Homing of mesenchymal stem cells in induced degenerative intervertebral discs in a whole organ culture system

STUDY DESIGN.: Homing of human bone marrow-derived mesenchymal stem cells (BMSCs) was studied using ex vivo cultured bovine caudal intervertebral discs (IVDs). OBJECTIVE.: To investigate in a whole organ culture whether metabolic and mechanical challenges can induce BMSC recruitment into the IVD. SUMMARY OF BACKGROUND DATA.: Cells from injured tissues release cytokines and mediators that enable the recruitment of progenitor cells. BMSCs have the ability to survive within the IVD. METHODS.: Bovine IVDs with or without endplates were cultured for 1 week under simulated physiological or degenerative conditions; disc cells were analyzed for cell viability and gene expression, whereas media was analyzed for nitric oxide production and chemotaxis. Homing of BMSCs was investigated by supplying PKH-labeled human BMSCs onto cultured IVDs (1 × 10 cells/disc on d 8, 10, and 12 of culture); on day 14, the number of homed BMSCs was microscopically assessed. Moreover, a comparative study was performed between transduced BMSCs (transduced with an adenovirus encoding for insulin-like growth factor 1 [IGF-1]) and nontransduced BMSCs. Disc proteoglycan synthesis rate was quantified via S incorporation. The secretion of IGF-1 was evaluated by enzyme-linked immunosorbent assay on both simulated physiological and degenerative discs. RESULTS.: Discs cultured under degenerative conditions showed reduced cell viability, upregulation of matrix degrading enzymes, and increased nitric oxide production compared with simulated physiological discs. Greater homing occurred under degenerative compared with physiological conditions with or without endplate. Media of degenerative discs demonstrated a chemoattractive activity toward BMSCs. Finally, discs homed with IGF-1-transduced BMSCs showed increased IGF-1 secretion and significantly higher proteoglycan synthesis rate than discs supplied with nontransduced BMSCs. CONCLUSION.: We have demonstrated for the first time that degenerative conditions induce the release of factors promoting BMSC recruitment in an ex vivo organ culture. Moreover, IGF-1 transduction of BMSCs strongly increases the rate of proteoglycan synthesis within degenerative discs. This finding offers a new delivery system for BMSCs and treatment strategy for IVD regeneration.     

Proficiency testing of immunohistochemical biomarker assays in breast cancer

Steroid hormone receptor expression and HER2 status have become an integral part of histopathologic characterization of breast cancer and corresponding biomarker assays have gained important prognostic and predictive impact. Because testing inaccuracy could provide a major hazard to modern breast cancer therapy, a laboratory proficiency testing program has been implemented in Germany using tissue microarrays (TMAs). In four consecutive annual trials with 142 laboratories participating on average per trial, estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (Her2) were determined immunohistochemically by participating laboratories followed by central review of all immunostains. Performance strongly depended on the ambiguity of expression of the target molecule in the test samples. In clearly positive (Allred score 7–8; Her2 3+) or negative tissue samples, the majority of participants (86%) achieved concordance rates exceeding 85%. By contrast, low expression of ER or PR (Allred score 3–4) as well as Her2 status 2+ led to considerable lower concordance rates ranging from 41% (Her2 2+) to 75% (PR). Poor reproducibility was predominantly due to inadequate laboratory performance whereas interobserver agreement (weighted kappa statistics) usually was high (>0.81). Laboratories that participated in more than one of the four subsequent trials (n = 110) showed a highly significant improvement of performance. In conclusion, a TMA-based proficiency testing of biomarkers in breast cancer has been implemented in Germany over a 5-year period and revealed reliable assessment of unambiguously positive and negative test samples. Low-expressing tumor samples with regard to steroid hormone receptor expression and Her2 status 2+ led to inaccurate evaluations by up to 59% of participants. Regularly participating laboratories showed a significant improvement of performance. Reinhard von Wasielewski and Svenja Hasselmann contributed equally to this work.     

Comparative effectiveness of medical treatment vs. metabolic surgery for histologically proven non-alcoholic steatohepatitis and fibrosis: a matched network meta-analysis

BackgroundNon-alcoholic steatohepatitis (NASH) comprises a major healthcare problem affecting up to 30% of patients with obesity and the associated risk for cardiovascular and liver-related mortality. Several new drugs for NASH-treatment are currently investigated. No study thus far directly compared surgical and non-surgical therapies for NASH. This network meta-analysis compares for the first time the effectiveness of different therapies for NASH using a novel statistical approach.MethodsThe study was conducted according to the PRISMA guidelines for network meta-analysis. PubMed, CENTRAL and Web of Science were searched without restriction of time or language using a validated search strategy. Studies investigating therapies for NASH in adults with liver biopsies at baseline and after at least 12 months were selected. Patients with liver cirrhosis were excluded. Risk of bias was assessed with ROB-2 and ROBINS-I-tools. A novel method for population-adjusted indirect comparison to include and compare single-arm trials was applied. Main outcomes were NASH-resolution and improvement of fibrosis.ResultsOut of 7,913 studies, twelve randomized non-surgical studies and twelve non-randomized surgical trials were included. NASH-resolution after non-surgical intervention was 29% [95% confidence interval (CI): 23–40%] and 79% (95% CI: 72–88%) after surgery. The network meta-analysis showed that surgery had a higher chance of NASH-resolution than medication [odds ratio (OR) =2.68; 95% CI: 1.44–4.97] while drug treatment was superior to placebo (OR =2.24; 95% CI: 1.55–3.24). Surgery (OR =2.18; 95% CI: 1.34–3.56) and medication (OR =1.79; 95% CI: 1.39–2.31) were equally effective to treat fibrosis compared to placebo without difference between them. The results did not change when only new drugs specifically developed for the treatment of NASH were included.ConclusionsMetabolic surgery has a higher effectiveness for NASH-therapy than medical therapy while both were equally effective regarding improvement of fibrosis. Trials directly comparing surgery with medication must be urgently conducted. Patients with NASH should be informed about surgical treatment options.     

EMCDDA framework and practical guidance for naming synthetic cannabinoids

Synthetic cannabinoids (SCs), often sold as “legal” replacements for cannabis, are the largest group of new psychoactive substances monitored by the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA). Currently, close to 240 structurally heterogeneous SCs are monitored through the European Union (EU) Early Warning System, and attributing consistent, informative, and user-friendly names to SCs has been a challenge in the past. Over time, several naming conventions have been employed with the aim of making SCs more easily recognizable by non-chemists, including regulators. To achieve this, the names assigned need to contain detailed information on the structural features present in the substance. This work provides a theoretical framework and a practical hands-on guideline for consistent naming of SCs, which is easy to understand and can be applied by the forensic community, researchers, clinical practitioners, and policy-makers. The proposed framework builds on the established letter code system for molecular building blocks (core, linker, linked group, and tail) implemented by the EMCDDA in 2013 and has been expanded to incorporate additional structural features through substitution. The scope of the issue of attributing semi-systematic code names is illustrated, and earlier approaches used for naming SCs are discussed. The concepts and rules of the EMCDDA framework are described through a flowchart that provides a basis for naming new SCs, a graphical overview of the chemical diversity of SCs, and a detailed list of the SCs identified in the EU by the Early Warning System of the EMCDDA for reference.     

Comparing radiographic scores for prediction of complications and outcome of aneurysmal subarachnoid hemorrhage: Which performs best?

Background and purpose

Aneurysmal subarachnoid hemorrhage (aSAH) is characterized by high morbidity and mortality proceeding from the initial severity and following complications of aSAH. Various scores have been developed to predict these risks. We aimed to analyze the clinical value of different radiographic scores for prognostication of aSAH outcome.

Methods

Initial computed tomography scans (≤48 h after ictus) of 745 aSAH cases treated between January 2003 and June 2016 were reviewed with regard to Subarachnoid Hemorrhage Early Brain Edema Score (SEBES), and Claassen, Barrow Neurological Institute (BNI), Hijdra, original Graeb and Fisher scale scores. The primary endpoints were development of delayed cerebral ischemia (DCI), in-hospital mortality and unfavorable outcome (modified Rankin Scale score >3) at 6 months after subarachnoid hemorrhage. Secondary endpoints included the different complications that can occur during aSAH. Clinically relevant cutoffs were defined using receiver-operating characteristic curves. The radiographic scores with the highest values for area under the curve (AUC) were included in the final multivariate analysis.

Results

The Hijdra sum score had the most accurate predictive value and independent associations with all primary endpoints: DCI (AUC 0.678, adjusted odds ratio [aOR] 2.83; p < 0.0001); in-hospital mortality (AUC 0.704, aOR 2.83; p < 0.0001) and unfavorable outcome (AUC 0.726, aOR 2.91; p < 0.0001). Multivariate analyses confirmed the independent predictive value of the radiographic scales for risk of decompressive craniectomy (SEBES and Fisher score), cerebral vasospasm (SEBES, BNI score and Fisher score) and shunt dependency (Hijdra ventricle score and Fisher score) after aSAH.

Conclusions

Initial radiographic severity of aSAH was independently associated with occurrence of different complications during aSAH and the final outcome. The Hijdra sum score showed the highest diagnostic accuracy and robust predictive value for early detection of risk of DCI, in-hospital mortality and unfavorable outcome after aSAH.     

Tödlicher Sturz in ein Laugebecken

Notfall + Rettungsmedizin - In einer Firma für Metallveredelung stürzt ein 59-jähriger Mitarbeiter in ein Becken mit Kaliumlauge. Trotz erfolgreicher Rettung aus der Flüssigkeit...