Atypical transmissible spongiform encephalopathies in ruminants: a challenge for disease surveillance and control

Since 1987, when bovine spongiform encephalopathy (BSE) emerged as a novel disease in cattle, enormous efforts were undertaken to monitor and control the disease in ruminants worldwide. The driving force was its high economic impact, which resulted from trade restrictions and the loss of consumer confidence in beef products, the latter because BSE turned out to be a fatal zoonosis, causing variant Creutzfeldt-Jakob disease in human beings. The ban on meat and bone meal in livestock feed and the removal of specified risk materials from the food chain were the main measures to successfully prevent infection in cattle and to protect human beings from BSE exposure. However, although BSE is now under control, previously unknown, so-called atypical transmissible spongiform encephalopathies (TSEs) in cattle and small ruminants have been identified by enhanced disease surveillance. This report briefly reviews and summarizes the current level of knowledge on the spectrum of TSEs in cattle and small ruminants and addresses the question of the extent to which such atypical TSEs have an effect on disease surveillance and control strategies.

Computer-assisted liver surgery: clinical applications and technological trends

Oncological liver surgery and interventions aim for removal of tumor tissue while preserving a sufficient amount of functional tissue to ensure organ regeneration. This requires detailed understanding of the patient-specific internal organ anatomy (blood vessel system, bile ducts, tumor location). The introduction of computer support in the surgical process enhances anatomical orientation through patient-specific 3D visualization and enables precise reproduction of planned surgical strategies though stereotactic navigation technology. This article provides clinical background information on indications and techniques for the treatment of liver tumors, reviews the technological contributions addressing the problem of organ motion during navigated surgery on a deforming organ, and finally presents an overview of the clinical experience in computer-assisted liver surgery and interventions. The review concludes that several clinically applicable solutions for computer aided liver surgery are available and small-scale clinical trials have been performed. Further developments will be required more accurate and faster handling of organ deformation and large clinical studies will be required for demonstrating the benefits of computer aided liver surgery.

Cholesteryl ester accumulation and accelerated cholesterol absorption in intestine-specific hormone sensitive lipase-null mice

Hormone sensitive lipase (HSL) regulates the hydrolysis of acylglycerols and cholesteryl esters (CE) in various cells and organs, including enterocytes of the small intestine. The physiological role of this enzyme in enterocytes, however, stayed elusive. In the present study we generated mice lacking HSL exclusively in the small intestine (HSLiKO) to investigate the impact of HSL deficiency on intestinal lipid metabolism and the consequences on whole body lipid homeostasis. Chow diet-fed HSLiKO mice showed unchanged plasma lipid concentrations. In addition, feeding with high fat/high cholesterol (HF/HC) diet led to unaltered triglyceride but increased plasma cholesterol concentrations and CE accumulation in the small intestine. The same effect was observed after an acute cholesterol load. Gavaging of radioactively labeled cholesterol resulted in increased abundance of radioactivity in plasma, liver and small intestine of HSLiKO mice 4h post-gavaging. However, cholesterol absorption determined by the fecal dual-isotope ratio method revealed no significant difference, suggesting that HSLiKO mice take up the same amount of cholesterol but in an accelerated manner. mRNA expression levels of genes involved in intestinal cholesterol transport and esterification were unchanged but we observed downregulation of HMG-CoA reductase and synthase and consequently less intestinal cholesterol biosynthesis. Taken together our study demonstrates that the lack of intestinal HSL leads to CE accumulation in the small intestine, accelerated cholesterol absorption and decreased cholesterol biosynthesis, indicating that HSL plays an important role in intestinal cholesterol homeostasis.

Macrophage activating syndrome is associated with lobular hepatitis and severe bile duct injury with cholestasis

Macrophage activating syndrome (MAS) is a rare hematological disorder associated with uncontrolled systemic T-cell activation. Persistent fever, fatigue and hepatosplenomegaly are frequent clinical manifestations, whereas hyperferritinemia, elevated serum lactate dehydrogenase levels and cytopenia are key criteria for the diagnosis of MAS. The nature of liver pathology in MAS has been partially elucidated but destructive biliary lesions have been rarely described. This report illustrates four cases of MAS developing marked cholestasis, leading to one case of biliary cirrhosis necessitating liver transplantation. Histologically, liver involvement was characterized in all cases by acute lobular hepatitis, marked hepatocyte apoptosis and small bile duct injury similar to the vanishing bile duct syndrome. Immuno-histological studies showed that the inflammatory changes and bile duct lesions were dominated by the presence of activated macrophages and T-cells, in particular CD8+ lymphocytes, and in part NK-cells. These findings suggest that in MAS, various T-cell triggers such as infection, autoimmune disease and malignancy might result in the release of cytokines, which in turn activate macrophages to trigger a systemic acute phase response and local tissue damage. This communication suggests that a macrophage, T- and NK-cell network is operational in the pathogenesis of the cholangiocyte, hepatocyte and sinus endothelial cell damage in MAS.

Protein synthesis in jejunum and liver of neonatal calves fed vitamin A and lactoferrin

Rates of protein synthesis (PS) and turnover are more rapid during the neonatal period than during any other stage of postnatal life. Vitamin A and lactoferrin (Lf) can stimulate PS in neonates. However, newborn calves are vitamin A deficient and have a low Lf status, but plasma vitamin A and Lf levels increase rapidly after ingestion of colostrum. Neonatal calves (n = 6 per group) were fed colostrum or a milk-based formula without or with vitamin A, Lf, or vitamin A plus Lf to study PS in the jejunum and liver. l-[(13)C]Valine was intravenously administered to determine isotopic enrichment of free (nonprotein-bound) Val (AP(Free)) in the protein precursor pool, atom percentage excess (APE) of protein-bound Val, fractional protein synthesis rate (FSR) in the jejunum and liver, and isotopic enrichment of Val in plasma (APE(Pla)) and in the CO(2) of exhaled air (APE(Ex)). The APE, AP(Free), and FSR in the jejunum and liver did not differ significantly among groups. The APE(Ex) increased, whereas APE(Pla) decreased over time, but there were no group differences. Correlations were calculated between FSR(Jej) and histomorphometrical and histochemical data of the jejunum, and between FSR(Liv) and blood metabolites. There were negative correlations between FSR(Liv) and plasma albumin concentrations and between FSR(Jej) and the ratio of villus height:crypt depth, and there was a positive correlation between FSR(Jej) and small intestinal cell proliferation in crypts. Hence, there were no effects of vitamin A and Lf and no interactions between vitamin A and Lf on intestinal and hepatic PS. However, FSR(Jej) was correlated with histomorphometrical traits of the jejunum and FSR(Liv) was correlated with plasma albumin concentrations.

Outcomes and patterns of failure in solitary plasmacytoma: a multicenter Rare Cancer Network study of 258 patients

PURPOSE: To assess the outcomes and patterns of failure in solitary plasmacytoma (SP). METHODS AND MATERIALS: The data from 258 patients with bone (n = 206) or extramedullary (n = 52) SP without evidence of multiple myeloma (MM) were collected. A histopathologic diagnosis was obtained for all patients. Most (n = 214) of the patients received radiotherapy (RT) alone; 34 received chemotherapy and RT, and 8 surgery alone. The median radiation dose was 40 Gy. The median follow-up was 56 months (range 7-245). RESULTS: The median time to MM development was 21 months (range 2-135), with a 5-year probability of 45%. The 5-year overall survival, disease-free survival, and local control rate was 74%, 50%, and 86%, respectively. On multivariate analyses, the favorable factors were younger age and tumor size <4 cm for survival; younger age, extramedullary localization, and RT for disease-free survival; and small tumor and RT for local control. Bone localization was the only predictor of MM development. No dose-response relationship was found for doses >30 Gy, even for larger tumors. CONCLUSION: Progression to MM remains the main problem. Patients with extramedullary SP had the best outcomes, especially when treated with moderate-dose RT. Chemotherapy and/or novel therapies should be investigated for bone or bulky extramedullary SP.

Spatial Assessment of Erosion and its Impact on Soil Fertility in the Tajik Foothills

Efficient planning of soil conservation measures requires, first, to understand the impact of soil erosion on soil fertility with regard to local land cover classes; and second, to identify hot spots of soil erosion and bright spots of soil conservation in a spatially explicit manner. Soil organic carbon (SOC) is an important indicator of soil fertility. The aim of this study was to conduct a spatial assessment of erosion and its impact on SOC for specific land cover classes. Input data consisted of extensive ground truth, a digital elevation model and Landsat 7 imagery from two different seasons. Soil spectral reflectance readings were taken from soil samples in the laboratory and calibrated with results of SOC chemical analysis using regression tree modelling. The resulting model statistics for soil degradation assessments are promising (R2=0.71, RMSEV=0.32). Since the area includes rugged terrain and small agricultural plots, the decision tree models allowed mapping of land cover classes, soil erosion incidence and SOC content classes at an acceptable level of accuracy for preliminary studies. The various datasets were linked in the hot-bright spot matrix, which was developed to combine soil erosion incidence information and SOC content levels (for uniform land cover classes) in a scatter plot. The quarters of the plot show different stages of degradation, from well conserved land to hot spots of soil degradation. The approach helps to gain a better understanding of the impact of soil erosion on soil fertility and to identify hot and bright spots in a spatially explicit manner. The results show distinctly lower SOC content levels on large parts of the test areas, where annual crop cultivation was dominant in the 1990s and where cultivation has now been abandoned. On the other hand, there are strong indications that afforestations and fruit orchards established in the 1980s have been successful in conserving soil resources.

The vascular ectonucleotidase CD39 is permissive for sinusoidal endothelial cell proliferation during liver regeneration: evidence for synergism between growth factors and extracellular nucleotides

Crosstalk between elements of the sinusoidal vasculature, platelets and hepatic parenchymal cells influences regenerative responses to liver injury and/or resection. Such paracrine interactions include hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF), IL-6 and small molecules such as serotonin and nucleotides. CD39 (nucleoside triphosphate diphosphohydrolase-1) is the dominant vascular ectonucleotidase expressed on the luminal surface of endothelial cells and modulates extracellular nucleotide signaling. We have previously shown that integrity of P2-receptors, as maintained by CD39, is required for angiogenesis in Matrigel plugs in vivo and that there is synergism between nucleotide P2-receptor- and growth factor-mediated cell proliferation in vitro. We have now explored effects of CD39 on liver regeneration and vascular endothelial growth factor responses in a standard small animal model of partial hepatectomy. The expression of CD39 on liver sinusoidal endothelial cells (LSEC) is substantially boosted during liver regeneration. This transcriptional upregulation precedes maximal sinusoidal endothelial cell proliferation, noted at day 5-8 in C57BL6 wild type mice. In matched mutant mice null for CD39 (n=14), overall survival is decreased to 71% by day 10. Increased lethality occurs as a consequence of extensive LSEC apoptosis, decreased endothelial proliferation and failure of angiogenesis leading to hepatic infarcts and regenerative failure in mutant mice. This aberrant vascular remodeling is associated with biochemical liver injury, elevated serum levels of VEGF (113.9 vs. 65.5pg/ml, p=0.013), and decreased circulating HGF (0.89 vs. 1.43 ng/ml, p=0.001) in mice null for CD39. In agreement with these observations, wild type LSEC but not CD39 null cultures upregulate HGF expression and secretion in response to exogenous VEGF in vitro. CD39 null LSEC cultures show poor proliferation responses and heightened levels of apoptosis when contrasted to wild type LSEC where agonists of P2Y receptors augment cell proliferation in the presence of growth factors. These observations are associated with features of P2Y-desensitization, normal levels of the receptor tyrosine kinase VEGFR-1 (Flt-1) and decreased expression of VEGFR-2 (FLK/KDR) in CD39 null LSEC cultures. We provide evidence that CD39 and extracellular nucleotides impact upon growth factor responses and tyrosine receptor kinases during LSEC proliferation. We propose that CD39 expression by LSEC might co-ordinate angiogenesis-independent liver protection by facilitating VEGF-induced paracrine release of HGF to promote vascular remodeling in liver regeneration.

Hypereosinophilic syndrome: a multicenter, retrospective analysis of clinical characteristics and response to therapy

BACKGROUND: Hypereosinophilic syndrome (HES) is a heterogeneous group of rare disorders defined by persistent blood eosinophilia > or =1.5 x 10(9)/L, absence of a secondary cause, and evidence of eosinophil-associated pathology. With the exception of a recent multicenter trial of mepolizumab (anti-IL-5 mAb), published therapeutic experience has been restricted to case reports and small case series. OBJECTIVE: The purpose of the study was to collect and summarize baseline demographic, clinical, and laboratory characteristics in a large, diverse cohort of patients with HES and to review responses to treatment with conventional and novel therapies. METHODS: Clinical and laboratory data from 188 patients with HES, seen between January 2001 and December 2006 at 11 institutions in the United States and Europe, were collected retrospectively by chart review. RESULTS: Eighteen of 161 patients (11%) tested were Fip1-like 1-platelet-derived growth factor receptor alpha (FIP1L1-PDGFRA) mutation-positive, and 29 of 168 patients tested (17%) had a demonstrable aberrant or clonal T-cell population. Corticosteroid monotherapy induced complete or partial responses at 1 month in 85% (120/141) of patients with most remaining on maintenance doses (median, 10 mg prednisone equivalent daily for 2 months to 20 years). Hydroxyurea and IFN-alpha (used in 64 and 46 patients, respectively) were also effective, but their use was limited by toxicity. Imatinib (used in 68 patients) was more effective in patients with the FIP1L1-PDGFRA mutation (88%) than in those without (23%; P < .001). CONCLUSION: This study, the largest clinical analysis of patients with HES to date, not only provides useful information for clinicians but also should stimulate prospective trials to optimize treatment of HES.

Phenotypic associations of Crohn's disease with antibodies to flagellins A4-Fla2 and Fla-X, ASCA, p-ANCA, PAB, and NOD2 mutations in a Swiss Cohort

BACKGROUND: Distinct Crohn's disease (CD) phenotypes correlate with antibody reactivity to microbial antigens. We examined the association between antibody response to 2 new flagellins called A4-Fla2 and Fla-X, anti-Saccharomyces cerevisiae antibodies (ASCA), anti-neutrophil cytoplasmic antibodies (p-ANCA), anti-pancreas antibodies (PAB), NOD2 mutations (R702W, G908R, and L1007fsinsC), and clinical CD phenotypes (according to Vienna criteria). METHODS: All the above-mentioned antibodies as well as NOD2 mutations were determined in 252 CD patients, 53 with ulcerative colitis (UC), and 43 healthy controls (HC) and correlated with clinical data. RESULTS: A seroreactivity for A4-Fla2/Fla-X/ASCA/p-ANCA/PAB (in percent) was found in 59/57/62/12/22 of CD patients, 6/6/4/51/0 of UC patients, and 0/2/5/0/0 of healthy controls. CD behavior: 37% B1, 36% B2, and 27% B3. In multivariate logistic regression, antibodies to A4-Fla2, Fla-X, and ASCA were significantly associated with stricturing phenotype (P = 0.027, P = 0.041, P < 0.001), negative associations were found with inflammatory phenotype (P = 0.001, P = 0.005, P < 0.001). Antibodies to A4-Fla2, Fla-X, ASCA, and NOD2 mutations were significantly associated with small bowel disease (P = 0.013, P = 0.01, P < 0.001, P = 0.04), whereas ASCA was correlated with fistulizing disease (P = 0.007), and small bowel surgery (P = 0.009). Multiple antibody responses against microbial antigens were associated with stricturing (P < 0.001), fistulizing disease (P = 0.002), and small bowel surgery (P = 0.002). CONCLUSIONS: Anti-flagellin antibodies and ASCA are strongly associated with complicated CD phenotypes. CD patients with serum reactivity against multiple microbes have the greatest frequency of strictures, perforations, and small bowel surgery. Further prospective longitudinal studies are needed to show that antibody-based risk stratification improves the clinical outcome of CD patients.

Melan-a-positive "pseudomelanocytic nests": a pitfall in the histopathologic and immunohistochemical diagnosis of pigmented lesions on sun-damaged skin

We encountered recently 3 cases with a histopathologic diagnosis of melanoma in situ on sun-damaged skin (male = 2, female = 1; median age: 59 years; range: 52-60 years). The diagnosis was based mainly on the finding of actinic elastosis in the dermis and increased number of melanocytes in the epidermis and was confirmed by strong positivity for Melan-A in single cells and in small nests ("pseudomelanocytic nests"), located at the dermoepidermal junction. Indeed, examination of slides stained with hematoxylin and eosin revealed the presence of marked hyperpigmentation and small nests of partially pigmented cells at the dermoepidermal junction, positive for Melan-A. The histologic and especially the immunohistochemical features were indistinguishable from those of melanoma in situ on chronic sun-damaged skin. In addition, a variably dense lichenoid inflammation was present. Clinicopathologic correlation, however, showed, in all patients, the presence of a lichenoid dermatitis (phototoxic reaction, 1 case; lichen planus pigmentosus, 1 case; and pigmented lichenoid keratosis, 1 case). Our cases clearly show the histopathologic pitfalls represented by lichenoid reactions on chronic sun-damaged skin. Immunohistochemical investigations, especially if performed with Melan-A alone, may lead to confusing and potentially disastrous results. The unexpected staining pattern of Melan-A in cases like ours raises concern about the utility of this antibody in the setting of a lichenoid tissue reaction on chronic sun-damaged skin. It should be underlined that pigmented lesions represent a paradigmatic example of how immunohistochemical results should be interpreted carefully and always in conjunction with histologic and clinical features.

Protein changes and proteolytic degradation in red and white clover plants subjected to waterlogging

Red (Trifolium pratense L., cv. “Start”) and white clover varieties (Trifolium repens L., cv. “Debut” and cv. “Haifa”) were waterlogged for 14 days and subsequently recovered for the period of 21 days. Physiological and biochemical responses of the clover varieties were distinctive, which suggested different sensitivity toward flooding. The comparative study of morphological and biochemical parameters such as stem length, leaflet area, dry weight, protein content, protein pattern and proteolytic degradation revealed prominent changes under waterlogging conditions. Protease activity in the stressed plants increased significantly, especially in red clover cv. “Start”, which exhibited eightfold higher azocaseinolytic activity compared to the control. Changes in the protein profiles were detected by SDS-PAGE electrophoresis. The specific response of some proteins (Rubisco, Rubisco-binding protein, Rubisco activase, ClpA and ClpP protease subunits) toward the applied stress was assessed by immunoblotting. The results characterized the red clover cultivar “Start” as the most sensitive toward waterlogging, expressing reduced levels of Rubisco large and small subunits, high content of ClpP protease subunits and increased activity of protease isoforms.

Linked Services for Enabling Interoperability in the Sensing Enterprise

In future, the so called “sensing enterprise”, as part of the Future Internet, will play a crucial role in the success or the failure of an enterprise. We present our vision of an enterprise interacting with the physical world based on a retail scenario. One of the main challenges is the interoperability not only between the enterprise IT systems themselves, but also between these systems and the sensing devices. We will argue that semantically enriched service descriptions, the so called linked services will ease interoperability between two or more enterprises IT systems, and between enterprise systems and the physical environment.

Epidemiologic survey in Swiss group-housed breeding rabbits: extent of lesions and potential risk factors

In Switzerland, group-housing for breeding rabbit does is not explicitly required by law, but label programmes, as well as the general public and animal welfare groups, are advocating it. Although group-housing is of great benefit to the gregariously living rabbits, the establishment of a social hierarchy within the group might lead to stress and lesions. In the present epidemiological study, lesions were scored twice on 30% of the breeding does on all 28 commercial Swiss farms with group-housed breeding does. Additionally, a detailed questionnaire was filled out with all producers to determine risk factors potentially associated with lesions. Data were analysed using hierarchical proportional odds models. About 33% of the does examined had lesions, including wounds that were almost healed and small scratches. Severe lesions were counted on 9% of the animals. Differences between seasons in lesions score were identified, with the extent of lesions being higher in summer than in spring. Fewer lesions occurred on farms on which mastitis was more common. More lesions were found on farms where the does were isolated between littering and artificial insemination than on farms without isolation. According to the producers, most of the aggression occurred directly after the isolation phase when the does were regrouped again. We conclude that lesions in group-housed breeding does might be reduced by appropriate reproductive management.

Language and executive functioning: Children’s benefit from induced verbal strategies in different tasks

The interplay of language and cognition in children’s development has been subject to research for a long time. The present study followed up on recently reported deleterious effects of articulatory suppression on children’s executive functioning (Fatzer & Roebers, 2012), aiming to provide more empirical evidence on the differential influence of language on executive functioning. In the present study, verbal strategies were induced in three executive functioning tasks. The tasks were linked to the three central executive functioning dimensions of updating (Complex Span task), shifting (Cognitive Flexibility task) and inhibition (Flanker task). It was expected that the effects of the verbal strategy instruction would counter the results of articulatory suppression and thus be strong in the Complex Span task, weak but present in the Cognitive Flexibility task and small or nonexistent in the Flanker task. N = 117 children participated in the study, with n = 39 four-year-olds, n = 38 six-year-olds, and n = 40 nine-year-olds. As expected, results revealed a benefit from induced verbal strategies in the Complex Span and the Cognitive Flexibility task, but not in the Flanker task. The positive effect of strategy instruction declined with increasing age, pointing to more frequent spontaneous and self-initiated use of verbal strategies over the course of development. The effect of strategy instruction in the Cognitive Flexibility task was unexpectedly strong in the light of the only small detrimental effect of articulatory suppression in the preceding study. Implications for language’s involvement in the different executive functioning dimensions and for practice are discussed.