Occurrence and co-localization of amyloid beta-protein and apolipoprotein E in perivascular drainage channels of wild-type and APP-transgenic mice

The deposition of the amyloid beta-protein (Abeta) is a hallmark of Alzheimer's disease (AD). One reason for Abeta-accumulation and deposition in the brain may be an altered drainage along perivascular channels. Extracellular fluid is drained from the brain towards the cervical lymph nodes via perivascular channels. The perivascular space around cerebral arteries is the morphological correlative of these drainage channels. Here, we show that Abeta is immunohistochemically detectable within the perivascular space of 25 months old wild-type and amyloid precursor protein (APP)-transgenic mice harboring the Swedish double mutation driven by a neuron specific promoter. Only small amounts of Abeta can be detected immunohistochemically in the perivascular space of wild-type mice. Cerebrovascular and parenchymal Abeta-deposits were absent. In APP-transgenic mice, large amounts of Abeta were found in the perivascular drainage channels accompanied with cerebrovascular and parenchymal Abeta-deposition. The apolipoprotein E (apoE) immunostaining within the perivascular channels did not vary between wild-type and APP-transgenic mice. Almost 100% of the area that represents the perivascular space was stained with an antibody directed against apoE. Here, Abeta co-localized with apoE indicating an involvement of apoE in the perivascular clearance of Abeta. Fibrillar congophilic amyloid was not seen in wild-type mice. In APP-transgenic animals, congophilic fibrillar amyloid material was seen in the wall of cerebral blood vessels but not in the perivascular space. In conclusion, our results suggest that non-fibrillar forms of Abeta are drained along perivascular channels and that apoE is presumably involved in this clearance mechanism. Overloading such a clearance mechanism in APP-transgenic mice appears to result in insufficient Abeta-clearance, increased Abeta-levels in the brain and the perivascular drainage channels, and finally in Abeta-deposition. In so doing, our results strengthen the hypothesis that an alteration of perivascular drainage supports Abeta-deposition and the development of AD.     

A comprehensive in vitro investigation of a portable magnetic separator device for human blood detoxification

A portable magnetic separator device is being developed for a proposed magnetically based detoxification system. In this paper, the performance of this device was evaluated via preliminary in vitro flow experiments using simple fluids and a separator unit consisting of one tube and two metal wires, each at the top and bottom of the tube. The effects of the following factors were observed: mean flow velocity U(o) (0.14-45 cm s(-1)), magnetic field strength micro(o)H(o) (0.125-0.50 T), wire size R(w) (0.125, 0.250 and 0.500 mm), wire length L(w) (2, 5 and 10 cm), wire materials (nickel, stainless steel 304 and 430) and tube size (outer radius R(o) = 0.30 mm and inner radius R(i) = 0.25 mm; R(o) = 0.50 mm and R(i) = 0.375 mm; and R(o) = 2.0 mm and R(i) = 1.0 mm). Our observations showed that the experimental results fit well with the corresponding theoretical results from the model we previously developed at a low flow velocity area (for example, U(o) < or = 20 cm s(-1)), strong external magnetic field (for example, > or = 0.30 T) and long wire length (for example, L(w) = 10 cm). The experimental results also showed that more than 90% capture efficiency is indeed achievable under moderate systemic and operational conditions. Pressure drop measurements revealed that the device could work well under human physiological and clinical conditions, and sphere buildup would not have any considerable effect on the pressure drop of the device. The breakthrough experiments demonstrated that a lower flow rate V, higher applied magnetic field micro(o)H(o) and diluted sphere suspension, i.e. lower C(o), would delay the breakthrough. All the results indicate the promise of this portable magnetic separator device to efficiently in vivo sequestrate nano-/micro-spheres from blood flow in the future magnetically based detoxification system.     

Implementation and validation of portal dosimetry with an amorphous silicon EPID in the energy range from 6 to 25 MV

The purpose of this study was to develop, implement and validate a method for portal dosimetry with an amorphous silicon EPID for a wide energy range. Analytic functions were applied in order to correct for nonlinearities in detector response with dose rate, irradiation time and total dose. EPID scattering processes were corrected for by means of empirically determined convolution kernels. For a variety of rectangular and irregularly shaped fields, head scatter factors determined from central axis portal dose values and those measured with an ionization chamber showed a maximum deviation of 0.5%. The accuracy of our method was further investigated for pretreatment IMRT verification (i.e. without absorbers in the beam). The agreement between EPID and film dosimetry was quantified using gamma (gamma) evaluation, with 2% dose and 2 mm distance-to-agreement criteria. All gamma-distributions showed a gamma(mean) < 0.5, a 99th percentile <1.5 and a fraction of pixels with gamma > 1 smaller than 7%. The number of monitor units delivered by single segments of the IMRT fields could be extracted from the portal images with high accuracy. Measured and delivered doses were within +/-3% for more than 98% of data points. Ghosting effects were found to have limited effects on dosimetric IMRT verification.     

Rapid antidepressant effect of S-ketamine in schizophrenia

Rapid anti-suicidal and antidepressant effects of ketamine have repeatedly been confirmed in unipolar and bipolar depression. Although meaningful antidepressant efficacy of ketamine has also been shown in depressed patients with a history of psychotic symptoms, its administration in psychotic disorders has largely been neglected due to its potential to exacerbate dissociative or psychotic symptoms. Presenting a case of a young female inpatient suffering from schizophrenia with a severe post-psychotic depression, we demonstrate a robust anti-suicidal and antidepressant effect of S-ketamine infusions administered thrice weekly for 3 weeks in total. Importantly, no relevant psychotic or dissociative symptoms occurred during the whole augmentation treatment period leading to a sustained remission of depressive symptoms and suicidality. Our safe and effective experience with intravenous S-ketamine might encourage researchers and clinicians to widen its administration range beyond the diagnosis of depression to enrich the current knowledge of ketamine effects in psychotic disorders.     

Die Unfallchirurgie und die Deutsche Gesellschaft für Unfallchirurgie

Die Unfallchirurgie -     

Are our expectations bigger than the results we achieve? A comparative study analysing potential advantages of ankle arthroplasty over arthrodesis

Purpose

Prior studies have reported improved gait performance and kinematics after total ankle arthroplasty (TAR) compared to ankle arthrodesis (AAD). Given these findings, AAD has been primarily considered as a salvage procedure that may lead to adjacent joint degeneration.

Methods

A total of 101 TAR and 40 screw arthrodeses were enrolled in a retrospective study with a prospectively designed follow-up examination that included gait analysis and outcome assessment with the AOFAS hindfoot score and FAOS questionnaire.

Results

Significant asymmetry in gait and reduced range of motion compared to normal remained after both procedures. Subjective outcome improved after both procedures, and pain was significantly better after TAR. Limited functional gains after TAR and joint degeneration to the same degree after both procedures was seen in the mid-term. Hindfoot fusion seemed to have a greater impact on postoperative function than ankle arthrodesis.

Conclusion

Considering only minor functional gains of TAR compared to AAD the implantation of current TAR designs in large patient series may be questioned.     

Customised osteotomy guides and endoprosthetic reconstruction for periacetabular tumours

Purpose

We sought to analyse clinical and oncological outcomes of patients after guided resection of periacetabular tumours and endoprosthetic reconstruction of the remaining defect.

Methods

From 1988 to 2008, we treated 56 consecutive patients (mean age 52.5 years, 41.1 % women). Patients were followed up either until death or February 2011 (mean follow up 5.5 years, range 0.1–22.5, standard deviation ± 5.3). Kaplan–Meier analysis was used to estimate survival rates.

Results

Disease-specific survival was 59.9 % at five years and 49.7 % at ten and 20 years, respectively. Wide resection margins were achieved in 38 patients, whereas 11 patients underwent marginal and seven intralesional resection. Survival was significantly better in patients with wide or marginal resection than in patients with intralesional resection (p = 0.022). Survival for patients with secondary tumours was significantly worse than for patients with primary tumours (p = 0.003). In 29 patients (51.8 %), at least one reoperation was necessary, resulting in a revision-free survival of 50.5 % at five years, 41.1 % at ten years and 30.6 % at 20 years. Implant survival was 77.0 % at five years, 68.6 % at ten years and 51.8 % at 20 years. A total of 35 patients (62.5 %) experienced one or more complications after surgery. Ten of 56 patients (17.9 %) experienced local recurrence after a mean of 8.9 months. The mean postoperative Musculoskeletal Tumor Society (MSTS) score was 18.1 (60.1 %).

Conclusion

The surgical approach assessed in this study simplifies the process of tumour resection and prosthesis implantation and leads to acceptable clinical and oncological outcomes.     

Quality of Life After Surgical Treatment of Early Barrett’s Cancer: A Prospective Comparison of the Ivor-Lewis Resection Versus the Modified Merendino Resection

Introduction

The Merendino (MER) procedure has been evaluated as an alternative to transthoracic esophageal resection (TER) for early stage Barrett’s carcinoma. Apart from reducing morbidity and mortality, improvements concerning postoperative health-related quality of life (HRQL) have been postulated. The aim of our study was to compare HRQL between these procedures.

Materials and methods

Between July 2000 and July 2007, 117 patients with early Barrett’s carcinoma underwent surgery. Patients with tumor recurrence were excluded from the study. HRQL was assessed 1 and 2 years after surgery using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Core Questionnaire (EORTC-QLQ-C30) and the QLQ-OES18 module. Patients recently diagnosed with early Barrett’s carcinoma served as controls. Symptoms that showed a difference of more than ten between the control and the study groups were considered clinically relevant and were tested for significant differences between the study groups using the Mann–Whitney U test (p < 0.05).

Results

The response rates for the questionnaires ranged between 70 and 93 %. In the MER group, more items reflected a clinical relevant impairment of HRQL than in the TER group. Significant complaints in the MER group included nausea/vomiting, appetite loss, local pain, difficulties with social eating, and choking. Moreover, we found a significant restriction concerning global health and emotional and social functioning in this group 1 year after surgery. 2 years postoperatively, hardly any differences between the operative techniques could be detected. The only symptom in favor of the MER procedure was a better dysphagia score postoperatively.

Conclusion

Our study suggests that MER procedure is not superior to subtotal esophagectomy with regard to HRQL.     

Pre-treatment of peripheral blood progenitor cells with macrophage inflammatory protein-1α induces prolonged survival of early progenitor cells over 6 weeks of long-term culture

It has previously been shown that a combination of macrophage inflammatory protein-1α (MIP-1α) and interleukin (IL)-3 maintained human bone marrow (BM)-derived long-term culture-initiating cells (LTC-IC) for at least 8 weeks in vitro . We investigated colony- and cobblestone area-formation potential of peripheral blood progenitor cells (PBPC) at week 6 of long-term culture (LTC) in the absence of exogenous MIP-1α, but using cells which had been pre-incubated in the presence of MIP-1α for 40 h in liquid culture. The recovery of colony-forming cells (CFC) and cobblestone-area-forming cells (CAFC) after pre-incubation of PBPC with MIP-1α was up to threefold higher ( P  < 0.05, n  =5) than that of untreated controls. These results demonstrate that short-term pre-treatment of PBPC with MIP-1α induces long-lasting survival effects on early PBPC-derived progenitors in vitro .