Gymnasts utilize visual and auditory information for behavioural synchronization in trampolining.

In synchronized trampolining, two gymnasts perform the same routine at the same time. While trained gymnasts are thought to coordinate their own movements with the movements of another gymnast by detecting relevant movement information, the question arises how visual and auditory information contribute to the emergence of synchronicity between both gymnasts. Therefore the aim of this study was to examine the role of visual and auditory information in the emergence of coordinated behaviour in synchronized trampolining. Twenty female gymnasts were asked to synchronize their leaps with the leaps of a model gymnast, while visual and auditory information was manipulated. The results revealed that gymnasts needed more leaps to reach synchronicity when only either auditory (12.9 leaps) or visual information (10.8 leaps) was available, as compared to when both auditory and visual information was available (8.1 leaps). It is concluded that visual and auditory information play significant roles in synchronized trampolining, whilst visual information seems to be the dominant source for emerging behavioural synchronization, and auditory information supports this emergence.

A phase II study of the combination of endocrine treatment and bortezomib in patients with endocrine-resistant metastatic breast cancer.

The majority of patients with hormone receptor-positive metastatic breast cancer die from disease progression despite different types of anti-hormonal treatments. Preclinical studies have indicated that resistance to anti-hormonal therapies may be the result of an activated NF-κB signalling pathway in breast cancer. Bortezomib is a proteasome inhibitor that blocks the NF-κB pathway. Recent pharmacodynamic and pharmaco-kinetic xenograft studies have shown that drug exposure may be a crucial factor for the efficacy of bortezomib in solid tumours. The aim was to investigate whether the addition of bortezomib to anti-hormonal therapy would result in regained antitumour activity in patients with progressive and measurable disease being treated with an endocrine agent. Clinical benefit was defined as patients obtaining stable disease, partial response or complete response after 2 cycles, lasting for at least another five weeks. Bortezomib was administered on days 1, 8, 15 and 22 of a 5-week regimen (1.6 mg/m2). Eight patients received an aromatase inhibitor and bortezomib, while one received tamoxifen and bortezomib. There were 3 grade 3 gastrointestinal toxicities. Median time to treatment failure was 69 days (range, 35-140). Two out of the 9 patients had stable disease for more than 10 weeks. Despite an effective target inhibition, suggested in peripheral blood mononuclear cells and available tumour samples, no objective antitumour responses were observed. Addition of a proteasome inhibitor to anti-hormonal therapy resulted in a clinical benefit rate of 22% in a limited number of patients with endocrine resistant and progressive metastatic breast cancer. The demonstrated proteasome inhibition in tumour tissue provides evidence that the lack of clinical responses is not attributed to deficient drug exposure.

The differential effects of atypical antipsychotics on prolactin elevation are explained by their differential blood-brain disposition: a pharmacological analysis in rats.

All atypical antipsychotics avoid extrapyramidal side-effects yet differ in their propensity to cause other side-effects, like prolactin elevation. We proposed that the atypical antipsychotics with a propensity for prolactin elevation would show a higher pituitary versus striatal D2 receptor occupancy. To investigate this hypothesis, we tested four atypical antipsychotics, two that are commonly associated with prolactin elevation (amisulpride and risperidone) and two that are less frequently associated (quetiapine and olanzapine). In particular, we calculated their ED(50) values to increase plasma prolactin and block peripheral pituitary D2 receptors to their ED(50) values to antagonize apomorphine-induced stereotypy and occupy central striatal D2 receptors. All antipsychotics dose dependently increased prolactin levels and antagonized apomorphine-induced stereotypy. However, the central to peripheral potency (ED(50) for apomorphine antagonism to ED(50) for prolactin elevation) differed remarkably across these drugs: amisulpride (21764), risperidone (14), quetiapine (10), and olanzapine (1.7). Compounds displaying a higher peripheral potency brought about higher prolactin levels for a given level of functional central antagonism. This dissociation between central and peripheral effects was explained by the differential occupancy of D2 receptors in the striatum versus in the pituitary [ratio of striatal/pituitary ED(50) values (milligram per kilogram) for D2 occupancy): amisulpride (17/0.026 = 654), risperidone (0.89/0.081 = 14), quetiapine (24/4.1 = 6), olanzapine (0.30/0.43 = 0.7). These results indicate that dissociation between central and peripheral D2 receptor occupancy is a major determinant of the degree of prolactin elevation observed at therapeutic doses.

Strategies for handling unexpected endocrine findings in early safety assessment.

Early assessment of the endocrine toxicity of pharmaceuticals has received increasing scientific attention due to the important issue of endocrine disrupters, and the need to evaluate mechanisms and relevance to humans of early toxicity findings in animals. Pharmaceuticals can directly alter an endocrine organ, or indirectly regulatory systems. The strategy for handling unexpected endocrine findings in early toxicity studies is by definition extremely variable and should be adapted case by case. Using three examples: (i) thyroid hyperplasia; (ii) prolactin-induced mammary gland hyperplasia in rats; and (iii) aromatase inhibition, the usefulness and limitation of serum endocrine analyses in classical toxicological studies, the need for specific mechanistic studies and the major importance of integration between pharmacodynamic, pharmacokinetic and toxicological data will be discussed. Finally, the importance of assessment of relevance and the extrapolation of preclinical findings to humans at an early stage in clinical development is highlighted.