Distinct glutaminyl cyclase expression in Edinger–Westphal nucleus, locus coeruleus and nucleus basalis Meynert contributes to pGlu-Aβ pathology in Alzheimer’s disease

Glutaminyl cyclase (QC) was discovered recently as the enzyme catalyzing the pyroglutamate (pGlu or pE) modification of N-terminally truncated Alzheimer’s disease (AD) Aβ peptides in vivo. This modification confers resistance to proteolysis, rapid aggregation and neurotoxicity and can be prevented by QC inhibitors in vitro and in vivo, as shown in transgenic animal models. However, in mouse brain QC is only expressed by a relatively low proportion of neurons in most neocortical and hippocampal subregions. Here, we demonstrate that QC is highly abundant in subcortical brain nuclei severely affected in AD. In particular, QC is expressed by virtually all urocortin-1-positive, but not by cholinergic neurons of the Edinger–Westphal nucleus, by noradrenergic locus coeruleus and by cholinergic nucleus basalis magnocellularis neurons in mouse brain. In human brain, QC is expressed by both, urocortin-1 and cholinergic Edinger–Westphal neurons and by locus coeruleus and nucleus basalis Meynert neurons. In brains from AD patients, these neuronal populations displayed intraneuronal pE-Aβ immunoreactivity and morphological signs of degeneration as well as extracellular pE-Aβ deposits. Adjacent AD brain structures lacking QC expression and brains from control subjects were devoid of such aggregates. This is the first demonstration of QC expression and pE-Aβ formation in subcortical brain regions affected in AD. Our results may explain the high vulnerability of defined subcortical neuronal populations and their central target areas in AD as a consequence of QC expression and pE-Aβ formation.     

How much are radiological parameters related to clinical symptoms and function in osteoarthritis of the shoulder?

Loss of joint space, formation of osteophytes and deformation are common features of osteoarthritis. Little information exists about the radiological features of arthrosis in relation to clinical findings and the radiological appearance in degenerative shoulder joint disease especially with regard to decision making about the timing of joint replacement. We retrospectively examined 120 standardised X-rays of patients with advanced osteoarthritis of the shoulder. Exclusion criteria included rotator cuff tear, severe glenoid erosion or protrusion. Measurements of joint space width at three levels in each plane (anteroposterior and axillary view), humeral head diameter and size of humeral osteophytes were made by two independent examiners. Osteoarthritis was graded according to Samilson and Prieto. Seventy-five of these patients had a complete record from the clinical investigation (pain record on VAS scale, active and passive range of motion) and the constant score (CS). Mean joint space width in the central anteroposterior level was 1.46 mm ± 1.08 and in the central axillary 0.98 mm ± 1.02. Increasing age was positively correlated with joint space narrowing at all measured levels. The joint space width was not correlated with the Samilson grade or the size of osteophytes. The joint space width was neither correlated with pain nor active or passive ROM. Pain was correlated with active and passive flexion and abduction but not for internal or external rotation. The size of the osteophytes was negatively correlated (active and passive) with flexion, abduction and external and internal rotation. The study illustrates that joint space narrowing and development of osteophytes are reliable but independent parameters of primary shoulder arthrosis and should be recorded separately. The size of the caudal humeral osteophyte is a predictive factor for function and should be taken into account for clinical decision making. The primary clinical feature, pain, as the main indication for surgery is not related to radiological parameters.     

The clinical psychological diagnostic system (KPD‐38): Sensitivity to change and validity of a self‐report instrument for outcome monitoring and quality assurance

Background: Monitoring psychotherapeutic progress requires valid and economic measures to detect change of clinical relevance. We addressed validity and sensitivity to change of the ‘Klinisch Psychologisches Diagnosesystem 38’ (KPD‐38, Clinical Psychological Diagnosis System), an instrument for outcome monitoring and quality assurance. Methods: Data from an inpatient sample (n = 1.377) were used to investigate the concurrent validity, the sensitivity to change, and the criterion validity of the KPD‐38 in comparison to the Outcome Questionnaire (OQ‐45) and the Brief Symptom Inventory (BSI). Results: Sensitivity‐specificity analyses showed similar sensitivity and higher specificity for the KPD‐38 scales compared with the BSI and OQ total scores. Change rates on the KPD‐38 distress scale (DIS) were found to be lower than on the BSI (KPD‐38 DIS: 36.6%, GSI: 67.7%) and the OQ‐45 (KPD‐38 DIS: 44.3%, OQ tot: 57.1%) total scores. Concordance was low with the BSI ([κ = 0.24] and moderate with the OQ‐45 [κ = 0.45]). Discussion: Implications for applications in the field of outcome assessment and the challenge of further validation are discussed. The relation between sensitivity to change and criterion validity is highlighted. Copyright © 2010 John Wiley & Sons, Ltd. Key Practitioner Messages: ? The KPD‐38 is a self‐report questionnaire for outcome monitoring and quality assurance, which is free of charge for research purposes. ? Both OQ‐45 and BSI show higher sensitivity to change than the KPD‐38, overall concordance of change is moderate. ? Aspects of validity should be considered in the evaluation of sensitivity to change.     

Comparing the error‐related negativity across groups: The impact of error‐ and trial‐number differences

The error‐related negativity (ERN or Ne) is increasingly being investigated as a marker discriminating interindividual factors and moves toward a surrogate marker for disorders or interventions. Although reproducibility and validity of neuroscientific and psychological research has been criticized, clear data on how different quantification methods of the ERN and their relation to available trial numbers affect within‐ and across‐participant studies is sparse. Within a large sample of 863 healthy human participants, we demonstrate that, across participants, the number of errors correlates with the amplitude of the ERN independently of the number of errors included in ERN quantification per participant, constituting a possible confound when such variance is unaccounted for. Additionally, we find that ERN amplitudes reach high consistency within participants at lower trial numbers, yet when comparisons between groups of participants are desired, increasing error‐trial numbers lead to higher statistical power. We derive concrete suggestions for specific types of analyses, which may help researchers to more effectively design studies and analyze error‐related EEG data with the most appropriate measurement technique for the question at hand and trial number available.     

Penetration enhancement of two topical 5‐aminolaevulinic acid formulations for photodynamic therapy by erbium:YAG laser ablation of the stratum corneum: continuous versus fractional ablation

Please cite this paper as: Penetration enhancement of two topical 5‐aminolaevulinic acid formulations for photodynamic therapy by erbium:YAG laser ablation of the stratum corneum: continuous versus fractional ablation. Experimental Dermatology 2010; 19 : 806–812. Abstract: 5‐Aminolaevulinic acid (ALA) is used in photodynamic therapy (PDT). Response rates of PDT vary widely, which may be because of the limited uptake of topically applied photosensitisers. We investigated skin penetration and fluorescence induction of protoporphyrin IX (PpIX) after applying either 20% ALA cream or 20% aminolaevulinic acid solution on laser‐stripped stratum corneum (SC) in an ex vivo full‐thickness porcine skin model. Both formulations are used in clinical practice. To enhance the skin penetration of ALA, we used two different 2940‐nm erbium:yttrium–aluminium–garnet (Er:YAG) laser systems to partially ablate the SC: continuous and fractional ablation. Different fluences were applied ranging from 0.5 to 1.5 J/cm² (continuous ablation) and from 4 to 24 J/cm² (fractional ablation). Fluorescence microscopy was used for detecting PpIX‐induced fluorescence. Compared to skin without laser pretreatment, mean fluorescence intensity (MFI) of PpIX was enhanced 13.8‐fold after continuous ablation with 1.0 J/cm² and 7.3‐fold after fractional ablation with 4 J/cm²; each laser procedure was followed by 4‐h incubation with lipophilic ALA cream. Optimal parameters for continuous ablation without damage to the epidermis were 1 J/cm² for both formulations, fractional ablation was best with 4 J/cm². Histological evaluations of laser‐treated skin showed necrosis and apoptosis, depending on light dose. In laser‐stripped skin, PpIX fluorescence was detected earlier and reached deeper epidermal layers than in untreated skin. Continuous laser ablation induced higher PpIX fluorescence levels than fractional ablation. This method offers a promising new tool for enhancing ALA penetration in PDT without damaging the underlying tissue.     

The European Trauma Course (ETC) and the team approach: Past,present and future

The European Trauma Course (ETC) was officially launched during the international conference of the European Resuscitation Council (ERC) in 2008. The ETC was developed on behalf of ESTES (European Society of Trauma and Emergency Surgery), EuSEM (European Society of Emergency Medicine), the ESA (European Society of Anaesthesiology) and the ERC. The objective of the ETC is to provide an internationally recognised and certified life support course, and to teach healthcare professionals the key principles of the initial care of severely injured patients. Its core elements, that differentiates it from other trauma courses, are a strong focus on team training and a novel modular design that is adaptable to the differing regional European requirements.This article describes the lessons learnt during the European Trauma Course development and provides an outline of the planned future development.     

Degradation of cytoplasmic substrates by FtsH,a membrane-anchored protease with many talents

Control of cellular processes by regulated proteolysis is conserved among all organisms. FtsH, the only membrane-anchored AAA protease in bacteria, fulfills a variety of regulatory functions. This review focuses on soluble FtsH substrates in Escherichia coli and in other bacteria and outlines emerging substrate recognition principles.