High expression of CPT1b in skeletal muscle in metabolically healthy older subjects.

AIM: Ageing is often associated with metabolic abnormalities such as insulin resistance, although some people remain metabolically healthy throughout their lives. The aim of this study was to gain more insight into metabolic health with increasing age. METHODS: Two groups of robust and of frail subjects, respectively, were identified based on a composite ageing indicator and recruited from the French SU.VI.MAX 2 cohort of older disease-free subjects. In all, 14 men and 12 women, aged 67±4 years, with similar anthropometric and metabolic characteristics at baseline (BMI: 24.5±2.9kg.m-2) were included in the Compaliclamp study. Skeletal muscle biopsy was performed to assess expression of a set of metabolic and sirtuin (SIRT) genes. Also, whole-body substrate oxidation and insulin sensitivity were determined using the euglycaemic-hyperinsulinaemic clamp and indirect calorimetry techniques. RESULTS: Robust subjects were more insulin-sensitive, oxidized more lipid in a fasting state and stored more glucose during the euglycaemic - hyperinsulinaemic clamp than did frail subjects. At the gene-expression level in skeletal muscle, carnitine palmitoyltransferase 1b (CPT1b) messenger RNA (mRNA) levels were around four times higher in the robust compared with frail counterparts. Moreover, both SIRT2 and SIRT6 expression was lower in robust subjects and correlated with CPT1b expression. CONCLUSION: CPT1b overexpression could be helping to maintain metabolic health with increasing age. Thus, it is suggested that targeting CPT1b expression might be an interesting strategy to counteract frailty at an early stage. In addition, future studies should examine the role of sirtuin in CPT1b expression regulation.

Biosynthesis-driven structure-activity relationship study of premonensin-derivatives.

The controlled derivatization of natural products is of great importance for their use in drug discovery. The ideally rapid generation of compound libraries for structure-activity relationship studies is of particular concern. We here use modified biosynthesis for the generation of such a library of reduced polyketides to interfere with the oncogenic KRas pathway. The polyketide is derivatized via side chain alteration, and variations in its redox pattern and in its backbone chain length through manipulation in the corresponding polyketide synthase. Structural and biophysical analyses revealed the nature of the interaction between the polyketides and KRas-interacting protein PDE6δ. Non-natural polyketides with low nanomolar affinity to PDE6δ were identified.

[Pediatric drug development: ICH harmonized tripartite guideline E11 within the United States of America, the European Union, and Japan]. / ICH E11 : développement d'un médicament pédiatrique : comparaison entre les États-Unis, l'Union Européenne et le Japon.

To address the lack of appropriate pediatric drugs available on the global market, in 2000 the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) issued the ICH E11 guideline regarding the Clinical Investigation of Medicinal Products in the Pediatric Population. This guideline considerably changes the environment of drug development for children. It has been written specifically to harmonize, promote, and facilitate high-quality and ethical clinical research for children within the ICH regions, i.e., the United States of America (USA), the European Union (EU), and Japan. This article details the various regulations applicable in each ICH region following the publication of the guideline. The framework of rewards, incentives, and obligations for pharmaceutical companies established for the development of pediatric drugs are compared. It appears that the USA and the EU have both developed specific regulations for pediatric drug development while Japan has not. However, in Japan, pharmaceutical companies (PCs) are encouraged to develop pediatric drugs voluntarily, and they may be granted additional months of market exclusivity or the postponement of the drug re-examination deadline. In both the USA and the EU, regulations aimed to increase the number of clinical studies conducted in children, in order to ensure that the necessary data are generated, determining the conditions in which a drug may be authorized to treat the pediatric population. PCs are encouraged to develop pediatric assessment, including pediatric clinical trials, which is described in a pediatric plan submitted to the relevant authorities. A system of rewards for PCs submitting an application for marketing authorization containing pediatric use information has been put in place to cover the additional investment for testing drugs in children. Subject to conditions, these rewards consist in a 6-month extension of the patent or supplementary protection. Regarding the approval for new medicinal products in these two regions, regulations require PCs to include, when it is relevant, a pediatric assessment in their drug research and development plan, which must be approved. Although these regions have implemented the ICH guideline, the regulation differs with respect to the timing of studies in children relative to adults and approval of a pediatric drug development plan. Except for special cases, the pediatric investigation plan in the EU is required to be prepared and submitted to the competent authorities upon availability of adult pharmacokinetic studies (after phase I), which means at an early phase of a new drug development plan. In the USA, the pediatric plan is requested later during the phase II or III trials. In practice, it has become difficult for pharmaceutical industries to develop a practicable clinical program for pediatrics including timelines for studies in children that satisfy both EU and USA authorities. Nevertheless, at an early stage of the development strategy, direct support and advice from competent authorities can be obtained. For the ICH regions, pediatric committees are well-established albeit less structured in Japan. Their roles are to review and assess pediatric plans, to issue recommendations, to advise pharmaceutical companies on the content and format of pediatric data to be methodically collected and analyzed, and to avoid exposing children to unnecessary or redundant clinical trials. This regulatory framework encourages the study and the development of pediatric drugs, but it is still quite difficult to actually measure the impact of the ICH E11 on increasing the number of drugs for pediatric use.

Connectivity measures applied to human brain electrophysiological data.

Connectivity measures are (typically bivariate) statistical measures that may be used to estimate interactions between brain regions from electrophysiological data. We review both formal and informal descriptions of a range of such measures, suitable for the analysis of human brain electrophysiological data, principally electro- and magnetoencephalography. Methods are described in the space-time, space-frequency, and space-time-frequency domains. Signal processing and information theoretic measures are considered, and linear and nonlinear methods are distinguished. A novel set of cross-time-frequency measures is introduced, including a cross-time-frequency phase synchronization measure.

Sensory gating in the human hippocampal and rhinal regions: regional differences.

To further explore the roles of medial temporal structures in mediating sensory gating of incoming irrelevant or redundant auditory input, twenty-seven patients with intractable epilepsy with depth electrodes implanted in the medial temporal lobe for presurgery evaluation underwent evoked response recording to auditory paired-stimuli (S1-S2). Seventeen subjects were diagnosed with left medial temporal lobe epilepsy (MTLE) and 10 with right MTLE. Only data from the nonlesion side were included. Twenty-three records from rhinal and anterior hippocampal regions, and 21 from posterior hippocampal regions were included in the analysis. The rhinal region had two prominent components (a negativity peaking around 200 ms followed by a positivity peaking around 400 ms). Both the anterior and posterior hippocampal regions exhibited a dominant negative potential peaking around 400 ms. These components were all composed predominantly of slower frequencies. In contrast, a negativity in the posterior hippocampus at around 100 ms was composed of slow and fast frequencies. All components but the early rhinal negativity were attenuated by stimulus repetition. This is the first report documenting that different regions of the medial temporal area are differentially involved in the processing of auditory input, most likely reflecting separate steps of processing. The data support the need for further exploration of the contribution of these regions to sensory gating. This information helps to increase our understanding of this basic but important and complex function.

Regional resolving power of combined MEG/EEG.

Different modeling frameworks (such as error analyses for dipole localization [Fuchs, 1998] [Huizenga, 2001]; crosstalk and point spread analyses for linear estimators [Liu, 2002]; etc.) have demonstrated improved three-dimensional (3D) resolution for combined MEG/EEG (or EMEG) source estimation. Complementary to these, an empirical analysis of 2D surface data suggested that MEG and EEG information content could be superadditive [Pflieger, 2000]. Taking a hybrid approach in the present study, we made simulations within a regional activity estimation (REGAE, [Pflieger, 2001]) framework, which quantifies the ability of EMEG to discriminate brain activity originating within a 3D region of interest (ROI) from simultaneous non-ROI activity. Two metrics were employed: Kullback-Leibler divergence (KLD) and area under the receiver operator characteristic curve (AUROC). High-density sensor configurations (248 magnetometers, 256 electrodes) were combined with a gray matter source space model (7931 dipole triples, maximum entropy activities), assuming magnetic 3-shell sphere and electric BEM head models. Superadditive KLD was observed frequently across 89 representative brain ROIs and 3 ROI sizes (5, 10, and 15 mm radii), especially for regions already fairly visible to each modality. We also report an observed functional relationship between AUROC and KLD.

Dynamic neuroimaging of brain function.

To fully characterize the brain processes underlying sensorimotor and cognitive function, the spatial distribution of active regions, their interconnected regions must be measured. We describe methods for imaging brain sources from surface-recorded EEG and magnetoencephalographic data, called electromagnetic source imaging (EMSI). EMSI provides brain source locations within the common framework of magnetic resonance (MR) images of brain anatomy. This allows integration of data from other functional brain imaging methods, like positron emission tomography and functional MR imaging, which can improve the accuracy of EMSI localization. EMSI also provides submillisecond temporal resolution of the dynamic processes within brain systems. Examples are given of applications to visual perceptual and attentional studies.