Thermodynamic signatures of quantum criticality in cuprate superconductors.

The three central phenomena of cuprate (copper oxide) superconductors are linked by a common doping level p*-at which the enigmatic pseudogap phase ends and the resistivity exhibits an anomalous linear dependence on temperature, and around which the superconducting phase forms a dome-shaped area in the phase diagram1. However, the fundamental nature of p* remains unclear, in particular regarding whether it marks a true quantum phase transition. Here we measure the specific heat C of the cuprates Eu-LSCO and Nd-LSCO at low temperature in magnetic fields large enough to suppress superconductivity, over a wide doping range2 that includes p*. As a function of doping, we find that Cel/T is strongly peaked at p* (where Cel is the electronic contribution to C) and exhibits a log(1/T) dependence as temperature T tends to zero. These are the classic thermodynamic signatures of a quantum critical point3-5, as observed in heavy-fermion6 and iron-based7 superconductors at the point where their antiferromagnetic phase comes to an end. We conclude that the pseudogap phase of cuprates ends at a quantum critical point, the associated fluctuations of which are probably involved in d-wave pairing and the anomalous scattering of charge carriers.

Chronic, acute and protocol-dependent effects of exercise on psycho-physiological health during long-term isolation and confinement.

Exercise could prevent physical and psychological deteriorations, especially during pandemic times of lock-down scenarios and social isolation. But to meet both, the common exercise protocols require optimization based on holistic investigations and with respect to underlying processes. This study aimed to explore individual chronic and acute effects of continuous and interval running exercise on physical and cognitive performance, mood, and affect and underlying neurophysiological factors during a terrestrial simulated space mission. Six volunteers (three females) were isolated for 120 days. Accompanying exercise training consisted of a continuous and interval running protocol in a cross-over design. Incremental stage tests on a treadmill were done frequently to test physical performance. Actigraphy was used to monitor physical activity level. Cognitive performance, mood (MoodMeter®), affect (PANAS), brain-derived neurotrophic factor (BDNF), insulin-like growth factor 1 (IGF-1), vascular-endothelial growth factor (VEGF), and saliva cortisol were investigated prior to, four times during, and after isolation, pre- and post-exercise on two separate days, respectively. As a chronic effect, physical performance increased (and IGF-1 tended) in the course of isolation and training until the end of isolation. Subjective mood and affect state, as well as cognitive performance, basal BDNF and VEGF levels, were well-preserved across the intervention. No acute effects of exercise were detected, besides slower reaction time after exercise in two out of nine cognitive tests, testing sensorimotor speed and memory of complex figures. Consistently higher basal IGF-1 concentrations and faster reaction time in the psychomotor vigilance test were found for the continuous compared to the interval running protocol. The results suggest that 120 days of isolation and confinement can be undergone without cognitive and mental deteriorations. Regular, individual aerobic running training supporting physical fitness is hypothesized to play an important role in this regard. Continuous running exercise seems to trigger higher IGF-1 levels and vigilance compared to interval running. Systematic and prolonged investigations and larger sample size are required to follow up on exercise-protocol specific differences in order to optimize the exercise intervention for long-term psycho-physiological health and well-being.

Magnetically Hidden State on the Ground Floor of the Magnetic Devil's Staircase.

We investigated the low-temperature and high-field thermodynamic and ultrasonic properties of SrCu_{2}(BO_{3})_{2}, which exhibits various plateaux in its magnetization curve above 27 T, called a magnetic Devil's staircase. The results of the present study confirm that magnetic crystallization, the first step of the staircase, occurs above 27 T as a first-order transition accompanied by a sharp singularity in heat capacity C_{p} and a kink in the elastic constant. In addition, we observe a thermodynamic anomaly at lower fields around 26 T, which has not been previously detected by any magnetic probes. At low temperatures, this magnetically hidden state has a large entropy and does not exhibit Schottky-type gapped behavior, which suggests the existence of low-energy collective excitations. Based on our observations and theoretical predictions, we propose that magnetic quadrupoles form a spin-nematic state around 26 T as a hidden state on the ground floor of the magnetic Devil's staircase.

Pharmacogenetic information in Swiss drug labels - a systematic analysis.

Implementation of pharmacogenetics (PGx) and individualization of drug therapy is supposed to obviate adverse drug reactions or therapy failure. Health care professionals (HCPs) use drug labels (DLs) as reliable information about drugs. We analyzed the Swiss DLs to give an overview on the currently available PGx instructions. We screened 4306 DLs applying natural language processing focusing on drug metabolism (pharmacokinetics) and we assigned PGx levels following the classification system of PharmGKB. From 5979 hits, 2564 were classified as PGx-relevant affecting 167 substances. 55% (n = 93) were classified as "actionable PGx". Frequently, PGx information appeared in the pharmacokinetics section and in DLs of the anatomic group "nervous system". Unstandardized wording, appearance of PGx information in different sections and unclear instructions challenge HCPs to identify and interpret PGx information and translate it into practice. HCPs need harmonization and standardization of PGx information in DLs to personalize drug therapies and tailor pharmaceutical care.

Live interactive teledermatology compared to in-person care - a systematic review.

Teledermatology is a rapidly developing field of dermatological care, giving the opportunity to deliver more efficient healthcare to patients in remote areas. Live interactive (LI) teledermatology uses videoconferencing and, hence, allows for direct communication. A current overview on effectiveness, costs, feasibility and accuracy of LI applications compared to standard care is missing. The present systematic review provides this overview on LI teledermatology. Two databases were searched until April 2019, followed by title, abstract and full-text screening. Additionally, reference lists of the detected eligible articles were screened for further eligible studies. Studies comparing LI applications with standard care were included. Data on study design, sample size, country, objectives, main findings and characteristics of LI applications were extracted. Results on time effectiveness, costs, accuracy and feasibility of LI applications were synthesized. Additionally, the quality of included studies was assessed. Twenty-three publications were included in the final analysis: seventeen case-control studies and six randomized controlled trials. Included studies were published between 1997 and 2017. Study quality differed across studies. The studies were carried out in eight different countries. Eleven studies focused on patient consultation, three on patient organization and nine on combined applications of the aforementioned. Nine studies investigated applications facilitating patient-provider interaction. Fourteen studies evaluated applications combining patient-provider and provider-provider interaction, meaning the patient sits next to one provider while using LI applications to interact with another provider. This review reveals that LI applications can be a time effective substitute of or supplement to standard dermatological care. Results demonstrated that LI and standard care are comparable with regard to feasibility and accuracy. No clear tendencies can be reported with regard to costs. However, there is a lack of current comparative studies.

Unusual Interplay between Superconductivity and Field-Induced Charge Order in YBa_{2}Cu_{3}O_{y}.

We present a detailed study of the temperature (T) and magnetic field (H) dependence of the electronic density of states (DOS) at the Fermi level, as deduced from specific heat and Knight shift measurements in underdoped YBa_{2}Cu_{3}O_{y}. We find that the DOS becomes field independent above a characteristic field H_{DOS}, and that the H_{DOS}(T) line displays an unusual inflection near the onset of the long-range 3D charge-density wave order. The unusual S shape of H_{DOS}(T) is suggestive of two mutually exclusive orders that eventually establish a form of cooperation in order to coexist at low T. On theoretical grounds, such a collaboration could result from the stabilization of a pair-density wave state, which calls for further investigation in this region of the phase diagram.

Comparison of effectiveness of 5'-regulatory sequences in transplastomic tobacco chloroplasts.

The development of tools which ensure the desired level of transgene expression in plastids is a prerequisite for the effective utilization of these plant organelles for the deployment of bioactive proteins. High-level accumulation of target proteins is considered as a positive feature of transplastomic plants, but excessive accumulation of foreign proteins may have deleterious effects on host plants. On the other hand, expression at low levels can result in ineffective phenotypes. We compared the effectiveness of different 5'-regulatory sequences in driving the expression of a reporter gene, ß-glucuronidase (uidA), in tobacco chloroplasts. To achieve varying expression levels, we have chosen heterologous 5'-regulatory sequences which either differ significantly from their homologous counterparts or depend on specific nuclear encoded factors. The Medicago truncatula psbA promoter/5'-UTR supported the highest levels of protein accumulation, surpassing the other tested sequences by two to three orders of magnitude. The heterologous regulatory sequence of Phaseolus vulgaris rbcL gene was as efficient in tobacco chloroplasts as the corresponding homologous promoter/5'-UTR. The Arabidopsis thaliana ndhF promoter/5'-UTR supported as high reporter activity levels as the rbcL 5'-sequences, whereas the effectiveness of A. thaliana psbN promoter/5'-UTR was three fold lower. The characterized regulatory sequences can be utilized to establish transplastomic lines with desirable levels of target protein accumulation. The ability to control transgene expression should be useful for achieving appropriate levels of protein accumulation and thereby avoid their negative impacts on host plant physiology.

Protective Effects of Liraglutide and Linagliptin in C. elegans as a New Model for Glucose-Induced Neurodegeneration.

Liraglutide and linagliptin are novel drugs for the treatment of diabetes. Antioxidative and neuroprotective effects have been described for both compounds. However, it is not yet known, whether these mechanisms are also protective against diabetic retinal neurodegeneration. We assessed the antioxidative and neuroprotective capabilities of liraglutide and linagliptin as well as the signaling pathways involved, by using C. elegans as a model for glucose-induced neurodegeneration. C. elegans were cultivated under conditions, which mimic clinical hyperglycemia, and treated with 160 µmol/l liraglutide or 13 µmol/l linagliptin. Oxidative stress was reduced by 29 or 78% and methylglyoxal-derived advanced glycation endproducts (AGEs) by 33 or 22%, respectively. This resulted in an improved neuronal function by 42 or 60% and an extended mean lifespan by 9 or 11%, respectively. Antioxidative and AGE reducing effects of liraglutide and linagliptin were not dependent on v-akt murine thymoma viral oncogene homologue 1/forkhead box O1 (AKT1/FOXO). Neuroprotection by liraglutide was AKT1/FOXO dependent, yet AKT1/FOXO independent upon linagliptin treatment. Both liraglutide and linagliptin exert neuroprotective effects in an experimental model for glucose-induced neurodegeneration, however, the signaling pathways differ in the present study. Further pharmacological intervention with these pathways may help to delay the clinical onset of diabetic retinopathy by preserving neuronal integrity.

Gliptin-mediated neuroprotection against stroke requires chronic pretreatment and is independent of glucagon-like peptide-1 receptor.

Gliptins are anti-type 2 diabetes (T2D) drugs that regulate glycaemia by preventing endogenous glucagon-like peptide-1 (GLP-1) degradation. Chronically administered gliptins before experimental stroke can also induce neuroprotection, and this effect is potentially relevant for reducing brain damage in patients with T2D and high risk of stroke. It is not known, however, whether acute gliptin treatment after stroke (mimicking a post-hospitalization treatment) is neuroprotective or whether gliptin-mediated neuroprotection occurs via GLP-1-receptor (GLP-1R) activation. To answer these two questions, wild-type and glp-1r(-/-) mice were subjected to transient middle cerebral artery occlusion (MCAO). Linagliptin was administered acutely (50 mg/kg intravenously), at MCAO time or chronically (10 mg/kg orally) for 4 weeks before and 3 weeks after MCAO. Neuroprotection was assessed by stroke volume measurement and quantification of NeuN-positive surviving neurons. Plasma/brain GLP-1 levels and dipeptidyl peptidase-4 activity were also measured. The results show that the linagliptin-mediated neuroprotection against stroke requires chronic pretreatment and does not occur via GLP-1R. The findings provide essential new knowledge with regard to the potential clinical use of gliptins against stroke, as well as a strong impetus to identify gliptin-mediated neuroprotective mechanisms.

Revisiting the immunocytochemical detection of Neurogenin 3 expression in mouse and man.

During embryonic development, endocrine cells of the pancreas are specified from multipotent progenitors. The transcription factor Neurogenin 3 (NEUROG3) is critical for this development and it has been shown that all endocrine cells of the pancreas arise from endocrine progenitors expressing NEUROG3. A thorough understanding of the role of NEUROG3 during development, directed differentiation of pluripotent stem cells and in models of cellular reprogramming, will guide future efforts directed at finding novel sources of ß-cells for cell replacement therapies. In this article, we review the expression and function of NEUROG3 in both mouse and human and present the further characterization of a monoclonal antibody directed against NEUROG3. This antibody has been previously been used for detection of both mouse and human NEUROG3. However, our results suggest that the epitope recognized by this antibody is specific to mouse NEUROG3. Thus, we have also generated a monoclonal antibody specifically recognizing human NEUROG3 and present the characterization of this antibody here. Together, these antibodies will provide useful tools for future studies of NEUROG3 expression, and the data presented in this article suggest that recently described expression patterns of NEUROG3 in human foetal and adult pancreas should be re-examined.

Robust anti-obesity and metabolic effects of a dual GLP-1/glucagon receptor peptide agonist in rodents and non-human primates.

AIMS: To characterize the pharmacology of MEDI0382, a peptide dual agonist of glucagon-like peptide-1 (GLP-1) and glucagon receptors. MATERIALS AND METHODS: MEDI0382 was evaluated in vitro for its ability to stimulate cAMP accumulation in cell lines expressing transfected recombinant or endogenous GLP-1 or glucagon receptors, to potentiate glucose-stimulated insulin secretion (GSIS) in pancreatic ß-cell lines and stimulate hepatic glucose output (HGO) by primary hepatocytes. The ability of MEDI0382 to reduce body weight and improve energy balance (i.e. food intake and energy expenditure), as well as control blood glucose, was evaluated in mouse models of obesity and healthy cynomolgus monkeys following single and repeated daily subcutaneous administration for up to 2 months. RESULTS: MEDI0382 potently activated rodent, cynomolgus and human GLP-1 and glucagon receptors and exhibited a fivefold bias for activation of GLP-1 receptor versus the glucagon receptor. MEDI0382 produced superior weight loss and comparable glucose lowering to the GLP-1 peptide analogue liraglutide when administered daily at comparable doses in DIO mice. The additional fat mass reduction elicited by MEDI0382 probably results from a glucagon receptor-mediated increase in energy expenditure, whereas food intake suppression results from activation of the GLP-1 receptor. Notably, the significant weight loss elicited by MEDI0382 in DIO mice was recapitulated in cynomolgus monkeys. CONCLUSIONS: Repeated administration of MEDI0382 elicits profound weight loss in DIO mice and non-human primates, produces robust glucose control and reduces hepatic fat content and fasting insulin and glucose levels. The balance of activities at the GLP-1 and glucagon receptors is considered to be optimal for achieving weight and glucose control in overweight or obese Type 2 diabetic patients.

ABO-incompatible heart transplants.

A month-old baby girl with blood type O positive received a donor heart organ from a donor with blood type B. This was the first institutional ABO-incompatible heart transplant. Infants listed for transplantation may be considered for an ABO-incompatible heart transplant based on their antibody levels and age. The United Network of Organ Sharing (UNOS) protocol is infants under 24 months with titers less than or equal to 1:4.(1) This recipient's anti-A and anti-B antibodies were monitored with titer assays to determine their levels; antibody levels less than 1:4 are acceptable pre-transplant in order to proceed with donor and transplant arrangements.1 Immediately prior to initiating cardiopulmonary bypass (CPB), a complete whole body exchange transfusion of at least two-times the patient's circulating blood volume was performed with packed red blood cells (pRBC), fresh frozen plasma (FFP) and 25% albumin. Titer assays were sent two minutes after initiation of full CPB and then hourly until the cross-clamp was removed. Institutionally, reperfusion of the donor heart is not restored until the antibody level from the titer assay is known and reported as less than 1:4; failing to achieve an immulogically tolerant recipient will provide conditions for hyperacute rejection. The blood collected during the transfusion exchange was immediately processed through a cell saver so the pRBC's could be re-infused to the patient during CPB, as necessary. The remainder of the transplant was performed in the same fashion as an ABO-compatible heart transplant. The patient has shown no signs of rejection following transplantation.

[Therapy of pediatric femoral fractures. Two versus three elastic stable intramedullary nails]. / Therapie kindlicher Femurfrakturen. Zwei vs. drei elastisch-stabile intramedulläre Nägel.

BACKGROUND: The conservative treatment of pediatric femoral fractures can be socially and financially burdensome for patients and families due to the long period of immobilization. New operative techniques have consistently gained significance in the treatment of such fractures due to a shorter period of immobilization. Elastic stable intramedullary nailing (ESIN) in particular has been proven to lead to better outcome in comparison to conservative treatment. This article presents the first study that compares the outcome of three versus two ESINs in the treatment of pediatric femoral shaft fractures. MATERIAL AND METHODS: A retrospective analysis of all patients who underwent operative treatment of femoral fractures with ESINs in our hospital from 2009-2012 was carried out. A follow-up examination was performed in mid-2013 by standardized evaluation of leg length discrepancy and the movement capacity of the hip and knee joint. RESULTS: The follow-up examination revealed a leg length discrepancy of the injured leg when three ESINs were used (p = 0.013) and an impairment of the movement capacity in the hip joint of the injured leg (p = 0.029). In addition the surgery time for metal removal of three ESINs was higher (p = 0.046). All other evaluated parameters did not show any differences. CONCLUSION: In this study population the treatment of pediatric femoral shaft fractures with three ESINs showed no benefit in comparison to two ESINs and therefore should not be used to treat femoral fractures. The leg length discrepancy using three ESINs may be explained by a nonsymmetrical distribution of support points leading to an increased micromovement of the bone with increased callus formation.

Arginase inhibition prevents inflammation and remodeling in a guinea pig model of chronic obstructive pulmonary disease.

Airway inflammation and remodeling are major features of chronic obstructive pulmonary disease (COPD), whereas pulmonary hypertension is a common comorbidity associated with a poor disease prognosis. Recent studies in animal models have indicated that increased arginase activity contributes to features of asthma, including allergen-induced airway eosinophilia and mucus hypersecretion. Although cigarette smoke and lipopolysaccharide (LPS), major risk factors for COPD, may increase arginase expression, the role of arginase in COPD is unknown. This study aimed to investigate the role of arginase in pulmonary inflammation and remodeling using an animal model of COPD. Guinea pigs were instilled intranasally with LPS or saline twice weekly for 12 weeks and pretreated by inhalation of the arginase inhibitor 2(S)-amino-6-boronohexanoic acid (ABH) or vehicle. Repeated LPS exposure increased lung arginase activity, resulting in increased l-ornithine/l-arginine and l-ornithine/l-citrulline ratios. Both ratios were reversed by ABH. ABH inhibited the LPS-induced increases in pulmonary IL-8, neutrophils, and goblet cells as well as airway fibrosis. Remarkably, LPS-induced right ventricular hypertrophy, indicative of pulmonary hypertension, was prevented by ABH. Strong correlations were found between arginase activity and inflammation, airway remodeling, and right ventricular hypertrophy. Increased arginase activity contributes to pulmonary inflammation, airway remodeling, and right ventricular hypertrophy in a guinea pig model of COPD, indicating therapeutic potential for arginase inhibitors in this disease.

Cellular immune function monitoring after allogeneic haematopoietic cell transplantation: evaluation of a new assay.

Managing the patient's immune system after haematopoietic cell transplantation (HCT) is a challenge, mainly in the unstable period immediately after the transplant. Currently there is no standardized non-invasive diagnostic tool for the evaluation of immunological complications such as graft-versus-host disease (GVHD) and for managing the cellular immune function of the transplant recipient. The ImmuKnow assay for cellular immune function monitoring has been incorporated successfully into the clinical follow-up routine of solid organ transplant recipients. This study aims to explore the relevance and potential contribution of immune monitoring using the assay in the setting of HCT. We found that ImmuKnow-level measurement can distinguish between states of immune function quiescence and between events of acute GVHD. ImmuKnow levels were significantly higher in patients going through GVHD than the levels measured for the same patients during immunological stability. Moreover, we demonstrate a patient case where longitudinal monitoring using the ImmuKnow assay provided a trustworthy depiction of the patient's cellular immune function post-HCT. In conclusion, we provide evidence for the potential contribution of the ImmuKnow assay for longitudinal individualized cellular immune function monitoring of patients following HCT. Further studies are necessary in order to establish the optimal practice for utilizing the assay for this purpose.

Creep behavior and in-depth microstructural characterization of dissimilar joints.

The 700 °C power plants currently under development will utilize Ni-base alloys such as alloy 617 for components to be operated at temperatures >650 °C. Due to economic reasons for components or parts of components which are subjected to temperatures <650 °C, 2% Cr or 9-12% Cr steels is used, depending on the required mechanical properties. This makes the dissimilar joining of Ni-base alloys and Cr steels a necessity in these plants. Experimental investigations show that these joints have to be identified as weak points with regard to damage development under creep and creep-fatigue loading. The present investigation focuses on welds between the alloy 617 and 2% Cr steel. Under creep load the fracture occurs near the fusion line between the 2% Cr steel base metal and alloy 617 weld metal. To explain the reasons for this fracture location, the microstructure of this fusion line was investigated using TEM and FIB techniques after welding and after creep loading. The TEM investigations have shown a small zone in the weld metal near the fusion line exhibiting chromium depletion and clearly reduced amounts of chromium carbides, leading to a weakening of this zone.

[Early results of gender-specific posterior stabilized total knee arthroplasty without patella resurfacing]. / Konventionelle und geschlechtsspezifische kreuzbandersetzende Knietotalendoprothesenimplantation. Vergleich frühfunktioneller Ergebnisse.

INTRODUCTION: To address anatomical gender differences in total knee arthroplasty (TKA) specific total knee prostheses have been developed for women. Potential benefits of these modified prostheses are currently under debate. The present study investigated whether the modified design features bring benefits compared to uni-sex TKA. METHODS: A total of 80 prospectively blinded and randomized patients underwent implantation of unilateral TKAs with NexGen LPS Gender Solutions (Zimmer, Warsaw, USA, group gender-specific GS prosthesis, n = 40) or NexGen LPS Flex (Zimmer, Warsaw, USA, control group standard prosthesis ST, n = 40) The follow-up was carried out 10 days and 6 weeks postoperatively. Clinical data and the subjective assessment of quality of life were evaluated using the Knee Society Clinical Rating System (KSS), the short form 36-item health survey (SF-36) and the Western Ontario and McMaster Universities OA Index (WOMAC). RESULTS: The two groups showed equal values in KSS, SF-36 and WOMAC preoperatively and ten days postoperatively the GS group reached an average KSS knee score of 62.6 ± 16.1 points (ST group 56.9 ± 14.7, p = 0.184) and a functional score of 28.5 ± 12.1 (ST group 24.3 ± 15.3, p = 0.082). In the overall score the GS group reached 91.1 ± 24.1 points (ST group 81.0 ± 27.1, p = 0.104). The GS group reached a knee score of 85.5 ± 14.4 points (ST group 77.8 ± 16.8, p = 0.03) and a functional score of 68.1 ± 20.7 points (ST group 62.3 ± 18.5, p = 0.185) 6 weeks postoperatively. In the overall score the GS group reached 153.7 ± 30.7 points (ST group 139.6 ± 32.4, p = 0.048). The analysis of SF-36 and WOMAC showed no significant differences at all time points. No evidence of loosening or migration was observed in both groups. CONCLUSIONS: Based on the data presented, gender-specific TKA type NexGen LPS Gender Solutions has advantages in terms of early functional outcome. This result is not reflected in the patient satisfaction and is not considered to be clinically relevant.

[Monteggia lesions and equivalent lesions in children]. / Monteggia-Läsionen und Monteggia-Äquivalent-Läsionen im Kindesalter.

BACKGROUND: Missed Monteggia lesions results in chronic luxation and deficits in the range of motion. The overall therapeutic goal is a quick and stable anatomical repositioning of the lesion. The prognosis of Monteggia lesions in comparison to its equivalents is better, especially with early diagnosis. OBJECTIVE: Comparison of the types of lesion, treatment modalities, hospitalization, immobilization, movement deficits, perioperative complications and outcome. MATERIAL AND METHODS: Retrospective study of 62 patients treated with acute Monteggia lesions and its equivalents during the period of 2009-2020. RESULTS: 2 patients were treated with cast immobilization only, 11 with repositioning under general anesthesia, 39 with intramedullary nailing and 10 with screw osteosynthesis. The average observation period was 4.1 months. Patients with cast immobilization needed only a short hospitalization (2 days), patients with repositioning or osteosynthesis had longer hospitalization (3.4 or 4.3 days, respectively). Deficits of the range of motion did not appear in simple cast immobilization or intramedullary nailing without reduction; however, patients with closed reduction or screw osteosynthesis showed some degree of deficits (9% and 40%, respectively). Monteggia lesions needed shorter hospitalization than their equivalents (3.7 vs. 4.5 days) and had less deficits in the range of motion (7% vs. 21%). CONCLUSION: Most patients were treated with osteosynthesis (79%). Patients with Monteggia lesions had a better outcome than patients with equivalent lesions.