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Red foxes (Vulpes vulpes) are susceptible to viral diseases of domestic carnivores. In this study, by screening rectal swabs collected from 34 red foxes in Italy, we identified kobuvirus RNA in five samples. Based on analysis of partial RdRp and full-length VP1 genes, all of the strains shared the highest identity with canine kobuviruses (CaKVs) recently detected in the US, the UK and Italy. These findings provide the first evidence of the circulation of these novel viruses in foxes.

Background: Although population-based screening has the potential to reduce inequalities in breast cancer survival, evidence on this topic is controversial. The objective of this study was to evaluate whether the full implementation of a mammography screening programme in Emilia-Romagna in Italy had an impact on variations in breast cancer survival by educational level., Methods: A cohort study was performed, including all women <70 years and residing in Emilia-Romagna who had infiltrating breast cancer registered in 1997-2000 (transitional screening period) or 2001-03 (consolidation screening period). Cancer cases were retrieved from the regional Breast Cancer Registry and followed up for 5 years. Educational level was determined from census data and allocated to cancer cases by individual record linkage. Age at diagnosis was classified into two groups (30-49, 50-69: screening target population)., Results: A total of 9639 cases were analyzed. In the 1997-2000 period, low-educated women had significantly lower survival compared with high-educated women, both in the younger and in the older age-groups. After the full implementation of the screening programme, these differences decreased in both age-groups, until disappearing completely among women in the age-group invited to screening., Conclusions: Our findings suggest that a fee-free population-based organized mammography screening programme with active invitation of the whole target population could be effective in reducing differences in survival in the population targeted by the screening.

Thymosin beta 4 (Tβ4) and thymosin beta 10 (Tβ10) are two members of the beta-thymosin family involved in many cellular processes such as cellular motility, angiogenesis, inflammation, cell survival and wound healing. Recently, a role for beta-thymosins has been proposed in the process of carcinogenesis as both peptides were detected in several types of cancer. The aim of the present study was to investigate the expression pattern of Tβ4 and Tβ10 in hepatocellular carcinoma (HCC). To this end, the expression pattern of both peptides was analyzed in liver samples obtained from 23 subjects diagnosed with HCC. Routinely formalin-fixed and paraffin-embedded liver samples were immunostained by indirect immunohistochemistry with polyclonal antibodies to Tβ4 and Tβ10. Immunoreactivity for Tβ4 and Tβ10 was detected in the liver parenchyma of the surrounding tumor area. Both peptides showed an increase in granular reactivity from the periportal to the periterminal hepatocytes. Regarding HCC, Tβ4 reactivity was detected in 7/23 cases (30%) and Tβ10 reactivity in 22/23 (97%) cases analyzed, adding HCC to human cancers that express these beta-thymosins. Intriguing finding was seen looking at the reactivity of both peptides in tumor cells infiltrating the surrounding liver. Where Tβ10 showed a strong homogeneous expression, was Tβ4 completely absent in cells undergoing stromal invasion. The current study shows expression of both beta-thymosins in HCC with marked differences in their degree of expression and frequency of immunoreactivity. The higher incidence of Tβ10 expression and its higher reactivity in tumor cells involved in stromal invasion indicate a possible major role for Tβ10 in HCC progression.

Objective: Evaluation of neuronal changes in an animal experimental model of normocapnic hypoxia- reoxygenation., Materials and Methods: Fifty male piglets were the study subjects; normocapnic hypoxia was induced in 40 piglets and ten were sham-operated (controls). When bradycardia and/or severe hypotension occurred, reoxygenation was initiated. Animals were allocated in 4 groups according to the oxygen concentration, they were resuscitated with 18%, 21%, 40%, and 100% O2. Persisting asystole despite 10 minutes of cardiopulmonary resuscitation and return of spontaneous circulation were the endpoints of the experiment. Surviving animals were euthanized and brain cortex samples were collected, hematoxylin and eosin-stained, and examined for apoptotic bodies observing 10 consecutive high power fields., Results: Histological examination of the control group did not show any pathological change. On the contrary, apoptosis of neurons was found in 87.5% of treated animals. When specimens were examined according to the oxygen concentration used for resuscitation, we found marked intergroup variability; a higher percentage of apoptotic neurons was observed in piglets of group 4 (100% oxygen) compared to the others (P=0.001)., Conclusions: This preliminary data shows that normocapnic hypoxia and reoxygenation in Landrace/Large White piglets resulted in significant histological changes in the brain cortex. The degree of pathological changes in cortical neurons was significantly associated with the oxygen concentration used for reoxygenation, with a higher percentage of apoptotic neurons being observed in piglets reoxygenated with 100% compared to 18% O2 and to 21% O2.

In this study, fecal specimens (n=260) collected from Italian healthy pigs aged between 6 and 10 months were screened by RT-PCR using generic kobuvirus primers. Porcine kobuviruses (PKVs) were detected in 3.85% of the samples tested. Based on the analysis of the partial 3D gene, the Italian sequences identified here were more closely related to PKVs previously identified in Japan, Thailand, Korea, China and Brazil than to the European PKVs recently detected in Hungary and in the Netherlands., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Canine kobuviruses (CaKVs) are newly recognized picornaviruses recently detected in dogs in the US. By molecular analysis of the whole genome, CaKV that appeared genetically closest to the murine kobuvirus (MuKV) and to the human Aichi virus (AiV), may be classified in the Kobuvirus genus as new genotype (CaKV type 1) within the species Aichivirus A. To date, there are no information on the epidemiology of these novel viruses in other continents. In this study, by screening a collection of 256 dog fecal samples either from diarrhoeic or asymptomatic animals, CaKV was identified in six specimens with an overall prevalence of 2.34% (6/256). All the positive dogs presented diarrhea and were found to be infected by CaKV alone or in mixed infections with canine coronavirus (CCoV) and/or canine parvovirus type 2 (CPV-2). By molecular analysis of the partial 3D gene, all the strains detected displayed a close relatedness with the CaKVs recently identified in the US. This study provides evidence that CaKVs circulate in diarrhoeic dogs in Italy and are not geographically restricted to the North American continent, where they were first signaled., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Aichi virus (AiV) is suspected to play a role in viral gastroenteritis in humans. In this study, we assessed the presence of AiV in untreated influent sewage samples collected at four wastewater treatment plants in central Italy. AiV was detected in 6 (12.5 %) of the 48 specimens and in all plants. All of the Italian strains showed the highest nucleotide and amino acid sequence identity to genotype B AiV detected recently in Asia, especially in China.

Objective: Thymosin beta 4 (Tβ4) is a ubiquitous peptide that plays pivotal roles in the cytoskeletal system and in cell differentiation. Recently, a role for Tβ4 has been proposed in experimental and human carcinogenesis, including gastrointestinal cancer. This study was aimed at evaluating the relationship between Tβ4 immunoreactivity and the initial steps of carcinogenesis., Methods: In total, 60 intestinal biopsies, including 10 hyperplastic polyps, 10 sessile serrated adenomas/polyps, 15 colorectal adenomas with low-grade dysplasia, 15 adenomas with high-grade dysplasia, 15 adenocarcinomas and 10 samples of normal colon mucosa, were analyzed for Tβ4 expression by immunohistochemistry., Results: Weak cytoplasmic reactivity for Tβ4 was detected in the normal colon mucosa. No reactivity for Tβ4 was found in hyperplastic and sessile serrated polyps/adenomas. Tβ4 expression was observed in 10/15 colorectal adenocarcinomas. In adenomas with low-grade dysplasia, Tβ4 immunoreactivity was mainly detected in dysplastic glands but was absent in hyperplastic glands. Tβ4 immunoreactivity was characterized by spot-like perinuclear staining. In high-grade dysplastic polyps, immunostaining for Tβ4 appeared diffuse throughout the entire cytoplasm of dysplastic cells. Spot-like perinuclear reactivity was detected in adenocarcinoma tumor cells., Conclusions: Our study shows for the first time that Tβ4 is expressed during different steps of colon carcinogenesis. The shift of Tβ4 immunolocalization from low-grade to high-grade dysplastic glands suggests a role for Tβ4 in colorectal carcinogenesis. However, the real meaning of Tβ4 reactivity in dysplastic intestinal epithelium remains unknown.

Thymosin beta-4 (Tβ4) is an ubiquitous multi-functional regenerative peptide, related to many critical biological processes, with a dynamic and flexible conformation which may influence its functions and its subcellular distribution. For these reasons, the intracellular localization and trafficking of Tβ4 is still not completely defined and is still under investigation in in vivo as well as in vitro studies. In the current study we used HepG2 cells, a human hepatoma cell line; cells growing in normal conditions with fetal bovine serum expressed high levels of Tβ4, restricted to the cytoplasm until 72 h. At 84 h, a diffuse Tβ4 cytoplasmic immunostaining shifted to a focal perinuclear and nuclear reactivity. In the absence of serum, nuclear reactivity was localized in small granules, evenly dispersed throughout the entire nuclear envelop, and was observed as earlier as at 48 h. Cytoplasmic immunostaining for Tβ4 in HepG2 cells under starvation appeared significantly lower at 48 h and decreased progressively at 72 and at 84 h. At these time points, the decrease in cytoplasmic staining was associated with a progressive increase in nuclear reactivity, suggesting a possible translocation of the peptide from the cytoplasm to the nuclear membrane. The normal immunocytochemical pattern was restored when culture cells submitted to starvation for 84 h received a new complete medium for 48 h. Mass spectrometry analysis, performed on the nuclear and cytosolic fractions of HepG2 growing with and without serum, showed that Tβ4 was detectable only in the cytosolic and not in the intranuclear fraction. These data suggest that Tβ4 is able to translocate from different cytoplasmic domains to the nuclear membrane and back, based on different stress conditions within the cell. The punctuate pattern of nuclear Tβ4 immunostaining associated with Tβ4 absence in the nucleoplasm suggest that this peptide might be localized in the nuclear pores, where it could regulate the pore permeability.

Thymosin beta 4 (Tβ4) and thymosin beta 10 (Tβ10) are two members of the β-thymosin family, involved in multiple cellular activities in different organs in multiple animal species. Here we report the expression pattern of Tβ4 and Tβ10 in rat tissues, in the gut and in annexed glands. The two peptide were differently expressed: Tβ4 was absent in salivary glands whereas Tβ10 was expressed in parotid and in submandibular glands. Tβ4 was mildly expressed in the tongue and in the oesophagus, where Tβ10 was absent. A similar expression was found in the stomach, ileum and colon mucosa. In pancreas Tβ4 reactivity was restricted to the Langerhans islet cells; Tβ4 was also detected in the exocrine cells. Both peptide were not expressed in liver cells. When the rat expression pattern in rat organs was compared to reactivity for Tβ4 and Tβ10 in humans, marked differences were found. Our data clearly indicate a species-specific expression of Tβ4 and Tβ10, characterized by the actual unpredictability of the expression of these peptides in different cells and tissues. The common high expression of Tβ4 in mast cells, both in humans and in rats, represents one of the few similarities between these two species.

The protein insulin-like growth factor II mRNA binding protein 3 (IMP3) is an important factor for cell migration and adhesion in malignancies. Recent studies have shown a remarkable overexpression of IMP3 in different human malignant neoplasms and also revealed it as an important prognostic marker in some tumor entities. The purpose of this study is to compare IMP3 immunostaining in squamous cellular skin tumor and determine whether IMP3 can aid in the differential diagnosis of these lesions. To our knowledge, IMP3 expression has not been investigated in skin squamous cell proliferations thus far. Immunohistochemical staining for IMP3 was performed on slides organized by samples from 67 patients, 34 with keratoacanthoma and 33 with primary squamous cell carcinoma (16 invasive and 17 in situ). The majority of our KAs (25/34) were negative for IMP-3 staining. The majority of SCCs (19/33) are positive for IMP3 staining. The percentage of IMP3 positive cells increases significantly in group SCC (p=0.0111), and in particular in the SCC in situ group (p=0.0021) with respect to the KA group.  IMP3 intensity staining increases significantly in SCCs (p=0.0213), and particularly in SCCs (p=0.008) with respect to KA. Our data show that IMP3 expression is different in keratoacanthomas with respect to squamous cell carcinoma. IMP3 assessment and staining pattern, together with a careful histological study, can be useful in the differential diagnosis between KA e SCC.

Faecal samples obtained from either asymptomatic or diarrhoeic calves in Italy were screened for bovine kobuviruses (BKVs) using specific primers. BKV RNA was detected in 4.9 % of the samples, with higher positivity rates in diarrhoeic calves (5.3 %) than in asymptomatic animals (4.8 %), although the difference was not statistically significant. Upon sequence analysis, all of the Italian viruses formed a tight group along with BKV-like sequences previously detected in Thailand and Japan.

The identification of the different cell types involved in human nephrogenesis, when solely based on morphology, may lead to errors in its interpretation, given the complexity of the histological picture of the fetal and of the newborn kidney. In this study, the most recent works utilizing immunohistochemistry for the identification of the multiple cell types involved in human nephrogenesis are reviewed. The role of WT1, MUC1, Thymosin beta 10, Thymosin beta 4, CD10 and CD44 in the different phases of glomerulogenesis and of tubulogenesis is here described, with particular emphasis on their expression in the early phases of nephrogenesis. On the basis of our data, immunohistochemistry appears to be a useful tool in the study of human nephrogenesis, giving new data on the different steps of the differentiation of metanephric mesenchyme towards the multiple cell types characterizing the mature human kidney. Moreover, allowing a better knowledge of the protein products involved in the generation of new nephrons, immunohistochemistry could open new perspectives in the field of renal regenerating medicine, evidencing the factors able to prolong nephrogenesis after birth, helping us to reach our goal: allowing newborn kidneys to restore their nephron endowment, escaping susceptibility to hypertension and renal disease in adulthood.

Objectives: Little is known about the effects of exposure to petroleum refinery emissions on respiratory health in children. We evaluated lung function and markers of inflammation and oxidative stress in children and adolescents with and without asthma or wheezing symptoms living in a petrochemical polluted area (Sarroch, Sardinia) versus a reference area (Burcei)., Methods: Parents of 275/300 6- to 14-year-old children living in Sarroch and parents of 214/323 children living in Burcei answered a questionnaire on respiratory symptoms and risk factors. Measurements of forced expiratory volume after 1 second (FEV(1)) and of forced expiratory flow rates at 25-75% of vital capacity (FEF(25-75)) were available in 27 and 23 asthma/wheezing-positive subjects and in 7 and 54 asthma/wheezing-negative subjects in Sarroch and in Burcei, respectively; for fractional exhaled nitric oxide (FE(NO)) corresponding figures were 27 and 24 and 8 and 55 in Sarroch and in Burcei, respectively. Malondialdehyde-deoxyguanosine (MDA-dG) adduct levels in nasal mucosa were measured in 12- to 14-year-old adolescents (8 and 14 asthma/wheezing-positive and 20 and 28 asthma/wheezing-negative subjects in Sarroch and in Burcei, respectively). Air pollutants were assessed during 3 weeks, starting 1 week before lung function, FE(NO), and MDA-dG measurements. Generalized linear models were used to estimate the effect of the area of residence adjusting for confounders., Results: Weekly average concentrations of sulfur dioxide were 6.9-61.6 μg/m(3) in Sarroch versus 0.3-7.6 μg/m(3) in the rural area of Burcei; of nitrogen dioxide, 5.2-28.7 μg/m(3) versus 1.7-5.3 μg/m(3); and of benzene, 1.8-9.0 μg/m(3) versus 1.3-1.5 μg/m(3), respectively. Children living in Sarroch versus children living in the reference area showed an increase in wheezing symptoms {adjusted prevalence ratio=1.70 [90% confidence interval (CI)=1.01; 2.86]}; a decrease in lung function [variation in FEV(1)=-10.3% (90% CI=-15.0; -6.0%) and in FEF(25-75)=-12.9% (90% CI=-20.7; -4.3%)]; an increase in bronchial inflammation [variation in FE(NO)=+35% (90% CI=11.7; 80.1%)]; and an increase in MDA-dG adducts of +83% (90% CI=22.9; 174.1%)., Conclusions: Data from this small study are consistent with the role of environmental pollutants on lung function and inflammation.

People with HIV/AIDS (PWHA) have increased risk of some cancers. The introduction of highly active antiretroviral therapies (HAART) has improved their life expectancy, exposing them to the combined consequences of aging and of a prolonged exposure to cancer risk factors. The aim of this study was to estimate incidence rates (IR) in PWHA in Italy, before and after the introduction of HAART, after adjusting for sex and age through direct standardization. An anonymous record linkage between Italian AIDS Registry (21,951 cases) and Cancer Registries (17.3 million, 30% of Italian population) was performed. In PWHA, crude IR, sex- and age-standardized IR and age-specific IR were estimated. The standardized IR for Kaposi sarcoma and non-Hodgkin lymphoma greatly declined in the HAART period. Although the crude IR for all non-AIDS-defining cancers increased in the HAART period, standardized IR did not significantly differ in the 2 periods (352 and 379/100,000, respectively). Increases were seen only for cancer of the liver (IR ratio = 4.6, 95% CI: 1.3-17.0) and lung (IR ratio = 1.8, 95% CI: 1.0-3.2). Age-specific IRs for liver and lung cancers, however, largely overlapped in the 2 periods pointing to the strong influence of the shift in the age distribution of PWHA on the observed upward trends. In conclusion, standardized IRs for non-AIDS-defining cancers have not risen in the HAART period, even if crude IRs of these cancers increased. This scenario calls, however, for the intensification of cancer-prevention strategies, notably smoking cessation and screening programs, in middle-aged HIV-patients.

A cohort of 1039 consecutive cases of thyroid carcinoma treated at a single institution and followed for an average of 11.9 years or until death included 102 encapsulated well-differentiated follicular-patterned tumors that had been diagnosed as carcinoma because of complete capsular invasion and/or papillary carcinoma-type nuclei. None of these cases were among the 67 patients from the cohort who died as a result of their thyroid carcinoma. The results of this study and a critical review of the pertinent literature indicate that tumors with these features are associated with an extremely favorable outcome and that they do not play a significant role in the fatality rate of thyroid carcinoma.

The stools of slaughtered pigs were screened for hepatitis E virus (HEV). HEV RNA was detected in 7.3% of the samples. HEV strains were characterized as genotype 3 subtype c, a cluster previously not described in Italy. These findings provide evidence that slaughterhouse workers may be exposed to HEV infection.

Background: This study was aimed at evaluating the correlation between Hepatocyte paraffin 1 (Hep par 1) and colorectal cancer., Methods: To this end, 50 intestinal biopsies were analyzed including 10 colorectal polyps with low grade dysplasia, 10 with high grade dysplasia, 10 colorectal adenocarcinomas, 10 specimens of normal ileum and 10 of normal colon mucosa. Tissue sections were immunostained for Hep par 1 utilizing a commercial antibody. Normal colonic mucosa did not express Hep par 1., Results: Immunoreactivity for Hep par 1 was detected in 20% of polyps with low grade dysplasia, 50% of polyps with high grade dysplasia and 60% of colorectal carcinomas. Hep par 1 was frequently detected in the deepest areas of adenocarcinomas mainly in infiltrating tumour cells., Conclusions: Our data show that Hep par 1 immunoreactivity in human colon carcinogenesis is correlated with progression from low grade to high grade dysplasia and adenocarcinoma. In clinical practice, our data show that caution should be taken in utilizing Hep par 1 as the sole tool in differentiating hepatocellular carcinoma from a liver metastasis of colon adenocarcinoma. Our data encourage further investigations into the potential role played by Hep par 1 in gastrointestinal carcinogenesis.

Objective: the study evaluates the accuracy of an algorithm based on hospital discharge data (HDD) in order to estimate breast cancer incidence in three italian regions (Emilia-Romagna, Toscana and Veneto) covered by cancer registries (CR). The evolution of computer-based information systems in health organization suggests automatic processing of HDD as a possible alternative to the time-consuming methods of CR. The study intends to verify whether HDD quickly provides reliable cancer incidence estimates for diagnosis and therapy evaluations., Design and Setting: an algorithm based on discharge diagnosis and surgical therapy of hospitalized breast cancer patients was developed in order to provide breast cancer incidence. Results were compared with the corresponding incidence data of cancer registries. The accuracy of the automatic method was also verified by a direct record-linkage between HDD output and registries' files. The overall survival of cases lost to "HDD method" was analyzed., Results: in the period covered by the study (3,125,425 person/year) CR enrolled 6,079 incident cases, compared to 6,000 cases recorded through the HDD flow. Incidence rates of the two methods (CR 194.5; HDD 192.0 x 100.000) showed no statistical differences. However, matched cases by the two methods were only 5,038. The sensitivity of the HDD algorithm was 82.9% and its predictive positive value (PPV) was 84.0%. False positive cases were 9.9%. On the other hand, 12.3% CR incident cases were not identified by the algorithm: these were mainly made up of older women, not eligible for surgical therapy. Their three-years survival was 62.0% vs 88.8% of the whole incidence group., Conclusion: HDD flow performance was similar to observations reported in the literature. The agreement between HDD and CR incidence rates is a result of a cross effect of both sensitivity and specificity limitations of the HDD algorithm. This can seriously impair the reliability of the latter method with regard to the evaluation of diagnostic and therapeutic strategies in cohort studies (i.e. the most effective approach to health setting in oncology).s.

Background: Thymosin beta(4), its sulfoxide, and thymosin beta(10) were detected in whole saliva of human pre-term newborns by reversed-phase high performance chromatography coupled to electrospray ion-trap mass spectrometry., Methodology/principal Findings: Despite high inter-individual variability, concentration of beta-thymosins increases with an inversely proportional trend to postmenstrual age (PMA: gestational age plus chronological age after birth) reaching a value more than twenty times higher than in adult whole saliva at 190 days (27 weeks) of PMA (thymosin beta(4) concentration: more than 2.0 micromol/L versus 0.1 micromol/L). On the other hand, the ratio between thymosin beta(4) and thymosin beta(10) exhibits a constant value of about 4 along all the range of PMA (190-550 days of PMA) examined. In order to investigate thymosin beta(4) origin and to better establish the trend of its production as a function of gestational age (GA), immunohistochemical analysis of major and minor salivary glands of different pre-term fetuses were carried out, starting from 84 days (12 weeks) of gestational age. Reactive granules were seen in all glands with a maximum of expression around 140-150 days of GA, even though with high inter- and intra-individual variability. In infants and adults reactive granules in acinar cells were not observed, but just a diffuse cytoplasmatic staining in ductal cells., Significance: This study outlines for the first time that salivary glands during foetal life express and secrete peptides such as beta-thymosins probably involved in the development of the oral cavity and its annexes. The secretion increases from about 12 weeks till to about 21 weeks of GA, subsequently it decreases, almost disappearing in the period of expected date of delivery, when the gland switches towards the secretion of adult specific salivary peptides. The switch observed may be an example of further secretion switches involving other exocrine and endocrine glands during foetal development.