Key Messages for a Frailty Prevention and Management Policy in Europe from the ADVANTAGE JOINT ACTION Consortium.

In the 2015 Ageing Report, the European Commission (EC) and the Economic Policy Committee stated that coping with the challenge posed by an ageing population will require determined policy action in Europe, particularly in reforming pension, health care and long-term care systems. The concern for this situation motivated the EC, the Parliament and many of the Member States (MS) to co-fund, in the 2015 call of the Third European Health Programme of the European Union 2014-2020, the first Joint Action (JA) on the prevention of frailty. ADVANTAGE JA brings together 33 partners from 22 MSs for 3 years. It aims to build a common understanding on frailty to be used in the MSs by policy makers and other stakeholders involved in the management, both at individual and population level, of older people who are frail or at risk for developing frailty throughout the European Union (EU). It is a formidable challenge but also a great opportunity for concerted action resulting in fostering effective and successful policies in frailty prevention and management in the participating MS. The Consortium has 2 years of hard work ahead to contribute to the needed change for frailty related disability free Europe. The first practical step towards this aim was the preparation of a document: the State of the Art on Frailty Report to support an overview of evidence of what works and what does not work on frailty prevention and management. Subsequently, this will be reflected in the advice that the JA will give to policy makers at MS level. Overall, these messages intend to be an instrument of added value to advocate for policy driven decisions on frailty prevention and management in the JA participating MSs and subsequently towards a frailty related disability free older population in Europe. The aim of this paper is to describe ADVANTAGE JA general structure, approach and recommendations towards a European health and social policy which will support frailty prevention in the participating MS.

PML is required for telomere stability in non-neoplastic human cells.

Telomeres interact with numerous proteins, including components of the shelterin complex, whose alteration, similarly to proliferation-induced telomere shortening, initiates cellular senescence. In tumors, telomere length is maintained by Telomerase activity or by the Alternative Lengthening of Telomeres mechanism, whose hallmark is the telomeric localization of the promyelocytic leukemia (PML) protein. Whether PML contributes to telomeres maintenance in normal cells is unknown. We show that in normal human fibroblasts the PML protein associates with few telomeres, preferentially when they are damaged. Proliferation-induced telomere attrition or their damage due to alteration of the shelterin complex enhances the telomeric localization of PML, which is increased in human T-lymphocytes derived from patients genetically deficient in telomerase. In normal fibroblasts, PML depletion induces telomere damage, nuclear and chromosomal abnormalities, and senescence. Expression of the leukemia protein PML/RARα in hematopoietic progenitors displaces PML from telomeres and induces telomere shortening in the bone marrow of pre-leukemic mice. Our work provides a novel view of the physiologic function of PML, which participates in telomeres surveillance in normal cells. Our data further imply that a diminished PML function may contribute to cell senescence, genomic instability, and tumorigenesis.

A Nutritional Approach to the Prevention of Cancer: from Assessment to Personalized Intervention.

Among lifestyle factors, nutrition is one of the most important determinants of health, and represents a pivotal element of cancer risk. Nonetheless, epidemiological evidences of the relationship between several cancers and specific foods and nutrients is still inadequate, and solid conclusions are missing. Indeed, caloric restriction without malnutrition is associated to cancer prevention. Food may be also the primary route of exposure to contaminants such as metals, persistent organic pollutants, and pesticides. Exposuredisease associations and the interplay with genetic susceptibility requires further studies on genetic variation, environment, lifestyle, and chronic disease in order to eliminate and reduce associated health risks, thus contributing to improve health outcomes for the population. A primary nutritional approach for Active and Healthy Ageing (AHA) has been developed by the Nutrition group of the European Innovation Partnership (EIP) on AHA. The working group on lifestyles of the Italian Ministry of Health has developed a comprehensive approach to adequate nutrition using a consensus methodology to collect and integrate the available evidences from the literature and from the Italian experiences at the regional level, to raise the interest of other experts and relevant stakeholders to outline and scale-up joint strategies for a primary nutritional approach to cancer prevention.

Response to HBV vaccine in relation to anti-HCV and anti-HBc positivity: a study in intravenous drug addicts.

Drug addicts represent the group of young adults with the lowest response to hepatitis B virus (HBV) vaccine. A study was carried out on 110 current intravenous heroin users attending the service providing assistance to intravenous drug users (IVDUs) (SERT) in Padua: 66.4% of them were found anti-hepatitis C virus (HCV)-positive and 33.6% were anti-HBc positive; 29.9% were positive for both. The subjects were vaccinated with 10 microg of yeast-derived vaccine at months 0, 1 and 2 (fast schedule). The overall response rate was 66.4%. Response seems to be affected by positivity to anti-HBc, but not to HCV infection.

MDMA ('ecstasy') consumption in the context of polydrug abuse: a report on 150 patients.

The present study examined the characteristics and the possible psychopathological consequences of ecstasy (MDMA, 3,4-methylenedioxymethamphetamine) use. One hundred and fifty consecutive patients, presenting to the Padova (Italy) Addiction Treatment Unit and who had taken ecstasy on at least one occasion, were examined and studied using a semi-structured interview. Ninety-five percent of the patients had experimented with another drug of abuse at least once in their lifetime. Ecstasy was mainly self-administered at disco clubs, and reported acute psychoactive effects confirmed previous reports. Fifty-three percent of the total sample were found to be affected by one or more psychopathological problems; the most frequent were depression, psychotic disorders, cognitive disturbances, bulimic episodes, impulse control disorders, panic disorders, social phobia. Those who were free from any psychopathological problem, compared to the others, had taken a smaller number of MDMA tablets in their lifetime, for a shorter duration and with a lower frequency. Again, they were less likely to have used alcohol together with ecstasy but more likely to have used opiates. Longer-term, larger dosage (acute or cumulative) MDMA consumers were found to be at high risk of developing psychopathological disturbances. The results are discussed, taking into account both the ecstasy suggested serotonin (5-hydroxytryptamine) neurotoxicity and the various methodological issues pertaining to this kind of large-scale clinical study describing people for whom MDMA is far from being the only drug of abuse.

A double blind randomized study of oral clodronate in the treatment of bone metastases from tumors poorly responsive to chemotherapy.

Bisphosphonates are used in oncology as a means of decreasing complications due to bone metastases, in association with anticancer treatment, especially in patients with breast cancer, prostate cancer and myeloma. Little is known about the effects of bisphosphonates on bone metastases from other tumors and in particular from tumors for which no effective treatment is available. We conducted a randomized, double-blind placebo-controlled trial of oral clodronate in patients with bone metastases from tumors poorly responsive to chemotherapy, with the aims of evaluating the effects of this drug on symptoms control and bone metastases evolution. Sixty-six patients with poorly responsive tumors such as non-small cell lung cancer (NSCLC), bladder cancer, gastrointestinal cancers, kidney cancer, melanoma and metastatic carcinoma of unknown origin entered the study. Patients were randomized to receive either clodronate 1,600 mg/day for one year or identical placebo-containing tablets. Various parameters such as Karnofsky performance status, pain score (measured by a visual-analogue scale) and analgesic requirement were recorded at monthly intervals. Of the 66 patients enrolled, 9 were observed for one month or less; 7 were followed for two months; only 50 patients were followed for more than 2 months and could be adequately evaluated. At 3 months both clodronate and placebo-treated patients had a decrease in Karnofsky performance status, with the decrease being more evident in the placebo group. Mean pain scores showed an increase of pain in patients receiving placebo and a decrease of pain in patients receiving clodronate, although the difference failed to be statistically significant. Analgesics requirement increased in both groups, but significantly more in patients receiving placebo (p = 0.042), in whom increase in opioid requirements was particularly evident. Toxicity was low, with occasional gastroenteric discomfort in both groups. The main problem of this study was the difficulty in recruiting an adequate number of patients and following them for a sufficient period of time: general conditions rapidly deteriorated in many patients, and approximately 25% of the 66 enrolled were not considered evaluable; few patients survived for the length of the study, one year. This might partly account for the lack of significance of some of the parameters under study. With these limits, oral clodronate demonstrated some efficacy in symptom control and in reducing the need for analgesics.

[Surgical and radiologic treatment of cancer of the uterine body. Results of 12 years]. / Il trattamento radiochirurgico del cancro del corpo dell'utero. Risultati di 12 anni.

Findings were reviewed of 518 female patients with carcinoma of the body of the uterus treated and followed up during the 12 year period 1970-1982. For the patients treated with total hysterectomy and bilateral salpingo-oophorectomy followed by postoperative radiation therapy, the five-year overall survival was 88% for stage I histologic grade G1, as compared with 73% for stage I grade G2 + G3 and 48% for stages II + III. The survival rates were also analyzed in terms of myometrial infiltration. The rates of pelvic and paraaortic nodal metastases were analyzed; these observations suggested that routine postoperative radiotherapy should be considered.

Intravenous propafenone for suppression of symptomatic atrial fibrillation and atrial flutter in a first aid hospital.

The efficacy and safety of propafenone (PPF) were prospectively evaluated in 20 patients (13 men and 7 women, age 39 +/- 14 years) with atrial arrhythmias (AA) (atrial fibrillation: n = 13; atrial flutter: n = 7). All patients had arrhythmias from 109 +/- 63 minutes, (iT) without clinical evidence of heart failure. Intravenous PPF was given as a 1 mg/kg bolus over 5 minutes, with a therapeutical possibility of a second bolus (1 mg/kg) after 10 minutes if sinus rhythm was not restored. The conversion time (cT) was 6.4 +/- 2.2 minutes (range 3 to 18 minutes). In 19 patients (95%) sinus rhythm was restored and no serious adverse and proarrhythmic effects were noted in each patient. We conclude that 1) PPF is effective and acted significantly faster in controlling AA; 2) PPF appears to be well tolerated and relative safe with a low incidence of adverse and proarrhythmic effects in patients in a first aid station.

The value of necropsy in oncology.

The effectiveness of diagnostic procedures in cancer patients was evaluated by comparing clinical with necropsy findings. Necropsy and clinical records of 102 patients were reviewed for primary site and histology of tumour, metastatic sites, presence of second neoplasms, associated non-neoplastic diseases, terminal illness and cause of death. Major discordances between clinical and postmortem findings were found in 34 (33%) cases: in 10 of these a correct clinical definition of site and histology of the primary tumour would have resulted in a change of management and prognosis; in 4 cases in which a major non-neoplastic pathology had been responsible for death, correct diagnosis might have resulted in prolongation of survival. Spread of disease was generally underestimated, even for metastases in clinically accessible organs. Even more disappointing were the clinical data related to terminal illness and cause of death (43% overall concordance).

A phase II study with teniposide (VM26) in patients with progressed or relapsed small cell lung cancer (SCLC).

Sixteen patients with advanced small cell lung cancer who relapsed or progressed under first-line therapy, were treated with second-line chemotherapy consisting of: teniposide, 60 mg/m2, i.v. days 1-5, every 3 weeks until further progression. The response rate was: 3 minor responses, 6 stable disease, 5 progressive disease, 1 early death and 1 not evaluable. After the introduction of teniposide, median survival was 4.5 (range 1-11) months, compared to the median survival (2 months, range 1-11) observed in 40 contemporary patients of our series, who relapsed or progressed and subsequently received no treatment. The assessment of the difference was significant: chi-square = 4.05, P less than 0.05. In addition a particular comparison was performed with 15/40 patients who matched according to the major predictive parameters of disease. These patients experienced 2 months (range 1-7) of median survival which was significantly shorter than that of the teniposide treated group (chi-square = 4.48, P less than 0.05). On these bases, teniposide appeared to be effective, but the small size of the study suggests caution in evaluating the results.

Metabolism of rat granular pneumocytes isolated in primary culture.

Granular pneumocytes (GP) were isolated by trysinization of minced rat lungs followed by short-term primary culture. The yield from the lungs of one rat was approximately 3.5 X 10(6) GP representing 25 micrograms DNA and 0.5 mg protein. Depending on the method to remove cells from attachment to plastic, the purity was 82--92% GP of which > 90% excluded erythrosin B. Resting O2 consumption (37 degrees C) of cells was 202 +/- 29 (mean +/- SE, n = 3) nmol.h-1.(10(6) cells)-1 with a 2.5 times increase in the presence of an uncoupler of oxidative phosphorylation. ATP content of resting pneumocytes was 4.1 +/- 0.18 nmol.(10(6) cells)-1 and was markedly depressed by the "uncoupling" agent. During incubation with [U-14C]glucose, production of metabolites in nmol.h-1.(10(6) cells)-1 was lactate 58.0 +/- 7.9, pyruvate 25.8 +/- 3.2, and 14CO2 56.4 +/- 2.1, and glucose utilization was 104 +/- 38.5. Sonicated GP had higher activities of both lactate and succinate dehydrogenases compared with alveolar macrophages. Alkaline phosphatase activity was localized predominantly to GP, whereas macrophages contained predominantly acid phosphatase. The intracellular water space for granular pneumocytes was 0.55 +/- 0.05 ml.(10(6) cells)-1 and was 71% greater for alveolar macrophage. The presence of active glycolytic and oxidative pathways and appropriate responses to metabolic inhibitors and substrates suggest the presence of intact cell membranes and the retention of metabolic control mechanisms in this isolated lung epithelial cell preparation.

Cytochrome P-450 content and mixed-function oxidation by microsomes from rabbit alveolar macrophages.

Cytochrome P-450 content and p-nitroanisole demethylation (a mixed-function oxidation) were investigated in the microsomal fraction from rabbit alveolar macrophages. The content of cytochrome P-450 was 0.13 +/- 0.024 (mean +/- S.E., n = 9) nmol/mg protein and was not stimulated by pretreatment of rabbits with chlorpromazine. Pretreatment with BCG resulted in decreased cytochrome P-450-specific content, suggesting that the microsomal protein pool was diluted by de novo synthesis of noncytochrome proteins. Demethylation of p-nitroanisole by alveolar macrophage microsomes during a 1 hr incubation was 17.1 +/- 1.4 nmol X hr-1 X mg protein-1. The microsomal fraction from homogenates of whole lungs had a cytochrome P-450 content of 0.32 +/- 0.078 nmol/mg protein and p-nitroanisole demethylase activity of 26.6 +/- 8.7 nmol X hr-1 X mg protein-1. The results indicate the presence of cytochrome P-450 in rabbit alveolar macrophages and show that the microsomal fraction can catalyze a mixed-function oxidation reaction. Comparison of alveolar macrophage and whole lung microsomal preparations indicates that alveolar macrophage cytochrome P-450 comprises a minor fraction of the total pulmonary pool.

Evidence for lipid synthesis by the dihydroxyacetone phosphate pathway in rabbit lung subcellular fractions.

Lipid synthesis by the lung requires a 3-carbon skeleton that can be provided by sn-glycerol-3-phosphate derived from glycolysis. This study investigated whether acylation of dihydroxyacetone-phosphate can serve as an alternate pathway for lung lipid synthesis. Rabbit lung microsomal and mitochondrial fractions were incubated with radiolabelled sn-glycerol-3-P and/or dihydroxyacetone-P. Palmitoyl CoA was used as acyl donor. The lipid fraction was subsequently isolated and radioactive incorporation was determined. Glycerol-3-P and dihydroxyacetone-P were both incorporated into the lipid fraction when each substrate was present alone. During incubation in the presence of equimolar concentrations of both substrates dihydroxyacetone-P accounted for 41 per cent of the total incorporation. These results show that acylation of dihydroxyacetone phosphate is a potential alternate to the glycerol-3-phosphate pathway for lung lipid synthesis.

Evaluation of redox state of isolated perfused rat lung.

The metabolic responsiveness of lung tissue to inhibition of oxidative metabolism was determined by measurement of the redox state of the isolated perfused and ventilated rat lung. Changes in redox state were evaluated by fluorescence from the lung surface at wavelengths suitable for reduced pyridine nucleotides and by measurement of the ratios of redox couples in rapidly frozen lung tissue. Maximal change of redox state was observed during ventilation with carbon monoxide; surface fluorescence increased 6.6%, lactate/pyruvate increased 5.8 times, glycerol 3-P/dihydroxyacetone-P increased fourfold and glutamate/alpha-ketoglutarate doubled. KCN infusion resulted in similar changes. Hypoxia produced with N2 ventilation resulted in less than maximal changes in redox couple ratios until alveolar PO2 was reduced below 0.1 mmHg. Redox changes observed during infusion of 0.5 mM aminoxyacetic acid suggested that maintenance of cytoplasmic redox state depended on functioning of a malate-aspartate "shuttle." The isolated perfused lung appears suitable to study factors controlling pulmonary parenchymal oxidative metabolism. The results emphasize the need for ventilation with CO to establish intracellular anoxia.