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Summary: Objective: A highly sensitive thyroglobulin assay (Elecsys® Tg II, Roche Diagnostics, Penzberg, Germany) has become available for monitoring patients with differentiated thyroid cancer (DTC). Here, we evaluated the clinical performance of Elecsys® Tg II assay in a multicentre patients series and compare it with the established Access® Tg assay (Beckman Coulter, Brea, CA, USA). Design: Retrospective analysis on prospectively selected patients in four thyroid cancer referral centres with uniform DTC management. Participants: All DTC cases diagnosed, treated and followed up in four tertiary referral centres for thyroid cancer since January 2005 (n = 1456) were retrieved, and predefined selection criteria were applied to prevent relevant enrolment biases. A series of 204 patients was finally selected for this study. Measurements: Samples had been stored at −80°C. Tg was measured by fully automated immunometric Elecsys® Tg II and Access® Tg assays in a centralized laboratory. Results: Two hundred and four DTC were finally included. Of these, 10.8% had structural recurrence (sREC), and 81.4% showed no evidence of disease (NED) at the end of follow‐up. There was a significant analytical bias between methods that cannot be used interchangeably. Using ROC curve analysis, the best basal and rhTSH‐stimulated Tg cut‐offs to detect sREC were 0.41 μg/L and 1.82 μg/L for Elecsys® and 0.36 μg/L and 1.62 μg/L for Access® assay, respectively. Using Cox proportional hazard regression, Tg was the only independent predictor of cancer relapse. Conclusions: Using appropriate assay‐specific cut‐offs, the clinical performance of the Elecsys® Tg II assay was comparable to that provided by the well‐established Access® Tg assay. [ABSTRACT FROM AUTHOR]

Since the discovery of bisphosphonate-related osteonecrosis of the jaw, there has been increasing evidence in recent years of osteonecrosis induced by drugs other than bisphosphonates, mainly agents with antiangiogenic and antiosteoclastic activity. Mandibular osteonecrosis was observed in a 51-year-old female with medullary thyroid cancer receiving cabozantinib, a new tyrosine kinase inhibitor having antiangiogenic activity. The bone necrosis appeared after a dental extraction. The clinical, radiographic and histologic picture of a chronic non-healing extraction socket was consistent with drug-induced osteonecrosis of the jaw. Healing was achieved by segmental ostectomy. The osteonecrosis was likely associated with a vascular endothelial growth factor (VEGF) pathway inhibition, implying inhibition of angiogenesis and hampering of the local host defence mechanisms. [ABSTRACT FROM AUTHOR]

ABSTRACT Phenological investigations that adopt aerobiological monitoring methodologies are frequently used for species that rely on the wind for pollen grain dispersion, such as the olive in the Mediterranean basin. The present study of olive flowering dates was carried out in the Calabria region (southern Italy). These were calculated on the basis of a phenological study of pollen levels in the atmosphere in three typical olive-growing areas over an 11 year study period (1999-2009). This phenological method provides olive flowering maps that are based on temperatures (as the growing degree days: GDDs), which are highly correlated with the release of the pollen grains. According to the model developed, the average GDDs corresponding to the flowering dates were calculated for the baseline period of 1981-2000. Moreover, with the use of meteorological data derived from the Intergovernmental Panel on Climate Change scenarios, the future olive flowering dates are estimated for the 20 year period from 2081 to 2100. The close relationships between the spring temperature trends and the reproductive phenological phases in the olive are highly sensitive to climatic change, which has implications in terms of potential latitude and altitude shifts in the olive cultivation areas. In some cultivation areas in southern Italy, the present particular combination of microclimate, soil status and level of erosion is considered as limiting to regular vegetative plant development. However, the use of olive cultivars that are specifically adapted to extremely stressful environments, in terms of high temperatures and water deficit, might represent the main solution for the mitigation of the consequences of climatic change. [ABSTRACT FROM AUTHOR]

A statistical test is described to verify the characteristics of the biological information contained in the dynamics of the flowering process. The test focuses on interactions between the pollen index and climatic variables to investigate if the biological indicator can synthesise the information of the pre-flowering phases. The multiple-regression model is built upon two pre-flowering climate macro-indicators extracted by Principal Component Analysis (PCA) and the optimised pollen index is obtained by non-parametric estimation. The empirical analysis is applied to 15 stations located in southern Italy in regions that have a longstanding tradition of olive production. Using the variance explained, we find that an optimised pollen index is fairly well predicted by the pre-flowering climatic data. We conclude that the optimised pollen index makes more parsimonious the modelling for predicting olive production. [ABSTRACT FROM AUTHOR]

Objectives To assess the feasibility of measuring nasal bone length in first-trimester pregnancy and to confirm if the absence of a fetal nasal bone is a marker for Down syndrome. Methods Fetal nasal bone assessment was attempted in 1089 consecutive singleton pregnancies between 11 and 14 weeks' gestation. All ultrasound examinations were performed transabdominally in three separate centers. If the nasal bone was present, nasal bone length was measured. Results Nasal bone assessment was successfully achieved in 1027 of 1089 (94.3%) ultrasound examinations. Within this group nasal bone was absent in 10 of 1000 (1.0%) unaffected cases, 10 of 15 (66.7%) Down syndrome cases and 5 of 12 (41.7%) cases with other pathological conditions. Regression analysis showed a significant increase (P < 0.0001) in nasal bone length from 2.48 mm at a crown-rump length of 45 mm to 3.12 mm at a crown-rump length of 84 mm. The nasal bone length in the five cases of Down syndrome in which the nasal bone was present was less than the median measurement of unaffected cases. Using modeling, the combination of nasal bone with maternal age, nuchal translucency, free beta-human chorionic gonadotropin (hCG) and pregnancy associated plasma protein-A (PAPP-A) achieved a detection rate of 95% with a false-positive rate of 2.9%. At a fixed 1% falsepositive rate, the detection rate was 91%. Conclusions Absence of the nasal bone can be used as a marker for Down syndrome in the first trimester of pregnancy. Inclusion of the nasal bone in the current first-trimester screening protocol along with nuchal translucency, free beta-hCG and PAPP-A can achieve high detection at a very low false-positive rate. Large datasets are needed to confirm whether the measurement of nasal bone length provides additional benefits beyond the assessment of the presence or absence of the nasal bone. [ABSTRACT FROM AUTHOR]

- The present study is concerned with changes in the number and localization of S-phase cells in the liver of rats exposed to dimethylnitrosamine (DMN). S-phase cells were detected by immunohistochemistry after injection of bromodeoxyuridine (BrdU) and exposure of paraffin sections of liver tissue to the antibody anti-BrdU. With respect to controls, the number of S-phase cells increased four to fivefold in DMN-treated animals in the first week of treatment and remained significantly higher thereafter, in association with the formation of septa. At all times, the labelling index was higher in littoral cells than in hepatocytes. No labelling was observed in biliary cells. This behaviour is different from that reported in other situations, for instance in regeneration after partial hepatectomy, which suggests that besides hepatocytes and littoral cells replacement, an involvement of the latter cell line in the inflammatory reaction, synthesis of extracellular matrix components and formation of septa may account for this particular pattern. [ABSTRACT FROM AUTHOR]

ABSTRACT- The aim of the present study was to determine if data on the number and acinar distribution of apoptotic bodies (AB) in normal liver could help in the understanding of cell kinetics in the liver, and the mechanism of early ethanol-induced liver damage. Normal male Sprague-Dawley rats were studied. They had free access to Purina chow and drinking water. Ethanol-treated rats received the drug at increasing concentration in drinking water for 5 weeks. The following parameters were measured: number of AB in the lobule, topographical localization, distance from terminal hepatic veins (THV), i.e. row of hepatocytes concerned, H1 being the closest to the THV. The results show that AB are rare in the normal liver and are always observed in zone 3, next to the THV. Of 149 THV examined, 56 showed one associated AB, exceptionally two. 74% of the AB were confined to the first row of hepatocytes (H1), 21% to H2, 4% to H3, and 1% to H4. In ethanol-treated rats the mean number of AB was 2 or 3 for each THV. 42% were found in H1, 32% in H2, 15% in H3, 7% in H4, and 4% in H5. The data show that AB are not randomly dispersed in normal liver but show a preferential acinar distribution. In addition, most AB are located in the row of liver cells immediately adjacent to the THV. If apoptosis is indeed an expression of physiological cell renewal, these findings support the concept that zone 3 contains older hepatocytes. In ethanol-treated animals, besides the O2 lobular gradient and increased rate of formation of intermediate metabolites, the age of pericentral hepatocytes may represent an additional risk factor in ethanol-induced liver damage. [ABSTRACT FROM AUTHOR]

ABSTRACT- Horseradish peroxidase (HRP) and lanthanum chloride (LaCl3) are useful tools for, respectively, the study of vesicular transport through the hepatocyte and the study of the permeability of junctional complexes. These tracers have been used to detect the changes associated with the choleresis independent of bile acids induced by valproic acid (VPA) in rats. The animals were given a single dose of VPA (600 mg/kg, ip). HRP (100 mg/kg) or 5 mM LaCl3 were given intraportally after 1 h, when bile flow had increased twofold. The excretion of HRP in bile was measured colorimetrically up to 2 h after HRP. Ultrastructural morphometry was conducted on liver of intact rats taken from 1 to 40 min after HRP. The volume density (VD) of HRP-containing vesicles and of HRP-containing multivesicular bodies (MVB) was counted. In VPA-treated rats, HRP appeared in bile with a peak showing at 5 min against 20 min in controls, but the total amount of HRP excreted was less than in controls. The intrahepatocytic vesicular transport of HRP was also modified, showing a peak at 3 min in VPA-treated rats compared to 10 min in controls, together with a decreased VD of pericanalicular vesicles. This was accompanied by an increase of HRP-containing MVB, already evident at 5 min. VPA-induced changes in HRP transport through the hepatocytes appeared twofold: 1) during VPA-induced stimulation of bile flow, there was an early and short-lived increase of transcellular transport and biliary elimination of HRP: 2) a diversion of HRP towards the indirect, lysosomal pathway apparently occurred, in agreement with previous findings concerning the formation of numerous cytolysomes induced by VPA ( Hepatology 1984: 4: 1159-1166). The decreased amount of HRP excreted in bile could be accounted for by a diversion of HRP towards the degradation pathway. The pattern of distribution of LaCl3 was similar in VPA-treated animals and in controls, suggesting that gross structural alterations of the junctional complexes are unlikely to occur during VPA-induced choleresis. [ABSTRACT FROM AUTHOR]

ABSTRACT- The frequency of fibrosis of the terminal hepatic venule (FTHV) has been investigated by two observers unaware of the patient's history, in needle biopsy specimens showing normal histology (n = 23), alcoholic steatosis (n = 23), steatosis in diabetes or overweight (n = 26), alcoholic hepatitis (n = 21), or virus-related chronic active hepatitis (n = 44). FTHV was coded following a scale from 0 to 3 of severity. Minimal (grade 1) FTHV was seen in most venules of biopsies with a normal histological pattern, and was considered a normal feature. Grade 2 of FTHV was absent in the group showing normal histology but was evident in 17.4% - 39.7% of the venules observed in the other groups without attaining diagnostic relevance. The percentage rate of severe (grade 3) FTHV was 0.0, 4.9, 6.6, 18.7 and 2.9 in the respective groups as delineated above. In alcoholic hepatitis, severe FTHV therefore showed a higher frequency than in virus-related chronic hepatitis (p<0.001), with high values of sensitivity (0.75), specificity (0.93), and predictivity (0.84 positive, 0.98 negative) for ethanol aetiology. The ethanol-related diagnostic value of FTHV however, was low in steatosis. [ABSTRACT FROM AUTHOR]

ABSTRACT- The study reports functional and morphological findings in eight male subjects undergoing anticonvulsant therapy for periods from 20 days up to 15 years. All subjects showed an increased activity of the hepatic microsomal NADPH cytochrome c reductase and an increased amount of smooth membranes in hepatocytes. The enzymatic activity was higher in the first years of treatment. Quantitative ultrastructural analysis showed that a twofold increase of the smooth membranes of hepatocytes had already been reached after 20 days of therapy, with a modest additional increase occurring thereafter. Both enzymatic and structural changes appear to be related to therapy. In addition, abnormal lipofuscin-related cytoplasmic formations were present in the hepatocytes of five subjects. Such formations are thought to represent an accumulation of abnormal degradation products, possibly related to an interaction of the drug(s) metabolites with cellular components. [ABSTRACT FROM AUTHOR]

Xenogeneic melanosomal differentiation antigens, delivered in the form of a plasmid DNA vaccine, can overcome host immune ignorance/tolerance in preclinical animals to melanoma by: 1) generating humoral and cytotoxic T cell responses and 2) inducing protection from tumor challenge. Initial trials of human tyrosinase(huTyr) DNA vaccination of dogs with advanced malignant melanoma(Bergmanet al, 2003) demonstrated safety and prolongation of survival with this therapeutic modality. We investigated antigen-specific immunity in dogs receiving huTyr DNA vaccination.Three cohorts of three dogs each with advanced(WHO stage II-IV) canine malignant melanoma(CMM) received four biweekly IM injections(dose levels 100, 500, or 1,500 ug, respectively/vaccination) of huTyr plasmid DNA via the Biojector2000 jet delivery device. Sera samples were taken before and after vaccination to detect specific antibody formation to huTyr by Enzyme-Linked ImmunoSorbent Assays(ELISAs) and flow-cytometry.Three dogs have measurable, 2 to 4 fold huTyr-specific antibody titers. Preliminary studies by flow-cytometry have confirmed antibody response to huTyr by positive binding to endogenous human tyrosinase in SK-Mel188 cells using post-vaccinate serum.Xenogeneic(huTyr) DNA vaccination generates antigen-specific humoral responses, which may partially explain the previously reported clinical efficacy and anti-tumor responses. Ongoing studies include: 1) a comprehensive analysis by flow-cytometry to detect huTyr-specific antibodies and 2) a quantitative measure of potential cytotoxic T-cell responses in these dogs by the DNA vaccination. [ABSTRACT FROM AUTHOR]