Visual Attention Modulates Glutamate-Glutamine Levels in Vestibular Cortex: Evidence from Magnetic Resonance Spectroscopy.

Attending to a stimulus enhances the neuronal responses to it, while responses to nonattended stimuli are not enhanced and may even be suppressed. Although the neural mechanisms of response enhancement for attended stimuli have been intensely studied, the neural mechanisms underlying attentional suppression remain largely unknown. It is uncertain whether attention acts to suppress the processing in sensory cortical areas that would otherwise process the nonattended stimulus or the subcortical input to these cortical areas. Moreover, the neurochemical mechanisms inducing a reduction or suppression of neuronal responses to nonattended stimuli are as yet unknown. Here, we investigated how attention directed toward visual processing cross-modally acts to suppress vestibular responses in the human brain. By using functional magnetic resonance spectroscopy in a group of female and male subjects, we find that attention to visual motion downregulates in a load-dependent manner the concentration of excitatory neurotransmitter (glutamate and its precursor glutamine, referred to together as Glx) within the parietoinsular vestibular cortex (PIVC), a core cortical area of the vestibular system, while leaving the concentration of inhibitory neurotransmitter (GABA) in PIVC unchanged. This makes PIVC less responsive to excitatory thalamic vestibular input, as corroborated by functional magnetic resonance imaging. Together, our results suggest that attention acts to suppress the processing of nonattended sensory cues cortically by neurochemically rendering the core cortical area of the nonattended sensory modality less responsive to excitatory thalamic input.SIGNIFICANCE STATEMENT Here, we address a fundamental problem that has eluded attention research for decades, namely, how the brain ignores irrelevant stimuli. To date, three classes of solutions to this problem have been proposed: (1) enhancement of GABAergic interneuron activity in cortex, (2) downregulation of glutamatergic cell activity in cortex; and (3) downregulation of neural activity in thalamic projection areas, which would then provide the cortex with less input. Here, we use magnetic resonance spectroscopy in humans and find support for the second hypothesis, implying that attention to one sensory modality involves the suppression of irrelevant stimuli of another sensory modality by downregulating glutamate in the cortex.

Vestibular Stimulation Modulates Neural Correlates of Own-body Mental Imagery.

There is growing evidence that vestibular information is not only involved in reflexive eye movements and the control of posture but it also plays an important role in higher order cognitive processes. Previous behavioral research has shown that concomitant vestibular stimuli influence performance in tasks that involve imagined self-rotations. These results suggest that imagined and perceived body rotations share common mechanisms. However, the nature and specificity of these effects remain largely unknown. Here, we investigated the neural mechanisms underlying this vestibulocognitive interaction. Participants (n = 20) solved an imagined self-rotation task during caloric vestibular stimulation. We found robust main effects of caloric vestibular stimulation in the core region of the vestibular network, including the rolandic operculum and insula bilaterally, and of the cognitive task in parietal and frontal regions. Interestingly, we found an interaction of stimulation and task in the left inferior parietal lobe, suggesting that this region represents the modulation of imagined body rotations by vestibular input. This result provides evidence that the inferior parietal lobe plays a crucial role in the neural integration of mental and physical body rotation.

Transfer mechanisms in semiconductor hybrids with colloidal core/shell quantum dots on ZnSe substrates.

Hybrid systems consisting of colloidal CdS/ZnS core/shell quantum dots on ZnSe semiconductor substrates have been studied by continuous-wave and nanosecond time-resolved photoluminescence. On the basis of kinetic calculations, we studied the interplay between the possible transfer processes in these hybrids. The considered transfer mechanisms were resonance energy transfer, photon reabsorption, electron and hole tunneling. Depending on the size of the CdS cores the dominating transfer mechanism is changing. Carrier tunneling was found only for quantum dots in direct contact to the substrate. For large quantum dots a hole tunneling was found, whereas in case of small dots the fast electron tunneling is decisive. Eventually, we were able to determine the conduction band offset between CdS and ZnSe to 0.56 eV at 10 K.

Effects of whole plant brown algae (Laminaria japonica) on zootechnical performance, apparent total tract digestibility, faecal characteristics and blood plasma urea in weaned piglets.

Two trials were conducted with 48 newly weaned piglets (28 d old) each 8.6 ± 0.05 kg to study how Laminaria japonica plants (LJ) affect zootechnical performance, feed conversion and the apparent total tract digestibility (ATTD) of crude nutrients. All basal diets consisted of cereals, soybean meal, skim milk powder and premixes according to recommendations (no growth promoters or enzymes). For Trial 1, piglets from 16 litters (50% male-castrated, 50% female) were assigned to three treatment groups (n = 16) in a completely randomised block design. Groups received either 2.5% supplementation with sun dried (SD) or drum dried (DD) LJ powder or 2.5% of diatomaceous earth (control). For Trial 2, piglets from 12 litters received either 5% of diatomaceous earth (control) or one of three mixtures of diatomaceous earth + DD LJ powder (3.3%+1.7%, 1.7%+3.3% or 0.0%+5%; n = 12). Data collection included zootechnical performance, faecal consistency, blood plasma urea (Trial 1 and 2) and ATTD (Trial 2). Metabolisable energy (ME) of DD LJ and diets in Trial 2 was estimated using digestible nutrients. Statistical analysis included two-way ANOVA (treatment, block) and mixed linear regression. During both trials, LJ at dosages ≥2.5% significantly reduced feed:gain ratio compared to control (p ≤ 0.0001, = 0.01 for Trial 1, Trial 2) irrespective of the drying method. ATTD from Trial 2 significantly increased digestibilities of dry matter (DM) and crude ash (CA) (p ≤ 0.01) and significantly decreased digestibilities of organic matter and crude fibre in animals fed ≥3.33% DD LJ (p = 0.01). Fractional digestibility of the DD LJ resulted in limited ME of ~9.3 ± 2.5 MJ/kg DM. Dietary conversion ratios of ME and digestible DM of DD LJ diets from Trial 2 decreased linearly with increasing algal supplementation (R2 = 0.93, 0.94 and pslope = 0.002, 0.002 for MCR, DCR). In conclusion, dried LJ powder was included up to 5% into diets without impairing zootechnical performance. The improved feed conversion in the presence of LJ was partly due to slightly higher ME within the algae diets compared to control. However, piglets receiving LJ during Trial 2 needed significantly lower dietary ME and digestible DM to maintain growth performance. Thus, LJ exerted a performance enhancing effect on weaned piglets. The precise mode-of-action is yet unclear.

Adaption of body zinc pools in weaned piglets challenged with subclinical zinc deficiency.

The effects of subclinical Zn deficiency on depletion and redistribution of body Zn were studied in weaned piglets. Forty-eight weaned piglets (German-Large-White×Land-Race×Piétrain; 50 % female, 50 % male-castrated; body weight 8·5 (sd 0·27) kg) were fed restrictively (450 g/d) a basal maize-soyabean meal-based diet supplemented with varying amounts of ZnSO4.7H2O (analysed dietary Zn: 28·1, 33·6, 38·8, 42·7, 47·5, 58·2, 67·8, 88·0 mg/kg diet) for an experimental period of 8 d. Analyses comprised Zn concentrations in soft tissues. Statistical analyses included regression models and k-means cluster analysis. Jejunum and kidney Zn correlated positively with dietary Zn (P<0·05). Other Zn pools responded in a non-linear fashion by declining (colon, epidermis, spleen) or increasing (mesenteric lymph follicles, thymus, skeletal muscle) below 63·6, 48·0, 47·5, 68·0, 43·0 and 53·1 mg Zn/kg diet, respectively (P<0·01). Above these thresholds, Zn concentrations in epidermis, mesenteric lymph follicles and skeletal muscle plateaued (P<0·0001), whereas they exhibited a decrease in colon and thymus (P<0·01) as well as a numerical increase in spleen. Clustering by dietary Zn concentration indicated clusters of varying Zn supply status and pathophysiological status. Clustering by biological matrices revealed a discrimination between storage, transport and excretion media as well as soft tissues. Taken together, novel response patterns indicated compensation reactions in tissues that are essential for the acute survival of growing animals (heart, skeletal muscle, immune tissues). Furthermore, this is to our knowledge the first study that mapped the gross Zn requirement by clustering tissue Zn concentrations between treatment groups.

Immune cells regulate VEGF signalling via release of VEGF and antagonistic soluble VEGF receptor-1.

Vascular endothelial growth factor (VEGF) is an important regulator of physiological and pathological angiogenesis. Besides malignant and stromal cells, local immune cells shape VEGF signalling in the tumour microenvironment. Aminobisphosphonates such as zoledronic acid (Zol) are drugs known to inhibit osteoclast activity and bone resorption, but also have immunomodulatory and anti-tumour effects. These properties have been linked previously to the down-regulation of VEGF and interference with tumour neo-angiogenesis. It was therefore surprising to find that treatment with Zol in combination with low-dose interleukin (IL)-2 increased serum VEGF levels in cancer patients. In this study we aimed to characterize the effect of Zol and IL-2 on VEGF signalling of blood-derived immune cells in vitro. Upon stimulation with IL-2, T cells and natural killer (NK) cells increase production of VEGF consecutively to the release of proinflammatory interferon (IFN)-γ, and Zol accelerates this response specifically in γδ T cells. VEGF can, in turn, be antagonized by soluble VEGF receptor (sVEGFR)-1, which is released depending on stimulatory conditions and the presence of monocytes. Additionally, malignant cells represented by leukaemia and lymphoma cell lines produce VEGF and some release sVEGFR-1 simultaneously. Our findings indicate a mechanism by which the VEGF and the sVEGFR-1 production by immune cells regulates local VEGF signalling. Therefore, immunotherapeutic interventions may enable both pro- as well as anti-tumour effects via immune cell-mediated alterations of VEGF homeostasis.

Short-Term Subclinical Zinc Deficiency in Weaned Piglets Affects Cardiac Redox Metabolism and Zinc Concentration.

Background: Subclinical zinc deficiency (SZD) represents the common zinc malnutrition phenotype. However, its association with oxidative stress is not well understood. The heart muscle may be a promising target for studying early changes in redox metabolism.Objective: We investigated the effects of short-term SZD on cardiac redox metabolism in weaned piglets.Methods: Forty-eight weaned German Large White × Landrace × Piétrain piglets (50% castrated males and 50% females; body weight of 8.5 kg) were fed diets with different zinc concentrations for 8 d. Measurements included cardiac parameters of antioxidative capacity, stress-associated gene expression, and tissue zinc status. Analyses comprised (linear, broken-line) regression models and Pearson correlation coefficients.Results: Glutathione and α-tocopherol concentrations as well as catalase, glutathione reductase, B-cell lymphoma 2-associated X protein, and caspase 9 gene expression plateaued in response to reduction in dietary zinc from 88.0 to 57.6, 36.0, 36.5, 41.3, 55.3, and 33.8 mg/kg, respectively (P < 0.0001). Further reduction in dietary zinc promoted a linear decrease of glutathione and α-tocopherol (30 and 0.6 nmol/mg dietary Zn, respectively; P < 0.05) and a linear increase of gene expression [0.02, 0.01, 0.003, and 0.02 Log10(2-ΔΔCt)/mg dietary Zn, respectively; P < 0.05)]. Tissue zinc declined linearly with reduction in dietary zinc (0.21 mg tissue Zn/mg dietary Zn; P = 0.004) from 88.0 to 42.7 mg/kg (P < 0.0001), below which it linearly increased inversely to further reduction in dietary zinc (0.57 mg tissue Zn/mg dietary Zn; P = 0.006). H2O2-detoxification activity and metallothionein 1A gene expression decreased linearly with reduction in dietary zinc from 88.0 to 28.1 mg/kg [0.02 mU and 0.008 Log10(2-ΔΔCt)/mg dietary Zn, respectively; P < 0.05]. Fas cell-surface death receptor, etoposide-induced 2.4 and cyclin-dependent kinase inhibitor 1A gene expression correlated positively to cardiac zinc in piglets fed ≤42.7 mg Zn/kg (r ≥ 0.97; P < 0.05).Conclusions: Short-term SZD decreased cardiac antioxidative capacity of weaned piglets while simultaneously increasing stress-associated gene expression and zinc concentration. This is the first report to our knowledge on the effects of SZD on redox metabolism.

Effects of different iron supply to pregnant sows (Sus scrofa domestica L.) on reproductive performance as well as iron status of new-born piglets.

The present study aimed to investigate the effects of different iron (Fe) supply to sows during gestation on their reproductive performance and placental Fe load. Additionally, the Fe status of the corresponding offspring was assessed. Twenty multiparous sows were fed from insemination to farrowing with isoenergetic and isonitrogenic balanced diets differing in Fe content. The diet low in Fe (Group -Fe) was mainly composed of soybean meal and maize meal and had a Fe content of 114 mg/kg DM. For the diet high in Fe (Group +Fe), the diet was supplemented with Fe(II)SO4 · 7H2O to a total Fe content of 256 mg/kg. Blood characteristics (haemoglobin, haematocrit, mean corpuscular haem concentration, total Fe-binding capacity, transferrin saturation) of all sows were measured at the beginning and at the end of gestation. Daily Fe retention was calculated at the day of farrowing. After birth, reproductive performance (litter size, piglet weight, litter weight), placental Fe content and Fe blood characteristics of the piglets were determined. Apparent daily Fe retention tended to be greater in Group +Fe (p < 0.1). Blood parameters of the sows did not show any variations between feeding groups, neither at the beginning nor at the end of pregnancy, whereas placental Fe content was lower in Group -Fe (p < 0.05). In addition, Fe supply during gestation improved litter size (p < 0.01) and litter weight (p < 0.05). Although all sows were supplied according to the current Fe recommendations, a significant decline in reproductive performance of Group -Fe was recognised. Therefore, it was concluded that the re-evaluation of the gross Fe requirements of pregnant sows is inevitable to accommodate the current feeding recommendations.

Determination of physical emulsion stabilization mechanisms of wood hemicelluloses via rheological and interfacial characterization.

Materials manufacturing industries seek efficient, economic, and sustainable compounds for stabilizing dispersed systems such as emulsions. In this study, novel, abundant biobased hydrocolloids spruce galactoglucomannans (GGM) and birch glucuronoxylans (GX) were obtained from a forestry biorefining process and characterized as versatile stabilizers of rapeseed oil-in-water emulsions. For the first time, GGM and GX isolated by pressurized hot water extraction (PHWE) of spruce and birch saw meal, respectively, were studied in emulsions. The PHWE wood hemicelluloses-polysaccharides with relatively low molar mass-facilitated the formation of emulsions with small average droplet size and efficiently prevented droplet coalescence. GGM and GX lowered the surface tension of emulsions' oil-water interface and increased the viscosity of the continuous phase. However, viscosity of the wood hemicellulose-based systems was low compared to that of commercial polymeric stabilizers. GGM-stabilized emulsions with varying oil volume fractions were characterized in terms of their rheological properties, including large amplitude oscillation shear (LAOS) measurements, and compared to emulsions prepared with a classical small-molecular surfactant, Tween20. The physical emulsion stabilization mechanisms of GGM and GX are suggested as steric repulsion assisted by Pickering-type stabilization. Wood hemicelluloses have potential as highly promising future bioproducts for versatile industrial applications involving colloidal systems and soft materials.

Subclinical zinc deficiency impairs pancreatic digestive enzyme activity and digestive capacity of weaned piglets.

This study investigated the effects of short-term subclinical Zn deficiency on exocrine pancreatic activity and changes in digestive capacity. A total of forty-eight weaned piglets were fed ad libitum a basal diet (maize and soyabean meal) with adequate Zn supply (88 mg Zn/kg diet) during a 2-week acclimatisation phase. Animals were then assigned to eight dietary treatment groups (n 6) according to a complete randomised block design considering litter, live weight and sex. All pigs were fed restrictively (450 g diet/d) the basal diet but with varying ZnSO4.7H2O additions, resulting in 28·1, 33·6, 38·8, 42·7, 47·5, 58·2, 67·8 and 88·0 mg Zn/kg diet for a total experimental period of 8 d. Pancreatic Zn concentrations and pancreatic activities of trypsin, chymotrypsin, carboxypeptidase A and B, elastase and α-amylase exhibited a broken-line response to stepwise reduction in dietary Zn by declining beneath thresholds of 39·0, 58·0, 58·0, 41·2, 47·5, 57·7 and 58·0 mg Zn/kg diet, respectively. Furthermore, carboxypeptidase B and α-amylase activities were significantly lower in samples with reduced pancreatic Zn contents. Coefficients of faecal digestibility of DM, crude protein, total lipids and crude ash responded similarly to pancreatic enzyme activities by declining below dietary thresholds of 54·7, 45·0, 46·9 and 58·2 mg Zn/kg diet, respectively. In conclusion, (1) subclinical Zn deficiency impaired pancreatic exocrine enzymes, (2) this response was connected to pancreatic Zn metabolism and (3) the decline in catalytic activity impaired faecal digestibility already after 1 week of insufficient alimentary Zn supply and very early before clinical deficiency symptoms arise.

Impact of endo- and exogenous estrogens on heart rate variability in women: a review.

Measurement of heart rate variability (HRV) is an established method to assess the activity of the autonomic nervous system. The aim of this review was to examine the link between HRV, reproductive life stages and menopausal hormone therapy. A literature review was performed using the Medline database. Based on title and abstract, 45 studies were extracted out of 261 citations screened. Due to different study designs and evaluation methods, HRV indices were not directly comparable. Qualitative comparisons in between the vast majority of studies, however, demonstrated a decrease of the vagal dominance on the heart from the follicular to the luteal cycle phase, although some studies asserted no change. The intake of oral contraceptives appeared not to alter the vagal modulation of the heart. All investigations agreed on a decline of HRV towards higher sympathetic control after menopause. Different menopausal hormone therapy approaches showed a supporting impact of estrogen on HRV in most studies. A combined therapy of estrogen and progestogens revoked this benefit. Further research is needed to demonstrate how this process might be attenuated by different menopausal hormone therapies.

Mito-FLAG with Ara-C as bolus versus continuous infusion in recurrent or refractory AML--long-term results of a prospective randomized intergroup study of the East German Study Group Hematology/Oncology (OSHO) and the Study Alliance Leukemia (SAL).

BACKGROUND: For patients with primary refractory or relapsed acute myeloid leukemia (AML), no treatment of choice has until now been defined to date. Cytarabine (Ara-C) is a key drug in the treatment of AML patients, there is still uncertainly regarding its optimal dose and infusion schedule. The aim of this study is to examine the impact of the Ara-C infusion schedule used as part of an intensive salvage regimen, in patients with relapsed or refractory AML. PATIENTS AND METHODS: A total of 252 adult patients (median age 59 years) with relapsed or refractory AML were randomly allocated to receive either Mito-FLAG with Ara-C as bolus (B) (1000 mg/m(2) over 1 h, every 12 h, days 1-5), or continuous infusion (CI) (150 mg/m(2) over 24 h, days 1-5) in combination with mitoxantrone, fludarabine, and granulocyte colony-stimulating factor (G-CSF). Autologous or allogeneic hematopoietic stem-cell transplantation was offered as consolidation therapy. Primary end point was the rate of complete remissions (CRs) after the first cycle of Mito-FLAG. RESULTS: The CR rates after Mito-FLAG (B) and Mito-FLAG (CI) were 54% and 43%, respectively (P = 0.1). There was no statistical difference between rates of grade 3/4 neutropenia, thrombocytopenia, mucositis, renal, and liver toxicity. More infections occurred, however, after Mito-FLAG (B) compared with Mito-FLAG (CI) (80% versus 69%, P = 0.01). The early death rate by day 42 was 13% in both arms. Median disease-free survival was comparable in the two arms (7.8 versus 7.1 months, P = 0.53) as was overall survival (7.1 versus 6.6 months, P = 0.53). CONCLUSION: A 5-day course of Ara-C 2 × 1000 mg/m(2) administered as bolus versus Ara-C 150 mg/m(2) administered by CI (in combination with mitoxantrone, fludarabine, and G-CSF), resulted in a nonsignificant trend in response rates in favor of Mito-FLAG (B) at the selected dose levels, but no differences in the survival outcome in relapsed or refractory AML. CLINICAL TRIAL NUMBER: LN_NN_2004_39/EudraCT number 2014-000083-18.

Biannual otolith-zone formation of young shallow-water hake Merluccius capensis in the northern Benguela: age verification using otoliths sampled by a top predator.

Otoliths collected at least monthly from scat samples of Cape fur seals Arctocephalus pusillus are used to show that shallow-water hake Merluccius capensis from the northern Benguela develop three translucent zones in their first 1·5 years of life. The novel sampling approach provided otoliths that belonged to four M. capensis cohorts of approximate known age (hatched in 1996, 1998, 2002 and 2005), allowing age verification. Following spawning in austral winter, translucent zones consistently formed first in summer and autumn (T1), then in winter and spring (T2) and again in summer and autumn (T3), with no difference in appearance of the zones (biannuli) for the four cohorts considered. The second translucent zone is usually the first true annulus (year mark). It forms during July to September in fish of 15-20 cm total length (LT ). Formation of the translucent zones appears to be determined by fish length or age, rather than by exogenous cues. It is suggested that length measurements should be used to help determine the first age group; fish with a translucent zone marked at otolith lengths >7·5 mm should be termed 1 year-old fish. Ages of M. capensis used in previous stock assessment models have been overestimated. Biannuli are an unusual occurrence in fish otoliths in general, but have been observed in other Merluccius species.

ENCCA WP17-WP7 consensus paper on teenagers and young adults (TYA) with bone sarcomas.

Teenagers and young adults (TYA) cancer contributes substantially to morbidity and mortality in a population with much to offer society. TYA place distinct challenges upon cancer care services, many reporting feeling marginalized and their needs not being met in adult or paediatric cancer services. Bone tumours such as osteosarcoma and Ewing sarcoma, because of their age at presentation and the complexity of their care, are where challenges in managing (TYA) with cancer have often been most readily apparent. Bone sarcomas may be managed by paediatric or medical oncologists, and require fastidious attention to protocol. A lack of recent improvement in survival in TYA with bone tumours may be linked to a lack of specialist care, poor concordance with therapy in some situations and TYA-specific pharmacology. Participation in clinical trials, particularly of young adults, is low, hindering progress. All these requirements may be best met by a concerted effort to create collaborative care between adult and paediatric experts in bone sarcoma, working together to meet TYA patients' needs.

Shear-modulus investigations of monohydroxy alcohols: evidence for a short-chain-polymer rheological response.

Liquids composed of small-molecule monohydroxy alcohols are demonstrated to display rheological behavior typical for oligomeric chains. This observation was made possible by rheological experiments in which more than seven decades in frequency and more than five decades on the mechanical modulus scale are covered. The singly hydrogen-bonded monohydroxy alcohols were chosen because they display significant, but surprisingly poorly understood effects of intermolecular association. Based on the present shear study, one can apply theoretical concepts of polymer science to understand the anomalous physical behavior of a wide range of hydrogen-bonded liquids.

Associations of fatty liver disease and other factors affecting serum SHBG concentrations: a population based study on 1657 subjects.

Sex hormone binding globulin (SHBG) is a glycoprotein expressed predominantly in the hepatocytes. It regulates the transport of sex steroid hormones in the blood stream to their target tissues. The expression of the SHBG gene is subject to multifactorial regulation including hormonal, metabolic, and nutritional aspects. Against this background, we investigated the effect of fatty liver and metabolic syndrome, together with other parameters, on serum SHBG concentrations in a population-based cohort in Germany. This cross-sectional study included 870 women and 787 men (average age 42.3±12.8 years), who underwent ultrasound screening for fatty liver in addition to providing a complete medical history and undergoing physical and laboratory examination. Fatty liver was diagnosed on ultrasound criteria in 159 women (18.3%) and 287 men (36.5%). Fatty liver was shown to exert a significant influence on serum SHBG concentrations in men and in premenopausal women. Men with grade 1 fatty liver had a 1.96-fold increased risk (95%-confidence interval=1.28-3.02; p=0.0022) and postmenopausal women with grade 1 fatty liver a 2.4-fold risk (95%-confidence interval=1.11-5.27; p=0.0267) for low SHBG concentrations. Among metabolic parameters, HDL-C represented as affecting factor in men (p=0.0058) and premenopausal women (p=0.0002), while cholesterol only showed an association in premenopausal women (p=0.0439) and triglyceride in postmenopausal women (p=0.0436). No association of concentrations of SHBG and metabolic syndrome was observed. Age, BMI and waist-to-hip ratio also influence the SHBG concentration. Based on these findings, we conclude that fat accumulation in the liver influences SHBG concentrations in men and premenopausal women.

Inflammation and atrial remodeling after a mountain marathon.

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

Alleviating the burden of depression: a simulation study on the impact of mental health services.

AIMS: Depressive disorders are ranked as the single leading cause of disability worldwide. Despite immense efforts, there is no evidence of a global reduction in the disease burden in recent decades. The aim of the study was to determine the public health impact of the current service system (status quo), to quantify its effects on the depression-related disease burden and to identify the most promising strategies for improving healthcare for depression on the population level. METHODS: A Markov model was developed to quantify the impact of current services for depression (including prevention, treatment and aftercare interventions) on the total disease burden and to investigate the potential of alternative scenarios (e.g., improved reach or improved treatment effectiveness). Parameter settings were derived from epidemiological information and treatment data from the literature. Based on the model parameters, 10,000,000 individual lives were simulated for each of the models, based on monthly transition rates between dichotomous health states (healthy vs. diseased). Outcome (depression-related disease burden) was operationalized as the proportion of months spent in depression. RESULTS: The current healthcare system alleviates about 9.5% (95% confidence interval [CI]: 9.2%-9.7%) of the total disease burden related to depression. Chronic cases cause the majority (83.2%) of depression-related burden. From a public health perspective, improving the reach of services holds the largest potential: Maximum dissemination of prevention (26.9%; CI: 26.7%-27.1%) and treatment (26.5%; CI: 26.3%-26.7%) would result in significant improvements on the population level. CONCLUSIONS: The results confirm an urgent need for action in healthcare for depression. Extending the reach of services is not only more promising but also probably more achievable than increasing their effectiveness. Currently, the system fails to address the prevention and treatment of chronic cases. The large proportion of the disease burden associated with chronic courses highlights the need for improved treatment policies and clinical strategies for this group (e.g., disease management and adaptive or personalized interventions). The model complements the existing literature by providing a new perspective on the depression-related disease burden and the complex interactions between healthcare services and the lifetime course.

Stratification of Patients with Renal Cell Carcinoma by the Abundance of Sarcomatoid Features Reveals Differences in Survival and the Underlying Pathobiology.

Sarcomatoid renal cell carcinoma (sRCC) is histologically heterogeneous, with variable sarcomatoid amounts intermixed within epithelial carcinoma. However, the current classification for this aggressive disease is homogeneous and agnostic to the sarcomatoid proportion. We investigated whether sRCC subclassification has prognostic value and can reveal the biology underlying dedifferentiation and its clinical aggressiveness. On the basis of the intratumoral abundance of sarcomatoid features, cases were classified as sarcomatoid-high (≥10% sarcomatoid features) or sarcomatoid-low (<10% sarcomatoid features) in a cohort of 104 consecutive patients with sRCC undergoing nephrectomy at a single center. In comparison to sarcomatoid-low patients (n = 52), sarcomatoid-high patients (n = 52) had significantly shorter overall survival (median 14.5 vs 62.9 mo; p < 0.001), which was confirmed on multivariable analysis, and significantly shorter median metastasis-free survival among patients with clinically localized disease (10.7 vs 39.0 mo; p = 0.043). Transcriptomic analyses of 45 sRCC tumors revealed significant upregulation of nine hallmark pathways related to cell cycle/proliferation, epithelial-to-mesenchymal transition, reactive oxidative species, and interferon-α signaling among sarcomatoid-high (n = 24) versus sarcomatoid-low (n = 21) tumors. Categorization into transcriptomic clusters revealed predominance of proliferative, inflammatory, and immune effector phenotypes among sarcomatoid-high tumors, versus a hypoxia/angiogenesis phenotype among sarcomatoid-low tumors. Overall, these findings indicate prognostic value for sRCC subclassification into high versus low sarcomatoid groups and highlight key biology underlying the differences in clinical outcomes. PATIENT SUMMARY: Sarcomatoid renal cell carcinoma (sRCC) is a highly aggressive form of kidney cancer. The percentage of sarcomatoid features varies among tumors, but sRCC is still defined as a single kidney cancer type. Our results show that grouping patients according to their percentage of sarcomatoid features improves prediction of whether their tumors will become metastatic or lethal, and reveal molecular differences that may be important for this disease. Future assignment of sRCC to high and low sarcomatoid groups may help in guiding research and patient management.

Osteosarcoma of the mobile spine.

BACKGROUND: The aims of this analysis were to investigate features and outcome of high-grade osteosarcomas of the mobile spine. PATIENTS AND METHODS: Since 1977, 20 Cooperative Osteosarcoma Study Group patients had a diagnosis of high-grade osteosarcomas of the mobile spine and were included in this retrospective analysis of patient-, tumor- and treatment-related variables and outcome. RESULTS: The median age was 29 years (range 5-58). Most frequent tumor sites were thoracic and lumbar spine. All but three patients had nonmetastatic disease at diagnosis. Treatment included surgery and chemotherapy for all patients, 13 were also irradiated. Eight patients failed to achieve a macroscopically complete surgical remission (five local, one primary metastases, two both), six died, two are alive, both with radiotherapy. Of 12 patients with complete remission at all sites, three had a recurrence (two local, one metastases) and died. The median follow-up of the 11 survivors was 8.7 years (range 3.1-22.3), 5-year overall and event-free survival rates were 60% and 43%. Age <40 years, nonmetastatic disease at diagnosis and complete remission predicted for better overall survival (OS, P < 0.05). CONCLUSIONS: Osteosarcomas of the mobile spine are rare. With complete resection (and potentially radiotherapy) and chemotherapy, prognosis may be comparable with that of appendicular osteosarcomas.