Extreme obesity reduces bone mineral density: complementary evidence from mice and women.
To evaluate the effects of body adiposity on bone mineral density in the presence and absence of ovarian hormones in female mice and postmenopausal women. We assessed percentage body fat, serum leptin levels, and bone mineral density in ovariectomized and non-ovariectomized C57BL/6 female mice that had been fed various calorically dense diets to induce body weight profiles ranging from lean to very obese. Additionally, we assessed percentage body fat and whole body bone mineral density in 37 overweight and extremely obese postmenopausal women from the Women's Contraceptive and Reproductive Experiences study. In mice, higher levels of body adiposity (>40% body fat) were associated with lower bone mineral density in ovariectomized C57BL/6 female mice. A similar trend was observed in a small sample of postmenopausal women. The complementary studies in mice and women suggest that extreme obesity in postmenopausal women may be associated with reduced bone mineral density. Thus, extreme obesity (BMI > 40 kg/m2) may increase the risk for osteopenia and osteoporosis. Given the obesity epidemic in the U.S. and in many other countries, and, in particular, the rising number of extremely obese adult women, increased attention should be drawn to the significant and interrelated public health issues of obesity and osteoporosis.


Experimental generation of multi-photon Fock states.
We experimentally demonstrate the generation of multi-photon Fock states with up to three photons in well-defined spatial-temporal modes synchronized with a classical clock. The states are characterized using quantum optical homodyne tomography to ensure mode selectivity. The three-photon Fock states are probabilistically generated by pulsed spontaneous parametric down conversion at a rate of one per second, enabling complete characterization in 12 hours.


Successful gene therapy in the RPGRIP1-deficient dog: a large model of cone-rod dystrophy.
For the development of new therapies, proof-of-concept studies in large animal models that share clinical features with their human counterparts represent a pivotal step. For inherited retinal dystrophies primarily involving photoreceptor cells, the efficacy of gene therapy has been demonstrated in canine models of stationary cone dystrophies and progressive rod-cone dystrophies but not in large models of progressive cone-rod dystrophies, another important cause of blindness. To address the last issue, we evaluated gene therapy in the retinitis pigmentosa GTPase regulator interacting protein 1 (RPGRIP1)-deficient dog, a model exhibiting a severe cone-rod dystrophy similar to that seen in humans. Subretinal injection of AAV5 (n = 5) or AAV8 (n = 2) encoding the canine Rpgrip1 improved photoreceptor survival in transduced areas of treated retinas. Cone function was significantly and stably rescued in all treated eyes (18-72% of those recorded in normal eyes) up to 24 months postinjection. Rod function was also preserved (22-29% of baseline function) in four of the five treated dogs up to 24 months postinjection. No detectable rod function remained in untreated contralateral eyes. More importantly, treatment preserved bright- and dim-light vision. Efficacy of gene therapy in this large animal model of cone-rod dystrophy provides great promise for human treatment.


Clinical Characteristics and Outcomes of COVID-19 in Turkish Patients with Hematological Malignancies
Patients with solid malignancies are more vulnerable to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection than the healthy population. The outcome of SARS-CoV-2 infection in highly immunosuppressed populations, such as in patients with hematological malignancies, is a point of interest. We aimed to analyze the symptoms, complications, intensive care unit admissions, and mortality rates of patients with hematological malignancies infected with SARS-CoV-2 in Turkey. In this multicenter study, we included 340 adult and pediatric patients diagnosed with SARS-CoV-2 from March to November 2020. Diagnosis and status of primary disease, treatment schedules for hematological malignancies, time from last treatment, life expectancy related to the hematological disease, and comorbidities were recorded, together with data regarding symptoms, treatment, and outcome of SARS-CoV-2 infection. Forty four patients were asymptomatic at diagnosis of SARS-CoV- 2 infection. Among symptomatic patients, fever, cough, and dyspnea were observed in 62.6%, 48.8%, and 41.8%, respectively. Sixty-nine (20%) patients had mild SARS-CoV-2 disease, whereas moderate, severe, and critical disease was reported in 101 (29%), 71 (20%), and 55 (16%) patients, respectively. Of the entire cohort, 251 (73.8%) patients were hospitalized for SARS-CoV-2. Mortality related to SARS-CoV-2 infection was 26.5% in the entire cohort; this comprised 4.4% of those patients with mild disease, 12.4% of those with moderate disease, and 83% of those with severe or critical disease. Active hematological disease, lower life expectancy related to primary hematological disease, neutropenia at diagnosis of SARS-CoV-2, ICU admission, and first-line therapy used for coronavirus disease-2019 treatment were found to be related to higher mortality rates. Treatments with hydroxychloroquine alone or in combination with azithromycin were associated with a higher rate of mortality in comparison to favipiravir use. Patients with hematological malignancy infected with SARS-CoV-2 have an increased risk of severe disease and mortality.


Intrinsic ferromagnetism and quantum anomalous Hall effect in a CoBr2 monolayer.
The electronic, magnetic, and topological properties of a CoBr2 monolayer are studied in the framework of density-functional theory (DFT) combined with tight-binding (TB) modeling in terms of the Wannier basis. Our DFT investigation and Monte Carlo simulation show that there exists intrinsic two-dimensional ferromagnetism in the CoBr2 monolayer, thanks to the large out-of-plane magnetocrystalline anisotropic energy. Our further study indicates that the spin-orbit coupling makes it become a topologically nontrivial insulator with a quantum anomalous Hall effect and topological Chern number [script C] = 4 and its edge states can be manipulated by changing the width of its nanoribbons and applying strains. The CoBr2 monolayer can be exfoliated from the layered CoBr2 bulk material because its exfoliation energy is between those of graphene and the MoS2 monolayer and it is dynamically stable. These results make us believe that the CoBr2 monolayer can make a promising spintronic material for future high-performance devices.


Customized computer models of eyes with intraocular lenses.
We compared experimental wave aberrations in pseudophakic eyes with aspheric intraocular lenses (IOLs) to simulate aberrations from numerical ray tracing on customized computer eye models using corneal topography, angle lambda, ocular biometry, IOL geometry, and IOL tilt and decentration measured on the same eyes. We found high correlations between real and simulated aberrations even for the eye with only the cornea, and these increased on average when the IOL geometry and position were included. Relevant individual aberrations were well predicted by the complete eye model. Corneal spherical aberration and horizontal coma were compensated by the IOL, and in 58.3% of the cases IOL tilt and decentration contributed to compensation of horizontal coma. We conclude that customized computer eye models are a good representation of real eyes with IOLs and allow understanding of the relative contribution of optical, geometrical and surgically-related factors to image quality. Corneal spherical aberration is reduced by aspheric IOLs, although other corneal high order aberrations are still a major contributor to total aberrations in pseudophakic eyes. Tilt and decentration of the IOLs represent a relatively minor contribution of the overall optical quality of the eye.


A conceptual model for outcome assessment.
Nurse practitioners are concerned with demonstrating quality of care. Of the three variables which compose quality assessment, the third variable, outcome, provides the most direct and appropriate way to judge the nurse practitioner's special health orientation. Most studies have judged nurse practitioners' care based on medical standards and criteria. Starfield's conceptual model of outcome measures is health oriented. This model is a multi-dimensional health profile with categories that incorporate a longitudinal approach to outcome assessment. It allows for identification and evaluation of nursing effectiveness in primary care.


Validating measures of stigma against those with mental illness among a community sample in Kilifi Kenya.
Stigma against persons with mental illness is a universal phenomenon, but culture influences the understanding of etiology of mental illness and utilization of health services. We validated Kiswahili versions of three measures of stigma which were originally developed in the United Kingdom: Community Attitudes Toward the Mentally Ill Scale (CAMI), Reported and Intended Behaviors Scale (RIBS) and Mental Health Awareness Knowledge Schedule (MAKS) and evaluated their psychometric properties using a community sample (N = 616) in Kilifi, Kenya. Confirmatory factor analysis confirmed the one-factor solution for RIBS [root mean-squared error of approximation (RMSEA) < 0.01, comparative fit index (CFI) = 1.00, Tucker-Lewis index (TLI) = 1.01] and two-factor solution for MAKS (RMSEA = 0.04, CFI = 0.96, TLI = 0.95). A 23-item, three-factor model provided the best indices of goodness of fit for CAMI (RMSEA = 0.04, CFI = 0.90, TLI = 0.89). MAKS converged with both CAMI and RIBS. Internal consistency was good for the RIBS and acceptable for CAMI and MAKS. Test-retest reliabilities were excellent for RIBS and poor for CAMI and MAKS, but kappa scores for inter-rater agreement were relatively low for these scales. Results support validity of the original MAKS and RIBS scale and a modified CAMI scale and suggest that stigma is not an enduring trait in this population. The low kappa scores are consistent with first kappa paradox which is due to adjustment for agreements by chance in case of marginal prevalence values. Kiswahili versions of the MAKS, RIBS and a modified version of the CAMI are valid for use in the study population. Stigma against people with mental illness may not be an enduring trait in this population.


Measures of arch height and their relationship to pain and dysfunction in people with lower limb impairments.
Debate surrounds the theory that foot structure, and more specifically, the attitude of the midfoot as typified by the longitudinal arch, is associated with complaints of pain and injuries of the lower extremity. Recently, two simple clinical measures of arch height, the arch ratio (AR) and the longitudinal arch angle (LAA), have been reported as valid and reliable in the literature. The LAA has been found to approximate the lowest point of the arch during walking and running while the main strengths of the AR are that the measure takes into account foot size and arch mobility. We modified the AR so that the modified AR (mAR) would be measured in a similar fashion as the LAA to investigate if this new measure, which would account for foot size, correlated well with an established measure (LAA) that estimated the behaviour of the arch with walking and running. Also, we hoped to contribute to the literature correlating longitudinal arch height with pain - numeric pain rating scale - and dysfunction - Lower Extremity Functional Scale (LEFS) and Single Assessment Numeric Evaluation (SANE). Thirty-five subjects for this prospective correlational study were recruited from a community based outpatient practice that was part of a tertiary care academic medical centre. Reliability and validity of our investigator and of the mAR was first examined. We then examined the correlation of the clinical classification of arch height (high, normal, or low) produced by these two measures with each other. We also explored the correlation of multiple measures of dysfunction and pain with arch height. Intrarater reliability and validity of the LAA showed an intraclass correlation (ICC) of 0.978 and Pearson's correlation coefficient (PCC) of 0.885, respectively. Intrarater reliability and validity of the mAR showed an ICC of 0.961 and PCC of 0.827, respectively. The LAA and our new measure, the mAR, were correlated with each other. The self-report measures of general health and activity level were significantly positively correlated (PCC = 0.598). Also significant and positively correlated were the LEFS and the SANE (PCC = 0.617), two measures of function. Pain and dysfunction may be positively correlated but longitudinal arch height does not predict either pain or dysfunction.


Aggressive behaviour in childhood and adolescence: the role of smoking during pregnancy, evidence from four twin cohorts in the EU-ACTION consortium.
Maternal smoking during pregnancy (MSDP) has been linked to offspring's externalizing problems. It has been argued that socio-demographic factors (e.g. maternal age and education), co-occurring environmental risk factors, or pleiotropic genetic effects may account for the association between MSDP and later outcomes. This study provides a comprehensive investigation of the association between MSDP and a single harmonized component of externalizing: aggressive behaviour, measured throughout childhood and adolescence. Data came from four prospective twin cohorts - Twins Early Development Study, Netherlands Twin Register, Childhood and Adolescent Twin Study of Sweden, and FinnTwin12 study - who collaborate in the EU-ACTION consortium. Data from 30 708 unrelated individuals were analysed. Based on item level data, a harmonized measure of aggression was created at ages 9-10; 12; 14-15 and 16-18. MSDP predicted aggression in childhood and adolescence. A meta-analysis across the four samples found the independent effect of MSDP to be 0.4% (r = 0.066), this remained consistent when analyses were performed separately by sex. All other perinatal factors combined explained 1.1% of the variance in aggression across all ages and samples (r = 0.112). Paternal smoking and aggressive parenting strategies did not account for the MSDP-aggression association, consistent with the hypothesis of a small direct link between MSDP and aggression. Perinatal factors, including MSDP, account for a small portion of the variance in aggression in childhood and adolescence. Later experiences may play a greater role in shaping adolescents' aggressive behaviour.


A new canine model of proximal internal carotid embolism.
A new model of internal carotid artery embolism was developed using autologous clot. The clot was prepared by incubating blood at room temperature for 2 hours to inactivate plasminogen activators and then refrigerating it at 4 degrees C for 22 hours. The purpose of the experiment was to devise a model of the intravascular lesion and not of stroke itself. The dog was chosen as the experimental animal since it has a maxillocarotid artery which permits collateral flow beyond proximal internal carotid artery occlusions. A volume of clot measuring 0.25 to 0.30 cc was sufficient to occlude the artery for 48 hours in 80% of the animals without causing major strokes. We have used this model to study clot radiolabeling and suggest it may also have application for evaluating thrombolytic drugs.


Varying task difficulty in the Go/Nogo task: the effects of inhibitory control, arousal, and perceived effort on ERP components.
Similar to other executive functions, inhibitory control is thought to be a dynamic process that can be influenced by variations in task difficulty. However, little is known about how different task parameters alter inhibitory performance and processing as a task becomes more difficult. The aim of this study was to investigate the influence of varying task difficulty, via manipulation of reaction time deadline (RTD), on measures of inhibitory control, perceived effort, and task-related arousal (indexed by skin conductance level). Sixty adults completed a visual Go/Nogo task (70% Go) after being randomly assigned to one of three task difficulty conditions: High, Medium and Low, with RTDs of 300, 500 or 1000 ms, respectively. Results revealed incremental increases in Go/Nogo errors and greater perceived effort with increasing difficulty. No condition differences were found for arousal, but the amplitude of the Nogo N2 increased and peaked earlier with increasing task difficulty. In contrast, the Nogo P3 effect was reduced in the High condition compared to the Low and Medium conditions. Finally, the amplitude of N1 and P2 showed differential effects, with Nogo N1 increasing with task difficulty, while the Nogo P2 decreased. This study provides valuable baseline behavioural and ERP data for appropriately manipulating difficulty (via RTD) in Go/Nogo tasks - highlighting the potential key role of not only the N2 and P3, but also the N1 and P2 components for task performance.


Digital holographic moiré for the direct and simultaneous estimation of strain and slope fields.
A novel method is proposed for the direct and simultaneous estimation of multiple phase derivatives corresponding to strain and slope fields from a single moiré fringe pattern in digital holographic moiré. The interference field in a given row/column is a multicomponent complex exponential signal and is represented as a spatially-varying autoregressive (SVAR) process. The spatially-varying coefficients of the SVAR model are computed by approximating them as the linear combination of linearly independent basis functions. Further, the spatially varying poles of the transfer function corresponding to the SVAR model are computed which provide the accurate estimation of the multiple phase derivatives. The simulation and experimental results are provided to substantiate the effectiveness of the proposed method.


Strategic planning of proteins in ionic liquids: future solvents for the enhanced stability of proteins against multiple stresses.
Ionic liquids (ILs) present a vast number of solvents capable of replacing toxic organic solvents in chemical, biotechnology and biomedical applications. ILs are inexpensive and environmentally friendly as the materials can be recycled conveniently. Chemists use a variety of cation and anion combinations to produce an IL that fits the requirements of the sustainable future through the pursuit of greener chemical processes. As such, the development of various types of ILs has been recognized as the emergence of environmentally friendly solvents to attain enhanced protein stability in vitro. The literature survey reveals that there exist a large number of scholarly articles as well as elegant reviews on protein stability in ILs. Biomolecules have adapted to antagonistic environmental stresses that normally denature proteins, and the mechanism of adaptation that protects the cellular components against denaturation involves the intracellular concentration of co-solvents. In this regard, recent experimental results distinctly demonstrated that ILs are stabilizing proteins against denaturing stresses, and their presence in the cells does not alter protein functional activities. However, a review focusing particularly on the refolding and counteracting effects of the ILs against denatured proteins by multiple stresses is still missing. This perspective unveils the studies that have been conducted to improve protein stabilities with ILs as well as the refolding and counteracting abilities of these ILs against the denatured proteins under the influence of multiple stresses. We believe that ILs can provide significant environmental and economic advantages for biochemical processes in the near future. Essentially, numerous investigations are required to allow us to further explore the stabilizing properties of ILs over proteins.


MDR1 pharmacogenetics: frequency of the C3435T mutation in exon 26 is significantly influenced by ethnicity.
P-glycoprotein (PGP), the product of the multidrug resistance gene (MDR1), acts as an energy-dependent efflux pump that exports its substrates out of the cell. PGP expression is an important factor regulating absorption of a wide variety of medications. It has also been associated with intrinsic and acquired cross resistance to a number of structurally unrelated anticancer drugs. A single nucleotide polymorphism (SNP) in exon 26 of the MDR1 gene, C3435T, was recently correlated with PGP protein levels and substrate uptake. Individuals homozygous for the T allele have more than four-fold lower PGP expression compared with CC individuals. As overexpression of PGP has been associated with altered drug absorption, therapy-resistant malignancies, and lower concentrations of HIV-1 protease inhibitors, this SNP may provide a useful approach to individualize therapy. To facilitate clinical application throughout the world, 1280 subjects from 10 different ethnic groups were evaluated for this SNP using the polymerase chain reaction-restriction fragment length polymorphism assay and the genotype and allele frequency for each group were ascertained. Marked differences in genotype and allele frequency were apparent between the African populations and the Caucasian/Asian populations (P < 0.0001). The Ghanaian, Kenyan, African American and Sudanese populations studied had frequencies of 83%, 83%, 84% and 73%, respectively, for the C allele. The British Caucasian, Portuguese, South-west Asian, Chinese, Filipino and Saudi populations had lower frequencies of the C allele compared to the African group (48%, 43%, 34%, 53%, 59%, and 55%, respectively). The high frequency of the C allele in the African group implies overexpression of PGP and may have important therapeutic and prognostic implications for use of PGP dependent drugs in individuals of African origin.


Colloidal porous gold nanoparticles.
Porous Au nanostructures have attracted much attention for their wide uses as catalysts, sensors, actuators and surface-enhanced Raman scattering (SERS) substrates. The synthesis of porous Au nanostructures has mainly relied on dealloying approaches, which generally involve high-temperature treatment to form alloys and subsequent harsh chemical etching. Herein we report on an ambient wet-chemistry method for the synthesis of colloidal porous Au nanoparticles. The synthesis takes advantage of the growth of Au on PbS nanocrystals accompanied by the etching of PbS by the growth solution. The obtained porous Au nanoparticles display a SERS enhancement factor of (1.23 ± 0.10) × 107 on the individual particles under off-resonance excitation and a catalytic activity that is several times those of previously reported porous Au particles and porous Au sheets. Our results will have high impact on many SERS-based analytical and biomedical applications and on the field of Au-based catalysis.


An age-stratified serosurvey against purified Salmonella enterica serovar Typhi antigens in the Lao People´s Democratic Republic.
The epidemiology of typhoid fever in Lao People`s Democratic Republic is poorly defined. Estimating the burden of typhoid fever in endemic countries is complex due to the cost and limitations of population-based surveillance; serological approaches may be a more cost-effective alternative. ELISAs were performed on 937 serum samples (317 children and 620 adults) from across Lao PDR to measure IgG antibody titers against Vi polysaccharide and the experimental protein antigens, CdtB and HlyE. We measured the significance of the differences between antibody titers in adults and children and fitted models to assess the relationship between age and antibody titers. The median IgG titres of both anti-HylE and CdtB were significantly higher in children compared to adults (anti-HylE; 351.7 ELISA Units (EU) vs 198.1 EU, respectively; p<0.0001 and anti-CdtB; 52.6 vs 12.9 EU; p<0.0001). Conversely, the median anti-Vi IgG titer was significantly higher in adults than children (11.3 vs 3.0 U/ml; p<0.0001). A non-linear trend line fitted to the anti-CdtB and anti-HlyE IgG data identified a peak in antibody concentration in children <5 years of age. We identified elevated titers of anti-HlyE and anti-CdtB IgG in the serum of children residing in Lao PDR in comparison to adults. These antigens are associated with seroconversion after typhoid fever and may be a superior measure of disease burden than anti-Vi IgG. This approach is scalable and may be developed to assess the burden of typhoid fever in countries where the disease may be endemic, and evidence is required for the introduction of typhoid vaccines.


Ocular rigidity in living human eyes.
To measure the rigidity coefficient of a large number of subjects at clinically encountered intraocular pressures (IOPs) and to examine the possible correlation of ocular rigidity with other factors, such as the age of the patients, ocular parameters (axial length and corneal thickness), and pathologic conditions affecting the eye. The pressure-volume relationship and the ocular rigidity coefficient (K) were determined in 79 eyes undergoing cataract surgery, by injecting 200 microL of saline solution (in steps of 4.5 microL) through the limbus into the anterior chamber, while continually monitoring the IOP with a transducer, up to the limit of 60 mm Hg. Data within an IOP range of 10 to 35 mm Hg were used to calculate the scleral rigidity coefficient. All measurements were taken at the same time of day, to eliminate any possible diurnal variation. The mean ocular rigidity coefficient was 0.0126 mm Hg/microL (95% confidence interval [CI], 0.0112-0.0149). A statistically significant positive correlation between the rigidity coefficient and age of the patient was found (P = 0.02), whereas similar findings were not observed for the examined ocular parameters (axial length, P = 0.09; and corneal thickness, P = 0.12). No correlation was found for patients with diabetes mellitus (P = 0.39), age-related macular degeneration (P = 0.55), and hypertension (P = 0.45). The present study provides quantitative data on the ocular rigidity coefficient based on measurements in a large series of living human eyes. A positive correlation between the ocular rigidity coefficient and the patient's age was documented.


Continuous non-contact vital sign monitoring in neonatal intensive care unit.
Current technologies to allow continuous monitoring of vital signs in pre-term infants in the hospital require adhesive electrodes or sensors to be in direct contact with the patient. These can cause stress, pain, and also damage the fragile skin of the infants. It has been established previously that the colour and volume changes in superficial blood vessels during the cardiac cycle can be measured using a digital video camera and ambient light, making it possible to obtain estimates of heart rate or breathing rate. Most of the papers in the literature on non-contact vital sign monitoring report results on adult healthy human volunteers in controlled environments for short periods of time. The authors' current clinical study involves the continuous monitoring of pre-term infants, for at least four consecutive days each, in the high-dependency care area of the Neonatal Intensive Care Unit (NICU) at the John Radcliffe Hospital in Oxford. The authors have further developed their video-based, non-contact monitoring methods to obtain continuous estimates of heart rate, respiratory rate and oxygen saturation for infants nursed in incubators. In this Letter, it is shown that continuous estimates of these three parameters can be computed with an accuracy which is clinically useful. During stable sections with minimal infant motion, the mean absolute error between the camera-derived estimates of heart rate and the reference value derived from the ECG is similar to the mean absolute error between the ECG-derived value and the heart rate value from a pulse oximeter. Continuous non-contact vital sign monitoring in the NICU using ambient light is feasible, and the authors have shown that clinically important events such as a bradycardia accompanied by a major desaturation can be identified with their algorithms for processing the video signal.


CYP3A5, ABCB1, and SLCO1B1 polymorphisms and pharmacokinetics and virologic outcome of lopinavir/ritonavir in HIV-infected children.
CYP3A5, MDR1 (ABCB1), and OATP1 (SLCO1B1) polymorphisms have been associated with variability in the pharmacokinetics (PK) of protease inhibitors. The aim of this study was to investigate the influence of CYP3A5 A6986G, ABCB1 (C3435T and G2677T), and SLCO1B1 (T521C and A388AG) polymorphisms on the PK and virologic outcome of lopinavir/ritonavir (LPV/RTV) in HIV-infected children. We conducted a prospective cohort study in children (4-18 years old) on stable antiretroviral therapy with LPV/RTV. CYP3A5, ABCB1, and SLCO1B1 genotypes were determined using polymerase chain reaction amplification with allelic discrimination assays. The 12-hour plasma area under the concentration-time curves (AUC) and clearances (CL) of LPV and RTV were estimated using noncompartmental models. HIV RNA viral load was evaluated every 12 weeks for a total study period of 52 weeks. Analysis of covariance models with adjustment for age and adherence and allometric adjustment of CL were used to assess associations between studied polymorphisms and AUC, CL, and HIV RNA. Fifty children (median age 11.2 years) were enrolled. Allele frequencies of the genotypes studied were in Hardy-Weinberg equilibrium. There was no statistically significant association between LPV or RTV AUC or CL, and CYP3A5, ABCB1, or SLCO1B1 A388G polymorphisms. There was a significant association between SLCO1B1 T521C genotype and increased LPV AUC (P = 0.042) and a nearly significant association with decreased LPV CL (P = 0.063). None of the studied polymorphisms, including SLCO1B1 T521C, were associated with virologic outcome during 52 weeks of study follow-up. There was no statistically significant influence of the CYP3A5, ABCB1, or SLCO1B1 A388AG polymorphisms on the PK and virologic outcome of LPV/RTV in HIV-infected children. SLCO1B1 T521C polymorphism was significantly associated with an increase in LPV AUC but was not associated with undetectable HIV RNA during the study period.


Five-year follow-up of total disc replacement compared to fusion: a randomized controlled trial.
To evaluate long-term clinical results of lumbar total disc replacement (TDR) compared with posterior lumbar fusion. This prospective randomized controlled trial comprised 152 patients; 80 were randomized to TDR and 72 to fusion. All patients had chronic low back pain (CLBP) and had not responded to nonsurgical treatment. Primary outcome measure was global assessment of back pain (GA), secondary outcome measures were back and leg pain, Oswestry Disability Index (ODI), EQ5D, and SF-36. All measures were collected from SweSpine (Swedish national register for spinal surgery) at 1, 2, and 5 years. Follow-up rate at 5 years was 99.3 %. Both groups showed clinical improvement at 5-year follow-up. For GA, 38 % (30/80) in the TDR group were totally pain free vs. 15 % (11/71) in the fusion group (p < 0.003). Back pain and improvement of back pain were better in the TDR group: VAS back pain at 5 years 23 ± 29 vs. 31 ± 27, p = 0.009, and VAS improvement of back pain at 5 years 40 ± 32 vs. 28 ± 32, p = 0.022. ODI and improvement in ODI were also better in the TDR group: ODI at 5 years 17 ± 19 vs. 23 + 17, p = 0.02 and ODI improvement at 5 years 25 ± 18 vs. 18 ± 19 (p = 0.02). There was no difference in complications and reoperations between the two groups. Global assessment of low back pain differed between the two surgical groups at all follow-up occasions. Significant differences between groups concerning back pain, pain improvement, and ODI were present at 1 year and disappeared at 2 years, but reappeared at the 5-year follow-up.


Modulation of the Endocannabinoids N-Arachidonoylethanolamine (AEA) and 2-Arachidonoylglycerol (2-AG) on Executive Functions in Humans.
Animal studies point to an implication of the endocannabinoid system on executive functions. In humans, several studies have suggested an association between acute or chronic use of exogenous cannabinoids (Δ9-tetrahydrocannabinol) and executive impairments. However, to date, no published reports establish the relationship between endocannabinoids, as biomarkers of the cannabinoid neurotransmission system, and executive functioning in humans. The aim of the present study was to explore the association between circulating levels of plasma endocannabinoids N-arachidonoylethanolamine (AEA) and 2-Arachidonoylglycerol (2-AG) and executive functions (decision making, response inhibition and cognitive flexibility) in healthy subjects. One hundred and fifty seven subjects were included and assessed with the Wisconsin Card Sorting Test; Stroop Color and Word Test; and Iowa Gambling Task. All participants were female, aged between 18 and 60 years and spoke Spanish as their first language. Results showed a negative correlation between 2-AG and cognitive flexibility performance (r = -.37; p<.05). A positive correlation was found between AEA concentrations and both cognitive flexibility (r = .59; p<.05) and decision making performance (r = .23; P<.05). There was no significant correlation between either 2-AG (r = -.17) or AEA (r = -.08) concentrations and inhibition response. These results show, in humans, a relevant modulation of the endocannabinoid system on prefrontal-dependent cognitive functioning. The present study might have significant implications for the underlying executive alterations described in some psychiatric disorders currently associated with endocannabinoids deregulation (namely drug abuse/dependence, depression, obesity and eating disorders). Understanding the neurobiology of their dysexecutive profile might certainly contribute to the development of new treatments and pharmacological approaches.


New transient ischemic attack and stroke: outpatient management by primary care physicians.
Patients with transient ischemic attack (TIA) or stroke frequently first contact their primary care physician rather than seeking care at a hospital emergency department. The purpose of the present study was to identify a group of patients seen by primary care physicians in an office setting for a first-ever TIA or stroke and characterize their evaluation and management. Practice audit based on retrospective, structured medical record abstraction from 27 primary care medical practices in 2 geographically separate communities in the eastern United States. Ninety-five patients with a first-ever TIA and 81 with stroke were identified. Seventy-nine percent of those with TIA vs 88% with stroke were evaluated on the day their symptoms occurred (P =.12). Only 6% were admitted to a hospital for evaluation and treatment on the day of the index visit (2% TIA; 10% stroke; P =.03); only an additional 3% were admitted during the subsequent 30 days. Specialists were consulted for 45% of patients. A brain imaging study (computed tomography or magnetic resonance imaging) was ordered on the day of the index visit in 30% (23% TIA, 37% stroke; P =.04), regardless of whether the patient was referred to a specialist. Carotid ultrasound studies were obtained in 28% (40% TIA, 14% stroke; P<.001), electrocardiograms in 19% (18% TIA, 21% stroke; P =.60), and echocardiograms in 16% (19% TIA, 14% stroke; P =.34). Fewer than half of patients with a prior history of atrial fibrillation (n = 24) underwent anticoagulation when evaluated at the index visit. Thirty-two percent of patients (31% TIA, 33% stroke; P =.70) were not hospitalized and had no evaluations performed during the first month after presenting to a primary care physician with a first TIA or stroke. Of these patients, 59% had a change in antiplatelet therapy on the day of the index visit. Further primary care physician education regarding the importance of promptly and fully evaluating patients with TIA or stroke may be warranted, and barriers to implementation of established secondary stroke prevention strategies need to be carefully explored. Arch Intern Med. 2000;160:2941-2946


Active gamma-secretase complexes contain only one of each component.
Gamma-secretase is an intramembrane aspartyl protease complex that cleaves type I integral membrane proteins, including the amyloid beta-protein precursor and the Notch receptor, and is composed of presenilin, Pen-2, nicastrin, and Aph-1. Although all four of these membrane proteins are essential for assembly and activity, the stoichiometry of the complex is unknown, with the number of presenilin molecules present being especially controversial. Here we analyze functional gamma-secretase complexes, isolated by immunoprecipitation from solubilized membrane fractions and able to produce amyloid beta-peptides and amyloid beta-protein precursor intracellular domain. We show that the active isolated protease contains only one presenilin per complex, which excludes certain models of the active site that require aspartate dyads formed between two presenilin molecules. We also quantified components in the isolated complexes by Western blot using protein standards and found that the amounts of Pen-2 and nicastrin were the same as that of presenilin. Moreover, we found that one Aph-1 was not co-immunoprecipitated with another in active complexes, evidence that Aph-1 is likewise present as a monomer. Taken together, these results demonstrate that the stoichiometry of gamma-components presenilin:Pen-2:nicastrin:Aph-1 is 1:1:1:1.


A retrospective record review and assessment of cost of quetiapine use in a community psychiatric setting in the Sedibeng district of Gauteng.
With the revision of the National Essential Medicines List in South Africa, quetiapine is only available at the discretion of individual institutions in the public health sector. However, quetiapine is effective in managing all aspects of bipolar disorder, including preventative treatment of depressive episodes, and may be a cost-effective option in severe illness. To present the first retrospective review of quetiapine use in a peri-urban health district of South Africa, describing the patient profile, clinical response and prescribing patterns. The clinical files of all patients in Sedibeng District who received quetiapine over a defined 3-year period (2011-2013) were reviewed. A positive clinical response was defined as both symptomatic and functional improvement. Demographic and clinical characteristics of responders were compared with that of non-responders. Pre- and post-quetiapine scripts of the responders were audited and costed. Patients who received quetiapine (n = 40) had chronic disabling illness, often with multiple medication trials and hospitalisations prior to quetiapine use. Bipolar II disorder (followed by bipolar I disorder) was the most common primary psychiatric diagnosis documented. Other than improvement in functioning (p < 0.0001), responders differed significantly from non-responders in terms of a higher level of polypharmacy and a significant reduction in median number of medications from pre- to post-quetiapine (p = 0.0057). Quetiapine use was associated with a highly significant improvement in functioning; however, it came at a 52% increase in medicine cost. Pre-quetiapine treatments, though, did not achieve an optimal level of functioning, and overall costs may be reduced by more rational prescribing habits.


Sleep in rheumatic diseases and other painful conditions.
Insufficient sleep is an under-recognized public health problem that is projected to increase in the next decade as the US population ages. Chronic insomnia alone impacts 10% to 15% of adults. Epidemiologic data indicate that pain, fatigue, and mood disturbance are common correlates of persistent insomnia. Rates of most sleep disorders are substantially elevated in rheumatologic diseases, with chronic insomnia impacting at least 50% of patients. Clinicians treating patients with rheumatologic disorders should screen for sleep disorders and possess a basic knowledge of sleep physiology and empirically based intervention approaches. Sleep disturbances occurring within the context of chronic medical illnesses, including rheumatologic diseases, do not typically respond to primary disease and/or pain management interventions. Identification of co-occurring sleep disorders followed by aggressive treatment is recommended and has the potential to improve quality of life, ameliorate pain, and improve psychosocial adaptation to the primary illness. In this report, we briefly highlight that sleep disturbance increases risk for both comorbidities and symptoms associated with rheumatologic diseases, we identify specific sleep disorders commonly encountered in rheumatologic populations, and we discuss pharmacologic and behavioral treatment approaches for the most common sleep disorder observed in rheumatologic conditions, chronic insomnia.


Laminated polymer waveguide fan-out device for uncoupled multi-core fibers.
A compact waveguide-type fan-out device for uncoupled multi-core fibers was demonstrated using a laminated polymer waveguide (LPW). The core spacing in the vertical direction was precisely controlled by the spin-coating of epoxy resin cladding with accurate viscosity control, while that in the lateral direction was determined precisely by using a photomask. The simultaneous coupling from the fan-out device to a seven-core MCF was successfully demonstrated. Next, we measured the offset loss characteristics of the cores of the LPW and calculated the spot size of the respective cores. The theoretical coupling losses evaluated from the spot size and the offset were as low as 0.2 - 7.5 dB.


Direct comparison of clinical decision limits for cardiac troponin T and I.
The 99th percentile upper reference limit of high-sensitivity cardiac troponin (hs-cTn) from a healthy reference population is used for diagnosing acute myocardial infarction (AMI). Accepted current thresholds of hs-cTnT (Roche) and hs-cTnI (Abbott) are 14 and 26 ng/L, respectively. Since thresholds for hs-cTnT and hs-cTnI were derived from different reference cohorts it is unclear whether they are biologically equivalent. We directly assessed sex-specific and age-specific 99th percentile upper reference limits of hs-cTnT and hs-cTnI in a single reference cohort, to investigate whether current divergent thresholds of hs-cTnT and hs-cTnI stem from intrinsic assay differences or reflect cohort variation. A healthy reference population was derived from a population-based cohort (the Maastricht Study: n=3451; age: 40-75 years). Individuals with diabetes mellitus, a history of cardiovascular disease, cardiac ischaemia on ECG, N-terminal pro-brain natriuretic peptide >125 ng/L or estimated glomerular filtration rate <60 mL/min/1.73 m(2) were excluded. Non-parametric analyses were performed to assess 99th percentile upper reference limits. 1540 individuals were included in the healthy reference population (age 57±8 years, 52.4% women). Overall 99th percentile upper reference limits of hs-cTnT and hs-cTnI were 15 and 13 ng/L, respectively. Upper reference limits were higher in men than women (hs-cTnT: 16 vs 12 ng/L), (hs-cTnI: 20 vs 11 ng/L) and increased with age. Direct comparison reveals numerically similar thresholds for hs-cTnT and hs-cTnI assays. This finding is in line with recently reported underdiagnosis of AMI with the current decision limit of 26 ng/L for hs-cTnI, especially among women. Downwards adjustment of the hs-cTnI threshold, differentiated for sex, would equalise clinical decision limits for both assays, and may prevent further underdiagnosis of AMI.


Basal ganglia modulation of thalamocortical relay in Parkinson's disease and dystonia.
Basal ganglia dysfunction has being implied in both Parkinson's disease and dystonia. While these disorders probably involve different cellular and circuit pathologies within and beyond basal ganglia, there may be some shared neurophysiological pathways. For example, pallidotomy and pallidal Deep Brain Stimulation (DBS) are used in symptomatic treatment of both disorders. Both conditions are marked by alterations of rhythmicity of neural activity throughout basal ganglia-thalamocortical circuits. Increased synchronized oscillatory activity in beta band is characteristic of Parkinson's disease, while different frequency bands, theta and alpha, are involved in dystonia. We compare the effect of the activity of GPi, the output nuclei of the basal ganglia, on information processing in the downstream neural circuits of thalamus in Parkinson's disease and dystonia. We use a data-driven computational approach, a computational model of the thalamocortical (TC) cell modulated by experimentally recorded data, to study the differences and similarities of thalamic dynamics in dystonia and Parkinson's disease. Our analysis shows no substantial differences in TC relay between the two conditions. Our results suggest that, similar to Parkinson's disease, a disruption of thalamic processing could also be involved in dystonia. Moreover, the degree to which TC relay fidelity is impaired is approximately the same in both conditions. While Parkinson's disease and dystonia may have different pathologies and differ in the oscillatory content of neural discharge, our results suggest that the effect of patterning of pallidal discharge is similar in both conditions. Furthermore, these results suggest that the mechanisms of GPi DBS in dystonia may involve improvement of TC relay fidelity.


Updating the OMERACT filter: core areas as a basis for defining core outcome sets.
The Outcome Measures in Rheumatology (OMERACT) Filter provides guidelines for the development and validation of outcome measures for use in clinical research. The "Truth" section of the OMERACT Filter presupposes an explicit framework for identifying the relevant core outcomes that are universal to all studies of the effects of intervention effects. There is no published outline for instrument choice or development that is aimed at measuring outcome, was derived from broad consensus over its underlying philosophy, or includes a structured and documented critique. Therefore, a new proposal for defining core areas of measurement ("Filter 2.0 Core Areas of Measurement") was presented at OMERACT 11 to explore areas of consensus and to consider whether already endorsed core outcome sets fit into this newly proposed framework. Discussion groups critically reviewed the extent to which case studies of current OMERACT Working Groups complied with or negated the proposed framework, whether these observations had a more general application, and what issues remained to be resolved. Although there was broad acceptance of the framework in general, several important areas of construction, presentation, and clarity of the framework were questioned. The discussion groups and subsequent feedback highlighted 20 such issues. These issues will require resolution to reach consensus on accepting the proposed Filter 2.0 framework of Core Areas as the basis for the selection of Core Outcome Domains and hence appropriate Core Outcome Sets for clinical trials.


Distribution of severity of asthma in childhood.
To estimate the distribution of asthma severity in a population-based sample of children from Salvador, Brazil. An epidemiologically oriented questionnaire (International Study of Asthma and Allergies in Childhood, ISAAC) and a questionnaire based on criteria used in clinical practice (The Global Initiative for Asthma, GINA) were administered simultaneously to 417 children aged 5 to 12 years who reported symptoms of asthma in the past 12 months. According to the ISAAC instrument, children were classified into severe and non-severe asthma, whereas GINA clinical criteria produced four categories of severity: intermittent, mild persistent, moderate persistent and severe asthma. Ninety children reported symptoms indicative of severity according to the ISAAC questionnaire. According to GINA criteria, 143 children had intermittent asthma, 160 mild persistent, 51 moderate and 43 severe asthma. Agreement between the two instruments was 81.3% (kappa = 0.5). Most asthmatic children in the Salvador urban area have persistent asthma. Agreement between epidemiological and clinical classifications of asthma severity was satisfactory.


2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative.
The 1987 American College of Rheumatology (ACR; formerly the American Rheumatism Association) classification criteria for rheumatoid arthritis (RA) have been criticised for their lack of sensitivity in early disease. This work was undertaken to develop new classification criteria for RA. A joint working group from the ACR and the European League Against Rheumatism developed, in three phases, a new approach to classifying RA. The work focused on identifying, among patients newly presenting with undifferentiated inflammatory synovitis, factors that best discriminated between those who were and those who were not at high risk for persistent and/or erosive disease--this being the appropriate current paradigm underlying the disease construct 'RA'. In the new criteria set, classification as 'definite RA' is based on the confirmed presence of synovitis in at least one joint, absence of an alternative diagnosis better explaining the synovitis, and achievement of a total score of 6 or greater (of a possible 10) from the individual scores in four domains: number and site of involved joints (range 0-5), serological abnormality (range 0-3), elevated acute-phase response (range 0-1) and symptom duration (two levels; range 0-1). This new classification system redefines the current paradigm of RA by focusing on features at earlier stages of disease that are associated with persistent and/or erosive disease, rather than defining the disease by its late-stage features. This will refocus attention on the important need for earlier diagnosis and institution of effective disease-suppressing therapy to prevent or minimise the occurrence of the undesirable sequelae that currently comprise the paradigm underlying the disease construct 'RA'.


Open-label trial of immunogenicity and safety of a 13-valent pneumococcal conjugate vaccine in adults ≥ 50 years of age in Mexico.
This open-label multicenter clinical trial conducted in Mexico assessed the immunogenicity and safety of a 13-valent pneumococcal conjugate vaccine (PCV13) in adults ≥ 50 years of age not previously vaccinated with the 23-valent pneumococcal polysaccharide vaccine (PPSV23). The PCV13 elicited a robust immune response in this study population, as reflected by the magnitude of fold rises in functional antibody levels measured by serotype-specific opsonophagocytic activity (OPA) assays before and 1 month after vaccination. Although the prevaccination OPA geometric mean titers (GMTs) for the majority of the serotypes were significantly lower in the 50- to 64-year age group than those in the ≥ 65-year age group, the postvaccination immune responses were generally similar. The overall immune responses were higher for the majority of the serotypes in the Mexican study population than those in similar adult study populations who received the PCV13 in Europe and the United States. PCV13 was well tolerated, and there were no vaccine-related serious adverse events. In conclusion, PCV13 is safe and immunogenic when administered to adults ≥ 50 years of age in Mexico and has the potential to protect against vaccine-type pneumococcal disease. (This study has been registered at ClinicalTrials.gov under registration no. NCT01432262.).


A pragmatic randomized clinical trial of behavioral activation for depressed pregnant women.
Depression among pregnant women is a prevalent public health problem associated with poor maternal and offspring development. Behavioral activation (BA) is a scalable intervention aligned with pregnant women's preference for nonpharmacological depression care. This is the first test of the effectiveness of BA for depression among pregnant women, which aimed to evaluate the effectiveness of BA as compared with treatment as usual (TAU). Pregnant women (mean age = 28.75 years; SD = 5.67) with depression symptoms were randomly assigned to BA (n = 86) or TAU (n = 77). Exclusion criteria included known bipolar or psychotic disorder or immediate self-harm risk. Follow-up assessment occurred 5 and 10 weeks postrandomization and 3 months postpartum using self-report measures of primary and secondary outcomes and putative targets. Compared with TAU, BA was associated with significantly lower depressive symptoms (d = 0.34, p = .04) and higher remission (56.3% vs. 30.3%, p = .003). BA also demonstrated significant advantage on anxiety and perceived stress. Participants attended most BA sessions and reported high satisfaction. Participants in BA reported significantly higher levels of activation (d = 0.69, p < .0002) and environmental reward (d = 0.54, p < .003) than those who received TAU, and early change in both of these putative targets significantly mediated subsequent depression outcomes. BA is effective for pregnant women, offering significant depression, anxiety, and stress benefits, with mediation analyses supporting the importance of putative targets of activation and environmental reward. (PsycINFO Database Record


Chronic kidney disease is associated with white matter hyperintensity volume: the Northern Manhattan Study (NOMAS).
White matter hyperintensities have been associated with increased risk of stroke, cognitive decline, and dementia. Chronic kidney disease is a risk factor for vascular disease and has been associated with inflammation and endothelial dysfunction, which have been implicated in the pathogenesis of white matter hyperintensities. Few studies have explored the relationship between chronic kidney disease and white matter hyperintensities. The Northern Manhattan Study is a prospective, community-based cohort of which a subset of stroke-free participants underwent MRIs. MRIs were analyzed quantitatively for white matter hyperintensities volume, which was log-transformed to yield a normal distribution (log-white matter hyperintensity volume). Kidney function was modeled using serum creatinine, the Cockcroft-Gault formula for creatinine clearance, and the Modification of Diet in Renal Disease formula for estimated glomerular filtration rate. Creatinine clearance and estimated glomerular filtration rate were trichotomized to 15 to 60 mL/min, 60 to 90 mL/min, and >90 mL/min (reference). Linear regression was used to measure the association between kidney function and log-white matter hyperintensity volume adjusting for age, gender, race-ethnicity, education, cardiac disease, diabetes, homocysteine, and hypertension. Baseline data were available on 615 subjects (mean age 70 years, 60% women, 18% whites, 21% blacks, 62% Hispanics). In multivariate analysis, creatinine clearance 15 to 60 mL/min was associated with increased log-white matter hyperintensity volume (beta 0.322; 95% CI, 0.095 to 0.550) as was estimated glomerular filtration rate 15 to 60 mL/min (beta 0.322; 95% CI, 0.080 to 0.564). Serum creatinine, per 1-mg/dL increase, was also positively associated with log-white matter hyperintensity volume (beta 1.479; 95% CI, 1.067 to 2.050). The association between moderate-severe chronic kidney disease and white matter hyperintensity volume highlights the growing importance of kidney disease as a possible determinant of cerebrovascular disease and/or as a marker of microangiopathy.


Causal relationship between adiponectin and metabolic traits: a Mendelian randomization study in a multiethnic population.
Adiponectin, a secretagogue exclusively produced by adipocytes, has been associated with metabolic features, but its role in the development of the metabolic syndrome remains unclear. We investigated the association between serum adiponectin level and metabolic traits, using both observational and genetic epidemiologic approaches in a multiethnic population assembled in Canada. Clinical data and serum adiponectin level were collected in 1,157 participants of the SHARE/SHARE-AP studies. Participants were genotyped for the functional rs266729 and rs1260326 SNPs in ADIPOQ and GCKR genes. Adiponectin level was positively associated with HDL cholesterol and negatively associated with body mass index, waist-to-hip ratio, triglycerides, fasting glucose, fasting insulin, systolic and diastolic pressure (all P<0.002). The rs266729 minor G allele was associated with lower adiponectin and higher HOMA-IR (P = 0.004 and 0.003, respectively). The association between rs266729 SNP and HOMA-IR was no longer significant after adjustment for adiponectin concentration (P = 0.10). The rs266729 SNP was associated with HOMA-IR to an extent that exceeded its effect on adiponectin level (0.15 SD 95% C.I. [0.06, 0.24], P<0.001). There was no significant interaction between rs266729 SNP and ethnicity on adiponectin or HOMA-IR. In contrast, the SNP rs1260326 in GCKR was associated with HOMA-IR (P<0.001), but not with adiponectin level (P = 0.67). The association of the functional promoter polymorphism rs266729 with lower serum adiponectin and increased insulin resistance in diverse ethnic groups may suggest a causal relationship between adiponectin level and insulin resistance.


Maternal and fetal risk factors for stillbirth: population based study.
To assess the main risk factors associated with stillbirth in a multiethnic English maternity population. Cohort study. National Health Service region in England. 92,218 normally formed singletons including 389 stillbirths from 24 weeks of gestation, delivered during 2009-11. Risk of stillbirth. Multivariable analysis identified a significant risk of stillbirth for parity (para 0 and para ≥ 3), ethnicity (African, African-Caribbean, Indian, and Pakistani), maternal obesity (body mass index ≥ 30), smoking, pre-existing diabetes, and history of mental health problems, antepartum haemorrhage, and fetal growth restriction (birth weight below 10th customised birthweight centile). As potentially modifiable risk factors, maternal obesity, smoking in pregnancy, and fetal growth restriction together accounted for 56.1% of the stillbirths. Presence of fetal growth restriction constituted the highest risk, and this applied to pregnancies where mothers did not smoke (adjusted relative risk 7.8, 95% confidence interval 6.6 to 10.9), did smoke (5.7, 3.6 to 10.9), and were exposed to passive smoke only (10.0, 6.6 to 15.8). Fetal growth restriction also had the largest population attributable risk for stillbirth and was fivefold greater if it was not detected antenatally than when it was (32.0% v 6.2%). In total, 195 of the 389 stillbirths in this cohort had fetal growth restriction, but in 160 (82%) it had not been detected antenatally. Antenatal recognition of fetal growth restriction resulted in delivery 10 days earlier than when it was not detected: median 270 (interquartile range 261-279) days v 280 (interquartile range 273-287) days. The overall stillbirth rate (per 1000 births) was 4.2, but only 2.4 in pregnancies without fetal growth restriction, increasing to 9.7 with antenatally detected fetal growth restriction and 19.8 when it was not detected. Most normally formed singleton stillbirths are potentially avoidable. The single largest risk factor is unrecognised fetal growth restriction, and preventive strategies need to focus on improving antenatal detection.


Delusional ideation, manic symptomatology and working memory in a cohort at clinical high-risk for psychosis: a longitudinal study.
We followed up a cohort (n=35) of clients with an "At Risk Mental State" (ARMS) for almost 2 years (mean 21.3 months). At baseline, these clients had taken part in research looking at the relationship between reasoning biases, memory, personality styles and delusional ideation. During the follow-up period, clients underwent a package of intervention from a specialist early detection team. Eighty percent (n=28) of these clients were successfully re-interviewed. There was improvement across the cohort as a whole, however five participants (17.9%) had made the transition to psychosis at follow-up. Those who had become psychotic had lower levels of manic symptomatology at baseline than those who did not enter the first episode. Further, across the cohort, impaired working memory and delusional ideation at baseline combined to predict 45% of the delusional ideation at follow-up. These preliminary findings suggest that working memory impairments may be linked to the persistence of delusional ideation and that manic symptoms in someone with an ARMS may suggest that such an individual is less likely to develop a frank psychotic episode.


Multiple sensory neuronal correlates of site-specific sensitization in Aplysia.
Noxious stimulation of a restricted site on the skin of Aplysia (training) causes site-specific sensitization of the tail-withdrawal reflex that is associated with several sensory correlates that are evident both 10 min and 2 hr after training. First, extracellularly recorded afferent activity evoked by test stimulation of the trained site increases, indicating peripheral sensory changes. Second, central sensory alterations are manifested by tail sensory neurons within the pleural VC cluster that innervate the trained site and are activated during training. These mechanosensory/nociceptive cells display a number of differences from unactivated tail sensory neurons innervating other sites: slow depolarization of the soma observed immediately after training, decrease in soma action potential threshold, and enhancement of monosynaptic EPSPs to identified motor neurons. Noxious stimulation of a more extensive region also produces site-specific sensitization of the tail-withdrawal reflex and site-specific enhancement of EPSP amplitude measured 1 d after training. This training produced a novel cellular correlate of behavioral enhancement in Aplysia--regenerative bursting responses (2-35 spikes) in response to brief depolarization of the sensory neuron soma. The changes in peripheral and central excitability appear similar to changes associated with mammalian models of primary hyperalgesia. Site-specific enhancement of nociceptive signaling also occurs during aversive associative conditioning in a noxious unconditioned stimulus (US) pathway. These site-specific changes involve activity-dependent extrinsic modulation (ADEM) of the VC sensory neurons, suggesting a close relationship to changes underlying associative conditioning in conditioned stimulus (CS) pathways in Aplysia.


Intimate partner violence victimisation in early adulthood: psychometric properties of a new measure and gender differences in the Avon Longitudinal Study of Parents and Children.
To evaluate the psychometric properties of a novel, brief measure of physical, psychological and sexual intimate partner violence (IPV) and estimate the overall prevalence of and gender differences in this violence. Data are from the Avon Longitudinal Study of Parents and Children (ALSPAC), a birth-cohort study. Avon, UK. 2128 women and 1145 men who completed the questionnaire assessment at age 21. Participants responded to eight items on physical, psychological and sexual IPV victimisation at age 21. Participants indicated whether the violence occurred before age 18 and/or after and led to any of eight negative impacts (eg, fear). We estimated the prevalence of IPV and tested for gender differences using χ2 or t-tests. We evaluated the IPV victimisation measure based on internal consistency (alpha coefficient), dimensionality (exploratory factor analysis) and convergent validity with negative impacts. Overall, 37% of participants reported experiencing any IPV and 29% experienced any IPV after age 18. Women experienced more frequent IPV, more acts of IPV and more negative impacts than men (p<0.001 for all comparisons). The IPV measure showed high internal consistency (α=0.95), strong evidence for unidimensionality and was highly correlated with negative impacts (r=0.579, p<0.001). The prevalence of IPV victimisation in the ALSPAC cohort was considerable for both women and men. The strong and consistent gender differences in the frequency and severity of IPV suggest clinically meaningful differences in experiences of this violence. The ALSPAC measure for IPV victimisation was valid and reliable, indicating its suitability for further aetiological investigations.


Digital-signal-processor-based dynamic imaging system for optical tomography.
In this article, we introduce a dynamic optical tomography system that is, unlike currently available analog instrumentation, based on digital data acquisition and filtering techniques. At the core of this continuous wave instrument is a digital signal processor (DSP) that collects, collates, processes, and filters the digitized data set. The processor is also responsible for managing system timing and the imaging routines which can acquire real-time data at rates as high as 150 Hz. Many of the synchronously timed processes are controlled by a complex programmable logic device that is also used in conjunction with the DSP to orchestrate data flow. The operation of the system is implemented through a comprehensive graphical user interface designed with LABVIEW software which integrates automated calibration, data acquisition, data organization, and signal postprocessing. Performance analysis demonstrates very low system noise (approximately 1 pW rms noise equivalent power), excellent signal precision (<0.04%-0.2%) and long term system stability (<1% over 40 min). A large dynamic range (approximately 190 dB) accommodates a wide scope of measurement geometries and tissue types. First experiments on tissue phantoms show that dynamic behavior is accurately captured and spatial location can be correctly tracked using this system.


Impact of protein shedding on detection of Mycobacterium avium subsp. paratuberculosis by a whole-cell immunoassay incorporating surface-enhanced Raman scattering.
The etiological agent of Johne's disease is Mycobacterium avium subsp. paratuberculosis. Controlling the spread of this disease is hindered by the lack of sensitive, selective, and rapid detection methods for M. avium subsp. paratuberculosis. By using a recently optimized sandwich immunoassay (B. J. Yakes, R. J. Lipert, J. P. Bannantine, and M. D. Porter, Clin. Vaccine Immunol. 15:227-234, 2008), which incorporates a new monoclonal antibody for the selective capture and labeling of M. avium subsp. paratuberculosis and surface-enhanced Raman scattering for sensitive readout, detection limits of approximately 630 and approximately 740 M. avium subsp. paratuberculosis cells/ml are achieved in phosphate-buffered saline and whole milk samples, respectively, after spiking with heat-treated M. avium subsp. paratuberculosis. Surprisingly, these detection limits are 3 orders of magnitude lower than expected based on theoretical predictions. Experiments designed to determine the origin of the improvement revealed that the major membrane protein targeted by the monoclonal antibody was present in the sample suspensions as shed protein. This finding indicates that the capture and labeling of shed protein function as a facile amplification strategy for lowering the limit of detection for M. avium subsp. paratuberculosis that may also be applicable to the design of a wide range of highly sensitive assays for other cells and viruses.


Identification of host-pathogen-disease relationships using a scalable multiplex serology platform in UK Biobank.
Certain infectious agents are recognised causes of cancer and other chronic diseases. To understand the pathological mechanisms underlying such relationships, here we design a Multiplex Serology platform to measure quantitative antibody responses against 45 antigens from 20 infectious agents including human herpes, hepatitis, polyoma, papilloma, and retroviruses, as well as Chlamydia trachomatis, Helicobacter pylori and Toxoplasma gondii, then assayed a random subset of 9695 UK Biobank participants. We find seroprevalence estimates consistent with those expected from prior literature and confirm multiple associations of antibody responses with sociodemographic characteristics (e.g., lifetime sexual partners with C. trachomatis), HLA genetic variants (rs6927022 with Epstein-Barr virus (EBV) EBNA1 antibodies) and disease outcomes (human papillomavirus-16 seropositivity with cervical intraepithelial neoplasia, and EBV responses with multiple sclerosis). Our accessible dataset is one of the largest incorporating diverse infectious agents in a prospective UK cohort offering opportunities to improve our understanding of host-pathogen-disease relationships with significant clinical and public health implications.


IgG4-related pleural disease with aortitis and submandibular glands involvement successfully treated with corticosteroid: case-based review.
IgG4-related disease (IgG4-RD) is a fibro-inflammatory condition characterized by increased serum IgG4 level, infiltration of lymphocytes and IgG4-positive (IgG4+) plasma cells and fibrosis. It can occur in almost all organs, commonly affecting the pancreas, biliary tract, salivary and lacrimal glands and kidneys. However, reports of IgG4-RD accompanied by pathologically confirmed, IgG4-related pleural disease are scarce. Here, we present a case of a 64-year-old man with suspected malignant pleural mesothelioma based on imaging findings but finally diagnosed with IgG4-RD (including pleuritis, periaortitis and bilateral submandibular gland enlargement) based on a high serum IgG4 level and pleural histopathological findings such as lymphoplasmacytic infiltration including IgG4+ plasma cells and fibrosis. Systemic corticosteroid therapy was effective at reducing serum IgG4, improving bilateral submandibular gland enlargement, and regressing pleural thickening and periaortic soft tissue. We also discuss clinical characteristics and pleural pathological features of previously reported cases with IgG4-related pleural disease based on a comprehensive literature review. Our case of IgG4-RD with pleura, aorta and submandibular gland involvement, pathologically confirmed by pleural specimen might be unique and very rare.


FDA-ARGOS is a database with public quality-controlled reference genomes for diagnostic use and regulatory science.
FDA proactively invests in tools to support innovation of emerging technologies, such as infectious disease next generation sequencing (ID-NGS). Here, we introduce FDA-ARGOS quality-controlled reference genomes as a public database for diagnostic purposes and demonstrate its utility on the example of two use cases. We provide quality control metrics for the FDA-ARGOS genomic database resource and outline the need for genome quality gap filling in the public domain. In the first use case, we show more accurate microbial identification of Enterococcus avium from metagenomic samples with FDA-ARGOS reference genomes compared to non-curated GenBank genomes. In the second use case, we demonstrate the utility of FDA-ARGOS reference genomes for Ebola virus target sequence comparison as part of a composite validation strategy for ID-NGS diagnostic tests. The use of FDA-ARGOS as an in silico target sequence comparator tool combined with representative clinical testing could reduce the burden for completing ID-NGS clinical trials.


Molecular basis of substrate selection by the N-end rule adaptor protein ClpS.
The N-end rule is a conserved degradation pathway that relates the stability of a protein to its N-terminal amino acid. Here, we present crystal structures of ClpS, the bacterial N-end rule adaptor, alone and engaged with peptides containing N-terminal phenylalanine, leucine, and tryptophan. These structures, together with a previous structure of ClpS bound to an N-terminal tyrosine, illustrate the molecular basis of recognition of the complete set of primary N-end rule amino acids. In each case, the alpha-amino group and side chain of the N-terminal residue are the major determinants of recognition. The binding pocket for the N-end residue is preformed in the free adaptor, and only small adjustments are needed to accommodate N-end rule residues having substantially different sizes and shapes. M53A ClpS is known to mediate degradation of an expanded repertoire of substrates, including those with N-terminal valine or isoleucine. A structure of Met53A ClpS engaged with an N-end rule tryptophan reveals an essentially wild-type mechanism of recognition, indicating that the Met(53) side chain directly enforces specificity by clashing with and excluding beta-branched side chains. Finally, experimental and structural data suggest mechanisms that make proteins with N-terminal methionine bind very poorly to ClpS, explaining why these high-abundance proteins are not degraded via the N-end rule pathway in the cell.


'Through my eyes': health-promoting factors described by photographs taken by children with experience of cancer treatment.
Health promotion for children with cancer should be based on the children's own needs and desires. Because there is a lack of knowledge in this area, the aim of this study was to explore what promotes health from the perspective of children with experience of cancer treatment. Fifteen children between 8 and 12 years of age participated in focus groups with three children in each group. The children were given a camera and instructions to photograph subjects that promote their health. Focus group discussions were based on the photographs and the children's own description of those photographs. The analysis of focus group discussions and photographs was conducted using inductive content analysis. According to the children, health-promoting factors are defined as meaningful relationships, recreational activities and a trustful environment. Meaningful relationships include togetherness within the family, affection for pets and friendship with peers. Recreational activities include engagement in play and leisure, withdrawal for relaxation and feeling enjoyment. Trustful environment includes confidence in significant others and feeling safe. Knowledge from this study can contribute to health promotion interventions and quality improvements in the health care of children with experience of cancer treatment. Children's experiences with what promotes health in their everyday lives provide a better understanding of the type of support children prefer when promoting their own health.


PHGDH is required for germinal center formation and is a therapeutic target in MYC-driven lymphoma.
The synthesis of serine from glucose is a key metabolic pathway supporting cellular proliferation in healthy and malignant cells. Despite this, the role that this aspect of metabolism plays in germinal center biology and pathology is not known. Here, we performed a comprehensive characterization of the role of the serine synthesis pathway in germinal center B cells and lymphomas derived from these cells. We demonstrate that upregulation of a functional serine synthesis pathway is a metabolic hallmark of B cell activation and the germinal center reaction. Inhibition of phosphoglycerate dehydrogenase (PHGDH), the first and rate-limiting enzyme in this pathway, led to defective germinal formation and impaired high-affinity antibody production. In addition, overexpression of enzymes involved in serine synthesis was a characteristic of germinal center B cell-derived lymphomas, with high levels of expression being predictive of reduced overall survival in diffuse large B cell lymphoma. Inhibition of PHGDH induced apoptosis in lymphoma cells, reducing disease progression. These findings establish PHGDH as a critical player in humoral immunity and a clinically relevant target in lymphoma.


Using Soil-Applied Fungicides to Manage Phytophthora Crown and Root Rot on Summer Squash.
Phytophthora crown and root rot (Phytophthora capsici) of summer squash is especially difficult to manage because all commercial cultivars are highly susceptible to P. capsici. Producers have traditionally relied on foliar fungicide applications to control Phytophthora crown and root rot despite their limited efficacy. Soil fungicide applications, including via subsurface drip chemigation, have recently gained interest as a method of improving control of P. capsici infections. In this study, soil drenches and foliar applications of 11 fungicides were compared for control of Phytophthora crown and root rot of summer squash in replicated field and greenhouse trials. Fungicides were applied at 7-day intervals. Incidence (%) of plant death was assessed from 7 to 42 days post inoculation (dpi) in field trials. Crown rot severity was rated on a scale of 1 (no wilting) to 5 (plant death) from 5 to 21 dpi in greenhouse trials. Results of field and greenhouse trials were similar. Plant death of 'Cougar' following inoculation with P. capsici isolate 12889 occurred at all growth stages from first true-leaf to full maturity in field trials. Plant death 42 dpi differed significantly (P ≤ 0.0001) among fungicides and application methods. The fungicide-application method interaction also was significant. Some fungicides were ineffective regardless of application method. In general, soil drenches were more effective than foliar applications at limiting plant death but no treatment completely controlled disease symptoms. Mean plant death 42 dpi was 41% for soil drenches and 92% for foliar sprays. Drenches of fluopicolide, mandipropamid, or dimethomorph limited plant death to ≤10% and prevented yield loss associated with root and crown rot. Foliar applications generally did not reduce plant death compared with the untreated, inoculated control, and were unable to prevent yield loss in field trials. In greenhouse trials, crown rot severity differed significantly (P ≤ 0.0001) among fungicides, application methods, and cultivars when plants were inoculated with P. capsici isolate 12889 or SP98. Crown rot was less severe and disease progress was slower following soil drenches than foliar applications. Some fungicide treatments were more effective on 'Leopard,' which was less susceptible to P. capsici than 'Cougar.' Soil application methods, including soil drench and drip chemigation, should be evaluated when fungicides are registered for soilborne disease control, because these methods provide better control of Phytophthora crown and root rot than foliar application.


Lysozyme-magnesium aluminum silicate microparticles: Molecular interaction, bioactivity and release studies.
The objectives of this study were to investigate the adsorption behavior of lysozyme (LSZ) onto magnesium aluminum silicate (MAS) at various pHs and to characterize the LSZ-MAS microparticles obtained from the molecular interaction between LSZ and MAS. The results showed that LSZ could be bound onto the MAS layers at different pHs, leading to the formation of LSZ-MAS microparticles. The higher preparation pH permitted greater adsorption affinity but a lower adsorption capacity of LSZ onto MAS. LSZ could interact with MAS via hydrogen bonds and electrostatic forces, resulting in the formation of intercalated nanocomposites. The particle size, %LSZ adsorbed, and LSZ release rate of LSZ-MAS microparticles increased when the LSZ-MAS ratio was increased. The secondary structure of LSZ bound onto the MAS layers in microparticles prepared at various pHs was altered compared with that of native LSZ. Moreover, the LSZ extracted from microparticles prepared at pH 4 showed an obvious change in the tertiary structure, leading to a decrease in the biological activity of the LSZ released. These findings suggested that LSZ can strongly interact with MAS to form microparticles that may potentially be used as delivery systems for sustained protein release.


Choice of low-pass filter influences practical interpretation of ball kicking motions: the effect of a time-frequency filter method.
When studying ball kicking, conventional low-pass filters may distort kick leg kinematics near the time of foot-to-ball contact, leading to flawed practical interpretation of the skill. Time-frequency filters are a viable alternative but are not widely used. This study compared a fractional Fourier filter (FrFF) with conventional filters (CF) methods for estimating common parameters used to define kicking performance. Instep kicks from 23 experienced soccer players were captured by 3D motion analysis (1000 Hz), and kick leg foot velocities, knee angular velocities and ankle dorsi-plantarflexion angles compared between the FrFF and variations of a Butterworth CF. The FrFF and CFs using a higher cut-off frequency (>70 Hz) successfully detected lower leg motion prior to, during and following impact, whereas CFs with low cut-off frequencies (<20 Hz) attenuated motion near impact. Truncating data at impact provided valid pre-impact kinematics, but ignored information thereafter. Rather than decelerating the lower leg to conserve accuracy, 'kicking through the ball' should be considered a valid coaching cue. Further, controlling ankle plantar flexion to ensure efficient impact mechanics may be important for skilled kicking. Practitioners should consider how choice of filter will affect their data, and use of time-frequency methods can help inform empirically grounded coaching practices.


An influenza A/H1N1/2009 hemagglutinin vaccine produced in Escherichia coli.
The A/H1N1/2009 influenza pandemic made evident the need for faster and higher-yield methods for the production of influenza vaccines. Platforms based on virus culture in mammalian or insect cells are currently under investigation. Alternatively, expression of fragments of the hemagglutinin (HA) protein in prokaryotic systems can potentially be the most efficacious strategy for the manufacture of large quantities of influenza vaccine in a short period of time. Despite experimental evidence on the immunogenic potential of HA protein constructs expressed in bacteria, it is still generally accepted that glycosylation should be a requirement for vaccine efficacy. We expressed the globular HA receptor binding domain, referred to here as HA(63-286)-RBD, of the influenza A/H1N1/2009 virus in Escherichia coli using a simple, robust and scalable process. The recombinant protein was refolded and purified from the insoluble fraction of the cellular lysate as a single species. Recombinant HA(63-286)-RBD appears to be properly folded, as shown by analytical ultracentrifugation and bio-recognition assays. It binds specifically to serum antibodies from influenza A/H1N1/2009 patients and was found to be immunogenic, to be capable of triggering the production of neutralizing antibodies, and to have protective activity in the ferret model. Projections based on our production/purification data indicate that this strategy could yield up to half a billion doses of vaccine per month in a medium-scale pharmaceutical production facility equipped for bacterial culture. Also, our findings demonstrate that glycosylation is not a mandatory requirement for influenza vaccine efficacy.


Below the belt: approach to chronic pelvic pain.
To present a practical approach to the symptom complex called chronic pelvic pain (CPP). Chronic pelvic pain is defined as nonmenstrual pain lasting 6 months or more that is severe enough to cause functional disability or require medical or surgical treatment. MEDLINE, EMBASE, and the Cochrane Database of Systematic Reviews were searched from January 1996 to December 2004. While the source of pain in CPP can be gynecologic, urologic, gastrointestinal, musculoskeletal, or psychoneurologic, 4 conditions account for most CPP: endometriosis, adhesions, interstitial cystitis, and irritable bowel syndrome. More than one source of pain can be found in the same patient. Management involves treating the underlying condition, the pain itself, or both. Nonnarcotic analgesics are first-line therapy for pain relief; hormonal therapies are beneficial if the pain has a cyclical component. A multidisciplinary approach addressing environmental factors and incorporating medical management with physiotherapy, psychotherapy, and dietary modifications works best. Although caring for patients with CPP can be challenging and frustrating, family physicians are in an ideal position to manage and coordinate their care.


Differential display analysis of gene expression indicates that age-related changes are restricted to a small cohort of genes.
It is clear that there is a genetic component associated with the ageing process. Although evolutionary theory has suggested that the activity of certain genes may facilitate ageing by favouring resource utilisation by the germ cells at the expense of somatic cells, there is reason to believe that the senescent phenotype, which is the endpoint of the ageing process, may be due to alterations in the levels of expression of other genes. To investigate this situation we have used the differential display technique to survey gene expression during ageing of the rat brain, heart and liver. By optimising this technique it is possible to identify up to 10000-14000 PCR products, which represent genes expressed in the tissue under study. Interestingly, only a relatively small cohort (approximately 2%) of these genes appear to show significant changes in their levels of expression during ageing. Characterisation of the latter has so far revealed certain genes, such as glial fibrillary acidic protein, which are associated with the senescent phenotype. It has also revealed that the level of fos, a component of the AP-1 transcription factor, decreases with age, which has implications for AP-1 regulated genes. The differential display technique has also revealed an increase in mitochondrial RNA during ageing of the heart, which may be due to a gene dosage effect caused by the presence of increased numbers of mitochondrial genomes in myocytes in old age. The differential display technique therefore appears to offer a powerful tool for identifying genes which contribute to the emergence of a senescent phenotype.


Improved field emission performance of carbon nanotube by introducing copper metallic particles.
To improve the field emission performance of carbon nanotubes (CNTs), a simple and low-cost method was adopted in this article. We introduced copper particles for decorating the CNTs so as to form copper particle-CNT composites. The composites were fabricated by electrophoretic deposition technique which produced copper metallic particles localized on the outer wall of CNTs and deposited them onto indium tin oxide (ITO) electrode. The results showed that the conductivity increased from 10-5 to 4 × 10-5 S while the turn-on field was reduced from 3.4 to 2.2 V/μm. Moreover, the field emission current tended to be undiminished after continuous emission for 24 h. The reasons were summarized that introducing copper metallic particles to decorate CNTs could increase the surface roughness of the CNTs which was beneficial to field emission, restrain field emission current from saturating when the applied electric field was above the critical field. In addition, it could also improve the electrical contact by increasing the contact area between CNT and ITO electrode that was beneficial to the electron transport and avoided instable electron emission caused by thermal injury of CNTs.


Reprogramming of skeletal myoblasts for induction of pluripotency for tumor-free cardiomyogenesis in the infarcted heart.
Skeletal myoblasts (SMs) with inherent myogenic properties are better candidates for reprogramming to pluripotency. To reprogram SMs to pluripotency and show that reprogrammed SMs (SiPS) express embryonic gene and microRNA profiles and that transplantation of predifferentiated cardiac progenitors reduce tumor formation. The pMXs vector containing mouse cDNAs for Yamanaka's quartet of stemness factors were used for transduction of SMs purified from male Oct4-GFP(+) transgenic mouse. Three weeks later, GFP(+) colonies of SiPS were isolated and propagated in vitro. SiPS were positive for alkaline phosphatase, expressed SSEA1, and displayed a panel of embryonic stem (ES) cell-specific pluripotency markers. Embryoid body formation yielded beating cardiomyocyte-like cells, which expressed early and late cardiac-specific markers. SiPS also had an microRNA profile that was altered during their cardiomyogenic differentiation. Noticeable abrogation of let-7 family and significant up-regulation of miR-200a-c was observed in SiPS and SiPS-derived cardiomyocytes, respectively. In vivo studies in an experimental model of acute myocardial infarction showed extensive survival of SiPS and SiPS-derived cardiomyocytes in mouse heart after transplantation. Our results from 4-week studies in DMEM without cells (group 1), SMs (group-2), SiPS (group-3), and SiPS-derived cardiomyocytes (group 4) showed extensive myogenic integration of the transplanted cells in group 4 with attenuated infarct size and improved cardiac function without tumorgenesis. Successful reprogramming was achieved in SMs with ES cell-like microRNA profile. Given the tumorgenic nature of SiPS, their predifferentiation into cardiomyocytes would be important for tumor-free cardiogenesis in the heart.


Maternal factors and monoamine changes in stress-resilient and susceptible mice: cross-fostering effects.
Genetic factors influence stressor-provoked monoamine changes associated with anxiety and depression, but such effects might be moderated by early life experiences. To assess the contribution of maternal influences in determining adult brain monoamine responses to a stressor, strains of mice that were either stressor-reactive or -resilient (BALB/cByJ and C57BL/6ByJ, respectively) were assessed as a function of whether they were raising their biological offspring or those of the other strain. As adults, offspring were assessed with respect to stressor-provoked plasma corticosterone elevations and monoamine variations within discrete stressor-sensitive brain regions. BALB/cByJ mice demonstrated poorer maternal behaviors than C57BL/6ByJ dams, irrespective of the pups being raised. In response to a noise stressor, BALB/cByJ mice exhibited higher plasma corticosterone levels and elevated monoamine turnover in several limbic and hypothalamic sites. The stressor-provoked corticosterone increase in BALB/cByJ mice was diminished among males (but not females) raised by a C57BL/6ByJ dam. Moreover, increased prefrontal cortical dopamine utilization was attenuated among BALB/cByJ mice raised by a C57BL/6ByJ dam. These effects were asymmetrical as a C57BL/6ByJ mice raised by a BALB/cByJ dam did not exhibit increased stressor reactivity. It appears that stressors influence multiple neurochemical systems that have been implicated in anxiety and affective disorders. Although monoamine variations were largely determined by genetic factors, maternal influences contributed to stressor-elicited neurochemical changes in some regions, particularly dopamine activation within the prefrontal cortex.


[Multisystemic involvement in obstructive sleep apnea].
Obstructive Sleep Apnea (OSA) is characterized by repetitive upper airway collapse with apnea/hypopnea and recurrent hypoxia during sleep, which results in fragmented sleep and intermittent drops in arterial blood oxygen saturation (hypoxemia). Several dysfunctions of neurocognitive, endocrine, cardiovascular, and metabolic systems are recognized in patients with OSA. The most commonly reported associations are with obesity, increased cardiovascular risk, dyslipidemia, diabetes mellitus 2 and liver damage. However, there is a proven relationship between OSA and other diseases, such as polycystic ovary syndrome, gastroesophageal reflux, and chronic kidney disease. The aim of this review is to analyze clinical and experimental evidence linking OSA with other diseases.


The trans-Golgi network GRIP-domain proteins form alpha-helical homodimers.
A recently described family of TGN (trans-Golgi network) proteins, all of which contain a GRIP domain targeting sequence, has been proposed to play a role in membrane transport. On the basis of the high content of heptad repeats, GRIP domain proteins are predicted to contain extensive coiled-coil regions that have the potential to mediate protein-protein interactions. Four mammalian GRIP domain proteins have been identified which are targeted to the TGN through their GRIP domains, namely p230, golgin-97, GCC88 and GCC185. In the present study, we have investigated the ability of the four mammalian GRIP domain proteins to interact. Using a combination of immunoprecipitation experiments of epitope-tagged GRIP domain proteins, cross-linking experiments and yeast two-hybrid interactions, we have established that the GRIP proteins can self-associate to form homodimers exclusively. Two-hybrid analysis indicated that the N- and C-terminal fragments of GCC88 can interact with themselves but not with each other, suggesting that the GRIP domain proteins form parallel coiled-coil dimers. Analysis of purified recombinant golgin-97 by CD spectroscopy indicated a 67% alpha-helical structure, consistent with a high content of coiled-coil sequences. These results support a model for GRIP domain proteins as extended rod-like homodimeric molecules. The formation of homodimers, but not heterodimers, indicates that each of the four mammalian TGN golgins has the potential to function independently.


Phase II trial of gefitinib in combination with bevacizumab as first-line therapy for advanced non-small cell lung cancer with activating EGFR gene mutations: the Okayama Lung Cancer Study Group Trial 1001.
Whether bevacizumab enhances the effect of the epidermal growth factor receptor (EGFR) inhibitor gefitinib on EGFR mutant non-small cell lung cancers (NSCLCs) remains unknown. We conducted a phase II trial to investigate the efficacy and safety of gefitinib when combined with bevacizumab as first-line therapy in patients with advanced NSCLC harboring EGFR gene mutations. In this trial, 42 patients with a performance status of 0 to 2 received gefitinib (250 mg/d) and bevacizumab (15 mg/kg, every 3 weeks). The primary end point of this study was the 1-year progression-free survival (PFS) rate. We assumed that a 1-year PFS rate of 55% would indicate potential usefulness and that a 1-year PFS rate of 40% would constitute the lower limit of interest. Forty-two patients were enrolled in the study with a median age of 73 (range 42-86) years. Activating EGFR gene mutations included exon 19 deletion (57%) and L858R point mutations in exon 21 (38%). The objective response rate was 73.8% and included two complete responses. The 1-year PFS rate and median PFS time were 56.7% (95% confidence interval [CI] 39.9-70.5) and 14.4 months (95% CI 10.1-19.2), respectively. The median PFS differed significantly between EGFR exon 19 deletion and the L858R point mutation (18.0 versus 9.4 months, respectively; p = 0.006). The median overall survival had not yet been reached. Severe adverse events included grade 3 skin rash (15%), hypertension (17%), aspartate transaminase/alanine aminotransferase elevation (17%), proteinuria (7%), intracranial hemorrhage (2%), and grade 4 perforation of the digestive tract (2%). There were no treatment-related deaths. Gefitinib in combination with bevacizumab as first-line therapy seems to be a favorable and well-tolerated treatment for patients with advanced NSCLC with activating EGFR gene mutations, especially those with EGFR exon 19 deletion mutations, although the primary end point was not met because the lower limit of the CI was less than 40%.


Replication occurs at discrete foci spaced throughout nuclei replicating in vitro.
Demembranated Xenopus sperm nuclei were induced to replicate synchronously in a low-speed supernatant (LSS) of Xenopus eggs by preincubation in a high-speed supernatant (HSS). DNA replication was observed by incorporation of [alpha-32P]dATP, BrdUTP or biotin-dUTP. Biotin-dUTP incorporation, visualised with fluorescent streptavidin, reveals a striking pattern of replication foci throughout replicating nuclei. We show that this represents a precursor to the bright uniform fluorescence seen later. Confocal microscopic analysis of nuclei fixed early in replication reveals that these foci of DNA replication number about 100-300 for each nucleus and probably represent the replicon clusters already described for tissue culture cells. Foci are evenly distributed throughout the nuclei and are not concentrated at or near the nuclear envelope. Complete replication of each nucleus occurs in an average time of only one hour in this system. Hence we calculate that there must be at least 300-1000 replication forks together in each cluster. Furthermore, pulse labelling at later times in the period of replication reveals a similar pattern of foci indicating that replication forks remain tightly clustered in groups of at least 300 throughout the period of DNA replication.