Topological magnons driven by the Dzyaloshinskii-Moriya interaction in the centrosymmetric ferromagnet Mn5Ge3.

The phase of the quantum-mechanical wave function can encode a topological structure with wide-ranging physical consequences, such as anomalous transport effects and the existence of edge states robust against perturbations. While this has been exhaustively demonstrated for electrons, properties associated with the elementary quasiparticles in magnetic materials are still underexplored. Here, we show theoretically and via inelastic neutron scattering experiments that the bulk ferromagnet Mn5Ge3 hosts gapped topological Dirac magnons. Although inversion symmetry prohibits a net Dzyaloshinskii-Moriya interaction in the unit cell, it is locally allowed and is responsible for the gap opening in the magnon spectrum. This gap is predicted and experimentally verified to close by rotating the magnetization away from the c-axis with an applied magnetic field. Hence, Mn5Ge3 realizes a gapped Dirac magnon material in three dimensions. Its tunability by chemical doping or by thin film nanostructuring defines an exciting new platform to explore and design topological magnons. More generally, our experimental route to verify and control the topological character of the magnons is applicable to bulk centrosymmetric hexagonal materials, which calls for systematic investigation.

Structural insight into the cooperativity of spin crossover compounds.

Spin-crossover (SCO) compounds are promising materials for a wide variety of industrial applications. However, the fundamental understanding of their nature of transition and its effect on the physical properties are still being fervently explored; the microscopic knowledge of their transition is essential for tailoring their properties. Here an attempt is made to correlate the changes in macroscopic physical properties with microscopic structural changes in the orthorhombic and monoclinic polymorphs of the SCO compound Fe(PM-Bia)2(NCS)2 (PM = N-2'-pyridylmethylene and Bia = 4-aminobiphenyl) by employing single-crystal X-ray diffraction, magnetization and DSC measurements. The dependence of macroscopic properties on cooperativity, highlighting the role of hydrogen bonding, π-π and van der Waals interactions is discussed. Values of entropy, enthalpy and cooperativity are calculated numerically based on the Slichter-Drickamer model. The particle size dependence of the magnetic properties is probed along with the thermal exchange and the kinetic behavior of the two polymorphs based on the dependence of magnetization on temperature scan rate and a theoretical model is proposed for the calculation of the non-equilibrium spin-phase fraction. Also a scan-rate-dependent two-step behavior observed for the orthorhombic polymorph, which is absent for the monoclinic polymorph, is reported. Moreover, it is found that the radiation dose from synchrotron radiation affects the spin-crossover process and shifts the transition region to lower temperatures, implying that the spin crossover can be tuned with radiation damage.

Effective communications on invasive alien species: Identifying communication needs of Swedish domestic garden owners.

Invasive alien species threaten biodiversity with domestic gardens acting as a major pathway for the introduction of alien species. Even though the Nordic region is not currently a hotspot for biological invasions, the number of invasions in the Nordic area has been predicted to increase due to climate change. Given a time lag between introduction and invasion, many non-invasive horticultural alien species already introduced into gardens may become invasive in the future. This study aimed to identify the communication needs of Swedish garden owners regarding their management of invasive alien species. A survey among domestic garden owners, informed by topic specialists and local area experts, and interviews with garden owners were conducted in three different bio-climatic areas in a latitudinal gradient across Sweden. The questions targeted invasive alien species and their relations to biodiversity loss and climate change, as well as measures taken to control these species. Analysing the survey data collected in relation to measures taken to control invasive species, Bayesian Additive Regression Tree (BART) modelling was used to identify geographically varying communication needs of the domestic garden owners. In all study areas, the garden owners' measures taken to control invasive alien species were correlated with their strength of beliefs in having experienced local biodiversity loss. A majority of the garden owners were, moreover, uncertain about the impact of climate change on the invasiveness of alien species. In addition, the garden owners' capacity for identifying invasive alien species was often in need of improvement, in particular with respect to the species Impatiens glandulifera, Reynoutria japonica and Rosa rugosa. The results suggest that the evidence-based guidelines for effective communications we developed, have the potential to help communicators meet the local communication needs of garden owners across Sweden, in relation to the management of invasive alien garden species.

Dorsomedial prefrontal theta burst stimulation to treat anhedonia, avolition, and blunted affect in schizophrenia or depression - a randomized controlled trial.

BACKGROUND: Intermittent theta burst stimulation (iTBS) over the dorsomedial prefrontal cortex (DMPFC) has shown promise in open-label trials of depression. METHODS: In this randomized, double-blind, sham controlled trial we evaluate iTBS over the DMPFC for anhedonia, avolition, and blunted affect in patients with schizophrenia or depression. Active iTBS was delivered over the DMPFC with 1200 pulses per session, twice daily over ten weekdays at target intensity with an angled figure-of eight coil. Sham condition comprised the magnetically shielded side of the coil and simultaneous transcutaneous electrical nerve stimulation. Primary outcome was change on the Clinical Assessment Interview for Negative Symptoms (CAINS). RESULTS: Twenty-eight patients were randomized to active iTBS and 28 to sham. Mean (standard deviation) change in CAINS score from baseline to the day after last treatment was -5.3 (8.1) in active iTBS and -2.1 (7.1) in sham. A linear model showed no significant effect of treatment, accounting for baseline scores p=.088. Sub analyses per diagnostic group showed a significant effect in patients with depression, p=.038, but not in the schizophrenia group, p=.850. However, overall depressive symptoms did not change significantly in patients with depression. There were three serious adverse events, all in the sham group. LIMITATIONS: Possibly too short treatment course and few patients with schizophrenia. CONCLUSION: In this first transdiagnostic randomized controlled trial of iTBS over DMPFC for anhedonia, avolition, and blunted affect it can be concluded that it was generally tolerable and safe but only more effective than sham in the subgroup of patients with depression.

Completion of radical hysterectomy does not improve survival of patients with cervical cancer and intraoperatively detected lymph node involvement: ABRAX international retrospective cohort study.

BACKGROUND: The management of cervical cancer patients with intraoperative detection of lymph node involvement remains controversial. Since all these patients are referred for (chemo)radiation after the surgery, the key decision is whether radical hysterectomy should be completed as originally planned, taking into account an additional morbidity associated with extensive surgical dissection prior to adjuvant treatment. The ABRAX study investigated whether completing a radical uterine procedure is associated with an improved oncological outcome of such patients. PATIENTS AND METHODS: We performed retrospective analyses of 515 cervical cancer patients (51 institutions, 19 countries) who were referred for primary curative surgery between 2005 and 2015 (stage IA-IIB, common tumour types) in whom lymph node involvement was detected intraoperatively. Patients were stratified according to whether the planned uterine surgery was completed (COMPL group, N = 361) or abandoned (ABAND group, N = 154) to compare progression-free survival. Definitive chemoradiation was given to 92.9% patients in the ABAND group and adjuvant (chemo)radiation or chemotherapy to 91.4% of patients in the COMPL group. RESULTS: The risks of recurrence (hazard ratio [HR] 1.154, 95% confidence intervals [CI] 0.799-1.666, P = 0.45), pelvic recurrence (HR 0.836, 95% CI 0.458-1.523, P = 0.56), or death (HR 1.064, 95% CI 0.690-1.641, P = 0.78) were not significantly different between the two groups. No subgroup showed a survival benefit from completing radical hysterectomy. Disease-free survival reached 74% (381/515), with a median follow-up of 58 months. Prognostic factors were balanced between the two groups. FIGO stage and number of pelvic lymph nodes involved were significant prognostic factors in the whole study cohort. CONCLUSION: We showed that the completion of radical hysterectomy does not improve survival in patients with intraoperatively detected lymph node involvement, regardless of tumour size or histological type. If lymph node involvement is confirmed intraoperatively, abandoning uterine radical procedure should be considered, and the patient should be referred for definitive chemoradiation. CLINICAL TRIALS IDENTIFIER: NCT04037124.

Intermittent theta burst stimulation over the dorsomedial prefrontal cortex modulates resting-state connectivity in depressive patients: A sham-controlled study.

The mechanisms underlying repetitive transcranial magnetic stimulation (rTMS) treatment are largely unknown. Although there is a general lack of sham controlled studies, findings show altered functional connectivity to the stimulated region following treatment. When targeting the dorsolateral prefrontal cortex (dlPFC), connectivity with the subgenual anterior cingulate cortex (sgACC) is predictive of response, but less is known about the effects on functional connectivity of targeting the dorsomedial PFC (dmPFC). Here, 30 patients with an ongoing depressive episode were recruited and randomized to 20 sessions at target intensity of either active or sham intermittent theta burst stimulation (iTBS) over dmPFC. Those receiving sham were offered active treatment in a subsequent open phase. A seven minute resting-state scan and depressive symptom assessment was performed before and after treatment. After exclusions due to attrition and excessive head movements 23 patients remained for analysis. Seed-based resting-state connectivity was calculated using two seeds for the dmPFC target as well as the sgACC. A symptom related increase in dmPFC connectivity after active treatment, compared to sham treatment, was found. The effect was observed in a region overlapping the precuneus and the posterior cingulate cortex (PCC), suggesting an increase in the connectivity between the targeted salience network and the default mode network mediating improvement in depressive symptoms. Connectivity between the precuneus and both the sgACC and the treatment target was predictive of symptom improvement following active treatment. The findings have implications for understanding the mechanisms behind iTBS and may inform future efforts to individualize the treatment.

Childhood allergy is preceded by an absence of gut lactobacilli species and higher levels of atopy-related plasma chemokines.

Alterations in the composition and reduced diversity of the infant microbiome are associated with allergic disease in children. Further, an altered microbiota is linked to immune dysregulation, including skewing of different T helper (Th) subsets, which is also seen in atopic individuals. The aim of this study was, therefore, to investigate the associations between gut lactobacilli and Th-related plasma factors in allergy development during childhood. A total of 194 children with known allergy status at 1 year of age were followed to 10 years of age. We used real-time polymerase chain reaction (PCR) to investigate the presence of three lactobacilli species (Lactobacillus casei, L. paracasei, L. rhamnosus) in infant fecal samples (collected between 1 week and 2 months of age) from a subgroup of children. Plasma chemokines and cytokines were quantified at 6 months and at 1, 2, 5 and 10 years of age with Luminex or enzyme-linked immunosorbent assay (ELISA). Fractional exhaled nitrogen oxide (FeNO) was measured and spirometry performed at 10 years of age. The data were analysed by non-parametric testing and a logistic regression model adjusted for parental allergy. An absence of these lactobacilli and higher levels of the chemokines BCA-1/CXCL13, CCL17/TARC, MIP-3α/CCL20 and MDC/CCL22 in plasma at 6 months of age preceded allergy development. The presence of lactobacilli associated with lower levels of atopy-related chemokines during infancy, together with higher levels of interferon (IFN)-γ and lower FeNO during later childhood. The results indicate that the presence of certain lactobacilli species in the infant gut may influence allergy-related parameters in the peripheral immune system, and thereby contribute to allergy protection.

Immunosuppressive properties of cytochalasin B-induced membrane vesicles of mesenchymal stem cells: comparing with extracellular vesicles derived from mesenchymal stem cells.

Extracellular vesicles derived from mesenchymal stem cells (MSCs) represent a novel approach for regenerative and immunosuppressive therapy. Recently, cytochalasin B-induced microvesicles (CIMVs) were shown to be effective drug delivery mediators. However, little is known about their immunological properties. We propose that the immunophenotype and molecular composition of these vesicles could contribute to the therapeutic efficacy of CIMVs. To address this issue, CIMVs were generated from murine MSC (CIMVs-MSCs) and their cytokine content and surface marker expression determined. For the first time, we show that CIMVs-MSCs retain parental MSCs phenotype (Sca-1+, CD49e+, CD44+, CD45-). Also, CIMVs-MSCs contained a cytokine repertoire reflective of the parental MSCs, including IL-1ß, IL-2, IL-3, IL-4, IL-5, IL-6, IL-9, IL-10, IL-12(p40), IL-13, IL-17, CCL2, CCL3, CCL4, CCL5, CCL11, G-CSF, GM-CSF and TNF-α. Next, we evaluated the immune-modulating properties of CIMVs-MSCs in vivo using standard preclinical tests. MSCs and CIMVs-MSCs reduced serum levels of anti-sheep red blood cell antibody and have limited effects on neutrophil and peritoneal macrophage activity. We compared the immunomodulatory effect of MSCs, CIMVs and EVs. We observed no immunosuppression in mice pretreated with natural EVs, whereas MSCs and CIMVs-MSCs suppressed antibody production in vivo. Additionally, we have investigated the biodistribution of CIMVs-MSCs in vivo and demonstrated that CIMVs-MSCs localized in liver, lung, brain, heart, spleen and kidneys 48 h after intravenous injection and can be detected 14 days after subcutaneous and intramuscular injection. Collectively our data demonstrates immunomodulatory efficacy of CIMVs and supports their further preclinical testing as an effective therapeutic delivery modality.

Autonomic modulation networks in schizophrenia: The relationship between heart rate variability and functional and structural connectivity in the brain.

Heart rate variability (HRV), a measurement of autonomic nervous system (ANS) activity, has been found reduced in schizophrenia. The anterior cingulate cortex (ACC), which is important in regulating the ANS, is structurally and functionally affected in schizophrenia. We investigate the relationship between HRV and functional and structural connectivity of the ACC in patients with schizophrenia and healthy controls. Ten patients with a diagnosis of schizophrenia and ten healthy controls were recruited. Heart rate was monitored in a naturalistic out-of-clinic setting. Magnetic resonance imaging (MRI) was performed, including resting-state functional MRI and diffusion tensor imaging. Patients with schizophrenia had significantly lower HRV compared to controls. A positive correlation between ACC connectivity with the bilateral cerebellum and HRV was found in the patients. HRV was also positively correlated with amplitude of low frequency fluctuations (ALFF) in the cerebellum, and with axial diffusivity in the middle cerebellar peduncle, in the patients. There was a significant negative relationship between antipsychotic medication dosage, HRV and all neuroimaging measures related to HRV. We conclude that ACC connectivity seems to be affected in schizophrenia, both structurally and functionally, and that the ACC-cerebellum connectivity, as well as cerebellar function, is associated with ANS regulation in patients with schizophrenia.

New candidate genes for ST-elevation myocardial infarction.

BACKGROUND: Despite extensive research in atherosclerosis, the mechanisms of coronary atherothrombosis in ST-elevation myocardial infarction (STEMI) patients are undetermined. OBJECTIVES: Our aim was to find candidate genes involved in STEMI by analysing leucocyte gene expression in STEMI patients, without the influence of secondary inflammation from innate immunity, which was assumed to be a consequence rather than the cause of coronary atherothrombosis. METHODS: Fifty-one patients were included at coronary angiography because of STEMI. Arterial blood was sampled in the acute phase (P1), at 24-48 h (P2) and at 3 months (P3). Leucocyte RNA was isolated and gene expression analysis was performed by Affymetrix Human Transcriptome Array 2.0. By omission of up- or downregulated genes at P2, secondary changes from innate immunity were excluded. Genes differentially expressed in P1 when compared to the convalescent sample in P3 were determined as genes involved in STEMI. RESULTS: Three genes were upregulated at P1 compared to P3; ABCG1 (P = 5.81 × 10-5 ), RAB20 (P = 3.69 × 10-5 ) and TMEM2 (P = 7.75 × 10-6 ) whilst four were downregulated; ACVR1 (P = 9.01 × 10-5 ), NFATC2IP (P = 8.86 × 10-5 ), SUN1 (P = 3.87 × 10-5 ) and TTC9C (P = 7.18 × 10-6 ). These genes were also highly expressed in carotid atherosclerotic plaques. CONCLUSIONS: We found seven genes involved in STEMI. The study is unique regarding the blood sampling in the acute phase and omission of secondary expressed genes from innate immunity. However, the results need to be replicated by future studies.

Multicentre study of multidisciplinary team assessment of pancreatic cancer resectability and treatment allocation.

BACKGROUND: Multidisciplinary team (MDT) meetings have been adopted widely to ensure optimal treatment for patients with cancer. Agreements in tumour staging, resectability assessments and treatment allocation between different MDTs were assessed. METHODS: Of all patients referred to one hospital, 19 patients considered to have non-metastatic pancreatic cancer for evaluation were selected randomly for a multicentre study of MDT decisions in seven units across Northern Europe. Anonymized clinical information and radiological images were disseminated to the MDTs. All patients were reviewed by the MDTs for radiological T, N and M category, resectability assessment and treatment allocation. Each MDT was blinded to the decisions of other teams. Agreements were expressed as raw percentages and Krippendorff's α values, both with 95 per cent confidence intervals. RESULTS: A total of 132 evaluations in 19 patients were carried out by the seven MDTs (1 evaluation was excluded owing to technical problems). The level of agreement for T, N and M categories ranged from moderate to near perfect (46·8, 61·1 and 82·8 per cent respectively), but there was substantial variation in assessment of resectability; seven patients were considered to be resectable by one MDT but unresectable by another. The MDTs all agreed on either a curative or palliative strategy in less than half of the patients (9 of 19). Only fair agreement in treatment allocation was observed (Krippendorff's α 0·31, 95 per cent c.i. 0·16 to 0·45). There was a high level of agreement in treatment allocation where resectability assessments were concordant. CONCLUSION: Considerable disparities in MDT evaluations of patients with pancreatic cancer exist, including substantial variation in resectability assessments.

Interleukin 4 induces rapid mucin transport, increases mucus thickness and quality and decreases colitis and Citrobacter rodentium in contact with epithelial cells.

Citrobacter rodentium infection is a murine model for pathogenic intestinal Escherichia coli infection. C. rodentium infection causes an initial decrease in mucus layer thickness, followed by an increase during clearance. We aimed to identify the cause of these changes and to utilize this naturally occurring mucus stimulus to decrease pathogen impact and inflammation. We identified that mucin production and speed of transport from Golgi to secretory vesicles at the apical surface increased concomitantly with increased mucus thickness. Of the cytokines differentially expressed during increased mucus thickness, IFN-γ and TNF-α decreased the mucin production and transport speed, whereas IL-4, IL-13, C. rodentium and E. coli enhanced these aspects. IFN-γ and TNF-α treatment in combination with C. rodentium and pathogenic E. coli infection negatively affected mucus parameters in vitro, which was relieved by IL-4 treatment. The effect of IL-4 was more pronounced than that of IL-13, and in wild type mice, only IL-4 was present. Increased expression of Il-4, Il-4-receptor α, Stat6 and Spdef during clearance indicate that this pathway contributes to the increase in mucin production. In vivo IL-4 administration initiated 10 days after infection increased mucus thickness and quality and decreased colitis and pathogen contact with the epithelium. Thus, during clearance of infection, the concomitant increase in IL-4 protects and maintains goblet cell function against the increasing levels of TNF-α and IFN-γ. Furthermore, IL-4 affects intestinal mucus production, pathogen contact with the epithelium and colitis. IL-4 treatment may thus have therapeutic benefits for mucosal healing.

Validation of instruments for the assessment of dysphagia due to malignancy of the esophagus.

The aim of the study was to validate the Watson scale, the Ogilvie scale, and the Goldschmid scale for assessment of dysphagia due to malignancy of the esophagus. After translation of the scales to Swedish, 35 patients with dysphagia due to esophageal malignancy were asked to participate. On day 1, patients were asked to fill in the questionnaires. The patients also kept a food diary for 4 consecutive days, for assessment of actual swallowing ability. On day 10, the patients were asked to fill in the scales again, to control for individual variability. As an external control group, 29 healthy volunteers were asked to fill in the questionnaires once. External validation was done against actual swallowing ability, and against the European Organization for Research and Treatment of Cancer scales QLQ-C30 and QLQ-OG25, which are already validated quality of life scales for malignancy. Reliability in the categorical variables (Ogilvie and Goldschmid) showed weighted kappa values of 0.52 and 0.54, respectively. For the Watson scale and the Dysphagia module of QLQ-OG25, the intraclass correlation coefficients were 0.68 and 0.80, respectively. Correlations between all scales were good to excellent with values of correlation coefficients (rs) between 0.69 and 0.88, with the strongest correlations between the Ogilvie score and the dysphagia module in QLQ-OG25. These latter two scales had the strongest correlation to the food diary (rs = 0.72). Although the Ogilvie scale was superior, all the three scales showed good reliability and are thus judged to have good validity for assessment of dysphagia due to esophageal malignancy.

Spin Fluctuations Drive the Inverse Magnetocaloric Effect in Mn_{5}Si_{3}.

Inelastic neutron scattering measurements are performed on single crystals of the antiferromagnetic compound Mn_{5}Si_{3} in order to investigate the relation between the spin dynamics and the magnetothermodynamics properties. It is shown that, among the two stable antiferromagnetic phases of this compound, the high temperature one has an unusual magnetic excitation spectrum where propagative spin waves and diffuse spin fluctuations coexist. Moreover, it is evidenced that the inverse magnetocaloric effect of Mn_{5}Si_{3}, the cooling by adiabatic magnetization, is associated with field induced spin fluctuations.

Dental treatment and caries prevention preceding treatment under general anaesthesia in healthy children and adolescents: a retrospective cohort study.

AIM: This was to examine healthy children and adolescents treated under general anaesthesia (GA) and a matched control group not receiving GA to compare treatment and preventive care received prior to GA treatment. METHODS: This retrospective cohort study included 71 healthy subjects and 213 age- and gender-matched control subjects. The treatment group had been consecutively referred from the Public Dental Health Service (PDS) in Stockholm to the Department of Paediatric Dentistry, Eastman Institute, Stockholm during 2006-2007. Data was extracted from the patient records at the PDS, including variables such as number of dental visits, treatment/prophylaxis prior to GA, number of missed and cancelled appointments, and number of decayed teeth. RESULTS: On average, the treatment group had significantly more decayed teeth (p < 0.001) than the control group. Furthermore, the treatment group had significantly more restorations (p < 0.01), had visited the dentist significantly more often (p < 0.001), and had undergone significantly more behaviour management treatment and preventive treatment (p < 0.001). In the treatment group 65% of the children and adolescents, had received no behaviour management treatment and 48%, no preventive treatment. CONCLUSIONS: In the Stockholm PDS, over half of the children and adolescents referred by general dentists to paediatric specialists had no behaviour management treatment and nearly half, no preventive treatment, despite receiving significantly more operative treatment compared with matched controls. General dentists should target high caries-risk patients for additional behaviour management and preventive care to reduce the need for treatment under GA.

Recovery of Voice After Reconstruction of the Recurrent Laryngeal Nerve and Adjuvant Nimodipine.

BACKGROUND: Transection injury to the recurrent laryngeal nerve (RLN) has been associated with permanent vocal fold palsy, and treatment has been limited to voice therapy or local treatment of vocal folds. Microsurgical repair has been reported to induce a better function. The calcium channel antagonist nimodipine improves functional recovery after experimental nerve injury and also after cranial nerve injury in patients. This study aims to present voice outcome in patients who underwent repair of the RLN and received nimodipine during regeneration. METHODS: From 2002-2016, 19 patients were admitted to our center with complete unilateral injury to the RLN and underwent microsurgical repair of the RLN. After nerve repair, patients received nimodipine for 2-3 months. Laryngoscopy was performed repeatedly up to 14 months postoperatively. The Voice Handicap Index (VHI) was administered, and patients' maximum phonation time (MPT) was recorded during the follow-up. RESULTS: All patients recovered well after surgery, and nimodipine was well tolerated with no dropouts. None of the patients suffered from atrophy of the vocal fold, and some patients even showed a small ab/adduction of the vocal fold on the repaired side with laryngoscopy. During long-term follow-up (>3 years), VHI and MPT normalized, indicating a nearly complete recovery from unilateral RLN injury. CONCLUSIONS: In this cohort study, we report the results of the first 19 consecutive cases at our center subjected to reconstruction of the RLN and adjuvant nimodipine treatment. The outcome of the current strategy is encouraging and should be considered after iatrogenic RLN transection injuries.

No evidence of increased growth or mortality in fish exposed to oxazepam in semi-natural ecosystems.

An increasing number of short-term laboratory studies on fish reports behavioral effects from exposure to aquatic contaminants or raised carbon dioxide levels affecting the GABAA receptor. However, how such GABAergic behavioral modifications (GBMs) impact populations in more complex natural systems is not known. In this study, we induced GBMs in European perch (Perca fluviatilis) via exposure to a GABA agonist (oxazepam) and followed the effects on growth and survival over one summer (70days) in replicated pond ecosystems. We hypothesized that anticipated GBMs, expressed as anti-anxiety like behaviors (higher activity and boldness levels), that increase feeding rates in laboratory assays, would; i) increase growth and ii) increase mortality from predation. To test our hypotheses, 480 PIT tagged perch of known individual weights, and 12 predators (northern pike, Esox lucius) were evenly distributed in 12 ponds; six control (no oxazepam) and six spiked (15.5±4µgl-1 oxazepam [mean±1S.E.]) ponds. Contrary to our hypotheses, even though perch grew on average 16% more when exposed to oxazepam, we found no significant difference between exposed and control fish in growth (exposed: 3.9±1.2g, control: 2.9±1g [mean±1S.E.], respectively) or mortality (exposed: 26.5±1.8individuals pond-1, control: 24.5±2.6individuals pond-1, respectively). In addition, we show that reduced prey capture efficiency in exposed pike may explain the lack of significant differences in predation. Hence, our results suggest that GBMs, which in laboratory studies impact fish behavior, and subsequently also feeding rates, do not seem to generate strong effects on growth and predation-risk in more complex and resource limited natural environments.

Striatal phosphodiesterase 10A and medial prefrontal cortical thickness in patients with schizophrenia: a PET and MRI study.

The enzyme phosphodiesterase 10A (PDE10A) is abundant in striatal medium spiny neurons and has been implicated in the pathophysiology of schizophrenia in animal models and is investigated as a possible new pharmacological treatment target. A reduction of prefrontal cortical thickness is common in schizophrenia, but how this relates to PDE10A expression is unknown. Our study aim was to compare, we believe for the first time, the striatal non-displaceable binding potential (BPND) of the new validated PDE10A ligand [11C]Lu AE92686 between patients with schizophrenia and healthy controls. Furthermore, we aimed to assess the correlation of PDE10A BPND to cortical thickness. Sixteen healthy male controls and 10 male patients with schizophrenia treated with clozapine, olanzapine or quetiapine were investigated with positron emission tomography (PET) and magnetic resonance imaging (MRI). Striatal binding potential (BPND) of [11C]Lu AE92686 was acquired through dynamic PET scans and cortical thickness by structural MRI. Clinical assessments of symptoms and cognitive function were performed and the antipsychotic dosage was recorded. Patients with schizophrenia had a significantly lower BPND of [11C]Lu AE92686 in striatum (P=0.003) than healthy controls. The striatal BPND significantly correlated to cortical thickness in the medial prefrontal cortex and superior frontal gyrus across patients with schizophrenia and healthy controls. No significant correlation was observed between the BPND for [11C]Lu AE92686 in striatum and age, schizophrenia symptoms, antipsychotic dosage, coffee consumption, smoking, duration of illness or cognitive function in the patients. In conclusion, PDE10A may be important for functioning in the striato-cortical interaction and in the pathophysiology of schizophrenia.

The collagen cross-linking enzyme lysyl oxidase is associated with the healing of human atherosclerotic lesions.

BACKGROUND: Acute clinical complications of atherosclerosis such as myocardial infarction (MI) and ischaemic stroke are usually caused by thrombus formation on the ruptured plaque surface. Collagen, the main structural protein of the fibrous cap, provides mechanical strength to the atherosclerotic plaque. The integrity of the fibrous cap depends on collagen fibre cross-linking, a process controlled by the enzyme lysyl oxidase (LOX). METHODS AND RESULTS: We studied atherosclerotic plaques from human carotid endarterectomies. LOX was strongly expressed in atherosclerotic lesions and detected in the regions with ongoing fibrogenesis. Higher LOX levels were associated with a more stable phenotype of the plaque. In the studied population, LOX mRNA levels in carotid plaques predicted the risk for future MI. Within the lesion, LOX mRNA levels correlated positively with levels of osteoprotegerin (OPG) and negatively with markers of immune activation. The amount of LOX-mediated collagen cross-links in plaques correlated positively also with serum levels of OPG. CONCLUSIONS: Lysyl oxidase may contribute to the healing of atherosclerotic lesions and to the prevention of its lethal complications. Mediators of inflammation may control LOX expression in plaques and hence plaque stability.

Heme oxygenase-1 derived carbon monoxide permits maturation of myeloid cells.

Critical functions of the immune system are maintained by the ability of myeloid progenitors to differentiate and mature into macrophages. We hypothesized that the cytoprotective gas molecule carbon monoxide (CO), generated endogenously by heme oxygenases (HO), promotes differentiation of progenitors into functional macrophages. Deletion of HO-1, specifically in the myeloid lineage (Lyz-Cre:Hmox1(flfl)), attenuated the ability of myeloid progenitors to differentiate toward macrophages and decreased the expression of macrophage markers, CD14 and macrophage colony-stimulating factor receptor (MCSFR). We showed that HO-1 and CO induced CD14 expression and efficiently increased expansion and differentiation of myeloid cells into macrophages. Further, CO sensitized myeloid cells to treatment with MCSF at low doses by increasing MCSFR expression, mediated partially through a PI3K-Akt-dependent mechanism. Exposure of mice to CO in a model of marginal bone marrow transplantation significantly improved donor myeloid cell engraftment efficiency, expansion and differentiation, which corresponded to increased serum levels of GM-CSF, IL-1α and MCP-1. Collectively, we conclude that HO-1 and CO in part are critical for myeloid cell differentiation. CO may prove to be a novel therapeutic agent to improve functional recovery of bone marrow cells in patients undergoing irradiation, chemotherapy and/or bone marrow transplantation.