Grouping of chemicals into mode of action classes by automated effect pattern analysis using the zebrafish embryo toxicity test.

A central element of high throughput screens for chemical effect assessment using zebrafish is the assessment and quantification of phenotypic changes. By application of an automated and more unbiased analysis of these changes using image analysis, patterns of phenotypes may be associated with the mode of action (MoA) of the exposure chemical. The aim of our study was to explore to what extent compounds can be grouped according to their anticipated toxicological or pharmacological mode of action using an automated quantitative multi-endpoint zebrafish test. Chemical-response signatures for 30 endpoints, covering phenotypic and functional features, were generated for 25 chemicals assigned to 8 broad MoA classes. Unsupervised clustering of the profiling data demonstrated that chemicals were partially grouped by their main MoA. Analysis with a supervised clustering technique such as a partial least squares discriminant analysis (PLS-DA) allowed to identify markers with a strong potential to discriminate between MoAs such as mandibular arch malformation observed for compounds interfering with retinoic acid signaling. The capacity for discriminating MoAs was also benchmarked to an available battery of in vitro toxicity data obtained from ToxCast library indicating a partially similar performance. Further, we discussed to which extent the collected dataset indicated indeed differences for compounds with presumably similar MoA or whether other factors such as toxicokinetic differences could have an important impact on the determined response patterns.

[Hospital paramedic. An interprofessional blended learning concept to qualify paramedics and medical personnel for deployment in intensive care units and emergency departments during the COVID-19 pandemic]. / Kliniksanitäter. Ein interprofessionelles Blended-Learning-Konzept zur Weiterqualifikation von Rettungsdienst- und medizinischem Personal zum Einsatz auf Intensivstationen und in Notaufnahmen während der COVID-19-Pandemie.

BACKGROUND: The COVID-19 pandemic necessitated a time-critical expansion of medical staff in intensive care units (ICU) and emergency rooms (ER). OBJECTIVE: This article describes the development, performance and first results of an interprofessional blended learning concept called hospital paramedics, qualifying paramedics and additional medical personnel to support ICUs and ERs. MATERIAL AND METHODS: The Protestant Hospital of the Bethel Foundation (EvKB), University Hospital OWL, University of Bielefeld in cooperation with the Study Institute Westfalen-Lippe, developed a 2-stage blended learning concept (stage 1 e­learning with online tutorials, stage 2 practical deployment) comprising 3 modules: ICU, ER and in-hospital emergency medicine. At the beginning, the participants were asked about their sociodemographic data (age, gender, type of medical qualifications) and subjective feeling of confidence. At the end, a final discussion with the participant, the practice instructor and the supervising physician took place and an evaluation of the deployment by the head of the practice and the hospital paramedic was carried out using questionnaires. RESULTS: Within 6 weeks 58 (63%) of the 92 participants completed the online course and 17 (29%) additionally completed their traineeship. In the ICU they assisted with preparing catheter systems, medication and nursing, performed Manchester triage and initial care in the ER. After completion hospital paramedics were significantly more confident when working in a hospital, catheterization and tracheostoma care (p < 0.05). Of the supervisors 94% deemed the deployment as useful and 100% of the participants were prepared to be available at short notice in their areas as compensation for the COVID-19-pandemic in the event of a staff shortage. Through the provision of additional intensive care ventilators and monitoring units in the period from March to the beginning of May 2020 and the personnel management that was carried out, the EvKB was in a position to increase the number of previously provided ventilator beds by potentially >40 ventilation places. CONCLUSION: Blended learning concepts, such as hospital paramedics, can quickly qualify medical personnel for use in system-relevant settings, relieve nursing staff and thus create an expansion of intensive care capacities. Existing or pending pandemic and contingency plans should be complemented by such blended learning training so that they are immediately available in case of a second pandemic wave, future pandemics or other crisis situations.

Large-scale pathway specific polygenic risk and transcriptomic community network analysis identifies novel functional pathways in Parkinson disease.

Polygenic inheritance plays a central role in Parkinson disease (PD). A priority in elucidating PD etiology lies in defining the biological basis of genetic risk. Unraveling how risk leads to disruption will yield disease-modifying therapeutic targets that may be effective. Here, we utilized a high-throughput and hypothesis-free approach to determine biological processes underlying PD using the largest currently available cohorts of genetic and gene expression data from International Parkinson's Disease Genetics Consortium (IPDGC) and the Accelerating Medicines Partnership-Parkinson's disease initiative (AMP-PD), among other sources. We applied large-scale gene-set specific polygenic risk score (PRS) analyses to assess the role of common variation on PD risk focusing on publicly annotated gene sets representative of curated pathways. We nominated specific molecular sub-processes underlying protein misfolding and aggregation, post-translational protein modification, immune response, membrane and intracellular trafficking, lipid and vitamin metabolism, synaptic transmission, endosomal-lysosomal dysfunction, chromatin remodeling and apoptosis mediated by caspases among the main contributors to PD etiology. We assessed the impact of rare variation on PD risk in an independent cohort of whole-genome sequencing data and found evidence for a burden of rare damaging alleles in a range of processes, including neuronal transmission-related pathways and immune response. We explored enrichment linked to expression cell specificity patterns using single-cell gene expression data and demonstrated a significant risk pattern for dopaminergic neurons, serotonergic neurons, hypothalamic GABAergic neurons, and neural progenitors. Subsequently, we created a novel way of building de novo pathways by constructing a network expression community map using transcriptomic data derived from the blood of PD patients, which revealed functional enrichment in inflammatory signaling pathways, cell death machinery related processes, and dysregulation of mitochondrial homeostasis. Our analyses highlight several specific promising pathways and genes for functional prioritization and provide a cellular context in which such work should be done.

NF1 mutations in conjunctival melanoma.

BACKGROUND: Conjunctival melanoma is a potentially deadly eye tumour. Despite effective local therapies, tumour recurrence and metastasis remain frequent. The genetics of conjunctival melanomas remain incompletely understood. METHODS: A large cohort of 63 conjunctival melanomas was screened for gene mutations known to be important in other melanoma subtypes by targeted next-generation sequencing. Mutation status was correlated with patient prognosis. RESULTS: Frequent mutations in genes activating the MAP kinase pathway were identified. NF1 mutations were most frequent (n = 21, 33%). Recurrent activating mutations were also identified in BRAF (n = 16, 25%) and RAS genes (n = 12, 19%; 11 NRAS and 1 KRAS). CONCLUSIONS: Similar to cutaneous melanomas, conjunctival melanomas can be grouped genetically into four groups: BRAF-mutated, RAS-mutated, NF1-mutated and triple wild-type melanomas. This genetic classification may be useful for assessment of therapeutic options for patients with metastatic conjunctival melanoma.

Optical properties of strain-compensated CdSe/ZnSe/(Zn,Mg)Se quantum well microdisks.

Strain-compensated CdSe/ZnSe/(Zn,Mg)Se quantum well structures that were grown on (In,Ga)As allow for efficient room-temperature photoluminescence and spectral tuning over the whole visible range. We fabricated microdisk cavities from these samples by making use of a challenging chemical structuring technique for selective and homogeneous removal of the (In,Ga)As sacrificial layer below the quantum structure. The observed whispering gallery modes in our microdisks are mainly visible up to photon energies of ~ 2.3 eV due to strong self-absorption. As extinction coefficients and effective refractive indices are dominated by the quantum well material CdSe, thick quantum wells (> 3 monolayer) are necessary to observe resonances in the corresponding quantum well emission.

Filtration effects of zebra mussels on pathogens and total bacterial burden in the Odra Lagoon (South Baltic).

As a result of their mode of filter feeding, zebra mussels (Dreissena polymorpha Pall.) have been observed to purify natural water bodies and in vitro. Therefore, the possibility of using zebra mussels for water purification was investigated in a slightly brackish water body of a large lagoon. In this study, water samples were taken above, near and at distance from zebra mussel beds (MB) in the Odra Lagoon in North East Germany. Near typical bacterial species like Aeromonas spp. pathogenic bacteria with potential relation to hospital wastewater pollution (Burkholderia cepacia, Staphylococcus aureus, Weeksella spp.) were detected. There were no correlations found between either total bacteria or pathogens and distance to MB and no antimicrobial effect of the mussels could be deduced. For bioremediation in larger water bodies like lagoons, natural zebra MB do not seem to play a major antimicrobial role and the effect of artificial mussel grids especially against hospital pathogens should be investigated.

TERT promoter mutations in ocular melanoma distinguish between conjunctival and uveal tumours.

BACKGROUND: Recently, activating mutations in the TERT promoter were identified in cutaneous melanoma. We tested a cohort of ocular melanoma samples for similar mutations. METHODS: The TERT promoter region was analysed by Sanger sequencing in 47 uveal (ciliary body or choroidal) melanomas and 38 conjunctival melanomas. RESULTS: Mutations of the TERT promoter were not identified in uveal melanomas, but were detected in 12 (32%) conjunctival melanomas. Mutations had a UV signature and were identical to those found in cutaneous melanoma. CONCLUSION: Mutations of TERT promoter with UV signatures are frequent in conjunctival melanomas and favour a pathogenetic kinship with cutaneous melanomas. Absence of these mutations in uveal melanomas emphasises their genetic distinction from cutaneous and conjunctival melanomas.

Alternatives to in vivo tests to detect endocrine disrupting chemicals (EDCs) in fish and amphibians--screening for estrogen, androgen and thyroid hormone disruption.

Endocrine disruption is considered a highly relevant hazard for environmental risk assessment of chemicals, plant protection products, biocides and pharmaceuticals. Therefore, screening tests with a focus on interference with estrogen, androgen, and thyroid hormone pathways in fish and amphibians have been developed. However, they use a large number of animals and short-term alternatives to animal tests would be advantageous. Therefore, the status of alternative assays for endocrine disruption in fish and frogs was assessed by a detailed literature analysis. The aim was to (i) determine the strengths and limitations of alternative assays and (ii) present conclusions regarding chemical specificity, sensitivity, and correlation with in vivo data. Data from 1995 to present were collected related to the detection/testing of estrogen-, androgen-, and thyroid-active chemicals in the following test systems: cell lines, primary cells, fish/frog embryos, yeast and cell-free systems. The review shows that the majority of alternative assays measure effects directly mediated by receptor binding or resulting from interference with hormone synthesis. Other mechanisms were rarely analysed. A database was established and used for a quantitative and comparative analysis. For example, a high correlation was observed between cell-free ligand binding and cell-based reporter cell assays, between fish and frog estrogenic data and between fish embryo tests and in vivo reproductive effects. It was concluded that there is a need for a more systematic study of the predictive capacity of alternative tests and ways to reduce inter- and intra-assay variability.

Variation of the intercalating proline in artificial peptides mimicking the DNA binding and bending IHF protein.

The integration host factor (IHF) is a protein which sequence specifically induces a bend of double-stranded DNA by more than 160°. Based on IHF as lead structure, a peptide mimic was introduced resembling the positively charged body of the protein by a lysine dendrimer and the minor groove recognition loop by a cyclopeptide. The proline located close to the tip of the recognition loop intercalates between the base pair plane. It was modified in order to evaluate the influence of the side chain residue with respect to size (1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid), aromaticity (phenylalanine), conformation of the five-membered ring [(4R)-fluoroproline, (4S)-fluoroproline, 3,4-dehydroproline], and the peptide backbone conformation (α-methylproline) on binding dsDNA and bending the double strand. Binding and bending studies were carried out by fluorescence resonance energy transfer experiments and gel electrophoresis using DNA sequences prepared by PCR with the IHF binding site in central or terminal position. Whereas aromatic residues and α-methylproline were not tolerated as proline substitute, incorporation of (4S)-fluoroproline and 3,4-dehydroproline provided enhanced binding.

[In-hospital emergency care in the Federal Republic of Germany. A site survey of hospitals in the German Resuscitation Registry]. / Innerklinische Notfallversorgung in der Bundesrepublik Deutschland. Eine Standortbefragung der Kliniken des Deutschen Reanimationsregisters.

BACKGROUND: In contrast to prehospital care there is a lack of specifications for the organization and equipment of medical emergency teams for in-hospital emergency care. OBJECTIVE: Evaluation of the organization, team composition, training, equipment and tasks of medical emergency teams in the Federal Republic of Germany. MATERIAL AND METHODS: Evaluation of a web-based survey of all hospitals participating in the German Resuscitation Register between February and March2020. The participants were asked about team composition; emergency equipment; type, content and scope of special training or further training as well as other additional tasks in the everyday clinical routine when participating in the medical emergency team. Hospitals with ≤ or >600 beds were compared. RESULTS: A total of 21 (>600 beds: 10, 48%; ≤600 beds: 11, 52%) hospitals participated in the survey. Team composition requirements were present at 76% (n = 16; ≤600 beds: 8, 72% vs. >600 beds: 8, 80%), training requirements for medical emergency teams at 38% (n = 16; ≤600 beds: 4, 36% vs. >600 beds: 4, 40%) of hospitals, with a focus on cardiac life support (n = 6, 28%; ≤600 beds: 3, 27% vs. >600 beds: 3, 30%) and airway management (n = 4, 19%; ≤600 beds: 3, 27% vs. >600 beds: 1, 10%). A 12-lead electrocardiogram (n = 7, 33%; ≤600 beds: 1, 9% vs. >600 beds: 6, 60%; p = 0.02), video laryngoscope (n = 7, 33%; ≤600 beds: 2, 18% vs. >600 beds: 5, 50%), ventilator without (n = 7, 33%; ≤600 beds: 2, 18% vs. >600 beds: 5, 50%) or with the possibility of non-invasive ventilation was part of the standard equipment in n = 4, 19% (≤600 beds: 1, 9% vs. >600 beds: 3, 30%). A total of 85% (n = 18; ≤600 beds: 10, 100% vs. >600 beds 8, 72%), had additional tasks in the daily clinical routine. While clinics with >600 beds staffed medical emergency teams 100% of the time from the intensive care units, in clinics ≤600 beds medical emergency teams were deployed significantly more often in the emergency department (n = 5, 45%) and in the normal wards (n = 5, 45%, p = 0.03). CONCLUSION: Training and equipment of medical emergency teams in the Federal Republic of Germany is heterogeneous. They should at least meet the standards commonly used in prehospital emergency medicine and include the availability of a portable 12-lead electrocardiogram, a ventilator with the possibility of noninvasive ventilation and a video laryngoscope. Regardless of the size of the hospital, continuous availability of all members of the medical emergency teams should be ensured.

Tris(methylthio)methane produced by Mortierella hyalina affects sulfur homeostasis in Arabidopsis.

Microbial volatiles are important factors in symbiotic interactions with plants. Mortierella hyalina is a beneficial root-colonizing fungus with a garlic-like smell, and promotes growth of Arabidopsis seedlings. GC-MS analysis of the M. hyalina headspace and NMR analysis of the extracted essential oil identified the sulfur-containing volatile tris(methylthio)methane (TMTM) as the major compound. Incorporation of the sulfur from the fungal volatile into plant metabolism was shown by 34S labeling experiments. Under sulfur deficiency, TMTM down-regulated sulfur deficiency-responsive genes, prevented glucosinolate (GSL) and glutathione (GSH) diminishment, and sustained plant growth. However, excess TMTM led to accumulation of GSH and GSL and reduced plant growth. Since TMTM is not directly incorporated into cysteine, we propose that the volatile from M. hyalina influences the plant sulfur metabolism by interfering with the GSH metabolism, and alleviates sulfur imbalances under sulfur stress.

Wafer-scale epitaxial modulation of quantum dot density.

Precise control of the properties of semiconductor quantum dots (QDs) is vital for creating novel devices for quantum photonics and advanced opto-electronics. Suitable low QD-densities for single QD devices and experiments are challenging to control during epitaxy and are typically found only in limited regions of the wafer. Here, we demonstrate how conventional molecular beam epitaxy (MBE) can be used to modulate the density of optically active QDs in one- and two- dimensional patterns, while still retaining excellent quality. We find that material thickness gradients during layer-by-layer growth result in surface roughness modulations across the whole wafer. Growth on such templates strongly influences the QD nucleation probability. We obtain density modulations between 1 and 10 QDs/µm2 and periods ranging from several millimeters down to at least a few hundred microns. This method is universal and expected to be applicable to a wide variety of different semiconductor material systems. We apply the method to enable growth of ultra-low noise QDs across an entire 3-inch semiconductor wafer.

Continuous S-(+)-ketamine administration during elective coronary artery bypass graft surgery attenuates pro-inflammatory cytokine response during and after cardiopulmonary bypass.

BACKGROUND: Coronary artery bypass surgery (CABG) with cardiopulmonary bypass (CPB) leads to elevated circulating plasma cytokines. In this prospective randomized study, the effect of an S-(+)-ketamine-based anaesthetic protocol on perioperative plasma cytokine levels was compared with standard anaesthesia with propofol and sufentanil during CPB. METHODS: Patients undergoing elective on-pump CABG were randomly allocated to anaesthesia with sufentanil-propofol-midazolam (Sufentanil) or S-(+)-ketamine-propofol-midazolam (Ketamine). Blood samples were obtained before induction of anaesthesia (baseline) and also at 1, 6, and 24 h after aortic unclamping. Plasma levels of the interleukins (IL)-6, IL-8, IL-10, and tumour necrosis factor (TNF)-alpha were determined by enzyme-linked immunosorbent assay. RESULTS: One hundred and twenty-eight patients were studied (Ketamine: n=60; Sufentanil: n=68). All measured cytokines increased during and after CPB. However, the increase in the pro-inflammatory cytokines IL-6 and IL-8 6 h after aortic unclamping was significantly lower in the Ketamine group compared with the Sufentanil group [mean (sd): IL-6 56.75 (46.28) pg ml⁻¹ (Ketamine) vs 172.64 (149.93) pg ml⁻¹ (Sufentanil), P<0.01; IL-8 7.74 (14.72) pg ml⁻¹ (Ketamine) vs 26.3 (47.12) pg ml⁻¹ (Sufentanil), P<0.01]. In contrast, the anti-inflammatory cytokine IL-10 showed higher levels 1 h after unclamping in the Ketamine group compared with the Sufentanil group [mean (sd): 69.59 (78.78) vs 24.63 (37.7) pg ml⁻¹, P<0.001]. CONCLUSION: Our data demonstrate that S-(+)-ketamine possesses anti-inflammatory potential. Anaesthesia with S-(+)-ketamine may have beneficial effects in attenuating the CPB-induced systemic inflammatory response.

[Analysing the work of medical and nursing staff: comparison between PsychPV requirements and everyday activities on psychiatric wards]. / Tätigkeitsanalyse im ärztlichen und pflegerischen Dienst : Abgleich der PsychPV-Vorgaben mit dem Arbeitsalltag auf einer stationären psychiatrischen Einrichtung.

BACKGROUND: Since 1991 the German psychiatry personnel regulation act (PsychPV) defines the number and tasks of medical doctors and nursing staff on a psychiatric ward. However, there is the suspicion that there are differences, especially with regard to an increased proportion of activities not involving patients, such as documentation and administrative work. METHODS: To detect differences between requirements from the PsychPV and the actual amount of time spent on different activities, a task analysis was performed on a general psychiatric and a gerontological psychiatric ward. In this study the proportions of working time spent on five different types of activities with time that should have been spent according to the PsychPV were compared. RESULTS: Discrepancies were found on both psychiatric wards and for medical doctors as well as for nursing staff. Tasks of documentation and administrative work took significantly higher proportions of working time than required in the PsychPV. On the other hand psychiatric personnel spent less time for treatment or nursing in direct contact with the patients. CONCLUSION: The results of this study confirmed the suspicion that shifting tasks on psychiatric wards has led to changed treatment settings.

[Prerequisites for a new health care model for elderly people with multiple morbidities: results and conclusions from 3 years of research in the PRISCUS consortium]. / Voraussetzungen für ein neues Versorgungsmodell für ältere Menschen mit Multimorbidität: Ergebnisse und Schlussfolgerungen aus 3-jähriger Forschung im PRISCUS-Verbund.

BACKGROUND: The concurrent presence or manifestation of multiple chronic conditions, i.e. multimorbidity, poses a challenge to affected patients and their relatives, physicians, and practitioners, and to the health care system in general. Aiming to improve medical care for different chronic diseases, the Chronic Care Model also appears to be suited for multimorbidity. The established research consortium PRISCUS is trying to create some of the prerequisites for a new care model for multimorbid, elderly patients oriented along the lines of the Chronic Care Model. METHODS AND RESULTS: Four out of seven subprojects of the research consortium provide an overview of some of their findings. Topics in a sports medicine subproject were the assessment of physical activity by means of a newly developed questionnaire and the development and feasibility testing of an exercise program for elderly people with chronic conditions and mobility impairment. Partners from family medicine implemented geriatric assessment in a primary care setting and evaluated its consequences. In a pharmacological subproject, potentially inappropriate medication as well as drug-drug interactions and dosing errors were addressed. The health economic subproject investigated quality of life impairment due to multiple chronic diseases and the effects of multimorbidity on costs. CONCLUSIONS: The results of the PRISCUS research consortium allow a better description of consequences of multimorbidity and illustrate at least some new approaches towards prevention, diagnosis, and treatment of patients suffering from multimorbidity. Ongoing projects will test the efficacy of a physical activity program and a new complex intervention to reduce potentially inappropriate medication in the elderly. With this, the research consortium will create some prerequisites for a new health care model for patients with multimorbidity comparable to the Chronic Care Model.

Parkin and PINK1 mutations in early-onset Parkinson's disease: comprehensive screening in publicly available cases and control.

BACKGROUND: Mutations in parkin and PTEN-induced protein kinase (PINK1) represent the two most common causes of autosomal recessive parkinsonism. The possibility that heterozygous mutations in these genes also predispose to disease or lower the age of disease onset has been suggested, but currently there is insufficient data to verify this hypothesis conclusively. OBJECTIVE: To study the frequency and spectrum of parkin and PINK1 gene mutations and to investigate the role of heterozygous mutations as a risk factor for early-onset Parkinson's disease (PD). METHODS: All exons and exon-intron boundaries of PINK1 and parkin were sequenced in 250 patients with early-onset PD and 276 normal controls. Gene dosage measurements were also performed, using high-density single-nucleotide polymorphism arrays. RESULTS: In total 41 variants were found, of which 8 have not been previously described (parkin: p.A38VfsX6, p.C166Y, p.Q171X, p.D243N, p.M458L; PINK1: p.P52L, p.T420T, p.A427E). 1.60% of patients were homozygous or compound heterozygous for pathogenic mutations. Heterozygosity for pathogenic parkin or PINK1 mutations was over-represented in patients compared with healthy controls (4.00% vs. 1.81%) but the difference was not significant (p = 0.13). The mean age at disease onset was significantly lower in patients with homozygous or compound heterozygous mutations than in patients with heterozygous mutations (mean difference 11 years, 95% CI 1.4 to 20.6, p = 0.03). There was no significant difference in the mean age at disease onset in heterozygous patients compared with patients without a mutation in parkin or PINK1 (mean difference 2 years, 95% CI -3.7 to 7.0, p = 0.54). CONCLUSIONS: Our data support a trend towards a higher frequency of heterozygosity for pathogenic parkin or PINK1 mutations in patients compared with normal controls, but this effect was small and did not reach significance in our cohort of 250 cases and 276 controls.

Electrode Afterload: A Valuable Technique in a Case of Short Electrode Insertion.

Introduction. The location of the electrode inside the cochlea is important for speech performance. However, many variables, including array length, insertion depth, and individual anatomy, may affect the intracochlear position of the electrode. Insertion deeper than 20 mm and revision surgery are critical situations in which residual hearing and electrode integrity may be at risk. This case report challenges this hypothesis and raises the following question: is it possible to achieve a better speech understanding with an electrode afterload without compromising residual hearing? Case Report. A 73-year-old female patient showed up for evaluation of hearing loss. The patient was operated four times in an external hospital due to cholesteatoma formation in the right ear. Related to a poor aided speech understanding, a CI-surgery was performed. 5 months after the surgery, the subject returned with poor speech understanding. A revision surgery was performed, where the first white marker of the electrode was seen in the round window (20 mm). The electrode was inserted 4 mm deeper into the cochlea. After six and twelve months, the results of the Freiburger monosyllabic speech test improved till 25% and 45%, respectively. Discussion. Hearing preservation is possible with a revisional deeper insertion from 20 mm to 24 mm. In this case, a partial obliteration of an open cavity made the electrode surgically easily accessible. This allowed the deeper insertion during the revision surgery. In a regular surgical field with a posterior tympanotomy, the revision surgery is more challenging and brings the electrode into the risk of an iatrogenic destruction. Conclusion. This case of an electrode afterload after having inserted the electrode initially to mm, demonstrates that hearing can be preserved and speech perception can improve after performing this maneuver.

[Usage of drugs with potential adverse effects on cognition in a memory-clinic]. / Verwendung von Medikamenten mit ungünstigen Wirkungen auf die Kognition in einer Gedächtnissprechstunde.

Cognitive decline is a frequent clinical symptom in elderly patients. In particular, memory disturbances are an early sign and a risk factor for subsequent development of neurodegenerative dementia. At the same time, elderly patients often receive multiple medications due to an increasing number of acquired diseases. Certain drugs have adverse side effects on cognition due to interference with the cholinergic or GABA-ergic system. This could lead to underestimation of the actual cognitive status at initial clinical presentation. In the present study we included 221 patients (mean age 68,5 years) who presented for the first time in a specialized memory-clinic and who had or developed dementia during follow up. Most patients had mixed vascular-degenerative dementia (57 %). On average, patients took 2.1 drugs. 19.9 % of the patients had medications with potential adverse effects on cognition. Patients with medication affecting cognition had a worse cognitive performance than patients with a medication not influencing cognitive functioning (Mini-Mental vs. 18.8. 22.01, p = 0.01) in univariate analysis. Psychotropic drugs were used less frequently (38 %) than primary non-CNS medication. The results remained unchanged even after performing a case-control study with the mixed dementia population with age and gender matched patients. However, in multivariate analysis, only the absolute number of medication taken remained as an independent factor. Our data highlight the clinical importance of medication history in the diagnostic work-up of cognitive impairment. The absolute number of medication taken seems to be more important than medication with possible adverse side effects on cognition.

Structure-function analysis of the interaction between Bax and the cytomegalovirus-encoded protein vMIA.

The viral mitochondrial inhibitor of apoptosis (vMIA) encoded by the human cytomegalovirus exerts cytopathic effects and neutralizes the proapoptotic endogenous Bcl-2 family member Bax by recruiting it to mitochondria, inducing its oligomerization and membrane insertion. Using a combination of computational modeling and mutational analyses, we addressed the structure-function relationship of the molecular interaction between the protein Bax and the viral antiapoptotic protein vMIA. We propose a model in which vMIA exhibits an overall fold similar to Bcl-X(L). In contrast to Bcl-X(L), however, this predicted conformation of vMIA does not bind to the BH3 domain of Bax and rather engages in electrostatic interactions that involve a stretch of amino acids between the BH3 and BH2 domains of Bax and an alpha-helical domain located within the previously defined Bax-binding domain of vMIA, between the putative BH1-like and BH2-like domains. According to this model, vMIA is likely to bind Bax preferentially in its membrane-inserted conformation. The capacity of vMIA to cause fragmentation of the mitochondrial network and disorganization of the actin cytoskeleton is independent of its Bax-binding function. We found that Delta131-147 vMIA mutant, which lacks both the Bax-binding function and cell-death suppression but has intact mitochondria-targeting capacity, is similar to vMIA in its ability to disrupt the mitochondrial network and to disorganize the actin cytoskeleton. vMIADelta131-147 is a dominant-negative inhibitor of the antiapoptotic function of wild-type vMIA. Our experiments with vMIADelta131-147 suggest that vMIA forms homo-oligomers, which may engage in cooperative and/or multivalent interactions with Bax, leading to its functional neutralization.