Adipo-glial signaling mediates metabolic adaptation in peripheral nerve regeneration.

The peripheral nervous system harbors a remarkable potential to regenerate after acute nerve trauma. Full functional recovery, however, is rare and critically depends on peripheral nerve Schwann cells that orchestrate breakdown and resynthesis of myelin and, at the same time, support axonal regrowth. How Schwann cells meet the high metabolic demand required for nerve repair remains poorly understood. We here report that nerve injury induces adipocyte to glial signaling and identify the adipokine leptin as an upstream regulator of glial metabolic adaptation in regeneration. Signal integration by leptin receptors in Schwann cells ensures efficient peripheral nerve repair by adjusting injury-specific catabolic processes in regenerating nerves, including myelin autophagy and mitochondrial respiration. Our findings propose a model according to which acute nerve injury triggers a therapeutically targetable intercellular crosstalk that modulates glial metabolism to provide sufficient energy for successful nerve repair.

Cancer Control, Toxicity, and Secondary Malignancy Risks of Proton Radiation Therapy for Stage I-IIB Testicular Seminoma.

Purpose: This study's objective was to report cancer control and toxicity outcomes after proton radiation therapy (RT) in testicular seminoma and to compare secondary malignancy (SMN) risks with photon-based treatment alternatives. Methods and Materials: Consecutive patients with stage I-IIB testicular seminoma treated with proton RT at a single institution were retrospectively analyzed. Kaplan-Meier estimates for disease-free and overall survival were computed. Toxicities were scored using Common Terminology Criteria for Adverse Events version 5.0. Photon comparison plans, including 3-dimensional conformal RT (3D-CRT) and intensity modulated RT (IMRT)/volumetric arc therapy (VMAT), were created for each patient. Dosimetric parameters and SMN risk predictions for different in-field organs-at-risk were compared between the techniques. Excess absolute SMN risks were estimated with organ equivalent dose modeling. Results: Twenty-four patients were included (median age, 38.5 years). The majority of patients had stage II disease (IIA, 12 [50.0%]; IIB, 11 [45.8%]; IA, 1 [4.2%]). Seven (29.2%) and 17 (70.8%) patients had de novo and recurrent disease, respectively (de novo/recurrent: IA, 1/0; IIA, 4/8; IIB, 2/9). Most acute toxicities were mild (grade 1 [G1], 79.2%; G2, 12.5%) with G1 nausea being most common (70.8%). No serious events (G3-5) occurred. With a median follow-up time of 3 years (interquartile range, 2.1-3.6 years), 3-year disease-free and overall survival rates were 90.9% (95% confidence interval, 68.1%-97.6%) and 100% (95% confidence interval, 100%-100%), respectively. There were no documented late toxicities in the follow-up period, including worsening serial creatinine levels suggestive of early nephrotoxicity. Proton RT had significant reductions in mean organ-at-risk doses to the kidneys, stomach, colon, liver, bladder, and body compared with both 3D-CRT and IMRT/VMAT. Proton RT had significantly lower SMN risk predictions compared with 3D-CRT and IMRT/VMAT. Conclusions: Cancer control and toxicity outcomes using proton RT in stage I-IIB testicular seminoma are consistent with existing photon-based RT literature. However, proton RT may be associated with significantly lower SMN risks.

Importance of Antixenosis and Antibiosis Resistance to the Cabbage Whitefly (Aleyrodes proletella) in Brussels Sprout Cultivars.

The cabbage whitefly Aleyrodes proletella (L.) (Hemiptera: Aleyrodidae) is an important pest of a wide range of vegetable Brassicas. Since the control of this pest is still challenging, new approaches such as the use of resistant cultivars are required. For this, we screened 16 commercialised Brussels sprout cultivars for resistance against this species. Antibiosis was tested with no-choice experiments in a climate chamber, using reproduction, mortality, longevity, developmental time and weight as parameters. Antixenosis was screened in three choice experiments with circular design in a greenhouse to detect cultivar preferences. A field trial with both antibiosis and antixenosis tests was done to verify results under natural conditions. Finally, for several cultivars, also the leaf glucosinolate concentrations were analysed. Cabbage whiteflies showed on certain cultivars significantly increased mortality, prolonged developmental times and reduced weights. Besides, some cultivars were significantly less infested. However, the incidence of antibiosis and antixenosis as well as the glucosinolate patterns were partly inconsistent. Although a number of moderately resistant cultivars could be identified, the detected resistance is certainly not strong and consistent enough as an exclusive measure of a plant protection strategy but might become a component of a multi-layered strategy against cabbage whiteflies.

Aqua-chlorido-(2-{[6-(di-methyl-amino)-pyrimidin-4-yl]sulfan-yl}pyrimidine-4,6-di-amine)-copper(II) chloride hydrate.

A copper(II) complex of the non-symmetric bidentate ligand 2-{[6-(di-methyl-amino)-pyrimidin-4-yl]sulfan-yl}pyrimidine-4,6-di-amine (L1) is reported. The single-crystal X-ray structure of aqua-[aqua/chlorido-(0.49/0.51)](2-{[6-(di-methyl-amino)-pyrimidin-4-yl]sulfan-yl}pyrimidine-4,6-di-amine)-copper(II) 0.49-chloride 1.51-hydrate, [CuCl1.51(C10H13N7S)(H2O)1.49]Cl0.49·1.51H2O or [(L1)Cl1.51(H2O)1.49Cu]0.49Cl·1.51H2O, exhibits distorted square-pyramidal geometry around the metal centre, with disorder in the axial position, occupied by chloride or water. The six-membered metal-chelate ring is in a boat conformation, and short inter-molecular S⋯S inter-actions are observed. In addition to its capacity for bidentate metal coordination, the ligand has the ability to engage in further supra-molecular inter-actions as both a hydrogen-bond donor and acceptor, and multiple inter-actions with lattice solvent water mol-ecules are present in the reported structure.

Successful Treatment of Fibrosing Organising Pneumonia Causing Respiratory Failure with Mycophenolic Acid.

Organising pneumonia (OP) is usually promptly responsive to corticosteroid treatment. We describe a series of 3 cases of severe, progressive, biopsy-proven fibrosing OP causing respiratory failure. All cases presented with peribronchial and subpleural consolidations, had a fibro-inflammatory infiltrative component in the alveolar septa, and only had a partial and unsatisfactory response to corticosteroids. However, they responded to mycophenolic acid (MPA) treatment with resolution of respiratory failure as well as clinical and functional improvement. MPA as an additional treatment option for aggressive forms of fibrosing OP and interstitial lung disease needs to be further explored.

Quantification of Various Inflammatory Cells in Advanced Atherosclerotic Plaques.

INTRODUCTION: Atherosclerosis, the pathological basis of coronary artery disease is being extensively studied as understanding of the complex processes involved in the formation and progression that can provide an insight into prevention and treatment of the same. This is an autopsy study to identify and quantify various inflammatory cells in advanced atherosclerotic plaques. AIM: This study aims at identifying and categorizing the various inflammatory cells present in advanced atherosclerotic plaques, noting their distribution in the plaque, quantifying them using histomorphometry and comparing them across plaques of different AHA types. MATERIALS AND METHODS: Post-mortem angiogram was performed on 3 heart specimens obtained at autopsy of random Road Traffic Accident (RTA) cases which revealed evidence of coronary artery disease. End-arterectomy was done and the arteries with atherosclerotic plaques were cut into serial sections and made into tissue blocks. Sections from these blocks were stained with H & E stain and the plaques were classified based on AHA classification. 50 advanced atherosclerotic plaques of AHA Type IV and V were chosen for this study and were screened for inflammatory cells, first with H & E stain and then with different immunohistochemical stains for T-lymphocytes, B-lymphocytes and neutrophils. The T-lymphocytes thus identified was further sub-typed into CD4+ and CD8+ cells again using IHC markers and the percentage area of each was measured using histomorphometry. Then, these values were compared between AHA Type IV and AHA Type V lesions. RESULTS: It was found that the inflammatory cells found in advanced atherosclerotic plaques were predominantly T-lymphocytes as evidenced by their CD3 positivity and they were found to be distributed mainly around the shoulder region and fibrous cap of the plaque. When categorized further, it was found that CD8+ T-cells were always more than CD4+ T-cells in advanced lesions. Meloperoxidase stain for neutrophils was negative in all the plaques examined. The difference in the amount of inflammatory cells between AHA type IV and Type V was not statistically significant. CONCLUSION: The study of the amount of inflammatory cells in atherosclerotic plaques and understanding their role in the pathophysiology of advanced plaques may have therapeutic implications.

Early Palliative Care-Health services research and implementation of sustainable changes: the study protocol of the EVI project.

BACKGROUND: International medical organizations such as the American Society of Medical Oncology recommend early palliative care as the "gold standard" for palliative care in patients with advanced cancer. Nevertheless, even in Comprehensive Cancer Centers, early palliative care is not yet routine practice. The main goal of the EVI project is to evaluate whether early palliative care can be implemented-in the sense of "putting evidence into practice"-into the everyday clinical practice of Comprehensive Cancer Centers. In addition, we are interested in (1) describing the type of support that patients would like from palliative care, (2) gaining information about the effect of palliative care on patients' quality of life, and (3) understanding the economic burden of palliative care on patients and their families. METHODS/DESIGN: The EVI project is a multi-center, prospective cohort study with a sequential control group design. The study is a project of the Palliative Care Center of Excellence (KOMPACT) in Baden-Württemberg, Germany, which was recently established to combine the expertise of five academic, specialist palliative care departments. The study is divided into two phases: preliminary phase (months 1-9) and main study phase (months 10-18). In each of all five participating academic Comprehensive Cancer Centers, an experienced palliative care physician will be hired for 18 months. During the preliminary phase, the physician will be allowed time to establish the necessary structures for early palliative care within the Comprehensive Cancer Center. In the main study phase, patients with metastatic cancer will be offered a consultation with the palliative care physician within eight weeks of diagnosis. After the initial consultation, follow-up consultations will be offered as needed. The study is built upon a convergent parallel design. In the quantitative arm, patients will be surveyed in both the preliminary and main study phase at three points in time (baseline, 12 weeks, 24 weeks). Standardized questionnaires will be used to measure patients' quality of life, symptom burden and mood. Using interviews with palliative care physicians, oncologists, department heads, patients and their caregivers, the qualitative arm will explore (1) what factors encourage and hinder the early integration of palliative care into standard oncology care, (2) what support patients and their caregivers would like from palliative care, and (3) what effect palliative care has on the economic disease burden of patients and their families. DISCUSSION: The study proposed is meant to serve as a catalyzer. Local palliative care teams should be put in position to routinely cooperate with the primary treating department at their respective cancer center. The long-term goal of this project is to create sustainable improvements in the care of patients with incurable cancer. TRIAL REGISTRATION: DRKS00006162 ; date of registration: 19/05/2014.

Age-dependent astroglial vulnerability to hypoxia and glutamate: the role for erythropoietin.

Extracellular accumulation of toxic concentrations of glutamate (Glu) is a hallmark of many neurodegenerative diseases, often accompanied by hypoxia and impaired metabolism of this neuromediator. To address the question whether the multifunctional neuroprotective action of erythropoietin (EPO) extends to the regulation of extracellular Glu-level and is age-related, young and culture-aged rat astroglial primary cells (APC) were simultaneously treated with 1mM Glu and/or human recombinant EPO under normoxic and hypoxic conditions (NC and HC). EPO increased the Glu uptake by astrocytes under both NC and especially upon HC in culture-aged APC (by 60%). Moreover, treatment with EPO up-regulated the activity of glutamine synthetase (GS), the expression of glutamate-aspartate transporter (GLAST) and the level of EPO mRNA. EPO alleviated the Glu- and hypoxia-induced LDH release from astrocytes. These protective EPO effects were concentration-dependent and they were strongly intensified with age in culture. More than a 4-fold increase in apoptosis and a 2-fold decrease in GS enzyme activity was observed in APC transfected with EPO receptor (EPOR)-siRNA. Our in vivo data show decreased expression of EPO and a strong increase of EPOR in brain homogenates of APP/PS1 mice and their wild type controls during aging. Comparison of APP/PS1 and age-matched WT control mice revealed a stronger expression of EPOR but a weaker one of EPO in the Alzheimer's disease (AD) model mice. Here we show for the first time the direct correlation between the extent of differentiation (age) of astrocytes and the efficacy of EPO in balancing extracellular glutamate clearance and metabolism in an in-vitro model of hypoxia and Glu-induced astroglial injury. The clinical relevance of EPO and EPOR as markers of brain cells vulnerability during aging and neurodegeneration is evidenced by remarkable changes in their expression levels in a transgenic model of AD and their WT controls.

Systematic review of studies comparing 24-hour and spot urine collections for estimating population salt intake / Revisión sistemática de estudios comparativos entre recolección de muestras de orina de 24 horas y puntual para calcular el consumo de sal en la población

Objective. To examine the usefulness of urine sodium (Na) excretion in spot or timed urine samples to estimate population dietary Na intake relative to the gold standard of 24-hour (h) urinary Na. Methods. An electronic literature search was conducted of MEDLINE (from 1950) and EMBASE (from 1980) as well as the Cochrane Library using the terms “sodium,” “salt,” and “urine.” Full publications of studies that examined 30 or more healthy human subjects with both urinary Na excretion in 24-h urine and one alternative method (spot, overnight, timed) were examined. Results. The review included 1 380 130 participants in 20 studies. The main statistical method for comparing 24-h urine collections with alternative methods was the use of a correlation coefficient. Spot, timed, and overnight urine samples were subject to greater intraindividual and interindividual variability than 24-h urine collections. There was a wide range of correlation coefficients between 24-h urine Na and other methods. Some values were high, suggesting usefulness (up to r = 0.94), while some were low (down to r = 0.17), suggesting a lack of usefulness. The best alternative to collecting 24-h urine (overnight, timed, or spot) was not clear, nor was the biological basis for the variability between 24-h and alternative methods. Conclusions. There is great interest in replacing 24-h urine Na with easier methods to assess dietary Na. However, whether alternative methods are reliable remains uncertain. More research, including the use of an appropriate study design and statistical testing, is required to determine the usefulness of alternative methods.

Objetivo. Analizar la utilidad de la medicion de la excrecion urinaria de sodio a partir de la recoleccion puntual o cronometrada de muestras de orina para calcular la ingesta de sodio alimentario en la poblacion, en relacion con la prueba de referencia que mide la excrecion de sodio en orina de 24 horas. Métodos. Se realizo una busqueda de bibliografia electronica en MEDLINE (desde 1950) y EMBASE (desde 1980), asi como en la Biblioteca Cochrane, empleando los terminos “sodium”, “salt” y “urine” (sodio, sal y orina). Se examinaron las publicaciones completas de los estudios que incluian 30 o mas sujetos humanos sanos en los que se hubiera determinado la excrecion de sodio mediante la recoleccion de orina de 24 horas o un metodo alternativo (recoleccion puntual, de toda la noche, cronometrada). Resultados. La revision incluyo a 1 380 130 participantes de 20 estudios. El principal metodo estadistico adoptado para comparar las recolecciones de orina de 24 horas con los metodos alternativos fue el uso de un coeficiente de correlacion (r). Las muestras de orina recolectadas de forma puntual, cronometrada y de toda la noche estaban sujetas a mayor variabilidad intra e interindividual que las recolecciones de orina de 24 horas. Se obtuvo una amplia gama de coeficientes de correlacion entre las determinaciones de sodio en orina de 24 horas y mediante los otros metodos. Algunos valores fueron elevados, lo que indica su utilidad (r de hasta 0,94), mientras que otros fueron bajos (r por debajo de 0,17), lo que indica su falta de utilidad. La mejor alternativa a la obtencion de orina de 24 horas (de toda la noche, cronometrada, o puntual) no resulto evidente, ni tampoco la base biologica de la variabilidad entre el metodo de 24 horas y los alternativos. Conclusiones. Hay mucho interes en remplazar la determinacion de sodio en orina de 24 horas por otros metodos mas faciles de evaluacion del sodio alimentario. Sin embargo, sigue habiendo incertidumbre sobre la fiabilidad de los metodos alternativos. Es preciso ampliar la investigacion, incluido el uso de un diseno de estudio y pruebas estadisticas apropiados, para determinar la utilidad de los metodos alternativos.

Systematic review of studies comparing 24-hour and spot urine collections for estimating population salt intake.

OBJECTIVE: To examine the usefulness of urine sodium (Na) excretion in spot or timed urine samples to estimate population dietary Na intake relative to the gold standard of 24-hour (h) urinary Na. METHODS: An electronic literature search was conducted of MEDLINE (from 1950) and EMBASE (from 1980) as well as the Cochrane Library using the terms "sodium," "salt," and "urine." Full publications of studies that examined 30 or more healthy human subjects with both urinary Na excretion in 24-h urine and one alternative method (spot, overnight, timed) were examined. RESULTS: The review included 1 380 130 participants in 20 studies. The main statistical method for comparing 24-h urine collections with alternative methods was the use of a correlation coefficient. Spot, timed, and overnight urine samples were subject to greater intra-individual and interindividual variability than 24-h urine collections. There was a wide range of correlation coefficients between 24-h urine Na and other methods. Some values were high, suggesting usefulness (up to r = 0.94), while some were low (down to r = 0.17), suggesting a lack of usefulness. The best alternative to collecting 24-h urine (overnight, timed, or spot) was not clear, nor was the biological basis for the variability between 24-h and alternative methods. CONCLUSIONS: There is great interest in replacing 24-h urine Na with easier methods to assess dietary Na. However, whether alternative methods are reliable remains uncertain. More research, including the use of an appropriate study design and statistical testing, is required to determine the usefulness of alternative methods.