Physical Frailty: ICFSR International Clinical Practice Guidelines for Identification and Management.

OBJECTIVE: The task force of the International Conference of Frailty and Sarcopenia Research (ICFSR) developed these clinical practice guidelines to overview the current evidence-base and to provide recommendations for the identification and management of frailty in older adults. METHODS: These recommendations were formed using the GRADE approach, which ranked the strength and certainty (quality) of the supporting evidence behind each recommendation. Where the evidence-base was limited or of low quality, Consensus Based Recommendations (CBRs) were formulated. The recommendations focus on the clinical and practical aspects of care for older people with frailty, and promote person-centred care. Recommendations for Screening and Assessment: The task force recommends that health practitioners case identify/screen all older adults for frailty using a validated instrument suitable for the specific setting or context (strong recommendation). Ideally, the screening instrument should exclude disability as part of the screening process. For individuals screened as positive for frailty, a more comprehensive clinical assessment should be performed to identify signs and underlying mechanisms of frailty (strong recommendation). Recommendations for Management: A comprehensive care plan for frailty should address polypharmacy (whether rational or nonrational), the management of sarcopenia, the treatable causes of weight loss, and the causes of exhaustion (depression, anaemia, hypotension, hypothyroidism, and B12 deficiency) (strong recommendation). All persons with frailty should receive social support as needed to address unmet needs and encourage adherence to a comprehensive care plan (strong recommendation). First-line therapy for the management of frailty should include a multi-component physical activity programme with a resistance-based training component (strong recommendation). Protein/caloric supplementation is recommended when weight loss or undernutrition are present (conditional recommendation). No recommendation was given for systematic additional therapies such as cognitive therapy, problem-solving therapy, vitamin D supplementation, and hormone-based treatment. Pharmacological treatment as presently available is not recommended therapy for the treatment of frailty.

International Clinical Practice Guidelines for Sarcopenia (ICFSR): Screening, Diagnosis and Management.

OBJECTIVES: Sarcopenia, defined as an age-associated loss of skeletal muscle function and muscle mass, occurs in approximately 6 - 22 % of older adults. This paper presents evidence-based clinical practice guidelines for screening, diagnosis and management of sarcopenia from the task force of the International Conference on Sarcopenia and Frailty Research (ICSFR). METHODS: To develop the guidelines, we drew upon the best available evidence from two systematic reviews paired with consensus statements by international working groups on sarcopenia. Eight topics were selected for the recommendations: (i) defining sarcopenia; (ii) screening and diagnosis; (iii) physical activity prescription; (iv) protein supplementation; (v) vitamin D supplementation; (vi) anabolic hormone prescription; (vii) medications under development; and (viii) research. The ICSFR task force evaluated the evidence behind each topic including the quality of evidence, the benefit-harm balance of treatment, patient preferences/values, and cost-effectiveness. Recommendations were graded as either strong or conditional (weak) as per the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. Consensus was achieved via one face-to-face workshop and a modified Delphi process. RECOMMENDATIONS: We make a conditional recommendation for the use of an internationally accepted measurement tool for the diagnosis of sarcopenia including the EWGSOP and FNIH definitions, and advocate for rapid screening using gait speed or the SARC-F. To treat sarcopenia, we strongly recommend the prescription of resistance-based physical activity, and conditionally recommend protein supplementation/a protein-rich diet. No recommendation is given for Vitamin D supplementation or for anabolic hormone prescription. There is a lack of robust evidence to assess the strength of other treatment options.

Building Bridges for Innovation in Ageing: Synergies between Action Groups of the EIP on AHA.

The Strategic Implementation Plan of the European Innovation Partnership on Active and Healthy Ageing (EIP on AHA) proposed six Action Groups. After almost three years of activity, many achievements have been obtained through commitments or collaborative work of the Action Groups. However, they have often worked in silos and, consequently, synergies between Action Groups have been proposed to strengthen the triple win of the EIP on AHA. The paper presents the methodology and current status of the Task Force on EIP on AHA synergies. Synergies are in line with the Action Groups' new Renovated Action Plan (2016-2018) to ensure that their future objectives are coherent and fully connected. The outcomes and impact of synergies are using the Monitoring and Assessment Framework for the EIP on AHA (MAFEIP). Eight proposals for synergies have been approved by the Task Force: Five cross-cutting synergies which can be used for all current and future synergies as they consider overarching domains (appropriate polypharmacy, citizen empowerment, teaching and coaching on AHA, deployment of synergies to EU regions, Responsible Research and Innovation), and three cross-cutting synergies focussing on current Action Group activities (falls, frailty, integrated care and chronic respiratory diseases).

Sarcopenia Trials in Specific Diseases: Report by the International Conference on Frailty and Sarcopenia Research Task Force.

Muscle atrophy occurs as a consequence of a number of conditions, including cancer, chronic obstructive pulmonary disease (COPD), diabetes mellitus, heart failure, and other chronic diseases, where it is generally a predictor of poor survival. It also occurs as a consequence of disuse and an age-related loss of muscle mass and strength (sarcopenia). The aims of the 2016, International Conference on Frailty and Sarcopenia Research (ICFSR) Task Force were to examine how these specific chronic conditions have been employed in treatment trials thus far and how future trials using these patient groups might be designed for efficient identification of effective sarcopenia interventions. Functional limitations assessed as gait speed, distance walked over a set time period, or other attributes of physical performance have been suggested as outcome measures in sarcopenia trials. Indeed, such measures have already been used successfully in a number of trials aimed at preventing disability in older adults.

FM19G11 reverses endothelial dysfunction in rat and human arteries through stimulation of the PI3K/Akt/eNOS pathway, independently of mTOR/HIF-1α activation.

BACKGROUND AND PURPOSE: FM19G11 up-regulates mammalian target of rapamycin (mTOR)/hypoxia inducible factor-1α (HIF-1α) and PI3K/Akt pathways, which are involved in endothelial function. We evaluated the effects of FM19G11 on defective endothelial vasodilatation in arteries from rats and humans and investigated the mechanisms involved. EXPERIMENTAL APPROACH: Effects of chronic in vivo administration of FM19G11 on aortic endothelial vasodilatation were evaluated together with ex vivo treatment in aortic and mesenteric arteries from control and insulin-resistant rats (IRR). Its effects on vasodilator responses of penile arteries (HPRAs) and corpus cavernosum (HCC) from men with vasculogenic erectile dysfunction (ED) (model of human endothelial dysfunction) were also evaluated. Vascular expression of phosphorylated-endothelial NOS (p-eNOS), phosphorylated-Akt (p-Akt) and HIF-1α was determined by immunodetection and cGMP by elisa. KEY RESULTS: Chronic administration of FM19G11 reversed the impaired endothelial vasodilatation in IRR. Ex vivo treatment with FM19G11 also significantly improved endothelium-dependent vasodilatation in aorta and mesenteric arteries from IRR. These effects were accompanied by the restoration of p-eNOS and cGMP levels in IRR aorta and were prevented by either NOS or PI3K inhibition. p-Akt and p-eNOS contents were increased by FM19G11 in aortic endothelium of IRR. FM19G11-induced restoration of endothelial vasodilatation was unaffected by mTOR/HIF-1α inhibitors. FM19G11 also restored endothelial vasodilatation in HPRA and HCC from ED patients. CONCLUSIONS AND IMPLICATIONS: Stimulation of the PI3K/Akt/eNOS pathway by FM19G11 alleviates impaired NO-mediated endothelial vasodilatation in rat and human arteries independently of mTOR/HIF-1α activation. This pharmacological strategy could be beneficial for managing pathological conditions associated with endothelial dysfunction, such as ED.

Promoting access to innovation for frail old persons. IAGG (International Association of Gerontology and Geriatrics), WHO (World Health Organization) and SFGG (Société Française de Gériatrie et de Gérontologie) Workshop--Athens January 20-21, 2012.

UNLABELLED: Frailty tends to be considered as a major risk for adverse outcomes in older persons, but some important aspects remain matter of debate. OBJECTIVES: The purpose of this paper is to present expert's positions on the main aspects of the frailty syndrome in the older persons. PARTICIPANTS: Workshop organized by International Association of Gerontology and Geriatrics (IAGG), World Health Organization (WHO) and Société Française de Gériatrie et de Gérontologie (SFGG). RESULTS: Frailty is widely recognized as an important risk factor for adverse health outcomes in older persons. This can be of particular value in evaluating non-disabled older persons with chronic diseases but today no operational definition has been established. Nutritional status, mobility, activity, strength, endurance, cognition, and mood have been proposed as markers of frailty. Another approach calculates a multidimensional score ranging from "very fit" to "severely frail", but it is difficult to apply into the medical practice. Frailty appears to be secondary to multiple conditions using multiple pathways leading to a vulnerability to a stressor. Biological (inflammation, loss of hormones), clinical (sarcopenia, osteoporosis etc.), as well as social factors (isolation, financial situation) are involved in the vulnerability process. In clinical practice, detection of frailty is of major interest in oncology because of the high prevalence of cancer in older persons and the bad tolerance of the drug therapies. Presence of frailty should also be taken into account in the definition of the cardiovascular risks in the older population. The experts of the workshop have listed the points reached an agreement and those must to be a priority for improving understanding and use of frailty syndrome in practice. CONCLUSION: Frailty in older adults is a syndrome corresponding to a vulnerability to a stressor. Diagnostic tools have been developed but none can integrate at the same time the large spectrum of factors and the simplicity asked by the clinical practice. An agreement with an international common definition is necessary to develop screening and to reduce the morbidity in older persons.

Higher levels of endogenous estradiol are associated with frailty in postmenopausal women from the toledo study for healthy aging.

BACKGROUND: Adverse effects of higher endogenous estradiol (E2) levels on various clinical outcomes and on determinants of the frailty syndrome have recently been reported. However, there are no data about the potential relationship between E2 and frailty. We aimed to study the association between E2 levels and frailty among older postmenopausal women not taking hormonal therapy. METHODS: We used data from the Toledo Study for Healthy Aging, a Spanish population-based cohort study. Frailty was defined according to Fried's approach. Multivariate odds ratios (OR) and 95% confidence intervals (CI) associated with E2 levels were estimated using polytomous logistic regression. RESULTS: E2 levels decreased significantly with age and educational level, whereas they increased with body mass index, high-sensitivity C-reactive protein (hs-CRP), and impairment in Katz activities of daily living. Higher E2 levels were associated with the prevalence of frailty among women younger than 79 yr, but not in the oldest group (p interaction = 0.047). After adjustment, OR of frailty associated with a 1 sd increase of E2 was 1.51 (95% CI, 1.04-2.20; P = 0.03). We identified an interaction between E2 and hs-CRP on the prevalence of frailty (P value = 0.042). Women with both higher E2 and hs-CRP (defined as values into the upper tertile) had an age-adjusted OR of 4.2 (95% CI, 1.7-10.5; P = 0.002), compared with women with low levels of both E2 and hs-CRP. CONCLUSION: Higher E2 levels were associated with frailty in postmenopausal women. The synergism between higher E2 and hs-CRP levels suggests the existence of physiopathological mechanisms connecting inflammation and estrogen to frailty.

Amylin effect in extrapancreatic tissues participating in glucose homeostasis, in normal, insulin-resistant and type 2 diabetic state.

Amylin is co-secreted with insulin, responds to the same stimuli, is anorectic, lowers body weight by reducing fat mass, and is proposed for diabetes treatment. We examined the effect of a 3-day constant infusion of close to physiological doses of amylin in Wistar rats, on glucotransporter expression, glycogen content (G), glycogen synthase a activity (GSa) and glucose transport (GT), in liver, muscle and fat from insulin resistant (IR) and type 2 diabetic (T2D) models, compared to normal (N) animals; plasma glucose and insulin were measured. Plasma insulin in IR was higher than in N or T2D, and amylin normalized the value. In both, IR and T2D, liver G was lower than normal, accompanied by GLUT-2, mRNA and protein, higher and lower, respectively, than in N; amylin normalized G in both groups, without changes in GLUT-2, except for an mRNA increase in T2D. In IR and T2D, muscle GSa was reduced, together with respective over- and under-GLUT-4 expression; amylin induced only a trend toward GSa normalization in both groups. In isolated adipocytes, GT and GLUT-4 in IR and T2D were lower and higher, respectively, than in N; after amylin, not only GT was normalized in both groups but also the response to insulin was much more pronounced, including that in N, without major changes in GLUT-4. This suggests that the beneficial effect of amylin in states running with altered glucose homeostasis could occur by partially acting on the hexose metabolism of the liver and mainly on that of the adipose tissue.

Changes in the human peritoneal mesothelial cells during aging.

The number of older patients admitted to peritoneal dialysis (PD) programmes is growing. At the same time, there is increasing data about the role of mesothelial cells in determining the functional alteration of the peritoneum during PD. However, little is known about the functional changes accompanying the ageing process in mesothelial cells. We aimed to evaluate whether the aging process is accompanied by changes in some functional characteristic of the human peritoneal mesothelial cells (HPMC), which could account for the poor prognosis observed in old patients with PD. HPMCs were isolated from patients undergoing a nonurgent, nonseptic abdominal surgical procedure, without renal, vascular or inflammatory disease. Cytokine levels (by enzyme-linked immunosorbent assay (ELISA)), nitrates+nitrites, and cyclooxygenase (COX) activity (by a chemiluminescence assay), cytokines, COX, nitric oxide synthase (NOS), and nuclear factor (NF)-kappaB1, two messenger ribonucleic acid (mRNA) gene expressions (by reverse transcriptase (RT)-Multiplex PCR), COX, and NOS promoter gene activities, and NF-kappaB-dependent transcription (by transient transfection assays) were determined. Our data show a significant increase in cytokines, COX, and NOS activities, and mRNA expression of cytokines, COX-2, inducible nitric oxide synthase (iNOS) and precursors of NF-kappaB in HPMCs from old people. This was also the case for COX-2 and iNOS promoter gene activities and NF-kappaB-dependent transcription. There was a positive correlation between the age of the donor's cell and the proinflammatory profile of the HPMCs. Such age-dependent increase (around two-three times) is partially abolished by different antioxidant or free-radical scavengers. Thus, aging is accompanied by the presence of an inflammatory state in HPMCs, which involves the participation of different reactive oxygen species.

[Prevalence of renal involvement in a population of type Ii diabetics followed up in primary care]. / Prevalencia de la afectación renal en una población de diabéticos tipo 2 seguidos en atención primaria.

UNLABELLED: Patients with type 2 diabetes use to be managed in their primary care settings during the early stages of the disease. The main objective of the study was to determine renal impairment prevalence, and to assess its significance, within type 2 diabetics controlled by their family physicians. PATIENTS AND METHOD: Transverse observation of patients with type 2 diabetes who were the first 20 unselected cases seen by 183 family physicians from 16 of the 17 Autonomic Communities of our country. The following variables were determined: serum creatinine, glucose, and HbA1c concentrations, proteinuria (dipstick test in a first-voided morning urine sample), blood pressure levels, and associated cardiovascular disease. RESULTS: Data from 3,583 type 2 diabetic subjects were evaluated. Mean age was 64 +/- 10 years and 45% were male. A serum creatinine > or = 1.2 mg/dl was observed in 523 (15.5%) patients. Proteinuria was present in 794 (23.5%) cases, being > or = 2 + in 215 (6.5%) subjects. Patients with a serum creatinine > or = 1.2 mg/dl were older, shower higher blood pressure levels, and suffered from more cardiovascular disease (32.0 vs 19.5%) than those with a serum creatinine < 1.2 mg/dl. In a multivariate analysis, this difference continued to be significant (OR 1.47; 95% CI 1.14 to 1.90; p = 0.002. Patients with proteinuria showed a higher prevalence of cardiovascular disease (OR 1.83; 95% CI 1.47 to 2.27; p < 0.0001) than those without proteinuria. This association was continuous through no proteinuria to the > or = 2 + proteinuria (p < 0.001). Blood pressure level was > or = 140/90 mmHg in 69% of the cases, being < 130/85 mmHg in only 8% of the subjects. CONCLUSIONS: There is a high prevalence of renal impairment, approximately of 25% within type 2 diabetic patients seen at the primary care level. Optimal blood pressure level seems to be extremely infrequent bearing in mind the diagnosis of diabetes and the associated cardiovascular disease.

Thapsigargin induces apoptosis in cultured human aortic smooth muscle cells.

Vascular remodeling is a key feature of many pathologic states, including atherosclerosis, or hypertension. Vascular smooth muscle cells participate in determining the vessel structure by several mechanisms such as cell migration, cell growth, or cell death (necrosis or apoptosis). Here we report that thapsigargin, an inhibitor of endoplasmic reticulum Ca2+ -adenosine triphosphatase (ATPase), is able to induce apoptosis in human vascular smooth muscle cells (HVSMCs). Apoptosis was assessed by three different methods: differential chromatin binding dye staining. cytoplasmic histone-associated DNA fragments detection by enzyme-linked immunosorbent assay (ELISA) and terminal deoxyribonucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL). When HVSMCs were treated for 1 h with thapsigargin (100 nM-10 microM), there was a concentration-dependent increase in both parameters 24 h after the thapsigargin pulse. When a time-course experiment was performed, both parameters were significantly enhanced from 3 to 6 h after the exposure to thapsigargin. We conclude that thapsigargin promotes apoptosis in HVSMCs, providing a useful tool for the study of programmed cell death in human vascular smooth muscle.

Highly glycated oxyhaemoglobin impairs nitric oxide relaxations in human mesenteric microvessels.

AIMS/HYPOTHESIS: It has been recently shown that glycated human haemoglobin induces endothelial dysfunction in rat vessels by generating superoxide anions that interfere with nitric oxide mediated responses. Our study analysed the effect of glycated human haemoglobin on the endothelium-dependent relaxations of human vessels. METHODS: Omental microvessels were obtained from patients (without diabetes, hypertension or vascular disease) during surgery and mounted in a small vessel myograph to study their vasoactive responses (vessels from 3-7 patients for each set of experiments). RESULTS: Cumulative vasodilatory responses to bradykinin (10 nmol/l to 3 mumol/l) were induced in vessels precontracted with 35-50 mmol/l potassium chloride. Addition of 100 mumol/l NG-nitro-L-arginine methyl ester reduced the relaxation evoked by bradykinin, but preincubation with both NG-nitro-L-arginine methyl ester and 10 mumol/l indomethacin was needed to abolish it. Bradykinin-induced responses were inhibited by 1 mumol/l non-glycated oxyhaemoglobin whereas no effect was obtained with 10 nmol/l oxyhaemoglobin. At these low concentrations (10 nmol/l), glycated human oxyhaemoglobin caused an impairment of bradykinin-induced relaxation when the percentage of glycation was 10% or higher. This effect was prevented by preincubating the vessels with ascorbic acid (10 mumol/l), superoxide dismutase (100 U/ml) and gliclazide (1 and 10 mumol/l), but not with indomethacin (10 mumol/l), catalase (400-600 U/ml), dimethylthiourea (1 mmol/l) or glibenclamide (10 mumol/l). In vessels preincubated with NG-nitro-L-arginine methyl ester (100 mumol/l), glycohaemoglobin did not add any additional effect. CONCLUSION/INTERPRETATION: Highly glycated human oxyhaemoglobin, at physiological plasmatic concentrations, impairs nitric oxide-mediated responses by a mechanism involving superoxide anions but not cyclooxygenase derivatives.

Endothelial stimulation of sodium pump in cultured vascular smooth muscle.

We studied vascular sodium pump activity and its regulation by vasoactive agents and endothelium in cultured aortic vascular smooth muscle cells from normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). Baseline sodium pump activity (ouabain-inhibitable 86Rb+ uptake) was similar in cells from both rat strains. Angiotensin II and endothelin-1 increased ouabain-inhibitable 86Rb+ uptake more in SHR than WKY cells, whereas no effects were obtained with sodium nitroprusside, 8-bromo-cGMP, or iloprost. We examined the influence of endothelium on vascular sodium pump activity either by coculturing smooth muscle and endothelial cells or by using conditioned medium. Both coculture for 24 hours with endothelial cells and treatment with conditioned medium increased smooth muscle cell sodium pump activity, this effect being higher in SHR cells. These results suggest that the endothelium may modulate sodium pump activity in the underlying smooth muscle by releasing a diffusible compound, which is more active on SHR smooth muscle. The conditioned medium obtained in the presence of inhibitors of angiotensin-converting enzyme, endothelin-1-converting enzyme, cyclooxygenase, lipoxygenase, and nitric oxide synthase had no effect on the ability of conditioned medium to increase sodium pump activity, suggesting that angiotensin II, endothelin-1, eicosanoids, and nitric oxide are not involved in this stimulatory effect. The nature of the possible endothelial factor involved is still unknown, but it possesses a molecular weight between 25 and 50 kD, is heat stable, and is sensitive to trypsin treatment. We propose it could be a growth factor.

Endothelial modulation of the vascular sodium pump.

Endothelial interference with ouabain effects on vascular smooth muscle was analyzed in isolated human placental arteries and veins, carotid arteries from reserpinized guinea pigs (to eliminate the adrenergic actions of the glycoside), and aorta from Wistar-Kyoto (WKY) rats that were 5 weeks, 3, 6, 12, and 18 months old. After endothelium removal, ouabain-evoked contractions were increased in human placental vessels and guinea pig carotid arteries. These effects were not mimicked by the blockade of nitric oxide, prostaglandin, or leukotriene synthesis. Bioassay experiments suggest the release of an endothelial diffusable factor(s). 86Rb+ uptake, a method to measure sodium-pump activity, was significantly reduced by the removal of endothelium. In aortas from WKY rats, ouabain caused contractions that were increased with the age of animals until 12 months. Endothelium removal increased ouabain effects in vessels from animals of 3 and 6 months but not in older ages. These results suggest (a) that there is an inhibitory endothelial modulation of ouabain-induced vasoconstriction by the release of a diffusible factor(s); (b) that this substance is not related to nitric oxide, prostaglandins, or leukotrienes; (c) that its mechanism of action could be stimulating the activity of vascular sodium pump and/or antagonizing its inhibition by ouabain; and (d) that the endothelial modulation is lost in the elderly.