Linkage in narratives: A comparison between monolingual speakers of French and Italian, and early and late French-Italian bilinguals

In the course of language acquisition learners have to deal with the task of producing narrative texts that are coherent across a range of conceptual domains (space, time, entities) -- both within as well as across utterances. The organization of information is analyzed in this study, on the basis of retellings of a silent film, in terms of devices used in the coordination and subordination of events within the narrative sequence. The focus on subordination reflects a core grammatical difference between Italian and French, as Italian is a null-subject language while French is not. The implications of this contrast for information structure include differences in topic management within the sequence of events. The present study investigates in how far Italian-French bilingual speakers acquire the patterns of monolingual speakers of Italian. It compares how early and late bilinguals of these two languages proceed when linking information in narratives in Italian.

Urinary metabolomics in Fxr-null mice reveals activated adaptive metabolic pathways upon bile acid challenge

Farnesoid X receptor (FXR) is a nuclear receptor that regulates genes involved in synthesis, metabolism, and transport of bile acids and thus plays a major role in maintaining bile acid homeostasis. In this study, metabolomic responses were investigated in urine of wild-type and Fxr-null mice fed cholic acid, an FXR ligand, using ultra-performance liquid chromatography (UPLC) coupled with electrospray time-of-flight mass spectrometry (TOFMS). Multivariate data analysis between wild-type and Fxr-null mice on a cholic acid diet revealed that the most increased ions were metabolites of p-cresol (4-methylphenol), corticosterone, and cholic acid in Fxr-null mice. The structural identities of the above metabolites were confirmed by chemical synthesis and by comparing retention time (RT) and/or tandem mass fragmentation patterns of the urinary metabolites with the authentic standards. Tauro-3alpha,6,7alpha,12alpha-tetrol (3alpha,6,7alpha,12alpha-tetrahydroxy-5beta-cholestan-26-oyltaurine), one of the most increased metabolites in Fxr-null mice on a CA diet, is a marker for efficient hydroxylation of toxic bile acids possibly through induction of Cyp3a11. A cholestatic model induced by lithocholic acid revealed that enhanced expression of Cyp3a11 is the major defense mechanism to detoxify cholestatic bile acids in Fxr-null mice. These results will be useful for identification of biomarkers for cholestasis and for determination of adaptive molecular mechanisms in cholestasis.

Examination of FGFRL1 as a candidate gene for diaphragmatic defects at chromosome 4p16.3 shows that Fgfrl1 null mice have reduced expression of Tpm3, sarcomere genes and Lrtm1 in the diaphragm

Fgfrl1 (also known as Fgfr5; OMIM 605830) homozygous null mice have thin, amuscular diaphragms and die at birth because of diaphragm hypoplasia. FGFRL1 is located at 4p16.3, and this chromosome region can be deleted in patients with congenital diaphragmatic hernia (CDH). We examined FGFRL1 as a candidate gene for the diaphragmatic defects associated with 4p16.3 deletions and re-sequenced this gene in 54 patients with CDH. We confirmed six known coding single nucleotide polymorphisms (SNPs): c.209G > A (p.Pro20Pro), c.977G > A (p.Pro276Pro), c.1040T > C (p.Asp297Asp), c.1234C > A (p.Pro362Gln), c.1420G > T (p.Arg424Leu), and c.1540C > T (p.Pro464Leu), but we did not identify any gene mutations. We genotyped additional CDH patients for four of these six SNPs, including the three non-synonymous SNPs, to make a total of 200 chromosomes, and found that the allele frequency for the four SNPs, did not differ significantly between patients and normal controls (p > or = 0.05). We then used Affymetrix Genechip Mouse Gene 1.0 ST arrays and found eight genes with significantly reduced expression levels in the diaphragms of Fgfrl1 homozygous null mice when compared with wildtype mice-Tpm3, Fgfrl1 (p = 0.004), Myl2, Lrtm1, Myh4, Myl3, Myh7 and Hephl1. Lrtm1 is closely related to Slit3, a protein associated with herniation of the central tendon of the diaphragm in mice. The Slit proteins are known to regulate axon branching and cell migration, and inhibition of Slit3 reduces cell motility and decreases the expression of Rac and Cdc42, two genes that are essential for myoblast fusion. Further studies to determine if Lrtm1 has a similar function to Slit3 and if reduced Fgfrl1 expression can cause diaphragm hypoplasia through a mechanism involving decreased myoblast motility and/or myoblast fusion, seem indicated.

Identification of noninvasive biomarkers for alcohol-induced liver disease using urinary metabolomics and the Ppara-null mouse

Alcohol-induced liver disease (ALD) is a leading cause of nonaccident-related deaths in the United States. Although liver damage caused by ALD is reversible when discovered at the earlier stages, current risk assessment tools are relatively nonspecific. Identification of an early specific signature of ALD would aid in therapeutic intervention and recovery. In this study, the metabolic changes associated with ALD were examined using alcohol-fed male Ppara-null mouse as a model of ALD. Principal components analysis of the mass spectrometry-based urinary metabolic profile showed that alcohol-treated wild-type and Ppara-null mice could be distinguished from control animals without information on history of alcohol consumption. The urinary excretion of ethyl-sulfate, ethyl-beta-d-glucuronide, 4-hydroxyphenylacetic acid, and 4-hydroxyphenylacetic acid sulfate was elevated and that of the 2-hydroxyphenylacetic acid, adipic acid, and pimelic acid was depleted during alcohol treatment in both wild-type and the Ppara-null mice albeit to different extents. However, indole-3-lactic acid was exclusively elevated by alcohol exposure in Ppara-null mice. The elevation of indole-3-lactic acid is mechanistically related to the molecular events associated with development of ALD in alcohol-treated Ppara-null mice. This study demonstrated the ability of a metabolomics approach to identify early, noninvasive biomarkers of ALD pathogenesis in Ppara-null mouse model.

UPLC-MS-based urine metabolomics reveals indole-3-lactic acid and phenyllactic acid as conserved biomarkers for alcohol-induced liver disease in the Ppara-null mouse model

Since the development and prognosis of alcohol-induced liver disease (ALD) vary significantly with genetic background, identification of a genetic background-independent noninvasive ALD biomarker would significantly improve screening and diagnosis. This study explored the effect of genetic background on the ALD-associated urinary metabolome using the Ppara-null mouse model on two different backgrounds, C57BL/6 (B6) and 129/SvJ (129S), along with their wild-type counterparts. Reversed-phase gradient UPLC-ESI-QTOF-MS analysis revealed that urinary excretion of a number of metabolites, such as ethylsulfate, 4-hydroxyphenylacetic acid, 4-hydroxyphenylacetic acid sulfate, adipic acid, pimelic acid, xanthurenic acid, and taurine, were background-dependent. Elevation of ethyl-β-d-glucuronide and N-acetylglycine was found to be a common signature of the metabolomic response to alcohol exposure in wild-type as well as in Ppara-null mice of both strains. However, increased excretion of indole-3-lactic acid and phenyllactic acid was found to be a conserved feature exclusively associated with the alcohol-treated Ppara-null mouse on both backgrounds that develop liver pathologies similar to the early stages of human ALD. These markers reflected the biochemical events associated with early stages of ALD pathogenesis. The results suggest that indole-3-lactic acid and phenyllactic acid are potential candidates for conserved and pathology-specific high-throughput noninvasive biomarkers for early stages of ALD.

Cholesteryl ester accumulation and accelerated cholesterol absorption in intestine-specific hormone sensitive lipase-null mice

Hormone sensitive lipase (HSL) regulates the hydrolysis of acylglycerols and cholesteryl esters (CE) in various cells and organs, including enterocytes of the small intestine. The physiological role of this enzyme in enterocytes, however, stayed elusive. In the present study we generated mice lacking HSL exclusively in the small intestine (HSLiKO) to investigate the impact of HSL deficiency on intestinal lipid metabolism and the consequences on whole body lipid homeostasis. Chow diet-fed HSLiKO mice showed unchanged plasma lipid concentrations. In addition, feeding with high fat/high cholesterol (HF/HC) diet led to unaltered triglyceride but increased plasma cholesterol concentrations and CE accumulation in the small intestine. The same effect was observed after an acute cholesterol load. Gavaging of radioactively labeled cholesterol resulted in increased abundance of radioactivity in plasma, liver and small intestine of HSLiKO mice 4h post-gavaging. However, cholesterol absorption determined by the fecal dual-isotope ratio method revealed no significant difference, suggesting that HSLiKO mice take up the same amount of cholesterol but in an accelerated manner. mRNA expression levels of genes involved in intestinal cholesterol transport and esterification were unchanged but we observed downregulation of HMG-CoA reductase and synthase and consequently less intestinal cholesterol biosynthesis. Taken together our study demonstrates that the lack of intestinal HSL leads to CE accumulation in the small intestine, accelerated cholesterol absorption and decreased cholesterol biosynthesis, indicating that HSL plays an important role in intestinal cholesterol homeostasis.

Intra-subject variability in attention-deficit hyperactivity disorder

BACKGROUND: This study is based on a comprehensive survey of the neuropsychological attention-deficit hyperactivity disorder (ADHD) literature and presents the first psychometric analyses of different parameters of intra-subject variability (ISV) in patients with ADHD compared to healthy controls, using the Continuous Performance Test, a Go-NoGo task, a Stop Signal Task, as well as N-back tasks. METHODS: Data of 57 patients with ADHD and 53 age- and gender-matched controls were available for statistical analysis. Different parameters were used to describe central tendency (arithmetic mean, median), dispersion (standard deviation, coefficient of variation, consecutive variance), and shape (skewness, excess) of reaction time distributions, as well as errors (commissions and omissions). RESULTS: Group comparisons revealed by far the strongest effect sizes for measures of dispersion, followed by measures of central tendency, and by commission errors. Statistical control of ISV reduced group differences in the other measures substantially. One (patients) or two (controls) principal components explained up to 67% of the inter-individual differences in intra-individual variability. CONCLUSIONS: Results suggest that, across a variety of neuropsychological tests, measures of ISV contribute best to group discrimination, with limited incremental validity of measures of central tendency and errors. Furthermore, increased ISV might be a unitary construct in ADHD.

Repeated measurements of learned irrelevance by a novel within-subject paradigm in humans

Learned irrelevance (LIrr) refers to the retardation of classical conditioning following preexposure of the to-be-associated stimuli. Healthy volunteers have been tested on three occasions with a new LIrr paradigm avoiding methodological problems which afflict traditional paradigms. A significant LIrr effect was demonstrated on each occasion. Thus, the new paradigm enables repeated measurements of LIrr and might be useful in evaluating long-term effects of medication in psychiatric disorders exhibiting aberrant LIrr.

Within-subject comparison of two rigid bar designs connecting two interforaminal implants: patients' satisfaction and prosthetic results

BACKGROUND: There is evidence for the superiority of two-implant overdentures over complete dentures in the mandible. Various anchorage devices were used to provide stability to overdentures. The aim of the present study was to compare two designs of a rigid bar connecting two mandibular implants. MATERIALS AND METHODS: Completely edentulous patients received a new denture in the maxilla and an implant-supported overdenture in the mandible. They were randomly allocated to two groups (A or B) with regard to the bar design. A standard U-shaped bar (Dolder bar) was used connecting the two implants in a straight line. For comparison, precision attachments were soldered distal to the bar copings. Group A started the study with the standard bar (S-bar), while group B started with the attachment-bar (A-bar). After 3 months, they had to answer a questionnaire (visual analogue scale [VAS]); then the bar design was changed in both groups. After a period of another 3 months, the patients had to answer the same questions; then they had the choice to keep their preferred bar. Now the study period was extended to another year of observation, and the patients answered again the same questionnaire. In vivo force measurements were carried out with both bar types at the end of the test periods. The prosthetic maintenance service carried out during the 6-month period was recorded for both bar types in both groups. Statistical analysis as performed with the SPSS statistical package (SPSS Inc., Chicago, IL, USA). RESULTS: Satisfaction was high in both groups. Group B, who had entered the study with the attachment bar, gave slightly better ratings to this type for four items, while in group A, no differences were found. At the end of the 6-month comparison period, all but one patient wished to continue to wear the attachment bar. Prosthetic service was equal in groups A and B, but the total number of interventions is significantly higher in the attachment bar. Force patterns of maximum biting were similar in both bar designs, but exhibited significantly higher axial forces in the attachment bar. CONCLUSIONS: Both bar designs provide good retention and functional comfort. High stability appears to be an important factor for the patients' satisfaction and oral comfort. Rigid retention results in a higher force impact and appears to evoke the need for the retightening of occlusal screws, resulting in more maintenance service.

Subject-ventilator synchrony during neural versus pneumatically triggered non-invasive helmet ventilation

OBJECTIVE: Patient-ventilator synchrony during non-invasive pressure support ventilation with the helmet device is often compromised when conventional pneumatic triggering and cycling-off were used. A possible solution to this shortcoming is to replace the pneumatic triggering with neural triggering and cycling-off-using the diaphragm electrical activity (EA(di)). This signal is insensitive to leaks and to the compliance of the ventilator circuit. DESIGN: Randomized, single-blinded, experimental study. SETTING: University Hospital. PARTICIPANTS AND SUBJECTS: Seven healthy human volunteers. INTERVENTIONS: Pneumatic triggering and cycling-off were compared to neural triggering and cycling-off during NIV delivered with the helmet. MEASUREMENTS AND RESULTS: Triggering and cycling-off delays, wasted efforts, and breathing comfort were determined during restricted breathing efforts (<20% of voluntary maximum EA(di)) with various combinations of pressure support (PSV) (5, 10, 20 cm H(2)O) and respiratory rates (10, 20, 30 breath/min). During pneumatic triggering and cycling-off, the subject-ventilator synchrony was progressively more impaired with increasing respiratory rate and levels of PSV (p < 0.001). During neural triggering and cycling-off, effect of increasing respiratory rate and levels of PSV on subject-ventilator synchrony was minimal. Breathing comfort was higher during neural triggering than during pneumatic triggering (p < 0.001). CONCLUSIONS: The present study demonstrates in healthy subjects that subject-ventilator synchrony, trigger effort, and breathing comfort with a helmet interface are considerably less impaired during increasing levels of PSV and respiratory rates with neural triggering and cycling-off, compared to conventional pneumatic triggering and cycling-off.