A randomized, double-blind, placebo-controlled, multicenter study of a ginger extract in the management of chemotherapy-induced nausea and vomiting (CINV) in patients receiving high-dose cisplatin.

BACKGROUND: The activity of ginger in the management of chemotherapy-induced nausea and vomiting (CINV) has been suggested, but design inadequacies, heterogeneity of the population, small numbers and poor quality of tested products limit the possibility to offer generalizable results. PATIENTS AND METHODS: We conducted a randomized, double-blind, placebo-controlled, multicenter study in patients planned to receive ≥2 chemotherapy cycles with high dose (>50 mg/m2) cisplatin. Patients received ginger 160 mg/day (with standardized dose of bioactive compounds) or placebo in addition to the standard antiemetic prophylaxis for CINV, starting from the day after cisplatin administration. CINV was assessed through daily visual-analogue scale and Functional Living Index Emesis questionnaires. The main objective was protection from delayed nausea; secondary end points included intercycle nausea and nausea anticipatory symptoms. RESULTS: In total, 121 patients received ginger and 123 placebo. Lung (49%) and head and neck cancer (HNC; 35%) were the most represented tumors. No differences were reported in terms of safety profile or compliance. The incidence of delayed, intercycle and anticipatory nausea did not differ between the two arms in the first cycle and second cycle. A benefit of ginger over placebo in Functional Living Index Emesis nausea score differences (day 6-day 1) was identified for females (P = 0.048) and HNC patients (P = 0.038). CONCLUSIONS: In patients treated with high-dose cisplatin, the daily addition of ginger, even if safe, did not result in a protective effect on CINV. The favorable effect observed on nausea in subgroups at particular risk of nausea (females; HNC) deserves specific investigation.

Predictors of mortality of idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF), a disease with histological features corresponding to usual interstitial pneumonia (UIP), is a disorder of unknown cause. Not only it is the most common subtype of idiopathic interstitial pneumonias but it is also associated with the highest mortality rate. Despite a good number of studies investigating the mortality of patients with UIP the prognostic factors that have been studied have several limitations. To date it is unclear when in the course of the disease and with what modality these patients should be treated. According to the literature we subcategorized predictors of mortality into (a) baseline predictors; (b) dynamic predictors. IPF perspectives in therapy have been also analyzed. Moreover, the principal aims of this review were: (1) to analyze and to clarify the clinical utility of different prognostic factors for IPF; (2) to enable clinicians to better evaluate the eligibility criteria for lung transplantation in the clinical practice.

[Mesothelioma incidence and time trend in the worlds]. / Incidenza e variazioni temporali dei mesoteliomi nel mondo.

BACKGROUND: Due to its adaptability to different uses, asbestos was increasingly employed in many working and domestic areas up to the 1970s-1980s, when its aetiological role in the onset of pleural mesothelioma (Mm) was recognized. Since then Mm cases have been continuously increasing and no decline is expected until 2020, despite the fact that most industrialized countries banned asbestos use a few decades ago. OBJECTIVES: The aim of this study was to analyse Mm incidence in the World during the last ten years, also considering asbestos consumption in diferent areas. METHODS: Incidence age-standardized rates (ASR) from Cancer Registries included in Cancer Incidence in Five Continents, Vol. VII and VIII, and, when appropriate, standardized rate ratio (SRR) with confidence interval were estimated. RESULTS: The highest incidence rates among males were observed in Liguria and Australia. After Liguria, Maastricht and Scotland in Europe, North East Regions and Piedmont in Italy showed high rates. Among females, the highest incidence rates were observed in Liguria, among black women in New Orleans and in the province of Varese. SRRs revealed increased rates, not always significant, in almost all areas among males and in about 50% of the areas among females, although the variation was significant only in Varese. CONCLUSIONS: These results confirmed a relationship between Mm risk and asbestos use, revealing high incidence rates in Australia (mining), Italy (shipyards, building, goods handling, heavy industries and sea trade) and Great Britain (shipyards). Mm cases increased in areas with elevated incidence rates, suggesting that larger amounts of asbestos were probably used for a longer period. Finally, no Mm cases were registered in some areas, which probably signifies a lack (or a delay) of risk referred to the investigated period.

Incidence of pleural mesothelioma in Liguria Region, Italy (1996-2002).

In this study, incidence of pleural malignant mesothelioma (PMM) in the Liguria Region (Italy) (approximately 1.6 million inhabitants), in the presence of asbestos exposure was investigated. New PMM cases recorded by the Mesothelioma Registry of Liguria, from 1996 to 2002 and interviews reported on a standardised questionnaire were analysed according to demographical and etiological characteristics. Nine hundred and forty five PMM cases were recorded (757 males and 188 females); the age standardised (European population) incidence rates per 100,000 were 8.51 and 1.43, respectively. The rates among the four provinces ranged between 1.18 and 13.7 for males and 0.68 and 1.44 for females. The questionnaire was evaluated for 786 PMM cases (or next-of-kin). Higher incidence rates were reported in the provinces with larger industrial and harbour areas, including shipyards (construction and repair), dockyards, building activities, chemical and heavy industrial activities. Asbestos exposure was unlikely or unknown for 57.5% females and 15% males. A major role of environmental asbestos exposure in the etiology of PMM is hypothesised for females and for a minor proportion of males.

Epidemiologic surveillance for primary prevention of malignant mesothelioma: the Italian experience.

BACKGROUND: The Italian National Mesothelioma Registry (ReNaM) was set up at the National Institute for Occupational Safety and Health (ISPESL) to estimate Italian incidence of malignant mesothelioma (MM), define modalities of asbestos exposures, assess impact and diffusion of MM, identify underestimated sources of environmental contamination. OBJECTIVES: To describe ReNaM activity, database dimension and epidemiological characteristics of the caselist. METHODS: Regional Operating Centers (COR) in 16 Italian regions were set up to identify and investigate all cases of MM diagnosed in each region, applying national guidelines. COR collect cases in health care institutions. Occupational history, lifestyle and residence are obtained by direct interview using a standard questionnaire. Exposure modalities are classified by industrial hygienists, evaluating whether work, private life or any particular environmental condition could have involved asbestos exposure. RESULTS: Data refer to 3,446 cases collected in 9 Italian regions during 1993-2001. Pleural mesothelioma affected 94% cases, pleural/peritoneal ratio was 16:1. Gender ratio (M/F) was 2.7:1 (1.3:1 for peritoneum). There was a variety of occupational exposures, some already known as high risk sectors and others unexpected. The most common exposures occurred in building and construction, metallurgy and steel, shipbuilding, and railway stock. High risk categories were encountered such as bricklayers, plumbers, carpenters, electricians, welders, installers and maintenance workers in metallurgy and the steel industry, general labourers, tool makers and painters in shipbuilding/repair/demolition. CONCLUSIONS: Despite some ReNam's limitations, identification of MM cases and analysis of modality of exposure, with standardized criteria, are a fundamental tool for primary prevention of asbestos related diseases.

Targeting dystroglycan in the brain.

The dystrophin-glycoprotein complex is a multisubunit complex that connects the extracellular matrix components to the cytoskeletal matrix of muscle fiber cells and is required for muscle integrity. Mutations in this complex are associated with muscular dystrophy. Although the role of dystroglycan has been explored mainly in the context of muscle, recent work has also demonstrated a novel role for dystroglycan in the CNS and thus provides potential insights into the brain abnormalities associated with some forms of muscular dystrophy.

[Occupational exposure to asbestos and recognition of pleural mesothelioma as occupational disease in the province of Genoa]. / Esposizione professionale ad amianto e riconoscimento del mesotelioma pleurico come malattia professionale nella provincia di Genova.

The present study compares the data of pleural mesothelioma (PM) patients resident in the province of Genoa (Italy) who, in the period 1994-1996, applied to the Italian National Insurance Institute for Work Accident (INAIL), for workers' compensation for asbestos-related diseases due to occupational exposure, with the dataset of PM patients collected by the Mesothelioma Registry of Liguria (REM) in the same period and in the same area. As PM is a malignant tumor of a prevalently occupational origin, it is recognized and acknowledged as such by INAIL when clinical and etiological characteristics are matched. Objectives of this study were to describe observed PM cases, to evaluate completeness of collected data and differences between those who requested compensation and those who did not. The REM describes the incidence of PM among Ligurian residents, proposing patients with a specific questionnaire to assess occupational, environmental and indoor asbestos exposures. The REM collected 199 new cases of PM among the residents of both the city of Genoa (1994-96) and the province of Genoa (1995-96). In the same period, INAIL received 48 (24%) applications for compensation. Among these, 43 subjects were included in a subgroup of 98 patients registered in the REM as cases with definite diagnosis and ascertained asbestos exposure; 32 were awarded compensation, while 11 are under evaluation. The data collected by REM do not show proven asbestos exposure and/or PM diagnosis for five other subjects (two compensated and three under judgment). This study reveals that: a) only a 24% of the patients with a diagnosis of PM and asbestos exposure apply for compensation; b) an exchange of information among institutions involved in primary prevention, in the evaluation of occupational exposures to carcinogens and in insurance compensation is useful.

Mesothelioma and lung tumors attributable to asbestos among petroleum workers.

BACKGROUND: Asbestos exposure has been definitively found to be associated with both mesothelioma and lung cancer. Nevertheless, in the overall population of oil refinery workers potentially exposed to asbestos, many studies clearly show a definitely increased risk of mesothelioma, but no proven excess of lung cancer after comparison to the general population. Through the presentation of new data and the re-appraisal of two recent and independent epidemiological studies conducted in Liguria, Italy, and Ontario, Canada, we attempt to shed light on this apparently paradoxical finding. METHODS: Lung cancer mortality was studied among maintenance workers exposed to asbestos, and among two other subgroups of refinery employees: blue collar and white collar workers. The comparison with blue collar workers was performed in order to take into account the role of healthy worker effect, smoking habit, and the socioeconomic level. The comparison with white collar workers was performed to control for other occupational lung carcinogens. RESULTS AND CONCLUSIONS: Results reveal a consistency between the two studies and show that 96-100% of the mesotheliomas and 42-49% of the lung tumors arising among maintenance workers were attributable to asbestos exposure. Our new analysis, estimating two cases of asbestos-related lung cancer for each case of mesothelioma, confirms published findings on the magnitude of asbestos-related tumors in oil refineries.

[Mesothelioma registry of the Liguria region. Incidence and occupational etiology in a high risk area]. / Registro mesoteliomi della Liguria. Incidenza ed eziologia professionale in un'area ad alto rischio.

This paper presents the epidemiological analyses based on the first 5 years of activity of the Mesothelioma Registry of Liguria (REM). REM is a population-based cancer registry specialized in the study of both the incidence and etiology of primary pleural and peritoneal mesothelioma in Liguria (Italy). The REM completes normal clinical information with occupational and environmental anamnestic data in order to identify working and living areas at risk for asbestos-related pathologies. The REM started its activity in 1994 describing the incidence of pleural mesothelioma (PM) exclusively in the population resident in the city of Genoa (660,000 inhabitants); since 1996 the REM has studied the entire Liguria Region (1,640,000 inhabitants), where nearly 120 new cases of PM are diagnosed annually (20% are women). In the city of Genoa, between 1986-1987 and 1997-1998, PM crude incidence rate rose from 13.8 to 26.7 per 100,000 males over 40 years old. From 1994 to 1998 the REM registered 495 new patients with histologically (62%) and cytologically (9%) confirmed diagnosis of PM. 54% of them were immunocytohistochemically evaluated. Occupational information has been gathered for 248 subjects, i.e., 61% of cases with sure or probable diagnosis of PM. For 126 patients, occupational asbestos exposure (direct, indirect or only presence in the workplace) was identified on average 40 years before diagnosis. In particular, asbestos exposure was documented in shipyards, docks and cargo handling settings, building trades, iron and steel industries. Interestingly, during the same period (1955-1960), a large fraction of subjects without proved or declared direct asbestos exposure claimed to have worked in the same occupational settings. This suggests a possible unconscious indirect exposure to asbestos fibers in the workplace.

Whipple's disease. Description of a case and survey of the literature.

A case of Whipple's disease (WD) personally observed is described. A 28-year-old male was admitted to hospital for evaluation of weakness, intermittent fever and weight loss arisen since a month. On clinical investigation, he complained of vomit and diarrhea since three months. He had neither familial and personal past history of gastrointestinal diseases, nor any other important diseases. He denied use of drugs. Physical examination was negative. Laboratory findings showed anemia, low blood lymphocytes, low serum iron and total iron binding capacity, low total serum protein and low serum albumin and high level of ESR. Stool were negative for parasites and occult blood. Cultures of blood and urine were negative. Stool fat assay was > 7 g/24 h and D-xylose test showed a two-hour serum concentration < 25 mg/dl. Abdominal TC showed lumbo-aortic and mesenteric enlarged lymph nodes. An upper video endoscopy showed a duodenal lymphangectasia. Histological examination showed villar atrophy with massive infiltration of large PAS-positive diastase-resistant foamy cells. Ziehl-Nielsen staining was negative. WD was diagnosed and patient underwent therapy based on cotrimoxazole. This report emphasizes the difficulty to diagnose WD correctly, because of its rareness and clinical polymorphism. Recently, studies have identified a bacillus, Tropheryma whippelii, associated with WD, so that, in the next future, the diagnosis of WD will be faster and more accurate. Finally, it is important to administer antibiotics which can cross the blood brain barrier for at least one year, in order to prevent neurological relapse, often lethal.

alpha-Dystroglycan is a laminin receptor involved in extracellular matrix assembly on myotubes and muscle cell viability.

alpha-Dystroglycan (alpha-DG) is a laminin-binding protein and member of a glycoprotein complex associated with dystrophin that has been implicated in the etiology of several muscular dystrophies. To study the function of DG, C2 myoblasts were transfected stably with an antisense DG expression construct. Myotubes from two resulting clones (11F and 11E) had at least a 40-50% and 80-90% reduction, respectively, in alpha-DG but normal or near normal levels of alpha-sarcoglycan, integrin beta1 subunit, acetylcholine receptors (AChRs), and muscle-specific kinase (MuSK) when compared with parental C2 cells or three clones (11A, 9B, and 10C) which went through the same transfection and selection procedures but expressed normal levels of alpha-DG. Antisense DG-expressing myoblasts proliferate at the same rate as parental C2 cells and differentiate into myotubes, however, a gradual loss of cells was observed in these cultures. This loss correlates with increased apoptosis as indicated by greater numbers of nuclei with condensed chromatin and more nuclei labeled by the TUNEL method. Moreover, there was no sign of increased membrane permeability to Trypan blue as would be expected with necrosis. Unlike parental C2 myotubes, 11F and 11E myotubes had very little laminin (LN) on their surfaces; LN instead tended to accumulate on the substratum between myotubes. Exogenous LN bound to C2 myotubes and was redistributed into plaques along with alpha-DG on their surfaces but far fewer LN/alpha-DG plaques were seen after LN addition to 11F or 11E myotubes. These results suggest that alpha-DG is a functional LN receptor in situ which is required for deposition of LN on the cell and, further, implicate alpha-DG in the maintenance of myotube viability.

alpha-Dystroglycan functions in acetylcholine receptor aggregation but is not a coreceptor for agrin-MuSK signaling.

alpha-dystroglycan (alpha-DG) is an agrin-binding protein that has been implicated in acetylcholine receptor (AChR) clustering, but it is unclear whether it acts as a coreceptor involved in initial agrin signaling or as a component involved in later events. To investigate its role, we have generated antisense derivatives of the C2 mouse muscle cell line, which have reduced alpha-DG expression. When compared with wild-type cells, the alpha-DG-deficient myotubes have a dramatic reduction in the number of spontaneous and agrin-induced AChR clusters. Several findings suggest that this decrease in AChR clustering is likely not because of a defect in agrin signaling through the MuSK receptor tyrosine kinase. Compared with wild-type cells, the alpha-DG-deficient cell lines showed only a transient reduction in the level of agrin-induced MuSK tyrosine phosphorylation and no reduction in AChR beta-subunit tyrosine phosphorylation. Additionally, agrin-induced phosphorylation of MuSK in wild-type myotubes was not decreased using agrin fragments that lack the domain primarily responsible for binding to alpha-DG. Finally, neural agrin-induced phosphorylation of MuSK was unaffected by treatments such as excess muscle agrin or anti-alpha-DG antibodies, both of which block agrin-alpha-DG binding. Together, these results suggest that alpha-DG is not required for agrin-MuSK signaling but rather that it may play a role elsewhere in the clustering pathway, such as in the downstream consolidation or maintenance of AChR clusters.

Laminin and alpha-dystroglycan mediate acetylcholine receptor aggregation via a MuSK-independent pathway.

Specific isoforms of laminin (LN) are concentrated at neuromuscular junctions (NMJs) where they may participate in synaptic organization or function. In myotubes from C2 cells, LN is concentrated within the majority of spontaneous acetylcholine receptor (AChR) aggregates. Neural agrin substantially increases this colocalization, suggesting that agrin can recruit LN into AChR aggregates. Addition of LN to C2 myotubes induces a more than twofold increase in the number of AChR aggregates. These aggregates have a larger size and are more dense than are those induced by agrin, suggesting that LN is involved in the growth and/or stabilization of AChR aggregates. Consistent with this hypothesis, an antiserum to LN reduces the size of individual AChR aggregates but increases their number. In C2 myotubes, extracellular matrix receptors containing the integrin beta1 subunit are poorly colocalized with AChR aggregates, suggesting that integrins may not be involved in LN-induced aggregation. In contrast, almost all AChR aggregates are associated with dystroglycan immunoreactivity, and monoclonal antibody (mAb) IIH6 against alpha-dystroglycan (alpha-DG), a LN and agrin receptor, causes a concentration-dependent inhibition of LN-induced aggregation. Moreover, S27 cells, which lack a functional alpha-DG, and two C2-derived cell lines expressing antisense DG mRNA fail to aggregate AChRs in response to LN. Finally, LN-induced AChR aggregation does not involve the phosphorylation of the muscle-specific tyrosine kinase receptor (MuSK) or the AChR beta subunit. We hypothesize that the interaction of LN with alpha-DG contributes to the growth and/or stabilization of AChR microaggregates into macroaggregates at the developing NMJ via a MuSK-independent mechanism.

Bioactive long chain N-acylethanolamines in five species of edible bivalve molluscs. Possible implications for mollusc physiology and sea food industry.

Several long chain N-acylethanolamines, including the proposed endogenous ligands of cannabinoid receptors, anandamide (N-arachidonoylethanolamine, C20:4 NAE) and N-palmitoylethanolamine (C16:0 NAE), as well as some of their putative biosynthetic precursors, the N-acyl-phosphatidylethanolamines, were found in lipid extracts of five species of bivalve molluscs, including Mytilus galloprovincialis, commonly used as sea food. The amounts of these metabolites, the most abundant being C16:0 NAE and N-stearoylethanolamine, appeared to increase considerably when mussels were extracted 24h post-mortem, but were not significantly affected by boiling the tissue prior to extraction. In particulate fractions of homogenates from Mytilus, where the existence of a highly selective cannabinoid receptor with an immunomodulatory function has been previously described, an enzymatic activity capable of catalyzing the hydrolysis of C20:4 NAE amide bond, and displaying similar pH dependency and inhibitor sensitivity profiles as the recently characterized 'fatty acid amide hydrolase' was found. The enzyme Km and Vmax for C20:4 NAE were 29.6 microM and 73 pmol/mg protein/min, respectively. These findings support the hypothesis that C20:4 NAE, never reported before in the phylum Mollusca, may be a mollusc physiological mediator, and suggest that edible bivalves may be a dietary, albeit limited, source of C16:0 NAE, whose anti-inflammatory properties, when administered orally in amounts higher than those reported here, have been previously reported.

Mortality in a cohort of tannery workers.

OBJECTIVES: To evaluate the mortality of a group of tannery workers. METHODS: The cohort consisted of 1244 workers (870 men and 374 women) employed at a chrome tannery between 1955 and 1988. A total of 36414 person-years of follow up was calculated (369 people had died). National and regional mortalities were used to estimate the expected numbers. RESULTS: All cause mortality was similar to that of the general population. The most remarkable excess was for bladder cancer (observed 10, standardised mortality ratio (SMR) 242, 95% confidence interval (95% CI) 116 to 446). An excess of colorectal cancer (observed 17, SMR 180, 95% CI 105 to 288) was also found, based on an increased risk of both colon (SMR 166) and rectal cancer (SMR 206). No recognisable patterns emerged from the analyses by years since first employment, calendar year of hire, or lagging exposures. CONCLUSIONS: The increased mortality from bladder cancer is likely due to exposure to benzidine based leather dyes. If the apparent excess of colorectal cancer is real, its causes are as yet unknown.

Is human exposure to styrene a cause of cytogenetic damage? A re-analysis of the available evidence.

Abstract The possibility that occupational exposure to styrene causes genotoxic effects in humans has been the focus of many biomonitoring studies based on classic cytogenetic biomarkers. Contrasting results have been reported, positive studies being counterbalanced by a number of negative findings. The strength of the conclusions of single studies, either positive or negative, was often weakened by factors such as limited sample size, inadequate exposure assessment, poor epidemiological design, or inappropriate statistical analysis. We have undertaken a meta-analysis of 25 biomonitoring studies of occupational exposure to styrene, in the attempt to discover whether, regardless of the limitations of the individual studies, a general trend could be evinced from a quantitative review of the available evidence on this topic. Essentially, our approach involved a dichotomic classification of all studies according to the median environmental exposure level to styrene, i.e. 125 mg m(-3) (30 p pm), anda quantitative evaluation of the biological effects comparable among the studies considered, i.e. frequency ratio (FR). In order to provide combined estimates of effect across all studies, a weight was attributed to each study depending on its sample variance, andweighted frequency ratios (w FR) were calculated for the endpoints considered, i.e. chromosome aberrations (CA), sister-chromatid exchanges (SCE), andmicronuclei (MN). A significant increase of the wFR was found for CA from the studies performed on workers with 'high level' exposure to styrene (wFR = 2.18; 95%.CI = 1.52-3.13), while inconclusive data were obtained for SCE andMN.

Dystroglycan expression in the wild type and mdx mouse neural retina: synaptic colocalization with dystrophin, dystrophin-related protein but not laminin.

Alpha- and beta-dystroglycan (alpha- and beta-DG) are members of a dystrophin-associated glycoprotein complex (DGC) in skeletal muscle which binds to agrin and laminin, and has been postulated to be involved in myoneural snyapse formation. The absence of functional dystrophin in Duchenne muscular dystrophy (DMD) and in one of its animal models, the mdx mouse, leads to a reduction of alpha- and beta-DG in muscle, and is often associated with mental retardation and abnormal retinal synaptic transmission in DMD. Using immunohistochemistry, we find that alpha- and beta-DG are expressed in the outer plexiform layer of both wild type and mdx retina, where both dystrophin and dystrophin-related protein (DRP), but not laminin are present. In situ hybridization identifies two neuronal populations, photoreceptors and retinal ganglion cells, that express DG mRNA. Alpha- and beta-DG are also expressed in the inner limiting membrane and around blood vessels where they colocalize with laminin and DRP. Western blot analysis revealed the expression of several dystrophin isoforms in wild type and mdx retina, possibly explaining the unaltered expression of alpha- and beta-dystroglycan in the mdx central nervous system (CNS). Our results support the hypothesis that alpha- and beta-DG can interact with dystrophin and DRP in the CNS and perform functions analogous to those of the DGC in muscle.

Hepatitis B vaccination: universal vaccination of newborn babies and children at 12 years of age versus high risk groups. A comparison in the field.

From 1983 to 1993 two anti-hepatitis B vaccinal strategies were adopted in two small towns of Southern Italy at high incidence for HBV infections: Afragola (prevalence of HBsAg carriers of 13.4%) and Frattamaggiore (prevalence of HBsAg carriers of 12.9%). In Afragola, the universal vaccination of infants in their first year of life and adolescents at 12 years of age was carried out, while in Frattamaggiore the selective vaccination of high risk groups of population was introduced. During this study, the changes in the HBV infection endemicity in both towns has been tested by monitoring the incidence of new cases of viral hepatitis B and by the prevalence study of HBsAg carriers prior to and 10 years after the beginning of the immunization programme (1978-1993). The results suggest that universal vaccination of infants in the first year of life and adolescents at 12 years of age has a greater efficiency on the improvement on the endemic status of the infection in the general population in comparison with selective vaccination, when the incidence of new cases of disease and the prevalence of number of HBsAg and anti-HBc carriers in the two populations are considered.