Mathematical modelling in risk/exposure assessment of tobacco related lung cancer

The existence of a dose-related increase of lung cancer riskin cigarette smokers has been indisputably established. Thisfinding, however, is not confirmed at low doses (< 5 cigarettes/day),there still being a lack of epidemiological data. The use ofmathematical models of carcinogenesis to extrapolate from higherdoses allows estimation of the risk for very light smokers.The present study has been designed to compare a set of mathematicalmodels, i.e. one-hit, two-stage, multi-stage, logit, probit,and Weibull, in extrapolating relative risks at low doses fromthe data of nine large cohort studies on cigarette smokers reportedin the IARC Scientific Monograph on tobacco smoking. All modelsevaluated, apart from the one-hit, achieved a good fit, withthe proportion of explained variance ranging between 61% and67%. The relative risk estimates for passive smokers from themost updated epidemiological studies were taken into accountto evaluate, on the basis of these models, the correspondingexposure in terms of ‘cigarette equivalent’ smoked.These values ranged from 0.21 to 0.43 cigarettes/day for thetwo-stage and multistage model, while probit, logit and Weibullmodels, yielded estimates one or even two orders of magnitudelower. The authors emphasize the substantial agreement betweenthe estimates of ‘cigarette equivalent9 based on the applicationof two-stage and multi-stage models to the epidemiological evidenceon the effect of passive smoking and to the data based on thecomparison of tobacco metabolites in active and passive smokers.     

Prognostic value of pharmacological stress echocardiography in diabetic and nondiabetic patients with known or suspected coronary artery disease.

OBJECTIVES: We sought to compare the prognostic value of pharmacological stress echocardiography (SE) in diabetic and nondiabetic patients with known or suspected coronary artery disease. BACKGROUND: Although SE is a useful tool for risk stratification of patients with diabetes, it has not been established whether it retains the same prognostic information in diabetic patients compared with nondiabetic patients. METHODS: A total of 5,456 patients (749 diabetics) undergoing dipyridamole (n = 3,306) or dobutamine (n = 2,150) SE were prospectively followed up for the occurrence of hard events (death and/or nonfatal myocardial infarction). RESULTS: During a median time of 31 months, 411 deaths and 236 infarctions occurred. There were 132 events in diabetic patients and 515 in nondiabetic patients (18% vs. 11%, respectively; p < 0.0001). Moreover, 1,607 (29%) patients underwent coronary revascularization and were censored. Ischemia at SE, resting wall motion score index, and age were independent predictors of death and hard events in both diabetic and nondiabetic patients. Compared with a normal test, ischemia and scar test patterns were associated to significantly lower age-corrected five-year hard event-free survival in diabetic as well as nondiabetic patients. However, a normal test was associated with a greater than two-fold annual event rate in diabetic patients as compared with nondiabetics who were either younger (2.6% vs. 1.0%) or older (5.5% vs. 2.2%) than 65 years of age. CONCLUSIONS: Stress echocardiography is equally effective in risk stratifying diabetic and nondiabetic patients independently of age. However, the normal test result predicts a less favorable outcome in diabetic than in nondiabetic patients.     

Effect of climacteric transition and hormone replacement therapy on body weight and body fat distribution.

In the present study we evaluated the effects of climacteric modifications on body weight and fat distribution. From women attending a menopause clinic we selected 2175 untreated, normal healthy women who were divided into three groups: premenopausal (n = 540), perimenopausal (n = 750) and postmenopausal (n = 885), and compared them with 354 postmenopausal women receiving different forms of hormone replacement therapy (HRT). The total body fat tissue mass and distribution were analyzed using dual-energy X-ray absorptiometry. Body weight and body mass index (BMI) were significantly higher in perimenopausal and postmenopausal than in premenopausal women. Mean total body fat and fat as a percentage of soft tissue were significantly (p < 0.05) higher in the perimenopausal and postmenopausal groups than in the premenopausal group. Fat tissue and regional fat tissue as a percentage of total fat tissue were higher in the trunk (p < 0.0001) and arms (p < 0.0001) in perimenopausal and postmenopausal than in premenopausal women. In postmenopausal women, leg fat tissue was significantly (p < 0.05) lower than in premenopausal and perimenopausal groups. Total body and leg lean tissue were significantly lower (p < 0.05) in postmenopausal than in premenopausal and perimenopausal women. In age-matched women with similar BMI, total body fat as a percentage of soft tissue was significantly (p < 0.001) higher in the perimenopausal and postmenopausal groups than in the premenopausal group. As for body fat distribution, fat as a percentage of total fat tissue was significantly higher in the trunk (p < 0.0001) region in perimenopausal and postmenopausal women compared with the premenopausal group. In the legs, fat as a percentage of total fat tissue was significantly higher (p < 0.05) in the premenopausal than in the postmenopausal group. In the arms a slight but not significant (p < 0.18) difference was shown in fat distribution between the three untreated groups. In age-matched HRT-treated postmenopausal women, the fat tissue was similar to that in the premenopausal group. The present results confirm that endocrine changes during the menopausal transition, rather than the aging process, are related to changes in body weight and fat distribution. Perimenopausal and postmenopausal women show a shift to a central, android fat distribution that can be counteracted by HRT.     

Regional Variation and Use of Exception Letters for Cadaveric Liver Allocation in Children with Chronic Liver Disease

The Pediatric End-Stage Liver Disease (PELD) score was designed to reduce subjectivity in liver allocation and to advantage patients with a higher probability of waiting list mortality. The aims of this study were to determine the impact of PELD implementation for children with chronic liver disease and to assess whether PELD met its goal of standardization of liver allocation for children. This study used data reported to the United Network for Organ Sharing (UNOS) registry for children with chronic liver disease receiving primary cadaveric liver transplant between January 2000 and December 2001 (pre-PELD) and March 2002 and July 2003 (PELD). PELD reduced the percentage of children transplanted while in an intensive care unit and as status 1. A calculated PELD score was used for allocation in only 52% of recipients. Thirty percent were status 1 at transplant and PELD scores granted by exception were used for allocation in 18% of patients. There was regional variation in PELD score at allocation and use of exception scores with a significant relationship between PELD score and percentage of exception cases. Regional variation suggests that PELD has not resulted in standardization of listing practices in pediatric liver transplantation.     

Assessment of the scatter fraction evaluation methodology using Monte Carlo simulation techniques

To evaluate scatter fraction and scatter pair spatial distribution, experimental methods are generally used. These methods make use of a line source, placed along the FOV axis, inserted in a cylindrical phantom filled with air or water. The accuracy of these experimental methodologies can be tested by the use of a Monte Carlo method. In fact, the simulation allows the shape of the scatter event projection and the scatter fraction to be defined. An example of this application is the simulation package PETSI (PET SImulation). In this paper the comparison between the predicted scatter fraction and the experimentally evaluated one, obtained using an ECAT III PT 911/02 double ring whole body scanner are presented. PETSI permits additional data to be obtained: a) the true and scatter component of the energy spectrum; b) the spatial distribution, in the FOV plane, of the detected scatter events at different energy thresholds; c) the scatter to total detected events ratio; d) the predicted scatter fraction at both energy thresholds and FOV diameters. This information is very useful for optimizing both energy threshold and FOV size and to improve the accuracy of the currently used methods for the scatter fraction evaluation. Preliminary results of the predicted scatter fraction in a uniform phantom are presented.This article was presented at the 1st EEC workshop on accuracy determination in PET, January 19–20th. 1989 Pisa, Italy (COMAC-BME Concerted Project Characterization and Standardization of PET Instrumentation)     

Human isolated small intestine: motor responses of the longitudinal muscle to field stimulation and exogenous neuropeptides

Summary (1) Longitudinal muscle strips from the human small intestine (jejunum/ileum) responded to electrical field stimulation (1–50 Hz) with frequency-related primary contractions which were largely atropine- (3 M) sensitive. When the tone was raised by addition of galanin (0.3 – 1 M), prostaglandin (PG) E₂ (1–10 M) or neurokinin A (NKA, 0.1 M), a frequency-related relaxation was evident which was potentiated by atropine. All the responses to field stimulation were abolished by tetrodotoxin (1 M), thus indicating their neural origin. (2) The atropine-sensitive primary contraction to field stimulation was virtually abolished by omega conotoxin fraction GVIA (CTX, 0.1–0.3 M) while the relaxations were CTX-resistant. The field stimulation-induced relaxations, which were observed in the presence of atropine and guanethidine (3 M), were also unaffected by apamin (0.1 M). (3) NKA and substance P (SP) produced a concentration- (1 nM–1 M for both peptides) related contraction, NKA being about 53 times more potent than SP. [Pro⁹]SP sulphone and [MePhe⁷]-NKB, selective agonists of the NK-1 and NK-3 receptor, respectively, were barely effective. On the other hand, [\Ala⁸]NKA(4–10), a selective NK-2 receptor agonist, had a potent contractile activity, similar to that of NKA. (4) Galanin (1 nM–1M) produced an atropine- and tetrodotoxin-resistant concentration-related contraction of longitudinal muscle of human isolated small intestine. The response to galanin did not show any sign of fading and was particularly suitable to study the evoked relaxations. (5) Calcitonin gene-related peptide (CGRP) (10–100 nM) consistently inhibited the nerve-mediated contractions of strips from the ileum while the effect on the jejunum was less pronounced. Vasoactive intestinal polypeptide (VIP, 0.1–1 M) inhibited nerve-mediated contractions both in the ileum and the jejunum. (6) These experiments indicate that both cholinergic excitatory and non-adrenergic non-cholinergic nerves affect motility of the longitudinal muscle of the human small intestine. Furthermore, several neuropeptides produce potent motor effects, the contractile response to tachykinins being apparently mediated by activation of NK-2 receptors.     

Reference values for vital capacity and flow-volume curves from a general population study

A longitudinal epidemiological respiratory study has been started in the North of Italy to investigate the natural history of obstructive airways disease and the long-term effect of SO2 exposure. The first cross-sectional study was completed in this unpolluted area before the activation of a thermoelectric power plant (500 tons of SO2 produced daily). Follow-up surveys are planned after pollution emission starts for a period of ten years. A sample (n = 3289) representative of the general population was drawn from the villages of the area according to the different risks of pollution exposure. Subjects completed questionnaires and performed lung function tests, including forced expiratory (FVC) manoeuvres. For 801 'normal' subjects, prediction equations have been derived in age/sex groups for slow vital capacity (VC) and variables from the FVC manoeuvre. Comparisons with predictions of other studies are reported. Differences among FVC predictions were found, indicating that the use of different criteria for determination of the FVC manoeuvre end-point can affect results. In 'normals' VC was higher than FVC in older subjects. The difference between VC and FVC may be hypothesized as an epidemiological indication of the ageing effect on the mechanical properties of the ventilatory system.     

Giant ragweed specific immunotherapy is not effective in a proportion of patients sensitized to short ragweed: analysis of the allergenic differences between short and giant ragweed

BACKGROUND: Short ragweed and giant ragweed pollen allergens are considered largely cross-reactive, and it is generally believed that 1 species is sufficient for skin testing and immunotherapy. However, in the area north of Milan (a zone widely invaded only by short ragweed), about 50% of patients submitted to injection specific immunotherapy with giant ragweed showed little or no clinical response, but showed an excellent outcome if they were shifted to short ragweed specific immunotherapy. OBJECTIVE: To investigate allergenic differences between short and giant ragweed. METHODS: IgE reactivity to short ragweed of sera from 16 patients allergic to ragweed was assessed by immunoblot before and after absorption with short and giant ragweed. Moreover, 41 ragweed-monosensitive patients underwent skin prick test with both ragweed species. RESULTS: In several cases, preabsorption of sera with giant ragweed extract was unable to inhibit IgE reactivity fully against both a 43-kd allergen and other allergens at different molecular weights in short ragweed. On skin prick test, short ragweed induced larger wheals than giant ragweed in the majority of patients, and 6 of 41 (15%) patients were strongly short ragweed-positive but giant ragweed-negative. The immunoblot with the serum from 1 of these subjects showed a strong IgE reactivity to short ragweed at about 43 kd in the absence of any reactivity to giant ragweed. CONCLUSION: Short and giant ragweed are not allergenically equivalent. Allergenic differences involve both the major allergens Amb a 1-2/Amb t 1-2 and some minor allergens. In patients allergic to ragweed, both diagnosis in vivo and immunotherapy should always be performed by using the ragweed species present in that specific geographic area.