Limits on Anisotropy in the Nanohertz Stochastic Gravitational Wave Background.

The paucity of observed supermassive black hole binaries (SMBHBs) may imply that the gravitational wave background (GWB) from this population is anisotropic, rendering existing analyses suboptimal. We present the first constraints on the angular distribution of a nanohertz stochastic GWB from circular, inspiral-driven SMBHBs using the 2015 European Pulsar Timing Array data. Our analysis of the GWB in the ~2-90 nHz band shows consistency with isotropy, with the strain amplitude in l>0 spherical harmonic multipoles ≲40% of the monopole value. We expect that these more general techniques will become standard tools to probe the angular distribution of source populations.

Digit ratio (2D:4D) and physical fitness (Eurofit test battery) in school children.

BACKGROUND: The relative lengths of the index finger to the ring finger (2D:4D) is sexually dimorphic and is thought to be a correlate of prenatal sex steroids (low 2D:4D=high prenatal testosterone and low prenatal oestrogen). In adults there have been reports that low 2D:4D is consistently associated with high sports performance. AIMS: To investigate correlations between 2D:4D and fitness levels in children. STUDY DESIGN: Right 2D:4D and body size were measured, in addition to flexibility, speed, endurance and strength (Eurofit tests). SUBJECTS: 922 boys and 835 girls (mean ages (years): 10.8 ± 1.01 and 10.07 ± 1.00 respectively). OUTCOME MEASURES: height, mass, BMI, triceps and subscapular skinfolds, 20 m shuttle run, sit and reach, standing broad jump, hand grip strength, 10 × 5m sprint, and the sit and reach test. RESULTS: Boys significantly outperformed the girls in the 10 × 5m sprints, the 20 m shuttle run, standing broad jump, and hand grip strength. In boys but not girls, 2D:4D was significantly negatively correlated with scores in all these tests except the standing broad jump. In girls but not boys, 2D:4D was significantly positively correlated to stature, mass, BMI and waist circumference. CONCLUSIONS: It is suggested that high prenatal testosterone and low prenatal oestrogen (low 2D:4D) is implicated in high sprinting speed, endurance and hand grip strength in boys. In girls low prenatal testosterone and high prenatal oestrogen is associated with large body size.

Multiphasic changes in systemic VEGF following intravitreal injections of ranibizumab in a child.

PURPOSE: To investigate whether intravitreal ranibizumab injections administered to a child alter systemic plasma levels of total and free VEGF 165. METHODS: A 9-year-old child sustained a choroidal rupture from blunt trauma. He subsequently developed a secondary choroidal neovascular membrane, which was treated with five ranibizumab injections over a period of 8 months. Peripheral venous blood samples were taken at each visit over a period of 12 months and plasma was extracted. Plasma VEGF 165 levels were determined using enzyme-linked immunosorbent assay and were assayed both pre- and post-immunodepletion to remove complexed VEGF. RESULTS: Plasma VEGF 165 levels proved labile following intravitreal injection of ranibizumab. Levels increased by 30% above baseline following the first intravitreal ranibizumab injection, but then returned to baseline despite two subsequent injections. There was then a rebound increase of 67% in total plasma VEGF levels following a further injection, which remained above baseline for 12 weeks despite two further intravitreal ranibizumab injections. Baseline levels were re-attained 26 weeks after the final injection. CONCLUSIONS: These results suggest intravitreal ranibizumab injections can cause significant, multiphasic changes in systemic VEGF levels. This may be of particular clinical significance in children as VEGF is known to be vital in the development of major organs, in addition to its role in the maintenance of normal organ function in adults.

Pegylated interferon-α-2b reduces corticosteroid requirement in patients with Behçet's disease with upregulation of circulating regulatory T cells and reduction of Th17.

OBJECTIVE: To determine whether the addition of 26 weeks of subcutaneous peginterferon-α-2b could reduce the requirement for systemic corticosteroids and conventional immunosuppressive medication in patients with Behçet's disease (BD). METHODS: We conducted a multicentre randomised trial in patients with BD requiring systemic therapy. Patients were randomised to 26 weeks of peginterferon-α-2b in addition to their standard care or to standard care only and followed 6-monthly for 3 years with BD activity scores and quality of life questionnaires. Patients at one centre had blood taken to measure regulatory T cells (Tregs) and Th17 cells. RESULTS: 72 patients were included. At months 10-12, while among the entire patient population there was no difference in the corticosteroid dose or immunosuppression use between the treatment groups (adjusted OR 1.04, 95% CI 0.34 to 3.19), post hoc analysis revealed that in patients who were on corticosteroids at baseline the corticosteroid requirement was significantly lower in the peginterferon-α-2b (6.5 (5-15) mg/day) compared with the non-interferon group (10 (8.25-16.5) mg/day, p=0.039). Furthermore, there was a trend towards an improved quality of life that became significant by 36 months (p=0.008). This was associated with a significant rise in Tregs and a decrease in Th17 cells which was still present at 1 year and 6 months after the interferon was stopped. The safety profile was similar with adverse events in 10% in both groups. CONCLUSIONS: The addition of peginterferon-α-2b to the drug regime of BD patients did not significantly reduce their corticosteroid dose required at 1 year. However, in those on corticosteroids at baseline post hoc analysis demonstrated that the addition of peginterferon-α-2b did result in a significant reduction in corticosteroid dose with a significantly improved quality of life and trend to reduce other required immunosuppressive agents. This effect was seen at 1 year and associated with a rise in Tregs suggesting a possible mode for interferon action. TRIAL REGISTRATION NUMBER: ISRCTN 36354474; EudraCT 2004-004301-18.

Heparin-binding epidermal growth factor-like growth factor (HB-EGF) and proteolytic processing by a disintegrin and metalloproteinases (ADAM): a regulator of several pathways.

HB-EGF is a member of the EGF family of ligands that is initially synthesized as a membrane-bound growth factor termed, proHB-EGF. The membrane bound proHB-EGF undergoes extensive proteolytic processing by several metalloproteinases capable of stimulating cellular proliferation. Soluble, mature HB-EGF binds to and activates EGF receptors. HB-EGF is a critical molecular component to a number of normal physiological processes including but not limited to tissue injury and wound healing, reproduction, angiogenesis and recently, adipogenesis. Misexpression of HB-EGF is linked to tumor formation and cancer including hepatocellular, pancreatic, gastric, breast, colon and melanoma, gliomas and glioblastomas. HB-EGF is a likely tool for therapeutic approaches to enhance treatment of injuries as well as a target for prevention of several cancers and obesity.

Role of disrupted in schizophrenia 1 (DISC1) in stress-induced prefrontal cognitive dysfunction.

Recent genetic studies have linked mental illness to alterations in disrupted in schizophrenia 1 (DISC1), a multifunctional scaffolding protein that regulates cyclic adenosine monophosphate (cAMP) signaling via interactions with phosphodiesterase 4 (PDE4). High levels of cAMP during stress exposure impair function of the prefrontal cortex (PFC), a region gravely afflicted in mental illness. As stress can aggravate mental illness, genetic insults to DISC1 may worsen symptoms by increasing cAMP levels. The current study examined whether viral knockdown (KD) of the Disc1 gene in rat PFC increases susceptibility to stress-induced PFC dysfunction. Rats were trained in a spatial working memory task before receiving infusions of (a) an active viral construct that knocked down Disc1 in PFC (DISC1 KD group), (b) a 'scrambled' construct that had no effect on Disc1 (Scrambled group), or (c) an active construct that reduced DISC1 expression dorsal to PFC (Anatomical Control group). Data were compared with an unoperated Control group. Cognitive performance was assessed following mild restraint stress that had no effect on normal animals. DISC1 KD rats were impaired by 1 h restraint stress, whereas Scrambled, Control, and Anatomical Control groups were unaffected. Thus, knocking down Disc1 in PFC reduced the threshold for stress-induced cognitive dysfunction, possibly through disinhibited cAMP signaling at neuronal network synapses. These findings may explain why patients with DISC1 mutations may be especially vulnerable to the effects of stress.

Cellular reprogramming into a brown adipose tissue-like phenotype by co-expression of HB-EGF and ADAM 12S.

Abnormal adipogenesis leads to excessive fat accumulation and several health disorders. Mouse fibroblasts (MLC) transfected with ADAM 12S and HB-EGF promoted lipid accumulation. Addition of KBR-7785, an ADAM 12S inhibitor, to HB-EGF/ADAM 12S expressing cells suppressed adipogenesis. BrdU incorporation was attenuated and enhanced mitotracker staining was observed in HB-EGF/ADAM 12S cells. Quantitative real time RT-PCR resulted in elevated levels of expression of three brown adipose tissue (BAT) genes (PRDM16, PGC-1α, and UCP-1), while expression levels of the three white adipose tissue (WAT) genes (PPARγ, C/EBPα, and AKT-1) were unaltered in HB-EGF/ADAM 12S cells. Amino- or carboxy-terminal deletions of HB-EGF (HB-EGFΔN and HB-EGFΔC) co-expressed with ADAM 12S stimulated lipid accumulation. Human epidermoid carcinoma cells (A431) also exhibited lipid accumulation by HB-EGF/ADAM 12S co-expression. These studies suggest ADAM 12S and HB-EGF are involved in cellular plasticity resulting in the production of BAT-like cells and offers insight into novel therapeutic approaches for fighting obesity.

Reliability of a field based 2D:4D measurement technique in children.

BACKGROUND: There is limited literature on the relationship between second to fourth finger digit ratio (2D:4D) and health- and skill-related fitness in children. To examine this relationship it is important to establish a reliable method of assessing 2D:4D for use with large groups of children. AIM: The aim of the study was to examine the reliability of a field-based 2D:4D measure in children. METHODS/RESEARCH DESIGN: Fifty 8-11 year olds had 2D:4D of the right hand measured using a Perspex table top, a digital camera, and Adobe Photoshop software. Second to fourth finger digit ratio (and 2D and 4D) intra-observer and inter-observer reliabilities were assessed on the same day and intraobserver reliability was measured between days. Limits of agreement (LoA), coefficient of variation (CV) and Pearson's correlation coefficient were used for statistical analysis. RESULTS: High correlation coefficients (r=0.95-0.99) and low CV's (0.4-1.2%) were reported for intra- and inter-observer reliabilities on the same day and between days. LoA revealed negligible systematic bias with random error ranging from 0.02 to 0.12. CONCLUSION: These findings suggest that 2D:4D (and 2D and 4D) assessment in children using digital photography provides a reliable measure of 2D:4D that can be used during field-based testing.

Distribution-based sensitivity metric for highly variable biochemical systems.

Classical sensitivity analysis is routinely used to identify points of fragility or robustness in biochemical networks. However, intracellular systems often contain components that number in the thousands to tens or less and consequently motivate a stochastic treatment. Although methodologies exist to quantify sensitivities in stochastic models, they differ substantially from those used in deterministic regimes. Therefore it is not possible to tell whether observed differences in sensitivity measured in deterministic and stochastic elaborations of the same network are the result of methodology or model form. The authors introduce here a distribution-based methodology to measure sensitivity that is equally applicable in both regimes, and demonstrate its use and applicability on a sophisticated mathematical model of the mouse circadian clock that is available in both deterministic and stochastic variants. The authors use the method to produce sensitivity measurements on both variants. They note that the rank-order sensitivity of the clock to parametric perturbations is extremely well conserved across several orders of magnitude. The data show that the clock is fragile to perturbations in parameters common to the cellular machinery ('global' parameters) and robust to perturbations in parameters that are clock-specific ('local' parameters). The sensitivity measure can be used to reduce the model from its original 73 ordinary differential equations (ODEs) to 18 ODEs and to predict the degree to which parametric perturbation can distort the phase response curve of the clock. Finally, the method is employed to evaluate the effect of transcriptional and translational noise on clock function. [Includes supplementary material].

Phacoemulsification in vitrectomized eyes under topical anesthesia.

PURPOSE: To study phacoemulsification in vitrectomized eyes under topical anesthesia, assessing anesthetic and intraoperative characteristics and complications. METHODS: A prospective study was performed on 52 eyes of 51 patients who underwent phacoemulsification of cataract with intraocular lens implantation under topical anesthesia, having previously undergone pars plana vitrectomy. Surgical and anesthetic observations and complications were recorded, as were visual outcomes. RESULTS: Ninety-two percent of patients had improved visual acuity postoperatively with only one patient having visual loss as a result of surgery. The most common intraoperative observations were of a deep anterior chamber, posterior capsular plaques, posterior synechiae, and nuclear sclerotic cataracts. Topical anesthesia proved satisfactory in 96%, with only two patients requiring intracameral lignocaine 1%; no patients required conversion to injection anesthesia. There were no major operative or postoperative complications. CONCLUSIONS: Phacoemulsification in vitrectomized eyes can be challenging, but is visually rewarding. Topical anesthesia proved satisfactory for the vast majority of cases, with none of our patients requiring conversion to injection anesthesia.

Cardiorespiratory fitness and body mass index of 9-11-year-old English children: a serial cross-sectional study from 1998 to 2004.

OBJECTIVE: To examine the changes over time in cardiorespiratory fitness and body mass index (BMI) of children. DESIGN: Serial cross-sectional, population-based study. SETTING: Primary schools in Liverpool, UK. PARTICIPANTS: A total of 15,621 children (50% boys), representing 74% of eligible 9-11-year olds in the annual school cohorts between 1998/9 and 2003/4, who took part in a 20m multi-stage shuttle run test (20mMST). MAIN OUTCOME MEASURES: Weight, height, BMI (kg/m(2)) and obesity using the International Obesity Taskforce definition. RESULTS: Median (95% confidence interval) 20mMST score (number of runs) fell in boys from 48.9 (47.9-49.9) in 1998/9 to 38.1 (36.8-39.4) in 2003/4, and in girls from 35.8 (35.0-36.6) to 28.1 (27.2-29.1) over the same period. Fitness scores fell across all strata of BMI (P<0.001). Moreover, BMI increased over the same 6-year period even among children in fittest third of 20mMST. CONCLUSION: In a series of uniform cross-sectional assessments of school-aged children, BMI increased whereas cardiorespiratory fitness levels decreased within a 6-year period. Even among lean children, fitness scores decreased. Public health measures to reduce obesity, such as increasing physical activity, may help raise fitness levels among all children - not just the overweight or obese.

Staircase-like potentiation of calcium release in mouse myotubes during repetitive short-term application of threshold caffeine.

The release of Ca2+ in response to caffeine at threshold concentration (5 mM) was studied in mouse skeletal myotubes. Repeated 5-s applications of caffeine, each followed by a 30-s washout, caused Ca2+ releases of consecutively growing amplitude (staircase phenomenon). Each response declined rapidly and had a slow tail. Repeated applications of threshold caffeine lowered the threshold concentration. The interval between threshold applications could be increased to 30 min without loss of potentiation. When threshold caffeine was applied continuously for up to 10 min, the increase in Ca2+ concentration as seen with staircase potentiation did not occur. Depolarization by elevated [K+] or by voltage-clamp steps potentiated caffeine-induced Ca2+ release rapidly as compared to the slow exponential growth of staircase-like potentiation. Gd3+ prevented the depolarization-induced potentiation, but not the staircase phenomenon. Staircase-like potentiation of Ca2+ release was evident even when the voltage sensors were clamped in their resting state; in contrast, potentiated Ca2+ release and its rapid termination apparently require conversion of the voltage sensors to an activated state. Staircase potentiation was blocked when Ca2+ was omitted from the bath, thus pinpointing the source of Ca2+. We suggest that staircase-like potentiation is conditioned by a caffeine-dependent Ca2+ influx across the plasma membrane.

Synthesis of phakellistatin 11: a micronesia (Chuuk) marine sponge cyclooctapeptide.

The cyclic octapeptide phakellistatin 11 (1), a constituent of The Federated States of Micronesia (Chuuk) marine sponge Phakellia sp., was synthesized using solid-phase techniques. An initial solution-phase synthesis proved to be inadequate owing to spontaneous deprotection of the Fmoc group at the heptapeptide stage. Using the PAL resin attachment and proceeding from Fmoc-Glu-alpha-allyl ester, linear elongation of the octapeptide was performed until the final unit Pro was added. The allyl ester was removed using Pd(0)[P(C(6)H(5))(3)](4). Cleavage of the final Fmoc group and cyclization with PyAOP provided phakellistatin 11 (1) in 17% overall yield. The synthetic specimen of phakellistatin 11 (1) was found to be chemically but not biologically (cancer cell lines) identical to the natural product. The result suggested a conformational difference or more likely the presence of a trace amount of a highly active antineoplastic agent that binds noncovalently to the natural cyclic octapeptide 1.

Sleep and 24 hour body temperatures: a comparison in young men, naturally cycling women and women taking hormonal contraceptives.

Body temperature has a circadian rhythm, and in women with ovulatory cycles, also a menstrual rhythm. Body temperature and sleep are believed to be closely coupled, but the influence on their relationship of gender, menstrual cycle phase and female reproductive hormones is unresolved. We investigated sleep and 24 h rectal temperatures in eight women with normal menstrual cycles in their mid-follicular and mid-luteal phases, and in eight young women taking a steady dose of oral progestin and ethinyl oestradiol (hormonal contraceptive), and compared their sleep and body temperatures with that of eight young men, sleeping in identical conditions. All subjects maintained their habitual daytime schedules. Rectal temperatures were elevated throughout 24 h in the luteal phase compared with the follicular phase in the naturally cycling women, consistent with a raised thermoregulatory set-point. Rectal temperatures in the women taking hormonal contraceptives were similar to those of the naturally cycling women in the luteal phase. Gender influenced body temperature: the naturally cycling women and the women taking hormonal contraceptives attained their nocturnal minimum body temperatures earlier than the men, and the naturally cycling women had blunted nocturnal body temperature drops compared with the men. Sleep architecture was essentially unaffected by either menstrual cycle phase or gender. The women taking hormonal contraceptives had less slow wave sleep (SWS), however, than the naturally cycling women. Gender, menstrual cycle phase and hormonal contraceptives significantly influenced body temperature, but had only minor consequences for sleep, in the young men and women in our study.

Anaesthesia and saccadic eye movements.

During the last 10 years, there has been a vast increase in day-case surgery under general anaesthesia, but this has not been accompanied by research into the residual cognitive and motor effects during recovery from anaesthesia. Part of the explanation for this phenomenon is the lack of a suitable biophysical monitor of anaesthetic sedation. This review discusses one of the most commonly used of these biophysical monitors - namely saccadic eye movements. In particular, the efficacy of peak saccadic velocity as a monitor of sedation will be evaluated. In addition, the physiology and pharmacology of saccadic eye movements will be discussed within the context of developing other parameters of saccadic eye movements as novel biophysical monitors of anaesthetic sedation.

A transient and a persistent calcium release are induced by chlorocresol in cultivated mouse myotubes.

The effect of 4-chloro-m-cresol (4-CmC), a stabilizing agent used in commercial preparations of the muscle relaxant succinylcholine, on intracellular free calcium levels in cultivated mouse myotubes was studied. Calcium signals were monitored with an inverted microscope equipped for fluorescence photometry using fura-2 as the calcium indicator. Upon bath application of 500 microM 4-CmC for 90 s, two separate calcium signals, a transient and a sustained one, could be regularly discriminated. First, with a delay of 2 s, the intracellular calcium concentration increased from 41+/-13 to 541+/-319 nM, peaked after 2-5 s and declined within 10 s to nearly resting values (n=36). Then, after a delay of up to 20 s, intracellular calcium rose quickly again to almost the same value and stayed elevated as long as the drug was applied. Upon drug removal, intracellular calcium rapidly decreased to a new level that was always slightly higher than the original base line. At 250 microM 4-CmC, the response was small, whereas at 500 microM it was at its maximum. Thus, the concentration-response curve was very steep. Replacement of extracellular calcium by EGTA and application of calcium channel blockers revealed that, for both the transient and the sustained response, calcium was released from intracellular stores. Pre-treatment with thapsigargin (0.1 microM) or ryanodine (10 microM) abolished both signal components. Repeated short-term applications of 4-CmC suggest that the two components may arise from different systems.

Effects of a low concentration of isoflurane on contrast sensitivity in volunteers.

The effects of 0.15% quasi steady-state end-tidal isoflurane on the contrast sensitivity of five healthy volunteers were investigated by measuring their performance in computer generated letter discrimination tasks. A series of letters were displayed on a computer screen so that the luminance of the letter differed from that of the background. Two protocols were used: in the static protocol, the letter remained displayed on the screen until the subject responded, whereas in the dynamic protocol, the letter was displayed for 1/72 s only. Isoflurane significantly decreased contrast sensitivity in both protocols in all subjects.

Different nocturnal body temperatures and sleep with forced-air warming in men and in women taking hormonal contraceptives.

We studied how forced-air warming, conventionally used to control body temperature during and after anaesthesia, affected the nocturnal rectal temperatures and sleep composition of young men and women. Seven healthy women who were taking oral or injection contraceptives, and six healthy men spent 3 nights in a controlled environment: an adaptation night followed by 2 nights when they slept under either a down duvet (baseline) or a quilt perfused with warm air (hot). Repeated analysis of variance (ANOVA) revealed significant gender differences in the body temperature responses. On the baseline night, despite sleeping under the same conditions, the women did not show a nocturnal drop in body temperature as shown by the men. Forced-air warming increased body temperature to a similar extent in the men and the women, and resulted in enhanced hyperthermia in the women, and blunted the drop in body temperature in the men, compared to their baseline nights. The significant increases in body temperature had no consequences, however, for the subjective sleep quality of either the men or women, and only minor consequences for objective sleep composition. Both men and women had increased amounts of Stage 2 sleep on the hot night (P < 0.04). In addition, the women had reduced rapid eye movement (REM) sleep when compared to their baseline night (P < 0.04). Our results confirm that in a passive thermal environment, women who are taking oral or injection contraceptives have higher nocturnal body temperatures than men. Also, as sleep architecture was minimally affected by the increases in body temperature of between 0.2 and 0.3 degree C on the hot night in the men and women, and subjective sleep quality was unaffected, our results question the existence of a tight association between sleep and body temperature.

Imaging caffeine-induced Ca2+ transients in individual fast-twitch and slow-twitch rat skeletal muscle fibers.

Fast-twitch and slow-twitch rat skeletal muscles produce dissimilar contractures with caffeine. We used digital imaging microscopy to monitor Ca2+ (with fluo 3-acetoxymethyl ester) and sarcomere motion in intact, unrestrained rat muscle fibers to study this difference. Changes in Ca2+ in individual fibers were markedly different from average responses of a population. All fibers showed discrete, nonpropagated, local Ca2+ transients occurring randomly in spots about one sarcomere apart. Caffeine increased local Ca2+ transients and sarcomere motion initially at 4 mM in soleus and 8 mM in extensor digitorum longus (EDL; approximately 23 degrees C). Ca2+ release subsequently adapted or inactivated; this was surmounted by higher doses. Motion also adapted but was not surmounted. Prolonged exposure to caffeine evidently suppressed myofilament interaction in both types of fiber. In EDL fibers, 16 mM caffeine moderately increased local Ca2+ transients. In soleus fibers, 16 mM caffeine greatly increased Ca2+ release and produced propagated waves of Ca2+ (approximately 1.5-2.5 microns/s). Ca2+ waves in slow-twitch fibers reflect the caffeine-sensitive mechanism of Ca2(+)-induced Ca2+ release. Fast-twitch fibers possibly lack this mechanism, which could account for their lower sensitivity to caffeine.