cGMP-dependent protein kinase type I is implicated in the regulation of the timing and quality of sleep and wakefulness.

Many effects of nitric oxide (NO) are mediated by the activation of guanylyl cyclases and subsequent production of the second messenger cyclic guanosine-3',5'-monophosphate (cGMP). cGMP activates cGMP-dependent protein kinases (PRKGs), which can therefore be considered downstream effectors of NO signaling. Since NO is thought to be involved in the regulation of both sleep and circadian rhythms, we analyzed these two processes in mice deficient for cGMP-dependent protein kinase type I (PRKG1) in the brain. Prkg1 mutant mice showed a strikingly altered distribution of sleep and wakefulness over the 24 hours of a day as well as reductions in rapid-eye-movement sleep (REMS) duration and in non-REM sleep (NREMS) consolidation, and their ability to sustain waking episodes was compromised. Furthermore, they displayed a drastic decrease in electroencephalogram (EEG) power in the delta frequency range (1-4 Hz) under baseline conditions, which could be normalized after sleep deprivation. In line with the re-distribution of sleep and wakefulness, the analysis of wheel-running and drinking activity revealed more rest bouts during the activity phase and a higher percentage of daytime activity in mutant animals. No changes were observed in internal period length and phase-shifting properties of the circadian clock while chi-squared periodogram amplitude was significantly reduced, hinting at a less robust oscillator. These results indicate that PRKG1 might be involved in the stabilization and output strength of the circadian oscillator in mice. Moreover, PRKG1 deficiency results in an aberrant pattern, and consequently a reduced quality, of sleep and wakefulness, possibly due to a decreased wake-promoting output of the circadian system impinging upon sleep.

Computed tomography commissioning programmes: how to obtain a reliable MTF with an automatic approach?

The purpose of this study was to assess the spatial resolution of a computed tomography (CT) scanner with an automatic approach developed for routine quality controls when varying CT parameters. The methods available to assess the modulation transfer functions (MTF) with the automatic approach were Droege's and the bead point source (BPS) methods. These MTFs were compared with presampled ones obtained using Boone's method. The results show that Droege's method is not accurate in the low-frequency range, whereas the BPS method is highly sensitive to image noise. While both methods are well adapted to routine stability controls, it was shown that they are not able to provide absolute measurements. On the other hand, Boone's method, which is robust with respect to aliasing, more resilient to noise and provides absolute measurements, satisfies the commissioning requirements perfectly. Thus, Boone's method combined with a modified Catphan 600 phantom could be a good solution to assess CT spatial resolution in the different CT planes.

A comparison of the imaging characteristics of the new Kodak Hyper Speed G film with the current T-MAT G/RA film and the CR 9000 system.

Three standard radiation qualities (RQA 3, RQA 5 and RQA 9) and two screens, Kodak Lanex Regular and Insight Skeletal, were used to compare the imaging performance and dose requirements of the new Kodak Hyper Speed G and the current Kodak T-MAT G/RA medical x-ray films. The noise equivalent quanta (NEQ) and detective quantum efficiencies (DQE) of the four screen-film combinations were measured at three gross optical densities and compared with the characteristics for the Kodak CR 9000 system with GP (general purpose) and HR (high resolution) phosphor plates. The new Hyper Speed G film has double the intrinsic sensitivity of the T-MAT G/RA film and a higher contrast in the high optical density range for comparable exposure latitude. By providing both high sensitivity and high spatial resolution, the new film significantly improves the compromise between dose and image quality. As expected, the new film has a higher noise level and a lower signal-to-noise ratio than the standard film, although in the high frequency range this is compensated for by a better resolution, giving better DQE results--especially at high optical density. Both screen-film systems outperform the phosphor plates in terms of MTF and DQE for standard imaging conditions (Regular screen at RQA 5 and RQA 9 beam qualities). At low energy (RQA 3), the CR system has a comparable low-frequency DQE to screen-film systems when used with a fine screen at low and middle optical densities, and a superior low-frequency DQE at high optical density.

Range-Wide Sex-Chromosome Sequence Similarity Supports Occasional XY Recombination in European Tree Frogs (Hyla arborea).

In contrast with mammals and birds, most poikilothermic vertebrates feature structurally undifferentiated sex chromosomes, which may result either from frequent turnovers, or from occasional events of XY recombination. The latter mechanism was recently suggested to be responsible for sex-chromosome homomorphy in European tree frogs (Hyla arborea). However, no single case of male recombination has been identified in large-scale laboratory crosses, and populations from NW Europe consistently display sex-specific allelic frequencies with male-diagnostic alleles, suggesting the absence of recombination in their recent history. To address this apparent paradox, we extended the phylogeographic scope of investigations, by analyzing the sequences of three sex-linked markers throughout the whole species distribution. Refugial populations (southern Balkans and Adriatic coast) show a mix of X and Y alleles in haplotypic networks, and no more within-individual pairwise nucleotide differences in males than in females, testifying to recurrent XY recombination. In contrast, populations of NW Europe, which originated from a recent postglacial expansion, show a clear pattern of XY differentiation; the X and Y gametologs of the sex-linked gene Med15 present different alleles, likely fixed by drift on the front wave of expansions, and kept differentiated since. Our results support the view that sex-chromosome homomorphy in H. arborea is maintained by occasional or historical events of recombination; whether the frequency of these events indeed differs between populations remains to be clarified.

Geographic variation in the frequency of isolation and fluconazole and voriconazole susceptibilities of Candida glabrata: an assessment from the ARTEMIS DISK Global Antifungal Surveillance Program.

Geographic differences in frequency and azole resistance among Candida glabrata may impact empiric antifungal therapy choice. We examined geographic variation in isolation and azole susceptibility of C. glabrata. We examined 23 305 clinical isolates of C. glabrata during ARTEMIS DISK global surveillance. Susceptibility testing to fluconazole and voriconazole was assessed by disk diffusion, and the results were grouped by geographic location: North America (NA) (2470 isolates), Latin America (LA) (2039), Europe (EU) (12 439), Africa and the Middle East (AME) (728), and Asia-Pacific (AP) (5629). Overall, C. glabrata accounted for 11.6% of 201 653 isolates of Candida and varied as a proportion of all Candida isolated from 7.4% in LA to 21.1% in NA. Decreased susceptibility (S) to fluconazole was observed in all geographic regions and ranged from 62.8% in AME to 76.7% in LA. Variation in fluconazole susceptibility was observed within each region: AP (range, 50-100% S), AME (48-86.9%), EU (44.8-88%), LA (43-92%), and NA (74.5-91.6%). Voriconazole was more active than fluconazole (range, 82.3-84.2% S) with similar regional variation. Among 22 sentinel sites participating in ARTEMIS from 2001 through 2007 (84 140 total isolates, 8163 C. glabrata), the frequency of C. glabrata isolation increased in 14 sites and the frequency of fluconazole resistance (R) increased in 11 sites over the 7-year period of study. The sites with the highest cumulative rates of fluconazole R were in Poland (22% R), the Czech Republic (27% R), Venezuela (27% R), and Greece (33% R). C. glabrata was most often isolated from blood, normally sterile body fluids and urine. There is substantial geographic and institutional variation in both frequency of isolation and azole resistance among C. glabrata. Prompt species identification and fluconazole susceptibility testing are necessary to optimize therapy for invasive candidiasis.

GPS analysis of human locomotion: further evidence for long-range correlations in stride-to-stride fluctuations of gait parameters.

During free walking, gait is automatically adjusted to provide optimal mechanical output and minimal energy expenditure; gait parameters, such as cadence, fluctuate from one stride to the next around average values. It was described that this fluctuation exhibited long-range correlations and fractal-like patterns. In addition, it was suggested that these long-range correlations disappeared if the participant followed the beep of metronome to regulate his or her pace. Until now, these fractal fluctuations were only observed for stride interval, because no technique existed to adequately analyze an extended time of free walking. The aim of the present study was to measure walking speed (WS), step frequency (SF) and step length (SL) with high accuracy (<1 cm) satellite positioning method (global positioning system or GPS) in order to detect long-range correlations in the stride-to-stride fluctuations. Eight participants walked 30 min under free and constrained (metronome) conditions. Under free walking conditions, DFA (detrended fluctuation analysis) and surrogate data tests showed that the fluctuation of WS, SL and SF exhibited a fractal pattern (i.e., scaling exponent alpha: 0.5 < alpha < 1) in a large majority of participants (7/8). Under constrained conditions (metronome), SF fluctuations became significantly anti-correlated (alpha < 0.5) in all participants. However, the scaling exponent of SL and WS was not modified. We conclude that, when the walking pace is controlled by an auditory signal, the feedback loop between the planned movement (at supraspinal level) and the sensory inputs induces a continual shifting of SF around the mean (persistent anti-correlation), but with no effect on the fluctuation dynamics of the other parameters (SL, WS).

Cumulative frequency-dependent selective episodes allow for rapid morph cycles and rock-paper-scissors dynamics in species with overlapping generations.

Rock-paper-scissors (RPS) dynamics, which maintain genetic polymorphisms over time through negative frequency-dependent (FD) selection, can evolve in short-lived species with no generational overlap, where they produce rapid morph frequency cycles. However, most species have overlapping generations and thus, rapid RPS dynamics are thought to require stronger FD selection, the existence of which yet needs to be proved. Here, we experimentally demonstrate that two cumulative selective episodes, FD sexual selection reinforced by FD selection on offspring survival, generate sufficiently strong selection to generate rapid morph frequency cycles in the European common lizard Zootoca vivipara, a multi-annual species with major generational overlap. These findings show that the conditions required for the evolution of RPS games are fulfilled by almost all species exhibiting genetic polymorphisms and suggest that RPS games may be responsible for the maintenance of genetic diversity in a wide range of species.

Reliable tidal volume estimates at the airway opening with an infant monitor during high-frequency oscillatory ventilation.

OBJECTIVE: To assess the suitability of a hot-wire anemometer infant monitoring system (Florian, Acutronic Medical Systems AG, Hirzel, Switzerland) for measuring flow and tidal volume (Vt) proximal to the endotracheal tube during high-frequency oscillatory ventilation. DESIGN: In vitro model study. SETTING: Respiratory research laboratory. SUBJECT: In vitro lung model simulating moderate to severe respiratory distress. INTERVENTION: The lung model was ventilated with a SensorMedics 3100A ventilator. Vt was recorded from the monitor display (Vt-disp) and compared with the gold standard (Vt-adiab), which was calculated using the adiabatic gas equation from pressure changes inside the model. MEASUREMENTS AND MAIN RESULTS: A range of Vt (1-10 mL), frequencies (5-15 Hz), pressure amplitudes (10-90 cm H2O), inspiratory times (30% to 50%), and Fio2 (0.21-1.0) was used. Accuracy was determined by using modified Bland-Altman plots (95% limits of agreement). An exponential decrease in Vt was observed with increasing oscillatory frequency. Mean DeltaVt-disp was 0.6 mL (limits of agreement, -1.0 to 2.1) with a linear frequency dependence. Mean DeltaVt-disp was -0.2 mL (limits of agreement, -0.5 to 0.1) with increasing pressure amplitude and -0.2 mL (limits of agreement, -0.3 to -0.1) with increasing inspiratory time. Humidity and heating did not affect error, whereas increasing Fio2 from 0.21 to 1.0 increased mean error by 6.3% (+/-2.5%). CONCLUSIONS: The Florian infant hot-wire flowmeter and monitoring system provides reliable measurements of Vt at the airway opening during high-frequency oscillatory ventilation when employed at frequencies of 8-13 Hz. The bedside application could improve monitoring of patients receiving high-frequency oscillatory ventilation, favor a better understanding of the physiologic consequences of different high-frequency oscillatory ventilation strategies, and therefore optimize treatment.

BK virus infection in hematopoietic stem cell transplant recipients: frequency, risk factors, and association with postengraftment hemorrhagic cystitis.

Blood samples from 132 consecutive hematopoietic stem cell transplant recipients were obtained and tested weekly for BK virus DNA by use of quantitative real-time PCR. Forty-four patients (33%) developed BK viremia at a median of 41 days (range, 9-91 days) after transplantation. Patients with hemorrhagic cystitis that occurred after platelet engraftment had higher levels of viremia than did patients without hemorrhagic cystitis (median, 9.7x10(3) vs. 0 copies/mL; P=.008) and patients with hemorrhagic cystitis that occurred before platelet engraftment (median, 9.7x10(3) vs. 0 copies/mL; P=.0006). BK viremia also was strongly associated with postengraftment hemorrhagic cystitis in a time-dependent analysis (P=.004).

Shift in cytotype frequency and niche space in the invasive plant Centaurea maculosa.

Polyploidy is often assumed to increase the spread and thus the success of alien plant species, but few empirical studies exist. We tested this hypothesis with Centaurea maculosa Lam., a species native to Europe and introduced into North America approximately 120 years ago where it became highly invasive. We analyzed the ploidy level of more than 2000 plants from 93 native and 48 invasive C. maculosa populations and found a pronounced shift in the relative frequency of diploid and tetraploid cytotypes. In Europe diploid populations occur in higher frequencies than tetraploids and only four populations had both cytotypes, while in North America diploid plants were found in only one mixed population and thus tetraploids clearly dominated. Our results showed a pronounced shift in the climatic niche between tetraploid populations in the native and introduced range toward drier climate in North America and a similar albeit smaller shift between diploids and tetraploids in the native range. The field data indicate that diploids have a predominately monocarpic life cycle, while tetraploids are often polycarpic. Additionally, the polycarpic life-form seems to be more prevalent among tetraploids in the introduced range than among tetraploids in the native range. Our study suggests that both ploidy types of C. maculosa were introduced into North America, but tetraploids became the dominant cytotype with invasion. We suggest that the invasive success of C. maculosa is partly due to preadaptation of the tetraploid cytotype in Europe to drier climate and possibly further adaptation to these conditions in the introduced range. The potential for earlier and longer seed production associated with the polycarpic life cycle constitutes an additional factor that may have led to the dominance of tetraploids over diploids in the introduced range.

Methods for Determining Frequency- and Region-Dependent Relationships Between Estimated LFPs and BOLD Responses in Humans

The relationship between electrophysiological and functional magnetic resonance imaging (fMRI) signals remains poorly understood. To date, studies have required invasive methods and have been limited to single functional regions and thus cannot account for possible variations across brain regions. Here we present a method that uses fMRI data and singe-trial electroencephalography (EEG) analyses to assess the spatial and spectral dependencies between the blood-oxygenation-level-dependent (BOLD) responses and the noninvasively estimated local field potentials (eLFPs) over a wide range of frequencies (0-256 Hz) throughout the entire brain volume. This method was applied in a study where human subjects completed separate fMRI and EEG sessions while performing a passive visual task. Intracranial LFPs were estimated from the scalp-recorded data using the ELECTRA source model. We compared statistical images from BOLD signals with statistical images of each frequency of the eLFPs. In agreement with previous studies in animals, we found a significant correspondence between LFP and BOLD statistical images in the gamma band (44-78 Hz) within primary visual cortices. In addition, significant correspondence was observed at low frequencies (<14 Hz) and also at very high frequencies (>100 Hz). Effects within extrastriate visual areas showed a different correspondence that not only included those frequency ranges observed in primary cortices but also additional frequencies. Results therefore suggest that the relationship between electrophysiological and hemodynamic signals thus might vary both as a function of frequency and anatomical region.

Frequency and chronology of extraintestinal manifestations in the Swiss Inflammatory Bowel Disease Cohort

Background: Data on the frequency of extraintestinal manifestations (EIM) in inflammatory bowel disease (IBD) is scarce, especially the one evaluating the time of occurrence of the EIM relative to IBD diagnosis. Aim: To assess the type and frequency of EIM in IBD patients and to evaluate when EIMs occur relative to IBD diagnosis. Methods: Analysis of data from the Swiss Inflammatory Bowel Disease Cohort (SIBDCS) which collects data on a large sample of IBD patients from hospitals and private practices across Switzerland starting in 2005. While parametric data are shown as mean ± SD, non-parametric data are presented as median and interquartile range (IQR). Results: A total of 1143 patients were analyzed (572 (50%) female, mean age 42.1 ± 14.4 years): 629 (55%) with Crohn's disease (CD), 501 (44%) with ulcerative colitis (UC), and 13 (1%) with indeterminate colitis (IC). Of 1143 patients, 374 (32.7%) presented with EIM (65% with CD, 33% with UC, 2% with IC). Of those patients suffering from EIMs, 37.4% presented with one, 41.7% with two, 12.4% with three, 5.3% with four, and 3.2% with five EIM during their lifetime. The IBD patients initially presented with the following EIMs: peripheral arthritis (PA) 63.4%, ankylosing spondylitis (AS) 8.1%, primary sclerosing cholangitis (PSC) 6.0%, uveitis 5.7%, oral aphthosis 5.7%, erythema nodosum (EN) 5.0%, pyoderma gangrenosum 1.8%, psoriasis 0.7%. While 92.9% of EIM occurred once IBD diagnosis was established (median 72 months, IQR 9-147 months, p < 0.001), 7.1% of EIMs preceded IBD diagnosis (median time 28 months before IBD diagnosis, IQR 7-60 months). Over a course of a lifetime, IBD patients presented with the following EIM (total exceeds 100 due to potential presence of multiple EIM): peripheral arthritis 69.3%, oral aphthosis 23%, ankylosing spondylitis 19.4%, uveitis 15.5%, erythema nodosum 14.5%, PSC 7.8%, pyoderma gangrenosum 6%, psoriasis 2.8%. Conclusion: EIMs frequently occur in a lifetime of IBD patients. The vast majority of patients present with EIMs once IBD diagnosis has been established. IBD patients most often present with peripheral arthritis, ankylosing spondylitis and PSC as their first EIM. However, peripheral arthritis, oral aphthosis, and ankylosing spondylitis are the most common EIMs in a lifetime of IBD patients.

Long-Term Trends of HIV Type 1 Drug Resistance Prevalence among Antiretroviral Treatment-Experienced Patients in Switzerland.

Background. Accurate quantification of the prevalence of human immunodeficiency virus type 1 (HIV-1) drug resistance in patients who are receiving antiretroviral therapy (ART) is difficult, and results from previous studies vary. We attempted to assess the prevalence and dynamics of resistance in a highly representative patient cohort from Switzerland. Methods. On the basis of genotypic resistance test results and clinical data, we grouped patients according to their risk of harboring resistant viruses. Estimates of resistance prevalence were calculated on the basis of either the proportion of individuals with a virologic failure or confirmed drug resistance (lower estimate) or the frequency-weighted average of risk group-specific probabilities for the presence of drug resistance mutations (upper estimate). Results. Lower and upper estimates of drug resistance prevalence in 8064 ART-exposed patients were 50% and 57% in 1999 and 37% and 45% in 2007, respectively. This decrease was driven by 2 mechanisms: loss to follow-up or death of high-risk patients exposed to mono- or dual-nucleoside reverse-transcriptase inhibitor therapy (lower estimates range from 72% to 75%) and continued enrollment of low-risk patients who were taking combination ART containing boosted protease inhibitors or nonnucleoside reverse-transcriptase inhibitors as first-line therapy (lower estimates range from 7% to 12%). A subset of 4184 participants (52%) had 1 study visit per year during 2002-2007. In this subset, lower and upper estimates increased from 45% to 49% and from 52% to 55%, respectively. Yearly increases in prevalence were becoming smaller in later years. Conclusions. Contrary to earlier predictions, in situations of free access to drugs, close monitoring, and rapid introduction of new potent therapies, the emergence of drug-resistant viruses can be minimized at the population level. Moreover, this study demonstrates the necessity of interpreting time trends in the context of evolving cohort populations.

Properties of functional brain networks correlate with frequency of psychogenic non-epileptic seizures.

Abnormalities in the topology of brain networks may be an important feature and etiological factor for psychogenic non-epileptic seizures (PNES). To explore this possibility, we applied a graph theoretical approach to functional networks based on resting state EEGs from 13 PNES patients and 13 age- and gender-matched controls. The networks were extracted from Laplacian-transformed time-series by a cross-correlation method. PNES patients showed close to normal local and global connectivity and small-world structure, estimated with clustering coefficient, modularity, global efficiency, and small-worldness (SW) metrics, respectively. Yet the number of PNES attacks per month correlated with a weakness of local connectedness and a skewed balance between local and global connectedness quantified with SW, all in EEG alpha band. In beta band, patients demonstrated above-normal resiliency, measured with assortativity coefficient, which also correlated with the frequency of PNES attacks. This interictal EEG phenotype may help improve differentiation between PNES and epilepsy. The results also suggest that local connectivity could be a target for therapeutic interventions in PNES. Selective modulation (strengthening) of local connectivity might improve the skewed balance between local and global connectivity and so prevent PNES events.

Evaluation of the reconstruction limits of a frequency-independent crosshole georadar waveform inversion scheme in the presence of dispersion

Waveform tomographic imaging of crosshole georadar data is a powerful method to investigate the shallow subsurface because of its ability to provide images of pertinent petrophysical parameters with extremely high spatial resolution. All current crosshole georadar waveform inversion strategies are based on the assumption of frequency-independent electromagnetic constitutive parameters. However, in reality, these parameters are known to be frequency-dependent and complex and thus recorded georadar data may show significant dispersive behavior. In this paper, we evaluate synthetically the reconstruction limits of a recently published crosshole georadar waveform inversion scheme in the presence of varying degrees of dielectric dispersion. Our results indicate that, when combined with a source wavelet estimation procedure that provides a means of partially accounting for the frequency-dependent effects through an "effective" wavelet, the inversion algorithm performs remarkably well in weakly to moderately dispersive environments and has the ability to provide adequate tomographic reconstructions.