Oxidative Stress Promotes Uptake,Accumulation, and Oligomerization of Extracellular α-Synuclein in Oligodendrocytes

The accumulation and aggregation of α-synuclein (α-Syn) in glial cytoplasmic inclusions originating in oligodendrocytes is a characteristic hallmark of multiple system atrophy, a progressive adult onset neurodegenerative disorder. The origin of α-Syn deposition in oligodendrocytes in multiple system atrophy is still unclear, but the uptake of α-Syn from the environment after neuronal secretion has been discussed. The present study was undertaken to investigate the consequences of α-Syn uptake from the environment in cultured oligodendroglial cells and its localization and potential to form intracellular aggregates in the absence or presence of the microtubule-associated protein tau, which has been demonstrated to act synergistically with α-Syn. Primary rat brain oligodendrocytes and clonal oligodendroglial OLN-93 cells were incubated with human recombinant soluble and pre-aggregated α-Syn. The data show that oligodendrocytes are capable to take up and internalize soluble and pre-aggregated α-Syn from their growth medium. In a time-dependent manner, α-Syn oligomerizes and small intracellular aggregates are formed. These do not exert cytotoxic responses or mitochondrial impairment. Oxidative stress exerted by hydrogen peroxide further promotes α-Syn oligomer formation and leads to an enlargement of the aggregates. This process is not affected or modified by the presence of tau in OLN-93 cells. Furthermore, membrane lipid modification by docosahexaenoic acid promotes α-Syn uptake and oligomerization, indicating that changing the membrane lipid composition and structure contributes to the protein aggregation process and pathological events. Hence, although α-Syn taken up by oligodendrocytes from the environment is not toxic per se, under conditions of oxidative stress, which might occur during chronic disease progression and aging, aggregates are enlarged and eventually may contribute to cytotoxicity and cellular death.     

Facilitating surgical decisions for patients who are uncertain: a pilot surgical option process within an interdisciplinary functional restoration program

Background contextFor chronic pain patients, recovery may be slowed by indecisiveness over optional surgery. These patients may be delayed from participating in interdisciplinary functional restoration (FR), pending resolution of the surgical decision. Uncertainty about surgery or rehabilitation leads to delayed recovery. A surgical option process (SOP) was developed to permit patients with chronic disabling occupational musculoskeletal disorders to enter FR, make a final determination halfway through treatment, and return to complete rehabilitation after surgery, if surgery was elected.PurposeThis study assessed the frequency with which an FR program can resolve an uncertain surgical option. It also assessed program completion rate and 1-year post-program outcomes for subgroups that decline surgery, request and receive surgery, or request surgery but are denied by surgeon or insurance carrier.Study designRetrospective study of a consecutive cohort.Patient sampleA cohort of 44 consecutively treated chronic disabling occupational musculoskeletal disorder patients were admitted to an FR program and identified as candidates for a surgical procedure but were either ambivalent about undergoing surgery, had a difference of opinion by two or more surgeons, or were denied a surgical request by an insurance carrier. Patients attended half (10 full day visits) of an FR program before making their own final determination to pursue a request or decline surgery.Outcome measuresPatients were assessed on surgical requests and whether surgery was ultimately performed, program completion status after the surgical determination, demographic variables, and 1-year outcomes on work status, additional surgery, and other health utilization measures.MethodsPatients became part of the SOP on program entry and were included in the study if they participated in a surgical-decision interview halfway through the program. Those who elected to decline surgery (DS) completed the program without delay, but those requesting surgery were placed on hold from the program while consultation and preauthorization steps took place. Those requesting surgery, but denied (RSD), and those undergoing surgery (US) were given the opportunity to complete FR following postoperative physical therapy or resolution of the surgical re-evaluation process.ResultsThere were 32 DS patients (73%), indicating that a large majority of patients declined the surgery that was still being considered when offered participation in the SOP. Of the 12 patients wanting a surgery, there were four US patients who received surgery previously denied (9% of cohort), and eight RSD patients (18% of cohort). Patients from the DS group completed the FR program at an 88% rate, as did 75% of US patients. However, despite an opportunity to re-enter and complete rehab, only 50% of RSD patients completed the FR option. Overall, patients who persistently sought surgery, contrary to the recommendations of a surgeon, had poorer outcomes. These 1-year post-FR outcomes included lower return-to-work and work retention rates, with higher rates of treatment seeking from new providers (resulting in higher rates of post-discharge surgery) and higher rates of recurrent injury claims after work return.ConclusionsA SOP tied to participation in an interdisciplinary FR program resolves uncertainty regarding surgical options in a high proportion of cases, resulting in a large majority declining surgery and completing the FR program. Timely surgery is also promoted decisively when needed. Findings suggest that patients who persistently seek surgery, contrary to the recommendations of a surgeon, frequently fail to complete FR and have poorer outcomes overall.     

Treatment strategies for infection after reverse shoulder arthroplasty

Introduction

Infection after reverse shoulder arthroplasty (RSA) is a disastrous complication. No clear guidelines describing specific management strategies for infection after RSA are available.

Methods

We retrospectively analyzed 20 patients treated for deep infection after RSA. Initial irrigation and debridement and exchange of the polyethylene inlay were performed in seven patients, and initial two-stage revision was performed in 12 and initial resection arthroplasty in one patient. Patient charts were reviewed for risk factors, clinical symptoms and investigations of those symptoms, pre- and postoperative X-rays, interval until revision surgery, causative bacteria, complications, final clinical outcome and patient satisfaction.

Results

The mean overall postoperative Constant–Murley Score (CMS) was 42.6 points, the mean UCLA score was 20.8, the mean simple shoulder test (SST) was 5.5, and the mean VAS was 1.5. When comparing the CMS, UCLA score and the SST between the revision RSA group and the resection group, significant differences between the groups were found (p < 0.05). Irrigation, debridement and exchange of the polyethylene inlay were successful only in two of the four patients with acute infection. The three patients with subacute infections were treated with initial irrigation and debridement and exchange of the polyethylene inlay, which were not successful.

Conclusion

The relatively high patient satisfaction can be explained by the low pain level once the patient is free from infection. However, functional results are poor in most cases, and this possible outcome must be discussed with the patient in the preoperative setting.     

Akute Pankreatitis

Acute pancreatitis is a potentially fatal disease with individually differing expression of systemic involvement. For this reason early diagnosis with subsequent risk stratification is essential in the clinical management of this frequent gastroenterological disorder. Severe forms of acute pancreatitis occur in approximately 20?% of cases often requiring intensive care monitoring and interdisciplinary therapeutic approaches. In the acute phase adequate fluid replacement and sufficient analgesic therapy is of major therapeutic importance. Concerning the administration of antibiotics and the nutritional support of patients with acute pancreatitis a change in paradigms could be observed in recent years. Furthermore, endoscopic, radiological or surgical interventions can be necessary depending on the severity of the disease and potential complications.     

TMPRSS2-ERG Fusions Are Strongly Linked to Young Patient Age in Low-grade Prostate Cancer

Based on next-generation sequencing of early-onset prostate cancer (PCa), we earlier demonstrated that PCa in young patients is prone to rearrangements involving androgen-regulated genes—such as transmembrane protease, serine 2 (TMPRSS2)–v-ets avian erythroblastosis virus E26 oncogene homolog (ERG) fusion—and provided data suggesting that this situation might be caused by increased androgen signaling in younger men. In the same study, an accumulation of chromosomal deletions was found in cancers of elderly patients. To determine how age-dependent molecular features relate to cancer phenotype, an existing data set of 11 152 PCas was expanded by additional fluorescence in situ hybridization analyses of phosphatase and tensin homolog (PTEN), 6q15 and 5q21. The results demonstrate that the decrease in TMPRSS2–ERG fusions with increasing patient age is limited to low-grade cancers (Gleason ≤3 + 4) and that the significant increase in the deletion frequency with age was strictly limited to ERG-negative cancers for 6q15 and 5q21 but to ERG-positive cancers for PTEN. These data suggest that the accumulation of non–androgen-linked genomic alterations with advanced patient age may require an appropriate microenvironment, such as a positive or negative ERG status. The strong link of ERG activation to young patient age and low-grade cancers may help to explain a slight predominance of low-grade cancers in young patients.     

Temporal delimitation of the healing phases via monitoring of fracture callus stiffness in rats

The healing process consists of at least three phases: inflammatory, repair, and remodeling phase. Because callus stiffness correlates with the healing phases, it is suitable for evaluating the fracture healing process. Our aim was to develop a method which allows determination of callus stiffness in vivo, the healing time and the duration of the repair phase. The right femurs of 16 Wistar rats were osteotomized and stabilized with either more rigid or more flexible external fixation. Fixator deformation was measured using strain gauges during gait analysis. The strains were recalculated as the callus stiffness over the time course of healing, and the healing phases were identified based on stiffness thresholds. Our hypothesis was that stabilization with more flexible external fixation prolongs the repair phase, therefore resulting in an extended healing time. Confirming our hypothesis, the duration of the repair phase (rigid: approximately 15 days, flexible: approximately 41 days) and the healing time (rigid: approximately 27 days, flexible: approximately 62 days) were significantly longer for more flexible external fixation. Our method allows the quantitative detection of differences in the healing time and duration of the repair phase without multiple time‐point sacrifices, which reduces the number of animals in experimental studies. © 2014 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 32:1589–1595, 2014.     

Parastomal hernia repair with a 3-D mesh device and additional flat mesh repair of the abdominal wall

Purpose

Parastomal hernias (PSHs) have been a major clinical problem. The aim of this study was to evaluate a new method of PSH repair in combination with an additional flat mesh reinforcement of the abdominal wall.

Methods

In a pilot case series, seven patients suffering from complex PSHs (≥5 cm diameter and/or recurrence) underwent surgery and were treated by intraperitoneal onlay technique (IPOM) with a synthetic 3-D funnel-shaped mesh implant. The demographics, perioperative, and follow-up data are presented in this report.

Results

The surgical strategy varied between purely laparoscopic (n = 1), laparoscopically assisted (hybrid n = 3), or open techniques (n = 3) using original or suture-reconstructed mesh devices. The funnel mesh implantations in IPOM technique were combined with attached flat meshes in the appropriate position of the abdominal wall. No procedure-related complications occurred. The mean length of hospital stay was 12 days and the mean operating time was 171 min. No recurrence of PSH or incisional hernias was observed during a mean follow-up period of 12.3 months (range from 7 to 22).

Conclusion

The use of a 3-D mesh implant has so far shown to be a promising option in the treatment of primary and recurrent PSHs. Its use proved to be reasonable in both laparoscopic and open IPOM technique. PSHs were preferably repaired using the original, unmodified implant, but when we also found it safe to incise, place and then suture the mesh around the pre-existing ostomy.