Assessment factors--applications in health risk assessment of chemicals

We review the scientific basis for default assessment factors used in risk assessment of nongenotoxic chemicals including the use of chemical- and pathways specific assessment factors, and extrapolation approaches relevant to species differences, age and gender. One main conclusion is that the conventionally used default factor of 100 does not cover all inter-species and inter-individual differences. We suggest that a species-specific default factor based on allometric scaling should be used for inter-species extrapolation (basal metabolic rate). Regarding toxicodynamic and remaining toxicokinetic differences we suggest that a percentile from a probabilistic distribution is chosen to derive the assessment factor. Based on the scarce information concerning the human-to-human variability it is more difficult to suggest a specific assessment factor. However, extra emphasis should be put on sensitive populations such as neonates and genetically sensitive subgroups, and also fetuses and children which may be particularly vulnerable during development and maturation. Factors that also need to be allowed for are possible gender differences in sensitivity, deficiencies in the databases, nature of the effect, duration of exposure, and route-to-route extrapolation. Since assessment factors are used to compensate for lack of knowledge we feel that it is prudent to adopt a "conservative" approach, erring on the side of protectiveness.     

In vitro binding of3H-acetylcholine to nicotinic receptors in rodent and human brain

Summary The binding of³H-acetylcholine (³H-ACh) to nicotinic receptors in rodent and human brain was measured in the presence of atropine to prevent binding to muscarinic binding sites.³H-ACh binds specifically and saturably to rodent brain. From saturation binding K_d was 30 nM in rat cerebral cortex, which is close to that calculated from kinetic experiments. The binding was temperature-dependent, being highest at low temperatures and decreasing at higher temperatures. The regional distribution of binding in mouse brain was not uniform. The binding was highest in the midbrain, intermediate in the cerebral cortex and striatum, and lowest in the cerebellum, hippocampus, hypothalamus and medulla oblongata. No significant correlation was found between the regional³H-ACh binding and the regional binding of³H-alpha-bungarotoxin (³H-BTX),³H-nicotine (³H-NIC),³H-tubocurarine and the endogenous acetylcholine content, although the correlation value for³H-ACh/³H-NIC was at the limit for significance.³H-ACh also bound specifically to human cerebral cortical tissue and this binding was approximately three times lower than in rodent brain, when a low³H-ACh concentration was used. In contrast to rat brain there appears to exist multiple binding sites for³H-ACh in human cerebral cortex as suggested by the curvelinear nature of the Scatchard plot. It was calculated that³H-ACh bound with K_d 4 nM and B_max 8 pmol/g protein and K_d 112 nM and B_max 67 pmol/g protein. The Hill number of 1.5 for the binding of low concentration and 2.5 for high concentration of³H-ACh also suggest that the³H-ACh-binding sites interaction exhibit positive cooperativity.     

Computer aided analysis of digitized dental stone replicas by dental CAD/CAM technology.

OBJECTIVES: To determine the reproducibility of digitized dental stone replicas compared to the master model and the reliability of the computer aided analysis. METHODS: Four master dies, prepared for complete crowns were fabricated in presintered yttria-stabilized tetragonal zirconia (Y-TZP). Eight vinyl polysiloxane impressions (PROVIL novo; Heraeus Kulzer) were taken of each die and stone replicas were poured in type IV stone (Vel-Mix Stone; Kerr). The master dies and the stone replicas were digitized in a touch-probe scanner (Procera Forte; Nobel Biocare AB), to create triangulated surface-models. The point-cloud from the first of the repeated digitizations of each master die was used as CAD-reference-models (CRM). Discrepancies between the points in the triangulated surface-models and the corresponding CRM were measured by a matching-software (CopyCAD 6.504 SP2; Delcam Plc). The distribution of the discrepancies was analyzed and presented in color-difference-maps. RESULTS: The precision of the measuring method, presented as the repeatability coefficient, ranged between 7 and 16 microm (entire surface), whereas the analysis of the stone replicas revealed a precision (repeatability coefficient) ranging from 19 to 26 microm. The accuracy of the replica to master (the mean discrepancy) ranged from 0.5 to 2.0 microm (95% confidence interval 1.5-2.9 microm). SIGNIFICANCE: The greatest precision of the measurement was seen in the jacket surface of the die. The size of the stone replicas varied and the repeatability coefficient was on average 15 microm (2-25 microm) greater for the replica-to-master alignment than the repeated digitizations of the master.     

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     

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.     

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.     

The intersubject variability of tissue factor mRNA production in human monocytes--relation with the toll-like receptor 4

OBJECTIVE: Tissue factor (TF) is known as the primary initiator of blood coagulation. Previous studies have suggested a considerable variation in the monocytic lipopolysaccharide (LPS) stimulated TF antigen levels and procoagulant activities between different individuals. Our aim with the present study was to investigate the replicability of LPS induced TF mRNA production in a series of standardised experiments with the purpose to identify putative factors influencing the TF high and low response. RESULTS: A constant and reproducible production of LPS induced TF mRNA was identified in five high responders and three low responders (out of 42 individuals) and followed-up in three subsequent experiments performed over 2 years. The LPS induced TF mRNA production correlated with the corresponding expressions of interleukin-8, tumor necrosis factor-alfa and interleukin-1 beta, indicating a common pathway with the TF high and low response. A strong and significant correlation between the LPS induced TF and toll-like receptor 4 mRNA expressions was subsequently identified and replicated. CONCLUSIONS: We demonstrated a high and low responder phenomenon of LPS induced TF mRNA in human monocytes. The production of toll-like receptor 4 mRNA was significantly enhanced in TF high responders.     

Effects of chronic stress on the immune response to oral human serum albumin-conjugated starch microparticles in rats

Uptake of antigens and bacteria over the follicle-associated epithelium (FAE) is increased after chronic psychological stress. We investigated whether stress affects the immune response to particle-conjugated antigens taken up via the FAE. Rats were submitted to two 10-day periods of water avoidance stress and orally immunized during these periods. Stressed immunized rats displayed altered cell populations and a Th1-skewed immune response within the lymphoid follicles, together with enhanced delayed-type hypersensitivity. We conclude that chronic stress affects the cell-mediated immune response after oral immunization, which may have implications for the understanding of allergic and autoimmune diseases and development of oral vaccines.     

Secondary prevention of hazardous alcohol consumption in psychiatric out-patients: a randomised controlled study

Background  

Hazardous alcohol use is associated with an increased risk for development of a substance use disorder, leading to negative outcomes in psychiatric patients.