Journal of negative results in biomedicine最新文献

Background: Drug-induced parkinsonism (DIP) has a high prevalence and is associated with poorer quality of life. To find a practical clinical tool to assess DIP in patients with severe mental illness (SMI), the association between blink rate and drug-induced parkinsonism (DIP) was assessed.

Methods: In a cohort of 204 SMI patients receiving care from the only mental health service of the previous Dutch Antilles, blink rate per minute during conversation was assessed by an additional trained movement disorder specialist. DIP was rated on the Unified Parkinson's Disease Rating Scale (UPDRS) in 878 assessments over a period of 18 years. Diagnostic values of blink rate were calculated.

Results: DIP prevalence was 36%, average blink rate was 14 (standard deviation (SD) 11) for patients with DIP, and 19 (SD 14) for patients without. There was a significant association between blink rate and DIP (p < 0.001). With a blink rate cut-off of 20 blinks per minute, sensitivity was 77% and specificity was 38%. A 10% percentile cut-off model resulted in an area under the ROC curve of 0.61. A logistic prediction model between dichotomous DIP and continuous blink rate per minute an area under the ROC curve of 0.70.

Conclusions: There is a significant association between blink rate and DIP as diagnosed on the UPDRS. However, blink rate sensitivity and specificity with regard to DIP are too low to replace clinical rating scales in routine psychiatric practice.

Trial registration: The study was started over 20 years ago in 1992, at the time registering a trial was not common practice, therefore the study was never registered.

Background: Work-related stress is a global problem with negative implications for individuals and society. The purpose of the current study was to evaluate a stress management intervention for patients on sick leave due to work-related stress complaints using a three-armed randomized controlled design.

Methods: Participants were patients referred from three municipalities to the regional Department of Occupational Medicine. Inclusion criteria were: 1) sick leave due to work-related stress complaints, 2) a diagnosis of adjustment disorder or reactions to severe stress (ICD 10 code: F43,2 - F 43,9 not PTSD) or mild depressive episode (F 32.0). Through a double randomization procedure patients (n = 163) were randomized to either an intervention group (n = 58), a 'control group A' receiving a clinical examination (n = 56), or 'control group B' (n = 49) receiving no offers at the department. The intervention comprised six sessions of individual cognitive behavioral therapy and the offer of a small workplace intervention. Questionnaire data were analyzed with multivariate repeated measurements analysis. Primary outcomes assessed were perceived stress and general mental health. Secondary outcomes were sleep quality and cognitive failures. Follow-up was at four and 10 months after baseline.

Results: Complaints were significantly reduced in all groups over time. No group effects were observed between the intervention group and control group A that was clinically assessed. Significant group effects were found for perceived stress and memory when comparing the intervention group to group B, but most likely not due to an intervention effect.

Conclusion: Psychological complaints improved substantially over time in all groups, but there was no significant treatment effect on any outcomes when the intervention group was compared to control group A that received a clinical assessment.

Trial registration: ISRCTN ISRCTN91404229. Registered 03 August 2012 (retrospectively registered).

Background: A series of human diseases are caused by the misfolding and aggregation of specific proteins or peptides into amyloid fibrils; nine of these diseases, referred to as polyglutamine diseases, are associated with proteins carrying an expanded polyglutamine (polyQ) region. While the presence of this latter is thought to be the determinant factor for the development of polyQ diseases, the non-polyQ regions of the host proteins are thought to play a significant modulating role.

Method: In order to better understand the role of non-polyQ regions, the toxic effects of model proteins bearing different polyQ regions (containing up to 79 residues) embedded at two distinct locations within the β-lactamase (BlaP) host enzyme were evaluated in Caenorhabditis elegans. This small organism can be advantageous for the validation of in vitro findings, as it provides a multicellular context yet avoids the typical complexity of common studies relying on vertebrate models. Several phenotypic assays were performed in order to screen for potential toxic effects of the different BlaP-polyQ proteins.

Results: Despite the significant in vitro aggregation of BlaP-polyQ proteins with long polyQ regions, none of the BlaP-polyQ chimeras aggregated in the generated transgenic in vivo models.

Conclusion: The absence of a toxic effect of the expression of BlaP-polyQ chimeras may find its cause in biochemical mechanisms present in vivo to cope with protein aggregation (e.g. presence of chaperones) or in C. elegans' limitations such as its short lifespan. It is plausible that the aggregation propensities of the different BlaP chimeras containing embedded polyQ sequences are too low in this in vivo environment to permit their aggregation. These experiments emphasize the need for several comparative and in vivo verification studies of biologically relevant in vitro findings, which reveal both the strengths and limitations of widely used model systems.

Background: To investigate the association between polymorphism rs547984, located in close proximity to the Zona Pellucida Glycoprotein 4 (ZP4) gene on human chromosome 1q43 and primary open angle glaucoma (POAG).

Method: Polymorphism rs547984 was genotyped using Taq-Man® assay in 185 subjects comprising of 90 unrelated POAG cases and 95 controls of Saudi origin.

Results: Association analysis between cases and controls revealed no significant genotype distribution under additive (p = 0.356), dominant (p = 0.517) and recessive (p = 0.309) models. Besides, the allele frequency distribution was also found to be non-significant (p = 0.70). The minor "A" allele frequency was found to be 0.49 and 0.50 among POAG cases and controls, respectively. In addition, specific clinical indices used to assess severity of glaucoma such as intraocular pressure (IOP), cup/disc ratio and number of anti-glaucoma medication also did not show any significant genotype distribution in POAG cases.

Conclusion: Polymorphism rs547984 is neither associated with any clinical indices important for POAG such as IOP and cup/disc ratio nor is a risk factor for POAG in the Saudi cohort.

Background: While the positive effect of balance training on age-related impairments in postural stability is well-documented, the neural correlates of such training adaptations in older adults remain poorly understood. This study therefore aimed to shed more light on neural adaptations in response to balance training in older adults.

Methods: Postural stability as well as spinal reflex and cortical excitability was measured in older adults (65-80 years) before and after 5 weeks of balance training (n = 15) or habitual activity (n = 13). Postural stability was assessed during one- and two-legged quiet standing on a force plate (static task) and a free-swinging platform (dynamic task). The total sway path was calculated for all tasks. Additionally, the number of errors was counted for the one-legged tasks. To investigate changes in spinal reflex excitability, the H-reflex was assessed in the soleus muscle during quiet upright stance. Cortical excitability was assessed during an antero-posterior perturbation by conditioning the H-reflex with single-pulse transcranial magnetic stimulation.

Results: A significant training effect in favor of the training group was found for the number of errors conducted during one-legged standing (p = .050 for the static and p = .042 for the dynamic task) but not for the sway parameters in any task. In contrast, no significant effect was found for cortical excitability (p = 0.703). For spinal excitability, an effect of session (p < .001) as well as an interaction of session and group (p = .009) was found; however, these effects were mainly due to a reduced excitability in the control group.

Conclusions: In line with previous results, older adults' postural stability was improved after balance training. However, these improvements were not accompanied by significant neural adaptations. Since almost identical studies in young adults found significant behavioral and neural adaptations after four weeks of training, we assume that age has an influence on the time course of such adaptations to balance training and/or the ability to transfer them from a trained to an untrained task.

Background: Medication effect is the sum of its drug, placebo, and drug*placebo interaction effects. It is conceivable that the interaction effect involves modulating drug bioavailability; it was previously observed that being aware of caffeine ingestion may prolong caffeine plasma half-life. This study was set to evaluate such concept using different drugs.

Methods: Balanced single-dose, two-period, two-group, cross-over design was used to compare the pharmacokinetics of oral cephalexin, ibuprofen, and paracetamol, each described by its name (overt) or as placebo (covert). Volunteers and study coordinators were deceived as to study aim. Drug concentrations were determined blindly by in-house, high performance liquid chromatography assays. Terminal-elimination half-life (t_½) (primary outcome), maximum concentration (C_max), C_max first time (T_max), terminal-elimination-rate constant (λ), area-under-the-concentration-time-curve, to last measured concentration (AUC_T), extrapolated to infinity (AUC_I), or to T_max of overt drug (AUC_Overttmax), and C_max/AUC_I were calculated blindly using standard non-compartmental method. Covert-vs-overt effect on drug pharmacokinetics was evaluated by analysis-of-variance (ANOVA, primary analysis), 90% confidence interval (CI) using the 80.00-125.00% bioequivalence range, and percentage of individual pharmacokinetic covert/overt ratios that are outside the +25% range.

Results: Fifty, 30, and 50 healthy volunteers (18%, 10%, and 6% females, mean (SD) age 30.8 (6.2), 31.4 (6.6), and 31.2 (5.4) years) participated in 3 studies on cephalexin, ibuprofen, and paracetamol, respectively. Withdrawal rate was 4%, 0%, and 4%, respectively. Eighteen blood samples were obtained over 6, 10, and 14 h in each study period of the three drugs, respectively. ANOVA showed no significant difference in any pharmacokinetic parameter for any of the drugs. The 90% CIs for AUC_T, AUC_I, C_max, AUC_Overttmax, and C_max/AUC_I were within the bioequivalence range, except for ibuprofen C_max (76.66-98.99), ibuprofen C_max/AUC_I (77.19-98.39), and ibuprofen (45.32-91.62) and paracetamol (51.45-98.96) AUC_Overttmax. Out of the 126 individual covert/overt ratios, 2.0-16.7% were outside the +25% range for AUC_T, 2.0-4.2% for AUC_I, 25.0-44.9% for C_max, 67.3-76.7% for AUC_Overttmax, and 45.8-71.4% for T_max.

Conclusions: This study couldn't confirm that awareness of drug ingestion modulates its bioavailability. However, it demonstrates the trivial effect of blinding in bioequivalence studies and the extent of bio-variability that would be expected when comparing a drug product to itself.

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