Assessing the Impact of Frailty on Cognitive Function in Older Adults Receiving Home Care.

It is commonly accepted that frailty and dementia-related cognitive decline are strongly associated. However, degree of this association is often debated, especially in homebound elders with disabilities. Therefore, this study aimed to investigate the association of frailty on cognitive function in older adults receiving homecare. A screening for frailty and cognitive function was conducted at 12 primary healthcare settings of the nationally funded program "Help at Home" in Heraklion Crete, Greece. Cognitive function and frailty were assessed using the Montreal Cognitive Assessment questionnaire and the SHARE-f index, respectively. Barthel-Activities of Daily Living and the Charlson Comorbidity Index were also used for the identification of disability and comorbidity, respectively. The mean age of the 192 participants (66% female) was 78.04 ± 8.01 years old. In depth-analysis using multiple linear regression, revealed that frailty was not significantly associated with cognitive decline (frail vs. non-frail (B'=-2.39, p=0.246) even after adjusting for depression and multi-comorbidity. Importantly, as protective factors for cognitive decline progression and thus dementia development, was scientifically correlated with annual individual income >4500 (B'=2.31, p=0.005) -poverty threshold-compared to those with <4500 and, higher education level as compared to Uneducated (B'=2.94, p=0.019). However, depression was associated with cognitive decline regardless of socioeconomic variables. In conclusion, our results suggest that health professionals caring for frail people with cognitive impairment, must focus on early recognition and management of depression.

The European Innovation Partnership on Active and Healthy Ageing Synergies: Protocol for a Prospective Observational Study to Measure the Impact of a Community-Based Program on Prevention and Mitigation of Frailty (ICP - PMF) in Community-Dwelling Older Adults.

Aim of this paper is to describe the protocol of the study "Impact of a Community-based Program on Prevention and Mitigation of Frailty in community-dwelling older adults" developed in the framework of the European Innovation Partnership on Active and Healthy Ageing. This proposal has been developed by the Partnership Action groups on frailty, fall prevention and polypharmacy in older. The proposal wants to assess the impact of community-based programs aimed to counteract three main outcomes related to frailty: hospitalization, institutionalization and death. Bringing together researchers from seven European countries, the proposal aims to achieve the critical mass and the geographical extension enough to provide information useful to all older European citizens. An observational study will be carried out to calculate the incidence of the different outcomes in relation to the various interventions that will be assessed; results will be compared with data coming from already established national, regional and local dataset using the observed/expected approach. The sample will be made up by at least 2000 citizens for each outcome. All the citizens will be assessed at the baseline with two multidimensional questionnaires: the RISC questionnaire and the Short Functional Geriatric Evaluation questionnaire. The outcomes will be assessed every six-twelve months.

Guidance synthesis. Medical research for and with older people in Europe: proposed ethical guidance for good clinical practice: ethical considerations.

INTRODUCTION: In Europe the population is ageing rapidly. Older people are taking many medicinal products daily and these may not necessarily be suitable for them. Publications show that older patients are underrepresented in clinical trials, especially those over 75 years, with multiple co-morbidities, concomitant treatments and/or frailty. This document provides a summary of recommendations on ethical aspects of clinical trials with older people, who may in some cases be considered a vulnerable patient population. The EFGCP's Geriatric Medicine Working Party (GMWP) has developed this guidance to promote such research and to support health care professionals in their efforts. ETHICAL, SCOPE AND CONTEXT: The definition of a geriatric patient is reviewed. Frail and vulnerable patients, who are a minority of geriatric patients, should be included whenever it is relevant. The legal context is described. THE PROCESS OF INFORMED CONSENT: All adults should be presumed capable of consent, unless proven otherwise; informed consent must be sought for all older people who are able to consent. A simple, short and easy-to-understand information sheet and consent form will contribute to improving the readability and understanding of the older participant. A participant guide and the use of a simple tool to ensure decision making capacity, are recommended. Whenever older people are unable to consent, their assent should be sought systematically using adequate information, in addition to seeking the consent of their legal or authorised representative as appropriate. ETHICS COMMITTEES: Research ethics committees need internal and/or external geriatric expertise to balance the benefits and risks of research in older people and to appreciate and recognise their autonomy. DESIGN AND ANALYSES: Design and Analyses should be adapted to the objectives with appropriate outcomes and are not different from other clinical trials. CONCLUSIONS: The absence of proper recruitment or insufficient presence of older patients in clinical development plans for new medicinal products is detrimental; there is a need to improve evidence-based knowledge, understanding and management of their conditions and treatment. The aim of this guidance is to facilitate clinical research for and with the older patient population. The long version of the guidance will be available on the EFGCP's website: www.efgcp.be/.

Comparative efficacy and tolerability of Ketomousse (ketoconazole foam 1%) and ketoconazole cream 2% in the treatment of pityriasis versicolor: results of a prospective, multicentre, randomised study.

Ketomousse (K), a new thermophobic formulation (ketoconazole 1%), has proven its efficacy in the treatment of dandruff, caused by the same agent as pityriasis versicolor (PV). The objective of this study was to compare the efficacy and tolerability of K thermophobic foam vs. ketoconazole cream 2% (N) in the treatment of PV. Forty-six patients (22 in K and 24 in N group) with PV involving no more than 15% of the total trunk surface were randomly assigned for treatment either with K or N once daily for 14 days. Three weeks after the completion of treatment, improvement rate and side-effects were evaluated by clinical and mycological examination (Wood's light). Follow-up was available for 81% of subjects. Complete resolution was observed in five patients (29%) in K group and in nine (47%) in N group (P = 0.291). One patient in the N group reported urticaria while no adverse events were reported for K. Both products were cosmetically acceptable with respect to feasibility of application and formulation with a preference for K. Ketomousse (1% ketoconazole) provides an equal efficacy and tolerability compared to ketoconazole cream 2%. Therefore, Ketomousse could be considered an excellent therapeutic option in the treatment of PV.

Potential usefulness of serum p53 for laboratory management of plasma cell dyscrasias.

We measured the serum levels of p53 mutant protein (p53M-ELISA) in 65 patients with plasma cell dyscrasia (PCD) and compared them with some conventional laboratory variables. Our aim was to assess, for the first time, the potential of this parameter as a new marker for laboratory management of PCD. Twenthy-tree out of 65 patients had monoclonal gammapathy of undetermined significance (MGUS) and 42 suffered from multiple myeloma (MM). MM patients, with no prior chemotherapy consecutively entered this study. They were treated with standard regimens of Melphalan and Prednisone (MP) and were analyzed for serum p53M level from the time of diagnosis to response to therapy or death. A subgroup of nine patients was regularly monitored for changes occurring in p53M levels during MP therapy. Serum levels of p53M were elevated in MM patients compared with MGUS and healthy controls (p = 0.002). Significantly higher p53M levels were shown by MM patients refractory to chemotherapy than by responding patients (0.38 ng/ml vs 0.22 ng/ml, p = 0.05). The measurement of serum p53M in the nine patients during the course of chemotherapy correlated with disease progression or response to therapy. If confirmed on a larger series of patients, these results suggest a potential role of serum p53 mutant levels in laboratory management of PCD patients.

Pharmacokinetics and safety of iomeprol in healthy volunteers and in patients with renal impairment or end-stage renal disease requiring hemodialysis.

RATIONALE AND OBJECTIVES: To present the results of two studies conducted to evaluate the pharmacokinetics and safety of iomeprol in healthy volunteers and in patients with various degrees of renal impairment. METHODS: In these two open-label, single-dose, phase I studies, a 50-mL dose of iomeprol 400 was administered intravenously to a total of 30 subjects of either sex. In study 1, six healthy volunteers with normal renal function, six patients with mild renal failure, six patients with moderate renal failure, and four patients with severe renal failure were enrolled. In study 2, eight patients with end-stage renal disease requiring hemodialysis were enrolled. Safety was determined by predose and postdose (up to 10 days) measurement of vital signs, hematology, blood chemistry, urinalysis, electrocardiogram, physical examinations, and the incidence of adverse events. Pharmacokinetics was determined by measuring iomeprol levels in plasma, urine, feces, and dialysate samples, by using a validated high-performance liquid chromatography assay, up to 7 days after administration. RESULTS: The plasma concentration of iomeprol declined biexponentially in both healthy subjects and patients. As expected, mean body and renal clearances decreased progressively with increasing renal impairment, with a significant correlation with the glomerular filtration rate. The elimination half-life increased progressively with increasing renal impairment. The extraction efficiency of dialyser was estimated as approximately 40%, and dialysis clearance of iomeprol was approximately 1.26 mL. min-1. kg-1 (80.6 mL/min), slightly less than the body clearance previously observed in healthy subjects. It appears that dialysis is almost as efficient as renal function in healthy subjects in the removal of iomeprol. After a single dialysis session, approximately 58% of the dose was recovered in dialysate. Mild to moderate adverse events were reported by 17 of 30 subjects; none was clinically meaningful. One serious adverse event, unrelated to iomeprol, was reported. No clinically meaningful findings were noted for other safety parameters. CONCLUSIONS: Iomeprol was almost completely eliminated both in patients with renal impairment and in patients receiving dialysis. No dose adjustment appears to be necessary either in patients with renal impairment or with end-stage renal disease requiring hemodialysis. In this risk population, iomeprol 400 was safe and well tolerated.

Activation of c-MYC and c-MYB proto-oncogenes is associated with decreased apoptosis in tumor colon progression.

BACKGROUND: An increasing amount of evidence suggests that progression from normal mucosa to colorectal cancer is accompanied by morphological and genetic alterations. Genetic abnormalities affect malignant transformation via a gradual imbalance of normal tissue homeostasis involving programmed cell death (PCD) or apoptosis. Therefore, it has been hypothesized that alterations in apoptosis may contribute to carcinogenesis. The aim of the present work was to investigate the relationship between frequency of spontaneous apoptosis during transition adenoma-to-carcinoma of the colorectal tract and the incidence of activation of c-myc and c-myb proto-oncogenes, involved both in colon tumorigenesis and apoptosis. MATERIALS AND METHODS: Ninety-five tissue specimens (60 polyps and 35 adenocarcinomas) were removed with autologous normal adjacent mucosa from colon cancer patients. Genomic DNA was extracted and analyzed for both apoptosis frequency (DNA fragmentation assay) and proto-oncogene activation (Southern blot analysis). On the same samples, Bcl-2 protein expression was evaluated by immunohistochemistry. RESULTS: Our results showed that: i) a significant relationship exists between apoptosis and genesis of colorectal cancer since, compared to adenomatous polyps and adjacent normal mucosa, cell death is markedly inhibited in tumors (p = 0.01); ii) during colon tumor progression, apoptosis and amplifications of c-myc/c-myb genes are inversely related; iii) Bcl-2 expression is retained in colon tumors even though at a significantly lower level with respect to adenomatous polyps. CONCLUSION: These results indicate that failure of the normal apoptotic process together with de-regulation of c-myc and c-myb proto-oncogenes might promote the development of colorectal tumors.

Safety and pharmacokinetics of a new liposomal liver-specific contrast agent for CT: results of clinical testing in nonpatient volunteers.

RATIONALE AND OBJECTIVES: To evaluate the safety and pharmacokinetics of BR21, a liposome-encapsulated iomeprol formulation, in nonpatient volunteers. METHODS: This was a single-blind, placebo-controlled, ascending dose study in 30 adult, male nonpatient volunteers, randomized to receive a single intravenous bolus (2 mL/s) of BR21 (0.5, 1.0, 1.5, 2.0, and 2.5 mL/kg, four volunteers per dose level) or matched volumes of placebo (0.9% saline, 10 volunteers). The safety controls performed consisted of preand postdose complete physical examinations, measurement of vital signs, electrocardiographic controls, clinical laboratory investigations (hematology, serum chemistry, and urinalysis), and monitoring of adverse events. The safety controls and monitoring of subjects for adverse events continued up to 7 days after the dose. For pharmacokinetic analysis, the determination of total iomeprol content was performed by a high-performance liquid chromatography assay procedure in blood, urine, and fecal samples collected before the dose and serially after the dose, up to 120 hours. RESULTS: No serious adverse events occurred throughout the study. All nonserious adverse events were minor and mild in intensity and rapidly resolved without treatment. No difference in the incidence of adverse events was observed among the various doses of BR21 and between BR21 and placebo. There were no clinically significant changes in vital signs, electrocardiographic parameters, or clinical laboratory findings. Iomeprol blood level decay can be described by a three-exponential function, consistent with a distribution phase (range, t1/2 0.12-0.21 hours), a fast elimination phase (range, t1/2 1.2-1.5 hours), and a slow elimination phase from a deep compartment (range, t1/2 3.3-4.5 hours). There was an apparent linearity in the relation between the area under the curve and the dose. Urinary elimination of unchanged iomeprol accounted for 89% to 90% of injected dose within 24 hours. CONCLUSIONS: BR21 appeared to be safe and well tolerated in nonpatient subjects. Its pharmacokinetic profile was compatible with nonspecific distribution into the extracellular fluid space and specific distribution into a deep compartment.

[IL-6, p53 and proto-oncogene c-myc play different roles as biological markers of plasma cell dyscrasias]. / IL-6, p53 e il proto-oncogene c-myc esercitano ruoli diversi come marcatori biologici di discrasie plasmacellulari.

PURPOSE: To determine the role of serum levels of IL-6 and p53 mutant protein as well as of c-myc proto-oncogene alterations: a) in discriminating between benign (MGUS) and malignant Plasma cell dyscrasias (Multiple and Microsecreting Myeloma, Plasmocytoma); b) in monitoring the clinical course of malignant forms of this disease. PATIENTS AND METHODS: Eighty-eight patients affected by Plasma cell dyscrasias (58 MGUS, 24 MM and 6 PLC) entered this study. Using commercially available ELISA kits, serum levels of IL-6 and p53 have been determined in all the patients. In addition, a selected group of patients (n = 30) was also analyzed for structural c-myc gene alterations by Southern blot technique. RESULTS: The results show that, conversely from p53 protein, IL-6 and c-myc gene may represent useful diagnostic markers for discriminating benign from malignant forms of Plasma cell dyscrasia. On the contrary, preliminary findings of the same work indicate a potential role for the mutant p53 protein in monitoring the response to chemotherapy of patients affected by MM or PLM. CONCLUSIONS: Overall, these data suggest that the combined use of IL-6, p53 and c-myc may provide a new approach for a more rational management of Plasma cell dyscrasia patients.

Serum interleukin-10 levels in patients affected with multiple-myeloma - correlation with the monoclonal component and disease progression.

Using a commercially available, competitive ELISA kit based on a polyclonal anti-interleukin-10 antibody, serum interleukin-10 (IL-10) levels were quantified in samples of different groups of patients: 20 healthy controls (CTR), 11 monoclonal gammopathies of uncertain significance (MGUS), 17 multiple myelomas (MM), 10 cancer patients (CANCER), 13 cancer patients + MGUS (MGUS-CA) and 7 MGUS patients after surgical removal of concomitant cancer (MGUS-SRCC). Results show significant differences of both the median levels of IL-10 and the monoclonal component (MC) in CTR, MGUS and MM (patients with increasing concentrations in the mentioned order). The IL-10 levels found in the three groups of cancer patients showed serum levels higher than those observed in the controls. Moreover, the surgical cancer removal was related to an IL-10 decrease. A higly significant correlation between serum IL-10 levels and the corresponding MC was also found in the MM-bearing patients and to a lesser extent, in MGUS patients, indicating that serum IL-10 is parallel to the amount of the activated clone causing the monoclonal gammopathy. Since human myeloma lines, cultured in vitro may release significant amounts of IL-10, the data presented support the hypothesis that serum IL-10, measured in myelomatous patients may, at least in part, derive from the activated clone causing the monoclonal gammopathy.

Platelet aggregation, ATP release and cytoplasmic Ca2+ movement: the effects of cloricromene.

A placebo-controlled, double-blind, randomized, cross-over study was performed in 24 healthy volunteers. 12 volunteers received Cloricromene (100mg gastroresistant capsules twice a day) for 7 days, the other volunteers received identical placebo capsules. Subsequently, after a 7-day wash-out period, at day 15, each subject received the other treatment. Blood samples were taken on days 1 and 15 (1st day of each treatment) as well as on days 7 and 21 (7th day of each treatment) before the morning drug administration and 2 and 4 hours later. Platelet aggregation and ATP secretion were studied in whole blood (WB) using ADP and collagen as stimulating agents. Ca2+ fluxes were studied in aequorin-loaded, washed platelets stimulated with ADP and collagen, while aggregation in platelet-rich plasma (PRP) was studied using PAF, ADP and adrenaline as agonists. Consistent inhibition of aggregation and release induced by both ADP and collagen was observed in WB after Cloricromene administration. Similarly, Ca2+ flux was also inhibited after drug administration. Platelet aggregation in PRP was inhibited only after 7 days of Cloricromene treatment with ADP and adrenaline as stimuli. We conclude that oral administration of Cloricromene leads to significant antiplatelet activity in healthy volunteers, in particular when platelets are studied in the presence of other blood elements.

Detection of C-myb genetic alterations and mutant p53 serum protein in patients with benign and malignant colon lesions.

C-myb structural alterations were analysed by Southern blot hybridization in 55 adenomatous polyps and 21 adenocarcinomas of the colon. Gene amplification was observed in 8 cases (14.5%) and c-myb rearrangements in 3 cases (5.4%) of the preneoplastic lesions analysed. A higher percentage of c-myb abnormalities (23.8%) was shown by malignant tumors. As far as mutant p53 protein is concerned, it was detected both in sera of adenoma and adenocarcinoma patients, though at different levels. No statistically significant correlations were found between c-myb or p53 abnormalities and clinico-pathological variables.

Selection of patients with monoclonal gammopathy of undetermined significance is mandatory for a reliable use of interleukin-6 and other nonspecific multiple myeloma serum markers.

Serum levels of various immunochemical markers of clinical interest, as interleukin-6 (IL-6), C-reactive protein (CRP) and beta 2-microglobulin (beta 2M), were measured in sera from 98 subjects affected with monoclonal gammopathy of undetermined significance (MGUS; 80% of which bearing cancer too) and from 39 patients with multiple myeloma (MM). In addition, the ratio between serum IgG/IgA amounts (GAR) was also calculated in monoclonal gammopathies of IgG type. Consistent with our previous investigations, we found that tumor presence significantly influenced the serum levels of the various markers (except GAR) in MGUS patients; in fact, only when comparing MGUS without tumor and MM patients, was a clear difference observed for all markers considered. The data presented discourage the use of IL-6, CRP and beta 2M as discriminant indices between MGUS and MM patients, unless a careful selection of MGUS subjects is performed. Further investigations on these potential markers are therefore needed for a more rational clinical application.

Great saphenous vein protection in arterial reconstructive surgery.

An original method of great saphenous vein bypass protection during reconstructive arterial surgery is described. The use of a reinforced prosthetic support (Ringed PTFE), surrounding the vein, avoids possible compression by anatomical structures and strangulation by scar tissue after reoperation. This technique can also prevent eventual dilatation of the vein graft. Since 1981, this technique has been successfully applied to 30 selected patients. On the basis of clinical experience, the authors conclude that this method is safe and effective, and may increase the long-term patency rate of saphenous vein grafts.

EEG monitoring, selective shunting and patch graft angioplasty in carotid endarterectomy. Early and longterm results.

From March 1980 to July 1986 at the Department of Vascular Surgery of the University of Padua, 182 patients underwent 210 carotid revascularizations for atherosclerotic stenosis involving the carotid bifurcation (28 operations were bilateral). Carotid endarterectomies (CE) and patch graft angioplasty totalled 192 (166 patients); an enlarging patch graft angioplasty of the internal carotid artery (ICA) without CE was performed in 14 cases (13 patients); in the remaining four surgical procedures (3 patients), for technical reasons prohibiting CE, the operation consisted of a great saphenous vein bypass between a donor vessel and the ICA distal to the lesion. The preoperative symptoms in 182 patients were as follows: TIAs (98 cases, 54%), non-hemispheric symptoms (21 cases (12%) and fixed stroke or TIAIR (10 cases, 5%). Fifty-three patients (29%) were asymptomatic. In all cases, continuous EEG monitoring was employed. The operation was performed without a temporary intraluminal shunt in the patients showing tolerance to carotid clamping. The protection of the shunt was required only in patients with EEG changes (47 cases). The arteriotomy was routinely closed with a PTFE patch graft angioplasty. Early results of the operation were excellent: none of the patients presented permanent or transient neurological deficits in the immediate postoperative period and none of them died. All patients were reassessed with C.W. Doppler sonography and Duplex scanning in the postoperative period. In all cases, the success of the operation was demonstrated. Longterm follow-up (6-72 months, mean follow-up: 35 months) was done in 121 patients (142 operations): 107 patients were completely asymptomatic, 5 remained stable or slightly improved the preoperative status. Five patients had a new or recurrent TIAs, 3 suffered a stroke, one showed a recurrence of non-hemispheric symptoms. With the exception of two patients suffering a stroke, all had a second arteriography but none of these patients showed extracranial lesions. Two patients presented an asymptomatic restenosis of the ICA. Eight patients (8.8%) revealed a significant evolution of the disease of the contralateral unoperated ICA.(ABSTRACT TRUNCATED AT 400 WORDS)

Stroke risk reduction in asymptomatic and symptomatic patients treated surgically: the effectiveness of carotid endarterectomy with patch graft angioplasty.

From March 1980 to March 1987, 217 consecutive patients underwent 252 carotid revascularisations with routine use of continuous EEG monitoring and selective use of an intraluminal shunt for symptomatic (70%) or asymptomatic (30%) internal carotid artery (ICA) atherosclerotic stenosis. All carotid endarterectomies were routinely performed with a patch graft angioplasty. None of the patients suffered permanent or transient neurological deficits in the immediate postoperative period and none of them died. There was an 0.8% stroke rate and 0.4% mortality rate in the early postoperative course. Neurological assessment, Doppler and Echo doppler sonography of both the operated and the contralateral ICA was performed every 6 months. One-hundred and twenty-one patients (142 carotid revascularisations) operated on up to December 31st 1985 were reassessed in July 1986. The mean follow-up time was 35 months (range: 6 months to 6 years). New neurological symptoms were present in 7.4% of the patients; 2.5% of patients developed a stroke and 8.9% showed progression of stenosis in the contralateral ICA. One patient had a common carotid artery stenosis 2 years after surgery. Re-stenosis of the ICA was found in two patients who underwent re-operation without difficulty. The late mortality was 21.4% (11.9% of the overall series). In only two patients (7.6%) was stroke the cause of death.

[Continuous EEG monitoring in carotid surgery]. / Il monitoraggio EEG continuo in chirurgia carotidea.

From March 1980 to March 1987, at the Department of Vascular Surgery of the University of Padua, 217 patients underwent 252 carotid revascularizations with routine use of an intraluminal shunt (IS) for symptomatic (70%) or asymptomatic (30%) internal carotid artery (ICA) atherosclerotic stenosis. All carotid endarterectomies (CEs) were routinely performed with patch graft angioplasty to prevent restenosis. In the immediate post-operative period, no patient presented permanent or transient neurological deficits; no patient died. In the early post-operative course there was a 0.9% (2 patients) stroke rate and 0.4% (1 patient) mortality rate. These results suggest that the selective use of the IS on the basis of EEG changes is able to reduce the perioperative morbidity and mortality to nearly zero.