The use of an electronic clinical rule to discontinue chronically used benzodiazepines and related Z drugs.

PURPOSE: The chronic use of benzodiazepines and benzodiazepine-related drugs (BZ/Z) in older people is common and not without risks. The objective of this study was to evaluate whether the implementation of a clinical rule promotes the discontinuation of chronically used BZ/Z for insomnia. METHODS: A clinical rule, generating an alert in case of chronic BZ/Z use, was created and applied to the nursing home (NH) setting. The clinical rule was a one-off intervention, and alerts did not occur over time. Reports of the generated alerts were digitally sent to NH physicians with the advice to phase out and eventually stop the BZ/Z. In cases where the advice was adopted, a follow-up period of 4 months on the use of BZ/Z was taken into account in order to determine whether the clinical rule alert led to a successful discontinuation of BZ/Z. RESULTS: In all, 808 NH patients were screened. In 161 (19.1%) of the patients, BZ/Z use resulted in a clinical rule alert. From these, the advice to phase out and stop the BZ/Z was adopted for 27 patients (16.8%). Reasons for not following the advice consisted of an unsuccessful attempt in the past (38 patients), patients family and/or patient resistance (37 patients), the non-continuous use of BZ/Z (32 patients) and indication still present (27 patients). Of the 12 NH physicians, seven adopted the advice. CONCLUSIONS: The success rate of a clinical rule for discontinuation of chronically used BZ/Z for insomnia was low, as reported in the present study. Actions should be taken to help caregivers, patients and family members understand the importance of limiting BZ/Z use to achieve higher discontinuation rates.

Energy consumption and water-soluble protein release by cell wall disruption of Nannochloropsis gaditana.

Several cell disruption methods were tested on Nannochloropsis gaditana, to evaluate their efficiency in terms of cell disintegration, energy input and release of soluble proteins. High-pressure homogenization (HPH) and bead milling were the most efficient with >95% cell disintegration, ±50% (w/w) release of total proteins and low energy input (<0.5kWh.kg-1biomass). Enzymatic treatment required low energy input (<0.34kWh.kg-1biomass), but it only released ±35% protein (w/w). Pulsed Electric Field (PEF) was neither energy-efficient (10.44kWh.kg-1biomass) nor successful for protein release (only 10% proteins w/w) and cell disintegration. The release of proteins after applying HPH and bead milling always required less intensive operating conditions for cell disruption. The energy cost per unit of released protein ranged from 0.15-0.25 €.kgProtein-1 in case of HPH, and up to 2-20 €.kgProtein-1 in case of PEF.

Biorefinery of microalgal soluble proteins by sequential processing and membrane filtration.

A mild biorefinery process was investigated on the microalga Nannochloropsis gaditana, to obtain an enriched fraction of water soluble proteins free from chlorophyll. After harvesting, a 100g.L-1 solution of cells was first subjected to cell disruption by either high-pressure homogenization (HPH) or enzymatic treatment (ENZ). HPH resulted in a larger release of proteins (49%) in the aqueous phase compared to the Alcalase incubation (35%). In both cases, an ultrafiltration/diafiltration (UF/DF) was then performed on the supernatant obtained from cell disruption by testing different membrane cut-off (1000kDa, 500kDa and 300kDa). After optimising the process conditions, the combination of ENZ→UF/DF ended in a larger overall yield of water soluble proteins (24.8%) in the permeate compared to the combination of HPH→UF/DF (17.4%). A gel polarization model was implemented to assess the maximum achievable concentration factor during ultrafiltration and the mass transfer coefficient related to the theoretical permeation flux rate.

Validity, Reliability and Feasibility of Tools to Identify Frail Older Patients in Inpatient Hospital Care: A Systematic Review.

BACKGROUND: The objective of this study is to identify and review screening tools for frailty in older adults admitted to inpatient hospital care with respect to their validity, reliability and feasibility. METHODS: Studies were identified through systematically searching PubMed, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Embase and PsycINFO and screening reference lists till June 2014. Papers dealing with screening tools aimed at identifying frail older patients in in-hospital care, and including information about validity, reliability or feasibility, were included in the review. The quality of the included studies was critically appraised via the Quality Assessment of Diagnostic Accuracy Studies (QUADAS). RESULTS: From the originally identified 2001 studies 32 studies met the inclusion criteria, in which 16 screening tools were presented. The screening tools showed different characteristics with respect to the number of items, the method of administration and the domains included. The most frequently studied tools with respect to predictive validity were the Identification Seniors At Risk (ISAR) and Triage Risk Stratification Tool (TRST). Studies retrieved poorer information about reliability and feasibility. Overall sensitivity was fairly good. The ISAR, ISAR-HP (Identification Seniors At Risk Hospitalized Patients) and Multidimensional Prognostic Index (MPI) generally had the best sensitivity. CONCLUSIONS: Many screening tools are available for daily practice. These tools to identify frail older patients in inpatient hospital care could be useful. For no tool, however, is clear evidence available yet regarding validity, reliability and feasibility. The overall sensitivity of the included screening tools was fairly good, whereas information on reliability and feasibility was lacking for most tools. In future research more attention should be given to the latter items.

Factors that influence treatment decision-making in elderly DLBCL patients: a case vignette study.

Elderly patients with diffuse large B-cell lymphoma (DLBCL) are frequently not treated with standard immunochemotherapy, and this influences survival negatively. The purpose of this study was to gain more insight into treatment decision-making by hematologists. Case vignettes concerning patients with DLBCL were presented to hematologists in the Netherlands. Patient characteristics (age, comorbidity) differed per case. Respondents were asked in each case if they would treat the patient with curative intent by means of full-dose chemotherapy or chemotherapy with dose reduction or if they would not treat the patient with curative intent. The vast majority of respondents would treat an elderly patient diagnosed with DLBCL without a relevant medical history with full-dose chemotherapy irrespective of age. In the presence of comorbidity, lack of social support, cognitive disorders, and untreated depression dose reductions in advance are frequently applied or patients are not treated with curative intent. This is most pronounced for patients aged older than 80 years. Respondents working in a university hospital more frequently refrain form full-dose chemotherapy with curative intent compared to respondents working in tertiary medical teaching hospitals or general hospitals. Patients without a relevant medical history are generally treated with curative intent irrespective of age. Cognitive disorders, comorbidity, and depression reduce the change of being treated with curative intent. This is most prominent in the eldest patient category.

Comorbidity and treatment decision-making in elderly non-Hodgkin's lymphoma patients: a survey among haematologists.

BACKGROUND: Elderly patients with non-Hodgkin's lymphoma (NHL) are often not treated with standard immunochemotherapy and this might have a negative impact on their survival. Little is known about the determinants that play a role in treatment decision-making of clinicians regarding elderly patients with NHL. The objective of this study was to gain more insight into these determinants. METHODS: A survey was conducted amongst haematologists in the Netherlands. The survey contained questions about comorbidity, polypharmacy, social setting, nutritional status, depression, mild cognitive impairment, dementia, activities of daily living (ADL) and instrumental activities of daily living (IADL) in relation to treatment decisions in elderly NHL patients. RESULTS: Of all comorbidities, respondents designated cognitive disorders and cardiovascular comorbidity as the most important factors when assessing whether an older patient with NHL is eligible for curative treatment. Also in decreasing degree of importance ADL, IADL and depressive disorder are frequently included in treatment decision-making. Almost half of the respondents feel that treatment of the elderly person is complicated as a result of a lack of scientific evidence. CONCLUSION: Haematologists are aware of coexisting problems in elderly patients and they frequently take comorbidities, cognitive disorders and functional status into consideration in treatment decision-making. Future studies are needed to determine the exact role that these factors should play in the treatment of elderly patients. Furthermore, haematologists feel that treatment of the elderly is complicated and there is a lack of scientific evidence, and therefore older adults should be better represented in clinical trials.

Influence of cell-internalization on relaxometric, optical and compositional properties of targeted paramagnetic quantum dot micelles.

Quantum dot micelles (pQDs) with a paramagnetic coating are promising nanoparticles for bimodal molecular imaging. Their bright fluorescence allows for optical detection, while their Gd payload enables visualization with contrast-enhanced MRI. A popular approach in molecular MRI is the targeting of abundantly expressed cell surface receptors. Ligand-receptor binding often results in cell internalization of the targeted contrast agent. The interpretation of molecular imaging with pQDs therefore requires knowledge about the consequences of cellular internalization for their relaxometric, optical and compositional properties. To study these, Cd-containing core-shell-shell QDs coated with a monolayer of lipids, of which 50 mol% was a Gd-containing lipid, were incubated with human umbilical vein-derived endothelial cells (HUVECs) for up to 24 h. α(ν) ß(3)-integrin targeted (RGD) and non-targeted (NT) pQDs were compared. pQDs uptake was monitored by fluorescence microscopy, FACS, ICP-MS, relaxometry and MRI. Cell-associated pQDs displayed longitudinal relaxation rates and fluorescent intensities which were linear with the cell-associated Gd and Cd concentrations, implying that the Gd and Cd uptake by HUVECs can be quantified using relaxometric and optical measurements, respectively. However, the Gd-to-Cd molar ratio in pellets of pQD-incubated cells was consistently higher than the Gd-to-Cd molar ratio of the pQDs as prepared. It is proposed that this increase in Gd-to-Cd molar ratio was due to non-specific lipid-transfer between the pQDs and the cellular membranes. These findings show that, in the case of contrast agents that are formed by non-covalent interactions, experimental procedures are needed with which representative components of the probes can be monitored.

Aquatic worms grown on biosolids: biomass composition and potential applications.

The increasing production of biological waste sludge from wastewater treatment plants is a problem, because stricter legislation inhibits the use of traditional disposal methods. The use of the aquatic worm Lumbriculus variegatus can minimise sludge production. Because the worms can feed and grow on this waste sludge, valuable compounds that are present in the sludge can be recovered by the worms. This paper describes a systematic approach for finding possible applications of the produced biomass. The worm biomass mainly consists of protein and smaller fractions of fat, sugar and ash. It also contains low concentrations of heavy metals. The potential produced amount is relatively small, compared to other waste streams, and is produced decentrally. Therefore, the most promising applications are specific components of the biomass, for example specific amino acids or fatty acids. However, until the process is optimized and there is a stable supply of worms, the focus should be on simple applications, later on followed by specific applications, depending on the market demand. Worm biomass grown on clean sludges has a broader application potential, for example as consumption fish feed.

Morphology, binding behavior and MR-properties of paramagnetic collagen-binding liposomes.

Collagen is an important component of the extracellular matrix (ECM) and plays an important role in normal tissue maturation and in pathological processes such as atherosclerosis and myocardial infarction. The diagnostics of the latter diseases using MRI could strongly benefit from the use of collagen-specific contrast agents. The current study aimed to develop a bimodal liposomal MR contrast agent that was functionalized with CNA35, a collagen adhesion protein of the Staphylococcus aureus bacterium. The liposomes were characterized in terms of CNA35 protein conjugation and loading. The overall morphology was assessed with DLS and cryo-TEM, while cryo-TEM tomography was used to visualize the protein coverage of the liposomes. The binding properties of the contrast agent were investigated using a fluorescence assay based on the rhodamine content of the liposomes. The bulk relaxivity was determined using regular relaxometry while the MR-properties of liposomes in their bound state were studied using NMR depth profiling. This CNA35 functionalized contrast agent and the set of in vitro experiments we performed indicate the potential of this technology for in vivo molecular imaging of collagen.

[Smoking and doctors: from 'therapeutic panacea' to 'tobacco use discouragement in the individual']. / Roken en artsen: van 'geneeskrachtig wondermiddel' tot 'individuele tabaksontmoediging'.

In The Netherlands smoking will be prohibited in bars, restaurants, pubs and enclosed public spaces on 1 July 2008, in accordance with European legislation. Smoking is already not allowed in most Dutch hospitals. Europeans have a long history of tobacco smoking, going back to the introduction of this habit by Columbus. For centuries tobacco was used as a medicine, and later as a recreational drug, especially after the introduction of the cigarette. There was no scientific understanding of the harmful effects of smoking until the 19th century, when nicotine was isolated and recognised as a poison. Despite the fact that health care professionals represent a valuable resource for tobacco control, doctors have generally shown a poor appreciation of their critical role in smoking control. A decreasing smoking prevalence in the general population however, will emphasize the function of physicians as role model.

Relaxivity of liposomal paramagnetic MRI contrast agents.

Paramagnetic liposomes, spherical particles formed by a lipid bilayer, are able to accommodate a high payload of Gd-containing lipid and therefore can serve as a highly potent magnetic resonance imaging contrast agent. In this paper the relaxation properties of paramagnetic liposomes were studied as a function of composition, temperature and magnetic field strength. The pegylated liposomes with a diameter of approximately 100 nm were designed for favorable pharmacokinetic properties in vivo. The proton relaxivity, i.e. the T1 relaxation rate per mmol of Gd(III) ions, of liposomes with unsaturated DOPC phospholipids was higher than those with saturated DSPC lipids. Addition of cholesterol was essential to obtain monodisperse liposomes and led to a further, although smaller, increase of the relaxivity. Nuclear magnetic relaxation dispersion measurements showed that the relaxivity was limited by water exchange. These results show that these paramagnetic liposomes are very effective contrast agents, making them excellent candidates for many applications in magnetic resonance imaging.

Renal function and renal disease in the elderly: Part II.

In all industrialized countries, life expectancy has risen in the past 100 years. The incidence of elderly patients reaching end-stage renal disease (ESRD) and requiring renal replacement therapy has also increased. During the past few decades, the pattern of ESRD has changed significantly with the emerging predominance of elderly patients. The causes of this phenomenon are manifold and include an increasing number of chronic diseases typical of the 'third age', such as type 2 diabetes mellitus and vascular disease. In many species, a consequence of aging includes deterioration of renal function, partly due to structural alterations, and partly as the result of a diminishing blood flow. In humans, the aging kidney is characterized by modifications resulting from organic and functional disturbances. In particular, type 2 diabetes mellitus has emerged as an important condition, the microvascular and macrovascular complications of which are a common cause of morbidity and mortality in older patients. In Part II of this review, the specific aspects of renal replacement therapy in the elderly will be discussed.

Renal function and renal disease in the elderly: Part I.

In all industrialized countries, life expectancy has risen in the past 100 years. The incidence of elderly patients reaching end-stage renal disease (ESRD) and requiring renal replacement therapy has also increased. During the past few decades, the pattern of ESRD has changed significantly with the emerging predominance of elderly patients. The causes of this phenomenon are manifold and include an increasing number of chronic diseases typical of the 'third age', such as type 2 diabetes mellitus and vascular disease. In many species, a consequence of aging includes deterioration of renal function, partly due to structural alterations, and partly as the result of a diminishing blood flow. In humans, the aging kidney is characterized by modifications resulting from organic and functional disturbances. In particular, type 2 diabetes mellitus has emerged as an important condition, the microvascular and macrovascular complications of which are a common cause of morbidity and mortality in older patients. In part I of this review, the morphological and functional changes of the aging kidney will be reviewed, as well as the pathological conditions leading to the loss of renal function in the elderly.

Magnesium pyridoxal-5'-phosphate glutamate, "A vitamin B6 derivative", does not affect lipoprotein levels in patients with familial hypercholesterolaemia.

OBJECTIVE: In this double-blind, randomized, placebo-controlled, dose-finding study we assessed the short-term efficacy and safety of increasing dosages of magnesium pyridoxal-5'-phosphate glutamate (MPPG) compared to placebo in patients with familial hypercholesterolaemia (FH). Twenty-three patients of either sex, over the age of 18 years and suffering from heterozygous FH, were treated with MPPG for a period of 16 weeks. RESULTS: Baseline characteristics and lipoprotein profiles of the patients were comparable in the two treatment groups. Overall compliance was 90%. Neither after the first 8 weeks treatment period with 450 mg MPPG daily nor after the second 8 weeks treatment period with 600 mg MPPG daily were statistically significant changes in plasma total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol or triglyceride levels observed between the treatment and placebo groups. Plasma levels of lipoprotein (Lp)(a), apolipoprotein (apo) A1, apo B100, very low density lipoprotein (VLDL) cholesterol and VLDL triglyceride also did not change. CONCLUSION: Although it has been demonstrated that MPPG improves lipoprotein levels in patients with different forms of dyslipidaemia, MPPG is not effective for the treatment of FH patients.

Comparison of high and low intensity training in well controlled rheumatoid arthritis. Results of a randomised clinical trial.

OBJECTIVE: To investigate the benefit of intensive dynamic exercises in comparison to range of motion (ROM) and isometric exercises in rheumatoid arthritis. METHODS: 100 consecutive rheumatoid arthritis patients on stable medication were randomly assigned to (1) intensive dynamic group exercises which included full weight bearing exercises and conditioning exercises on a stationary bicycle while the heart rate was maintained at 70-85% of the age predicted maximum heart rate, (2) range of motion (ROM) exercises and isometric exercises in a group, (3) individual isometric and ROM exercises, and (4) home instructions for isometric and ROM exercises. Variables of physical condition, muscle strength, joint mobility, daily functioning (HAQ), and disease activity were assessed before and after the 12 week exercise course, and 12 weeks thereafter. An intention to treat analysis was performed. RESULTS: Increases in aerobic capacity (n = 77), muscle strength, and joint mobility in the high intensity exercise programme were respectively 17%, 17% and 16% and differed significantly from the changes in aerobic capacity, muscle strength, and joint mobility in the other exercise groups. No deterioration of disease activity was observed. Twelve weeks after discontinuation of the exercise course the gain in physical capacity had disappeared. CONCLUSIONS: Intensive dynamic training is more effective in increasing aerobic capacity, joint mobility, and muscle strength than ROM exercises and isometric training in rheumatoid arthritis patients with well controlled disease.

Gemfibrozil treatment of the high triglyceride-low high-density lipoprotein cholesterol trait in men with established atherosclerosis.

OBJECTIVE: To study the short-term efficacy, tolerability and safety of the treatment with gemfibrozil 600 mg twice daily or placebo in male patients with established atherosclerosis, with a lipid profile matching the 'high triglyceride-low high-density lipoprotein (HDL) cholesterol trait'. DESIGN: Double-blind randomized placebo controlled prospective trial. SETTING: Amsterdam Lipid Research Clinic at the Academic Medical Centre of the University of Amsterdam and the Slotervaart Training Hospital affiliated to the University of Amsterdam, Amsterdam, the Netherlands. SUBJECTS: Thirty-five male patients, age 30-70, with established atherosclerosis and the high triglyceride-low HDL cholesterol trait. MAIN OUTCOME MEASURES: Plasma total cholesterol, triglycerides, lipoproteins, apolipoproteins A1 and B100, clinical and laboratory safety parameters. RESULTS: Seventeen patients in the gemfibrozil group and 16 patients in the placebo group completed the study period. Compliance was considered adequate. Mean (+/- standard deviation) plasma HDL cholesterol levels increased 20.3% (+/- 12.22) from 0.82 to 0.99 mmol L-1 in the gemfibrozil group against 9.9% (+/- 18.31) from 0.79 to 0.87 mmol L-1 in the placebo group (P = 0.001). Mean plasma triglyceride level fell 49.5% (+/- 14.27) from 3.65 to 1.82 mmol L-1 in the gemfibrozil group against an increase of 13.6% (+/- 40.31) from 3.62 to 4.01 mmol L-1 in the placebo group (P < 0.001). Although plasma HDL cholesterol and triglyceride levels improved in all patients, normalization of these lipoproteins was only observed in approximately half of them. Plasma total and low-density lipoprotein (LDL) cholesterol levels, as well as plasma levels of apolipoprotein (apo) A1, B100 and lipoprotein [Lp(a)], did not show significant alterations compared to the placebo. All safety parameters were comparable between the two groups and remained within the reference limits. Gemfibrozil was well tolerated during treatment. Minor inconveniences were equally distributed between the two treatment groups. CONCLUSIONS: Gemfibrozil is an effective and safe drug in patients with coronary heart disease (CHD) and the high triglyceride-low HDL cholesterol trait.

A compound heterozygote for lipoprotein lipase deficiency, Val69-->Leu and Gly188-->Glu: correlation between in vitro LPL activity and clinical expression.

We analyzed the molecular defects in the lipoprotein lipase gene of a patient with type I hyperlipidemia suffering from recurrent pancreatitis, indicative for lipoprotein lipase deficiency. Postheparin lipoprotein lipase activity in the patient was decreased by 70%. Direct genomic sequencing revealed compound heterozygosity for two mutation: the well-known Gly188-->Glu and a new Val69-->Leu substitution. Val69 is situated in a conserved hydrophobic region of the lipoprotein lipase protein, and the substitution with leucine gives rise to a 80% decrease in specific catalytic activity, as supported by site-directed mutagenesis experiments, followed by expression in COS-cells. The combination of both defects in the lipoprotein lipase gene was incidentally associated with severe clinical expression of disease, and triglyceride levels of more than 30 mmol/l were measured. In our patient, triglyceride levels wer usually below 10 mmol/l. We, therefore, postulate that the residual LPL activity in our patient is usually sufficient to keep the triglyceride level within bounds and expression of disease occurred only when conditions such as alcohol abuse or poor compliance to diet were present.