Addition of either pioglitazone or a sulfonylurea in type 2 diabetic patients inadequately controlled with metformin alone: impact on cardiovascular events. A randomized controlled trial.

BACKGROUND AND AIMS: Metformin is the first-line therapy in type 2 diabetes. In patients inadequately controlled with metformin, the addition of a sulfonylurea or pioglitazone are equally plausible options to improve glycemic control. However, these drugs have profound differences in their mechanism of action, side effects, and impact on cardiovascular risk factors. A formal comparison of these two therapies in terms of cardiovascular morbidity and mortality is lacking. The TOSCA.IT study was designed to explore the effects of adding pioglitazone or a sulfonylurea on cardiovascular events in type 2 diabetic patients inadequately controlled with metformin. METHODS: Multicentre, randomized, open label, parallel group trial of 48 month duration. Type 2 diabetic subjects, 50-75 years, BMI 20-45 Kg/m(2), on secondary failure to metformin monotherapy will be randomized to add-on a sulfonylurea or pioglitazone. The primary efficacy outcome is a composite endpoint of all-cause mortality, nonfatal myocardial infarction, nonfatal stroke, and unplanned coronary revascularization. Principal secondary outcome is a composite ischemic endpoint of sudden death, fatal and non-fatal myocardial infarction and stroke, endovascular or surgical intervention on the coronary, leg or carotid arteries, major amputations. Side effects, quality of life and economic costs will also be evaluated. Efficacy, safety, tolerability, and study conduct will be monitored by an independent Data Safety Monitoring Board. End points will be adjudicated by an independent external committee. CONCLUSIONS: TOSCA.IT is the first on-going study investigating the head-to-head comparison of adding a sulfonylurea or pioglitazone to existing metformin treatment in terms of hard cardiovascular outcomes. REGISTRATION: Clinicaltrials.gov ID NCT00700856.

T-cell precursors in mice bearing the Ehrlich ascites tumors.

Mice bearing Ehrlich ascites tumors and challenged with sheep erythrocytes produced fewer plaque-forming cells than did normal mice. At the same time the immunosuppression developed, the number of T lymphocytes in the thymus and spleen were reduced significantly. In the spleen, the number of B lymphocytes remained constant during carcinogenesis, whereas that of the macrophages increased significantly, as compared to the controls. In this paper, we demonstrated that the mechanism responsible for thymus and spleen depletion of theta antigen-bearing cells had to be ascribed to fewer T-lymphocyte precursors in the bone marrow of mice with cancer. The reduction of T-lymphocyte precursors was probably caused by the same "soluble factor(s)" produced by Ehrlich ascites tumor cells, which also interfered with the proliferation of myelopoietic stem cells in the bone marrow of mice with this neoplasm, as we previously reported. By performing several reconstitution experiments of lethally X-irradiated hosts, we determined that the immunodepression by Ehrlich ascites tumor cells was readily reversible, and the alteration of the T:B lymphocyte ratio in the spleen had a minor function, if any, in the pathogenesis of the immunosuppression.

Colony-stimulating factor produced by murine adrenocortical tumor cells.

Conditioned medium obtained from the adrenocortical LAF1 mouse tumor (Y-1) cell cultures was able to stimulate the proliferation and the differentiation of granulocyte-macrophage precursors in the normal murine bone marrow. Colony-stimulating factor (CSF) was spontaneously produced by Y-1 cells also in serum-free cultures. By two cycles of gel chromatography on Sephadex G-150 of concentrated conditioned medium two peaks of colony-stimulating activity were isolated that corresponded to apparent molecular radii of 100,000 and 29,000, respectively. At this step of purification, the two factors gave a similar dose-response curve, showed a remarkable resistance to the heat treatment and pH changes, and were not extracted by ether. Because Y-1 cells resulted in infection by retrovirus, they provide a useful model to investigate the relations between viral coded information and CSF production.

An assessment of dioxin exposure across gestation and lactation using a PBPK model and new data from Seveso.

On July 10, 1976, an explosion at a chemical plant in Seveso, Italy, released up to 30kg of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-the most potent dioxin congener. Twenty years later, the Seveso Women's Health Study (SWHS) initiated a follow-up assessment of a cohort of female Seveso residents. Researchers collected serial blood, measured for TCDD levels, and recorded information about the women's medical history after the explosion. The study's aims were to: 1) modify the human PBPK model for TCDD (Emond et al. 2004; Emond et al. 2005; NCEA-USEPA, 2010) to include repetitive gestation and lactation; 2) simulate TCDD blood concentrations during different life stages including pregnancy and lactation, under different exposure scenarios; and 3) use this PBPK model to compare the influence of gestation and lactation on elimination of TCDD. After optimization of the model, it was assessed using data from the SWHS cohort. The 23 women in Subcohort A, were 4-39years old and in Subcohort B, the 18 women were 3-17years old when the explosion occurred. The model accurately predicted the blood concentrations during the 20years post-exposure, including periods of pregnancy and lactation. The model was also used to analyze the contribution of gestation and lactation to the mother's elimination of TCDD. The results suggest that gestation and lactation do not significantly impact TCDD blood elimination. Future efforts will focus on using additional data to evaluate the PBPK model and improving the mathematical descriptions of lactation and multiple gestations.

The prevalence of Molar Incisor Hypomineralisation (MIH) in a group of Italian school children.

AIM: This epidemiological study in a group of Italian children was undertaken in order to increase our knowledge of the prevalence of Molar Incisor Hypomineralisation (MIH) in different European countries. METHOD: A population of school children aged 7.3 - 8.3 years, living in Lissone, Northern Italy, was examined for the presence and severity of MIH. RESULTS: Of a total of 227 children (113 females), 31 (13.7%) had MIH, the tooth prevalence in the permanent first molars being 5.8%. Fifteen children (6.6%) had demarcated opacities in the incisors with a tooth prevalence of 2.1%. The defects in the molars were mild with the exception of one child who had severe defects. CONCLUSION: MIH was quite common in this Italian town, and the prevalence figures were near those reported in Scandinavian countries but clearly higher than those from Dresden, Germany.

2,3,7,8-Tetrachlorodibenzo-p-dioxin plasma levels in Seveso 20 years after the accident.

In 1976, near Seveso, Italy, an industrial accident caused the release of large quantities of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) into the atmosphere, resulting in the highest levels of the toxicant ever recorded in humans. The contaminated area was divided into three zones (A, B, R) corresponding to decreasing TCDD levels in soil, and cohort including all residents was enumerated. The population of the surrounding noncontaminated area (non-ABR) was chosen as referent population. Two decades after the accident. plasma TCDD levels were measured in 62 subjects randomly sampled from the highest exposed zones (A and B) and 59 subjects from non-ABR, frequency matched for age, gender, and cigarette smoking status. Subjects living in the exposed areas have persistently elevated plasma TCDD levels (range = 1.2-89.9 ppt; geometric mean = 53.2 and 11.0 ppt for Zone A and Zone B, respectively). Levels significantly decrease by distance from the accident site (p = 0.0001), down to general population values (4.9 ppt) in non-ABR, thus validating the original zone classification based on environmental measurements. Women have higher TCDD levels than men in the entire study area (p = 0.0003 in Zone B; p = 0.007 in non-ABR). This gender difference persists after adjustment for location within the zone, consumption of meat derived from locally raised animals, age, body mass index, and smoking. There is no evidence for a gender difference in exposure, so variation in metabolism or elimination due to body fat or hormone-related factors may explain this finding. Elevated TCDD levels in women may contribute to adverse reproductive, developmental, and cancer outcomes.

Demographic and behavioural correlates of high density lipoprotein cholesterol. An international comparison between northern Italy and the United States.

Recently published results of longitudinal follow-up studies conducted in the US have identified high density lipoprotein (HDL)-cholesterol as an independent and strong predictive factor for coronary heart disease (CHD). Some inconsistencies in this association have been found when geographical comparisons were done, which could be explained by hypothesizing differences in population HDL-cholesterol determinants. We carried out a comparative analysis of demographic and behavioural correlates of HDL-cholesterol between Northern Italy and the US, two countries with well-known differences in CHD risk and HDL-cholesterol levels. The study was conducted on representative samples of these two countries (MONICA Project-Area Brianza for Northern Italy and NHANES II for the US) and used comparable methodologies for data collection and statistical analysis. Results indicate that gender, age, body mass, cigarette smoking and alcohol consumption are independently associated with HDL-cholesterol in both populations; physical activity is positively, but not significantly, associated with HDL-cholesterol mean levels, and education achievement is independently associated only in the American sample. The comparison of the magnitude of the multivariate regression coefficients between the two studies suggests similar functional relationships for most of the correlates considered. The small, albeit significant, discrepancies found for body mass and smoking status could be related either to some methodological inconsistencies between the two surveys, or to possible effects of other covariates, not available to be tested in this study, like dietary habits. Moreover, HDL-cholesterol mean level differences between populations could be also due to differences in the prevalence of the examined correlates.

Time trends of major coronary risk factors in a northern Italian population (1986-1994). How remarkable are socioeconomic differences in an industrialized low CHD incidence country?

BACKGROUND: The goals are to estimate time trends (1986-1994) of major coronary risk factors in an industrialized low CHD incidence population and to assess education class (EC) differences in risk factor prevalence and in time trends. METHODS: Three population surveys were conducted in 1986-1987, 1989-1990 and 1993- 1994 on independent and two-stage age- and gender-stratified random samples (1906 men and 1941 women) of 35-64 year old residents of Brianza, an affluent region of northern Italy. The protocol for data collection, clinical measurements and biochemical determinations adhered to the WHO MONICA manual and underwent repeated quality control assessments. EC were identified according to gender- and 5-year birth-cohort specific tertiles. RESULTS: In the initial, middle and final surveys 1258, 1259 and 1330 subjects were enrolled, corresponding to participation rates of 70.1%, 70.3% and 74.3%, respectively. Over the 8-year period, in men systolic blood pressure and smoking habits declined, body mass index and serum total cholesterol increased. In women systolic blood pressure showed a constant reduction, total cholesterol and BMI increased and the prevalence of smokers remained stable. Overall inverse associations with EC were found for body mass index, for prevalence of cigarette smokers in men and for systolic blood pressure in women. Decreases in blood pressure were more evident in the lowest EC. Cigarette smoking was on the decline in the higher EC in men. BMI and total cholesterol increased in all EC with the notable exception of the 'low' EC in women. CONCLUSIONS: Favourable changes of the risk factor profile in the low socio-economic classes may have contributed to reduce CHD rates in this population. Specific policies oriented to lowest socio-economic classes are needed to continue to combat the smoking epidemic.

Factors produced by macrophages and tumor cells: influence on the granulocytic precursor cells (CFU-C) in normal and tumor-bearing mice.

Some tumors are known to produce colony-stimulating factors (CSF). In mice bearing s.c. Ehrlich tumor (ET) we observed that tumor growth is responsible for hemopoietic perturbations in which the increase of granulocytic-macrophagic precursors (CFU-C) in bone marrow and in the spleen represents a remarkable aspect. CFU-C in bone marrow from ET-bearing mice are more sensitive than CFU-C from normal mice to CSF from L-cells (LC-CM), mouse embryo fibroblasts (MEF-CM) and from the same tumor (ET-CM). Macrophages from normal and from ET-bearing mice exert the same effect on the proliferation of normal bone marrow CFU-C. Bone marrow CFU-C from ET-bearing mice show an increased sensitivity to the inhibitory factors produced by macrophages from ET-bearing mice.

Inefficacy of moving average algorithm as principal quality control procedure on Technicon System H6000.

Bull's algorithm, in its "revisited" formulation, represents one of the main quality control (QC) procedures in several multichannel automatic hematological analyzers. Its efficacy, however, is reduced in the theoretical event that red blood cells (RBC) and hemoglobin (Hgb) undergo a concomitant analytical drift while mean corpuscular volume (MCV) remains unaffected, so that a null effect is registered on the related erythrocytic indices: mean corpuscular hemoglobin (MCH) and mean corpuscular hemoglobin concentration (MCHC). This particular phenomenon has been observed on the Technicon System H6000. Routine daily work was kept in control through the use of commercial controls and fresh blood samples: a reproducible positive drift of two directly measured erythrocytic parameters (RBC and Hgb) and of the calculated hematocrit (Hct) was observed proportional to the time of continuous use of the instrument. The usefulness of Bull's QC scheme was greatly reduced: it failed to detect "out of control" situation in 38%, 15%, and 13% of cases in the monitoring of MCV, MCH, and MCHC, respectively, when compared with the traditional 2 SD limits on QC samples.

Results of a pilot study of endoscopic screening of first degree relatives of colorectal cancer patients in Italy.

STUDY OBJECTIVE: Screening recommendations for colorectal cancer include sigmoidoscopy in asymptomatic, average risk persons aged 50 and over and colonoscopy every three to five years in high risk groups. Little is known about the eligible population's compliance with endoscopic screening. This is the first Italian report of an endoscopic screening programme for colorectal cancer patients' relatives. DESIGN: In 1986, a pilot project for colorectal cancer screening by endoscopy in high risk subjects was started in the Desio (Milan, Italy) public health service region. The results obtained after seven years are described. SETTING: The names of 536 inhabitants with colorectal cancer diagnosed between January 1975 and December 1984 and their relatives' addresses were obtained from the Regione Lombardia Health System records and from the municipal registry offices respectively. PARTICIPANTS: From October 1986 to October 1993, 778 first degree relatives aged 20-75 were offered colonoscopy. MAIN RESULTS: After seven years, 233 (29.9%) had undergone endoscopic examination, mostly up to the splenic flexure. Being > 60 in age at the start of the programme negatively affected the participation (p < 0.05). Two cancers were detected and adenomatous polyps were found in another 24 of those screened (frequencies 0.9% and 10.3% respectively). Male gender (p < 0.05), increasing age in males (p < 0.01), and two or more affected relatives in females (p < 0.01) positively affected the frequency of polyps detection. CONCLUSION: These results suggest that about 30% of the eligible population would comply at least with sigmoidoscopic screening. The collaboration of family doctors and more widespread public information about the ability to cure colorectal cancer are necessary for better compliance.

Training and continuous education of clinical laboratory technologists and technicians.

The profession of clinical laboratory technologist has undergone profound changes in the last decades and scientific as well as technological advancement will cause further continued evolution. Therefore, adaptability to a rapidly evolving environment and willingness to continuously update knowledge as well as skills seem to be the most important demands confronting technologists. I compare the current training of clinical laboratory technologist in industrialized countries with emerging educational schemes, which include curricula based on national requirements comprising a total of 3-4 years of formal lectures and practical training.

Increased urinary D-glucaric acid excretion by children living in an area polluted with tetrachlorodibenzoparadioxin (TCDD).

Extremely small doses of TCDD have been shown to induce hepatic microsomal enzymes in animals. Whether levels of environmental exposure to TCDD were sufficient to produce enzyme induction in man, has been investigated in Seveso, where in July 1976 explosion in a factory spread toxic substances, one of which was TCDD, to the surrounding area. The hepatic microsomal enzyme activity was assessed by estimating urinary d-glucaric acid (UGA) excretion in children 6-8 years old. In 31 children, urine samples were collected between August and December 1976; in 67 other children in February 1979. As a control group 60 children living in Busto Arsizio (a small industrial town near Milan) and 26 living Cannero (a non-industrialized village on Lake Maggiore) were chosen. In the first period of collection, children with chloracne (which is considered to be a characteristic manifestation of intoxication with chlorinated products), showed significantly increased levels of UGA compared with children without chloracne. In 1979, children living in the Seveso area showed a statistically significant enhancement of d-glucaric acid excretion compared to the control groups. In conclusion, this study demonstrates that many children living in the Seveso area have an increased activity of hepatic microsomal enzymes, since, although the urinary excretion of d-glucaric acid is only an indirect measure of enzyme activity, studies in man have indicated that it is both sensitive and quantitative. As far as the cause of this increase is concerned, since it is possible to exclude the influence of alcohol, contraceptives, phenobarbitone or other drugs, it is reasonable to conclude that TCDD, a potent inducer agent, could be responsible for this phenomenon.

Potential 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure of Seveso decontamination workers: a controlled prospective study.

In 1976, an explosion at the Industrie Chimiche-Meda-Società Azionaria (ICMESA) plant in Meda, near the Italian town of Seveso, released a cloud of aerosol containing 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), which contaminated the surrounding area. Clean-up of the highly polluted area of Seveso started on May 1980: in order to avoid exposure to significant levels of TCDD, safety measures are being used, but a potential exposure cannot be ruled out. A prospective study was set up at the beginning of the clean-up procedures, and laboratory tests are being used to evaluate trends among the decontamination workers. A reference group who met eligibility criteria at the preemployment examination was selected from employees of the same firm employing the decontamination was selected from employees of the same firm employing the decontamination workers. Medical examinations and laboratory tests have been performed on both the exposed and nonexposed groups at the same facilities. Analysis of the first follow-up period did not show any remarkable changes in a battery of laboratory tests of the exposed and nonexposed groups.

Effect of tumor-related factors on the in vivo and in vitro colony-forming ability of normal mouse marrow cells.

The effect of normal mouse marrow preincubation with Ehrlich tumor fluid (EAF) and Ehrlich tumor cell-conditioned medium (ET-CM) was investigated both on the in vivo assay for pluripotential stem cells (CFU-S) and on the in vitro assay for granulocytic-macrophagic progenitors (CFU-C). A significant reduction of the number of CFU-S was found when bone marrow cells were incubated with EAF. The morphological analysis showed a relative increase in the granulocytic type colonies besides an absolute increase in undifferentiated ones and an absolute decrease in erythroid colonies. The in vitro data show a decrease in CFU-C production, by stimulation with standard Colony Stimulating Factor (CSF), when the marrow cells are preincubated with EAF and ET-CM. When standard CAF (obtained from L-cells) is used at the higher concentrations, the CFU-C in the ET-CM treated marrow increases to the control values. EAF and ET-CM incubation also affects the CFU-C differentiation by increasing the number of pure granulocytic clones. The experimental data were discussed in order to explain an hypothesis about the activity of tumor-related factors.

Seveso Women's Health Study: a study of the effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on reproductive health.

Although reproductive effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure have been reported in numerous investigations of animals, studies of this association in humans are limited. In 1976, an explosion in Seveso, Italy exposed the surrounding population to among the highest levels of TCDD recorded in humans. The relatively pure exposure to TCDD and the ability to quantify individual level TCDD exposure from sera collected in 1976 for the Seveso cohort affords a unique opportunity to evaluate the potential dose-response relationship between TCDD exposure and a spectrum of reproductive endpoints. The Seveso Women's Health Study (SWHS) is the first comprehensive study of the reproductive health of a human population exposed to TCDD. The primary objectives of the study are to investigate the relationship of TCDD and the following endpoints: (1) endometriosis; (2) menstrual cycle characteristics; (3) age at menarche; (4) birth outcomes of pregnancies conceived after 1976; (5) time to conception and clinical infertility; and (6) age at menopause. Included in the SWHS cohort are women who were 0-40 yr old in 1976, who have adequate stored sera collected between 1976 and 1980, and who resided in Zones A or B at the time of the accident. All women were interviewed extensively about their reproductive and pregnancy history and had a blood draw. For an eligible subset of women, a pelvic exam and transvaginal ultrasound were conducted and a menstrual diary was completed. More than 95% of the women were located 20 yr after the accident and roughly 80% of the cohort agreed to participate. Data collection was completed in July 1998, serum TCDD analysis of samples for analysis of endometriosis as a nested case-control study was completed in October 1998, and statistical analysis of these data should be completed in early 1999. Serum samples are now being analyzed in order to relate TCDD levels with the remaining reproductive outcomes.

Seveso Women's Health Study: does zone of residence predict individual TCDD exposure?

The compound, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), is produced as an unwanted by-product of various chemical reactions and combustion processes, including the manufacture of chlorinated phenols and derivatives. In animals, TCDD exposure is associated with toxic, carcinogenic, developmental, and reproductive effects. In 1976, a chemical plant explosion in Seveso, Italy, exposed the residents in the surrounding community to the highest exposure to TCDD known in humans. Materials from an aerosol cloud of sodium hydroxide, sodium trichlorophenate and TCDD were deposited over an 18.1 km2 area. As evidence of the significant level of TCDD exposure, numerous animals died and 193 cases of chloracne were reported among residents of the area. Initially, the contaminated area was divided into three major exposure Zones (A, B, R) based on the concentration of TCDD in surface soils. To date, the majority of epidemiologic studies conducted in Seveso have used Zone of residence as a proxy measure of exposure. The purpose of the present study is to validate the use of Zone of residence in Seveso as a proxy measure of exposure against individual serum TCDD measurement, and to determine whether questionnaire information can improve the accuracy of the exposure classification. Using data collected from the Seveso Women's Health Study (SWHS), the first comprehensive epidemiologic study of the reproductive health of women in Seveso, we determined that Zone of residence is a good predictor of individual serum TCDD level, explaining 24% of the variance. Using questionnaire information could have improved prediction of individual exposure levels in Seveso, increasing the percent of the variation in serum TCDD levels explained to 42%.

Controlling persistent organic pollutants-what next?

Within the context of current international initiatives on the control of persistent organic pollutants (POPs), an overview is given of the scientific knowledge relating to POP sources, emissions, transport, fate and effects. At the regional scale, improvements in mass balance models for well-characterised POPs are resulting in an ability to estimate their environmental concentrations with sufficient accuracy to be of help for some regulatory purposes. The relevance of the parameters used to define POPs within these international initiatives is considered with an emphasis on mechanisms for adding new substances to the initial lists. A tiered approach is proposed for screening the large number of untested chemical substances according to their long-range transport potential, persistence and bioaccumulative potential prior to more detailed risk assessments. The importance of testing candidate POPs for chronic toxicity (i.e. for immunotoxicity, endocrine disruption and carcinogenicity) is emphasised as is a need for the further development of relevant SAR (structure activity relationship) models and in vitro and in vivo tests for these effects. Where there is a high level of uncertainty at the risk assessment stage, decision-makers may have to rely on expert judgement and weight-of-evidence, taking into account the precautionary principle and the views of relevant stake-holders. Close co-operation between the various international initiatives on POPs will be required to ensure that assessment criteria and procedures are as compatible as possible.

Granulocytic-macrophagic and macrophagic colony stimulating factors elicit colonies of mast cells in mouse bone marrow agar culture. An electron microscope study.

Granulocytic-macrophagic colony stimulating factor (GM-CSF) and macrophagic colony stimulating factor (M-CSF or CSF-1) stimulate bone marrow cells of mouse to produce in semisolid agar colonies in which mononuclear cells were reported to be macrophages. We verified in such colonies the ultrastructure of the mononuclear cells which had cytoplasmic granules of the mast cells and lacked lysosomes, therefore we considered them as mast cells. However, the granules content did not reach the degree of condensation typically found in granules of mouse peritoneal mature mast cells. The mast cells of colonies obtained in agar can be mast cells arrested at some point in the maturative process, mast cells of a yet unrecognized type or cells with mast cells ultrastructural features which behave as precursors for cells of myeloid lineage.

[Seveso: biological monitoring of dioxin pollution. An example of environmental medicine. Multicentric and interdisciplinary applied research]. / Seveso--Monitoraggio biologico di inquinamento da Diossina: Esempio di Medicina Ambientale. Ricerca Applicata Multicentrica e Interdisciplinare.

In 1976 the population of an area including Seveso (about 30,000) affected by the fallout of a toxic cloud containing 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) started a health monitoring plan which lasted until 1985. Smaller groups were monitored until 1997. The large number of people and the different toxic effects on organs have gathered different discipline experts including informatic. This work has permitted the not easy observation both of minor and bigger effects during two decades.