Chemical composition and biological effects of kratom (Mitragyna speciosa): In vitro studies with implications for efficacy and drug interactions.

The safety and efficacy of kratom (Mitragyna speciosa) for treatment of pain is highly controversial. Kratom produces more than 40 structurally related alkaloids, but most studies have focused on just two of these, mitragynine and 7-hydroxymitragynine. Here, we profiled 53 commercial kratom products using untargeted LC-MS metabolomics, revealing two distinct chemotypes that contain different levels of the alkaloid speciofoline. Both chemotypes were confirmed with DNA barcoding to be M. speciosa. To evaluate the biological relevance of variable speciofoline levels in kratom, we compared the opioid receptor binding activity of speciofoline, mitragynine, and 7-hydroxymitragynine. Mitragynine and 7-hydroxymitragynine function as partial agonists of the human µ-opioid receptor, while speciofoline does not exhibit measurable binding affinity at the µ-, δ- or ƙ-opioid receptors. Importantly, mitragynine and 7-hydroxymitragynine demonstrate functional selectivity for G-protein signaling, with no measurable recruitment of ß-arrestin. Overall, the study demonstrates the unique binding and functional profiles of the kratom alkaloids, suggesting potential utility for managing pain, but further studies are needed to follow up on these in vitro findings. All three kratom alkaloids tested inhibited select cytochrome P450 enzymes, suggesting a potential risk for adverse interactions when kratom is co-consumed with drugs metabolized by these enzymes.

Papillary renal cell carcinoma in contrast-enhanced ultrasound (CEUS) - A diagnostic performance study.

BACKGROUND: Renal cell carcinomas (RCC) represent a heterogeneous group of hypo- and hypervascularized malignancies. Using contrast-enhanced ultrasound (CEUS) specific imaging features of clear cell (ccRCC), papillary (pRCC) and chromophobe RCC (chRCC) subtypes have been demonstrated. However, some RCCs show atypical imaging features making it difficult to distinguish between the subtypes. OBJECTIVE: This study was performed to evaluate the observed enhancement features of pRCC in CEUS and to assess the sensitivity in the diagnosis of suspected renal malignancies in a 10 year retrospective analysis at our institution. METHODS: The study population consisted of 60 patients with histologically confirmed pRCC. All patients underwent CEUS imaging between 2005 and 2015 as part of their diagnostic workup. RESULTS: In 45 out of 60 (75%) cases the examined pRCC showed typical hypoenhancement and wash-out. 15 out of 60 (25%) pRCC showed atypical enhancement features; in 14 cases the contrast enhancement indicated a ccRCC. 1 complex cyst was falsely reported as IIF lesion. 59 out of 60 malignancies were reported as malignant using CEUS resulting in a sensitivity of 98.4%. CONCLUSIONS: CEUS is an eligible imaging technique to visualize the contrast enhancement features of pRCC. However, up to 25% of pRCCs show an atypical enhancement pattern making it difficult to distinguish it from other renal lesions.

[Cardiac support and replacement systems]. / Kardiale Unterstützungs- und Ersatzsysteme.

In recent years, the widespread use of partial mechanical cardiac support and even temporary complete replacement of cardiac function has been established in many intensive care units in the treatment of refractory cardiogenic shock. There is a difference between partial left-ventricular assist devices (LVAD) and the possibility of complete heart (and lung) replacement by extra corporeal life support (ECLS). Despite the use of mechanical support devices, the mortality of cardiogenic shock remains high. The consideration of using percutaneous LVAD and ECLS in cardiogenic shock should be considered in refractory cardiogenic shock patients in addition to support by catecholamines and after early revascularization in acute coronary syndromes. However, there are no large randomized studies evaluating mechanical support systems with respect to outcome in cardiogenic shock patients. German and international guidelines do not recommend the routine use of mechanical support as a first-line treatment in cardiogenic shock patients and emphasize that their application should be restricted to patients with therapy refractory shock. In other cases of noninfarct-related cardiogenic shock (e. g., poisoning, myocarditis), ECLS use should be considered as bridging therapy. ECLS may also be considered in cardiopulmonary resuscitation which is termed E­CPR. According to registry data, E­CPR may reduce mortality in selected patients. A possible application of ECLS is severe accidental hypothermia with cardiac arrest despite limited data. In these rare cases, early ECLS should be considered for rewarming and stabilization.

Protein and DNA-based assays as complementary tools for fish allergen detection.

BACKGROUND: Fish is one of the most important, allergenic foods worldwide. Parvalbumin is the well characterized, major allergen in fish muscle. In this study, we developed a protein- and a DNA-based method for the sensitive detection and authentication of eight commonly consumed fishes in food and compared their applicability. METHODS: Fish parvalbumins were purified. Polyclonal, anti-parvalbumin antibodies were raised in rabbits and mice. Protein extracts from food were analyzed by quantitative ELISA. Parvalbumin genes were cloned and sequenced for the design of parvalbumin gene-specific PCR-primers. DNA extracted from food was subjected to specific PCR. RESULTS: Increasing parvalbumin contents were quantified by ELISA in fresh fish, in the order of tuna < mackerel < cod < salmon/trout < redfish < carp < herring. The parvalbumin content of processed fish was up to 67% lower than in fresh fish. In spiked food samples, 1 to 15 ppm fresh fish and 30 to 170 ppm processed fish were still detectable by ELISA. The eight fishes were identified by specific PCR using 0.2 to 10 ng fish DNA. PCRs detected still 3 ppm fresh fish and 30 to 150 ppm processed fish in spiked samples. CONCLUSIONS: Both the protein- and the DNA-based method have sufficient sensitivity to protect fish-allergic consumers. The ELISA allows allergen quantification, while the PCR identifies the fish present in the food. The detection limits of both methods vary depending on different factors. Both methods need to be carefully validated for each fish and fish product when used in detection assays.

Reprogramming human B cells into induced pluripotent stem cells and its enhancement by C/EBPα.

B cells have been shown to be refractory to reprogramming and B-cell-derived induced pluripotent stem cells (iPSC) have only been generated from murine B cells engineered to carry doxycycline-inducible Oct4, Sox2, Klf4 and Myc (OSKM) cassette in every tissue and from EBV/SV40LT-immortalized lymphoblastoid cell lines. Here, we show for the first time that freshly isolated non-cultured human cord blood (CB)- and peripheral blood (PB)-derived CD19+CD20+ B cells can be reprogrammed to iPSCs carrying complete VDJH immunoglobulin (Ig) gene monoclonal rearrangements using non-integrative tetracistronic, but not monocistronic, OSKM-expressing Sendai Virus. Co-expression of C/EBPα with OSKM facilitates iPSC generation from both CB- and PB-derived B cells. We also demonstrate that myeloid cells are much easier to reprogram than B and T lymphocytes. Differentiation potential back into the cell type of their origin of B-cell-, T-cell-, myeloid- and fibroblast-iPSCs is not skewed, suggesting that their differentiation does not seem influenced by 'epigenetic memory'. Our data reflect the actual cell-autonomous reprogramming capacity of human primary B cells because biased reprogramming was avoided by using freshly isolated primary cells, not exposed to cytokine cocktails favoring proliferation, differentiation or survival. The ability to reprogram CB/PB-derived primary human B cells offers an unprecedented opportunity for studying developmental B lymphopoiesis and modeling B-cell malignancies.

Single-grating-mirror intracavity stretcher design for chirped pulse regenerative amplification.

We report for the first time, to the best of our knowledge, an innovative design concept for intracavity pulse stretching in a regenerative amplifier, employing a single "grating-mirror" based on a leaky-mode grating-waveguide design. The very compact and flexible layout allows for femtosecond pulses to be in principle easily stretched up to nanosecond durations. The design has been tested in a diode-pumped Yb:CALGO regenerative amplifier followed by a standard transmission grating compressor. Sub-200-fs pulses (stretched pulses ≈110 ps) with 205-µJ energy at 20-kHz repetition rate have been demonstrated. In order to prove the robustness and potential for energy scaling of leaky-mode grating-waveguide intracavity stretcher, we generated stretched pulses with energies of up to ≈700 µJ (400-ps long) at a lower repetition rate of 10 kHz. A simple model is proposed for the study of the cavity in presence of induced spatial chirp.

Enhanced efficiency of AlGaInP disk laser by in-well pumping.

The performance of a 665-nm GaInP disk laser operated continuous-wave at 15°C both in-well-pumped at 640 nm and barrier pumped at 532 nm is reported. The efficiency with respect to the absorbed power was enhanced by 3.5 times when using a 640-nm pump instead of a 532-nm pump. In-well pumping which is based on the absorption of the pump photons within the quantum-well heterostructures of the gain region instead of short-wavelength absorption in the barrier and spacer regions reduces the quantum defect between pump and laser photon and hence the heat generation. A slope efficiency of 60% with respect to the absorbed pump power was obtained by in-well pumping at 15°C. Continuous-wave laser operation was further demonstrated at heat sink temperatures of up to 55°C. Both the measurement of photoluminescence and COMSOL simulation show that the overall heat load in the in-well pumped laser is smaller than in the barrier-pumped laser. These results demonstrate the potential of optical in-well pumping for the operation of red AlGaInP disk lasers if combined with means for efficient pump-light absorption.

[Mechanical support in cardiogenic shock]. / Mechanische Unterstützung im kardiogenen Schock.

Treatment of patients in cardiogenic shock (CS) presenting with acute myocardial infarction (AMI) is still a challenge and mortality rates remain high, approaching 50 %. Hemodynamic stabilization before and/or after early revascularization remains the primary goal in these patients. In addition to hemodynamic support by inotropes and vasopressors, support with mechanical devices such as intra-aortic balloon pumping (IABP), percutaneous left ventricular assist devices (LVAD) and complete extracorporeal life support (ECLS) with extracorporeal membrane oxygenation (ECMO) may be considered. The use of IABP cannot be recommended anymore on a routine basis. Unfortunately, there are no large randomized data from studies evaluating treatment with mechanical support systems compared to standard treatment with respect to the clinical outcome of patients and no head-to-head comparison of different devices is available. Another important open question to be answered is which subgroups of patients may have a benefit from LVAD therapy. Guidelines discourage the routine use of mechanical support as a first-line treatment in CS patients and emphasize that the application should be restricted to those patients with refractory shock. This article gives an overview of the different devices for percutaneous mechanical support in CS and describes the available evidence and guideline recommendations.

["Fit4You"--A Programme for Prevention and Reduction of Overweight in Apprentices in the Workplace Setting]. / "Fit4U"--ein Präventionsprogramm zur Vermeidung und Verminderung von Übergewicht bei Auszubildenden im Betrieb.

The effect of health promotion at the worksite for overweight adolescents is not known. This 2-year intervention study examined the effect of a multimodal programme including nutrition counselling, sport, and life-skill training on medical and psychological outcomes. The body mass index increased slightly less in the intervention group. Semistructured interviews at the end showed that participants are highly interested in health promotion at the worksite.

Physiologically based pharmacokinetic modeling framework for quantitative prediction of an herb-drug interaction.

Herb-drug interaction predictions remain challenging. Physiologically based pharmacokinetic (PBPK) modeling was used to improve prediction accuracy of potential herb-drug interactions using the semipurified milk thistle preparation, silibinin, as an exemplar herbal product. Interactions between silibinin constituents and the probe substrates warfarin (CYP2C9) and midazolam (CYP3A) were simulated. A low silibinin dose (160 mg/day × 14 days) was predicted to increase midazolam area under the curve (AUC) by 1%, which was corroborated with external data; a higher dose (1,650 mg/day × 7 days) was predicted to increase midazolam and (S)-warfarin AUC by 5% and 4%, respectively. A proof-of-concept clinical study confirmed minimal interaction between high-dose silibinin and both midazolam and (S)-warfarin (9 and 13% increase in AUC, respectively). Unexpectedly, (R)-warfarin AUC decreased (by 15%), but this is unlikely to be clinically important. Application of this PBPK modeling framework to other herb-drug interactions could facilitate development of guidelines for quantitative prediction of clinically relevant interactions.CPT Pharmacometrics Syst. Pharmacol. (2014) 3, e107; doi:10.1038/psp.2013.69; advance online publication 26 March 2014.

Transcription factor-induced enhancer modulations during cell fate conversions.

The activity of transcription factors (TFs) has empowered the reprogramming of differentiated cells into induced pluripotent stem cells (iPSCs) and alternative lineages. Elucidation of the molecular mechanisms underpinning these processes has expanded our understanding of how novel gene expression programs become activated while old ones are silenced. How TFs modify chromatin and activate requisite enzymes during these processes has recently been discussed in several excellent reviews. Here we discuss the questions of how ectopically expressed TFs access chromatin to modulate enhancers and establish a novel transcriptome during cell reprogramming, lineage conversions and differentiation.

Propagation of Gaussian-apodized paraxial beams through first-order optical systems via complex coordinate transforms and ray transfer matrices.

We investigate the linear propagation of Gaussian-apodized solutions to the paraxial wave equation in free-space and first-order optical systems. In particular, we present complex coordinate transformations that yield a very general and efficient method to apply a Gaussian apodization (possibly with initial phase curvature) to a solution of the paraxial wave equation. Moreover, we show how this method can be extended from free space to describe propagation behavior through nonimaging first-order optical systems by combining our coordinate transform approach with ray transfer matrix methods. Our framework includes several classes of interesting beams that are important in applications as special cases. Among these are, for example, the Bessel-Gauss and the Airy-Gauss beams, which are of strong interest to researchers and practitioners in various fields.

Femtosecond Yb:CaGdAlO4 thin-disk oscillator.

A mode-locked thin-disk laser based on Yb:CALGO is demonstrated for the first time. At an average output power of 28 W we obtained pulses with a duration of 300 fs and a pulse energy of 1.3 µJ. 197 fs pulses with 0.9 µJ of energy were achieved at an average output power of 20 W. The shortest pulse duration measured in our experiments was 135 fs with a spectrum centered at 1043 nm. The experiments also revealed a very broad tunability from 1032 to 1046 nm with sub-200 fs pulses.

[Arterial hypertension in patients with coronary artery disease]. / Arterielle Hypertonie bei Patienten mit koronarer Herzerkrankung.

Arterial hypertension is the most important risk factor for coronary artery disease (CAD). There is a high coincidence of both diseases, whereby both impair coronary microcirculatory function synergistically, which can be measured functionally by decreased coronary flow reserve. This dysfunction leads to permanent damage to the left ventricular myocardium. Lifestyle changes play a central role in the primary and secondary prevention of CAD. Additionally, there are well-established options for antihypertensive drug therapy, which should be combined with aspirin and statins. Pharmacological treatment should follow distinctive blood pressure goals in relation to the severity of CAD. Particular attention is paid in this context to the relation between diastolic blood pressure values and cardiovascular endpoints, which displays a j-shaped curve with the lowest risk at levels between 70 and 90 mmHg.

Case report of a haemovigilance investigation using phylogenetic analysis of HIV-1 in Brazil.

OBJECTIVES: The aim of this work is to provide the first report of a transfusion-acquired HIV-1 infection and to verify transmission from the donor to the recipients using phylogenetic analysis of HIV-1 DNA sequences in a Brazilian blood bank. BACKGROUND: Although haemovigilance procedures based on phylogenetic analysis of HIV have been reported in several countries, this type of study has yet to be conducted in Latin America. MATERIALS AND METHODS: Upon identifying a HIV-1-positive repeat blood donor by enzyme immunoassay (EIA) blood screening, all recipients of the donor's previous donation were identified and tested for HIV-1 by EIA, nucleic acid amplification test and HIV-1 DNA sequencing and phylogenetic analysis. RESULTS: One of the recipients tested positive for HIV-1. The phylogenetic analysis showed a high genetic similarity among the viruses, thus supporting the hypothesis of transmission from the donor to the recipient. CONCLUSIONS: Phylogenetic analysis of HIV-1 DNA sequences has been a decisive tool in verifying suspected transmission of the virus from blood donor to recipient in Brazil.

Yb:CaGdAlO4 thin-disk laser.

We present the first demonstration of a Yb:CALGO thin-disk laser. In a slightly multimode configuration, we obtained up to 30 W of average power at a slope efficiency of 40% and an optical-to-optical efficiency of 32%. With a single-mode cavity, an average power of 25 W was achieved. A tuning range from 1018 to 1052 nm could be demonstrated by inserting a prism into the cavity. In the Q-switched regime, we obtained 1 mJ of pulse energy at a repetition rate of 100 Hz.

Is the proton radius a player in the redefinition of the International System of Units?

It is now recognized that the International System of Units (SI units) will be redefined in terms of fundamental constants, even if the date when this will occur is still under debate. Actually, the best estimate of fundamental constant values is given by a least-squares adjustment, carried out under the auspices of the Committee on Data for Science and Technology (CODATA) Task Group on Fundamental Constants. This adjustment provides a significant measure of the correctness and overall consistency of the basic theories and experimental methods of physics using the values of the constants obtained from widely differing experiments. The physical theories that underlie this adjustment are assumed to be valid, such as quantum electrodynamics (QED). Testing QED, one of the most precise theories is the aim of many accurate experiments. The calculations and the corresponding experiments can be carried out either on a boundless system, such as the electron magnetic moment anomaly, or on a bound system, such as atomic hydrogen. The value of fundamental constants can be deduced from the comparison of theory and experiment. For example, using QED calculations, the value of the fine structure constant given by the CODATA is mainly inferred from the measurement of the electron magnetic moment anomaly carried out by Gabrielse's group. (Hanneke et al. 2008 Phys. Rev. Lett. 100, 120801) The value of the Rydberg constant is known from two-photon spectroscopy of hydrogen combined with accurate theoretical quantities. The Rydberg constant, determined by the comparison of theory and experiment using atomic hydrogen, is known with a relative uncertainty of 6.6×10(-12). It is one of the most accurate fundamental constants to date. A careful analysis shows that knowledge of the electrical size of the proton is nowadays a limitation in this comparison. The aim of muonic hydrogen spectroscopy was to obtain an accurate value of the proton charge radius. However, the value deduced from this experiment contradicts other less accurate determinations. This problem is known as the proton radius puzzle. This new determination of the proton radius may affect the value of the Rydberg constant . This constant is related to many fundamental constants; in particular, links the two possible ways proposed for the redefinition of the kilogram, the Avogadro constant N(A) and the Planck constant h. However, the current relative uncertainty on the experimental determinations of N(A) or h is three orders of magnitude larger than the 'possible' shift of the Rydberg constant, which may be shown by the new value of the size of the proton radius determined from muonic hydrogen. The proton radius puzzle will not interfere in the redefinition of the kilogram. After a short introduction to the properties of the proton, we will describe the muonic hydrogen experiment. There is intense theoretical activity as a result of our observation. A brief summary of possible theoretical explanations at the date of writing of the paper will be given. The contribution of the proton radius puzzle to the redefinition of SI-based units will then be examined.

Randomized clinical trial of the i-gel™ and Magill tracheal tube or single-use ILMA™ and ILMA™ tracheal tube for blind intubation in anaesthetized patients with a predicted difficult airway.

BACKGROUND: The single-use supraglottic airway device i-gel™ has been described in several case reports as a conduit for intubation, but no prospective data about success rates of blind intubation are available. Therefore, we performed this prospective randomized controlled trial to compare the success rate of blind tracheal intubation with a Magill PVC tube through the i-gel™ with intubation using an sILMA™ PVC tube through the single-use intubating laryngeal mask airway (sILMA™). METHODS: With ethics committee approval and written informed consent, 80 patients with predictors of a difficult airway were computer randomized to either supraglottic airway device (SAD). The corresponding tracheal tube (TT) was introduced through the SAD under fibreoptic visualization but without fibreoptic guidance. Primary outcome was blind intubation success rate. Times, airway leak pressure, fibreoptic view, and adverse events were recorded. To control for the influence of the TT, we compared data from 40 patients described in an accompanying study (sILMA™ with Magill TT and i-gel™ with sILMA™ TT). RESULTS: Blind intubation success rate through the sILMA™ (69%) was higher than with the i-gel™ (15%, P<0.001). Data from the other patient group excluded the TT type as the primary cause for the difference in success rate. Removal of SADs was without problems with no difference between the type of SAD. CONCLUSIONS: Blind tracheal intubation using the sILMA™ tube through the sILMA™ is much more successful than blind intubation with a Magill PVC tube through the i-gel™. Because of its low success rate, we would not recommend blind intubation through the i-gel™.