A novel method for the identification of synchronization effects in multichannel ECoG with an application to epilepsy.

In this paper, we present a novel method for the identification of synchronization effects in multichannel electrocorticograms (ECoG). Based on autoregressive modeling, we define a dependency measure termed extrinsic-to-intrinsic power ratio (EIPR) which quantifies directed coupling effects in the time domain. Hereby, a dynamic input channel selection algorithm assures the estimation of the model parameters despite the strong spatial correlation among the high number of involved ECoG channels. We compare EIPR to the partial directed coherence, show its ability to indicate Granger causality and successfully validate a signal model. Applying EIPR to ictal ECoG data of patients suffering from temporal lobe epilepsy allows us to identify the electrodes of the seizure onset zone. The results obtained by the proposed method are in good accordance with the clinical findings.

Costs of Epilepsy in Austria: Unemployment as a primary driving factor.

PURPOSE: Epilepsy is one of the most common chronic neurological disorders, and long-term treatment with antiseizure medication is often central to its management. The costs of antiseizure medication are more evident than other disease-related costs; thus, we assessed the direct and indirect costs of epilepsy focusing on both drug expenditure and other cost-driving factors. METHODS: Outpatient records and questionnaires applied in a tertiary epilepsy centre in Vienna were used in this bottom-up cost-of-illness study to evaluate disease duration, age at onset, epilepsy syndrome, seizure frequency, sex, healthcare utilisation, diagnostic evaluations, antiseizure medication, and occupation. Cost data were clustered in a histogram-based data analysis, and multivariate regressions were performed to identify cost drivers. RESULTS: The average annual costs of 273 patients amounted to €9,256 ($10,459): €4,486 ($5,069) direct costs and €4,770 ($5,390) indirect costs. A histogram of semi-annual costs revealed distinct groups with low costs (< €2,500 = $2,825) and high costs (> €2,500 = $2,825). Seizure-free patients were clustered in the group with low costs; patients with ongoing seizures appeared more frequently in the group with high costs. Working patients were more often found in the group with low costs, whereas unemployed patients were more prevalent in the group with high costs. The regression analysis confirmed worklessness as the main cost driver. CONCLUSION: Non-productivity and poorly controlled disease with ongoing seizures are associated with higher costs in epilepsy. Providing high-level care and optimal drug treatment that enables patients to remain in work may help reduce the economic burden of epilepsy.

Interactions between CXCR4 and CXCL12 promote cell migration and invasion of canine hemangiosarcoma.

The CXCR4/CXCL12 axis plays an important role in cell locomotion and metastasis in many cancers. In this study, we hypothesized that the CXCR4/CXCL12 axis promotes migration and invasion of canine hemangiosarcoma (HSA) cells. Transcriptomic analysis across 12 HSA cell lines and 58 HSA whole tumour tissues identified heterogeneous expression of CXCR4 and CXCL12, which was associated with cell movement. In vitro, CXCL12 promoted calcium mobilization, cell migration and invasion that were directly proportional to surface expression of CXCR4; furthermore, these responses proved sensitive to the CXCR4 antagonist, AMD3100, in HSA cell lines. These results indicate that CXCL12 potentiates migration and invasion of canine HSA cells through CXCR4 signalling. The direct relationship between these responses in HSA cells suggests that the CXCR4/CXCL12 axis contributes to HSA progression.

Establishment of a Patient-Derived Xenograft of Canine Enteropathy-Associated T-Cell Lymphoma, Large Cell Type.

The pathogenesis of canine T-cell lymphoma remains incompletely understood, partly because there are no well-established in-vivo models to study these malignancies. For this study, we generated a patient-derived tumour xenograft (PDTX) from a 10-year-old neutered male golden retriever dog with enteropathy-associated intestinal T-cell lymphoma, large cell type. One of two female, 15-week-old beige/nude/XID mice developed a visible tumour 7 weeks after sections of tumour material from the spleen were surgically implanted. The histological appearance, immunophenotype and clonal antigen receptor rearrangements of the tumour from the recipient mouse showed that it was derived from the primary canine tumour. Our results indicate that immunodeficient mice are receptive hosts to develop in-vivo PDTX models to study the pathogenesis and management of canine T-cell lymphomas.

High correlation between molecular alterations of the c-myc oncogene and carcinoma of the uterine cervix.

We have examined 35 human tumors of the uterine cervix (carcinoma presenting the highest incidence in Mexico; about 34% of women's malignant tumors) for alterations of the cellular myc (c-myc) protooncogene. Elevated amplification and/or rearrangement of the c-myc oncogene were detected in most (approximately 90%) samples (48% showed amplification and 43% presented both alterations). Most tumors were stage II cervical carcinomas and for some of them we detected up to 60-fold amplification of c-myc. These results suggest an important role for c-myc oncogene in the development of tumors of the uterine cervix.

Identification of drug-resistant subpopulations in canine hemangiosarcoma.

Canine hemangiosarcoma is a rapidly progressive disease that is poorly responsive to conventional chemotherapy. Despite numerous attempts to advance treatment options and improve outcomes, drug resistance remains a hurdle to successful therapy. To address this problem, we used recently characterized progenitor cell populations derived from canine hemangiosarcoma cell lines and grown as non-adherent spheres to identify potential drug resistance mechanisms as well as drug-resistant cell populations. Cells from sphere-forming cultures displayed enhanced resistance to chemotherapy drugs, expansion of dye-excluding side populations and altered ATP-binding cassette (ABC) transporter expression. Invasion studies demonstrated variability between cell lines as well as between sphere and monolayer cell populations. Collectively, our results suggest that sphere cell populations contain distinct subpopulations of drug-resistant cells that utilize multiple mechanisms to evade cytotoxic drugs. Our approach represents a new tool for the study of drug resistance in hemangiosarcoma, which could alter approaches for treating this disease.

Canine osteosarcoma cells exhibit resistance to aurora kinase inhibitors.

We evaluated the effect of Aurora kinase inhibitors AZD1152 and VX680 on canine osteosarcoma cells. Cytotoxicity was seen in all four cell lines; however, half-maximal inhibitory concentrations were significantly higher than in human leukaemia and canine lymphoma cells. AZD1152 reduced Aurora kinase B phosphorylation, indicating resistance was not because of failure of target recognition. Efflux mediated by ABCB1 and ABCG2 transporters is one known mechanism of resistance against these drugs and verapamil enhanced AZD1152-induced apoptosis; however, these transporters were only expressed by a small percentage of cells in each line and the effects of verapamil were modest, suggesting other mechanisms contribute to resistance. Our results indicate that canine osteosarcoma cells are resistant to Aurora kinase inhibitors and suggest that these compounds are unlikely to be useful as single agents for this disease. Further investigation of these resistance mechanisms and the potential utility of Aurora kinase inhibitors in multi-agent protocols is warranted.

Association of Sphingosine-1-phosphate (S1P)/S1P Receptor-1 Pathway with Cell Proliferation and Survival in Canine Hemangiosarcoma.

BACKGROUND: Sphingosine-1-phosphate (S1P) is a key biolipid signaling molecule that regulates cell growth and survival, but it has not been studied in tumors from dogs. HYPOTHESIS/OBJECTIVES: S1P/S1P1 signaling will contribute to the progression of hemangiosarcoma (HSA). ANIMALS: Thirteen spontaneous HSA tissues, 9 HSA cell lines, 8 nonmalignant tissues, including 6 splenic hematomas and 2 livers with vacuolar degeneration, and 1 endothelial cell line derived from a dog with splenic hematoma were used. METHODS: This was a retrospective case series and in vitro study. Samples were obtained as part of medically necessary diagnostic procedures. Microarray, qRT-PCR, immunohistochemistry, and immunoblotting were performed to examine S1P1 expression. S1P concentrations were measured by high-performance liquid chromatography/mass spectrometry. S1P signaling was evaluated by intracellular Ca(2+) mobilization; proliferation and survival were evaluated using the MTS assay and Annexin V staining. RESULTS: Canine HSA cells expressed higher levels of S1P1 mRNA than nonmalignant endothelial cells. S1P1 protein was present in HSA tissues and cell lines. HSA cells appeared to produce low levels of S1P, but they selectively consumed S1P from the culture media. Exogenous S1P induced an increase in intracellular calcium as well as increased proliferation and viability of HSA cells. Prolonged treatment with FTY720, an inhibitor of S1P1 , decreased S1P1 protein expression and induced apoptosis of HSA cells. CONCLUSIONS AND CLINICAL IMPORTANCE: S1P/S1P1 signaling pathway functions to maintain HSA cell viability and proliferation. The data suggest that S1P1 or the S1P pathway in general could be targets for therapeutic intervention for dogs with HSA.

Gonadotropins pituitary secretion in systemic lupus erythematosus.

Hormonal abnormalities have been suggested to play a role in the pathogenesis of systemic lupus erythematosus (SLE). In order to define the regulatory mechanism involved, the pituitary reserve for gonadotropins secretion was investigated in eight untreated SLE patients with normal menstrual cycles. Serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) were determined on the fifth day of the menstrual cycle before and after intravenous administration of 25 micrograms synthetic luteinizing hormone-releasing hormone (LH-RH). The pulsatile LH and FSH resting values in SLE were not significantly higher than those found in the controls; after LH-RH stimulation no difference was observed between the SLE group and controls. The LH and FSH response to exogenous LH-RH administration in SLE demonstrate the integrity of the hypothalamic-pituitary-ovary axis that explains normal menses and fertility in this disease.

Delayed gastric emptying in subjects with Gilbert's syndrome.

BACKGROUND/AIMS: Recently, it has been proposed that decreased intestinal motility in fasting-induced hyperbilirubinemic rats probably results in an increase in the enterohepatic cycling of unconjugated bilirubin. We investigated the association among gastric emptying, intestinal transit time, and serum unconjugated levels in subjects with Gilbert's syndrome. METHODOLOGY: Ten subjects with Gilbert's syndrome were included in this study according to the following criteria: fasting hyperbilirubinemia; no hemolysis or gastrointestinal disorders and free of any medication. Five normal, healthy volunteers acted as controls. Gastric emptying and intestinal transit time were evaluated after overnight fasting by administration of a standard meal mixed with 1-2ci of 99Tc-labeled diethylene-triamine-pentacetic acid. Serum unconjugated bilirubin levels were determined by high-performance liquid chromatography. RESULTS: The gastric emptying in Gilbert's syndrome subjects was 134.1 +/- 38.9 and 90.9 +/- 6.5 min in controls, P < 0.03. It was a tendency to have a shorter intestinal transit time in subjects with Gilbert's syndrome, 138.3 +/- 59.0, than in control subjects, 183.8 +/- 11.3 min. Serum unconjugated bilirubin levels (mg/dL) were 2.6 +/- 1.04 and 0.95 +/- 0.34, P < 0.01. CONCLUSIONS: Gastric emptying is delayed significantly in Gilbert's syndrome, and intestinal transit time differences between Gilbert's syndrome subjects and controls were not significantly different.

Silent giant left atrium. A case report.

A sixty-two-year-old white woman with a 14.5 cm (145 mm) silent giant left atrial enlargement secondary probably to rheumatic heart disease is presented. Aside from mild progressive shortness of breath during the past year, the patient had been asymptomatic all her life. Her clinical picture was manifested for the first time by syncope secondary to slow atrial fibrillation, for which a permanent pacemaker was required. The correct diagnosis of the enlarged chamber was not possible through the routine chest roentgenogram. In this case, the echocardiogram, nuclear angiogram, and computed tomography were the pertinent studies needed to reach the diagnosis.

[The treatment of colonic and ovarian cancer with radioactive monoclonal antibodies against the CA l9-9 and CA 125 antigens]. / Tratamiento de cáncer de colon y ovario con anticuerpos monoclonales radiactivos contra antígenos Ca 19-9 y Ca 125.

The age of monoclonal antibodies arose with the papers by Köhler and Milstein in 1975. By means of a fusion between a neoplastic cell with one which produced a specific antibody they obtained a hybrid or clonal cell. Five years later, Nadler et al issued the first report of a patient with lymphoma treated with monoclonal antibodies. After the first announcement, diverse research centers have reported the clinical results obtained in various neoplasias treated with radioactive monoclonal antibodies directed against antigens associated with neoplasias, as well as non-specific tumoral antigens, including lymphomas, melanomas and cancers of the colon, ovary and breast.

Automated quantification of pulmonary perfused blood volume by dual-energy CTPA in chronic thromboembolic pulmonary hypertension.

OBJECTIVES: The aim of the study was to determine whether automated quantification of pulmonary perfused blood volume (PBV) in dual-energy computed tomography pulmonary angiography (DE-CTPA) can be used to assess the severity of chronic thromboembolic pulmonary hypertension (CTEPH). METHODS: Automated quantification of PBV was performed in 25 consecutive CTEPH patients undergoing DE-CTPA. PBV values were correlated with cardiac index and pulmonary vascular resistance quantified by right heart catheterization and walking distance in the 6-minute walk test using Pearson's correlation coefficient and multivariate linear regression analysis to control for age and gender. RESULTS: DE-CTPA derived PBV values inversely correlated with systolic (r = -0.64, p = 0.001) and mean (r = -0.57, p = 0.004) pulmonary arterial pressure. There was a trend for PBV values to inversely correlate with pulmonary vascular resistance (r = -0.20, p = 0.35). No significant correlation was found between PBV values and cardiac index or 6-minute walking distance. These correlations were confirmed to be independent of age and gender on multivariate linear regression analysis. CONCLUSION: DE-CTPA can be used for an automated quantification of pulmonary PBV in chronic thromboembolic pulmonary hypertension. PBV values correlate inversely with systolic and mean pulmonary arterial pressure and can thus be used to estimate the severity of pulmonary hypertension in these patients. Citation Format: • Meinel FG, Graef A, Thierfelder KM et al. Automated Quantification of Pulmonary Perfused Blood Volume by Dual-Energy CTPA in Chronic Thromboembolic Pulmonary Hypertension. Fortschr Röntgenstr 2014; 186: 151 - 156.

Dual-energy CT pulmonary angiography in patients with suspected pulmonary embolism: value for the detection and quantification of pulmonary venous congestion.

OBJECTIVE: To evaluate if vascular and pulmonary parenchymal enhancement values in dual-energy (DE) CT pulmonary angiography (CTPA) can suggest the diagnosis of pulmonary congestion. METHODS: DE-CTPA images of 90 out of 1321 patients negative for pulmonary embolism showed signs of congestive heart failure. We measured DE-derived pulmonary parenchymal [perfused blood volume (PBV)], pulmonary artery (PA) and left atrium (LA) enhancement values in these patients and in 142 control patients. Enhancement values were compared between the populations and correlated with serum values of B-type natriuretic peptide (BNP) and proBNP, where available. RESULTS: No significant difference of PBV but significant differences of mean PA and LA enhancement and individual enhancement differences (PA - LA) were found between the populations. PA - LA was higher in patients with elevated BNP and proBNP and was positively correlated with these values. Receiver operating characteristic analysis revealed a moderate discriminatory power of the PA - LA difference for the presence of cardiac biomarker elevations. CONCLUSION: PBV in DE-CTPA is not altered in patients with signs of congestive heart failure. However, differences in enhancement values in the pre- and post-pulmonary vessels were found in comparison with the control population. ADVANCES IN KNOWLEDGE: Altered pulmonary vascular haemodynamics in pulmonary venous congestion are not reflected in dual-energy-derived PBV maps. In the diagnosis of left heart failure in patients with chest pain and dyspnoea, density measurements in the pulmonary artery and in the left atrium in CTPA images may be a helpful diagnostic tool.

[Ventilation, diffusion and pulmonary perfusion studied by 133 Xe]. / Cuantificación de la ventilación, difusión y perfusión pulmonar con 133Xe. Comunicación preliminar.

The pulmonary function has been studied by several methods using radioactive gases since 1955. Knipping and col. reported the first study with 133Xe in the evaluation of the gas distribution in pulmonary ventilation. In this study, we report the pulmonary function in 40 normal persons, evaluated by injection in a peripherical vein of this radioactive substance. The elementary respiratory functions: ventilation, diffusion and perfusion were calculated by distribution curves of 133Xe and we obtained the V/P index is very important for the diagnosis and therapeutic evaluation of the pulmonary function. Comparative studies with several examples of human pulmonary disease are in progress in our laboratory.

Prolactin and gonadal hormones during pregnancy in systemic lupus erythematosus.

We performed prospective hormonal studies in 9 patients (5 active and 4 inactive) with systemic lupus erythematosus (SLE) during pregnancy (Weeks 10 to 37). Nine healthy pregnant women and 5 patients with rheumatoid arthritis (RA) were used for comparison. Serum prolactin (PRL), testosterone and estradiol (E2) levels were determined by RIA. The patients with SLE showed higher serum PRL levels, the difference being statistically significant at Week 20, and reaching the highest levels at Weeks 30 to 40 (p = 0.05 when compared to healthy pregnant women). The 5 patients with active SLE had the highest serum PRL levels; one of these had fetal wastage. In active SLE the serum testosterone and E2 levels were decreased significantly from Weeks 10 to 30 compared with controls (p = 0.001). In patients with RA serum PRL levels, although higher than in controls, did not differ significantly, nor did the lower testosterone and E2 levels. We conclude that gonadal hormones and PRL changes observed in SLE are present also during pregnancy and may be related to fetal wastage and reactivation of disease.

[Usefulness of pancreatic scintilography in clinical diagnosis]. / Valor de la centelleografía pancreática en el diagnóstico clínico.

Our experience in pancreatic scintigraphy is presented in this paper. It was used as radioactive substance 75 semetionina. 21 patients with pancreatic pathology and 6 controls constituted the clinical material. The scintigraphy studies showed an homogenous distribution of the radioactive material in the control group. In 7 cases a defect of concentration was showed. The diagnosis of carcinoma were made with surgery in all of them. Similar findings were demonstrated in cases of pancreatic pseudocyst. Irregular distribution was noted in patients with pancreatitis. We concluded that in same instances pancreatic scintigraphy can be useful for differential diagnosis in the clinical field.

[Effect of position with respect to gravitational force on the hydrodynamics of an experimental model of saccular aneurysm]. / Influencia de la posición con respecto a la fuerza de gravedad sobre la hidrodinámica de un modelo experimental de aneurisma sacular.

We wish to confirm the hypothesis that the hydrodynamics of brain aneurysms depend partially on their position, with respect to the force of gravitation, and so developed an experimental model of latex aneurysms, which was subjected to a pulsatile flow. Four different registers were made with an injection of ink and radioisotopes. A physical model was designed which allowed a quantitative analysis of the results and which allows a mathematical analysis of the aneurysm's hydrodynamics. The results suggest that when an aneurysm is oriented against the force of gravity, it has a very low risk of thrombosis, and the scarce turbulence of the flow condition a lower risk of growth and rupture, in comparison with other conditions. The greatest flow turbulence against the wall is found in the aneurysm oriented downwards, that is parallel to the force of gravity. Due to its hydrodynamics, the downwards aneurysm has the highest probability of complication, since it has; a) higher risk of rupture due to the impact of the stream upon the wall and to the turbulence this impact produces, b) a higher risk of thrombosis produced by the circulatory stasis which has a dome. This combination of factors (rupture and thrombosis) allows these aneurysms to grow more than others.

Correlation study between prolactin and androgens in male patients with systemic lupus erythematosus.

The hypothalamic-pituitary-gonadal axis was studied in 8 male patients with systemic lupus erythematosus (SLE), both before and after intravenous administration of luteinizing hormone-releasing hormone (LH-RH). We provide evidence herein that resting serum levels of estrone are increased and that resting serum testosterone (T) and dihydrotestosterone (DHT) levels are decreased in male patients with SLE. The decreased serum T levels were observed even after the IV administration of 25 micrograms of LH-RH. The high basal serum prolactin (PRL) levels observed in these patients with SLE is a novel finding not previously reported that could explain why serum T and DHT levels are low in this syndrome. We observed a decrease in the pituitary response to LH-RH stimulation; this low response could also be a hormonal manifestation of hyperprolactinemia. Furthermore, it has been suggested that PRL plays a role in immunocompetence, and therefore it could have influence either directly or indirectly in the altered immunoregulation observed in SLE.