Optical analysis of glutamate spread in the neuropil.

Fast synaptic communication uses diffusible transmitters whose spread is limited by uptake mechanisms. However, on the submicron-scale, the distance between two synapses, the extent of glutamate spread has so far remained difficult to measure. Here, we show that quantal glutamate release from individual hippocampal synapses activates extracellular iGluSnFr molecules at a distance of >1.5 µm. 2P-glutamate uncaging near spines further showed that alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-Rs and N-methyl-D-aspartate (NMDA)-Rs respond to distant uncaging spots at approximately 800 and 2000 nm, respectively, when releasing the amount of glutamate contained in approximately five synaptic vesicles. The uncaging-induced remote activation of AMPA-Rs was facilitated by blocking glutamate transporters but only modestly decreased by elevating the recording temperature. When mimicking release from neighboring synapses by three simultaneous uncaging spots in the microenvironment of a spine, AMPA-R-mediated responses increased supra-additively. Interfering with extracellular glutamate diffusion through a glutamate scavenger system weakly reduced field synaptic responses but not the quantal amplitude. Together, our data suggest that the neuropil is more permissive to short-range spread of transmitter than suggested by theory, that multivesicular release could regularly coactivate nearest neighbor synapses and that on this scale glutamate buffering by transporters primarily limits the spread of transmitter and allows for cooperative glutamate signaling in extracellular microdomains.

[Prognostic and predictive methylation biomarkers in HNSCC : Epigenomic diagnostics for head and neck squamous cell carcinoma (HNSCC)]. / Prognostische und prädiktive Methylierungsbiomarker für HNSCC : Epigenomische Diagnostika für Plattenepithelkarzinome des Kopf- und Halsbereichs (HNSCC).

BACKGROUND: Prognostic and predictive biomarkers for personalized treatment management in head and neck squamous cell carcinoma (HNSCC) are of great clinical interest. OBJECTIVE: DNA methylation is an epigenetic process involved in gene regulation and could be a source of potential prognostic and predictive biomarkers. METHODS: This study comprises literature research in PubMed and own studies. RESULTS: Gene methylation, e.g. of PITX2, is a strong, human papillomavirus (HPV)-independent prognostic biomarker. SHOX2 and SEPT9 methylation in circulating cell-free DNA within blood plasma correlates with tumor stage and prognosis. Methylation of diverse immune checkpoints, e.g., PD­1, PD-L1, and CTLA4, is also prognostic and correlates with gene expression. CONCLUSION: DNA methylation is a source of efficient prognostic blood plasma- and tissue-based biomarkers. However, prior to clinical implementation, studies must prove that biomarker-guided treatment selection can lead to better outcomes or reduced toxicity. The applicability of DNA methylation as a predictive biomarker for targeted drug-based cancer therapy seems promising, although further validation is needed.

Dynamic posterior stabilization for degenerative lumbar spine disease: a large consecutive case series with long-term follow-up by additional postal survey.

INTRODUCTION: Dynamic stabilization of the degenerated spine was invented to overcome the negative side effects of fusion surgery like adjacent segment degeneration. Amongst various different implants DSS(®) is a pedicle-based dynamic device for stabilizing the spine and preserving motion. Nearly no clinical data of the implant have been reported so far. The current analysis presents results from a single spine surgeon who has been using DSS(®) for the past 5 years and recorded all treatment and outcome data in the international Spine Tango registry. MATERIALS/METHODS: From the prospectively documented overall patient pool 436 cases treated with DSS(®) could be identified. The analysis was enhanced with a mailing of COMI patient questionnaires for generating longer-term follow-ups up to 4 years. RESULTS: 387 patients (189 male, 198 female; mean age 67.3 years) with degenerative lumbar spinal disease including degenerative spondylolisthesis (6.1 %) could be evaluated. The type of degeneration was mainly spinal stenosis (89.9 %). After a mean follow-up of 1.94 years, the COMI score and NRS back and leg pain improved significantly and to a clinically relevant extent. The postoperative trend analysis could not determine a relevant deterioration of these outcomes until 4 years postoperative. 10 patients were revised (2.6 %) and the implant was removed; in most cases, a fusion was performed. Another 5 cases (1.3 %) had an extension of the dynamic stabilization system to the adjacent level. 84.2 % of patients rated that the surgery had helped a lot or had helped. DISCUSSION: The results of this large consecutive series with a follow-up up to 4 years could demonstrate a good and stable clinical outcome after posterior dynamic stabilization with DSS(®). For degenerative diseases of the lumbar spine, this treatment seems to be a valid alternative to fusion surgery.

Bevacizumab continuation versus no continuation after first-line chemotherapy plus bevacizumab in patients with metastatic colorectal cancer: a randomized phase III non-inferiority trial (SAKK 41/06).

BACKGROUND: Chemotherapy plus bevacizumab is a standard option for first-line treatment in metastatic colorectal cancer (mCRC) patients. We assessed whether no continuation is non-inferior to continuation of bevacizumab after completing first-line chemotherapy. PATIENTS AND METHODS: In an open-label, phase III multicentre trial, patients with mCRC without disease progression after 4-6 months of standard first-line chemotherapy plus bevacizumab were randomly assigned to continuing bevacizumab at a standard dose or no treatment. CT scans were done every 6 weeks until disease progression. The primary end point was time to progression (TTP). A non-inferiority limit for hazard ratio (HR) of 0.727 was chosen to detect a difference in TTP of 6 weeks or less, with a one-sided significance level of 10% and a statistical power of 85%. RESULTS: The intention-to-treat population comprised 262 patients: median follow-up was 36.7 months. The median TTP was 4.1 [95% confidence interval (CI) 3.1-5.4] months for bevacizumab continuation versus 2.9 (95% CI 2.8-3.8) months for no continuation; HR 0.74 (95% CI 0.58-0.96). Non-inferiority could not be demonstrated. The median overall survival was 25.4 months for bevacizumab continuation versus 23.8 months (HR 0.83; 95% CI 0.63-1.1; P = 0.2) for no continuation. Severe adverse events were uncommon in the bevacizumab continuation arm. Costs for bevacizumab continuation were estimated to be ∼30,000 USD per patient. CONCLUSIONS: Non-inferiority could not be demonstrated for treatment holidays versus continuing bevacizumab monotheray, after 4-6 months of standard first-line chemotherapy plus bevacizumab. Based on no impact on overall survival and increased treatment costs, bevacizumab as a single agent is of no meaningful therapeutic value. More efficient treatment approaches are needed to maintain control of stabilized disease following induction therapy. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, number NCT00544700.

Geometry of mass.

We study the effect of mass on geometric descriptions of gauge field theories. In an approach in which the massless theory resembles general relativity, the introduction of the mass entails non-zero torsion and the generalization to Einstein-Cartan-Sciama-Kibble theories. The relationships to pure torsion formulations (teleparallel gravity) and to higher gauge theories are also discussed.

[Primary liver tumours in childhood]. / Primäre Lebertumoren im Kindesalter.

The reported prevalence of focal liver lesions in adult patients and children is different. The article discusses pediatric liver tumors under the criteria of histopathology and contrast enhanced ultrasound (CEUS) features. Aim of this article is also to support the already established Pediatric Registry of the European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB) to collect data on safety and applications of ultrasound contrast agents in children (www.efsumb.org).

Contrast enhanced ultrasound in pediatric patients: a real challenge.

Ultrasound (US) imaging in the paediatric population has been a routine technique for decades, in part because of the advantages it offers over other imaging modalities. Off-label use (and its funding) is of the utmost importance in paediatrics because many drugs have not been evaluated in randomised trials in children. As a consequence such drugs are not specifically approved for use in children. This is also true for the contrast agents used in CEUS. The off-label use of CEUS in paediatric patients illustrates the need to deal with unresolved legal issues while at the same time balancing this with the need for high diagnostic performance in daily clinical routine. In addition to approved indications with a focus on the liver and Doppler enhancement, CEUS is safe and effective for the examination of many organs, as recently highlighted by the European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB). This article provides a summary of the available literature describing the utility of CEUS in paediatric patients. Furthermore, we suggest the establishment of a registry to collect data on safety and applications of ultrasound contrast agents in children. A paediatric registry has recently been introduced by EFSUMB (www.efsumb.org).

Conventional ultrasound for lymph node evaluation, update 2013.

Conventional ultrasound is regarded as the first method of choice to evaluate lymph node disease due to its high resolution. The combination of various features obtained from the patients history including age, acute or chronic onset, symptoms, and a knowledge of underlying systemic diseases as well as imaging criteria, most importantly B-mode (gray-scale) and colour Doppler imaging (CDI) are the basis for the differential diagnosis of lymphadenopathy. New ultrasound techniques such as elastography and contrast-enhanced ultrasound may provide further information. In addition, ultrasound evaluation of lymph nodes is an essential adjunct to the clinical investigation in staging of malignant neoplasia and lymphoma. In this paper the current literature is reviewed regarding conventional B-mode and Doppler ultrasound for the evaluation of lymphadenopathy. The ultrasound criteria for the differential diagnosis of enlarged and structurally altered lymph nodes are summarized and also limitations are described.

Measurement of shear wave velocity using acoustic radiation force impulse imaging is not hampered by previous use of ultrasound contrast agents.

PURPOSE: To assess the inter-observer reproducibility of acoustic radiation force impulse imaging (ARFI) between 2 skilled physicians and to evaluate if ultrasound contrast agents (UCA) affect the measurement of shear wave velocity (SWV) using ARFI. PATIENTS AND METHODS: 53 patients (29 males, 24 females, 59 ± 15 [22-84] years) who underwent contrast enhanced ultrasound (CEUS) examination were included. ARFI was performed on liver segment V by physicians A and B before CEUS, and by physician A within 4-6 minutes and 7-10 minutes after contrast injection. In a subgroup of 31 patients (15 males, 16 females, 57 ± 18 [22-84] years), ARFI was also performed on focal liver lesions (FLL) by physician A before CEUS, and within 4-6 minutes and 7-10 minutes after contrast injection. RESULTS: The SWV values obtained by physician A and B before CEUS yielded an intra-class correlation coefficient value of 0.913 (95% CI, 0.849-0.950). No significant differences were shown between the SWV values of liver segment V in all 53 patients and of FLL in the subgroup of 31 patients obtained before CEUS and that of within 4-6 minutes and 7-10 minutes after contrast injection (all P > 0.05). CONCLUSION: ARFI showed excellent inter-observer reproducibility between 2 skilled physicians. UCA did not affect the measurement of SWV in both liver parenchyma and FLL, at least when performed 4 minutes after the contrast injection. ARFI may become an additional tool in the differential diagnosis of FLL.

Artifacts and pitfalls in contrast-enhanced ultrasound of the liver.

Ultrasound technology is always connected to possible artefacts. Since introduction of ultrasound technology the knowledge of those artefacts is eminent to avoid misinterpretations. It is important to know that with the introduction of new ultrasound technology the possibility of artefacts are rising.Whereas artefacts initially were limited to B-mode sonography, every technological step (colour Doppler sonography, contrast enhanced sonography) comes with a range of new artefacts. This article is written to explain the technological basics of ultrasound artefacts and provide the reader with examples in daily practice and how to avoid them.

SAKK57/16 Nab-paclitaxel and Gemcitabine in Soft Tissue Sarcoma (NAPAGE): a phase I/II trial.

BACKGROUND: To determine whether the combination of nab-paclitaxel with gemcitabine has activity in patients with pretreated soft tissue sarcoma (STS). PATIENTS AND METHODS: NAPAGE is a phase Ib/II clinical trial investigating the combination of nab-paclitaxel (nab-pc) with gemcitabine employing two cohorts. One of a dose-de-escalation phase and one of expansion. In phase I, nab-pc was given at 150 mg/m2 in combination with gemcitabine 1000 mg/m2 every two weeks, until disease progression or unacceptable toxicity. This dose was recommended for phase II (RP2D), as there was no dose limiting toxicity (DLT) or discontinuations due to adverse events (AEs). The primary endpoint of the phase II was progression-free rate (PFR) at 3 months (H0: 20%, H1:40%). The secondary endpoints included progression free survival (PFS), overall survival (OS), AEs, objective response and patient-reported outcomes (PRO). Efficacy analysis was by intention to treat. RESULTS: The 3-month PFR was 56.4% (95% confidence interval CI: 39.6-72.2%). The 3-month and 6-month PFS were 58.4% (95% CI: 41.3-72.1%) and 44.6% (95% CI: 28.4-59.5%), respectively. Median PFS was 5.3 months (95% CI: 1.4-8.2) and median OS was 12.8 months (95% CI: 10.5-39.2). The most common treatment-related grade ≥ 3 AE were neutropenia (18%), followed by anemia (2.6%), hypertension (2.6%) and alanine aminotransferase increase (2.6%). Grade 1 and grade 2 peripheral sensory neuropathy (PNP) occurred in 15.4% and 20.5%, respectively. No grade 3-4 PNP was reported. CONCLUSIONS: Combining nab-pc and gemcitabine is safe. Promising activity is observed in pretreated STS patients with manageable toxicity. This regimen should be considered for further exploration.

Littoral cell angioma of the spleen.

We report for the first time on the contrast-enhanced ultrasound (CEUS) features of littoral cell angioma of the spleen (LCA). A patient presented with the incidental finding of splenomegaly which was investigated using modern ultrasound techniques. B-mode technique revealed heterogenous splenic parenchyma and small hypoechoic lesions up to 30 mm in size. Colour Doppler imaging revealed no specific vascularity. CEUS showed arterial hyper- and hypoenhancement with pronounced demarcation in the late phase. In an assumption of malignancy the lesions were biopsied using ultrasound guidance. Histology showed LCA. In this case report we discuss LCA in the light of new ultrasound techniques and present a review of the literature.

The pancreatic head is larger than often assumed.

Reference values for B-mode abdominal ultrasound are controversially discussed in the literature mainly due to the lack of data and non-standardized examination techniques. A cohort of 100 patients was prospectively examined. Patients with hepatobiliary diseases including gallstones, acute or chronic pancreatitis (n = 13) and non-adequate visualization (n = 10) were excluded from statistical analysis. Therefore, 77 patients were analyzed including 52 female and 25 male healthy subjects regarding the biliopancreatic system (median age ± SD: 56 ± 18 years [minimum: 22 and maximum 93 years]). The mean value of the cranio-caudal diameter of the pancreatic head was 49 ± 10 [26 - 77] mm(mean ± SD [minimum - maximum]) which is larger than usually reported except in one study. The size of the pancreatic head is often larger than assumed which is of importance to know to exclude pancreatic pathology below the level of the common bile duct.

Pancreas mobile.

BACKGROUND AND AIM: Up to now, little is known about the mobility of the pancreas due to changes in posture. The present study was conducted to assess the position of the pancreas in the left recumbent posture (endoscopy posture), the pancreatic mobility during changes of the posture from supine to endoscopy posture and also evaluates the possible factors associated with pancreatic mobility. METHODS: 199 patients with (68) or without chronic pancreatitis were examined using conventional gray-scale transabdominal ultrasound to image the position and mobility of the pancreatic head with reference to the vertebral spine and aorta in the supine and left recumbent position. In a subgroup of 75 consecutive healthy subjects regarding the pancreas, the exact moving distance of the central line of the pancreatic head from the supine to left recumbent position was obtained regarding the central line of the spine as the reference. Besides the 199 patients, 50 patients without pancreatic pathology were evaluated by endoscopic ultrasound with radial transducers. RESULTS: On conventional ultrasound in supine (left lateral) position the percentage of patients with right-aortal, pre-aortal, left-aortal pancreatic head were 91.0 % (49 %), 8.0 % (31 %) and 1.0 % (20 %), respectively. Significant movement of the pancreatic head in relation to the aorta was observed in 48 % of patients. The moving distance was correlated to the age, sex and the presence of chronic pancreatitis. Pancreas mobility was more pronounced in young healthy females. No association was found between the moving distance and the body mass index (BMI) and splenic size. On endoscopic ultrasound, the orientation of the pancreas with a view of more (or equal) than 180o was observed in 48 % and less than 180o in 52 % of patients. CONCLUSION: Pancreas mobile is a common phenomenon (about 50 %) which has not often been recognized in daily routine. This phenomenon is more likely in healthy young females. This knowledge might be of importance for improved interpretation of endoscopic ultrasound imaging examinations in patients with and without peripancreatic infiltration.

Toxin content and cytotoxicity of algal dietary supplements.

Blue-green algae (Spirulina sp., Aphanizomenon flos-aquae) and Chlorella sp. are commercially distributed as organic algae dietary supplements. Cyanobacterial dietary products in particular have raised serious concerns, as they appeared to be contaminated with toxins e.g. microcystins (MCs) and consumers repeatedly reported adverse health effects following consumption of these products. The aim of this study was to determine the toxin contamination and the in vitro cytotoxicity of algae dietary supplement products marketed in Germany. In thirteen products consisting of Aph. flos-aquae, Spirulina and Chlorella or mixtures thereof, MCs, nodularins, saxitoxins, anatoxin-a and cylindrospermopsin were analyzed. Five products tested in an earlier market study were re-analyzed for comparison. Product samples were extracted and analyzed for cytotoxicity in A549 cells as well as for toxin levels by (1) phosphatase inhibition assay (PPIA), (2) Adda-ELISA and (3) LC-MS/MS. In addition, all samples were analyzed by PCR for the presence of the mcyE gene, a part of the microcystin and nodularin synthetase gene cluster. Only Aph. flos-aquae products were tested positive for MCs as well as the presence of mcyE. The contamination levels of the MC-positive samples were ≤ 1 µg MC-LR equivalents g(-1) dw. None of the other toxins were found in any of the products. However, extracts from all products were cytotoxic. In light of the findings, the distribution and commercial sale of Aph. flos-aquae products, whether pure or mixed formulations, for human consumption appear highly questionable.

Indication of reactor ν(e) disappearance in the Double Chooz experiment.

The Double Chooz experiment presents an indication of reactor electron antineutrino disappearance consistent with neutrino oscillations. An observed-to-predicted ratio of events of 0.944±0.016(stat)±0.040(syst) was obtained in 101 days of running at the Chooz nuclear power plant in France, with two 4.25 GW(th) reactors. The results were obtained from a single 10 m(3) fiducial volume detector located 1050 m from the two reactor cores. The reactor antineutrino flux prediction used the Bugey4 flux measurement after correction for differences in core composition. The deficit can be interpreted as an indication of a nonzero value of the still unmeasured neutrino mixing parameter sin(2)2θ(13). Analyzing both the rate of the prompt positrons and their energy spectrum, we find sin(2)2θ(13)=0.086±0.041(stat)±0.030(syst), or, at 90% C.L., 0.017

Naturalistic pharmacotherapy of acute episodes of schizophrenic disorders in comparison to treatment guidelines.

INTRODUCTION: This study was designed to investigate to what extent guidelines regarding the pharmacological treatment of patients suffering from schizophrenia-like psychosis are adopted in a naturalistic treatment setting. METHODS: Medical records of n=819 patients undergoing inpatient treatment for schizophrenia-like psychosis in 11 psychiatric hospitals in northwestern Germany were retrospectively analyzed and findings were compared to current schizophrenia guideline recommendations. RESULTS: The prescription rate of second generation antipsychotics increased from 47.1% on admission to 62.5% at discharge. Only half the patients (52.3%) received antipsychotic monotherapy while 47.7% took between 2 and 4 antipsychotic substances at a time. Dosage increases occurred most frequently (in 60%) within the first week of inpatient treatment, 16.6% experienced an elevation between days 15 and 29. A change within the atypical medication was found in 19.3%. Clozapine prescriptions increased throughout the treatment but were combined with other antipsychotic substances in the majority of cases. CONCLUSION: Under naturalistic conditions guideline recommendations for treatment of schizophrenia-like psychosis are adhered to only partially. Combination therapy with 2 or more antipsychotic drugs is quite common despite a clear recommendation for monotherapy.

The human relevant potency threshold: reducing uncertainty by human calibration of cumulative risk assessments.

The 2008 National Research Council report "Phthalates and Cumulative Risk Assessment: Tasks Ahead," rejected the underlying premises of TEQ-like approaches - e.g., chemicals are true congeners; are metabolized and detoxified similarly; produce the same biological effects by the same mode of action; exhibit parallel dose response curves - instead asserting that cumulative risk assessment should apply dose addition (DA) to all chemicals that produce "common adverse outcomes" (CAOS). Published mixtures data and a human health risk assessment for phthalates and anti-androgens were evaluated to determine how firmly the DA-CAOS concept is supported and with what level of statistical certainty the results may be extrapolated to lower doses in humans. Underlying assumptions of the DA-CAOS concept were tested for accuracy and consistency against data for two human pharmaceuticals and its logical predictions were compared to human clinical and epidemiological experience. Those analyses revealed that DA-CAOS is scientifically untenable. Therefore, an alternative approach was developed - the Human-Relevant Potency-Threshold (HRPT) - that appears to fit the data better and avoids the contradictions inherent in the DA-CAOS concept. The proposed approach recommends application of independent action for phthalates and other chemicals with potential anti-androgenic properties at current human exposure levels.

EFSUMB guidelines 2011: comments and illustrations.

The European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB) introduced the first guidelines on the use of contrast-enhanced ultrasound (CEUS) in 2004. This EFSUMB document focused mainly on liver applications. However, new applications extending beyond the liver were subsequently developed. Therefore, in the update of the clinical recommendations on the use of CEUS by the EFSUMB, applications in other organs were also described and published in 2008. Increased interest in recent years in the CEUS technique and in the application of CEUS in novel fields has resulted in CEUS indications and applications for nearly all organ systems. As a result, the EFSUMB initiated a new update of the guidelines in 2011 to include this additional knowledge. Some of the indications are established, whereas others are preliminary. The latter indications are categorized as emergent CEUS applications since the available evidence is insufficient for general recommendation. This article focuses on comments, illustrations and examples of the application of CEUS in the pancreas, spleen, gastrointestinal tract, kidney, adrenals, lymph nodes, perineum, and hepatobiliary system. The potential for endoscopic ultrasound to highlight the importance of CEUS in the daily routine is also addressed.