Search

Abstract Objective Neurofilament heavy‐chain gene (NEFH) variants are associated with multiple neurodegenerative diseases, however, their relationship with ALS has not been robustly explored. Still, NEFH is commonly included in genetic screening panels worldwide. We therefore aimed to determine if NEFH variants modify ALS risk. Methods Genetic data of 11,130 people with ALS and 7,416 controls from the literature and Project MinE were analysed. We performed meta‐analyses of published case–control studies reporting NEFH variants, and variant analysis of NEFH in Project MinE whole‐genome sequencing data. Results Fixed‐effects meta‐analysis found that rare (MAF

Osteosarcomas are the most common primary malignant bone tumors and mostly affect children, adolescents, and young adults. Despite current treatment options such as surgery and polychemotherapy, the survival of patients with metastatic disease remains poor. In recent studies, punicalagin has reduced the cell viability, angiogenesis, and invasion in cell culture trials. The aim of this study was to examine the effects of punicalagin on osteosarcomas in a 3D in vivo tumor model. Human osteosarcoma biopsies and SaOs-2 and MG-63 cells, were grown in a 3D in vivo chorioallantoic membrane (CAM) model. After a cultivation period of up to 72 h, the tumors received daily treatment with punicalagin for 4 days. Weight measurements of the CAM tumors were performed, and laser speckle contrast imaging (LSCI) and a deep learning-based image analysis software (CAM Assay Application v.3.1.0) were used to measure angiogenesis. HE, Ki-67, and Caspase-3 staining was performed after explantation. The osteosarcoma cell lines SaOs-2 and MG-63 and osteosarcoma patient tissue displayed satisfactory growth patterns on the CAM. Treatment with punicalagin decreased tumor weight, proliferation, and tumor-induced angiogenesis, and the tumor tissue showed pro-apoptotic characteristics. These results provide a robust foundation for the implementation of further studies and show that punicalagin offers a promising supplementary treatment option for osteosarcoma patients. The 3D in vivo tumor model represents a beneficial model for the testing of anti-cancer therapies.

BackgroundSingle-nucleotide variations (SNVs; formerly SNPs) are inherited genetic variants that can be easily determined in routine clinical practice using a simple blood or saliva test. SNVs have potential to serve as noninvasive biomarkers for predicting cancer-specific patient outcomes after resection of pancreatic ductal adenocarcinoma (PDAC). Two recent analyses led to the identification and validation of three SNVs in the CD44 and CHI3L2 genes (rs187115, rs353630, and rs684559), which can be used as predictive biomarkers to help select patients most likely to benefit from pancreatic resection. These variants were associated with an over 2-fold increased risk for tumor-related death in three independent PDAC study cohorts from Europe and the United States, including The Cancer Genome Atlas cohorts (reaching a P value of 1×10–8). However, these analyses were limited by the inherent biases of a retrospective study design, such as selection and publication biases, thereby limiting the clinical use of these promising biomarkers in guiding PDAC therapy. ObjectiveTo overcome the limitations of previous retrospectively designed studies and translate the findings into clinical practice, we aim to validate the association of the identified SNVs with survival in a controlled setting using a prospective cohort of patients with PDAC following pancreatic resection. MethodsAll patients with PDAC who will undergo pancreatic resection at three participating hospitals in Switzerland and fulfill the inclusion criteria will be included in the study consecutively. The SNV genotypes will be determined using standard genotyping techniques from patient blood samples. For each genotyped locus, log-rank and Cox multivariate regression tests will be performed, accounting for the relevant covariates American Joint Committee on Cancer stage and resection status. Clinical follow-up data will be collected for at least 3 years. Sample size calculation resulted in a required sample of 150 patients to sufficiently power the analysis. ResultsThe follow-up data collection started in August 2019 and the estimated end of data collection will be in May 2027. The study is still recruiting participants and 142 patients have been recruited as of November 2023. The DNA extraction and genotyping of the SNVs will be performed after inclusion of the last patient. Since no SNV genotypes have been determined, no data analysis has been performed to date. The results are expected to be published in 2027. ConclusionsThis is the first prospective study of the CD44 and CHI3L2 SNV–based biomarker signature in PDAC. A prospective validation of this signature would enable its clinical use as a noninvasive predictive biomarker of survival after pancreatic resection that is readily available at the time of diagnosis and can assist in guiding PDAC therapy. The results of this study may help to individualize treatment decisions and potentially improve patient outcomes. International Registered Report Identifier (IRRID)DERR1-10.2196/54042

Summary: Background: Evidence for the efficacy of nusinersen in adults with 5q-associated spinal muscular atrophy (SMA) has been demonstrated up to a period of 16 months in relatively large cohorts but whereas patients reach a plateau over time is still to be demonstrated. We investigated the efficacy and safety of nusinersen in adults with SMA over 38 months, the longest time period to date in a large cohort of patients from multiple clinical sites. Methods: Our prospective, observational study included adult patients with SMA from Germany, Switzerland, and Austria (July 2017 to May 2022). All participants had genetically-confirmed, 5q-associated SMA and were treated with nusinersen according to the label. The total Hammersmith Functional Motor Scale Expanded (HFMSE) and Revised Upper Limb Module (RULM) scores, and 6-min walk test (6 MWT; metres), were recorded at baseline and 14, 26, and 38 months after treatment initiation, and pre and post values were compared. Adverse events were also recorded. Findings: Overall, 389 patients were screened for eligibility and 237 were included. There were significant increases in all outcome measures compared with baseline, including mean HFMSE scores at 14 months (mean difference 1.72 [95% CI 1.19–2.25]), 26 months (1.20 [95% CI 0.48–1.91]), and 38 months (1.52 [95% CI 0.74–2.30]); mean RULM scores at 14 months (mean difference 0.75 [95% CI 0.43–1.07]), 26 months (mean difference 0.65 [95% CI 0.27–1.03]), and 38 months (mean difference 0.72 [95% CI 0.25–1.18]), and 6 MWT at 14 months (mean difference 30.86 m [95% CI 18.34–43.38]), 26 months (mean difference 29.26 m [95% CI 14.87–43.65]), and 38 months (mean difference 32.20 m [95% CI 10.32–54.09]). No new safety signals were identified. Interpretation: Our prospective, observational, long-term (38 months) data provides further real-world evidence for the continuous efficacy and safety of nusinersen in a large proportion of adult patients with SMA. Funding: Financial support for the registry from Biogen, Novartis and Roche.

Abstract Amyotrophic lateral sclerosis (ALS) has substantial heritability, in part shared with fronto-temporal dementia (FTD). We show that ALS heritability is enriched in splicing variants and in binding sites of 6 RNA-binding proteins including TDP-43 and FUS. A transcriptome wide association study (TWAS) identified 6 loci associated with ALS, including in NUP50 encoding for the nucleopore basket protein NUP50. Independently, rare variants in NUP50 were associated with ALS risk (P = 3.71.10−03; odds ratio = 3.29; 95%CI, 1.37 to 7.87) in a cohort of 9,390 ALS/FTD patients and 4,594 controls. Cells from one patient carrying a NUP50 frameshift mutation displayed a decreased level of NUP50. Loss of NUP50 leads to death of cultured neurons, and motor defects in Drosophila and zebrafish. Thus, our study identifies alterations in splicing in neurons as critical in ALS and provides genetic evidence linking nuclear pore defects to ALS.

Abstract Background Due to demographic change, the number of older people in Germany and worldwide will continue to rise in the coming decades. As a result, the number of elderly and frail patients undergoing total hip and knee arthroplasty is projected to increase significantly in the coming years. In order to reduce risk of complications and improve postoperative outcome, it can be beneficial to optimally prepare geriatric patients before orthopaedic surgery and to provide perioperative care by a multiprofessional orthogeriatric team. The aim of this comprehensive interventional study is to assess wether multimorbid patients can benefit from the new care model of special orthopaedic geriatrics (SOG) in elective total hip and knee arthroplasty. Methods The SOG study is a registered, monocentric, prospective, randomized controlled trial (RCT) funded by the German Federal Joint Committee (GBA). This parallel group RCT with a total of 310 patients is intended to investigate the specially developed multimodal care model for orthogeriatric patients with total hip and knee arthroplasty (intervention group), which already begins preoperatively, in comparison to the usual orthopaedic care without orthogeriatric co-management (control group). Patients ≥70 years of age with multimorbidity or generally patients ≥80 years of age due to increased vulnerability with indication for elective primary total hip and knee arthroplasty can be included in the study. Exclusion criteria are age

Objective Femoral head necrosis (FHN) affects mostly young and active people. The most common operative therapy is core decompression (CD) with optional cancellous bone grafting (CBG). Because little information is available on the long-term results of these procedures, we investigated the effectiveness of CD and CD + CBG in patients with ARCO stage II FHN in terms of postoperative pain, range of motion, patient-reported outcome measures (Harris Hip Score, Hip Disability and Osteoarthritis Outcome Score, EuroQol 5D, and Short Form 36 Questionnaire), and disease progression. Methods We retrospectively compared 11 patients treated with CD alone 48.0 months (range, 26.3–68.5 months) postoperatively versus 11 patients treated with CD + CBG 69.2 months (range, 38.0–92.9 months) postoperatively. All patients were assessed according to a routine clinical protocol involving a clinical examination, questionnaires, and radiological imaging (X-ray and magnetic resonance imaging). Results The clinical and radiological results showed no significant differences between the two groups. Both interventions demonstrated equal results according to clinical scores. Conclusions Our data may encourage application of the less invasive technique of CD alone without CBG, which is more surgically demanding. Further prospective studies with longer follow-up are necessary to clarify the risk factors for therapy failure.

Intestinal immunoglobulin A (IgA) is strongly involved in microbiota homeostasis. Since microbiota disruption is a major risk factor of acute graft-versus-host disease (GvHD), we addressed the kinetics of intestinal IgA-positive (IgA+) plasma cells by immunohistology in a series of 430 intestinal biopsies obtained at a median of 1,5 months after allogeneic stem cell transplantation (allo-SCT) from 115 patients (pts) at our center. IgA+ plasma cells were located in the subepithelial lamina propria and suppressed in the presence of histological aGvHD (GvHD Lerner stage 0: 131+/-8 IgA+ plasma cells/mm2; stage 1-2: 108+/-8 IgA+ plasma cells/mm2; stage 3-4: 89+/-16 IgA+ plasma cells/mm2; P=0.004). Overall, pts with IgA+ plasma cells below median had an increased treatment related mortality (P=0.04). Time courses suggested a gradual recovery of IgA+ plasma cells after day 100 in the absence but not in the presence of GvHD. Vice versa IgA+ plasma cells above median early after allo-SCT were predictive of relapse and relapse-related mortality (RRM): pts with low IgA+ cells had a 15% RRM at 2 and at 5 years, while pts with high IgA+ cells had a 31% RRM at 2 years and more than 46% at 5 years; multivariate analysis indicated high IgA+ plasma cells in biopsies (hazard ratio =2.7; 95% confidence interval: 1.04-7.00) as independent predictors of RRM, whereas Lerner stage and disease stage themselves did not affect RRM. In contrast, IgA serum levels at the time of biopsy were not predictive for RRM. In summary, our data indicate that IgA+ cells are highly sensitive indicators of alloreaction early after allo-SCT showing association with TRM but also allowing prediction of relapse independently from the presence of overt GvHD.

BackgroundThe team timeout (TTO) is a safety checklist to be performed by the surgical team prior to incision. Exchange of critical information is, however, important not only before but also during an operation and members of surgical teams frequently feel insufficiently informed by the operating surgeon about the ongoing procedure. To improve the exchange of critical information during surgery, the StOP?-protocol was developed: At appropriate moments during the procedure, the leading surgeon briefly interrupts the operation and informs the team about the current Status (St) and next steps/objectives (O) of the operation, as well as possible Problems (P), and encourages questions of other team members (?). The StOP?-protocol draws attention to the team. Anticipating the occurrence of StOP?-protocols may support awareness of team processes and quality issues from the beginning and thus support other interventions such as the TTO; however, it also may signal an additional demand and contribute to a phenomenon akin to “checklist fatigue.” We investigated if, and how, the introduction of the StOP?-protocol influenced TTO quality.MethodsThis was a prospective intervention study employing a pre-post design. In the visceral surgical departments of two university hospitals and one urban hospital the quality of 356 timeouts (out of 371 included operation) was assessed by external observers before (154) and after (202) the introduction of the StOP?-briefing. Timeout quality was rated in terms of timeout completeness (number of checklist items mentioned) and timeout quality (engagement, pace, social atmosphere, noise).ResultsAs compared to the baseline, after the implementation of the StOP?-protocol, observed timeouts had higher completeness ratings (F = 8.69, p = 0.003) and were rated by observers as higher in engagement (F = 13.48, p

Introduction: Caveolin-1 and Caveolin-2 (CAV1 and CAV2) are proteins associated with intercellular neurotrophic signalling. There is converging evidence that CAV1 and CAV2 (CAV1/2) genes have a role in amyotrophic lateral sclerosis (ALS). Disease-associated variants have been identified within CAV1/2 enhancers, which reduce gene expression and lead to disruption of membrane lipid rafts.Methods: Using large ALS whole-genome sequencing and post-mortem RNA sequencing datasets (5,987 and 365 tissue samples, respectively), and iPSC-derived motor neurons from 55 individuals, we investigated the role of CAV1/2 expression and enhancer variants in the ALS phenotype.Results: We report a differential expression analysis between ALS cases and controls for CAV1 and CAV2 genes across various post-mortem brain tissues and three independent datasets. CAV1 and CAV2 expression was consistently higher in ALS patients compared to controls, with significant results across the primary motor cortex, lateral motor cortex, and cerebellum. We also identify increased survival among carriers of CAV1/2 enhancer mutations compared to non-carriers within Project MinE and slower progression as measured by the ALSFRS. Carriers showed a median increase in survival of 345 days.Discussion: These results add to an increasing body of evidence linking CAV1 and CAV2 genes to ALS. We propose that carriers of CAV1/2 enhancer mutations may be conceptualised as an ALS subtype who present a less severe ALS phenotype with a longer survival duration and slower progression. Upregulation of CAV1/2 genes in ALS cases may indicate a causal pathway or a compensatory mechanism. Given prior research supporting the beneficial role of CAV1/2 expression in ALS patients, we consider a compensatory mechanism to better fit the available evidence, although further investigation into the biological pathways associated with CAV1/2 is needed to support this conclusion.

Abstract There is a strong genetic contribution to Amyotrophic lateral sclerosis (ALS) risk, with heritability estimates of up to 60%. Both Mendelian and small effect variants have been identified, but in common with other conditions, such variants only explain a little of the heritability. Genomic structural variation might account for some of this otherwise unexplained heritability. We therefore investigated association between structural variation in a set of 25 ALS genes, and ALS risk and phenotype. As expected, the repeat expansion in the C9orf72 gene was identified as associated with ALS. Two other ALS-associated structural variants were identified: inversion in the VCP gene and insertion in the ERBB4 gene. All three variants were associated both with increased risk of ALS and specific phenotypic patterns of disease expression. More than 70% of people with respiratory onset ALS harboured ERBB4 insertion compared with 25% of the general population, suggesting respiratory onset ALS may be a distinct genetic subtype.

BackgroundAmyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the loss of upper and lower motor neurons, leading to progressive weakness of voluntary muscles, with death following from neuromuscular respiratory failure, typically within 3 to 5 years. There is a strong genetic contribution to ALS risk. In 10% or more, a family history of ALS or frontotemporal dementia is obtained, and the Mendelian genes responsible for ALS in such families have now been identified in about 50% of cases. Only about 14% of apparently sporadic ALS is explained by known genetic variation, suggesting that other forms of genetic variation are important. Telomeres maintain DNA integrity during cellular replication, differ between sexes, and shorten naturally with age. Sex and age are risk factors for ALS and we therefore investigated telomere length in ALS.MethodsSamples were from Project MinE, an international ALS whole genome sequencing consortium that includes phenotype data. For validation we used donated brain samples from motor cortex from people with ALS and controls. Ancestry and relatedness were evaluated by principal components analysis and relationship matrices of DNA microarray data. Whole genome sequence data were from Illumina HiSeq platforms and aligned using the Isaac pipeline. TelSeq was used to quantify telomere length using whole genome sequence data. We tested the association of telomere length with ALS and ALS survival using Cox regression.ResultsThere were 6,580 whole genome sequences, reducing to 6,195 samples (4,315 from people with ALS and 1,880 controls) after quality control, and 159 brain samples (106 ALS, 53 controls). Accounting for age and sex, there was a 20% (95% CI 14%, 25%) increase of telomere length in people with ALS compared to controls (p = 1.1 × 10−12), validated in the brain samples (p = 0.03). Those with shorter telomeres had a 10% increase in median survival (p = 5.0×10−7). Although there was no difference in telomere length between sporadic ALS and familial ALS (p=0.64), telomere length in 334 people with ALS due to expanded C9orf72 repeats was shorter than in those without expanded C9orf72 repeats (p = 5.0×10−4).DiscussionAlthough telomeres shorten with age, longer telomeres are a risk factor for ALS and worsen prognosis. Longer telomeres are associated with ALS.

Background and purpose — Improving health care and demographic change have resulted in a steady increase in geriatric patients undergoing total hip (THA) and knee (TKA) arthroplasty. Postoperative delirium (POD) is a frequent and severe complication after major surgery. Therefore, we analyzed the impact of POD on outcome after THA and TKA. Patients and methods — In a consecutive series of 10,140 patients who had undergone elective THA or TKA between 2011 and 2020, rates of reoperation within 90 days, readmission within 90 days, complications, and responder rate as defined by the OMERACT-OARSI criteria were compared between patients with and without POD. Multivariable logistic regression models were used to assess the relationship between POD and other postoperative complications. Results — Patients with POD showed higher rates of reoperation (12% vs. 5%), readmission (15% vs. 5%), surgical complications (7% vs. 2%), non-surgical complications (8% vs. 4%), Clavien–Dindo IV° complications (10% vs. 2%) and transfusion (14% vs. 2%). POD led to lower responder rate (76% vs. 87%) 1 year after total joint replacement. All previous comparisons statistically significant. Multivariable logistic regression analyses revealed POD as an independent risk factor for reoperation (OR = 2; CI 1–3), readmission (OR = 2; CI 2–4) and Clavien–Dindo IV° complications (OR = 3; CI 2–5). Interpretation — POD is a serious problem in elective joint replacement. Affected patients suffer more complications and show poor patient-reported outcome 1 year postoperatively. Systematic prevention strategies and standardized therapy protocols are mandatory to avoid burden to patients and healthcare providers.

Background and purpose — There is growing evidence that hypoproteinemia is an important risk factor for adverse events after surgery. Less is known about the impact of vitamin deficiency on postoperative outcome. Therefore we evaluated the prevalence and impact of malnutrition and vitamin deficiency in geriatric patients undergoing elective orthopedic surgery. Patients and methods — In a retrospective analysis of 599 geriatric patients who had undergone elective orthopedic surgery in 2018 and 2019, hypoproteinemia, and deficiency of vitamin D, vitamin B12, and folate were assessed. Reoperation rates, readmission rates, complication rates, and transfusion rates were compared between malnourished patients and patients with normal parameters. Multivariable logistic regression models were used to assess the relationship between malnutrition and postoperative adverse events, controlling for confounding factors such as age, sex, diabetes mellitus, and frailty. Results — Patients with malnutrition showed a higher rate of reoperation (13% vs. 5.5%; p = 0.01) and exhibited more wound-healing disorders (7.4% vs. 1.3%, p = 0.001) as well as Clavien–Dindo IV° complications (7.4% vs. 2.4%; p = 0.03). Deficiency of vitamin D led to a higher rate of falls (8.4% vs. 2.9%, p = 0.006). Deficiency of vitamin B12 and folate did not affect postoperative adverse events. Although correlated to frailty (p = 0.004), multivariable regression analysis identified malnutrition as independent risk factor for reoperation (OR 2.6, 95% CI 1.1–6.2) and wound healing disorders (OR 7.1, CI 1.9–26). Interpretation — Malnutrition is common among geriatric patients undergoing elective orthopedic surgery and represents an independent risk factor for postoperative adverse events.

Abstract Background Mesenteric ischemia is associated with poor outcome and high overall mortality. The aim was to analyze an interdisciplinary treatment approach of vascular and visceral specialists focusing on the in-hospital outcome and follow-up in patients with acute and acute-on-chronic mesenteric ischemia. Methods From 2010 until 2017, 26 consecutive patients with acute or acute on chronic mesenteric ischemia were treated by an interdisciplinary team. Data were prospectively collected and retrospectively evaluated. Throughout the initial examination, the extent of bowel resection was determined by the visceral surgeon and the appropriate mode of revascularization by the vascular surgeon. The routine follow-up included clinical examination and ultrasound- or CT-imaging for patency assessment and overall survival as primary endpoint of the study. Results Out of 26 patients, 18 (69.2%) were rendered for open repair. Ten patients (38.5%) received reconstruction of the superior mesenteric artery with an iliac-mesenteric bypass. Seven patients (26.9%) underwent thrombembolectomy of the mesenteric artery. One patient received an infra-diaphragmatic aorto-celiac-mesenteric bypass. Out of the 8 patients, who were not suitable for open revascularization, 2 patients (7.7%) were treated endovascularly and 6 (23.1%) underwent explorative laparotomy. The in-hospital mortality was 23% (n = 6). The mean survival of the revascularized group (n = 20) was 51.8 months (95% CI 39.1–64.5) compared to 15.7 months in the non-revascularized group (n = 6) (95% CI − 4.8–36.1; p = 0.08). The median follow-up was 64.6 months. Primary patency in the 16 patients after open and 2 after interventional revascularization was 100% and 89.9% in the follow-up. Conclusion The interdisciplinary treatment of mesenteric ischemia improves survival if carried out in time. Hereby open revascularization measures are advantageous as they allow bowel assessment, resection, and revascularization in a one-stop fashion especially in advanced cases.

Abstract Background Primary anorectal melanoma can be a rare differential diagnosis of anorectal mass. Due to the low case number reported in the literature, physicians are not aware of this aggressive disease. Although no consensus exists, wide local excision and abdominoperineal resection are considered the mainstay therapy. Case presentation An 85-year-old female patient presented with fecal incontinence 5 years after local resection of a primary anorectal melanoma. In the rectoscopy, a tumor proximal to the dentate line was identified and later confirmed as a recurrent primary anorectal melanoma. There were no signs of locoregional or distant metastasis on the MRI and PET/CT. She underwent another wide local excision and regained fecal continence postoperatively. Conclusions Primary anorectal melanoma should belong to the differential diagnosis of anorectal mass. If technically feasible, wide local excision represents a less invasive treatment than abdominoperineal resection, retaining the anal sphincter and patient’s quality of life. Even though wide local excision has a higher recurrence rate than abdominoperineal resection, there is no difference in survival between the two procedures. This is only under the premise that patients are followed-up regularly after wide local excision so that recurrence can be spotted early on and locally excised.

Objective: To assess current management of diverticulitis in Switzerland.Methods: Prospective observational study of diverticulitis management and outcomes in surgical departments over a 3-month time period. Hospital category was graded according to the Swiss Medical Association (FMH) as: U: University; A: Cantonal; B: Regional; P: Private.Results: 75 participating hospitals treated 1,015 patients, among whom 214 patients (21%) had elective sigmoid resections in 49 hospitals. Indication for elective resection were recurrent diverticulitis, previous complicated diverticulitis, fistulas, and stenosis. Surgeries were performed completely laparoscopically in 185 cases (86%) and required conversion to open in 19 cases (9%). Overall postoperative complication rate was 18% (n = 39) and no mortality was observed. Operation time, surgeons experience and hospital stay differed considerably between hospital categories.Conclusions: Elective sigmoid resection for diverticulitis in Switzerland was mainly performed laparoscopically with low postoperative morbidity. Different practices and outcomes between institutions were observed.

The exact reconstruction of the tibial plateau and articular surface is the main operative aim in the treatment of tibial plateau depression fractures. For selected cases, a novel technique with the use of balloon tibioplasty in combination of bioabsorbable calcium phosphate cement is available. In this study, the first objective was to answer the question whether the clinical outcome parameters after balloon tibioplasty are comparable to open reduction procedures described in the literature. Secondly, we asked whether the cement absorption is safe in relation to adverse effects like osteolysis and measured the absorption ability during the bone conversion process in the proximal tibia bone. Eight patients (mean age 54 years; 4 males and 4 females) received the abovementioned surgical procedure. Mean follow-up period was 27 months. This study evaluated clinical outcome and radiological measured cement absorption within the postoperative course. Cement absorption was measured on X-rays and calculated based on the greatest extend on anterior–posterior and lateral view radiographs just after the operation on the latest available follow-up. WOMAC score showed a mean of 93. Radiologic absorption was 1/5 at a mean of 18 months. No osteolysis reaction was seen surrounding the cement. This far, promising clinical and radiological results have been shown with WOMAC scores comparable to the results of noninjured knees. The indication for this relatively new technique is restricted to isolated depression fractures. It is a useful tool to facilitate the reduction of select depressed tibial fractures. The radiologic absorption effect seems to be quite fast in bone remodeling and safe without any osteolysis or osseous reaction.

Purpose. Although laparoscopic Roux-en-Y gastric bypass (LRYGB) is a frequently performed bariatric procedure, there is still no consensus on its technical implementation. Methods. 211 patients treated with LRYGB in a single institution between March 2011 and October 2016 were analyzed retrospectively. A subgroup analysis for the linear (LSA) versus circular stapler technique (CSA) for gastrojejunal anastomosis (GJA) was performed to evaluate complications and outcomes. Results. 128 (60.6%) patients received GJA with CSA and 83 (39.4%) with LSA. Average weight loss one year after surgery, respectively, BMI after one year of follow-up (kg/m2), showed no significant difference. Median surgery time was significantly shorter in the LSA group. If the procedure was performed with CSA, significantly more wound infections occurred. Conclusions. Both the circular and the linear stapler techniques for gastrojejunal anastomosis in laparoscopic Roux-en-Y gastric bypass are safe methods with comparable outcomes. A disadvantage of CSA is the significantly higher rate of wound infections, a circumstance which requires increased attention.

Abstract Background In total hip arthroplasty, inadequate femoral component positioning can be associated with instability, impingement and component wear and subsequently with patient dissatisfaction. In this study, we investigated the influence of femoral neck resection height on the final three-dimensional position of a collarless straight tapered stem (Corail®). We asked two questions—(1) is neck resection height correlated with version, tilt, and varus/valgus alignment of the femoral component, and (2) dependent on the resection height of the femoral neck, which area of the stem comes into contact with the femoral cortical bone? Materials and methods Three-dimensional computed tomography scans of 40 patients who underwent minimally invasive, cementless total hip arthroplasty were analyzed retrospectively. We analyzed the relationship between femoral neck resection height and three-dimensional alignment of the femoral implant, as well as the contact points of the implant with the femoral cortical bone. This investigation was approved by the local Ethics Commission (No.10-121-0263) and is a secondary analysis of a larger project (DRKS00000739, German Clinical Trials Register May-02-2011). Results Mean femoral neck resection height was 10.4 mm (± 4.8) (range 0–20.1 mm). Mean stem version was 8.7° (± 7.4) (range − 2° to 27.9°). Most patients had a varus alignment of the implant. The mean varus/valgus alignment was 1.5° (± 1.8). All 40 patients (100%) had anterior tilt of the implant with a mean tilt of 2.2° (± 1.6). Femoral neck resection height did not correlate with stem version, varus/valgus alignment, or tilt. Independent from femoral neck resection height, in most patients the implant had contact with the ventral and ventromedial cortical bone in the upper third (77.5%) and the middle third (52.5%). In the lower third, the majority of the implants had contact with the lateral and dorsolateral cortical bone (92.5%). Conclusion Femoral neck resection height ranging between 0 and 20.1 mm does not correlate with the final position of a collarless straight tapered stem design (Corail®). Level of evidence Level 3.

Diffusion tensor spectroscopy (DTS) combines features of magnetic resonance spectroscopy and diffusion tensor imaging and permits evaluating cell-type specific properties of microstructure by probing the diffusion of intracellular metabolites. This exploratory study investigates for the first time microstructural changes in the neuronal and glial compartments of the brain of patients with amyotrophic lateral sclerosis (ALS) using DTS. To this end, the diffusion properties of the neuronal metabolite tNAA (N-acetylaspartate + N-acetylaspartylglutamate) and the predominantly glial metabolites tCr (creatine + phosphocreatine) and tCho (choline-containing compounds) were evaluated in the primary motor cortex of 24 ALS patients and 27 healthy controls. Significantly increased values in the diffusivities of all three metabolites were found in ALS patients relative to controls. Further analysis revealed more pronounced microstructural alterations in ALS patients with limb onset than with bulbar onset relative to controls. This observation may be related to the fact that the spectroscopic voxel was positioned in the part of the motor cortex where the motor functions of the limbs are represented. The higher diffusivities of tNAA may reflect neuronal damage and/or may be a consequence of mitochondrial dysfunction in ALS. Increased diffusivities of tCr and tCho are in line with reactive microglia and astrocytes surrounding degenerating motor neurons in the primary motor cortex of ALS patients. This pilot study demonstrates for the first time that cell-type specific microstructural alterations in the brain of ALS patients may be explored in vivo and non-invasively with DTS. In conjunction with other microstructural magnetic resonance imaging techniques, DTS may provide further insights into the pathogenic mechanisms that underlie neurodegeneration in ALS. Keywords: Amyotrophic lateral sclerosis, Neurodegeneration, Diffusion-weighted spectroscopy, Tissue microstructure, Intracellular metabolites

Abstract Cervical radiculopathy has become an increasing problem worldwide. Conservative treatment options have been recommended in many reviews on cervical radiculopathy, ranging from different types of physiotherapy to waiting for remission by natural history. No multimodal pain management concept (MPM) on an inpatient basis has been evaluated. This study aimed at showing the positive short-term effects of an inpatient multimodal pain management concept with focus on cervical translaminar epidural steroid injection for patients with cervical radiculopathy. 54 patients who had undergone inpatient MPM for 10 days were evaluated before and after 10-days treatment. The NRS (0–10) value for arm pain could be reduced from 6.0 (IQR 5.7–6.8) to 2.25 (IQR 2.0–3.1) and from 5.9 (IQR 4.8–6.0) to 2.0 (IQR 1.7–2.6) for neck pain. Neck pain was reduced by 57.4% and arm pain by 62.5%. 2 days after epidural steroid injection, pain was reduced by 40.1% in the neck and by 43.4% in the arms. MPM seems to be an efficient short-term approach to treating cervical radiculopathy. Cervical translaminar epidural steroid injection is an important part of this concept. In the absence of a clear indication for surgery, MPM represents a treatment option.

Abstract Impingement is a major source of dislocation and aseptic loosening in total hip arthroplasty (THA). We compared impingement free range of motion (ROM) using a novel computer navigated femur first approach to conventional THA. In addition, impingement between genders was also explored. In a retrospective analysis of 121 THA patients, subject-specific post-operative ROM was simulated using post-operative 3D-CT data, and compared with the benchmark ROM, essential for activities of daily living. Three parameters were defined to express both implant-to-implant (ITI) and bone-to-bone (BTB) impingement - coverage percentage, third angle, and impingement severity. Although coverage percentage was similar between the navigated and conventional group for both ITI (p = 0.69) and BTB (p = 0.82) impingement, third angle was significantly reduced in the navigation group for both ITI (p = 0.02) and BTB (p = 0.05) impingement. Impingement severity for both ITI (p = 0.01) and BTB (p = 0.05) was significantly decreased in the navigation group compared to the conventional. Impingement severity in men was considerably higher compared to women for both ITI (p = 0.002) and BTB (p = 0.02). Navigation guided femur first THA is able to improve alignment of ROM axis, and consequently, to reduce impingement in THA. Men seem to be more prone to impingement than women.

Abstract Training of young surgeons in total hip arthroplasty (THA) is crucial, but might affect operative time and outcome especially in minimally invasive (MIS) THA. We asked whether the learning curve of orthopaedic residents trained on MIS THA has an impact on (1) operative time (2) complication rates and (3) early postoperative outcome. In a retrospective analysis of over 1000 MIS THAs from our institutional joint registry, operative time, complication rates, patient reported outcome measures (Western Ontario and McMaster Universities Arthritis Index [WOMAC] and Euro-Qol 5D-5L [EQ-5D]) within the first year and responder rates for positive outcome as defined by the Outcome Measures in Rheumatology and Osteoarthritis Research Society International consensus responder (OMERACT-OARSI) criteria were compared between trainee and senior surgeons. Mean operative time was nine minutes longer for trainees compared to senior surgeons (78.1 ± 25.4 min versus 69.3 ± 23.8 min, p

In den meisten Universitäten sind Dienste rund um das Open-Access-Publizieren inzwischen gut etabliert. Open Educational Resources spielen dagegen in vielen Fällen eine eher untergeordnete Rolle. Grundsätzlich ist zu beobachten, dass OA-Angebote in einzelnen Fachbereichen unterschiedlich wahrgenommen werden. Ingenieurwissenschaften sind durch ihre Anwendungsorientierung durch Industriekooperationen gut mit Geldmitteln ausgestattet und weniger auf öffentliche Drittmittel angewiesen, was ein Grund für den geringeren Umfang von OA-Publikationen sein kann. Gleichzeitig standen sie bisher nicht im Fokus der OA-Dienste. Im OpenIng-Projekt wurde aus diesem Grund eine Umfrage durchgeführt, um das Publikationsverhalten von Ingenieurinnen und Ingenieuren zu untersuchen. Nur so ist es möglich, bedarfsorientierte und zielgerichtete Dienste zu entwickeln. Die Umfrage hat gezeigt, dass bei der anvisierten Zielgruppe durchaus ein OA-Bewusstsein vorhanden ist, aber dieses nicht ausreicht, das Publikationsverhalten zu verändern. Ein Grund dafür sind unter anderem die unklaren Rahmenbedingungen, wann und wie OA veröffentlicht werden kann. Darüber hinaus wünschen sich die Ingenieurinnen und Ingenieure ein klares Mandat der Universitätsleitung für OA.

Objectives: Disease-modifying therapies for amyotrophic lateral sclerosis (ALS) are still not satisfactory. The Rho kinase (ROCK) inhibitor fasudil has demonstrated beneficial effects in cell culture and animal models of ALS. For many years, fasudil has been approved in Japan for the treatment of vasospasm in patients with subarachnoid hemorrhage with a favorable safety profile. Here we describe a clinical trial protocol to repurpose fasudil as a disease-modifying therapy for ALS patients.Methods: ROCK-ALS is a multicenter, double-blind, randomized, placebo-controlled phase IIa trial of fasudil in ALS patients (EudraCT: 2017-003676-31, NCT: 03792490). Safety and tolerability are the primary endpoints. Efficacy is a secondary endpoint and will be assessed by the change in ALSFRS-R, ALSAQ-5, slow vital capacity (SVC), ECAS, and the motor unit number index (MUNIX), as well as survival. Efficacy measures will be assessed before (baseline) and immediately after the infusion therapy as well as on days 90 and 180. Patients will receive a daily dose of either 30 or 60 mg fasudil, or placebo in two intravenous applications for a total of 20 days. Regular assessments of safety will be performed throughout the treatment period, and in the follow-up period until day 180. Additionally, we will collect biological fluids to assess target engagement and evaluate potential biomarkers for disease progression. A total of 120 patients with probable or definite ALS (revised El Escorial criteria) and within 6–18 months of the onset of weakness shall be included in 16 centers in Germany, Switzerland and France.Results and conclusions: The ROCK-ALS trial is a phase IIa trial to evaluate the ROCK-inhibitor fasudil in early-stage ALS-patients that started patient recruitment in 2019.

Objective. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with involvement of the upper and lower motor neurons. Since the loss of fine motor skills is one of the earliest signs of ALS, the hypothesis was tested if the nine hole PEG test (NHPT) and transcranial magnet stimulation (TMS) with resting-motor threshold (RMT) could be useful in monitoring disease progression. Methods. We examined 28 ALS patients and 27 age-matched healthy controls. ALS patients and healthy controls underwent the nine hole peg test (NHPT) and TMS with RMT. Measurements in patients were repeated after three and six months. Results. At baseline, the median NHPT durations were 1,4-fold longer (p

Glacier mass-budget monitoring documents climate fluctuations, provides context for observed glacier-geometry changes, and can provide information on the glaciers’ states. We examine the mass-budget series and available geometries of three well-documented glaciers located in the same catchment area less than 10 km from one another in the Austrian Ötztal Alps. The altitudinal profiles of the 1981–2010 average specific mass budgets of each glacier serve as climatic reference. We apply these reference mass-budget profiles on all available glacier geometries, thereby retrieving for each glacier reference-climate mass budgets that reveal in a discrete way each glacier’s geometric adjustment over time and its impact on mass loss; interpolation of the reference-climate mass budgets over the 1981–2010 period provides the glaciers’ geometry signals. The geometric mass-budget anomalies derived with respect to these geometry signals indicate decreasing mass budgets over the 1981–2010 period by 0.020 m water equivalent (w.e.) a-2, or 31% additional mass loss compared to the centered anomalies derived with respect to the 1981–2010 averages of the conventional mass-budget series. Reference-climate mass budgets with respect to 1981–2010 of older geometries highlight Hintereisferner’s adapting geometry by almost continuous retreat since 1850. Further retreat is inevitable as Hintereisferner is the furthest from a steady state amongst the three glaciers. The relatively small Kesselwandferner has been also mostly retreating, while briefly advancing in response to short-term climatic trends. In a stable 1981–2010 climate, Kesselwandferner would relatively quickly reach a steady state. Vernagtferner’s geometry since 1979 favors mass loss by thinning, primarily due to extended surge-related mass losses since 1845; this inability to retreat has led to – and will further – Vernagtferner’s disintegration.

Background and purpose — In hip arthroplasty, acetabular inclination and anteversion—and also femoral stem torsion—are generally assessed by eye intraoperatively. We assessed whether visual estimation of cup and stem position is reliable. Patients and methods — In the course of a subgroup analysis of a prospective clinical trial, 65 patients underwent cementless hip arthroplasty using a minimally invasive anterolateral approach in lateral decubitus position. Altogether, 4 experienced surgeons assessed cup position intraoperatively according to the operative definition by Murray in the anterior pelvic plane and stem torsion in relation to the femoral condylar plane. Inclination, anteversion, and stem torsion were measured blind postoperatively on 3D-CT and compared to intraoperative results. Results — The mean difference between the 3D-CT results and intraoperative estimations by eye was −4.9° (−18 to 8.7) for inclination, 9.7° (−16 to 41) for anteversion, and −7.3° (−34 to 15) for stem torsion. We found an overestimation of > 5° for cup inclination in 32 hips, an overestimation of > 5° for stem torsion in 40 hips, and an underestimation

In the transfer from fossil fuels to renewable energies, grid operators, companies and farms develop an increasing interest in smart energy management systems which can reduce their energy expenses. This requires sufficiently detailed models of the underlying components and forecasts of generation and consumption over future time horizons. In this work, it is investigated via a real-world case study how data-based methods based on regression and clustering can be applied to this task, such that potentially extensive effort for physical modeling can be decreased. Models and automated update mechanisms are derived from measurement data for a photovoltaic plant, a heat pump, a battery storage, and a washing machine. A smart energy system is realized in a real household to exploit the resulting models for minimizing energy expenses via optimization of self-consumption. Experimental data are presented that illustrate the models’ performance in the real-world system. The study concludes that it is possible to build a smart adaptive forecast-based energy management system without expert knowledge of detailed physics of system components, but special care must be taken in several aspects of system design to avoid undesired effects which decrease the overall system performance.

The choice of a suitable vascular graft in infected anatomic sites can be demanding and is still an area of discussion. When urgent repair is needed and no appropriate autologous veins are available, self-made bovine grafts are a viable option. We present a possible solution for the technical aspects of an infected vascular reconstruction by a self-made bovine pericardial Y graft for aortic reconstruction in a primary aortoenteric fistula.

AIM OF THE STUDY Switzerland introduced the SwissDRG in 2012. The goal of this reimbursement system was to promote cost containment and efficiency in hospital care. To ensure that patients with care needs are not released prematurely because of constraints under the new hospital financing system, the Swiss law on Acute and Transitional Care (ATC) was introduced one year earlier. The objective of the present study was to investigate the impact of ATC and its effects on discharge of patients with persisting care needs after hospitalisation. METHODS Social service workers, nurses and palliative care team members at a Swiss municipal hospital were asked to complete a four-page closed-ended questionnaire about patients who require care after their hospital discharge. This included questions on discharge management, their perceptions of the appropriateness of discharge timing and details about conflicts regarding discharge. Information on length of stay, discharge location, age and sex was extracted from hospital records and matched to the information from the questionnaires. Demographic data are presented descriptively, differences between patients released to ATC and patients released elsewhere (home, nursing home, rehabilitation, etc.) were evaluated with chi-square tests. Logistic regression analyses were performed to evaluate differences between those sent to ATC and rehabilitation with age, length of stay and sex as predictors. ​ RESULTS: A total 1410 of valid questionnaires were collected, comprised of 746 female patients (52.9%) and 664 male patients (47.1%). The mean age of our patient cohort was 73.2 years (SD 15.1), and the mean hospital stay was 12.8 days (SD 9.1). After their hospital stay, 553 patients (39.2%) returned home either alone, or with the help of family members or Spitex. More than a quarter of the sample, 387 (27.4%) patients, was sent to rehabilitation. Less than a fifth, 199 (14.1%) patients, received ATC in an inpatient institution (e.g., nursing home). Compared with patients released elsewhere, significantly more problems/conflicts with regard to hospital discharge were reported for ATC patients (28.6 vs 20.6%, p = 0.01) and their relatives (12.6 vs 7.2%, p = 0.01). Women had a higher probability of being discharged to ATC (OR 1.522, p = 0.014) and a lower chance of receiving rehabilitation upon discharge (OR 0.733, p = 0.014). CONCLUSION The study identified important concerns related to receiving ATC after a hospital stay, that is, more problems/conflicts occur with patients discharged to ATC and that the introduction of ATC might particularly disadvantage female patients, who are less likely to receive rehabilitation care.

Training the next generation of orthopaedic surgeons in total knee arthroplasty (TKA) is crucial, but might affect operative time and outcome. We hypothesized that the learning curve of residents in TKA has an impact on (1) operative time, (2) complication rates and (3) early postoperative outcome. In a retrospective analysis of 738 primary TKAs from our institutional joint registry, operative time, complication rates, patient-reported outcome measures (EQ-5D, WOMAC) within the first year and responder rates for positive outcome as defined by the OMERACT-OARSI criteria were compared between trainee and senior surgeons differentiating between conventional and navigated TKA. Mean operative time was 69.5±18.5min for trainees compared to 77.3±25.8min for senior surgeons (95%CI of the difference 1.5-13.9min, p = 0.02) in conventional TKA and 80.4±22.1min to 84.1±27.6min (95%CI of the difference -0.9-8.2min, p = 0.12) for navigated TKA, respectively. Intraoperative fracture (p≥0.36), thrombosis (p≥0.90), neurological deficits (p≥0.90) and infection rates (p≥0.28) were comparably low in both groups. Patient-reported outcome measures one year after TKA were similar for trainee and senior surgeons with EQ-5D 0.83±0.17 to 0.80±0.21 (p = 0.25) and WOMAC 74.85±18.60 to 72.77±20.12 (p = 0.44) for conventional TKA and EQ-5D 0.80±0.20 to 0.82±0.18 (p = 0.23) and WOMAC 72.71±18.52 to 75.77±17.78 (p = 0.07) for navigated TKA, respectively. Similarly, responder rates for positive outcome were comparable between trainees and senior surgeons (90.7% versus 87.0% p = 0.39 for conventional TKA, 88.7% versus 89.4% p = 0.80 for navigated TKA). Supervised TKA is a safe procedure during the learning curve of young orthopaedic surgeons.

Amyotrophic lateral sclerosis (ALS) is underpinned by an oligogenic rare variant architecture. Identified genetic variants of ALS include RNA-binding proteins containing prion-like domains (PrLDs). We hypothesized that screening genes encoding additional similar proteins will yield novel genetic causes of ALS. The most common genetic variant of ALS patients is a G4C2-repeat expansion within C9ORF72. We have shown that G4C2-repeat RNA sequesters RNA-binding proteins. A logical consequence of this is that loss-of-function mutations in G4C2-binding partners might contribute to ALS pathogenesis independently of and/or synergistically with C9ORF72 expansions. Targeted sequencing of genomic DNA encoding either RNA-binding proteins or known ALS genes (n = 274 genes) was performed in ALS patients to identify rare deleterious genetic variants and explore genotype-phenotype relationships. Genomic DNA was extracted from 103 ALS patients including 42 familial ALS patients and 61 young-onset (average age of onset 41 years) sporadic ALS patients; patients were chosen to maximize the probability of identifying genetic causes of ALS. Thirteen patients carried a G4C2-repeat expansion of C9ORF72. We identified 42 patients with rare deleterious variants; 6 patients carried more than one variant. Twelve mutations were discovered in known ALS genes which served as a validation of our strategy. Rare deleterious variants in RNA-binding proteins were significantly enriched in ALS patients compared to control frequencies (p = 5.31E-18). Nineteen patients featured at least one variant in a RNA-binding protein containing a PrLD. The number of variants per patient correlated with rate of disease progression (t-test, p = 0.033). We identified eighteen patients with a single variant in a G4C2-repeat binding protein. Patients with a G4C2-binding protein variant in combination with a C9ORF72 expansion had a significantly faster disease course (t-test, p = 0.025). Our data are consistent with an oligogenic model of ALS. We provide evidence for a number of entirely novel genetic variants of ALS caused by mutations in RNA-binding proteins. Moreover we show that these mutations act synergistically with each other and with C9ORF72 expansions to modify the clinical phenotype of ALS. A key finding is that this synergy is present only between functionally interacting variants. This work has significant implications for ALS therapy development.

Intestinal microbiota disruption is associated with acute gastrointestinal (GI) Graft-versus-Host Disease (GvHD) and poor outcome after allogeneic stem cell transplantation (ASCT). Here, in a retrospective analysis of 200 patients undergoing ASCT at the Regensburg University Medical Center, we assessed the relative expression of Paneth cell antimicrobial peptides (AMPs), Human Defensins (HD) 5 and 6 and regenerating islet-derived 3α (Reg3α), in 292 human intestinal biopsies as well as Reg3α serum levels in relation to acute GI GvHD. In the absence of GI GvHD, the relative expression of Paneth cell AMPs was significantly higher in the small intestine (duodenum to ileum) than in the stomach and large intestine (cecum to rectum) for Reg3α (p≤0.001), HD5 (p≤0.002) and HD6 (p≤0.02). Acute stage 2-4 GI GvHD was associated with reduced expression of AMPs in the small intestine (p≤0.01) in comparison to stage 0-1 disease, accompanied by a decrease in Paneth cell count in case of severe acute GI GvHD (p

Non-invasive ventilation (NIV) and percutaneous gastrostomy (PEG) are guideline-recommended interventions for symptom management in amyotrophic lateral sclerosis (ALS). Their effect on survival is controversial and the impact on causes of death is unknown.To investigate the effect of NIV and PEG on survival and causes of death in ALS patients.Eighty deceased ALS patients underwent a complete post mortem analysis for causes of death between 2003 and 2015. Forty-two of these patients consented for genetic testing. Effects of NIV and PEG on survival and causes of death were analyzed in a multivariable Cox proportional hazard regression.Six patients, who requested assisted suicide causing drug-induced hypoxia, were excluded from final analysis. Respiratory failure was the main cause of death in 72 out of 74 patients. Fifteen out of 74 died of aspiration pneumonia 23/74 of bronchopneumonia and 8/74 of a combination of aspiration pneumonia and bronchopneumonia. Twenty died of hypoxia without concomitant infection, and six patients had pulmonary embolism alone or in combination with pneumonia. NIV (p = 0.01) and PEG (p

Cannabinoid receptor subtype 2 (CB2) has been shown to be up-regulated in activated microglia and therefore plays an important role in neuroinflammatory and neurodegenerative diseases such as multiple sclerosis, amyotrophic lateral sclerosis and Alzheimer’s disease. The CB2 receptor is therefore considered as a very promising target for therapeutic approaches as well as for imaging. A promising 2-oxoquinoline derivative designated KP23 was synthesized and radiolabeled and its potential as a ligand for PET imaging the CB2 receptor was evaluated. [11C]KP23 was obtained in 10%–25% radiochemical yield (decay corrected) and 99% radiochemical purity. It showed high stability in phosphate buffer, rat and mouse plasma. In vitro autoradiography of rat and mouse spleen slices, as spleen expresses a high physiological expression of CB2 receptors, demonstrated that [11C]KP23 exhibits specific binding towards CB2. High spleen uptake of [11C]KP23 was observed in dynamic in vivo PET studies with Wistar rats. In conclusion, [11C]KP23 showed promising in vitro and in vivo characteristics. Further evaluation with diseased animal model which has higher CB2 expression levels in the brain is warranted.

We present a technique based on high resolution imaging to measure the absolute temperature and the heating rate of a single ion trapped at the focus of a deep parabolic mirror. We collect the fluorescence light scattered by the ion during laser cooling and image it onto a camera. Accounting for the size of the point-spread function and the magnification of the imaging system, we determine the spatial extent of the ion, from which we infer the mean phonon occupation number in the trap. Repeating such measurements and varying the power or the detuning of the cooling laser, we determine the heating rate induced by any kind of effect other than photon scattering. In contrast to other established schemes for measuring the heating rate, the ion is always maintained in a state of thermal equilibrium at temperatures close to the Doppler limit.

Over the past two decades, our understanding of the endocannabinoid system has greatly improved due to the wealth of results obtained from exploratory studies. Currently, two cannabinoid receptor subtypes have been well characterized. The cannabinoid receptor type 1 (CB1) is widely expressed in the central nervous system, while the levels of the cannabinoid receptor type 2 (CB2) in the brain and spinal cord of healthy individuals are relatively low. However, recent studies demonstrated a CB2 upregulation on activated microglia upon neuroinflammation, an indicator of neurodegeneration. Our research group aims to develop a suitable positron emission tomography (PET) tracer to visualize the CB2 receptor in patients suffering from neurodegenerative diseases. Herein we report two novel thiophene-based 11C-labeled PET ligands designated [11C]AAT-015 and [11C]AAT-778. The reference compounds were synthesized using Gewald reaction conditions to obtain the aminothiophene intermediates, followed by amide formation. Saponification of the esters provided their corresponding precursors. Binding affinity studies revealed Ki values of 3.3 ± 0.5 nM (CB2) and 1.0 ± 0.2 µM (CB1) for AAT-015. AAT-778 showed similar Ki values of 4.3 ± 0.7 nM (CB2) and 1.1 ± 0.1 µM (CB1). Radiosynthesis was carried out under basic conditions using [11C]iodomethane as methylating agent. After semi-preparative HPLC purification both radiolabeled compounds were obtained in 99% radiochemical purity and the radiochemical yields ranged from 12 to 37%. Specific activity was between 96 - 449 GBq/µmol for both tracers. In order to demonstrate CB2 specificity of [11C]AAT-015 and [11C]AAT-778, we carried out autoradiography studies using CB2-positive mouse/rat spleen tissues. The obtained results revealed unspecific binding in spleen tissue that was not blocked by an excess of CB2-specific ligand GW402833. For in vivo analysis, [11C]AAT-015 was administered to healthy rats via tail-vein injection. Evaluation of the CB2-positive spleen, however, showed no accumulation of the radiotracer. Despite the promising in vitro binding affinities, specific binding of [11C]AAT-015 and [11C]AAT-778 could not be demonstrated.

BACKGROUND:Motor Unit Number Index (MUNIX) is a neurophysiological measure that provides an index of the number of lower motor neurons in a muscle. Its performance across centres in healthy subjects and patients with Amyotrophic Lateral Sclerosis (ALS) has been established, but inter-rater variability between multiple raters in one single subject has not been investigated. OBJECTIVE:To assess reliability in a set of 6 muscles in a single subject among 12 examiners (6 experienced with MUNIX, 6 less experienced) and to determine variables associated with variability of measurements. METHODS:Twelve raters applied MUNIX in six different muscles (abductor pollicis brevis (APB), abductor digiti minimi (ADM), biceps brachii (BB), tibialis anterior (TA), extensor dig. brevis (EDB), abductor hallucis (AH)) twice in one single volunteer on consecutive days. All raters visited at least one training course prior to measurements. Intra- and inter-rater variability as determined by the coefficient of variation (COV) between different raters and their levels of experience with MUNIX were compared. RESULTS:Mean intra-rater COV of MUNIX was 14.0% (±6.4) ranging from 5.8 (APB) to 30.3% (EDB). Mean inter-rater COV was 18.1 (±5.4) ranging from 8.0 (BB) to 31.7 (AH). No significant differences of variability between experienced and less experienced raters were detected. CONCLUSION:We provide evidence that quality control for neurophysiological methods can be performed with similar standards as in laboratory medicine. Intra- and inter-rater variability of MUNIX is muscle-dependent and mainly below 20%. Experienced neurophysiologists can easily adopt MUNIX and adequate teaching ensures reliable utilization of this method.

Mutations in superoxide dismutase-1 (SOD1) are a common known cause of amyotrophic lateral sclerosis (ALS). The neurotoxicity of mutant SOD1s is most likely caused by misfolded molecular species, but disease pathogenesis is still not understood. Proposed mechanisms include impaired mitochondrial function, induction of endoplasmic reticulum stress, reduction in the activities of the proteasome and autophagy, and the formation of neurotoxic aggregates. Here we examined whether perturbations in these cellular pathways in turn influence levels of misfolded SOD1 species, potentially amplifying neurotoxicity. For the study we used fibroblasts, which express SOD1 at physiological levels under regulation of the native promoter. The cells were derived from ALS patients expressing 9 different SOD1 mutants of widely variable molecular characteristics, as well as from patients carrying the GGGGCC-repeat-expansion in C9orf72 and from non-disease controls. A specific ELISA was used to quantify soluble, misfolded SOD1, and aggregated SOD1 was analysed by western blotting. Misfolded SOD1 was detected in all lines. Levels were found to be much lower in non-disease control and the non-SOD1 C9orf72 ALS lines. This enabled us to validate patient fibroblasts for use in subsequent perturbation studies. Mitochondrial inhibition, endoplasmic reticulum stress or autophagy inhibition did not affect soluble misfolded SOD1 and in most cases, detergent-resistant SOD1 aggregates were not detected. However, proteasome inhibition led to uniformly large increases in misfolded SOD1 levels in all cell lines and an increase in SOD1 aggregation in some. Thus the ubiquitin-proteasome pathway is a principal determinant of misfolded SOD1 levels in cells derived both from patients and controls and a decline in activity with aging could be one of the factors behind the mid-to late-life onset of inherited ALS.

Full expansions of the polyglutamine domain (polyQ≥34) within the polysome-associated protein ataxin-2 (ATXN2) are the cause of a multi-system neurodegenerative disorder, which usually presents as a Spino-Cerebellar Ataxia and is therefore known as SCA2, but may rarely manifest as Levodopa-responsive Parkinson syndrome or as motor neuron disease. Intermediate expansions (27≤polyQ≤33) were reported to modify the risk of Amyotrophic Lateral Sclerosis (ALS). We have now tested the reproducibility and the specificity of this observation. In 559 independent ALS patients from Central Europe, the association of ATXN2 expansions (30≤polyQ≤35) with ALS was highly significant. The study of 1490 patients with Parkinson's disease (PD) showed an enrichment of ATXN2 alleles 27/28 in a subgroup with familial cases, but the overall risk of sporadic PD was unchanged. No association was found between polyQ expansions in Ataxin-3 (ATXN3) and ALS risk. These data indicate a specific interaction between ATXN2 expansions and the causes of ALS, possibly through altered RNA-processing as a common pathogenic factor.

Climate change has a large impact on water resources and thus on hydropower. Hydroelectric power generation is closely linked to the regional hydrological situation of a watershed and reacts sensitively to changes in water quantity and seasonality. The development of hydroelectric power generation in the Upper Danube basin was modelled for two future decades, namely 2021–2030 and 2051–2060, using a special hydropower module coupled with the physically-based hydrological model PROMET. To cover a possible range of uncertainties, 16 climate scenarios were taken as meteorological drivers which were defined from different ensemble outputs of a stochastic climate generator, based on the IPCC-SRES-A1B emission scenario and four regional climate trends. Depending on the trends, the results show a slight to severe decline in hydroelectric power generation. Whilst the mean summer values indicate a decrease, the mean winter values display an increase. To show past and future regional differences within the Upper Danube basin, three hydropower plants at individual locations were selected. Inter-annual differences originate predominately from unequal contributions of the runoff compartments rain, snow- and ice-melt.

The cannabinoid receptor type 2 (CB2) has a very low expression level in brain tissue under basal conditions, but it is up-regulated in diverse pathological conditions. Two promising lead structures from the literature, N-((3S,5S,7S)-adamantan-1-yl)-8-methoxy-4-oxo-1-pentyl-1,4-dihydroquinoline-3-carboxamide and 8-butoxy-N-(2-fluoro-2-phenylethyl)-7-methoxy-2-oxo-1,2-dihydroquinoline-3-carboxamide – designated KD2 and KP23, respectively – were evaluated as potential PET ligands for imaging CB2. Both KD2 and KP23 were synthesized and labeled with carbon-11. In vitro autoradiographic studies on rodent spleen tissues showed that [11C]KD2 exhibits superior properties. A pilot study using [11C]KD2 on human post mortem ALS spinal cord slices indicated high CB2 expression level and specific binding, a very exciting finding if considering the future diagnostic application of CB2 ligands and their utility in therapy monitoring. In vivo blocking studies in rats with [11C]KD2 showed also high specific uptake in spleen tissue. Although the protein-bound fraction is relatively high, KD2 or KD2 derivatives could be very useful tools for the non-invasive investigation of CB2 levels under various neuroinflammatory conditions.

A variety of explanations have been provided to elucidate the requirement of the large islet mass that is essential for a successful treatment of patients with type I diabetes by intrahepatic transplantation. The purpose of this study was to investigate islet cell survival under the effect of prolonged hypoxia and/or nutrient withdrawal, which mimics posttransplantation environment of transplanted islets in the liver. We studied the influence of 24 h of hypoxia (1% O 2 ) in intact isolated human and rat islets as well as the effect of combined oxygen/nutrient deprivation in a mouse insulinoma cell line (MIN6). In intact human islets, 24 h of hypoxia led to central necrosis combined with apoptotic features such as nuclear pyknosis and DNA fragmentation. In the course of hypoxic treatment, ultrastructural analysis demonstrated a gradual transition from an apoptotic to a necrotic morphology particularly pronounced in central areas of large islets. In MIN6 cells, on the other hand, hypoxia led to a twofold (p < 0.01) increase in caspase-3 activity, an indicator of apoptosis, but not to necrosis, as determined by release of lactate dehydrogenase (LDH). Only in combination with nutrient/serum deprivation was a marked increase in LDH release observed (sixfold vs. control, p < 0.01). We therefore conclude that, similar to MIN6 cells, central necrosis in isolated hypoxic islets is the result of the combined effects of hypoxia and nutrient/serum deprivation, most likely due to limited diffusion. Provided that transplanted islets undergo a similar fate as shown in our in vitro study, future emphasis will require the development of strategies that protect the islet graft from early cell death and accelerate the revascularization process.