The helminth Trichuris suis suppresses TLR4-induced inflammatory responses in human macrophages.

Recent clinical trials in patients with inflammatory diseases like multiple sclerosis (MS) or inflammatory bowel disease (IBD) have shown the beneficial effects of probiotic helminth administration, although the underlying mechanism of action remains largely unknown. Potential cellular targets may include innate immune cells that propagate inflammation in these diseases, like pro-inflammatory macrophages. We here investigated the effects of the helminth Trichuris suis soluble products (SPs) on the phenotype and function of human inflammatory (granulocyte-macrophage colony-stimulating factor (GM-CSF)-differentiated) macrophages. Interestingly, we here show that T. suis SPs potently skew inflammatory macrophages into a more anti-inflammatory state in a Toll-like receptor 4 (TLR4)-dependent manner, and less effects are seen when stimulating macrophages with TLR2 or -3 ligands. Gene microarray analysis of GM-CSF-differentiated macrophages further revealed that many TLR4-induced inflammatory mediators, including interleukin (IL)-12B, CCL1 and CXCL9, are downregulated by T. suis SPs. In particular, we observed a strong reduction in the expression and function of P2RX7, a purinergic receptor involved in macrophage inflammation, leading to reduced IL-1ß secretion. In conclusion, we show that T. suis SPs suppress a broad range of inflammatory pathways in GM-CSF-differentiated macrophages in a TLR4-dependent manner, thereby providing enhanced mechanistic insight into the therapeutic potential of this helminth for patients with inflammatory diseases.

Echocardiographic screening for pulmonary arterial hypertension in HIV-positive patients.

Human immunodeficiency virus (HIV) infection is associated with an increased risk for pulmonary arterial hypertension (PAH). Upon the screening of 220 asymptomatic HIV-positive individuals by echocardiography, we detected and confirmed HIV-associated PAH in 0.45 % of cases. Mild elevations of systolic pulmonary arterial pressure most probably owing to left ventricular diastolic dysfunction were found in 7.7 % of cases, without progress after 2 years. We suggest that the screening of asymptomatic HIV-positive patients for PAH should not be performed.

Structure and Volta potential of lipid multilayers: effect of X-ray irradiation.

The effect of hard X-ray radiation on the structure and electrostatics of solid-supported lipid multilayer membranes is investigated using a scanning Kelvin probe (SKP) integrated with a high-energy synchrotron beamline to enable in situ measurements of the membranes' local Volta potential (V(p)) during X-ray structural characterization. The undulator radiation employed does not induce any detectable structural damage, but the V(p) of both bare and lipid-modified substrates is found to undergo strong radiation-induced shifts, almost immediately after X-ray exposure. Sample regions that are macroscopically distant (~cm) from the irradiated region experience an exponential V(p) growth with a characteristic time constant of several minutes. The V(p) variations occurring upon periodic on/off X-ray beam switching are fully or partially reversible depending on the location and time-scale of the SKP measurement. The general relevance of these findings for synchrotron-based characterization of biomolecular thin films is critically reviewed.

Xenobiotic metabolizing enzyme activities in cells used for testing skin sensitization in vitro.

For ethical and regulatory reasons, in vitro tests for scoring potential toxicities of cosmetics are essential. A test strategy for investigating potential skin sensitization using two human keratinocytic and two human dendritic cell lines has been developed (Mehling et al. Arch Toxicol 86:1273­1295, 2012). Since prohaptens may be metabolically activated in the skin, information on xenobiotic metabolizing enzyme (XME) activities in these cell lines is of high interest. In this study, XME activity assays, monitoring metabolite or cofactor, showed the following: all three passages of keratinocytic (KeratinoSens® and LuSens) and dendritic (U937 und THP-1) cells displayed N-acetyltransferase 1 (NAT1) activities (about 6­60 nmol/min/mg S9-protein for acetylation of para-aminobenzoic acid). This is relevant since reactive species of many cosmetics are metabolically controlled by cutaneous NAT1. Esterase activities of about 1­4 nmol fluorescein diacetate/min/mg S9-protein were observed in all passages of investigated keratinocytic and about 1 nmol fluorescein diacetate/min/mg S9-protein in dendritic cell lines. This is also of practical relevance since many esters and amides are detoxified and others activated by cutaneous esterases. In both keratinocytic cell lines, activities of aldehyde dehydrogenase (ALDH) were observed (5­17 nmol product/min/mg cytosolic protein). ALDH is relevant for the detoxication of reactive aldehydes. Activities of several other XME were below detection, namely the investigated cytochrome P450-dependent alkylresorufin O-dealkylases 7-ethylresorufin O-deethylase, 7-benzylresorufin O-debenzylase and 7-pentylresorufin O-depentylase (while NADPH cytochrome c reductase activities were much above the limit of quantification), the flavin-containing monooxygenase, the alcohol dehydrogenase as well as the UDP glucuronosyl transferase activities.

Mapping the local reaction kinetics by PEEM: CO oxidation on individual (100)-type grains of Pt foil.

The locally-resolved reaction kinetics of CO oxidation on individual (100)-type grains of a polycrystalline Pt foil was monitored in situ using photoemission electron microscopy (PEEM). Reaction-induced surface morphology changes were studied by optical differential interference contrast microscopy and atomic force microscopy (AFM). Regions of high catalytic activity, low activity and bistability in a (p,T)-parameter space were determined, allowing to establish a local kinetic phase diagram for CO oxidation on (100) facets of Pt foil. PEEM observations of the reaction front propagation on Pt(100) domains reveal a high degree of propagation anisotropy both for oxygen and CO fronts on the apparently isotropic Pt(100) surface. The anisotropy vanishes for oxygen fronts at temperatures above 465 K, but is maintained for CO fronts at all temperatures studied, i.e. in the range of 417 to 513 K. A change in the front propagation mechanism is proposed to explain the observed effects.

[Primary treatment of complicated flexor tendon injuries of the hand]. / Primärversorgung komplizierter Beugesehnenverletzungen an der Hand.

Complicated flexor tendon injuries are classified into lacerations, avulsions, ruptures, and defects. They are often a challenge for hand surgeons and frequently they present unsatisfactory functional results postoperatively. Lacerations and avulsions are usually treated by pull-out sutures and suture anchors. In ruptures, the causality should be sought. Tendon-linking, transposition and tenodesis/arthrodesis are the domain of rheumatoid arthritis. The primary transplantation of tendons is rarely indicated, ideally in non-contaminated flexor tendon defects in zones III-V with an uninjured surrounding soft tissue situation. Postoperative rehabilitation programs are very the same as in normal flexor tendon injuries.

Oxygen isotope ratios in eclogites from kimberlites.

The oxygen isotope compositions (delta(18)O) of eclogitic xenoliths from the Roberts Victor kimberlite range from 2 to 8 per mil relative to SMOW (standard mean ocean water). This surprising variation appears to be due to fractional crystallization: the eclogites rich in oxygen-18 represent early crystal accumulates; the eclogites poor in oxygen-18 represent residual liquids. Crystal-melt partitioning probably exceeded 3 per mil and is interpreted to be pressure-dependent. Anomalous enrichment of oxygen-18 in cumulate eclogites relative to ultramafic xenoliths suggests that crystal-melt partitioning increased after melt-formation but prior to crystallization.

Interventies na een gestructureerde medicatie-analyse door klinisch geriater en ziekenhuisapotheker bij klinisch opgenomen kwetsbare oudere patiënten.

EFFECTS OF A STRUCTURED MEDICATION REVIEW BY GERIATRICIAN AND CLINICAL PHARMACOLOGIST ON APPROPRIATENESS OF PHARMACOTHERAPY OF FRAIL ELDERLY INPATIENTS: Objective To study the results of a structured medication review of geriatric inpatients by both geriatrician and hospital pharmacist/clinical pharmacologist. Methods Patients who were present at the geriatric ward were eligible for a review of their medication and medical problems using a screening form. Recommendations and questions following these forms were subsequently discussed in the gerontopharmacologic meeting ('GFO') held every two weeks. Results In a 30 month-period 44 GFO's were held during which 184 patients were discussed. A total of 206 recommendations were made and 115 questions were asked. Of the recommended interventions,134 (65%) were accepted by the geriatrician. To stop a medication (64/206), to change the dosage of a medication (60/206) and to switch to another medication (44/206) were the types of interventions most accounted for. Conclusion Structured medication review led to a substantial number of medication changes in geriatric inpatients. Nearly two-thirds of the recommended interventions were accepted by the geriatricians. Seventy-two recommendations (35%) were not implemented due to logistic or patient-related reasons.

[Effects of a structured medication review by geriatrician and clinical pharmacologist on appropriateness of pharmacotherapy in frail elderly inpatients]. / Interventies na een gestructureerde medicatie-analyse door klinisch geriater en ziekenhuisapotheker bij klinisch opgenomen kwetsbare oudere patiënten.

OBJECTIVE: To study the results of a structured medication review of geriatric inpatients by both geriatrician and hospital pharmacist/clinical pharmacologist. METHODS: Patients who were present at the geriatric ward were eligible for a review of their medication and medical problems using a screening form. Recommendations and questions following these forms were subsequently discussed in the gerontopharmacologic meeting ('GFO') held every two weeks. RESULTS: In a 30 month-period 44 GFO's were held during which 184 patients were discussed. A total of 206 recommendations were made and 115 questions were asked. Of the recommended interventions,134 (65%) were accepted by the geriatrician. To stop a medication (64/206), to change the dosage of a medication (60/206) and to switch to another medication (44/206) were the types of interventions most accounted for. CONCLUSION: Structured medication review led to a substantial number of medication changes in geriatric inpatients. Nearly two-thirds of the recommended interventions were accepted by the geriatricians. Seventy-two recommendations (35%) were not implemented due to logistic or patient-related reasons.

Cognition errors in the treatment course of patients with anastomotic failure after colorectal resection.

BACKGROUND: Cognitive errors have a considerable effect on procedural outcome. They play a major role in situational judgement and decision making, especially during cognitively demanding tasks. As such they need to be considered an important factor in medical and surgical procedures. However, whereas cognitive diagnostic errors are well known, as of yet the occurrence of errors due to cognitive heuristics may have been downplayed, underestimated, or simply been ignored during the course of surgical treatment. METHODS: All colorectal resections with anastomosis in 2015 and 2016 (n = 230) were prospectively screened for anastomotic failure (n = 17/230). During structured Morbidity and Mortality Conferences (MMC) all anastomotic failures were analyzed for both tactical and technical decisions in the pre- and intraoperative setting with potential meaning for the postoperative course, based on the London Protocol. In order to demonstrate the significance of cognitive errors in surgical procedures a structured interview with the individual surgeon was conducted including the video and photo documentation of the individual surgical procedure. The interviews were coded by independent coders who were instructed to identify defined cognitive errors. Inter-coder agreement was calculated using Krippendorff's alpha. RESULTS: In 12/17 patients with anastomotic failure after colorectal surgery tactical or technical decisions with potential negative influence on anastomotic healing or the postoperative course were assessed during MMC. In 8/12 procedures a structured interview could be conducted with the operating surgeon. In 7/8 procedures cognitive errors could be identified. In particular we found Anchoring (n = 1), Availability Bias (n = 1), Commission Bias (n = 1), Overconfidence Bias (n = 1), Omission Bias (n = 2) and Sunk Costs (n = 1). CONCLUSION: Cognitive errors seem to play an important role during surgical therapy of patients with anastomotic failure after colorectal resection. Consequently, we suggest cognitive errors should attract more interest in research as well as attention in clinical practice.

Disturbed time experience during and after psychosis.

Disturbances in time experience have been argued to play a significant, if not causative role in the clinical presentation of schizophrenia. Phenomenological considerations suggest a fragmented or dis-articulated time experience causing both primary symptoms such as hallucinations, delusions, and self-disorders, as well as an intersubjective desynchronization. We employed content analysis on material collected from patients diagnosed with schizophrenia using the Time Questionnaire to generate hypotheses on possible disturbances of time experience in schizophrenia. As a key result we find evidence for the distinction between acute psychotic and post-psychotic syndromes. Acute psychosis is predominantly a disturbance of the passage of time, whereas the remission from psychosis is primarily defined by changes in the experience of the explicit structure of time integrating past, present, and future. We discuss our findings with regards to previous insights and observations on time experience and time perception. We suggest our findings hold significance for the diagnostic and therapeutic understanding of schizophrenia as well as for future integrative research on time experience in general.

Electrochemistry in ultra-high vacuum: The fully transferrable ultra-high vacuum compatible electrochemical cell.

A new experimental setup for in situ/operando investigations of redox reactions is introduced. This setup, in combination with ultra-high vacuum (UHV) methods from the field of surface science, provides completely new possibilities to investigate electrochemical redox reactions. Two types of cells are distinguished conceptionally: in the permeation configuration, the working electrode is electrochemically polarised on one side of a membrane (entry side), leading to atomic hydrogen uptake, and allowing proton and electron exchange between the entry and the other side (exit side) of the membrane. Here it is found that the applied potential on the entry side shows a 1:1 correlation with the measured potential on the exit side. The concept of the "window" cell requires ultra-thin, electron transparent "windows," such as single layer graphene, for X-ray photoelectron spectroscopy or X-ray transparent silicon nitride "windows" for X-ray absorption spectroscopy. In this case, the solid/liquid interface can be directly probed under applied potentials. In both configurations, the applied potential is measured with a palladium hydride reference electrode, with so far unseen precision and long-term stability. The cell design is constructed with regard to transferability within a UHV system, allowing sample preparation, and a modular construction, allowing a straightforward changeover between these two configurations. As a first application, an approach based on atomic hydrogen is presented. Further application concepts are discussed. The setup functionality is demonstrated by the example of in situ/operando investigation of the palladium oxide reduction.

Experimental reconstruction of the Berry curvature in a Floquet Bloch band.

Topological properties lie at the heart of many fascinating phenomena in solid-state systems such as quantum Hall systems or Chern insulators. The topology of the bands can be captured by the distribution of Berry curvature, which describes the geometry of the eigenstates across the Brillouin zone. Using fermionic ultracold atoms in a hexagonal optical lattice, we engineered the Berry curvature of the Bloch bands using resonant driving and show a full momentum-resolved measurement of the ensuing Berry curvature. Our results pave the way to explore intriguing phases of matter with interactions in topological band structures.

Optimal coronary balloon angioplasty with provisional stenting versus primary stent (OCBAS): immediate and long-term follow-up results.

OBJECTIVE: This study sought to compare two strategies of revascularization in patients obtaining a good immediate angiographic result after percutaneous transluminal coronary angioplasty (PTCA): elective stenting versus optimal PTCA. A good immediate angiographic result with provisional stenting was considered to occur only if early loss in minimal luminal diameter (MLD) was documented at 30 min post-PTCA angiography. BACKGROUND: Coronary stenting reduces restenosis in lesions exhibiting early deterioration (>0.3 mm) in MLD within the first 24 hours (early loss) after successful PTCA. Lesions with no early loss after PTCA have a low restenosis rate. METHODS: To compare angiographic restenosis and target vessel revascularization (TVR) of lesions treated with coronary stenting versus those treated with optimal PTCA, 116 patients were randomized to stent (n=57) or to optimal PTCA (n=59). After randomization in the PTCA group, 13.5% of the patients crossed over to stent due to early loss (provisional stenting). RESULTS: Baseline demographic and angiographic characteristics were similar in both groups of patients. At 7.6 months, 96.6% of the entire population had a follow-up angiographic study: 98.2% in the stent and 94.9% in the PTCA group. Immediate and follow-up angiographic data showed that acute gain was significantly higher in the stent than in the PTCA group (1.95 vs. 1.5 mm; p < 0.03). However, late loss was significantly higher in the stent than the PTCA group (0.63+/-0.59 vs. 0.26+/-0.44, respectively; p=0.01). Hence, net gain with both techniques was similar (1.32< or =0.3 vs. 1.24+/-0.29 mm for the stent and the PTCA groups, respectively; p=NS). Angiographic restenosis rate at follow-up (19.2% in stent vs. 16.4% in PTCA; p=NS) and TVR (17.5% in stent vs. 13.5% in PTCA; p=NS) were similar. Furthermore, event-free survival was 80.8% in the stent versus 83.1% in the PTCA group (p=NS). Overall costs (hospital and follow-up) were US $591,740 in the stent versus US $398,480 in the PTCA group (p < 0.02). CONCLUSIONS: The strategy of PTCA with delay angiogram and provisional stent if early loss occurs had similar restenosis rate and TVR, but lower cost than primary stenting after PTCA.

Argentine Randomized Study: Coronary Angioplasty with Stenting versus Coronary Bypass Surgery in patients with Multiple-Vessel Disease (ERACI II): 30-day and one-year follow-up results. ERACI II Investigators.

OBJECTIVE: The purpose of this study was to compare percutaneous transluminal coronary revascularization (PTCR) employing stent implantation to conventional coronary artery bypass graft surgery (CABG) in symptomatic patients with multivessel coronary artery disease. BACKGROUND: Previous randomized studies comparing balloon angioplasty versus CABG have demonstrated equivalent safety results. However, CABG was associated with significantly fewer repeat revascularization procedures. METHODS: A total of 2,759 patients with coronary artery disease were screened at seven clinical sites, and 450 patients were randomly assigned to undergo either PTCR (225 patients) or CABG (225 patients). Only patients with multivessel disease and indication for revascularization were enrolled. RESULTS: Both groups had similar clinical demographics: unstable angina in 92%; 38% were older than 65 years, and 23% had a history of peripheral vascular disease. During the first 30 days, PTCR patients had lower major adverse events (death, myocardial infarction, repeat revascularization procedures and stroke) compared with CABG patients (3.6% vs. 12.3%, p = 0.002). Death occurred in 0.9% of PTCR patients versus 5.7% in CABG patients, p < 0.013, and Q myocardial infarction (MI) occurred in 0.9% PTCR versus 5.7% of CABG patients, p < 0.013. At follow-up (mean 18.5 +/- 6.4 months), survival was 96.9% in PTCR versus 92.5% in CABG, p < 0.017. Freedom from MI was also better in PTCR compared to CABG patients (97.7% vs. 93.4%, p < 0.017). Requirements for new revascularization procedures were higher in PTCR than in CABG patients (16.8% vs. 4.8%, p < 0.002). CONCLUSIONS: In this selected high-risk group of patients with multivessel disease, PTCR with stent implantation showed better survival and freedom from MI than did conventional surgery. Repeat revascularization procedures were higher in the PTCR group.

Ras point mutations occur in acute myeloid leukemia with illegitimate T-cell receptor delta gene rearrangement.

Mutations in the ras proto-oncogenes are the most frequently observed molecular alteration in acute myeloid leukemia (AML). Whether ras mutations occur as late or relatively early events in the multistep process of myeloid transformation, remains an open question. We previously described illegitimate T-cell receptor (TCR)-delta gene rearrangements in a subset of AML. These recombinations were detected in 9 out of 100 de novo AML cases. Southern blot analysis suggested the presence of these recombinations in the vast majority of AML cells and thus could be used as clonal markers. In order to more accurately define the role of ras proto-oncogene mutations in the multistep process of malignant transformation in myeloid leukemias, we performed single strand conformation polymorphism (SSCP) assays, slot blot and direct sequencing analysis on these nine cases with illegitimate TCR delta gene rearrangements. Ras proto-oncogene mutations were found in three of nine cases. Interestingly, SSCP, slot blot and sequencing suggested the presence of the respective mutations in most of the leukemic cells. Thus, ras mutations presumably occurred early in the process of transformation in these three cases.

Identification and characterization of trypanocides by functional expression of an adenosine transporter from Trypanosoma brucei in yeast.

The causative agents of sleeping sickness, Trypanosoma brucei rhodesiense and T. brucei gambiense, do not synthesize purines de novo but salvage purine bases and nucleosides from their hosts. We used yeast as an expression system for functional characterization of the trypanosomal adenosine transporter TbAT1. A selection of purine analogs and flavonoids were tested for their ability to interfere with adenosine transport, with the aims of identifying (a) trypanocidal TbAT1 substrates, and (b) inhibitors of trypanosomal purine transport. Cordycepin (3'-deoxyadenosine) was a TbAT1 substrate of high activity against T. brucei rhodesiense (IC50 0.2 nM). Inhibitors of mammalian nucleoside transport were not active, while the flavonol silibinin was a potent, noncompetitive inhibitor of TbAT1-mediated adenosine transport in yeast. Silibinin also inhibited melarsen-induced lysis of bloodstream form trypanosomes. IC50 values to T. brucei rhodesiense and to human carcinoma cells were 0.6 and 140 microM, respectively, indicating a good selectivity towards the parasites. Further studies are necessary to elucidate the effects of flavonoids on trypanosomal purine transport and their potential as trypanocides.

Thermophilic anaerobic digester with ultrafilter for solids stabilization.

A thermophilic anaerobic digester with ultrafilter (TADU) for solids separation offers potential advantages of higher VS destruction, biomass retention, and pathogen removal. However, potential disadvantages include ultrafilter fouling, decreasing flux, and high VFA concentrations. In this study, a thermophilic anaerobic digester coupled to a sintered titanium, cross-flow ultrafilter was operated for over five months. Dairy manure was digested (HRT of 23 days). The filtrate VFA concentration was low (220 mg/L as HAc), average VS destruction was 49%, and a low average effluent fecal coliform concentration of 10(2) MPN/100 mL was observed. The low coliform value may be beneficial if dewatered biosolids are used for livestock bedding since low pathogen counts help prevent mastitis. Ultrafilter fluxes of 40-80 L/m2-hr were maintained by cleaning using caustic (3.5% NaOH) followed by water and acid (3% phosphoric acid). Sand from livestock bedding was found to damage the pump and ultrafilter. If TADU were implemented at full scale, then replacing sand bedding with dewatered biosolids should be considered.

Ultra high vacuum high precision low background setup with temperature control for thermal desorption mass spectroscopy (TDA-MS) of hydrogen in metals.

In this work, a newly developed UHV-based high precision low background setup for hydrogen thermal desorption analysis (TDA) of metallic samples is presented. Using an infrared heating with a low thermal capacity enables a precise control of the temperature and rapid cool down of the measurement chamber. This novel TDA-set up is superior in sensitivity to almost every standard hydrogen analyzer available commercially due to the special design of the measurement chamber, resulting in a very low hydrogen background. No effects of background drift characteristic as for carrier gas based TDA instruments were observed, ensuring linearity and reproducibility of the analysis. This setup will prove to be valuable for detailed investigations of hydrogen trapping sites in steels and other alloys. With a determined limit of detection of 5.9×10(-3)µg g(-1) hydrogen the developed instrument is able to determine extremely low hydrogen amounts even at very low hydrogen desorption rates. This work clearly demonstrates the great potential of ultra-high vacuum thermal desorption mass spectroscopy instrumentation.