Ataxia due to vertebral hemangiosarcoma with evidence of disseminated disease in a 20-year old Swiss Warmblood mare

A 20-year old Swiss Warmblood mare was referred to the Swiss Institute of Equine Medicine with a history of poor performance, coughing and ataxia and hindlimb weakness which progressed to recumbency. Lung auscultation revealed pronounced wheezing, blood work showed signs of chronic inflammation and increased bone turnover and thoracic ultrasound indicated patchy pulmonary consolidation. Cerebrospinal fluid revealed only mild, unspecific changes allowing exclusion of meningoencephalomyelitis and clinically relevant bleeding. Despite medical treatment and support in a sling the mare did not improve and was euthanized. Necropsy revealed a poorly demarcated, non-encapsulated and invasively growing mass dorsally in the musculature at the level of the forth cervical vertebra (C4) infiltrating the vertebral body and the spinal canal at the level of C1–C2. Multiple nodular, firm masses were present in all lobes of the lung and appeared to be mainly located in vessels. Histologically the masses were composed of spindle cells with marked anisocytosis, anisocaryosis, a high mitotic activity and showed invasive growth. These neoplastic cells stained positive for CD31, an endothelial cell marker, which confirmed diagnosis of a hemangiosarcoma. Definite ante mortem diagnosis of hemangiosarcoma, which is rare in horses, is challenging. Besides the vertebral localization, disseminated, locally invasive and cutaneous forms of hemangiosarcoma exist and can be either acquired or congenital. Prognosis for equine hemangiosarcoma and response to treatment are usually poor and progression of clinical signs is rapid. Vertebral hemangiosarcoma is an uncommon cause of spinal ataxia in horses.

Evidence for distinct modes of solar activity

The Sun shows strong variability in its magnetic activity, from Grand minima to Grand maxima, but the nature of the variability is not fully understood, mostly because of the insufficient length of the directly observed solar activity records and of uncertainties related to long-term reconstructions. Here we present a new adjustment-free reconstruction of solar activity over three millennia and study its different modes. Methods. We present a new adjustment-free, physical reconstruction of solar activity over the past three millennia, using the latest verified carbon cycle, 14C production, and archeomagnetic field models. This great improvement allowed us to study different modes of solar activity at an unprecedented level of details. Results. The distribution of solar activity is clearly bi-modal, implying the existence of distinct modes of activity. The main regular activity mode corresponds to moderate activity that varies in a relatively narrow band between sunspot numbers 20 and 67. The existence of a separate Grand minimum mode with reduced solar activity, which cannot be explained by random fluctuations of the regular mode, is confirmed at a high confidence level. The possible existence of a separate Grand maximum mode is also suggested, but the statistics is too low to reach a confident conclusion. Conclusions. The Sun is shown to operate in distinct modes – a main general mode, a Grand minimum mode corresponding to an inactive Sun, and a possible Grand maximum mode corresponding to an unusually active Sun. These results provide important constraints for both dynamo models of Sun-like stars and investigations of possible solar influence on Earth’s climate.

Role of adenosine signaling in penile erection and erectile disorders.

INTRODUCTION: Penile erection is a hemodynamic process, which results from increased flow and retention of blood in the penile organ due to the relaxation of smooth muscle cells. Adenosine, a physiological vasorelaxant, has been shown to be a modulator of penile erection. AIM: To summarize the research on the role of adenosine signaling in normal penile erection and erectile disorders. MAIN OUTCOME MEASURES: Evidence in the literature on the association between adenosine signaling and normal and abnormal penile erection, i.e., erectile dysfunction (ED) and priapism. METHODS: The article reviews the literature on the role of endogenous and exogenous adenosine in normal penile erection, as well as in erectile disorders namely, ED and priapism. RESULTS: Adenosine has been shown to relax corpus cavernosum from various species including human in both in vivo and in vitro studies. Neuromodulatory role of adenosine in corpus cavernosum has also been demonstrated. Impaired adenosine signaling through A(2B) receptor causes partial resistance of corpus cavernosum, from men with organic ED, to adenosine-mediated relaxation. Increased level of adenosine has been shown to be a causative factor for priapism. CONCLUSION: Overall, the research reviewed here suggests a general role of exogenous and endogenous adenosine signaling in normal penile erection. From this perspective, it is not surprising that impaired adenosine signaling is associated with ED, and excessive adenosine signaling is associated with priapism. Adenosine signaling represents a potentially important diagnostic and therapeutic target for the treatment of ED and priapism.

Morphoproteomic evidence of constitutively activated and overexpressed mTOR pathway in cervical squamous carcinoma and high grade squamous intraepithelial lesions.

Human papilloma virus (HPV) infection of the uterine cervix is linked to the pathogenesis of cervical cancer. Preclinical in vitro and in vivo studies using HPV-containing human cervical carcinoma cell lines have shown that the mammalian target of rapamycin (mTOR) inhibitor, rapamycin, and epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor, erlotinib, can induce growth delay of xenografts. Activation of Akt and mTOR are also observed in cervical squamous cell carcinoma and, the expression of phosphorylated mTOR was reported to serve as a marker to predict response to chemotherapy and survival of cervical cancer patients. Therefore, we investigated: a) the expression level of EGFR in cervical squamous cell carcinoma (SCC) and high-grade squamous intraepithelial lesions (HSIL) versus non-neoplastic cervical squamous epithelium; b) the state of activation of the mTOR pathway in these same tissues; and c) any impact of these signal transduction molecules on cell cycle. Formalin-fixed paraffin-embedded tissue microarray blocks containing 20 samples each of normal cervix, HSIL and invasive SCC, derived from a total of 60 cases of cervical biopsies and cervical conizations were examined. Immunohistochemistry was utilized to detect the following antigens: EGFR; mTOR pathway markers, phosphorylated (p)-mTOR (Ser2448) and p-p70S6K (Thr389); and cell cycle associated proteins, Ki-67 and S phase kinase-associated protein (Skp)2. Protein compartmentalization and expression were quantified in regard to proportion (0-100%) and intensity (0-3+). Mitotic index (MI) was also assessed. An expression index (EI) for pmTOR, p-p70S6K and EGFR, respectively was calculated by taking the product of intensity score and proportion of positively staining cells. We found that plasmalemmal EGFR expression was limited to the basal/parabasal cells (2-3+, EI = 67) in normal cervical epithelium (NL), but was diffusely positive in all HSIL (EI = 237) and SCC (EI 226). The pattern of cytoplasmic p-mTOR and nuclear p-p70S6K expression was similar to that of EGFR; all showed a significantly increased EI in HSIL/SCC versus NL (p<0.02). Nuclear translocation of p-mTOR was observed in all SCC lesions (EI = 202) and was significantly increased versus both HSIL (EI = 89) and NL (EI = 54) with p<0.015 and p<0.0001, respectively. Concomitant increases in MI and proportion of nuclear Ki-67 and Skp2 expression were noted in HSIL and SCC. In conclusion, morphoproteomic analysis reveals constitutive activation and overexpression of the mTOR pathway in HSIL and SCC as evidenced by: increased nuclear translocation of pmTOR and p-p70S6K, phosphorylated at putative sites of activation, Ser2448 and Thr389, respectively; correlative overexpression of the upstream signal transducer, EGFR, and increases in cell cycle correlates, Skp2 and mitotic indices. These results suggest that the mTOR pathway plays a key role in cervical carcinogenesis and targeted therapies may be developed for SCC as well as its precursor lesion, HSIL.

Expression, induction and regulation of the cytochrome P450 monooxygenase system in the rat glioma C6 cell line

The cytochrome P450 monooxygenase system consists of NADPH- cytochrome P450 reductase (P450 reductase) and cytochromes P450, which can catalyze the oxidation of a wide variety of endogenous and exogenous compounds, including steroid hormones, fatty acids, drugs, and pollutants. The functions of this system are as diverse as the substrates. P450 reductase transfers reducing equivalents from NADPH to P450, which in turn catalyzes metabolic reactions. This enzyme system has the highest level of activity in the liver. It is also present in other tissues, including brain. The functions of this enzyme system in brain seem to include: neurotransmission, neuroendocrinology, developmental and behavioral modulation, regulation of intracellular levels of cholesterol, and potential neurotoxicity.^ In this study, we have set up the rat glioma C6 cell line as an in vitro model system to examine the expression, induction, and tissue-specific regulation of P450s and P450 reductase. Rat glioma C6 cells were treated with P450 inducers phenobarbital (PB) or benzo(a)anthracene (BA). The presence of P450 reductase and of cytochrome P450 1A1, 1A2, 2A1, 2B1/2, 2C7, 2D1-5 and 2E1 was detected by reverse transcription followed by polymerase chain reaction (RT-PCR) and confirmed by restriction digestion. The induction of P450 1A1 and 2B1/2 and P450 reductase was quantified using competitive PCR. Ten- and five-fold inductions of P450 1A and 2B mRNA after BA or PB treatments, respectively, were detected. Western blot analysis of microsomal preparations of glioma C6 cells demonstrated the presence of P450 1A, 2B and P450 reductase at the protein level. ELISAs showed that BA and PB induce P450 1A and 2B proteins 7.3- and 13.5-fold, respectively. Microsomes prepared from rat glioma C6 cells showed cytochrome P450 CO difference spectra with absorption at or near 450 nm. Microsomes prepared from rat glioma C6 cells demonstrated much higher levels of ethoxyresorufin O-deethylase (EROD) and pentoxyresorufin O-dealkylase (PROD) activity, when treated with BA or PB, respectively. These experiments provide further evidence that the rat glioma C6 cell line contains an active cytochrome P450 monooxygenase system which can be induced by P450 inducers. The mRNAs of P450 1A1 and 2B1/2 can not bind to the oligo(dT) column efficiently, indicating they have very short poly(A) tails. This finding leads us to study the tissue specific regulation of P450s at post-transcriptional level. The half lives of P450 1A1 and 2B1/2 mRNA in glioma C6 cells are only 1/10 and 1/3 of that in liver. This may partly contribute to the low expression level of P450s in glial cells. The induction of P450s by BA or PB did not change their mRNA half lives, indicating the induction may be due to transcriptional regulation. In summary of this study, we believe the presence of the cytochrome P450 monooxygenase system in glial cells of the brain may be important in chemotherapy and carcinogenesis of brain tumors. ^

More Money, Fewer Problems? Cross-Level Effects of Economic Deprivation on Political Representation

While equal political representation of all citizens is a fundamental democratic goal, it is hampered empirically in a multitude of ways. This study examines how the societal level of economic inequality affects the representation of relatively poor citizens by parties and governments. Using CSES survey data for citizens’ policy preferences and expert placements of political parties, empirical evidence is found that in economically more unequal societies, the party system represents the preferences of relatively poor citizens worse than in more equal societies. This moderating effect of economic equality is also found for policy congruence between citizens and governments, albeit slightly less clear-cut.

Experimental evidence for the immediate impact of fertilization and irrigation upon the plant and invertebrate communities of mountain grasslands

The response of montane and subalpine hay meadow plant and arthropod communities to the application of liquid manure and aerial irrigation – two novel, rapidly spreading management practices – remains poorly understood, which hampers the formulation of best practice management recommendations for both hay production and biodiversity preservation. In these nutrient-poor mountain grasslands, a moderate management regime could enhance overall conditions for biodiversity. This study experimentally assessed, at the site scale, among low-input montane and subalpine meadows, the short-term effects (1 year) of a moderate intensification (slurry fertilization: 26.7–53.3 kg N·ha−1·year−1; irrigation with sprinklers: 20 mm·week−1; singly or combined together) on plant species richness, vegetation structure, hay production, and arthropod abundance and biomass in the inner European Alps (Valais, SW Switzerland). Results show that (1) montane and subalpine hay meadow ecological communities respond very rapidly to an intensification of management practices; (2) on a short-term basis, a moderate intensification of very low-input hay meadows has positive effects on plant species richness, vegetation structure, hay production, and arthropod abundance and biomass; (3) vegetation structure is likely to be the key factor limiting arthropod abundance and biomass. Our ongoing experiments will in the longer term identify which level of management intensity achieves an optimal balance between biodiversity and hay production.

The Quality of the Evidence According to GRADE Is Predominantly Low or Very Low in Oral Health Systematic Reviews

OBJECTIVES The main objective was to assess the credibility of the evidence using Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) in oral health systematic reviews on the Cochrane Database of Systematic Reviews (CDSR) and elsewhere. STUDY DESIGN AND SETTING Systematic Reviews or meta-analyses (January 2008-December 2013) from 14 high impact general dental and specialty dental journals and the Cochrane Database of Systematic Reviews were screened for meta-analyses. Data was collected at the systematic review, meta-analysis and trial level. Two reviewers applied and agreed on the GRADE rating for the selected meta-analyses. RESULTS From the 510 systematic reviews initially identified 91 reviews (41 Cochrane and 50 non-Cochrane) were eligible for inclusion. The quality of evidence was high in 2% and moderate in 18% of the included meta-analyses with no difference between Cochrane and non-Cochrane reviews, journal impact factor or year of publication. The most common domains prompting downgrading of the evidence were study limitations (risk of bias) and imprecision (risk of play of chance). CONCLUSION The quality of the evidence in oral health assessed using GRADE is predominantly low or very low suggesting a pressing need for more randomised clinical trials and other studies of higher quality in order to inform clinical decisions thereby reducing the risk of instituting potentially ineffective and/or harmful therapies.

In situ conversion of protochlorophyllide b to protochlorophyllide a in barley. Evidence for a novel role of 7-formyl reductase in the prolamellar body of etioplasts

We recently put forth a model of a protochlorophyllide (Pchlide) light-harvesting complex operative during angiosperm seedling de-etiolation (Reinbothe, C., Lebedev, N., and Reinbothe, S. (1999) Nature 397, 80–84). This model, which was based on in vitro reconstitution experiments with zinc analogs of Pchlide a and Pchlide b and the two NADPH:protochlorophyllide oxidoreductases (PORs), PORA and PORB, of barley, predicted a 5-fold excess of Pchlide b, relative to Pchlide a, in the prolamellar body of etioplasts. Recent work (Scheumann, V., Klement, H., Helfrich, M., Oster, U., Schoch, S., and Rüdiger, W. (1999) FEBS Lett. 445, 445–448), however, contradicted this model and reported that Pchlide b would not be present in etiolated plants. Here we demonstrate that Pchlide b is an abundant pigment in barley etioplasts but is rather metabolically unstable. It is rapidly converted to Pchlide a by virtue of 7-formyl reductase activity, an enzyme that had previously been implicated in the chlorophyll (Chl) b to Chl a reaction cycle. Our findings suggest that etiolated plants make use of 7-formyl reductase to fine tune the levels of Pchlide b and Pchlidea and thereby may regulate the steady-state level of light-harvesting POR-Pchlide comple

Development of a 3-Dimensional Mathematical Collision Risk Model Based on Recorded Aircraft Trajectories to Estimate the Safety Level in High Density En-Route Airspaces

Como en todos los medios de transporte, la seguridad en los viajes en avión es de primordial importancia. Con los aumentos de tráfico aéreo previstos en Europa para la próxima década, es evidente que el riesgo de accidentes necesita ser evaluado y monitorizado cuidadosamente de forma continúa. La Tesis presente tiene como objetivo el desarrollo de un modelo de riesgo de colisión exhaustivo como método para evaluar el nivel de seguridad en ruta del espacio aéreo europeo, considerando todos los factores de influencia. La mayor limitación en el desarrollo de metodologías y herramientas de monitorización adecuadas para evaluar el nivel de seguridad en espacios de ruta europeos, donde los controladores aéreos monitorizan el tráfico aéreo mediante la vigilancia radar y proporcionan instrucciones tácticas a las aeronaves, reside en la estimación del riesgo operacional. Hoy en día, la estimación del riesgo operacional está basada normalmente en reportes de incidentes proporcionados por el proveedor de servicios de navegación aérea (ANSP). Esta Tesis propone un nuevo e innovador enfoque para evaluar el nivel de seguridad basado exclusivamente en el procesamiento y análisis trazas radar. La metodología propuesta ha sido diseñada para complementar la información recogida en las bases de datos de accidentes e incidentes, mediante la provisión de información robusta de los factores de tráfico aéreo y métricas de seguridad inferidas del análisis automático en profundidad de todos los eventos de proximidad. La metodología 3-D CRM se ha implementado en un prototipo desarrollado en MATLAB © para analizar automáticamente las trazas radar y planes de vuelo registrados por los Sistemas de Procesamiento de Datos Radar (RDP) e identificar y analizar todos los eventos de proximidad (conflictos, conflictos potenciales y colisiones potenciales) en un periodo de tiempo y volumen del espacio aéreo. Actualmente, el prototipo 3-D CRM está siendo adaptado e integrado en la herramienta de monitorización de prestaciones de Aena (PERSEO) para complementar las bases de accidentes e incidentes ATM y mejorar la monitorización y proporcionar evidencias de los niveles de seguridad. ABSTRACT As with all forms of transport, the safety of air travel is of paramount importance. With the projected increases in European air traffic in the next decade and beyond, it is clear that the risk of accidents needs to be assessed and carefully monitored on a continuing basis. The present thesis is aimed at the development of a comprehensive collision risk model as a method of assessing the European en-route risk, due to all causes and across all dimensions within the airspace. The major constraint in developing appropriate monitoring methodologies and tools to assess the level of safety in en-route airspaces where controllers monitor air traffic by means of radar surveillance and provide aircraft with tactical instructions lies in the estimation of the operational risk. The operational risk estimate normally relies on incident reports provided by the air navigation service providers (ANSPs). This thesis proposes a new and innovative approach to assessing aircraft safety level based exclusively upon the process and analysis of radar tracks. The proposed methodology has been designed to complement the information collected in the accident and incident databases, thereby providing robust information on air traffic factors and safety metrics inferred from the in depth assessment of proximate events. The 3-D CRM methodology is implemented in a prototype tool in MATLAB © in order to automatically analyze recorded aircraft tracks and flight plan data from the Radar Data Processing systems (RDP) and identify and analyze all proximate events (conflicts, potential conflicts and potential collisions) within a time span and a given volume of airspace. Currently, the 3D-CRM prototype is been adapted and integrated in AENA’S Performance Monitoring Tool (PERSEO) to complement the information provided by the ATM accident and incident databases and to enhance monitoring and providing evidence of levels of safety.

Organizational determinants of substantive sustainability reporting practices: the role of company-level fit

As sustainability reporting (SR) practices have being increasingly adopted by corporations over the last twenty years, most of the existing literature on SR has stressed the role of external determinants (such as institutional and stakeholder pressures) in explaining this uptake. However, given that recent evidence points to a broader range of motives and uses (both external and internal) of SR, we contend that its role within company-level activities deserves greater academic attention. In order to address this research gap, this paper seeks to provide a more detailed examination of the organizational characteristics acting as drivers and/or barriers of SR integration within corporate sustainability practices at the company-level. More specifically, we suggest that substantive SR implementation can be predicted by assessing the level of fit between the organization and the SR framework being adopted. Building on this hypothesis, our theoretical model defines three forms of fit (technical, cultural and political) and identifies organizational characteristics associated to each of these fits. Finally, implications for academic research, businesses and policy-makers are derived.

Symbolic vs substantive sustainability reporting: examining the role of company-level characteristics

As sustainability reporting (SR) practices have being increasingly adopted by corporations over the last twenty years, most of the existing literature on SR has stressed the role of external determinants (such as institutional and stakeholder pressures) in explaining this uptake. However, given that recent evidence points to a broader range of motives and uses (both external and internal) of SR, we contend that its role within company-level activities deserves greater academic attention. In order to address this research gap, this paper seeks to provide a more integrated perspective of both institutional and efficiency explanations of SR dynamics, as well as to highlight the role of company-level characteristics in explaining its contribution to sustainability management practices. More specifically, we suggest that substantive SR implementation can be predicted by assessing the level of fit between the organization and the SR framework being adopted. Building on this idea, our theoretical model defines three forms of fit (technical, cultural and political) and identifies organizational characteristics associated to each of these fits. Finally, implications for academic research, businesses and policy-makers are derived.

Evidence of high expression of peptidylglycine α-amidating monooxygenase in the rat uterus: Estrogen regulation

In the present study, high levels of peptidylglycine α-amidating monooxygenase (PAM), which catalyzes the two-step formation of bioactive α-amidated peptides from their glycine-extended precursors, have been found in the uterus. Expression of PAM was evaluated in the uterus of intact cycling adult female rats and after experimental manipulation of the estrogen status of the rats. During the estrous cycle, PAM mRNA levels exhibited striking changes inversely related to the physiological variations of plasma estrogen levels. The levels of PAM transcripts changed markedly during the estrous cycle, reaching the highest levels at metestrus. There was a 15-fold increase in the abundance of PAM mRNA between metestrus and proestrus. Chronic treatment of ovariectomized rats with 17β-estradiol decreased PAM mRNA levels to values comparable with those found in intact rats at proestrus. Progesterone was without effect on PAM mRNA levels, indicating that the effect was specific for estradiol. In situ hybridization studies were conducted to determine the tissue disposition and cell types expressing PAM. High levels of PAM mRNA were localized in the endometrium at the level of luminal and glandular cells. A weak signal was observed in stromal cells, and the myometrium cells were negative. 17β-Estradiol treatment induced an overall decrease of the hybridization signal, as compared with ovariectomized rats. These results demonstrate the presence of high levels of PAM in the uterus and indicate that estrogens are involved in regulating the expression of the enzyme in this tissue. However, the present study provides no information regarding whether this regulation takes place at the level of transcription or influences mRNA stability.

Evidence of evolutionary up-regulation of the single active X chromosome in mammals based on Clc4 expression levels in Mus spretus and Mus musculus

Previous studies have shown that the chloride channel gene Clc4 is X-linked and subject to X inactivation in Mus spretus, but that the same gene is autosomal in laboratory strains of mice. This exception to the conservation of linkage of the X chromosome in one of two interfertile mouse species was exploited to compare expression of Clc4 from the X chromosome to that from the autosome. Clc4 was found to be highly expressed in brain tissues of both mouse species. Quantitative analyses of species-specific expression of Clc4 in brain tissues from mice resulting from M. spretus × laboratory strain crosses, demonstrate that each autosomal locus has half the level of Clc4 expression as compared with the single active X-linked locus. In contrast expression of another chloride channel gene, Clc3, which is autosomal in both mouse species is equal between alleles in F1 animals. There is no evidence of imprinting of the Clc4 autosomal locus. These results are consistent with Ohno’s hypothesis of an evolutionary requirement for a higher expression of genes on the single active X chromosome to maintain balance with autosomal gene expression [Ohno, S. (1967) Sex Chromosomes and Sex-Linked Genes (Springer, Berlin)].

Ca2+/calmodulin-binding peptides block phototransduction in Limulus ventral photoreceptors: Evidence for direct inhibition of phospholipase C

Phototransduction in Limulus photoreceptors involves a G protein-mediated activation of phospholipase C (PLC) and subsequent steps involving InsP3-mediated release of intracellular Ca2+. While exploring the role of calmodulin in this cascade, we found that intracellular injection of Ca2+/calmodulin-binding peptides (CCBPs) strongly inhibited the light response. By chemically exciting the cascade at various stages, we found the primary target of this effect was not in late stages of the cascade but rather at the level of G protein and PLC. That PLCδ1 contains a calmodulin-like structure raised the possibility that PLC might be directly affected by CCBPs. To test this possibility, in vitro experiments were conducted on purified PLC. The activity of this enzyme was strongly inhibited by CCBPs and also inhibited by calmodulin itself. Our results suggest that the calmodulin-like region of PLC has an important role in regulating this enzyme.