Increased Hepatic and Decreased Urinary Metallothionein in Rats after Cessation of Oral Cadmium Exposure

Abstract: We investigated the role of metallothionein (MT) in tissues after cessation of cadmium (Cd) exposure. Wistar rats of both genders were given CdCl₂ in drinking water at daily doses of 0, 2.5, 5.0 or 10.0 mg Cd/kg body‐weight for 12 weeks. Half of the animals were then killed; the others were given Cd‐free water for the following 16 weeks, i.e. until 28 weeks after start of the experiment (28‐week rats). We observed dose‐dependent increases in the levels of MT in the tissues of rats 12 weeks after beginning the experiment (12‐week rats). After the exposure ceased, levels of MT in the 28‐week rats changed in three ways: an increase in the liver, persistence in the kidney cortex and a decrease in the medulla, relative to those levels in their 12‐week counterparts. Biomarkers of kidney dysfunction were determined to be urinary MT (UMT) and urinary N‐acetyl‐β‐d ‐glucosaminidase (UNAG). After 12 weeks, we observed dose‐related statistically significant increases in UMT and UNAG in all of the Cd‐exposed groups. A statistically significant decrease for UNAG between the 12‐ and 28‐week rats occurred among males at the lowest Cd dose and for UMT in all of the Cd‐exposed groups. The unchanged tissue levels of MT in the kidney cortex suggest that decreased UMT is a sign either of (i) decreased transport of Cd‐MT from the liver via blood plasma to the renal tubules or (ii) increased tubular reabsorption and recovery of renal tubular function.     

Erythrocyte glutathione peroxidase and superoxide dismutase in Alzheimer''s disease and other dementias

Activities of 2 enzymes protecting from free radical damage, erythrocyte glutathione peroxidase and superoxide dismutase, were measured in 4 patients with Alzheimer's disease, in 4 with multi-infarct dementia, in 1 with Huntington's disease and in 1 with Hakola-Nasu disease. In none of these dementing diseases the activities were diminished compared to controls.     

Neonatal exposure to DDT and its fatty acid conjugate: effects on cholinergic and behavioural variables in the adult mouse

We have recently observed that DDT and a DDT metabolite, DDOH, conjugated to a fatty acid, palmitic acid, DDOH-PA, affects muscarinic cholinergic receptors (MAChR) in the neonatal mouse brain when given to suckling mice during rapid brain growth. This early exposure of the neonatal mouse also affects the behaviour of the animals as adults. When DDT and DDOH-PA was given as a single low oral dose of 1.4 mumol/kg body weight, DDT (0.5 mg), DDOH-PA (0.7 mg) and a 20% fat emulsion vehicle (10 ml) per kg body weight to 10-day-old NMRI mice, behavioural tests at adult age of four months, indicated disruption of a simple, non-associative learning process, i.e. habituation, in both DDT and DDOH-PA treated mice. There was also a significant increase in the potassium evoked release of ACh from slices of cerebral cortex and a tendency towards a decrease in the density of MAChR in mice receiving DDT. These effects in the adult mice could not be correlated to the concentration of DDT in the adult brain since DDT one month after its administration to the 10-day-old mouse no longer is present in the brain.     

Nurses' creativity, tedium and burnout during 1 year of clinical supervision and implementation of individually planned nursing care: comparisons between a ward for severely demented patients and a similar control ward

The aim of this study was to study creativity and innovative climate, tedium and burnout among the nurses on two wards during 1 year of systematic clinic supervision combined with the implementation of individualized care on an experimental ward (EW) for severely demented patients, as compared with a similar control ward (CW) EW nurses had systematic clinic supervision and each patient had his/her nursing care carefully planned, documented and evaluated The intervention was evaluated by means of the Creative Climate Questionnaire, Burnout Measure and the Maslach Burnout Inventory Creativity and innovative climate improved significantly among the EW nurses ( n = 19) in eight out of 10 factors during the year of intervention while there was no change on the control ward ( n = 20) Tedium and burnout decreased significantly among the EW nurses while no change was seen in this respect among the CW nurses It seems reasonable to assume that systematic clinical supervision and individualized planned care decreases the negative outcome of stress caused by the psychological burden imposed by nursing care It also increases nurses' creativity, which, in turn, may benefit patient care The findings of this study point to the necessity for a support system that focuses on the work itself, i e the nursing care Individualized planned care and systematic clinical supervision may offer this kind of support     

Accessibility and usability in housing: construct validity and implications for research and practice

Purpose: The aim of this study was to validate the conceptual definitions of accessibility and usability, and to explore differences between objective accessibility assessments and subjective ratings of usability in different client groups.

Method: The Housing Enabler and the Usability in My Home instruments were used for 131 persons above 18 years of age, living in ordinary housing and receiving a housing adaptation grant. Covariation between accessibility in four different housing sections and three different usability aspects were explored, for the total sample and for six sub-samples reflecting person-environment-activity transactions or demographic factors.

Results: Significant correlations were found in the total sample, among clients aged 75 - 84, women, clients living alone, as well as among clients with high dependence in personal and instrumental ADL and in outdoor activities. Subjective usability evaluations of activity aspects and physical environmental aspects were correlated to accessibility indoors and outdoors, while personal and social aspects of usability were correlated to outdoor accessibility.

Conclusions: Accessibility and usability are concluded to be different but related concepts. The results indicate that e.g. age, civil status and ADL dependence affect how clients assess aspects of their housing situation. For efficient planning and evaluation of housing adaptations, assessment of housing accessibility, usability, and dependence in ADL is recommended.     

Effects of Hesel-coil deep transcranial magnetic stimulation for depression – a systematic review

Background: One third of the depressed patients are not improved by antidepressant drugs and psychological treatments, and there is a need for additional treatments. Repetitive transcranial magnetic stimulation (rTMS) is being developed towards an alternative in treatment-resistant depression. Deep transcranial stimulation (dTMS) with the Hesel-coil (H-coil) is a further development of rTMS aiming to enhance the effect by getting the magnetic pulses to penetrate deeper into the brain.

Aims: This report aims to assess the evidence-base for dTMS for depression. The report also includes an assessment of the ethical and economic aspects involved.

Methods: A systematic review of the effects of H-coil dTMS on depression was conducted and the scientific support was evaluated using GRADE (Grading of Recommendations Assessment, Development and Evaluation).

Results: Only one controlled study was identified. In the sham-controlled randomized study, 212 participants with major depression that had not responded to antidepressant medication were enrolled. A two-point superiority in Hamilton Depression Rating Scale was observed in the dTMS arm vs the sham-arm at 4 weeks, but the difference was not statistically significant. No serious adverse events were reported apart from rare cases of epileptic seizures.

Conclusions: The existing scientific support for H-coil dTMS therapy for depression is insufficient. The clinical implication is that the use of dTMS in depression should be restricted to the framework of clinical trials pending further studies. Fortunately, additional studies are underway and the evidence base should presumably improve over the next several years.     

Oxidation of protein tyrosine phosphatases as a pharmaceutical mechanism of action: a study using 4-hydroxy-3,3-dimethyl-2H-benzo[g]indole-2,5(3H)-dione

Growth factor and insulin signal transduction comprise series of protein kinases and protein phosphatases whose combined activities serve to propagate the growth factor signal in a regulated fashion. It was shown previously that such signaling cascades generate hydrogen peroxide inside cells. Recent work has implied that one function of this might be to enhance the feed-forward signal through the reversible oxidation and inhibition of protein tyrosine phosphatases (PTPs). We identified compound 4-hydroxy-3,3-dimethyl-2H-benzo[g]indole-2,5(3H)-dione (BVT.948) as an agent that is able to inhibit PTP activity in vitro noncompetitively, a mechanism involving oxidation of the catalytic cysteine residue. We investigated the pharmaceutical utility of this compound by examining its effects in a series of in vitro cellular and in vivo assays. Results showed that BVT.948 was able to enhance insulin signaling in cells, although it did not increase tyrosine phosphorylation globally. Furthermore, the compound was active in vivo, enhancing insulin tolerance tests in ob/ob mice, therefore apparently enhancing insulin sensitivity. BVT.948 was able to inhibit several other PTPs tested and also was efficient at inhibiting several cytochrome P450 (P450) isoforms in vitro. The data suggest that inhibitors of PTPs that display noncompetitive kinetics must be viewed with caution because they may oxidize the enzyme irreversibly. Furthermore, although such compounds display interesting biological effects in vitro and in vivo, their general pharmaceutical utility may be limited due to undesired effects on P450 enzymes.     

The accuracy of quantitative parameters in 99mTc‐MAG3 dynamic renography: a national audit based on virtual image data

Assessment of image analysis methods and computer software used in ^99mTc‐MAG3 dynamic renography is important to ensure reliable study results and ultimately the best possible care for patients. In this work, we present a national multicentre study of the quantification accuracy in ^99mTc‐MAG3 renography, utilizing virtual dynamic scintigraphic data obtained by Monte Carlo‐simulated scintillation camera imaging of digital phantoms with time‐varying activity distributions. Three digital phantom studies were distributed to the participating departments, and quantitative evaluation was performed with standard clinical software according to local routines. The differential renal function (DRF) and time to maximum renal activity (T_max) were reported by 21 of the 28 Swedish departments performing ^99mTc‐MAG3 studies as of 2012. The reported DRF estimates showed a significantly lower precision for the phantom with impaired renal uptake than for the phantom with normal uptake. The T_max estimates showed a similar trend, but the difference was only significant for the right kidney. There was a significant bias in the measured DRF for all phantoms caused by different positions of the left and right kidney in the anterior–posterior direction. In conclusion, this study shows that virtual scintigraphic studies are applicable for quality assurance and that there is a considerable uncertainty associated with standard quantitative parameters in dynamic ^99mTc‐MAG3 renography, especially for patients with impaired renal function.     

Biomarkers for Alzheimer's disease therapeutic trials

The development of disease-modifying treatments for Alzheimer's disease requires innovative trials with large numbers of subjects and long observation periods. The use of blood, cerebrospinal fluid or neuroimaging biomarkers is critical for the demonstration of disease-modifying therapy effects on the brain. Suitable biomarkers are those which reflect the progression of AD related molecular mechanisms and neuropathology, including amyloidogenic processing and aggregation, hyperphosphorylation, accumulation of tau and neurofibrillary tangles, progressive functional, metabolic and structural decline, leading to neurodegeneration, loss of brain tissue and cognitive symptoms. Biomarkers should be used throughout clinical trial phases I-III of AD drug development. They can be used to enhance inclusion and exclusion criteria, or as baseline predictors to increase the statistical power of trials. Validated and qualified biomarkers may be used as outcome measures to detect treatment effects in pivotal clinical trials. Finally, biomarkers can be used to identify adverse effects. Questions regarding which biomarkers should be used in clinical trials, and how, are currently far from resolved. The Oxford Task Force continues and expands the work of our previous international expert task forces on disease-modifying trials and on endpoints for Alzheimer's disease clinical trials. The aim of this initiative was to bring together a selected number of key international opinion leaders and experts from academia, regulatory agencies and industry to condense the current knowledge and state of the art regarding the best use of biological markers in Alzheimer's disease therapy trials and to propose practical recommendations for the planning of future AD trials.