Cohort study of workers employed in an Italian tire manufacturing plant, 1962–2004

Purpose

To investigate mortality and bladder cancer incidence among workers of a tire manufacturing plant where antioxidants severely contaminated by beta-naphthylamine were never used.

Methods

Mortality follow-up was performed of 9,501 workers first hired between 1962 when the plant started operations and 2000. Person-years of observation from 1962 to 2004, expected deaths, and standardized mortality ratios (SMR) were calculated. Follow-up for bladder cancer incidence from 1988 to 2003 was carried out, and standardized incidence ratios (SIR) were calculated. Multivariable (Poisson) analyses of bladder cancer incidence and mortality by duration of employment (DOE) and time since first employment (TSFE) were performed.

Results

Among men, SMRs were significantly reduced for all causes, all cancers, lung cancer, cardiovascular, and ischemic heart diseases. Bladder cancer mortality and leukemia mortality were close to expectation but increased with TSFE. Seventy-two incident cases of bladder cancer were observed (SIR?=?1.15; 95?% confidence interval 0.90–1.44), and multivariable analysis suggested a possible increase in rate ratios with DOE. Among women, mortality was close to expectation, but the limited number of observed deaths prevented detailed analyses.

Conclusions

No significant cancer excess was observed. A suggestion of increased risks of bladder cancer and leukemias after extended TSFE was present in men, deserving consideration as exposure to carcinogens possibly occurred early in plant operation. Furthermore, this cohort of workers is still relatively young and less than 10?% have died. There was, thus, limited power to detect small increases in risk at rare cancer sites. Further epidemiological surveillance of this cohort is planned.     

Application of multi-locus analytical methods to identify interacting loci in case-control studies

To identify interacting loci in genetic epidemiological studies the application of multi-locus methods of analysis is warranted. Several more advanced classification methods have been developed in the past years, including multiple logistic regression, sum statistics, logic regression, and the multifactor dimensionality reduction method. The objective of our study was to apply these four multi-locus methods to simulated case-control datasets that included a variety of underlying statistical two-locus interaction models, in order to compare the methods and evaluate their strengths and weaknesses. The results showed that the ability to identify the interacting loci was generally good for the sum statistic method, the logic regression and MDR. The performance of the logistic regression was more dependent on the underlying model and multiple comparison adjustment procedure. However, identification of the interacting loci in a model with two two-locus interactions of common disease alleles with relatively small effects was impaired in all methods. Several practical and methodological issues that can be considered in the application of these methods, and that may warrant further research, are identified and discussed.     

Interferon beta-1b now also for the secondary progressive form of multiple sclerosis?]

Recently, a placebo-controlled multicentre randomised clinical trial was published on the efficacy of interferon beta-Ib in the treatment of secondary progressive multiple sclerosis. The study was stopped after the interim analysis because evidence of efficacy was already clear. However, the results appear to be considerably less convincing. The decision to prematurely stop the clinical trial was based more on an overestimate of the p-values than on the clinical relevance of the treatment effects. The efficacy of interferon should be investigated in relation to other treatment options, such as immunoglobulin, copolymer I, azathioprine and methotrexate.     

Efficacy and safety of ciclesonide once daily and fluticasone propionate twice daily in children with asthma

BackgroundCiclesonide is a new inhaled corticosteroid (ICS). Information about its clinical efficacy and safety in relation to other ICS in children is needed for clinical positioning.ObjectiveThis 12-week, randomized, double-blind, double-dummy, three-arm, parallel-group study compared the efficacy and safety of ciclesonide with fluticasone propionate in children with mainly moderate and severe persistent asthma.MethodsSeven hundred and forty-four patients (aged 6–11 years) were randomized to ciclesonide (80 or 160 μg once daily) or fluticasone propionate (88 μg twice daily), following a 2–4-week run-in. Efficacy measurements included forced expiratory flow in 1 s (FEV₁), morning peak expiratory flow (PEF), asthma symptom scores, rescue medication use and quality of life. Systemic effect was assessed by 24-hour urine free cortisol adjusted for creatinine.ResultsFEV₁ and morning PEF increased from baseline in all groups (p < 0.0001). Ciclesonide 160 μg was not inferior to fluticasone propionate 176 μg for FEV₁ (p = 0.0030, one-sided). In all groups, asthma symptom score sums and rescue medication use significantly improved (p < 0.0001). The percentages of asthma symptom-, rescue medication- and nocturnal awakening-free days were high, with no significant differences between treatments. Quality of life scores improved with all treatments (p < 0.0001). A significant dose–response occurred between low and higher doses of ciclesonide for exacerbations and asthma control definitions. The incidences of adverse events were comparable across treatments. Urine free cortisol levels decreased significantly with fluticasone propionate (p = 0.0103), but not with ciclesonide.ConclusionOnce-daily ciclesonide has a clinical effect similar to that of fluticasone propionate, but does not suppress cortisol excretion, in children with moderate and severe asthma.     

Spatially divergent cardiac responses to nicotinic stimulation of ganglionated plexus neurons in the canine heart

Ganglionated plexuses (GPs) are major constituents of the intrinsic cardiac nervous system, the final common integrator of regional cardiac control. We hypothesized that nicotinic stimulation of individual GPs exerts divergent regional influences, affecting atrial as well as ventricular functions. In 22 anesthetized canines, unipolar electrograms were recorded from 127 atrial and 127 ventricular epicardial loci during nicotine injection (100 mcg in 0.1 ml) into either the 1) right atrial (RA), 2) dorsal atrial, 3) left atrial, 4) inferior vena cava-inferior left atrial, 5) right ventricular, 6) ventral septal ventricular or 7) cranial medial ventricular (CMV) GP. In addition to sinus and AV nodal function, neural effects on atrial and ventricular repolarization were identified as changes in the area subtended by unipolar recordings under basal conditions and at maximum neurally-induced effects. Animals were studied with intact AV node or following ablation to achieve ventricular rate control. Atrial rate was affected in response to stimulation of all 7 GPs with an incidence of 50–95% of the animals among the different GPs. AV conduction was affected following stimulation of 6/7 GP with an incidence of 22–75% among GPs. Atrial and ventricular repolarization properties were affected by atrial as well as ventricular GP stimulation. Distinct regional patterns of repolarization changes were identified in response to stimulation of individual GPs. RAGP predominantly affected the RA and posterior right ventricular walls whereas CMVGP elicited biatrial and biventricular repolarization changes. Spatially divergent and overlapping cardiac regions are affected in response to nicotinic stimulation of neurons in individual GPs.     

Design, synthesis, and characterization of 7-methoxy-4-(aminomethyl)coumarin as a novel and selective cytochrome P450 2D6 substrate suitable for high-throughput screening.

In this study, a selective substrate for cytochrome P450 2D6 was designed using a small molecule model developed by M. J. De Groot et al. [(1997) Chem. Res. Toxicol. 10, 41-48]. The substrate, 7-methoxy-4-(aminomethyl)coumarin (MAMC), and its putative O-demethylated metabolite 7-hydroxy-4-(aminomethyl)coumarin (HAMC) were synthesized, and their respective fluorescence properties were characterized. The selectivity of MAMC for P450 2D6 was characterized using microsomes containing single human P450 isoenzymes and human liver microsomes. Formation of the metabolic product HAMC was easily assessed in real time with fluorescence spectroscopy, since MAMC and HAMC excitation and emission wavelengths differed significantly. HPLC analysis confirmed that HAMC was the single metabolic product of MAMC and that HAMC formation accounts for the total increase in fluorescence. It was found that, in microsomes from yeast or lymphoblastoid cells selectively expressing P450 isoenzymes, MAMC was selective for P450 2D6 at a concentration of 25 microM with only P450 1A2 contributing significantly to the formation of HAMC. P450s 2A6, 2B6, 2C8, 2C9, 2C19, 2E1, 3A4, and 3A5 were shown not to metabolize MAMC at a concentration of 25 microM. K(m) and v(max) values of MAMC for P450 2D6 were found to be 26.2 +/- 2.8 microM and 2.9 +/- 0.07 min(-)(1), respectively. For P450 1A2, MAMC was found to have a K(m) value of 29.7 +/- 6.2 microM and a v(max) of 0.57 +/- 0.07 min(-)(1). Formation of HAMC in human liver microsomes could be completely inhibited by quinidine, at a concentration of 0.5 microM selective for P450 2D6, and furafylline, at a concentration of 30 microM selective for P450 1A2. In conclusion, O-demethylation of 7-methoxy-4-(aminomethyl)coumarin is a rapid and easily determined parameter for P450 2D6 activity and, due to the fluorescent properties of the metabolite formed, may be a valuable new tool for high-throughput screening purposes.     

Evaluation of plasma testosterone: Which test and when?

Biochemical evaluation of androgenicity in men and women requires the determination of plasma testosterone (T). Because essentially only nonspecifically bound T appears to be available to tissues and to be bioactive (Bio-T), it may be required, in some instances, to determine the Bio-T fraction (free T [FT] and albumin-bound T). Surprisingly, a very important interlaboratory variation in T levels does exist and the lack of precision of current methods does not allow accurate measurement of T levels in women or prepubertal boys. Thus, each laboratory should establish its own range of normal values. As to parameters of FT or Bio-T, kits for direct measurement of FT are unreliable. Equilibrium dialysis, the gold standard of FT, is not suited for clinical routine, whereas the FT index (T/sex hormone-binding globulin [SHBG]) is a reliable parameter of FT in women only; calculation of FT and Bio-T (from T, SHBG, and albumin concentration) yields reliable results, but the absolute values depend on the association constants of SHBG and albumin for T used. In men (F)T is mainly used to confirm the clinical diagnosis of hypogonadism or to modulate androgen treatment. In otherwise healthy hypogonadal men, measurement of total T will suffice, but in patients with conditions affecting binding proteins (eg, thyroid or liver pathology, nephrotic syndrome, obesity) measurement of Bio-T may be required. In women, androgen measurement is generally required to evaluate androgen excess (eg, polycystic ovary syndrome, ovulatory dysfunction, hirsutism).