Paolo Mocarelli

C-Reactive Protein in Heart Failure Prognostic Value and the Effect of Valsartan

Background—The role of C-reactive protein (CRP) in heart failure is not well studied. We assessed the prognostic value of CRP in patients randomized in Val-HeFT (Valsartan Heart Failure Trial) and studied changes in CRP that were associated with valsartan. Methods and Results—Characteristics of patients with baseline CRP levels above and below the median value were compared. Univariable and multivariable Cox proportional hazards regression models were used to examine the relationship of CRP to mortality and morbidity. Interactions were tested to determine whether differences in CRP changes from baseline to 4 and 12 months between groups randomly assigned to valsartan or placebo depended on baseline ACE inhibitor use. Median plasma CRP was 3.23 mg/L (interquartile range 1.42 to 7.56 mg/L), which is higher than in the general population. Patients with CRP above the median had features of more severe heart failure than those with CRP levels below the median. The cumulative likelihood of death and first morbid event increased with increasing quartile of CRP. Relative to the lowest CRP quartile, the risk of mortality (hazard ratio 1.51, 95% CI 1.2 to 1.9) and first morbid event (hazard ratio 1.53, 95% CI 1.28 to 1.84) was increased in the highest CRP quartile in multivariable models. CRP added incremental prognostic information to that provided by brain natriuretic peptide alone. CRP did not change significantly over time in the placebo group; however, after 12 months, valsartan was associated with a decrease in CRP in patients not receiving ACE inhibitors but not in those receiving ACE inhibitors at 12 months. Conclusions—CRP is increased in heart failure. Higher levels are associated with features of more severe heart failure and are independently associated with mortality and morbidity. The ability of treatments to reduce CRP levels and the prognostic importance of reducing CRP require further study.

Prognostic Significance of the Long Pentraxin PTX3 in Acute Myocardial Infarction

Background—Inflammation has a pathogenetic role in acute myocardial infarction (MI). Pentraxin-3 (PTX3), a long pentraxin produced in response to inflammatory stimuli and highly expressed in the heart, was shown to peak in plasma ≈7 hours after MI. The aim of this study was to assess the prognostic value of PTX3 in MI compared with the best-known and clinically relevant biological markers. Methods and Results—In 724 patients with MI and ST elevation, PTX3, C-reactive protein (CRP), creatine kinase (CK), troponin T (TnT), and N-terminal pro-brain natriuretic peptide (NT-proBNP) were assayed at entry, a median of 3 hours, and the following morning, a median of 22 hours from symptom onset. With respect to outcome events occurring over 3 months after the index event, median PTX3 values were 7.08 ng/mL in event-free patients, 16.12 ng/mL in patients who died, 9.12 ng/mL in patients with nonfatal heart failure, and 6.88 ng/mL in patients with nonfatal residual ischemia (overall P<0.0001). Multivariate analysis including CRP, CK, TnT, and NT-proBNP showed that only age ≥70 years (OR, 2.11; 95% CI, 1.04 to 4.31), Killip class >1 at entry (OR, 2.20; 95% CI, 1.14 to 4.25), and PTX3 (>10.73 ng/mL) (OR, 3.55; 95% CI, 1.43 to 8.83) independently predicted 3-month mortality. Biomarkers predicting the combined end point of death and heart failure in survivors were the highest tertile of PTX3 and of NT-proBNP and a CK ratio >6. Conclusions—In a representative contemporary sample of patients with MI with ST elevation, the acute-phase protein PTX3 but not the liver-derived short pentraxin CRP or other cardiac biomarkers (NT-proBNP, TnT, CK) predicted 3-month mortality after adjustment for major risk factors and other acute-phase prognostic markers.

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.

Dioxin exposure, from infancy through puberty, produces endocrine disruption and affects human semen quality.

Background Environmental toxicants are allegedly involved in decreasing semen quality in recent decades; however, definitive proof is not yet available. In 1976 an accident exposed residents in Seveso, Italy, to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Objective The purpose of this study was to investigate reproductive hormones and sperm quality in exposed males. Methods We studied 135 males exposed to TCDD at three age groups, infancy/prepuberty (1–9 years), puberty (10–17 years), and adulthood (18–26 years), and 184 healthy male comparisons using 1976 serum TCDD levels and semen quality and reproductive hormones from samples collected 22 years later. Results Relative to comparisons, 71 men (mean age at exposure, 6.2 years; median serum TCDD, 210 ppt) at 22–31 years of age showed reductions in sperm concentration (53.6 vs. 72.5 million/mL; p = 0.025); percent progressive motility (33.2% vs. 40.8%; p < 0.001); total motile sperm count (44.2 vs. 77.5 × 106; p = 0.018); estradiol (76.2 vs. 95.9 pmol/L; p = 0.001); and an increase in follicle-stimulating hormone (FSH; 3.58 vs. 2.98 IU/L; p = 0.055). Forty-four men (mean age at exposure, 13.2 years; median serum TCDD, 164 ppt) at 32–39 years of age showed increased total sperm count (272 vs. 191.9 × 106; p = 0.042), total motile sperm count (105 vs. 64.9 ×106; p = 0.036), FSH (4.1 vs. 3.2 UI/L; p = 0.038), and reduced estradiol (74.4 vs. 92.9 pmol/L; p < 0.001). No effects were observed in 20 men, 40–47 years of age, who were exposed to TCDD (median, 123 ppt) as adults (mean age at exposure, 21.5 years). Conclusions Exposure to TCDD in infancy reduces sperm concentration and motility, and an opposite effect is seen with exposure during puberty. Exposure in either period leads to permanent reduction of estradiol and increased FSH. These effects are permanent and occur at TCDD concentrations < 68 ppt, which is within one order of magnitude of those in the industrialized world in the 1970s and 1980s and may be responsible at least in part for the reported decrease in sperm quality, especially in younger men.

Heat shock proteins in human cancer

The heat shock proteins (hsp) are ubiquitous molecules induced in cells exposed to sublethal heat shock, present in all living cells, and highly conserved during evolution. Their function is to protect cells from environmental stress damage by binding to partially denatured proteins, dissociating protein aggregates, to regulate the correct folding, and to cooperate in transporting newly synthesized polypeptides to the target organelles. The molecular chaperones are involved in numerous diseases, including cancer, revealing changes of expression. In this review, we mainly describe the relationship of hsp expression with human cancer, and discuss what is known about their post‐translational modifications according to malignancies.

Concentration-dependent TCDD elimination kinetics in humans: Toxicokinetic modeling for moderately to highly exposed adults from Seveso, Italy, and Vienna, Austria, and impact on dose estimates for the NIOSH cohort

Serial measurements of serum lipid 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) concentrations in 36 adults from Seveso, Italy, and three patients from Vienna, Austria, with initial serum lipid TCDD concentrations ranging from 130 to 144,000 ppt, were modeled using a modified version of a previously published toxicokinetic model for the distribution and elimination of dioxins. The original model structure accounted for a concentration-dependent increase in overall elimination rate for TCDD due to nonlinear distribution of TCDD to the liver (secondary to induction of the binding protein CYP1A2), from which elimination takes place via a first-order process. The original model structure was modified to include elimination due to lipid partitioning of TCDD from circulation into the large intestine, based on published human data. We optimized the fit of the modified model to the data by varying the hepatic elimination rate parameter for each of the 39 people. The model fits indicate that there is significant interindividual variability of TCDD elimination efficiency in humans and also demonstrate faster elimination in men compared to women, and in younger vs. older persons. The data and model results indicate that, for males, the mean apparent half-life for TCDD (as reflected in changes in predicted serum lipid TCDD level) ranges from less than 3 years at serum lipid levels above 10,000 ppt to over 10 years at serum lipid levels below 50 ppt. Application of the model to serum sampling data from the cohort of US herbicide-manufacturing workers assembled by the National Institute of Occupational Safety and Health (NIOSH) indicates that previous estimates of peak serum lipid TCDD concentrations in dioxin-exposed manufacturing workers, based on first-order back-extrapolations with half-lives of 7–9 years, may have underestimated the maximum concentrations in these workers and other occupational cohorts by several-fold to an order of magnitude or more. Such dose estimates, based on a single sampling point decades after last exposure, are highly variable and dependent on a variety of assumptions and factors that cannot be fully determined, including interindividual variations in elimination efficiency. Dose estimates for these cohorts should be re-evaluated in light of the demonstration of concentration-dependent elimination kinetics for TCDD, and the large degree of uncertainty in back-calculated dose estimates should be explicitly incorporated in quantitative estimates of TCDDs carcinogenic potency based on such data.

Perinatal Exposure to Low Doses of Dioxin Can Permanently Impair Human Semen Quality

Background In recent decades, young men in some industrialized areas have reportedly experienced a decrease in semen quality. Objective We examined effects of perinatal dioxin exposure on sperm quality and reproductive hormones. Methods We investigated sperm quality and hormone concentrations in 39 sons (mean age, 22.5 years) born between 1977 and 1984 to mothers exposed to dioxin after the accident in Seveso, Italy (1976), and 58 comparisons (mean age, 24.6 years) born to mothers exposed only to background dioxin. Maternal dioxin levels at conception were extrapolated from the concentrations measured in 1976 serum samples. Results The 21 breast-fed sons whose exposed mothers had a median serum dioxin concentration as low as 19 ppt at conception had lower sperm concentration (36.3 vs. 86.3 million/mL; p = 0.002), total count (116.9 vs. 231.1; p = 0.02), progressive motility (35.8 vs. 44.2%; p = 0.03), and total motile count (38.7 vs. 98 million; p = 0.01) than did the 36 breast-fed comparisons. The 18 formula-fed exposed and the 22 formula-fed and 36 breast-fed comparisons (maternal dioxin background 10 ppt at conception) had no sperm-related differences. Follicle-stimulating hormone was higher in the breast-fed exposed group than in the breast-fed comparisons (4.1 vs. 2.63 IU/L; p = 0.03) or the formula-fed exposed (4.1 vs. 2.6 IU/L; p = 0.04), and inhibin B was lower (breast-fed exposed group, 70.2; breast-fed comparisons, 101.8 pg/mL, p = 0.01; formula-fed exposed, 99.9 pg/mL, p = 0.02). Conclusions In utero and lactational exposure of children to relatively low dioxin doses can permanently reduce sperm quality.

Developmental dental aberrations after the dioxin accident in Seveso.

Children’s developing teeth may be sensitive to environmental dioxins, and in animal studies developing teeth are one of the most sensitive targets of toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Twenty-five years after the dioxin accident in Seveso, Italy, 48 subjects from the contaminated areas (zones A and B) and in patches lightly contaminated (zone R) were recruited for the examination of dental and oral aberrations. Subjects were randomly invited from those exposed in their childhood and for whom frozen serum samples were available. The subjects were frequency matched with 65 subjects from the surrounding non-ABR zone for age, sex, and education. Concentrations of TCDD in previously analyzed plasma samples (zone ABR subjects only) ranged from 23 to 26,000 ng/kg in serum lipid. Ninety-three percent (25 of 27) of the subjects who had developmental enamel defects had been < 5 years of age at the time of the accident. The prevalence of defects in this age group was 42% (15 of 36) in zone ABR subjects and 26% (10 of 39) in zone non-ABR subjects, correlating with serum TCDD levels (p = 0.016). Hypodontia was seen in 12.5% (6 of 48) and 4.6% (3 of 65) of the zone ABR and non-ABR subjects, respectively, also correlating with serum TCDD level (p = 0.05). In conclusion, developmental dental aberrations were associated with childhood exposure to TCDD. In contrast, dental caries and periodontal disease, both infectious in nature, and oral pigmentation and salivary flow rate were not related to the exposure. The results support our hypothesis that dioxins can interfere with human organogenesis.

Serum concentrations of 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin and test results from selected residents of Seveso, Italy

2,3,7,8-Tetrachlorodibenzo-p-dioxin levels (TCDD) were measured in serum specimens from Seveso, Italy, residents, who were potentially highly exposed to the 1976 explosion, and in controls. The residents were chosen so as to represent those who did and did not develop chloracne. Levels of TCDD as high as 56,000 parts per trillion (ppt) were found in these serum specimens that were collected in 1976. These TCDD levels are the highest ever reported, and yet almost all clinical laboratory tests on these individuals were normal; any abnormal test result was only transitory in nature. These findings are unique in linking clinical histories to TCDD levels following an acute exposure.

Dioxin Exposure and Cancer Risk in the Seveso Women’s Health Study

Background: 2,3,7,8-Tetrachlorodibenzo-para-dioxin (TCDD), a widespread environmental contaminant, disrupts multiple endocrine pathways. The International Agency for Research on Cancer classified TCDD as a known human carcinogen, based on predominantly male occupational studies of increased mortality from all cancers combined. Objectives: After a chemical explosion on 10 July 1976 in Seveso, Italy, residents experienced some of the highest levels of TCDD exposure in a human population. In 1996, we initiated the Seveso Women’s Health Study (SWHS), a retrospective cohort study of the reproductive health of the women. We previously reported a significant increased risk for breast cancer and a nonsignificant increased risk for all cancers combined with individual serum TCDD, but the cohort averaged only 40 years of age in 1996. Herein we report results for risk of cancer from a subsequent follow-up of the cohort in 2008. Methods: In 1996, we enrolled 981 women who were 0–40 years of age in 1976, lived in the most contaminated areas, and had archived sera collected near the explosion. Individual TCDD concentration was measured in archived serum by high-resolution mass spectrometry. A total of 833 women participated in the 2008 follow-up study. We examined the relation of serum TCDD with cancer incidence using Cox proportional hazards models. Results: In total, 66 (6.7%) women had been diagnosed with cancer. The adjusted hazard ratio (HR) associated with a 10-fold increase in serum TCDD for all cancers combined was significantly increased [adjusted HR = 1.80; 95% confidence interval (CI): 1.29, 2.52]. For breast cancer, the HR was increased, but not significantly (adjusted HR = 1.44; 95% CI: 0.89, 2.33). Conclusions: Individual serum TCDD is significantly positively related with all cancer incidence in the SWHS cohort, more than 30 years later. This all-female study adds to the epidemiologic evidence that TCDD is a multisite carcinogen.