interval (CI) = 2.5 to 9.5; P < 0.0001). Multivariate analysis showed that, in this ER+/HER2− cohort, EP results are an independent prognostic parameter after adjustment for age, grade, lymph node status, tumor size, treatment arm, ER and progesterone receptor (PR) status and proliferation index (Ki67). Using the predefined EPclin score, 13% of patients (n = 74) were assigned to the low-risk group, who had excellent outcomes and no distant recurrence events (absolute risk reduction vs high-risk group = 28%; P < 0.0001). Furthermore, EP was prognostic in premenopausal patients (HR = 6.7, 95% CI = 2.4 to 18.3; P = 0.0002) and postmenopausal patients (HR = 3.3, 95% CI = 1.3 to 8.5; P = 0.0109). There were no statistically significant differences in MFS between treatment arms (FEC vs FEC-P) in either the high- or low-risk groups. The interaction test results between the chemotherapy arm and the EP score were not significant. CONCLUSIONS: EP is an independent prognostic parameter in node-positive, ER+/HER2− BC patients treated with adjuvant chemotherapy followed by hormone therapy. EP did not predict a greater efficacy of FEC-P compared to FEC alone

Hyperhomocysteinemia in liver cirrhosis: mechanisms and role in vascular and hepatic fibrosis

Numerous clinical and epidemiological studies have identified elevated homocysteine levels in plasma as a risk factor for atherosclerotic vascular disease and thromboembolism. Hyperhomocysteinemia may develop as a consequence of defects in homocysteine-metabolizing genes; nutritional conditions leading to vitamin B(6), B(12), or folate deficiencies; or chronic alcohol consumption. Homocysteine is an intermediate in methionine metabolism, which takes place mainly in the liver. Impaired liver function leads to altered methionine and homocysteine metabolism; however, the molecular basis for such alterations is not completely understood. In addition, the mechanisms behind homocysteine-induced cellular toxicity are not fully defined. In the present work, we have examined the expression of the main enzymes involved in methionine and homocysteine metabolism, along with the plasma levels of methionine and homocysteine, in the liver of 26 cirrhotic patients and 10 control subjects. To gain more insight into the cellular effects of elevated homocysteine levels, we have searched for changes in gene expression induced by this amino acid in cultured human vascular smooth muscle cells. We have observed a marked reduction in the expression of the main genes involved in homocysteine metabolism in liver cirrhosis. In addition, we have identified the tissue inhibitor of metalloproteinases-1 and alpha1(I)procollagen to be upregulated in vascular smooth muscle cells and liver stellate cells exposed to pathological concentrations of homocysteine. Taken together, our observations suggest (1) impaired liver function could be a novel determinant in the development of hyperhomocysteinemia and (2) a role for elevated homocysteine levels in the development of liver fibrosis

Altered striatal endocannabinoid signaling in a transgenic mouse model of spinocerebellar ataxia type-3

Spinocerebellar ataxia type-3 (SCA-3) is the most prevalent autosomal dominant inherited ataxia. We recently found that the endocannabinoid system is altered in the post-mortem cerebellum of SCA-3 patients, and similar results were also found in the cerebellar and brainstem nuclei of a SCA-3 transgenic mouse model. Given that the neuropathology of SCA-3 is not restricted to these two brain regions but rather, it is also evident in other structures (e.g., the basal ganglia), we studied the possible changes to endocannabinoid signaling in the striatum of these transgenic mice. SCA-3 mutant mice suffer defects in motor coordination, balance and they have an abnormal gait, reflecting a cerebellar/brainstem neuropathology. However, they also show dystonia-like behavior (limb clasping) that may be related to the malfunction/deterioration of specific neurons in the striatum. Indeed, we found a loss of striatal projecting neurons in SCA-3 mutant mice, accompanied by a reduction in glial glutamate transporters that could potentially aggravate excitotoxic damage. In terms of endocannabinoid signaling, no changes in CB2 receptors were evident, yet an important reduction in CB1 receptors was detected by qPCR and immunostaining. The reduction in CB1 receptors was presumed to occur in striatal afferent and efferent neurons, also potentially aggravating excitotoxicity. We also measured the endocannabinoid lipids in the striatum and despite a marked increase in the FAAH enzyme in this area, no overall changes in these lipids were found. Collectively, these studies confirm that the striatal endocannabinoid system is altered in SCA-3 mutant mice, adding to the equivalent changes found in other strongly affected CNS structures in this type of ataxia (i.e.: the cerebellum and brainstem). These data open the way to search for drugs that might correct these changes.Funding: This study has been supported: (i) by MICINN (SAF2009-11847 and SAF2015-68580-C2-1-R), CIBERNED (CB06/05/0089) and “Fundación Eugenio Rodríguez Pascual”, to JFR; (ii) by the Research and Education Component of the Advancing a Healthier Wisconsin Endowment at the Medical College of Wisconsin, to CJH; and (iii) by Fundação para a Ciência e Tecnologia through the project POCI-01-0145-FEDER-016818 (PTDC/NEU-NMC/3648/2014) and co-financed by the Portuguese North Regional Operational Program (ON.2 – O Novo Norte) under the National Strategic Reference Framework (QREN), through the European Regional Development Fund (FEDER), to PM. Carmen Rodríguez-Cueto was a predoctoral fellow supported by FPI Program-Ministry of Science. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.info:eu-repo/semantics/publishedVersio

The Effect of a Physical Activity Program on the Total Number of Primary Care Visits in Inactive Patients: A 15-Month Randomized Controlled Trial

Abstract Background: Effective promotion of exercise could result in substantial savings in healthcare cost expenses in terms of direct medical costs, such as the number of medical appointments. However, this is hampered by our limited knowledge of how to achieve sustained increases in physical activity. Objectives: To assess the effectiveness of a Primary Health Care (PHC) based physical activity program in reducing the total number of visits to the healthcare center among inactive patients, over a 15-month period. Research Design: Randomized controlled trial. Subjects: Three hundred and sixty-two (n = 362) inactive patients suffering from at least one chronic condition were included. One hundred and eighty-three patients (n = 183; mean (SD); 68.3 (8.8) years; 118 women) were randomly allocated to the physical activity program (IG). One hundred and seventy-nine patients (n = 179; 67.2 (9.1) years; 106 women) were allocated to the control group (CG). The IG went through a three-month standardized physical activity program led by physical activity specialists and linked to community resources. Measures: The total number of medical appointments to the PHC, during twelve months before and after the program, was registered. Self-reported health status (SF-12 version 2) was assessed at baseline (month 0), at the end of the intervention (month 3), and at 12 months follow-up after the end of the intervention (month 15). Results: The IG had a significantly reduced number of visits during the 12 months after the intervention: 14.8 (8.5). The CG remained about the same: 18.2 (11.1) (P = .002). Conclusions: Our findings indicate that a 3-month physical activity program linked to community resources is a shortduration, effective and sustainable intervention in inactive patients to decrease rates of PHC visits. Trial Registration: ClinicalTrials.gov NCT0071483

The Newcastle 85+ study: biological, clinical and psychosocial factors associated with healthy ageing: study protocol

<p>Abstract</p> <p>Background</p> <p>The UK, like other developed countries, is experiencing a marked change in the age structure of its population characterised by increasing life expectancy and continuing growth in the older fraction of the population. There is remarkably little up-to-date information about the health of the <it>oldest old </it>(over 85 years), demographically the fastest growing section of the population. There is a need, from both a policy and scientific perspective, to describe in detail the health status of this population and the factors that influence individual health trajectories. For a very large proportion of medical conditions, age is the single largest risk factor. Gaining new knowledge about why aged cells and tissues are more vulnerable to pathology is likely to catalyse radical new insights and opportunities to intervene. The aims of the Newcastle 85+ Study are to expose the spectrum of health within an inception cohort of 800 85 year-olds; to examine health trajectories and outcomes as the cohort ages and their associations with underlying biological, medical and social factors; and to advance understanding of the biological nature of ageing.</p> <p>Methods</p> <p>A cohort of 800 85 year olds from Newcastle and North Tyneside will be recruited at baseline and followed until the last participant has died. Eligible individuals will be <it>all </it>those who turn 85 during the year 2006 (i.e. born in 1921) and who are registered with a Newcastle or North Tyneside general practice. Participants will be visited in their current residence (own home or institution) by a research nurse at baseline, 18 months and 36 months. The assessment protocol entails a detailed multi-dimensional health assessment together with review of general practice medical records. Participants will be flagged with the NHS Central Register to provide details of the date and cause of death.</p> <p>Discussion</p> <p>The Newcastle 85+ Study will address key questions about health and health-maintenance in the 85+ population, with a particular focus on quantitative assessment of factors underlying variability in health, and on the relationships between health, nutrition and biological markers of the fundamental processes of ageing.</p

Measurement of σ(Λb)/σ(B0)×BR(Λb→Λcπ−)/BR(B0→D+π−)\sigma(\Lambda_b)/\sigma(B^0) \times BR(\Lambda_b\to\Lambda_c\pi^-) / BR(B^0\to D^+\pi^-) in ppˉp\bar{p} Collisions at s=1.96\sqrt{s}=1.96 TeV

We present the first observation of the baryon decay $\Lambda_b\to\Lambda_c\pi^-$ followed by $\Lambda_c\to p K^-\pi^+$ in 106 pb-1 of $p\bar{p}$ collisions at $\sqrt{s} = 1.96$ TeV in the CDF experiment. In order to reduce systematic error, the measured rate for $\Lambda_b$ decay is normalized to the kinematically similar meson decay $B^0\to D^+\pi^-$ followed by $D^+\to\pi^+K^-\pi^+$. We report the ratio of production cross sections ($\sigma$) times the ratio of branching fractions (BR) for the momentum region integrated above $p_T > 6$ GeV/c and pseudorapidity range $|\eta| < 1.3$: $\sigma(p\bar{p}\to \Lambda_b X) / \sigma (p\bar{p}\to B^0 X) \times BR(\Lambda_b\to\Lambda_c\pi^-) / BR(B^0\to D^+\pi^-) = 0.82 \pm 0.08(stat) \pm 0.11(syst) \pm 0.22 (BR(\Lambda_c\to p K^-\pi^+))$.Comment: Submitted to Phys.Rev.Let

Macrophages direct cancer cells through a LOXL2-mediated metastatic cascade in pancreatic ductal adenocarcinoma

[Objective]: The lysyl oxidase-like protein 2 (LOXL2) contributes to tumour progression and metastasis in different tumour entities, but its role in pancreatic ductal adenocarcinoma (PDAC) has not been evaluated in immunocompetent in vivo PDAC models.[Design]: Towards this end, we used PDAC patient data sets, patient-derived xenograft in vivo and in vitro models, and four conditional genetically-engineered mouse models (GEMMS) to dissect the role of LOXL2 in PDAC. For GEMM-based studies, K-Ras +/LSL-G12D;Trp53 LSL-R172H;Pdx1-Cre mice (KPC) and the K-Ras +/LSL-G12D;Pdx1-Cre mice (KC) were crossed with Loxl2 allele floxed mice (Loxl2Exon2 fl/fl) or conditional Loxl2 overexpressing mice (R26Loxl2 KI/KI) to generate KPCL2KO or KCL2KO and KPCL2KI or KCL2KI mice, which were used to study overall survival; tumour incidence, burden and differentiation; metastases; epithelial to mesenchymal transition (EMT); stemness and extracellular collagen matrix (ECM) organisation.[Results]: Using these PDAC mouse models, we show that while Loxl2 ablation had little effect on primary tumour development and growth, its loss significantly decreased metastasis and increased overall survival. We attribute this effect to non-cell autonomous factors, primarily ECM remodelling. Loxl2 overexpression, on the other hand, promoted primary and metastatic tumour growth and decreased overall survival, which could be linked to increased EMT and stemness. We also identified tumour-associated macrophage-secreted oncostatin M (OSM) as an inducer of LOXL2 expression, and show that targeting macrophages in vivo affects Osm and Loxl2 expression and collagen fibre alignment.[Conclusion]: Taken together, our findings establish novel pathophysiological roles and functions for LOXL2 in PDAC, which could be potentially exploited to treat metastatic disease.JCL-G received support from a 'la Caixa' Foundation (ID 100010434) fellowship (LCF/BQ/DR21/11880011). This study was supported by ISCIII FIS grants PI18/00757 and PI21/01110 (BSJ) and PI18/00267 (LG-B), and grants from the Spanish Ministry of Economy and Innovation SAF2016-76504-R (ACan and FP), PID2019-111052RB-I00 (FP), PID2019-104644RB-I00 (GM-B), a Ramón y Cajal Merit Award RYC-2012–12104 (BSJ) and ISCIII, CIBERONC, CB16/12/00446 (ACar) and CB16/12/00295 (ACan and GM-B), all of them co-financed through Fondo Europeo de Desarrollo Regional (FEDER) 'Una manera de hacer Europa'; a Fero Foundation Grant (BSJ); a Coordinated grant (GC16173694BARB) from the Fundación Científica Asociación Española Contra el Cáncer (FC-AECC) (BSJ); a Miguel Servet award (CP16/00121) (PS); a DFG, German Research Foundation Grant—Project no: 492 436 553 (KG); and a Max Eder Fellowship of the German Cancer Aid (111746) (PCH

Are ‘Endurance’ Alleles ‘Survival’ Alleles? Insights from the ACTN3 R577X Polymorphism

Exercise phenotypes have played a key role for ensuring survival over human evolution. We speculated that some genetic variants that influence exercise phenotypes could be associated with exceptional survival (i.e. reaching ≥100years of age). Owing to its effects on muscle structure/function, a potential candidate is the Arg(R)577Ter(X) polymorphism (rs1815739) in ACTN3, the structural gene encoding the skeletal muscle protein α-actinin-3. We compared the ACTN3 R577X genotype/allele frequencies between the following groups of ethnically-matched (Spanish) individuals: centenarians (cases, n = 64; 57 female; age range: 100–108 years), young healthy controls (n = 283, 67 females, 216 males; 21±2 years), and humans who are at the two end-points of exercise capacity phenotypes, i.e. muscle endurance (50 male professional road cyclists) and muscle power (63 male jumpers/sprinters). Although there were no differences in genotype/allele frequencies between centenarians (RR:28.8%; RX:47.5%; XX:23.7%), and controls (RR:31.8%; RX:49.8%; XX:18.4%) or endurance athletes (RR:28.0%; RX:46%; XX:26.0%), we observed a significantly higher frequency of the X allele (P = 0.019) and XX genotype (P = 0.011) in centenarians compared with power athletes (RR:47.6%; RX:36.5%;XX:15.9%). Notably, the frequency of the null XX (α-actinin-3 deficient) genotype in centenarians was the highest ever reported in non-athletic Caucasian populations. In conclusion, despite there were no significant differences with the younger, control population, overall the ACTN3 genotype of centenarians resembles that of world-class elite endurance athletes and differs from that of elite power athletes. Our preliminary data would suggest a certain ‘survival’ advantage brought about by α-actinin-3 deficiency and the ‘endurance’/oxidative muscle phenotype that is commonly associated with this condition