Crystal structures of Staphylococcusaureus methionine aminopeptidase complexed with keto heterocycle and aminoketone inhibitors reveal the formation of a tetrahedral intermediate

High-resolution crystal structures of Staphylococcus aureus methionine aminopeptidase I in complex with various keto heterocycles and aminoketones were determined, and the intermolecular ligand interactions with the enzyme are reported. The compounds are effective inhibitors of the S. aureus enzyme because of the formation of an uncleavable tetrahedral intermediate upon binding. The electron densities unequivocally show the enzyme-catalyzed transition-state analogue mimicking that for amide bond hydrolysis of substrates.     

Use of brief depression screening tools in primary care: consideration of heterogeneity in performance in different patient groups

Heterogeneity of performance of screening tools in different patient groups has rarely been considered in the literature on depression screening in primary care. The objectives of the present study were to assess and to compare diagnostic accuracy of three screening questionnaires (Brief Patient Health Questionnaire, General Health Questionnaire-12, WHO-5) in identifying depression across various patient subpopulations and to assess the accuracy of the unaided clinical assessment of primary care physicians in the same subgroups. We conducted a cross-sectional validation study in 448 primary care patients. Two-by-two tables as well as receiver operating characteristics were applied. Results indicated that diagnostic accuracy (sensitivity, specificity) of the three screening instruments as well as of the clinical diagnoses differed in the various patient groups. Superiority of one screening tool over the other depends on the subgroup considered. Gender, age, form (subtype), and severity of depression influence the test characteristics of a screening tool. This should be considered if routine depression screening should be widely introduced. Of course, the benefit of routine screening also depends on efforts made for treatment and monitoring of patients in whom depression was diagnosed.     

Kinematical analysis of handwriting movements in depressed patients

OBJECTIVE: Motor disturbances are a relevant aspect of depression. Kinematical analysis of movements can be applied to explore which type of motor dysfunction is associated with depression. We hypothesized that depressed patients draw and write significantly slower than controls and that motor disturbances become more pronounced under bi-manual demands. METHOD: We examined 37 depressed patients and 37 healthy controls using a digitizing graphic tablet and subsequent kinematical analysis of handwriting and rapid drawing movements. RESULTS: Depressed patients performed drawing with significantly less regular velocity than controls (P < 0.001), but normal velocity. Motor differences between patients and controls did not increase under bi-manual demands. Handwriting of patients was abnormally slow (P = 0.04). CONCLUSION: Irregular patterns of velocity peaks in depressed patients point to basal ganglia dysfunction and/or deficient activity of the sensorimotor cortex and the supplementary motor area as a possible substrate of hand-motor disturbances in depression.     

Alterations in calretinin immunostaining in the ferret superior olivary complex after cochlear ablation

In this study, we used image analysis to assess changes in calretinin immunoreactivity in the lateral (LSO) and medial (MSO) superior olivary nuclei in ferrets 2 months after unilateral cochlear ablations at 30-40 days of age, soon after hearing onset. These two nuclei are the first significant sites of binaural convergence in the ascending auditory system, and both receive direct projections from the deafferented cochlear nucleus. Cochlear ablation results in a decrease in the overall level of calretinin immunostaining within the LSO ipsilaterally compared with the contralateral side and with control animals and within the MSO bilaterally compared with control ferrets. In addition, the level of calretinin immunostaining ipsilaterally within neurons in the LSO was significantly less in cochlear ablated than control animals. In contrast, there was no effect of cochlear ablation on the level of calretinin immunostaining within neurons either in the contralateral LSO or in the MSO. These results are consistent with a downregulation in calretinin within the neuropil of MSO bilaterally and LSO ipsilaterally, as well as a downregulation in calretinin within somata in the ipsilateral LSO as a result of unilateral cochlear ablation soon after hearing onset. Thus, cochlear-driven activity appears to affect calcium binding protein levels in both neuropil and neurons within the superior olivary complex.     

The role of cumulative physical work load in lumbar spine disease: risk factors for lumbar osteochondrosis and spondylosis associated with chronic complaints

OBJECTIVES—To investigate the relation with a case-control study between symptomatic osteochondrosis or spondylosis of the lumbar spine and cumulative occupational exposure to lifting or carrying and to working postures with extreme forward bending.
METHODS—From two practices and four clinics were recruited 229 male patients with radiographically confirmed osteochondrosis or spondylosis of the lumbar spine associated with chronic complaints. Of these 135 had additionally had acute lumbar disc herniation. A total of 197 control subjects was recruited: 107 subjects with anamnestic exclusion of lumbar spine disease were drawn as a random population control group and 90 patients admitted to hospital for urolithiasis who had no osteochondrosis or spondylosis of the lumbar spine radiographically were recruited as a hospital based control group. Data were gathered in a structured personal interview and analysed using logistic regression to control for age, region, nationality, and other diseases affecting the lumbar spine. To calculate cumulative forces to the lumbar spine over the entire working life, the Mainz-Dortmund dose model (MDD), which is based on an overproportional weighting of the lumbar disc compression force relative to the respective duration of the lifting process was applied with modifications: any objects weighing 5 kg were included in the calculation and no minimum daily exposure limits were established. Calculation of forces to the lumbar spine was based on self reported estimates of occupational lifting, trunk flexion, and duration.
RESULTS—For a lumbar spine dose >9×10⁶ Nh (Newton×hours), the risk of having radiographically confirmed osteochondrosis or spondylosis of the lumbar spine as measured by the odds ratio (OR) was 8.5 (95% confidence interval (95% CI) 4.1 to 17.5) compared with subjects with a load of 0 Nh. To avoid differential bias, forces to the lumbar spine were also calculated on the basis of an internal job exposure matrix based on the control subjects' exposure assessments for their respective job groups. Although ORs were lower with this approach, they remained significant.
CONCLUSIONS—The calculation of the sum of forces to the lumbar spine is a useful tool for risk assessment for symptomatic osteochondrosis or spondylosis of the lumbar spine. The results suggest that cumulative occupational exposure to lifting or carrying and extreme forward bending increases the risk for developing symptomatic osteochondrosis or spondylosis of the lumbar spine.


Keywords: case-control study; physical work load; lumbar osteochondrosis; lumbar spondylosis     

Symptoms from the spectrum of Attention-Deficit/Hyperactivity Disorder (ADHD) in sexual delinquents

The implications of ADHD for sexual delinquent behavior were investigated in a sample of 127 male sexual delinquents for whom social, forensic and psychiatric data were collected. For the retrospective evaluation of ADHD-symptoms, we used the Wender Utah Rating Scale (WURS, 61-item version). We also used the Eysenck Impulsiveness Questionnaire for the assessment of impulsivity. The prevalence of ADHD within the group of sexual delinquents was 27.6 % with a persistence rate of 14.2 % at a cut-off point of 90 in the WURS. The prevalence of ADHD within the control group was 7.8 % with a persistence rate of 3.0 %. The prevalence within the group of sexual delinquents dropped to 15.7 % for childhood ADHD-symptoms and 11.0 % for partial ADHD persistence in adulthood using a cut-off score of 100. In the control group the rates were 4.8 % and 2.4 % respectively. Based on ICD-10 criteria, 35.4 % of the sexual delinquents had no psychiatric disorder. We found personality disorders of the antisocial type (22.1 % of the sample) and paraphilias in 25.2 %. Approximately, half of the delinquents with paraphilia met the criteria of pedophilia. We also found schizophrenia, organic psychiatric disorders and mental retardations in less than 5 %. The criminal careers of the sexual delinquent group with a history of childhood ADHD symptoms started 10 years earlier. We also found a significant correlation between previous convictions and the retrospective diagnosis of ADHD symptoms. This was more prominent when a previous sexual offence could be found in their criminal record. These results illustrate the hypothesis, that in addition to paraphilias the presence of ADHD-symptoms might be an important vulnerability factor for sexual delinquency, esp. when there is a persistence into adulthood. This demonstrates the need for an early therapeutical intervention, since 44.1 % of the sample had previously undergone psychiatric treatment.