LRP1 Has a Predominant Role in Production over Clearance of Aβ in a Mouse Model of Alzheimer's Disease.

The low-density lipoprotein receptor-related protein-1 (LRP1) has a dual role in the metabolism of the amyloid precursor protein (APP). In cellular models, LRP1 enhances amyloid-β (Aβ) generation via APP internalization and thus its amyloidogenic processing. However, conditional knock-out studies in mice define LRP1 as an important mediator for the clearance of extracellular Aβ from brain via cellular degradation or transcytosis across the blood-brain barrier (BBB). In order to analyze the net effect of LRP1 on production and clearance of Aβ in vivo, we crossed mice with impaired LRP1 function with a mouse model of Alzheimer's disease (AD). Analysis of Aβ metabolism showed that, despite reduced Aβ clearance due to LRP1 inactivation in vivo, less Aβ was found in cerebrospinal fluid (CSF) and brain interstitial fluid (ISF). Further analysis of APP metabolism revealed that impairment of LRP1 in vivo shifted APP processing from the Aβ-generating amyloidogenic cleavage by beta-secretase to the non-amyloidogenic processing by alpha-secretase as shown by a decrease in extracellular Aβ and an increase of soluble APP-α (sAPP-α). This shift in APP processing resulted in overall lower Aβ levels and a reduction in plaque burden. Here, we present for the first time clear in vivo evidence that global impairment of LRP1's endocytosis function favors non-amyloidogenic processing of APP due to its reduced internalization and subsequently, reduced amyloidogenic processing. By inactivation of LRP1, the inhibitory effect on Aβ generation overrules the simultaneous impaired Aβ clearance, resulting in less extracellular Aβ and reduced plaque deposition in a mouse model of AD

Granularzelltumor des Larynx

Zusammenfassung: Granularzelltumoren (GZT) sind subkutan oder submukös gelegene, gutartige Tumoren neurogenen Ursprungs. Sie treten häufig im Kopf-Hals-Bereich auf, insbesondere in der Zunge. Bisher wurden etwa 200 laryngeale GZT beschrieben. Meist sind dabei die Stimmlippen und die posteriore Glottis betroffen. Eine Unterscheidung von einer chronischen Entzündung oder einem Malignom ist nur mittels Biopsie möglich. Als Therapie der Wahl wird die vollständige Exzision empfohlen, wobei Tumorausdehnung und zu erwartende Morbidität die Radikalität des Vorgehens bestimmen. Bei vollständiger Entfernung sind Rezidive selte

Laryngeales Kontaktgranulom: Ätiologie, Symptomatik, Diagnose und Therapie

Zusammenfassung: Kontaktgranulome sind gutartige, meist einseitige chronisch entzündliche Erkrankungen im Bereich des Processus vocalis des Kehlkopfs. Auf der Gegenseite findet sich oft an korrespondierender Stelle ein Kontaktulkus. Fremdkörpergefühl, Räusperzwang, Heiserkeit und eine verminderte stimmliche Belastbarkeit stehen klinisch im Vordergrund, insbesondere bei Patienten mit Sprechberufen und mangelnder Stimmtechnik. Ein Malignom kann nahezu immer anamnestisch und klinisch ausgeschlossen werden, weshalb eine Biopsie nur bei Malignomverdacht begründet ist. Bei Verdacht auf eine gastroösophageale Refluxkrankheit (GERD) ist eine entsprechende fachärztliche Abklärung angezeigt. Das Therapieprinzip sollte aufgrund der Multikausalität für jeden Patienten entsprechend angepasst werden. Dabei soll eine logopädische Stimmtherapie als Basis jeglicher Therapie angeordnet werden. Eine Antirefluxtherapie sowie eine psychologische Beratung können gelegentlich hilfreich sein. Operative Abtragungen sollen vermieden werden wegen der Gefahr des Rezidivs. Anhand von 2Fallbeispielen wird der klassische Verlauf des Krankheitsbildes geschildert und anschießend auf Ätiologie, Symptome, Diagnostik und Therapie eingegange

HSP70 Expression in Skeletal Muscle of Patients with Peripheral Arterial Occlusive Disease

AbstractObjectives: heat shock protein (HSP70) has been studied in the ischaemic myocardium and proven to provide protection against ischaemia. However, HSP70 in ischaemic skeletal muscle in patients with peripheral arterial occlusive disease (PAOD) has not been reported.Methods: thirty-four patients with PAOD (Fontaine's criteria: stage II: 15; III: 9 and IV: 10, respectively) and ten non-PAOD controls were enrolled in the study. Calf muscle samples were taken. HSP70 was quantitated by SDS-PAGE using ultrasensitive silver staining with reference to a series of standard HSP70, and HSP70 mRNA was estimated using RT-PCR.Results: in comparison with the controls [median with range: 24.8 (14.1–35.6) ng in 2.5μg total protein], HSP70 was increased significantly in PAOD [stage II: 93.1 (62.7–114.3); stage III: 110.1 (89.7–134.5) and stage IV: 77.4 (67.3–101.1)]. Similar results were obtained with HSP70 mRNA.Conclusions: HSP70 is increased in the ischaemic skeletal muscle in patients with PAOD, and HSP70 expression is different with regard to clinical stages, and the upregulation of HSP70 mRNA implies that the expression of HSP70 seems to be regulated at transcriptional level

Detection of Methicillin Resistance in Staphylococcus aureus From Agar Cultures and Directly From Positive Blood Cultures Using MALDI-TOF Mass Spectrometry-Based Direct-on-Target Microdroplet Growth Assay

Matrix-assisted laser desorption/ionization time-of-flight-mass spectrometry (MALDI-TOF MS)-based direct-on-target microdroplet growth assay (DOT-MGA) was recently described as a novel method of phenotypic antimicrobial susceptibility testing (AST). Here, we developed the application of MALDI-TOF MS-based DOT-MGA for Gram-positive bacteria including AST from agar cultures and directly from positive blood cultures (BCs) using the detection of methicillin resistance as example. Consecutively collected, a total of 14 methicillin-resistant Staphylococcus aureus (MRSA) and 14 methicillin-susceptible S. aureus (MSSA) clinical isolates were included. Furthermore, a collection of MRSA challenge strains comprising different SCCmec types, mec genes, and spa types was tested. Blood samples were spiked with MRSA and MSSA and positive BC broth processed by three different methods: serial dilution of BC broth, lysis/centrifugation, and differential centrifugation. Processed BC broth was directly used for rapid AST using DOT-MGA. Droplets of 6 μl with and without cefoxitin at the EUCAST breakpoint concentration were spotted in triplicates onto the surface of a MALDI target. Targets were incubated in a humidity chamber, followed by medium removal and on-target protein extraction with formic acid before adding matrix with an internal standard as a quality control (QC). Spectra were acquired and evaluated using MALDI Biotyper software. First, tests were considered as valid, if the growth control achieved an identification score of ≥1.7. For valid tests, same score criterion was used for resistant isolates when incubated with cefoxitin. An identification score <1.7 after incubation with cefoxitin defined susceptible isolates. On-target protein extraction using formic acid considerably improved detection of methicillin resistance in S. aureus and DOT-MGA showed feasible results for AST from agar cultures after 4 h incubation time. Comparing the different processing methods of positive BC broth, lysis/centrifugation method with a final dilution step 10–1 of the 0.5 McFarland suspension resulted in best test performance after 4 h incubation time. Overall, 96.4% test validity, 100% sensitivity, and 100% specificity were achieved for detection of methicillin resistance in clinical isolates. All strains of the MRSA challenge collection were successfully tested as methicillin-resistant. This first study on Gram-positive organisms showed feasibility and accuracy of MALDI-TOF MS-based DOT-MGA for rapid AST of S. aureus from agar cultures and directly from positive BCs

Structural and optical quality of GaN grown on Sc2O3/Y2O3/Si(111)

Thick (∼900 nm) GaN layers were grown by molecular beam epitaxy on cost-effective Sc2O3/Y2O3/Si(111) substrates and characterized by x-ray diffraction and photoluminescence. Samples grown in Ga-rich condition show superior structural and optical quality with reduced density of cubic GaN inclusions within the hexagonal matrix and a relatively strong photoluminescence emission at 3.45 eV at 10 K. Cubic inclusions are formed in the initial growth stage and their concentration is reduced with increasing film thickness and after rapid thermal annealing

Development of a Health-Related Quality of Life Questionnaire (HRQL) for patients with Extremity Soft Tissue Infections (ESTI)

BACKGROUND: Past clinical trials of antimicrobial treatment in soft tissue infections have focused on non-standardized clinical and physiological outcome variables, and have not considered the subjective experience of patients. The objective of this study was to develop a health-related quality of life questionnaire (HRQL) for patients with extremity soft tissue infections (ESTI) for future use in clinical trials. METHODS: The design of this study followed published guidelines and included item generation, item reduction, and questionnaire preparation. Study subjects were consenting English-speaking adults with acute ESTI requiring prescription of at least two days of outpatient intravenous antibiotic therapy. RESULTS: A list of 49 items that adversely impact the quality of life of patients with ESTI was generated by literature review, informal health professional feedback, and semi-structured interviews with twenty patients. A listing of these items was then administered to 95 patients to determine their relative importance on quality of life. A questionnaire was prepared that included the twenty most important items with a 5-point Likert scale response. Questionnaire domains included physical symptoms, problems performing their activities of daily living, impairment of their emotional functioning, and difficulties in their social interactions as related to their ESTI. The final questionnaire was pre-tested on a further ten patients and was named the ESTI-Score. CONCLUSION: The ESTI-Score is a novel instrument designed to quantify the impact of ESTI on quality of life. Future study is required to determine its validity and responsiveness before use as an outcome measure in clinical trials