Familial hemiplegic migraine with cerebellar ataxia and paroxysmal psychosis

Familial hemiplegic migraine is a rare autosomal dominant disorder associated with stereotypic neurologic au ra phenomena including hemiparesis, So far two chromosomal loci have been identified. Families linked to the chromosome 19 locus display missense mutations within the CACNL1A4 gene. Here we report on a family with familial hemiplegic migraine and cerebellar ataxia with recurrent episodes of acute paranoid psychosis with anxiety and visual hallucinations associated with migraine attacks. Based on the clinical and haplotype evidence indicating linkage to chromosome 19 in this family, we hypothesize that a dysfunction of the mutated calcium channel may be involved not only in the development of hemiplegic migraine but also in the acute psychotic episodes observed in these patients

|V_us| from Strange Hadronic Tau Data

We report on recent work to determine the CKM matrix element |V_{us}| using strange hadronic \tau decay data. We use the recent OPAL update of the strange spectral function, while on the theory side we update the dimension-two perturbative contribution including the recently calculated \alpha_s^3 terms. Our result |V_{us}|=0.2220 \pm 0.0033 is already competitive with the standard extraction from K_{e3} decays and other new proposals to determine |V_{us}|. The actual uncertainty on |V_{us}| from \tau data is dominated largely by experiment and will eventually be much reduced by B-factories and future \tau-charm factory data, providing one of the most accurate determinations of this Standard Model parameter.Comment: 7 pages, no figures. Invited talk given by J.P. at ICHEP'06, 26 July to 2 August, Moscow, Russi

Physiologically Based Precision Dosing Approach for Drug-Drug-Gene Interactions: A Simvastatin Network Analysis

Drug‐drug interactions (DDIs) and drug‐gene interactions (DGIs) are well known mediators for adverse drug reactions (ADRs), which are among the leading causes of death in many countries. Because physiologically based pharmacokinetic (PBPK) modeling has demonstrated to be a valuable tool to improve pharmacotherapy affected by DDIs or DGIs, it might also be useful for precision dosing in extensive interaction network scenarios. The presented work proposes a novel approach to extend the prediction capabilities of PBPK modeling to complex drug‐drug‐gene interaction (DDGI) scenarios. Here, a whole‐body PBPK network of simvastatin was established, including three polymorphisms (SLCO1B1 (rs4149056), ABCG2 (rs2231142), and CYP3A5 (rs776746)) and four perpetrator drugs (clarithromycin, gemfibrozil, itraconazole, and rifampicin). Exhaustive network simulations were performed and ranked to optimize 10,368 DDGI scenarios based on an exposure marker cost function. The derived dose recommendations were translated in a digital decision support system, which is available at simvastatin.precisiondosing.de. Although the network covers only a fraction of possible simvastatin DDGIs, it provides guidance on how PBPK modeling could be used to individualize pharmacotherapy in the future. Furthermore, the network model is easily extendable to cover additional DDGIs. Overall, the presented work is a first step toward a vision on comprehensive precision dosing based on PBPK models in daily clinical practice, where it could drastically reduce the risk of ADRs

Theoretical progress on the V_us determination from tau decays

A very precise determination of V_us can be obtained from the semi-inclusive hadronic decay width of the tau lepton into final states with strangeness. The ratio of the Cabibbo-suppressed and Cabibbo-allowed tau decay widths directly measures (V_us/V_ud)^2, up to very small SU(3)-breaking corrections which can be theoretically estimated with the needed accuracy. Together with previous LEP and CLEO data, the recent measurements by Babar and Belle of some Cabibbo-suppressed tau decays imply V_us= 0.2165 +- 0.0026_exp +- 0.0005_th, which is already competitive with the standard extraction from K_l3 decays. The uncertainty is largely dominated by experimental errors and should be easily reduced with the high statistics of the B factories, providing the most accurate determination of this parameter. A 1% experimental precision on the Cabibbo-suppressed tau decay width would translate into a 0.6% uncertainty on V_us

Theoretical progress on the V_us determination from tau decays

9 páginas.-- Comunicación presentada a la Kaon International Conference (KAON'07) celebrada del 21 al 25 de MAyo de 2007 en Frascati (Italia).A very precise determination of V_us can be obtained from the semi-inclusive hadronic decay width of the tau lepton into final states with strangeness. The ratio of the Cabibbo-suppressed and Cabibbo-allowed tau decay widths directly measures (V_us/V_ud)^2, up to very small SU(3)-breaking corrections which can be theoretically estimated with the needed accuracy. Together with previous LEP and CLEO data, the recent measurements by Babar and Belle of some Cabibbo-suppressed tau decays imply V_us= 0.2165 +- 0.0026_exp +- 0.0005_th, which is already competitive with the standard extraction from K_l3 decays. The uncertainty is largely dominated by experimental errors and should be easily reduced with the high statistics of the B factories, providing the most accurate determination of this parameter. A 1% experimental precision on the Cabibbo-suppressed tau decay width would translate into a 0.6% uncertainty on V_us.This work has been supported by the European Commission MRTN FLAVIAnet [MRTN-CT- 2006-035482], theMEC (Spain) and FEDER (EC) [FPA2005-02211 (M.J.), FPA2004-00996 (A.P.) and FPA2006-05294 (J.P.)], the Deutsche Forschungsgemeinschaft (F.S.), the Junta de Andalucía [P05-FQM-101 (J.P.), P05-FQM-437 (E.G. and J.P.) and Sabbatical Grant PR2006-0369 (J.P.)] and the Generalitat Valenciana [GVACOMP2007-156 (A.P.)].Peer reviewe

Identification of Cardiomyopathy-Associated Circulating miRNA Biomarkers in Muscular Dystrophy Female Carriers Using a Complementary Cardiac Imaging and Plasma Profiling Approach

Background: Different from males with Duchenne/Becker muscular dystrophy (DMD/BMD) in whom overt myopathy is the rule, muscular dystrophy (MD) female carriers are mostly free of skeletal muscle symptoms. However, similar to MD males, these females are also prone to cardiomyopathy. Since circulating microRNAs (miRNAs) have been proposed as diagnostic biomarkers for various cardiovascular diseases, the aim of the current study was to identify specific circulating miRNAs in the plasma of female DMD/BMD carriers that may allow an early and accurate diagnosis of cardiac involvement in these cases.Methods: Twenty-nine female MD carriers and 24 age-matched healthy female controls were prospectively enrolled. All MD carriers and controls underwent comprehensive cardiovascular magnetic resonance (CMR) studies as well as venous blood sampling on the same day.Results: An impaired left ventricular (LV) systolic function was detected in 4 (14%) MD carriers while late gadolinium enhancement (LGE) indicative of myocardial fibrosis was present in 13 female patients (45%)—with an exclusively non-ischemic pattern. Among the circulating miRNAs examined, six were significantly up-regulated in MD carriers compared to female controls: miR-206 (103-fold increase, p < 0.0001), miR-222 (41-fold, p < 0.0001), miR-26a (fourfold, p = 0.029), miR-342 (27-fold, p < 0.0001), miR-378a-3p (minimum 3,600-fold; almost undetectable in controls, p = 0.013), miR-378a-5p (64-fold, p < 0.0001); only two miRNAs were substantially down-regulated in MD carriers: miR-144 (p < 0.0001) and miR-29a (p = 0.002) (both undetectable in carriers). A significant down-regulation of the miR-29c (<0.001-fold, p = 0.006) was observed in MD carriers with abnormal CMR findings (comprising functional and/or structural abnormalities) compared to those with normal CMR examinations. Univariable analyses regarding the presence of abnormal CMR findings resulted in four significant variables: LV end-diastolic volume index (EDVi), LV end-systolic volume index (ESVi), an elevated plasma creatine kinase (CK), and decreased serum miR-29c levels. In subsequent multivariable analysis, the only independent predictor for an abnormal CMR among MD carriers was circulating miR-29c (OR 0.99, 95% CI 0.98–0.99, p = 0.037). Moreover, an elevated CK and/or a downregulated miR-29c level (<0.05 × 10-3) resulted in an improved AUC value of 0.79 (0.62–0.97, p = 0.007) (79, 80 and 80%, sensitivity, specificity and overall accuracy) for the CMR-based diagnosis of cardiomyopathy in MD carriers when compared to using the two parameters individually.Conclusion: In female MD carriers, down-regulation of circulating miR-29c relates to the presence of functional and/or structural cardiac abnormalities (as detected by CMR) and appears to be a promising novel biomarker—in addition to conventional CK plasma levels—for an early diagnosis of cardiomyopathy