Non-aqueous formulations for ram and screen extrusion-spheronisation.

The use of non-aqueous cellulose-based formulations for extrusion-spheronisation (E-S) is investigated. A 10 wt% hydroxypropyl cellulose/isopropyl alcohol solution (HPC/IPA) was identified as a suitable sticky liquid binder for preparing non-aqueous pastes. Preliminary tests were performed on a series of pastes using a ram as well as a laboratory roller screen extruder, since the former is commonly used in batch testing and the latter replicates the shear range in a manufacturing screen extruder. Pellets with acceptable size and shape distributions were obtained with Avicel® HFE-102 NF/HPC/IPA for ram E-S, and with Avicel® RC-591/HPC/IPA for screen E-S. Further investigation was performed with calcium carbonate added as a model active pharmaceutical ingredient. Both formulations were able to generate pellets with acceptable size and shape characteristics at up to 50 wt% carbonate loading: further work is required to optimise yields.

Can 5-methylcytosine analogues with extended alkyl side chains guide DNA methylation?

5-Methylcytosine (MeC) is an endogenous modification of DNA that plays a crucial role in DNA-protein interactions, chromatin structure, epigenetic regulation, and DNA repair. MeC is produced via enzymatic methylation of the C-5 position of cytosine by DNA-methyltransferases (DNMT) which use S-adenosylmethionine (SAM) as a cofactor. Hemimethylated CG dinucleotides generated as a result of DNA replication are specifically recognized and methylated by maintenance DNA methyltransferase 1 (DNMT1). The accuracy of DNMT1-mediated methylation is essential for preserving tissue-specific DNA methylation and thus gene expression patterns. In the present study, we synthesized DNA duplexes containing MeC analogues with modified C-5 side chains and examined their ability to guide cytosine methylation by the human DNMT1 protein. We found that the ability of 5-alkylcytosines to direct cytosine methylation decreased with increased alkyl chain length and rigidity (methyl > ethyl > propyl ∼ vinyl). Molecular modeling studies indicated that this loss of activity may be caused by the distorted geometry of the DNA-protein complex in the presence of unnatural alkylcytosines.

Phosphorylation of threonine residues on Shc promotes ligand binding and mediates crosstalk between MAPK and Akt pathways in breast cancer cells.

Scaffold proteins play important roles in regulating signalling network fidelity, the absence of which is often the basis for diseases such as cancer. In the present work, we show that the prototypical scaffold protein Shc is phosphorylated by the extracellular signal-regulated kinase, Erk. In addition, Shc threonine phosphorylation is specifically up-regulated in two selected triple-negative breast cancer (TNBC) cell lines. To explore how Erk-mediated threonine phosphorylation on Shc might play a role in the dysregulation of signalling events, we investigated how Shc affects pathways downstream of EGF receptor. Using an in vitro model and biophysical analysis, we show that Shc threonine phosphorylation is responsible for elevated Akt and Erk signalling, potentially through the recruitment of the 14-3-3 ζ and Pin-1 proteins.

Quasi-Particle Self-Consistent GW for Molecules.

We present the formalism and implementation of quasi-particle self-consistent GW (qsGW) and eigenvalue only quasi-particle self-consistent GW (evGW) adapted to standard quantum chemistry packages. Our implementation is benchmarked against high-level quantum chemistry computations (coupled-cluster theory) and experimental results using a representative set of molecules. Furthermore, we compare the qsGW approach for five molecules relevant for organic photovoltaics to self-consistent GW results (scGW) and analyze the effects of the self-consistency on the ground state density by comparing calculated dipole moments to their experimental values. We show that qsGW makes a significant improvement over conventional G0W0 and that partially self-consistent flavors (in particular evGW) can be excellent alternatives.

Electronically captured, patient-reported physical function: an important vital sign in obesity medicine.

OBJECTIVES: Impaired physical function (i.e., inability to walk 200 feet, climb a flight of stairs or perform activities of daily living) predicts poor clinical outcomes and adversely impacts medical and surgical weight management. However, routine assessment physical function is seldom performed clinically. The PROMIS Physical Function Short Form 20a (SF-20a) is a validated questionnaire for assessing patient reported physical function, which includes published T-score percentiles adjusted for gender, age and education. However, the effect that increasing levels of obesity has on these percentiles is unclear. We hypothesized that physical function would decline with increasing level of obesity independent of gender, age, education and comorbidity. MATERIALS AND METHODS: This study included 1,627 consecutive weight management patients [(mean ± SEM), 44.7 ± 0.3 years and 45.1 ± 0.2 kg/m2] that completed the PROMIS SF-20a during their initial consultation. We evaluated the association between obesity level and PROMIS T-score percentiles using multiple linear regression adjusting for gender, age, education and Charlson Comorbidity Index (CCI). RESULTS: Multiple linear regression T-score percentiles were lower in obesity class 2 (-12.4%tile, p < 0.0001), class 3 (-17.0%tile, p < 0.0001) and super obesity (-25.1%tile, p < 0.0001) compared to class 1 obesity. CONCLUSION: In patients referred for weight management, patient reported physical function was progressively lower in a dose-dependent fashion with increasing levels of obesity, independent of gender, age, education and CCI.

Total Thyroidectomy for Amiodarone-induced Thyrotoxicosis in the Hyperthyroid State.

Amiodarone is a potent antiarrhythmic agent, indicated for the treatment of refractory arrhythmias, which may lead to thyrotoxicosis. In these patients, thyroidectomy is a valid therapeutic option. Antithyroid therapy in the immediate preoperative setting and the subsequently accepted minimal delay until thyroidectomy have not been clearly defined yet. The aim of the present study was to show, that total thyroidectomy under general anaesthesia in patients with amiodarone-induced thyrotoxicosis (AIT) is safe without necessarily obtaining an euthyroid state preoperatively.We conducted a retrospective cohort study of prospectively gathered data on 11 patients undergoing total thyroidectomy under general anaesthesia between January 2008 and December 2013 for AIT at our University Hospital.All patients were preoperatively treated with carbimazole, steroids and ß-receptor antagonists. Additionally, 3 patients received potassium perchlorate and in one patient carbimazole was changed to propylthiouracil. Plasmapheresis was performed in 3 patients. Only one patient was euthyroid at the time of operation. There were no significant intra- and postoperative complications, especially no signs of thyroid storm. One patient could postoperatively be removed from the cardiac transplant waiting list due to improved cardiac function.Improvements in the interdisciplinary surgical management for AIT between cardiologists, endocrinologists, anaesthetists and endocrine surgeons provide the basis of safe total thyroidectomy under general anaesthesia in hyperthyroid state. Early surgery without long delay for medical antithyroid treatment (with its potential negative side effects) is recommended.

Inflammation and atrial remodeling after a mountain marathon.

Endurance athletes have an increased risk of atrial fibrillation. We performed a longitudinal study on elite runners of the 2010 Jungfrau Marathon, a Swiss mountain marathon, to determine acute effects of long-distance running on the atrial myocardium. Ten healthy male athletes were included and examined 9 to 1 week prior to the race, immediately after, and 1, 5, and 8 days after the race. Mean age was 34.9 ± 4.2 years, and maximum oxygen consumption was 66.8 ± 5.8 mL/kg*min. Mean race time was 243.9 ± 17.7 min. Electrocardiographic-determined signal-averaged P-wave duration (SAPWD) increased significantly after the race and returned to baseline levels during follow-up (128.7 ± 10.9 vs. 137.6 ± 9.8 vs. 131.5 ± 8.6 ms; P < 0.001). Left and right atrial volumes showed no significant differences over time, and there were no correlations of atrial volumes and SAPWD. Prolongation of the SAPWD was accompanied by a transient increase in levels of high-sensitivity C-reactive protein, proinflammatory cytokines, total leucocytes, neutrophil granulocytes, pro atrial natriuretic peptide and high-sensitivity troponin. In conclusion, marathon running was associated with a transient conduction delay in the atria, acute inflammation and increased atrial wall tension. This may reflect exercise-induced atrial myocardial edema and may contribute to atrial remodeling over time, generating a substrate for atrial arrhythmias.

[Evidence-based medicine in surgical practice - locating clinical studies and systematic reviews by searching the Medline database]. / Evidenzbasierte Medizin in der chirurgischen Praxis - Die Literatursuche nach klinischen Studien und systematischen Übersichtsarbeiten in der Datenbank Medline.

BACKGROUND: Every day approximately 75 clinical trials and 11 systematic reviews are published in the health-care intervention and medical field. Due to this growing number of publications it is a challenge for every practicing clinician to keep track with the latest research. The implementation of new and effective diagnostic and therapeutic interventions into daily clinical routine may thus be delayed. Conversely, ineffective or even harmful interventions might still be in use. Decision-making in evidence-based medicine (EBM) requires consideration of the most recent high quality evidence. Randomised controlled trials (RCTs) are regarded as the "gold standard" to prove the efficacy of surgical interventions in patient-oriented research. Systematic reviews combine results from RCTs by summarising single RCTs which answer a particular clinical question. Some basic knowledge in systematic literature searching is required and helpful for detecting relevant publications. MATERIAL AND METHODS: This article shows various possibilities for locating clinical studies and systematic reviews in the database Medline on the basis of illustrative step-by-step instructions. RESULTS AND CONCLUSION. Depending on the aim and topic of the literature search, the time required for the task may vary. In routine practice, a systematic literature search is unrealistic in most cases. Clinicians in need of a quick update of current evidence on a certain clinical topic may make use of up-to-date systematic reviews. During a systematic literature search, different approaches and strategies might be necessary.

Transport properties of individual C60-molecules.

Electrical and thermal transport properties of C60 molecules are investigated with density-functional-theory based calculations. These calculations suggest that the optimum contact geometry for an electrode terminated with a single-Au atom is through binding to one or two C-atoms of C60 with a tendency to promote the sp(2)-hybridization into an sp(3)-type one. Transport in these junctions is primarily through an unoccupied molecular orbital that is partly hybridized with the Au, which results in splitting the degeneracy of the lowest unoccupied molecular orbital triplet. The transmission through these junctions, however, cannot be modeled by a single Lorentzian resonance, as our results show evidence of quantum interference between an occupied and an unoccupied orbital. The interference results in a suppression of conductance around the Fermi energy. Our numerical findings are readily analyzed analytically within a simple two-level model.

A comparison of screen and ram extrusion-spheronisation of simple pharmaceutical pastes based on microcrystalline cellulose.

The performance of two laboratory-scale extrusion apparatuses used to approximate the action of an industrial screen extruder, namely a multi-holed die ram extruder and a roller screen extruder, were compared. Both devices featured short dies (ram 2mm, screen 1mm) with die diameter 1mm and hole area fraction approaching 0.25. A series of water/microcrystalline cellulose (MCC) pastes with water contents varying from 45 to 60 wt% were extruded and pellets obtained from subsequent spheronisation of the extrudates characterised in terms of size and shape. Each device exhibited a different range of processing windows for acceptable spheronised products, with the ram apparatus being able to extrude a wider range of paste water contents than the screen device. The pellets obtained from extrusion-spheronisation (E-S) of the pastes via the screen device were in general smaller, with a wider size distribution, than those from ram E-S. These results are attributed to the different mechanical histories experienced by the pastes in the two types of extruder, which lead to different extrudate densities being achieved. MCC/water/calcium carbonate pastes were also tested, where the latter component represented a 'hard' (non-deformable) active pharmaceutical ingredient. Addition of calcium carbonate increased the stiffness of the paste, which could be countered by adjusting the water content of the deformable MCC/water matrix within the extrudability limits of the latter material.

A novel lab-scale screen extruder for studying extrusion-spheronisation.

A novel apparatus, the laboratory roller screen extruder (termed the LRS), was developed to replicate key aspects of the geometry and shear strain rates generated near the screen of industrial screen extruders. The configuration of the LRS is reported alongside a commissioning study employing a cohesive 45 wt% water/microcrystalline cellulose paste. The key operating parameters which controlled the extrudate mass flowrate, force on the screen and roller torque were (i) the size of the gap between the top of the roller blade and the screen, and (ii) the roller rotational speed. The data suggest that the apparent shear rate, based on the blade-screen clearance, provides a quantitative criterion for scale-up. The amount of screen flex showed good agreement with a simple bending deformation model. Spheronisation of the extrudates gave pellets with a narrow size distribution and acceptable sphericity which would be acceptable for capsule filling. Optimisation of the pellet shape was not performed. The results indicate that the LRS can be used to assess formulations for industrial screen extrusion-spheronisation.

Clinical parameters associated with collateral development in patients with chronic total coronary occlusion.

OBJECTIVE: Well-developed collaterals provide survival benefit in patients with obstructive coronary artery disease (CAD). Therefore, in this study we sought to determine which clinical variables are associated with arteriogenesis. DESIGN: Clinical and laboratory variables were collected before percutaneous coronary intervention. Multivariate analysis was performed to determine which variables are associated with the collateral flow index (CFI). PATIENTS: Data from 295 chronic total occlusion (CTO) patients (Bern, Switzerland, Amsterdam, the Netherlands and Jena, Germany) were pooled. In earlier studies, patients had varying degrees of stenosis. Therefore, different stages of development of the collaterals were used. In our study, a unique group of patients with CTO was analysed. INTERVENTIONS: Instead of angiography used earlier, we used a more accurate method to determine CFI using intracoronary pressure measurements. CFI was calculated from the occlusive pressure distal of the coronary lesion, the aortic pressure and central venous pressure. RESULTS: The mean CFI was 0.39 ± 0.14. After multivariate analysis, ß blockers, hypertension and angina pectoris duration were positively associated with CFI (B: correlation coefficient ß=0.07, SE=0.03, p=0.02, B=0.040, SE=0.02, p=0.042 and B=0.001, SE=0.000, p=0.02). Furthermore also after multivariate analysis, high serum leucocytes, prior myocardial infarction and high diastolic blood pressure were negatively associated with CFI (B=-0.01, SE=0.005, p=0.03, B=-0.04, SE=0.02, p=0.03 and B=-0.002, SE=0.001, p=0.011). CONCLUSIONS: In this unique cohort, high serum leucocytes and high diastolic blood pressure are associated with poorly developed collaterals. Interestingly, the use of ß blockers is associated with well-developed collaterals, shedding new light on the potential action mode of this drug in patients with CAD.

Randomised clinical trial: a 1-week, double-blind, placebo-controlled study of pancreatin 25 000 Ph. Eur. minimicrospheres (Creon 25000 MMS) for pancreatic exocrine insufficiency after pancreatic surgery, with a 1-year open-label extension.

BACKGROUND: Pancreatic exocrine insufficiency (PEI) often occurs following pancreatic surgery. AIM: To demonstrate the superior efficacy of pancreatin 25 000 minimicrospheres (Creon 25000 MMS; 9-15 capsules/day) over placebo in treating PEI after pancreatic resection. METHODS: A 1-week, double-blind, randomised, placebo-controlled, parallel-group, multicentre study with a 1-year, open-label extension (OLE). Subjects ≥18 years old with PEI after pancreatic resection, defined as baseline coefficient of fat absorption (CFA) <80%, were randomised to oral pancreatin or placebo (9-15 capsules/day: 3 with main meals, 2 with snacks). In the OLE, all subjects received pancreatin. The primary efficacy measure was least squares mean CFA change from baseline to end of double-blind treatment (ancova). RESULTS: All 58 subjects randomised (32 pancreatin, 26 placebo) completed double-blind treatment and entered the OLE; 51 completed the OLE. The least squares mean CFA change in the double-blind phase was significantly greater with pancreatin vs. placebo: 21.4% (95% CI: 13.7, 29.2) vs. -4.2% (-12.8, 4.5); difference 25.6% (13.9, 37.3), P < 0.001. The mean ± s.d. CFA increased from 53.6 ± 20.6% at baseline to 78.4 ± 20.7% at OLE end (P < 0.001). Treatment-emergent adverse events occurred in 37.5% subjects on pancreatin and 26.9% on placebo during double-blind treatment, with flatulence being the most common (pancreatin 12.5%, placebo 7.7%). Only two subjects discontinued due to treatment-emergent adverse events, both during the OLE. CONCLUSIONS: This study demonstrates superior efficacy of pancreatin 25 000 over placebo in patients with PEI after pancreatic surgery, measured by change in CFA. Pancreatin was generally well tolerated at the high dose administered (EudraCT registration number: 2005-004854-29).

[Treatment practice in patients with isolated blunt splenic injuries. A survey of Swiss traumatologists]. / Die Behandlungspraxis bei Patienten mit isolierter stumpfer Milzverletzung. Eine Befragung der Schweizer Traumatologen.

BACKGROUND: The non-operative management (NOM) of blunt splenic injuries has gained widespread acceptance. However, there are still many controversies regarding follow-up of these patients. The purpose of this study was to survey active members of the Swiss Society of General and Trauma Surgery (SGAUC) to determine their practices regarding the NOM of isolated splenic injuries. MATERIALS AND METHODS: A survey of active SGAUC members with a written questionnaire was carried out. The questionnaire was designed to elicit information about personal and facility demographics, diagnostic practices, in-hospital management, preferred follow-up imaging and return to activity. RESULTS: Out of 165 SGAUC members 52 (31.5%) completed the survey and 62.8% of all main trauma facilities in Switzerland were covered by the sample. Of the respondents 14 (26.9%) have a protocol in place for treating patients with splenic injuries. For initial imaging in hemodynamically stable patients 82.7% of respondents preferred ultrasonography (US). In cases of suspected splenic injury 19.2% of respondents would abstain from further imaging. In cases of contrast extravasation from the spleen half of the respondents would take no specific action. For low-grade injuries 86.5% chose to admit patients for an average of 1.6 days (range 0-4 days) with a continuously monitored bed. No differences in post-discharge activity restrictions between moderate and high-grade splenic injuries were found. CONCLUSION: The present survey showed considerable practice variation in several important aspects of the NOM of splenic injuries. Not performing further CT scans in patients with suspected splenic injuries and not intervening in cases of a contrast extravasation were the most important discrepancies to the current literature. Standardization of the NOM of splenic injuries may be of great benefit for both surgeons and patients.

Smooth muscle caldesmon modulates peristalsis in the wild type and non-innervated zebrafish intestine.

BACKGROUND: The high molecular weight isoform of the actin-binding protein Caldesmon (h-CaD) regulates smooth muscle contractile function by modulating cross-bridge cycling of myosin heads. The normal inhibitory activity of h-CaD is regulated by the enteric nervous system; however, the role of h-CaD during intestinal peristalsis has never been studied. METHODS: We identified a zebrafish paralog of the human CALD1 gene that encodes an h-CaD isoform expressed in intestinal smooth muscle. We examined the role of h-CaD during intestinal peristalsis in zebrafish larvae by knocking down the h-CaD protein using an antisense morpholino oligonucleotide. We also developed transgenic zebrafish that express inhibitory peptides derived from the h-CaD myosin and actin-binding domains, and examined their effect on peristalsis in wild-type zebrafish larvae and sox10 (colourless) mutant larvae that lack enteric nerves. KEY RESULTS: Genomic analyses identified two zebrafish Caldesmon paralogs. The cald1a ortholog encoded a high molecular weight isoform generated by alternative splicing whose intestinal expression was restricted to smooth muscle. Propulsive intestinal peristalsis was increased in wild-type zebrafish larvae by h-CaD knockdown and by expression of transgenes encoding inhibitory myosin and actin-binding domain peptides. Peristalsis in the non-innervated intestine of sox10 (colourless) larvae was partially restored by h-CaD knockdown and expression of the myosin-binding peptide. CONCLUSIONS & INFERENCES: Disruption of the normal inhibitory function of h-CaD enhances intestinal peristalsis in both wild-type zebrafish larvae and mutant larvae that lack enteric nerves, thus confirming a physiologic role for regulation of smooth muscle contraction at the actin filament.

A comparison of ram extrusion by single-holed and multi-holed dies for extrusion-spheronisation of microcrystalline-based pastes.

The use of multi-holed dies as an alternative to single-holed dies for generating extrudates for spheronisation was investigated both in terms of extrusion and spheronisation performance. A model 45wt% microcrystalline cellulose (MCC)/water paste was employed in ram extrusion tests with square-ended dies with 1, 6, 33 and 137 holes, all of diameter 1mm and length 2mm. The extrudates generated using the multi-holed dies yielded pellets with comparable sphericity to those using the single-holed die. Multi-holed dies could also be operated with lower paste flow rates before encountering liquid phase migration (LPM). The characteristic processing velocity for the onset of LPM was determined for each die configuration and supported the hypothesis that LPM was caused by suction effects. A simple model of the flow pattern in a lab-scale Fuji-Paudal frontal screen extruder is presented which yields estimates of velocities and shear rates involved in these devices. The pressure required to extrude the paste through multi-holed dies was compared with the model proposed by Benbow and co-workers. The paste rheology was characterised using the Benbow-Bridgwater approach, employing 1, 2 and 3mm diameter dies of various lengths. The Benbow et al. model under-predicted the observed extrusion pressure, which was attributed to its failure to account for the redundant work contribution in these complex flows.

[Evidence-based antibiotic prophylaxis in general and visceral surgery]. / Evidenzbasierte Antibiotikaprophylaxe in der Allgemein- und Viszeralchirurgie.

The use of prophylactic perioperative antibiotic therapy if indicated could successfully and safely prevent surgical wound infections. The current guidelines (S1) for prophylactic perioperative antibiotic therapy of the Study Group of the Scientific Medical Associations (AWMF) of 2004 was replaced by a recommendation of the study group of the Paul-Ehrlich-Gesellschaft for Chemotherapy (PEG) in 2010. This recommendation includes recent research data from 2000 to 2008. Indications and choice of antibiotic agent depend on specific risk factors of the patient and the operation performed. The aim of this article is to describe the current recommendations of the PEG for general and visceral surgery.