bluuebunny/crossref_metadata_2025 huggingface dataset:
Dietary sodium citrate supplementation enhances rehydration and recovery from rapid body mass loss in trained wrestlers
Authors: Timpmann Saima , Burk Andres , Medijainen Luule , Tamm Maria , Kreegipuu Kairi , Vähi Mare , Unt Eve , Ööpik Vahur
Published: November 2012

This study assessed the effects of dietary sodium citrate supplementation during a 16 h recovery from 5% rapid body mass loss (RBML) on physiological functions, affective state, and performance in trained wrestlers. Sixteen wrestlers performed an upper body intermittent sprint performance (UBISP) test under three conditions: before RBML, after RBML, and after a 16 h recovery from RBML. During recovery, the subjects ate a prescribed diet supplemented with sodium citrate (600 mg·kg–1; CIT group, N = 8) or placebo (PLC group, N = 8) and drank water ad libitum. RBML reduced (p < 0.05) UBISP mean power and increased urine specific gravity (USG). Reduction in mean power was associated with changes in plasma volume (PV) (r = 0.649, p = 0.006) and USG (r = –0.553, p = 0.026). During the 16 h recovery, increases in body mass (BM) and PV were greater (p < 0.05) in the CIT group than in the PLC group. BM gain was associated with water retention in the CIT group (r = 0.899, p = 0.002) but not in the PLC group (r = 0.335, p = 0.417). Blood pH, HCO3–concentration, and base excess increased (p < 0.05) only in the CIT group. Changes in UBISP, general negative affect, and general positive affect did not differ in the two groups. In conclusion, ingestion of sodium citrate increases blood buffering capacity and PV and stimulates BM regain during a 16 h recovery from RBML in trained wrestlers. However, sodium citrate does not improve UBISP nor does it have an impact on the affective state.
Modulating fibroblast growth factor 21 in hyperphagic OLETF rats with daily exercise and caloric restriction
Authors: Fletcher Justin A. , Meers Grace M. , Laughlin M. Harold , Ibdah Jamal A. , Thyfault John P. , Rector R. Scott
Published: November 2012

Chronic treatment with fibroblast growth factor 21 (FGF-21) favorably improves obesity and nonalcoholic fatty liver disease (NAFLD) outcomes; however, FGF-21 expression is paradoxically elevated in obese conditions. Here, we sought to determine the effects of obesity prevention by daily exercise (EX) vs. caloric restriction (CR) on hepatic FGF-21 in the hyperphagic, Otsuka Long-Evans Tokushima Fatty (OLETF) rat. Four-week-old male OLETF rats were randomized into groups (n = 7–8 per group) of ad libitum fed, sedentary (OLETF-SED), voluntary wheel running exercise (OLETF-EX), or CR (OLETF-CR; 70% of SED) until 40 weeks of age. Nonhyperphagic, Long-Evans Tokushima Otsuka (LETO-SED) rats served as controls. Both daily EX and CR prevented obesity and NAFLD development observed in the OLETF-SED animals. This was associated with significantly (p < 0.01) lower serum FGF-21 (~80% lower) and hepatic FGF-21 mRNA expression (~65% lower) in the OLETF-EX and OLETF-CR rats compared with the OLETF-SED rats. However, hepatic FGF-21 protein content was reduced to the greatest extent in the OLETF-EX animals (50% of OLETF-SED) and did not differ between the OLETF-SED and OLETF-CR rats. Hepatic FGF-21 signaling mediators — hepatic FGF-21 receptor 2 (FGFR2, mRNA expression), hepatic FGF-21 receptor substrate 2 (FRS2, protein content), and co-receptor β-Klotho (protein content) — were all elevated (60%–100%, ~40%, and +30%–50%, respectively) in the OLETF-EX and OLETF-CR animals compared with the OLETF-SED animals. Daily exercise and caloric restriction modulate hepatic FGF-21 and its primary signaling mediators in the hyperphagic OLETF rat. Enhanced metabolic action of FGF-21 may partially explain the benefits of exercise and caloric restriction on NAFLD outcomes.
Predicting doubly labeled water energy expenditure from ambulatory activity
Authors: Tudor-Locke Catrine , Martin Corby K. , Brashear Meghan M. , Rood Jennifer C. , Katzmarzyk Peter T. , Johnson William D.
Published: November 2012

The purpose of this study was to evaluate the potential for using accelerometer-determined ambulatory activity indicators (steps per day and cadence) to predict total energy expenditure (TEE) and physical activity energy expenditure (PAEE) derived from doubly labeled water (DLW). Twenty men and 34 women (20–36 years of age) provided complete anthropometric, accelerometer, resting metabolic rate (RMR), and DLW data. TEE and PAEE were determined for the same week that accelerometers were worn during waking hours. Accelerometer data included mean steps per day, peak 30-min cadence (average steps per minute for the highest 30 min of the day), and time spent in each incremental cadence band: 0 (nonmovement), 1–19 (incidental movement), 20–39 (sporadic movement), 40–59 (purposeful steps), 60–79 (slow walking), 80–99 (medium walking), 100–119 (brisk walking), and 120+ steps·min–1 (indicative of all faster ambulatory activities). Regression analyses were employed to develop sex-specific equations for predicting TEE and PAEE. The final model predicting TEE included body weight, steps per day, and time in incremental cadence bands and explained 79% (men) and 65% (women) of the variability. The final model predicting PAEE included peak 30-min cadence, steps per day, and time in cadence bands and explained 76% (men) and 46% (women) of the variability. Time in cadence bands alone explained 39%–73% of the variability in TEE and 30%–63% of the variability in PAEE. Prediction models were stronger for men than for women.
Metabolic parameters for ramp versus step incremental cycle ergometer tests
Authors: Zuniga Jorge M. , Housh Terry J. , Camic Clayton L. , Bergstrom Haley C , Traylor Daniel A. , Schmidt Richard J. , Johnson Glen O.
Published: November 2012

The purpose of this study was to examine mean differences and the patterns of responses for oxygen uptake ([Formula: see text]O2), heart rate (HR), and rating of perceived exertion (RPE) for ramp (15 W·min–1) versus step (30 W increments every 2 min) incremental cycle ergometer tests. Fourteen subjects (age and body mass of 23.2 ± 3.1 (mean ± SD ) years and 71.1 ± 10.1 kg, respectively) visited the laboratory on separate occasions. Two-way repeated measures ANOVAs with appropriate follow-up procedures, as well as paired t tests, were used to analyze the data. In addition, polynomial regression analyses were used to determine the patterns of responses for each dependent variable for the ramp and step tests. The ramp protocol resulted in lower mean [Formula: see text]O2 and HR values at the common power outputs than the step protocol with no differences in RPE. The increased amount of work performed during the step (total work = 75.83 kJ) versus ramp (total work = 65.60 kJ) tests at the common power outputs may have contributed to the greater [Formula: see text]O2 and HR values. The polynomial regression analyses showed that most subjects had the same patterns of responses for the ramp and step incremental tests for HR (86%) and RPE (93%) but different patterns for [Formula: see text]O2 (71%). The findings from the present study suggested that the protocol selection for an incremental cycle ergometer test can affect the mean values for [Formula: see text]O2 and HR, as well as the [Formula: see text]O2 – power output relationship.
Anti-inflammatory effects of enhanced external counterpulsation in subjects with abnormal glucose tolerance
Authors: Martin Jeffrey S. , Braith Randy W.
Published: November 2012

Elevated markers of systemic inflammation are associated with impaired glucose tolerance and type 2 diabetes mellitus. Enhanced external counterpulsation (EECP) has been shown to decrease circulating concentrations of pro-inflammatory markers in coronary artery disease patients. Here we provide novel evidence that EECP intervention also has a beneficial effect on circulating markers of systemic inflammation coincident with improvements in glycemic control in subjects with abnormal glucose tolerance.
Impact of different resistance training protocols on muscular oxidative stress parameters
Authors: Scheffer Débora L. , Silva Luciano A. , Tromm Camila B. , da Rosa Guilherme L. , Silveira Paulo C.L. , de Souza Claudio T. , Latini Alexandra , Pinho Ricardo A.
Published: November 2012

This study analyzes oxidative stress in skeletal muscle using different resisted training protocols. We hypothesize that different types of training produce different specifics. To test our hypothesis, we defined 3 resistance training protocols and investigated the respective biochemical responses in muscle. Twenty-four male Wistar rats were distributed in 4 groups: untrained (UT), muscular resistance training (RT), hypertrophy training (HT), and strength training (ST). After 12 weeks of training on alternate days, the red portion of the brachioradialis was removed and the following parameters were assessed: lactate and glycogen content, superoxide production, antioxidant enzyme content, and activities (superoxide dismutase, SOD; catalase, CAT; GPx, glutathione peroxidase). Thiobarbituric acid-reactive substances (TBARS), carbonyl, and thiol groups were also measured. Results showed increased superoxide production (UT = 5.348 ± 0.889; RT = 5.117 ± 0,651; HT = 8.412 ± 0.431; ST = 6.354 ± 0.552), SOD (UT = 0.078 ± 0.0163; RT = 0.101 ± 0.013; HT = 0.533 ± 0.109; ST = 0.388 ± 0.058), GPx (UT = 0.290 ± 0.023; RT = 0.348 ± 0.014; HT = 0.529 ± 0.049; ST = 0.384 ± 0.038) activities, and content of GPx (HT = 3.8 times; ST = 3.0 times) compared with the UT group. CAT activity was lower (UT = 3.966 ± 0.670; RT = 3.474 ± 0.583; HT = 2.276 ± 0.302; ST = 2.028 ± 0.471) in HT and ST groups. Oxidative damage was observed in the HT group (TBARS = 0.082 ± 0.009; carbonyl = 0.73 ± 0.053; thiol = 12.78 ± 0.917) compared with the UT group. These findings indicate that HT causes an imbalance in oxidative parameters in favor of pro-oxidants, causing oxidative stress in skeletal muscle.
Methane biogenesis during sodium azide-induced chemical hypoxia in rats
Authors: Tuboly Eszter , Szabó Andrea , Garab Dénes , Bartha Gábor , Janovszky Ágnes , Ero″s Gábor , Szabó Anna , Mohácsi Árpád , Szabó Gábor , Kaszaki József , Ghyczy Miklós , Boros Mihály
Published: November 2012

Previous studies demonstrated methane generation in aerobic cells. Our aims were to investigate the methanogenic features of sodium azide (NaN3)-induced chemical hypoxia in the whole animal and to study the effects of l-α-glycerylphosphorylcholine (GPC) on endogenous methane production and inflammatory events as indicators of a NaN3-elicited mitochondrial dysfunction. Group 1 of Sprague-Dawley rats served as the sham-operated control; in group 2, the animals were treated with NaN3 (14 mg·kg−1·day−1 sc) for 8 days. In group 3, the chronic NaN3 administration was supplemented with daily oral GPC treatment. Group 4 served as an oral antibiotic-treated control (rifaximin, 10 mg·kg−1·day−1) targeting the intestinal bacterial flora, while group 5 received this antibiotic in parallel with NaN3 treatment. The whole body methane production of the rats was measured by means of a newly developed method based on photoacoustic spectroscopy, the microcirculation of the liver was observed by intravital videomicroscopy, and structural changes were assessed via in vivo fluorescent confocal laser-scanning microscopy. NaN3 administration induced a significant inflammatory reaction and methane generation independently of the methanogenic flora. After 8 days, the hepatic microcirculation was disturbed and the ATP content was decreased, without major structural damage. Methane generation, the hepatic microcirculatory changes, and the increased tissue myeloperoxidase and xanthine oxidoreductase activities were reduced by GPC treatment. In conclusion, the results suggest that methane production in mammals is connected with hypoxic events associated with a mitochondrial dysfunction. GPC is protective against the inflammatory consequences of a hypoxic reaction that might involve cellular or mitochondrial methane generation.
Copper stabilizes the Menkes copper-transporting ATPase (Atp7a) protein expressed in rat intestinal epithelial cells
Authors: Xie Liwei , Collins James F.
Published: November 2012

Iron deficiency decreases oxygen tension in the intestinal mucosa, leading to stabilization of hypoxia-inducible transcription factor 2α (Hif2α) and subsequent upregulation of genes involved in iron transport [e.g., divalent metal transporter (Dmt1) and ferroportin 1 (Fpn1)]. Iron deprivation also alters copper homeostasis, reflected by copper accumulation in the intestinal epithelium and induction of an intracellular copper-binding protein [metallothionein (Mt)] and a copper exporter [Menkes copper ATPase (Atp7a)]. Importantly, Atp7a is also a Hif2α target. It was, however, previously noted that Atp7a protein expression was induced more strongly than mRNA in the duodenum of iron-deprived rats, suggesting additional regulatory mechanisms. The current study was thus designed to decipher mechanistic aspects of Atp7a regulation during iron deprivation using an established in vitro model of the mammalian intestine, rat intestinal epithelial (IEC-6) cells. Cells were treated with an iron chelator and/or copper loaded to mimic the in vivo situation. IEC-6 cells exposed to copper showed a dose-dependent increase in Mt expression, confirming intracellular copper accumulation. Iron chelation with copper loading increased Atp7a mRNA and protein levels; however, contrary to our expectation, copper alone increased only protein levels. This suggested that copper increased Atp7a protein levels by a posttranscriptional regulatory mechanism. Therefore, to determine if Atp7a protein stability was affected, the translation inhibitor cycloheximide was utilized. Experiments in IEC-6 cells revealed that the half-life of the Atp7a protein was ∼41 h and, furthermore, that intracellular copper accumulation increased steady-state Atp7a protein levels. This investigation thus reveals a novel mechanism of Atp7a regulation in which copper stabilizes the protein, possibly complementing Hif2α-mediated transcriptional induction during iron deficiency.
Cellular Mechanisms of Tissue Fibrosis. 2. Contributory pathways leading to myocardial fibrosis: moving beyond collagen expression
Authors: Goldsmith Edie C. , Bradshaw Amy D. , Spinale Francis G.
Published: November 2012

While the term “fibrosis” can be misleading in terms of the complex patterns and processes of myocardial extracellular matrix (ECM) remodeling, fibrillar collagen accumulation is a common consequence of relevant pathophysiological stimuli, such as pressure overload (PO) and myocardial infarction (MI). Fibrillar collagen accumulation in both PO and MI is predicated on a number of diverse cellular and extracellular events, which include changes in fibroblast phenotype (transdifferentiation), posttranslational processing and assembly, and finally, degradation. The expansion of a population of transformed fibroblasts/myofibroblasts is a significant cellular event with respect to ECM remodeling in both PO and MI. The concept that this cellular expansion within the myocardial ECM may be due, at least in part, to endothelial-mesenchymal transformation and thereby not dissimilar to events observed in cancer progression holds intriguing future possibilities. Studies regarding determinants of procollagen processing, such as procollagen C-endopeptidase enhancer (PCOLCE), and collagen assembly, such as the secreted protein acidic and rich in cysteine (SPARC), have identified potential new targets for modifying the fibrotic response in both PO and MI. Finally, the transmembrane matrix metalloproteinases, such as MMP-14, underscore the diversity and complexity of this ECM proteolytic family as this protease can degrade the ECM as well as induce a profibrotic response. The growing recognition that the myocardial ECM is a dynamic entity containing a diversity of matricellular and nonstructural proteins as well as proteases and that the fibrillar collagens can change in structure and content in a rapid temporal fashion has opened up new avenues for modulating what was once considered an irreversible event - myocardial fibrosis.
Early life stress induces renal dysfunction in adult male rats but not female rats
Authors: Loria Analia S. , Yamamoto Tatsuo , Pollock David M. , Pollock Jennifer S.
Published: November 2012

Maternal separation (MatSep) is a model of behavioral stress during early life. We reported that MatSep exacerbates ANG II-induced hypertension in adult male rats. The aims of this study were to determine whether exposure to MatSep in female rats sensitizes blood pressure to ANG II infusion similar to male MatSep rats and to elucidate renal mechanisms involved in the response in MatSep rats. Wistar Kyoto (WKY) pups were exposed to MatSep 3 h/day from days 2 to 14, while control rats remained with their mothers. ANG II-induced mean arterial pressure (MAP; telemetry) was enhanced in female MatSep rats compared with control female rats but delayed compared with male MatSep rats. Creatinine clearance (Ccr) was reduced in male MatSep rats compared with control rats at baseline and after ANG II infusion. ANG II infusion significantly increased T cells in the renal cortex and greater histological damage in the interstitial arteries of male MatSep rats compared with control male rats. Plasma testosterone was greater and estradiol was lower in male MatSep rats compared with control rats with ANG II infusion. ANG II infusion failed to increase blood pressure in orchidectomized male MatSep and control rats. Female MatSep and control rats had similar Ccr, histological renal analysis, and sex hormones at baseline and after ANG II infusion. These data indicate that during ANG II-induced hypertension, MatSep sensitizes the renal phenotype in male but not female rats.
Initial orthostatic hypotension and cerebral blood flow regulation: effect of α1-adrenoreceptor activity
Authors: Lewis Nia C. S. , Ainslie Philip N. , Atkinson Greg , Jones Helen , Grant Emily J. M. , Lucas Samuel J. E.
Published: November 2012

We examined the hypothesis that α1-adrenergic blockade would lead to an inability to correct initial orthostatic hypotension (IOH) and cerebral hypoperfusion, leading to symptoms of presyncope. Twelve normotensive humans (aged 25 ± 1 yr; means ± SE) attempted to complete a 3-min upright stand, 90 min after the administration of either α1-blockade (prazosin, 1 mg/20 kg body wt) or placebo. Continuous beat-to-beat measurements of middle cerebral artery velocity (MCAv; Doppler), blood pressure (finometer), heart rate, and end-tidal Pco2were obtained. Compared with placebo, the α1-blockade reduced resting mean arterial blood pressure (MAP) (−15%; P < 0.01); MCAv remained unaltered ( P ≥ 0.28). Upon standing, although the absolute level of MAP was lower following α1-blockade (39 ± 10 mmHg vs. 51 ± 14 mmHg), the relative difference in IOH was negligible in both trials (mean difference in MAP: 2 ± 2 mmHg; P = 0.50). Compared with the placebo trial, the declines in MCAv and PetCO2during IOH were greater in the α1-blockade trial by 12 ± 4 cm/s and 4.4 ± 1.3 mmHg, respectively ( P ≤ 0.01). Standing tolerance was markedly reduced in the α1-blockade trial (75 ± 17 s vs. 180 ± 0 s; P < 0.001). In summary, while IOH was little affected by α1-blockade, the associated decline in MCAv was greater in the blockade condition. Unlike in the placebo trial, the extent of IOH and cerebral hypoperfusion failed to recover toward baseline in the α1-blockade trial leading to presyncope. Although the development of IOH is not influenced by the α1-adrenergic receptor pathway, this pathway is critical in the recovery from IOH to prevent cerebral hypoperfusion and ultimately syncope.
Chronic interstitial fibrosis in the rat kidney induced by long-term (6-mo) exposure to lithium
Authors: Walker Robert J. , Leader John P. , Bedford Jennifer J. , Gobe Glenda , Davis Gerard , Vos Frederiek E. , deJong Sylvia , Schollum John B. W.
Published: November 2012

There is a lack of suitable animal models that replicate the slowly progressive chronic interstitial fibrosis that is characteristic of many human chronic nephropathies. We describe a chronic long-term (6-mo) model of lithium-induced renal fibrosis, with minimal active inflammation, which mimics chronic kidney interstitial fibrosis seen in the human kidney. Rats received lithium via their chow (60 mmol lithium/kg food) daily for 6 mo. No animals died during the exposure. Nephrogenic diabetes insipidus was established by 3 wk and persisted for the 6 mo. Following metabolic studies, the animals were killed at 1, 3, and 6 mo and the kidneys were processed for histological and immunohistochemical studies. Progressive interstitial fibrosis, characterized by increasing numbers of myofibroblasts, enhanced transforming growth factor-β1expression and interstitial collagen deposition, and a minimal inflammatory cellular response was evident. Elucidation of the underlying mechanisms of injury in this model will provide a greater understanding of chronic interstitial fibrosis and allow the development of intervention strategies to prevent injury.
Role of dual-specificity protein phosphatase-5 in modulating the myogenic response in rat cerebral arteries
Authors: Wickramasekera Nadi T. , Gebremedhin Debebe , Carver Koryn A. , Vakeel Padmanabhan , Ramchandran Ramani , Schuett Aaron , Harder David R.
Published: November 2012

The present study examined the role of the dual-specificity protein phosphatase-5 (DUSP-5) in the pressure-induced myogenic responses of organ-cultured cerebral arterial segments. In these studies, we initially compared freshly isolated and organ-cultured cerebral arterial segments with respect to responses to step increases in intravascular pressure, vasodilator and vasoconstrictor stimuli, activities of the large-conductance arterial Ca2+-activated K+ (KCa) single-channel current, and stable protein expression of DUSP-5 enzyme. The results demonstrate maintained pressure-dependent myogenic vasoconstriction, DUSP-5 protein expression, endothelium-dependent and -independent dilations, agonist-induced constriction, and unitary KCa channel conductance in organ-cultured cerebral arterial segments similar to that in freshly isolated cerebral arteries. Furthermore, using a permeabilization transfection technique in organ-cultured cerebral arterial segments, gene-specific small interfering RNA (siRNA) induced knockdown of DUSP-5 mRNA and protein, which were associated with enhanced pressure-dependent cerebral arterial myogenic constriction and increased phosphorylation of PKC-βII. In addition, siRNA knockdown of DUSP-5 reduced levels of phosphorylated ROCK and ERK1 with no change in the level of phosphorylated ERK2. Pharmacological inhibition of ERK1/2 phosphorylation significantly attenuated pressure-induced myogenic constriction in cerebral arteries. The findings within the present studies illustrate that DUSP-5, native in cerebral arterial muscle cells, appears to regulate signaling of pressure-dependent myogenic cerebral arterial constriction, which is crucial for the maintenance of constant cerebral blood flow to the brain.
Does a basic deficit in force control underlie cerebellar ataxia?
Authors: Charles Steven K. , Okamura Allison M. , Bastian Amy J.
Published: November 2012

Because damage to the cerebellum results in characteristic movement incoordination known as “ataxia,” it has been hypothesized that it is involved in estimation of limb dynamics that occur during movement. However, cerebellar function may extend beyond movement to force control in general, with or without movement. Here we tested whether the cerebellum is involved in controlling force separate from estimating limb dynamics and whether ataxia could result from a deficit in force control. We studied patients with cerebellar ataxia controlling their arm force isometrically; in this condition arm dynamics are absent and there is no need for (or effect from an impairment in) estimations of limb dynamics. Subjects were required to control their force magnitude, direction, or both. Cerebellar patients were able to match force magnitude or direction similarly to control subjects. Furthermore, when controlling force magnitude, they intuitively chose directions (not specified) that required minimal effort at the joint level—this ability was also similar to control subjects. In contrast, cerebellar patients performed significantly worse than control subjects when asked to match both force magnitude and direction. This was surprising, since they did not exhibit significant impairment in doing either in isolation. These results show that cerebellum-dependent computations are not limited to estimations of body dynamics needed for active movement. Deficits occur even in isometric conditions, but apparently only when multiple degrees of freedom must be controlled simultaneously. Thus a fundamental cerebellar operation may be combining/coordinating degrees of freedom across many kinds of movements and behaviors.
Development of temporal structure in zebra finch song
Authors: Glaze Christopher M. , Troyer Todd W.
Published: November 2012

Zebra finch song has provided an excellent case study in the neural basis of sequence learning, with a high degree of temporal precision and tight links with precisely timed bursting in forebrain neurons. To examine the development of song timing, we measured the following four aspects of song temporal structure at four age ranges between 65 and 375 days posthatch: the mean durations of song syllables and the silent gaps between them, timing variability linked to song tempo, timing variability expressed independently across syllables and gaps, and transition probabilities between consecutive syllable pairs. We found substantial increases in song tempo between 65 and 85 days posthatch, due almost entirely to a shortening of gaps. We also found a decrease in tempo variability, also specific to gaps. Both the magnitude of the increase in tempo and the decrease in tempo variability were correlated on gap-by-gap basis with increases in the reliability of corresponding syllable transitions. Syllables had no systematic increase in tempo or decrease in tempo variability. In contrast to tempo parameters, both syllables and gaps showed an early sharp reduction in independent variability followed by continued reductions over the first year. The data suggest that links between syllable-based representations are strengthened during the later parts of the traditional period of song learning and that song rhythm continues to become more regular throughout the first year of life. Similar learning patterns have been identified in human sequence learning, suggesting a potentially rich area of comparative research.
The role of envelope shape in the localization of multiple sound sources and echoes in the barn owl
Authors: Baxter Caitlin S. , Nelson Brian S. , Takahashi Terry T.
Published: November 2012

Echoes and sounds of independent origin often obscure sounds of interest, but echoes can go undetected under natural listening conditions, a perception called the precedence effect. How does the auditory system distinguish between echoes and independent sources? To investigate, we presented two broadband noises to barn owls ( Tyto alba) while varying the similarity of the sounds' envelopes. The carriers of the noises were identical except for a 2- or 3-ms delay. Their onsets and offsets were also synchronized. In owls, sound localization is guided by neural activity on a topographic map of auditory space. When there are two sources concomitantly emitting sounds with overlapping amplitude spectra, space map neurons discharge when the stimulus in their receptive field is louder than the one outside it and when the averaged amplitudes of both sounds are rising. A model incorporating these features calculated the strengths of the two sources' representations on the map (B. S. Nelson and T. T. Takahashi; Neuron 67: 643–655, 2010). The target localized by the owls could be predicted from the model's output. The model also explained why the echo is not localized at short delays: when envelopes are similar, peaks in the leading sound mask corresponding peaks in the echo, weakening the echo's space map representation. When the envelopes are dissimilar, there are few or no corresponding peaks, and the owl localizes whichever source is predicted by the model to be less masked. Thus the precedence effect in the owl is a by-product of a mechanism for representing multiple sound sources on its map.
Targeting the Phosphoinositide 3-Kinase p110-α Isoform Impairs Cell Proliferation, Survival, and Tumor Growth in Small Cell Lung Cancer
Authors: Wojtalla Anna , Fischer Barbara , Kotelevets Nataliya , Mauri Francesco A. , Sobek Jens , Rehrauer Hubert , Wotzkow Carlos , Tschan Mario P. , Seckl Michael J. , Zangemeister-Wittke Uwe , Arcaro Alexandre
Published: November 2012

Purpose: The phosphoinositide 3-kinase (PI3K) pathway is fundamental for cell proliferation and survival and is frequently altered and activated in neoplasia, including carcinomas of the lung. In this study, we investigated the potential of targeting the catalytic class IA PI3K isoforms in small cell lung cancer (SCLC), which is the most aggressive of all lung cancer types.

Experimental Design: The expression of PI3K isoforms in patient specimens was analyzed. The effects on SCLC cell survival and downstream signaling were determined following PI3K isoform inhibition by selective inhibitors or downregulation by siRNA.

Results: Overexpression of the PI3K isoforms p110-α and p110-β and the antiapoptotic protein Bcl-2 was shown by immunohistochemistry in primary SCLC tissue samples. Targeting the PI3K p110-α with RNA interference or selective pharmacologic inhibitors resulted in strongly affected cell proliferation of SCLC cells in vitro and in vivo, whereas targeting p110-β was less effective. Inhibition of p110-α also resulted in increased apoptosis and autophagy, which was accompanied by decreased phosphorylation of Akt and components of the mTOR pathway, such as the ribosomal S6 protein, and the eukaryotic translation initiation factor 4E-binding protein 1. A DNA microarray analysis revealed that p110-α inhibition profoundly affected the balance of pro- and antiapoptotic Bcl-2 family proteins. Finally, p110-α inhibition led to impaired SCLC tumor formation and vascularization in vivo.

Conclusion: Together our data show the key involvement of the PI3K isoform p110-α in the regulation of multiple tumor-promoting processes in SCLC. Clin Cancer Res; 19(1); 96–105. ©2012 AACR.
Variation in Precursor Lesions of Pancreatic Cancer among High-Risk Groups
Authors: Potjer Thomas P. , Schot Ingrid , Langer Peter , Heverhagen Johannes T. , Wasser Martin N.J.M. , Slater Emily P. , Klöppel Günter , Morreau Hans M. , Bonsing Bert A. , de Vos tot Nederveen Cappel Wouter H. , Bargello Mathias , Gress Thomas M. , Vasen Hans F.A. , Bartsch Detlef K.
Published: November 2012

Purpose: Pancreatic ductal adenocarcinoma (PDAC) surveillance programs are currently offered to high-risk individuals aiming to detect precursor lesions or PDAC at an early stage. We assessed differences in frequency and behavior of precursor lesions and PDAC between two high-risk groups.

Experimental Design: Individuals with a p16-Leiden germline mutation (N = 116; median age 54 years) and individuals from familial pancreatic cancer (FPC) families (N = 125; median age 47 years) were offered annual surveillance by MRI and magnetic resonance cholangiopancreatography (MRCP) with or without endoscopic ultrasound (EUS) for a median surveillance period of 34 months (0–127 months) or 36 months (0–110 months), respectively. Detailed information was collected on pancreatic cystic lesions detected on MRCP and precursor lesions in surgical specimens of patients who underwent pancreatic surgery.

Results: Cystic lesions were more common in the FPC cohort (42% vs. 16% in p16-Leiden cohort), whereas PDAC was more common in the p16-Leiden cohort (7% vs. 0.8% in FPC cohort). Intraductal papillary mucinous neoplasm (IPMN) was a common finding in surgical specimens of FPC-individuals, and was only found in two patients of the p16-Leiden cohort. In the p16-Leiden cohort, a substantial proportion of cystic lesions showed growth or malignant transformation during follow-up, whereas in FPC individuals most cystic lesions remain stable.

Conclusion: In p16-Leiden mutation carriers, cystic lesions have a higher malignant potential than in FPC-individuals. On the basis of these findings, a more intensive surveillance program may be considered in this high-risk group. Clin Cancer Res; 19(2); 442–9. ©2012 AACR.
Secrets of Drug Resistance in NSCLC Exposed by New Molecular Definition of EMT
Authors: Neel Dana S. , Bivona Trever G.
Published: November 2012

Non–small cell lung carcinoma (NSCLC) metastasis and drug resistance has been associated with epithelial-to-mesenchymal transition (EMT). This study reports the development of a robust gene expression signature of EMT in NSCLC and reveals new insights into the key molecular events that underlie EMT and drug resistance in NSCLC. Clin Cancer Res; 19(1); 3–5. ©2012 AACR.
MicroRNAs Reprogram Normal Fibroblasts into Cancer-Associated Fibroblasts in Ovarian Cancer
Authors: Mitra Anirban K. , Zillhardt Marion , Hua Youjia , Tiwari Payal , Murmann Andrea E. , Peter Marcus E. , Lengyel Ernst
Published: November 2012

Cancer-associated fibroblasts (CAF) are a major constituent of the tumor stroma, but little is known about how cancer cells transform normal fibroblasts into CAFs. microRNAs (miRNA) are small noncoding RNA molecules that negatively regulate gene expression at a posttranscriptional level. Although it is clearly established that miRNAs are deregulated in human cancers, it is not known whether miRNA expression in resident fibroblasts is affected by their interaction with cancer cells. We found that in ovarian CAFs, miR-31 and miR-214 were downregulated, whereas miR-155 was upregulated when compared with normal or tumor-adjacent fibroblasts. Mimicking this deregulation by transfecting miRNAs and miRNA inhibitors induced a functional conversion of normal fibroblasts into CAFs, and the reverse experiment resulted in the reversion of CAFs into normal fibroblasts. The miRNA-reprogrammed normal fibroblasts and patient-derived CAFs shared a large number of upregulated genes highly enriched in chemokines, which are known to be important for CAF function. The most highly upregulated chemokine, CCL5, (C-C motif ligand 5) was found to be a direct target of miR-214. These results indicate that ovarian cancer cells reprogram fibroblasts to become CAFs through the action of miRNAs. Targeting these miRNAs in stromal cells could have therapeutic benefit.

Significance: The mechanism by which quiescent fibroblasts are converted into CAFs is unclear. The present study identifies a set of 3 miRNAs that reprogram normal fibroblasts to CAFs. These miRNAs may represent novel therapeutic targets in the tumor microenvironment. Cancer Discov; 2(12); 1100–8. ©2012 AACR.

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Elucidating Distinct Roles for NF1 in Melanomagenesis
Authors: Maertens Ophélia , Johnson Bryan , Hollstein Pablo , Frederick Dennie T. , Cooper Zachary A. , Messiaen Ludwine , Bronson Roderick T. , McMahon Martin , Granter Scott , Flaherty Keith , Wargo Jennifer A. , Marais Richard , Cichowski Karen
Published: November 2012

BRAF mutations play a well-established role in melanomagenesis; however, without additional genetic alterations, tumor development is restricted by oncogene-induced senescence (OIS). Here, we show that mutations in the NF1 tumor suppressor gene cooperate with BRAF mutations in melanomagenesis by preventing OIS. In a genetically engineered mouse model, Nf1 mutations suppress Braf-induced senescence, promote melanocyte hyperproliferation, and enhance melanoma development. Nf1 mutations function by deregulating both phosphoinositide 3-kinase and extracellular signal–regulated kinase pathways. As such, Nf1/Braf–mutant tumors are resistant to BRAF inhibitors but are sensitive to combined inhibition of mitogen-activated protein/extracellular signal–regulated kinase kinase and mTOR. Importantly, NF1 is mutated or suppressed in human melanomas that harbor concurrent BRAF mutations, NF1 ablation decreases the sensitivity of melanoma cell lines to BRAF inhibitors, and NF1 is lost in tumors from patients following treatment with these agents. Collectively, these studies provide mechanistic insight into how NF1 cooperates with BRAF mutations in melanoma and show that NF1/neurofibromin inactivation may have an impact on responses to targeted therapies.

Significance: This study elucidates the mechanism by which NF1 mutations cooperate with different BRAF mutations in melanomagenesis and shows that NF1/neurofibromin loss may desensitize tumors to BRAF inhibitors. Cancer Discov; 3(3); 338–49. ©2012 AACR.

See related commentary by Gibney and Smalley, p. 260

This article is highlighted in the In This Issue feature, p. 239
The Association between Pathological Internet Use and Comorbid Psychopathology: A Systematic Review
Authors: Carli V. , Durkee T. , Wasserman D. , Hadlaczky G. , Despalins R. , Kramarz E. , Wasserman C. , Sarchiapone M. , Hoven C.W. , Brunner R. , Kaess M.
Published: November 2012

Background: Pathological Internet use (PIU) has been conceptualized as an impulse-control disorder that shares characteristics with behavioral addiction. Research has indicated a potential link between PIU and psychopathology; however, the significance of the correlation remains ambiguous. The primary objective of this systematic review was to identify and evaluate studies performed on the correlation between PIU and comorbid psychopathology; the secondary aims were to map the geographical distribution of studies, present a current synthesis of the evidence, and assess the quality of available research. Sampling and Methods: An electronic literature search was conducted using the following databases: MEDLINE, PsycARTICLES, PsychINFO, Global Health, and Web of Science. PIU and known synonyms were included in the search. Data were extracted based on PIU and psychopathology, including depression, anxiety, symptoms of attention deficit and hyperactivity disorder (ADHD), obsessive-compulsive symptoms, social phobia and hostility/aggression. Effect sizes for the correlations observed were identified from either the respective publication or calculated using Cohen’s d or R2. The potential effect of publication bias was assessed using a funnel plot model and evaluated by Egger’s test based on a linear regression. Results: The majority of research was conducted in Asia and comprised cross-sectional designs. Only one prospective study was identified. Twenty articles met the preset inclusion and exclusion criteria; 75% reported significant correlations of PIU with depression, 57% with anxiety, 100% with symptoms of ADHD, 60% with obsessive-compulsive symptoms, and 66% with hostility/aggression. No study reported associations between PIU and social phobia. The majority of studies reported a higher rate of PIU among males than females. The relative risks ranged from an OR of 1.02 to an OR of 11.66. The strongest correlations were observed between PIU and depression; the weakest was hostility/aggression. Conclusions: Depression and symptoms of ADHD appeared to have the most significant and consistent correlation with PIU. Associations were reported to be higher among males in all age groups. Limitations included heterogeneity in the definition and diagnosis of PIU. More studies with prospective designs in Western countries are critically needed.
Can Long-Term Outcomes Be Improved by Shortening the Duration of Untreated Illness in Psychiatric Disorders? A Conceptual Framework
Authors: Dell’Osso Bernardo , Glick Ira D. , Baldwin David S. , Altamura A. Carlo
Published: November 2012

The duration of untreated illness (DUI), meaning the latency to the pharmacological treatment, has been increasingly investigated in the last decade as a predictor of outcome across different psychiatric conditions, particularly in psychotic disorders. DUI is essentially computed by subtracting the age of onset of a specific disorder from the age at which the first adequate pharmacological treatment is administered. Assessment of the latency to treatment represents one of the first steps in planning early interventions. This review examines the role of the DUI in psychotic and affective disorders, focusing on neuropathological, epidemiologic, clinical and prognostic factors related to a longer latency to treatment. Through a Medline and Cochrane Library search, relevant studies up to June 2011 and other pertinent articles including meta-analyses, randomized controlled trials, naturalistic studies and clinical reviews were identified. Converging evidence indicates that a prolonged DUI negatively influences the outcome of first-episode psychosis and schizophrenia in different ways, and increasing data point toward a similar conclusion in affective disorders. Even though methodological limitations related to investigation of the DUI need to be considered, research and interventions aimed to reduce latency to treatments are object of increasing implementation worldwide. The assessment of the DUI represents one of the most important parameters to consider in this perspective, in order to quantify different latency to treatment in specific disorders and to plan related, targeted interventions.
Short-Term Effects of a Home-Based Smoking Prevention Program on Antismoking Socialization and Smoking-Related Cognitions: A Cluster Randomized Controlled Trial
Authors: Hiemstra Marieke , Ringlever Linda , Otten Roy , van Schayck Onno C.P. , Engels Rutger C.M.E.
Published: November 2012

Objective: This study aims to evaluate the short-term effects of a home-based smoking prevention program called ‘Smoke-free Kids’ on antismoking socialization and smoking-related cognitions and the moderating role of parental smoking. Participants and Methods: A cluster randomized controlled trial was carried out using one intervention condition compared with a control condition. A total of 1,398 never-smoking children (mean age 10.11 years, SD 0.78) participated. Intention-to-treat and completers-only analyses were performed. Participants in the intervention condition (n = 728) received 5 activity modules by mail at 4-week intervals. Modules included communication sheets for their mothers. Participants in the control condition (n = 750) received a fact-based intervention only. The main outcomes were the frequency and quality of communication, nonsmoking agreement, house rules, availability of cigarettes, perceived maternal influence, anticipated maternal reactions, attitude, self-efficacy and social norms. Results: Significant effects of the program were found for frequency of communication (B = 0.11, p < 0.001), nonsmoking agreement (B = 0.07, p < 0.01), perceived maternal influences (B = 0.09, p < 0.05), self-efficacy (B = –0.09, p < 0.05) and social norms of friends (B = –0.08, p = 0.05) and best friends (B = –0.11, p < 0.05). Parental smoking had no moderating effect. Conclusions: The Smoke-free Kids program shows promising short-term effects on antismoking socialization and cognitions. Long-term follow-up on the effects of smoking behavior are needed.
Impact of Allergic Rhinitis Symptoms on Quality of Life in Primary Care
Authors: Bousquet Philippe Jean , Demoly Pascal , Devillier Philippe , Mesbah Kamal , Bousquet Jean
Published: November 2012

Background: Allergic rhinitis (AR) impairs quality of life (QoL), sleep and work. The Allergic Rhinitis and its Impact on Asthma (ARIA) classification is widely used, but the impact of the different symptoms on QoL is not clear. Objective: To describe characteristics of patients consulting in primary care for AR and to study the impact of AR symptoms and the ARIA classes on QoL. Methods: A multicenter prospective observational cross-sectional study assessed the visual analogue scale (VAS) in the management of AR in 990 patients consulting general practitioners for AR. Patients were classified according to the four classes of ARIA. VAS, Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) and total symptom score (TSS) for nasal and non-nasal symptoms were evaluated. VAS and TSS measures were compared with RQLQ. Results: Mild intermittent rhinitis was diagnosed in 20% of patients, mild persistent rhinitis in 17%, moderate/severe intermittent rhinitis in 15% and moderate/severe persistent rhinitis in 48%. The presence of treatments did not affect VAS levels. Both severity and duration of rhinitis had an impact on QoL and VAS levels. Ocular symptoms (OR: 2.78, 95% CI: 1.965–3.939) including eyelid edema (OR: 2.07, 95% CI: 1.274–3.360) and asthenia (OR: 2.73, 95% CI: 1.922–3.877) had more impact on RQLQ than nasal obstruction (OR: 1.61, 95% CI: 1.078–2.405) and nasal pruritus (OR 1.45, 95% CI: 1.028–2.042). Sneezing and rhinorrhea did not impact RQLQ. Conclusions: This study confirmed that ocular symptoms and, to a lesser degree, nasal obstruction and pruritus have a significant impact on QoL.
Accelerated Up-Dosing of Subcutaneous Immunotherapy with a Registered Allergoid Grass Pollen Preparation
Authors: Pfaar Oliver , van Twuijver Esther , Hecker Heike , Boot Johan Diderik , van Ree Ronald , Klimek Ludger
Published: November 2012

Background: Climatic changes causing early pollen flight and new allergens prolonging the pollen season render up-dosing of allergen-specific subcutaneous immunotherapy (SCIT) outside the pollen season considerably more difficult. In addition, for patients with multiple pollen allergies, patients coming near the beginning of pollen season, and patients who wish to up-dose faster, an accelerated induction regimen would be helpful. Methods: In an open, randomized, parallel group, multicenter safety trial, an accelerated up-dosing regimen (0.1–0.3–0.5 ml in weekly intervals) was compared to conventional up-dosing (0.05–0.1–0.2–0.3–0.4–0.5 ml in weekly intervals) with an allergoid grass pollen SCIT preparation. After up-dosing, the maintenance dose was given in monthly intervals. Results: A total of 146 adult patients with rhinitis or rhinoconjunctivitis with or without mild asthma (FEV1 >70%) due to grass pollen were randomized to either the conventional registered up-dosing or an accelerated regimen. In both groups (accelerated regimen, n = 69; conventional regimen, n = 75), a high proportion of patients (92.75 and 92.0%, respectively) successfully reached the maintenance dose without safety concerns. Furthermore, significant increases in specific IgG and IgG4 after 4 months of treatment were observed in both groups. Conclusion: The accelerated SCIT regimen was found to be as safe as the conventional regimen and might be used to up-dose patients within 2 weeks. Moreover, the immunological effects of both up-dosing regimens were comparable.