TIMES-SS--a mechanistic evaluation of an external validation study using reaction chemistry principles

The TImes MEtabolism Simulator platform used for predicting skin sensitization (TIMES-SS) is a hybrid expert system that was developed at Bourgas University using funding and data from a consortium comprised of industry and regulators. TIMES-SS encodes structure-toxicity and structure-skin metabolism relationships through a number of transformations, some of which are underpinned by mechanistic three-dimensional quantitative structure-activity relationships. Here, we describe an external validation exercise that was recently carried out. As part of this exercise, data were generated for 40 new chemicals in the murine local lymph node assay (LLNA) and then compared with predictions made by TIMES-SS. The results were promising with an overall good concordance (83%) between experimental and predicted values. The LLNA results were evaluated with respect to reaction chemistry principles for sensitization. Additional testing on a further four chemicals was carried out to explore some of the specific reaction chemistry findings in more detail. Improvements for TIMES-SS, where appropriate, were put forward together with proposals for further research work. TIMES-SS is a promising tool to aid in the evaluation of skin sensitization potential under legislative programs such as REACH.     

Mechanistic applicability domain classification of a local lymph node assay dataset for skin sensitization

The goal of eliminating animal testing in the predictive identification of chemicals with the intrinsic ability to cause skin sensitization is an important target, the attainment of which has recently been brought into even sharper relief by the EU Cosmetics Directive and the requirements of the REACH legislation. Development of alternative methods requires that the chemicals used to evaluate and validate novel approaches comprise not only confirmed skin sensitizers and non-sensitizers but also substances that span the full chemical mechanistic spectrum associated with skin sensitization. To this end, a recently published database of more than 200 chemicals tested in the mouse local lymph node assay (LLNA) has been examined in relation to various chemical reaction mechanistic domains known to be associated with sensitization. It is demonstrated here that the dataset does cover the main reaction mechanistic domains. In addition, it is shown that assignment to a reaction mechanistic domain is a critical first step in a strategic approach to understanding, ultimately on a quantitative basis, how chemical properties influence the potency of skin sensitizing chemicals. This understanding is necessary if reliable non-animal approaches, including (quantitative) structure-activity relationships (Q)SARs, read-across, and experimental chemistry based models, are to be developed.     

Increased Total Renin Levels but Not Angiotensin-Converting Enzyme Activity in Obese Patients with Polycystic Ovary Syndrome

Objective

To investigate the renin-angiotensin-aldosterone system and angiotensin-converting enzyme (ACE) activity in patients with polycystic ovarian syndrome (PCOS).

Subjects and Methods

In this case-control study, 41 obese (PCOS) women and 29 healthy controls, matched for age and body mass index, were enrolled. Anthropometric, metabolic, and hormonal patterns, including plasma aldosterone, plasma renin, and ACE activity, were measured in each subject.

Results

Plasma renin levels were significantly higher in PCOS patients (19.7 ± 14.5 µg/ml) compared with controls (12.9 ± 9.0 µg/ml, p < 0.05). ACE activity and aldosterone levels did not significantly differ between both groups (p = 0.15 and p = 0.18, respectively). Analysis of PCOS patients showed a significant correlation of fasting insulin levels with levels of renin (r = 0.305, p < 0.01) and free testosterone (r = 0.384, p = 0.001). Similarly, homeostasis model assessment index was positively correlated with total renin concentrations (r = 0.366, p < 0.01) and free testosterone (r = 0.352, p < 0.01).

Conclusion

Obese PCOS women had higher total renin levels, but not ACE activity and aldosterone levels, related to insulin resistance compared with controls.Key Words: Polycystic ovary syndrome, Angiotensin-converting enzyme, Renin     

Assessment of risks and dose thresholds for some effects of acute exposure

Findings from the analyses of the dose-response relationship are reviewed with regard to different effects of acute radiation exposure. The analyses have been performed based on the dosimetry and clinical data for the nuclear workers acutely exposed to gamma rays or gamma rays and neutrons as a result of radiation accidents at the Mayak Production Association (Russia). The statistically significant risk curves for morbidity and mortality from acute radiation syndrome (ARS), as well as risks of the onset of vomiting at the prodromal phase and agranulocytosis, have been obtained. The Weibull model appropriately describes the corresponding risk curves. Estimates of the dose thresholds have been obtained for ARS morbidity (～0.7 Gy) and mortality (～6-7 Gy), vomiting at the prodromal phase (～1.5 Gy), and agranulocytosis (～3.5 Gy). The statistically significant power dependence between the onset of vomiting at the prodromal phase and the onset of agranulocytosis, as well as the dose dependence for the onset of agranulocytosis, has been revealed.     

What is palliative medicine? motivations and skills

Palliative care began in the UK hospice movement in the late 1960s and has rapidly developed in many countries since. In some, it has become a fully recognized specialty with comprehensive training programs and recognized expertise in areas such as pain and symptom control. It is important to examine the formative influences and characteristic clinical expertise in palliative medicine. This article considers some of the conceptual, practical, and administrative challenges that have been faced in an effort to establish palliative medicine as a discrete field of specialized practice from a US perspective. We also comment on current issues in regard to education and research, and development of comprehensive palliative care programs in the United States.