Urinary oxalate and urate to creatinine ratios in a healthy pediatric population.

The purpose of the study was to determine reference percentiles for the urinary (U) oxalate (Ox) and urate (Ura) to creatinine (Cr) concentration ratios in the second morning urine of healthy infants, children, and adolescents. The urinary oxalate and urate to creatinine ratios were determined in the spontaneously voided second morning urine sample. To test reproducibility, two urine samples were analyzed on 2 consecutive weeks in 63% of the subjects. Three hundred eighty-four healthy children (181 girls, 203 boys), aged 1 month to 17 years, from nurseries, kindergartens, and schools of Lausanne, Switzerland, were studied. The 5th and 95th percentiles were determined from the total number of urine samples (627) after confirmation that there was no order effect between repeated measurements and there were no significant sex differences. A nonlinear regression analysis in terms of age was used to smooth the calculated percentiles. In this manner, curves were obtained from which the reference values can be read at any given age. The 95th percentiles decreased with age: for UOx/Cr from 0.175 mg/mg (0.22 mol/mol) at 1 to 6 months to 0.048 mg/mg (0.06 mol/mol) from 7 years and beyond; and UUra/Cr from 2.378 mg/mg (1.6 mol/mol) at 1 to 6 months to 0.594 mg/mg (0.4 mol/mol) in adolescence. We provide 5th and 95th percentile curves for the UOx/Cr and UUra/Cr ratios determined from the second morning urine samples in a large cohort of healthy infants, children, and adolescents. Values were determined by standard analytical chemical techniques and were analyzed by powerful statistical methods. The calculated 95th percentile for the UOx/Cr values fell rather rapidly and reached normal adult values by the age of 7 years, whereas for UUra/Cr, the 95th percentile decreased slowly and stabilized in adolescence.

Review of therapeutic drug monitoring of anticancer drugs part one - Cytotoxics.

Most anticancer drugs are characterised by a steep dose-response relationship and narrow therapeutic window. Inter-individual pharmacokinetic (PK) variability is often substantial. The most relevant PK parameter for cytotoxic drugs is the area under the plasma concentration versus time curve (AUC). Thus it is somewhat surprising that therapeutic drug monitoring (TDM) is still uncommon for the majority of agents. Goals of the review were to assess the rationale for more widely used TDM of cytotoxics in oncology. There are several reasons why TDM has never been fully implemented into daily oncology practice. These include difficulties in establishing appropriate concentration target ranges, common use of combination chemotherapies for many tumour types, analytical challenges with prodrugs, intracellular compounds, the paucity of published data from pharmacological trials and 'Day1=Day21' administration schedules. There are some specific situations for which these limitations are overcome, including high dose methotrexate, 5-fluorouracil infusion, mitotane and some high dose chemotherapy regimens. TDM in paediatric oncology represents an important challenge. Established TDM approaches includes the widely used anticancer agents carboplatin, busulfan and methotrexate, with 13-cis-retinoic acid also recently of interest. Considerable effort should be made to better define concentration-effect relationships and to utilise tools such as population PK/PD models and comparative randomised trials of classic dosing versus pharmacokinetically guided adaptive dosing. There is an important heterogeneity among clinical practices and a strong need to promote TDM guidelines among the oncological community.

Total IgE and eotaxin (CCL11) contents in tears of patients suffering from seasonal allergic conjunctivitis.

BACKGROUND: To prospectively investigate patients with seasonal allergic conjunctivitis (SAC) during the pollen season and test associations between tears total IgE, eotaxin concentrations, and SAC severity. METHODS: Enrolled patients presented ocular symptoms and clinical signs of SAC at the time of presentation. Ocular itching, hyperaemia, chemosis, eyelid swelling, and tearing were scored, and the sum of these scores was defined as the clinical score. Conjunctival papillae were separately graded. We measured eotaxin concentration in tears by an enzyme-linked immunosorbent assay (ELISA) and total tear IgE by Lacrytest strip. RESULTS: Among thirty patients (30 eyes), 11 showed neither tear IgE nor tear eotaxin, while 15 out of 19 patients with positive IgE values presented a positive amount of eotaxin in their tears (Fisher's test: p < 0.001). The mean eotaxin concentration was 641 ± 154 (SEM) pg/ml. In patients with no amount of tear IgE, we observed a lower conjunctival papilla grade than in patients whose tears contained some amount of IgE (trend test: p = 0.032). In the 15 patients whose tear eotaxin concentration was null, tear IgE concentration was 5.3 ± 3.5 arbitrary units; in the other 15 patients whose eotaxin was positive, IgE reached 21 ± 4.3 arbitrary U (Mann-Whitney: p < 0.001). We measured 127 ± 47 pg/ml eotaxin in patients with no history of SAC but newly diagnosed as suffering from SAC, and 852 ± 218 pg/ml eotaxin in patients with a known SAC (p = 0.008). In contrast, tear IgE concentrations of both groups did not differ statistically significantly (p = 0.947). CONCLUSIONS: If IgE and eotaxin secreted in tears are major contributors in SAC pathogenesis, they however act at different steps of the process.

Intravoxel incoherent motion perfusion imaging in acute stroke: initial clinical experience.

INTRODUCTION: Intravoxel incoherent motion (IVIM) imaging is an MRI perfusion technique that uses a diffusion-weighted sequence with multiple b values and a bi-compartmental signal model to measure the so-called pseudo-diffusion of blood caused by its passage through the microvascular network. The goal of the current study was to assess the feasibility of IVIM perfusion fraction imaging in patients with acute stroke. METHODS: Images were collected in 17 patients with acute stroke. Exclusion criteria were onset of symptoms to imaging >5 days, hemorrhagic transformation, infratentorial lesions, small lesions <0.5 cm in minimal diameter and hemodynamic instability. IVIM imaging was performed at 3 T, using a standard spin-echo Stejskal-Tanner pulsed gradients diffusion-weighted sequence, using 16 b values from 0 to 900 s/mm(2). Image quality was assessed by two radiologists, and quantitative analysis was performed in regions of interest placed in the stroke area, defined by thresholding the apparent diffusion coefficient maps, as well as in the contralateral region. RESULTS: IVIM perfusion fraction maps showed an area of decreased perfusion fraction f in the region of decreased apparent diffusion coefficient. Quantitative analysis showed a statistically significant decrease in both IVIM perfusion fraction f (0.026 ± 0.019 vs. 0.056 ± 0.025, p = 2.2 · 10(-6)) and diffusion coefficient D compared with the contralateral side (3.9 ± 0.79 · 10(-4) vs. 7.5 ± 0.86 · 10(-4) mm(2)/s, p = 1.3 · 10(-20)). CONCLUSION: IVIM perfusion fraction imaging is feasible in acute stroke. IVIM perfusion fraction is significantly reduced in the visible infarct. Further studies should evaluate the potential for IVIM to predict clinical outcome and treatment response.

A gene-rich, transcriptionally active environment and the pre-deposition of repressive marks are predictive of susceptibility to KRAB/KAP1-mediated silencing.

AbstractBACKGROUND: KRAB-ZFPs (Krüppel-associated box domain-zinc finger proteins) are vertebrate-restricted transcriptional repressors encoded in the hundreds by the mouse and human genomes. They act via an essential cofactor, KAP1, which recruits effectors responsible for the formation of facultative heterochromatin. We have recently shown that KRAB/KAP1 can mediate long-range transcriptional repression through heterochromatin spreading, but also demonstrated that this process is at times countered by endogenous influences.METHOD: To investigate this issue further we used an ectopic KRAB-based repressor. This system allowed us to tether KRAB/KAP1 to hundreds of euchromatic sites within genes, and to record its impact on gene expression. We then correlated this KRAB/KAP1-mediated transcriptional effect to pre-existing genomic and chromatin structures to identify specific characteristics making a gene susceptible to repression.RESULTS: We found that genes that were susceptible to KRAB/KAP1-mediated silencing carried higher levels of repressive histone marks both at the promoter and over the transcribed region than genes that were insensitive. In parallel, we found a high enrichment in euchromatic marks within both the close and more distant environment of these genes.CONCLUSION: Together, these data indicate that high levels of gene activity in the genomic environment and the pre-deposition of repressive histone marks within a gene increase its susceptibility to KRAB/KAP1-mediated repression.

Laser scanning-based recognition of rotational movements on a deep seated gravitational instability: The Cinque Torri case (North-Eastern Italian Alps)

The Cinque Torri group (Cortina d'Ampezzo, Italy) is an articulated system of unstable carbonatic rock monoliths located in a very important tourism area and therefore characterized by a significant risk. The instability phenomena involved represent an example of lateral spreading developed over a larger deep seated gravitational slope deformation (DSGSD) area. After the recent fall of a monolith of more than 10 000 m3, a scientific study was initiated to monitor the more unstable sectors and to characterize the past movements as a fundamental tool for predicting future movements and hazard assessment. To achieve greater insight on the ongoing lateral spreading process, a method for a quantitative analysis of rotational movements associated with the lateral spreading has been developed, applied and validated. The method is based on: i) detailed geometrical characterization of the area by means of laser scanner techniques; ii) recognition of the discontinuity sets and definition of a reference frame for each set, iii) correlation between the obtained reference frames related to a specific sector and a stable external reference frame, and iv) determination of the 3D rotations in terms of Euler angles to describe the present settlement of the Cinque Torri system with respect to the surrounding stable areas. In this way, significant information on the processes involved in the fragmentation and spreading of a former dolomitic plateau into different rock cliffs has been gained. The method is suitable to be applied to similar case studies.

Digitale politische Partizipation - Spannungsfeld zwischen MyPolitics und OurPolitics

Der Beitrag untersucht soziale und politische Aspekte digitaler politischer Partizipation. Einerseits müssen die Optionen für MyPolitics ausgeschöpft werden, indem Instrumente für elektronische Abstimmungen und Wahlen bereitgestellt werden. Andererseits sollte das Potenzial politischer Partizipation genutzt und Plattformen für OurPolitics gefördert werden. Solche Plattformen, ergänzt durch geeignete Matching-Verfahren, bringen Interessierte mit ähnlichen Anliegen zusammen und fördern politische Gestaltungskraft. Sie sind ein erster Schritt zum Public Memory einer digitalen Gesellschaft und bereichern nachfolgende Generationen mit ihrem Gedankengut.

PPARβ/δ prevents endoplasmic reticulum stress-associated inflammation and insulin resistance in skeletal muscle cells through an AMPK-dependent mechanism.

AIM/HYPOTHESIS: Endoplasmic reticulum (ER) stress, which is involved in the link between inflammation and insulin resistance, contributes to the development of type 2 diabetes mellitus. In this study, we assessed whether peroxisome proliferator-activated receptor (PPAR)β/δ prevented ER stress-associated inflammation and insulin resistance in skeletal muscle cells. METHODS: Studies were conducted in mouse C2C12 myotubes, in the human myogenic cell line LHCN-M2 and in skeletal muscle from wild-type and PPARβ/δ-deficient mice and mice exposed to a high-fat diet. RESULTS: The PPARβ/δ agonist GW501516 prevented lipid-induced ER stress in mouse and human myotubes and in skeletal muscle of mice fed a high-fat diet. PPARβ/δ activation also prevented thapsigargin- and tunicamycin-induced ER stress in human and murine skeletal muscle cells. In agreement with this, PPARβ/δ activation prevented ER stress-associated inflammation and insulin resistance, and glucose-intolerant PPARβ/δ-deficient mice showed increased phosphorylated levels of inositol-requiring 1 transmembrane kinase/endonuclease-1α in skeletal muscle. Our findings demonstrate that PPARβ/δ activation prevents ER stress through the activation of AMP-activated protein kinase (AMPK), and the subsequent inhibition of extracellular-signal-regulated kinase (ERK)1/2 due to the inhibitory crosstalk between AMPK and ERK1/2, since overexpression of a dominant negative AMPK construct (K45R) reversed the effects attained by PPARβ/δ activation. CONCLUSIONS/INTERPRETATION: Overall, these findings indicate that PPARβ/δ prevents ER stress, inflammation and insulin resistance in skeletal muscle cells by activating AMPK.

Mating system and avpr1a promoter variation in primates.

It has been suggested that primate mating and social behaviours may be influenced by variation in promoter region repetitive DNA of the vasopressin receptor 1a gene (avpr1a). We show that male mating behaviour does not covary in a simple way with promoter repetitive DNA in 12 Old World primates. We found that one microsatellite (-553 bp upstream) was present in all species, irrespective of their behaviour. By contrast, two microsatellites (-3956 and -3625 bp upstream) were present only in some species, yet this variation did not correlate with behaviour. These findings agree with a recent comparative analysis of voles and show that the variation in repetitive DNA in the avpr1a promoter region does not generally explain variation in male mating behaviour. Phylogenetic analysis revealed a GAGTA motif that has been independently deleted three times and involved in another larger deletion. Importantly, the presence/absence of this GAGTA motif leads to changes in predicted transcription factor-binding sites. Given the repeated loss of this motif, we speculate that it might be of functional relevance. We suggest that such non-repetitive variation, either in indels or in sequence variation, are likely to be important in explaining interspecific variation in avpr1a expression.

Le dieu à miracles: ambition et rayonnement de Bhagavan Shri Sathya Sai Baba

(Résumé de l'ouvrage) En Europe occidentale on hésite entre le fin des héros, saints et martyrs comme points d'ancrage et guide de collectivités (religieuses ou politiques), et les quêtes d'identité et d'identification. Scepticisme humaniste et individualisme dévaluent des héros nationaux au profit d'emballements médiatiques éphémères pour des vedettes du sport, de l'humanitaire (mère Teresa), des familles royales (la princesse Diana). Se raréfient des modèles stables, inspirant des conduites privées et sociales raisonnablement gérées, et une adhésion durable et fervente. L'ouvrage offre l'analyse de nouveaux contextes où s'effectuent la promotion et l'exaltation de la sainteté, de l'exemplarité ou du martyre, dans des sociétés extra-européennes (Maroc, Inde, Afghanistan) et apparemment laïcisées (France, Bulgarie).

Peripheral T-cell lymphoma with t(6;14)(p25;q11.2) translocation presenting with massive splenomegaly.

Recurrent chromosomal translocations associated to peripheral T-cell lymphomas (PTCL) are rare. Here, we report a case of PTCL, not otherwise specified (NOS) with the karyotype 46,Y,add(X)(p22),t(6;14)(p25;q11) and FISH-proved breakpoints in the IRF4 and TCRAD loci, leading to juxtaposition of both genes. A 64-year-old male patient presented with mild cytopenias and massive splenomegaly. Splenectomy showed diffuse red pulp involvement by a pleomorphic medium- to large-cell T-cell lymphoma with a CD2+ CD3+ CD5- CD7- CD4+ CD8+/- CD30- TCRbeta-F1+ immunophenotype, an activated cytotoxic profile, and strong MUM1 expression. The clinical course was marked by disease progression in the bone marrow under treatment and death at 4 months. In contrast with two t(6;14)(p25;q11.2)-positive lymphomas previously reported to be cytotoxic PTCL, NOS with bone marrow and skin involvement, this case was manifested by massive splenomegaly, expanding the clinical spectrum of PTCLs harboring t(6;14)(p25;q11.2) and supporting consideration of this translocation as a marker of biological aggressiveness.

Externalizing disorders and substance use: empirically derived subtypes in a population-based sample of adults.

PURPOSE: Attention-deficit/hyperactivity disorder (ADHD), conduct disorder (CD), and oppositional defiant disorder (ODD) are common externalizing disorders of childhood. The common effects of these disorders on substance abuse need further investigation. The current study investigated the joint clusters of childhood/adolescence ADHD, CD, and ODD, and their influence on substance abuse/dependence in a population-based sample of adults. METHODS: The data were drawn from the PsyCoLaus study (n = 3,720) conducted in Lausanne, Switzerland. The population-based sample included 238 subjects meeting criteria for ADHD/ODD/CD diagnoses before the age of 15. Latent class analyses (LCA) were performed to derive comorbidity subtypes, which were subsequently characterized with respect to psychosocial correlates and substance use. RESULTS: The best fit in LCAs was achieved with three latent classes: an ADHD subtype (35.7 %); an externalizing multimorbid subtype (33.6 %) involving ODD, ADHD, and CD; and a third subtype with CD (30.7 %). The CD subtype showed the highest association with substance use. Apart from this, the externalizing multimorbid subtype was also significantly linked to substance use. The ADHD subtype had only elevated frequencies for alcohol dependence in comparison with subjects that had no history of ADHD, ODD, and CD during childhood or adolescence. Finally, important interactions between subtypes and sex were observed with regard to substance use. CONCLUSIONS: This study provides evidence showing that subtyping the externalizing disorders, ADHD, ODD and CD, along their comorbidity patterns leads to important differences regarding substance use. This could have implications for the etiology, prevention, and treatment of substance use disorders.

Computed tomography angiography vs 3 T black-blood cardiovascular magnetic resonance for identification of symptomatic carotid plaques.

BACKGROUND: The purpose of this prospective study was to perform a head-to-head comparison of the two methods most frequently used for evaluation of carotid plaque characteristics: Multi-detector Computed Tomography Angiography (MDCTA) and black-blood 3 T-cardiovascular magnetic resonance (bb-CMR) with respect to their ability to identify symptomatic carotid plaques. METHODS: 22 stroke unit patients with unilateral symptomatic carotid disease and >50% stenosis by duplex ultrasound underwent MDCTA and bb-CMR (TOF, pre- and post-contrast fsT1w-, and fsT2w- sequences) within 15 days of symptom onset. Both symptomatic and contralateral asymptomatic sides were evaluated. By bb-CMR, plaque morphology, composition and prevalence of complicated AHA type VI lesions (AHA-LT6) were evaluated. By MDCTA, plaque type (non-calcified, mixed, calcified), plaque density in HU and presence of ulceration and/or thrombus were evaluated. Sensitivity (SE), specificity (SP), positive and negative predictive value (PPV, NPV) were calculated using a 2-by-2-table. RESULTS: To distinguish between symptomatic and asymptomatic plaques AHA-LT6 was the best CMR variable and presence / absence of plaque ulceration was the best CT variable, resulting in a SE, SP, PPV and NPV of 80%, 80%, 80% and 80% for AHA-LT6 as assessed by bb-CMR and 40%, 95%, 89% and 61% for plaque ulceration as assessed by MDCTA. The combined SE, SP, PPV and NPV of bb-CMR and MDCTA was 85%, 75%, 77% and 83%, respectively. CONCLUSIONS: Bb-CMR is superior to MDCTA at identifying symptomatic carotid plaques, while MDCTA offers high specificity at the cost of low sensitivity. Results were only slightly improved over bb-CMR alone when combining both techniques.

No experimental evidence that sibling competition induces young to switch nests in the colonial Alpine swift, Apus melba

Adoption is frequent in colonial animals where opportunities for dependent young to receive care from nonbiological parents are high. The departure of dependent young from their original family to seek adoption in neighbouring families is thought to be induced by sibling competition for access to limited resources provided by poor-quality parents. We tested this hypothesis in the colonial Alpine swift by manipulating the number of young reared per brood, with the prediction that offspring from enlarged broods switch nests more frequently than those from reduced broods. Although nestling swifts hatch with little locomotor activity, from 20 days until their first flight at 50-70 days they frequently move out of their nests to seek adoption in neighbouring families. Although nestlings reared in experimentally enlarged broods were lighter and their body mass at day 20 after hatching was more variable than in nestlings reared in reduced broods, there was no difference between the two treatments in the frequency of nests switching and in the age when nestlings switched nests for the first time. However, consistent with other evidence that nest switching by nestling swifts evolved as a strategy to reduce ectoparasite load, young from broods with naturally high numbers of the ectoparasitic louse fly Crataerina melbae were more prone to switch nests. This shows that ectoparasitism rather than sibling competition is a key proximate factor promoting the evolution of nest switching in the colonial Alpine swift. (c) 2006 The Association for the Study of Animal Behaviour Published by Elsevier Ltd. All rights reserved.