PharmML in Action: an Interoperable Language for Modeling and Simulation.

PharmML is an XML-based exchange format created with a focus on nonlinear mixed-effect (NLME) models used in pharmacometrics, but providing a very general framework that also allows describing mathematical and statistical models such as single-subject or nonlinear and multivariate regression models. This tutorial provides an overview of the structure of this language, brief suggestions on how to work with it, and use cases demonstrating its power and flexibility.

Mixed meal ingestion diminishes glucose excursion in comparison with glucose ingestion via several adaptive mechanisms in people with and without type 2 diabetes.

AIMS: To study the integrative impact of macronutrients on postprandial glycaemia, ß-cell function, glucagon and incretin hormones in humans. METHODS: Macronutrients were ingested alone (glucose 330 kcal, protein 110 kcal or fat 110 kcal) or together (550 kcal) by healthy subjects (n = 18) and by subjects with drug-naïve type 2 diabetes (T2D; n = 18). ß-cell function and insulin clearance were estimated by modelling glucose, insulin and C-peptide data. Secretion of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) were measured, and paracetamol was administered to estimate gastric emptying. RESULTS: In both groups, the mixed-meal challenge diminished glucose excursion compared with glucose challenge alone, and insulin levels, but not C-peptide levels, rose more than after the mixed meal than after glucose alone. ß-cell function was augmented, insulin clearance was reduced and glucagon levels were higher after the mixed meal compared with glucose alone. GLP-1 and GIP levels increased after all challenges and GIP secretion was markedly higher after the mixed meal than after glucose alone. The appearance of paracetamol was delayed after the mixed-meal challenge compared with glucose alone. CONCLUSIONS: Adding protein and fat macronutrients to glucose in a mixed meal diminished glucose excursion. This occurred in association with increased ß-cell function, reduced insulin clearance, delayed gastric emptying and augmented glucagon and GIP secretion. This suggests that the macronutrient composition regulates glycaemia through both islet and extra-islet mechanisms in both healthy subjects and in subjects with T2D.

Pharmacometrics Markup Language (PharmML): Opening New Perspectives for Model Exchange in Drug Development.

The lack of a common exchange format for mathematical models in pharmacometrics has been a long-standing problem. Such a format has the potential to increase productivity and analysis quality, simplify the handling of complex workflows, ensure reproducibility of research, and facilitate the reuse of existing model resources. Pharmacometrics Markup Language (PharmML), currently under development by the Drug Disease Model Resources (DDMoRe) consortium, is intended to become an exchange standard in pharmacometrics by providing means to encode models, trial designs, and modeling steps.

[Pleural mesothelioma in women in the Veneto Region who used to work as rag sorters for textile recycling and paper production]. / Mesoteliomi pleurici insorti in donne, residenti in Veneto, addette alla cernita di stracci presso "robe vecchie" e cartiere.

The paper reports 9 cases of mesothelioma diagnosed by means of histology or cytology that were observed among women resident in the Veneto Region, Northern Italy, whose only activity that could involve exposure to asbestos was as rag sorter. These cases are part of a group of about 260 subjects with mesothelioma whose entire working and residential history has been collected. The women worked as rag sorters between the 1940's and 1960's in textile recycling (8 cases) or (one case) at a paper mill where cotton was used for paper production. The work as rag sorter helps to explain the high proportion of mesotheliomas among women with an occupational exposure to asbestos.

[Return of immigrants: a cluster analysis of mesotheliomas among residents of the Veneto region who used to work at the ETERNIT AG factory at Niederurnen, Switzerland]. / Emigrazione di ritorno: un cluster di mesoteliomi in Veneto tra ex-lavoratori della Eternit AG di Niederurnen, Svizzera.

We identified 5 mesotheliomas among Italian migrant workers who returned home and settled in the Veneto Region, after employment at the ETERNIT AG factory in Switzerland. During the 1970s the factory employed about 1000 workers and the presence of Italian migrants was relevant. The cluster confirms that migration for work has caused exposures to carcinogenic substances and confirms that neoplastic diseases are occurring among those resettled in Italy and helps explaining the high occurrence of mesotheliomas in this country.

Longitudinal study of alveolitis in hypersensitivity pneumonitis patients: an immunologic evaluation.

Cells recovered from bronchoalveolar lavage were studied, both from a phenotypic and functional point of view, in 18 patients with hypersensitivity pneumonitis (HP) during a prolonged follow-up. A series of monoclonal antibodies against different lymphocyte subpopulations, including T cells, T cell subsets, and natural killer (NK) cells have been used. In some cases, an immunohistologic analysis of lung tissue sections has also been performed. The NK activity has been evaluated with regard to the in vitro function. At the time of the first evaluation, a high number of CD8+ cells with an imbalance of CD4/CD8 ratio had been demonstrated in patients with HP. Consecutive bronchoalveolar lavage evaluations demonstrated a persistent increase of CD8+ cells and a reversal of CD4/CD8 ratio in patients who continued to be regularly exposed to etiologic antigens at work (W+). In the same cases, a persistent increase of NK cells was demonstrated. Cytotoxic cells demonstrated a persistently enhanced in vitro lytic function during the follow-up, even though there appeared to be a trend toward the normal range. Patients who continued to live in agricultural environments but were not further exposed to specific antigens at work (W-) exhibited a recovery of CD4+ cells, a decrease in CD8+ cells, and an increase of CD4/CD8 ratio to the normal range 6 months after the first observation. Immunohistologic analysis, performed at the time of the first evaluation, demonstrated a diffuse infiltration of lung parenchyma by CD8+ cells, both in W+ and W- patients.(ABSTRACT TRUNCATED AT 250 WORDS)

[Comparison of various methods of evaluating auditory damage caused by chronic acoustic injury]. / Confronto di differenti metodiche di valutazione del danno uditivo da trauma acustico cronico.

The purpose of the present study was to compare the most common hearing damage criteria, based upon pure tone audiometric data. We examined 1086 workers with different intensity and duration of noise exposure. After consecutive selections, 455 subjects, subdivided into four exposure groups, were studied. The 12 considered criteria showed a widespread difference in their sensitivity: the percentage of hearing impaired subjects ranged from 3.3 to 24.2% in the whole population. The most sensitive criteria evaluated the hearing loss at 2 and 4 KHz. The evaluation of the hearing loss at 3 and 6 KHz did not modify the percentage of subjects bearing an handicap. The authors suggest the average hearing loss at 2 and 4 KHz as a criterion to be used for preventing and epidemiological purposes.