Parental well-being, couple relationship quality, and children's behavioral problems in the first 2 years of life.
Adverse effects of early exposure to parental mood disturbance on child adjustment have been documented for both mothers and fathers, but are rarely examined in tandem. Other under-researched questions include effects of changes over time in parental well-being, similarities and contrasts between effects of parental mood disturbance on children's internalizing versus externalizing problems, and potential mediating effects of couple relationship quality. The current study involved 438 couples who reported symptoms of depression and anxiety at each of four time points (i.e., last trimester of pregnancy and 4, 14, and 24 months postbirth). Mothers and fathers also rated their couple relationship quality and their child's socioemotional adjustment at 14 months, as well as internalizing and externalizing problems at 24 months. Latent growth models indicated direct effects of (a) maternal prenatal well-being on externalizing problems at 24 months, and (b) paternal prenatal well-being on socioemotional problems at 14 months. Internalizing symptoms at 24 months showed only indirect associations with parental well-being, with couple relationship quality playing a mediating role. Our findings highlight the importance of prenatal exposure to parental mood disturbance and demonstrate that, even in a low-risk sample, poor couple relationship quality explains the intergenerational stability of internalizing problems.


Pre-conditioning of smooth muscle cells via induction of the heat shock response limits proliferation following mechanical injury.
Arterial smooth muscle cell (SMC) proliferation is a significant component of post-angioplasty restenosis. We evaluated whether pre-conditioning of SMCs, via induction of the heat shock response prior to actual physical injury, would result in an alteration in cell proliferation following injury. Rat aortic SMCs were pretreated with either chemical or thermal heat shock inducers and then subjected to scrape-wound injury in vitro. Cell proliferation at 24 hrs was measured via 3H-thymidine (Tdr) incorporation and compared with scrape wounded unstressed controls. A significant decline in cell proliferation post scrape-wound injury was observed for both chemical and thermal heat shock pre-conditioned cultures, compared to untreated controls. Increased expression of heat shock protein 72 was confirmed serially throughout the 24 hr study period for both chemical and thermal inducers. Despite reduced proliferation heat shocked cells remained viable as evidenced by fluorescent cell viability assay and preserved migration. Pre-conditioning of SMCs through induction of the heat shock response prior to physical injury may be a useful approach to limit aggressive proliferation observed with mechanical revascularization injury.


Pro-inflammatory flagellin proteins of prevalent motile commensal bacteria are variably abundant in the intestinal microbiome of elderly humans.
Some Eubacterium and Roseburia species are among the most prevalent motile bacteria present in the intestinal microbiota of healthy adults. These flagellate species contribute "cell motility" category genes to the intestinal microbiome and flagellin proteins to the intestinal proteome. We reviewed and revised the annotation of motility genes in the genomes of six Eubacterium and Roseburia species that occur in the human intestinal microbiota and examined their respective locus organization by comparative genomics. Motility gene order was generally conserved across these loci. Five of these species harbored multiple genes for predicted flagellins. Flagellin proteins were isolated from R. inulinivorans strain A2-194 and from E. rectale strains A1-86 and M104/1. The amino-termini sequences of the R. inulinivorans and E. rectale A1-86 proteins were almost identical. These protein preparations stimulated secretion of interleukin-8 (IL-8) from human intestinal epithelial cell lines, suggesting that these flagellins were pro-inflammatory. Flagellins from the other four species were predicted to be pro-inflammatory on the basis of alignment to the consensus sequence of pro-inflammatory flagellins from the β- and γ- proteobacteria. Many fliC genes were deduced to be under the control of σ(28). The relative abundance of the target Eubacterium and Roseburia species varied across shotgun metagenomes from 27 elderly individuals. Genes involved in the flagellum biogenesis pathways of these species were variably abundant in these metagenomes, suggesting that the current depth of coverage used for metagenomic sequencing (3.13-4.79 Gb total sequence in our study) insufficiently captures the functional diversity of genomes present at low (≤1%) relative abundance. E. rectale and R. inulinivorans thus appear to synthesize complex flagella composed of flagellin proteins that stimulate IL-8 production. A greater depth of sequencing, improved evenness of sequencing and improved metagenome assembly from short reads will be required to facilitate in silico analyses of complete complex biochemical pathways for low-abundance target species from shotgun metagenomes.


The eukaryotic translation initiation factor eIF4E unexpectedly acts in splicing thereby coupling mRNA processing with translation: eIF4E induces widescale splicing reprogramming providing system-wide connectivity between splicing, nuclear mRNA export and translation.
Recent findings position the eukaryotic translation initiation factor eIF4E as a novel modulator of mRNA splicing, a process that impacts the form and function of resultant proteins. eIF4E physically interacts with the spliceosome and with some intron-containing transcripts implying a direct role in some splicing events. Moreover, eIF4E drives the production of key components of the splicing machinery underpinning larger scale impacts on splicing. These drive eIF4E-dependent reprogramming of the splicing signature. This work completes a series of studies demonstrating eIF4E acts in all the major mRNA maturation steps whereby eIF4E drives production of the RNA processing machinery and escorts some transcripts through various maturation steps. In this way, eIF4E couples the mRNA processing-export-translation axis linking nuclear mRNA processing to cytoplasmic translation. eIF4E elevation is linked to worse outcomes in acute myeloid leukemia patients where these activities are dysregulated. Understanding these effects provides new insight into post-transcriptional control and eIF4E-driven cancers.


Seasonal flows on warm Martian slopes.
Water probably flowed across ancient Mars, but whether it ever exists as a liquid on the surface today remains debatable. Recurring slope lineae (RSL) are narrow (0.5 to 5 meters), relatively dark markings on steep (25° to 40°) slopes; repeat images from the Mars Reconnaissance Orbiter High Resolution Imaging Science Experiment show them to appear and incrementally grow during warm seasons and fade in cold seasons. They extend downslope from bedrock outcrops, often associated with small channels, and hundreds of them form in some rare locations. RSL appear and lengthen in the late southern spring and summer from 48°S to 32°S latitudes favoring equator-facing slopes, which are times and places with peak surface temperatures from ~250 to 300 kelvin. Liquid brines near the surface might explain this activity, but the exact mechanism and source of water are not understood.


Combined ultrasound and isotope scanning is more informative in the diagnosis of congenital hypothyroidism than single scanning.
Thyroid imaging is helpful in confirming the diagnosis of congenital hypothyroidism and in establishing the aetiology. Although isotope scanning is the standard method of imaging, ultrasound assessment may be complementary. To determine the strengths and weaknesses of thyroid ultrasound and isotope scanning in neonates with thyroid stimulating hormone (TSH) elevation. Babies from the West of Scotland with raised capillary TSH (>15 mU/l) on neonatal screening between January 1999 and 2004 were recruited. Thyroid dimensions were measured using ultrasonography, and volumes were calculated. Isotope scanning was carried out with a pinhole collimator after an intravenous injection of 99m-technetium pertechnetate. 40 infants (29 female) underwent scanning at a median of 17 days (range 12 days to 15 months). The final diagnosis was athyreosis (n = 11), ectopia (n = 12), hypoplasia (n = 8; 3 cases of hemi-agenesis), dyshormonogenesis (n = 5), transient hypothyroidism (n = 2), transient hyperthyrotropinaemia (n = 1) and uncertain status with gland in situ (n = 1). 6 infants had discordant scans with no isotope uptake but visualisation of thyroid tissue on ultrasound. This was attributed to TSH suppression from thyroxine (n = 3); maternal blocking antibodies (n = 1); cystic degeneration of the thyroid (n = 1); and possible TSH receptor defect (n = 1). Isotope scanning was superior to ultrasound in the detection of ectopic tissue. However, ultrasound detected tissue that was not visualised on isotope scanning, and showed abnormalities of thyroid volume and morphology. We would therefore advocate dual scanning in newborns with TSH elevation as each modality provides different information.


Epithelia of the ovine and bovine forestomach express basolateral maxi-anion channels permeable to the anions of short-chain fatty acids.
It has long been established that the absorption of short-chain fatty acids (SCFA) across epithelia stimulates sodium proton exchange. The apically released protons are not available as countercations for the basolateral efflux of SCFA anions and a suitable transport model is lacking. Patch clamp and microelectrode techniques were used to characterize an anion conductance expressed by cultured cells of the sheep and bovine rumen and the sheep omasum and to localize the conductance in the intact tissue. Cells were filled with a Na-gluconate solution and superfused with sodium salts of acetate, propionate, butyrate, or lactate. Reversal potential rose and whole cell current at +100 mV decreased with the size of the anion. Anion-induced currents could be blocked by diisothiocyanato-stilbene-2,2'-disulfonic acid (DIDS), NPPB (200 μmol l(-1)), or pCMB (1 mmol l(-1)). In patches of bovine ruminal cells, single channels were observed with a conductance for chloride (327 ± 11 pS), acetate (115 ± 8 pS), propionate (102 ± 10 pS), butyrate (81 ± 2 pS), and gluconate (44 ± 3 pS). Channels expressed by sheep rumen and omasum were similar. Microelectrode experiments suggest basolateral localization. In conclusion, forestomach epithelia express basolateral maxi-anion channels with a permeability sequence of chloride > acetate > propionate > butyrate. SCFA absorption may resemble functionally coupled transport of NaCl, with the Na(+)/K(+)-ATPase driving the basolateral efflux of the anion through a channel. Since protons are apically extruded, the model accurately predicts that influx of buffers with saliva is essential for the pH homeostasis of the ruminant forestomach.


Electronic structure, optical and photocatalytic performance of SiC-MX2 (M = Mo, W and X = S, Se) van der Waals heterostructures.
The stacking of monolayers in the form of van der Waals heterostructures is a useful strategy for band gap engineering and the control of dynamics of excitons for potential nano-electronic devices. We performed first-principles calculations to investigate the structural, electronic, optical and photocatalytic properties of the SiC-MX2 (M = Mo, W and X = S, Se) van der Waals heterostructures. The stability of most favorable stacking is confirmed by calculating the binding energy and phonon spectrum. SiC-MoS2 is found to be a direct band gap type-II semiconducting heterostructure. Moderate in-plane tensile strain is used to achieve a direct band gap with type-II alignment in the SiC-WS2, SiC-MoSe2 and SiC-WSe2 heterostructures. A difference in the ionization potential of the corresponding monolayers and interlayer charge transfer further confirmed the type-II band alignment in these heterostructures. Furthermore, the optical behaviour is investigated by calculation of the absorption spectra in terms of ε2(ω) of the heterostructures and the corresponding monolayers. The photocatalytic response shows that the SiC-Mo(W)S2 heterostructures can oxidize H2O to O2. An enhanced photocatalytic performance with respect to the parent monolayers makes the SiC-Mo(W)Se2 heterostructures promising candidates for water splitting.


Familial risk for lifestyle-related chronic diseases: can family health history be used as a motivational tool to promote health behaviour in young adults?
Risk for colorectal cancer, breast cancer, heart disease and diabetes has both a familial and a lifestyle component. This quasi-experimental study aimed to determine whether a Family Health History (FHH) assessment and the subsequent provision of risk information would increase young adults' (17-29 years) intentions to modify health behaviours associated with the risk of these chronic diseases (i.e. alcohol consumption, fruit and vegetable intake and physical activity) and to talk to their family about their risk. After baseline measures of current and intended health-related behaviours, participants (n = 116) were randomly allocated to either a FHH assessment or control information. Based on the FHH provided, participants in the FHH condition were then classified as 'above-average risk' or 'average risk'. One week later, participants were provided with tailored health information and completed follow-up measures of intended health-related behaviours and perceived vulnerability. Participants classified as 'above-average risk' had increased perceptions of vulnerability to a chronic disease. Despite this, no group differences were found in intentions to change physical activity or fruit and vegetable consumption. Participants with above-average risk reported greater intentions to decrease the frequency of their alcohol consumption than average risk/control participants. In addition, completing a FHH assessment promoted intended communication with family members about chronic disease risk. FHH assessments may have the greatest value within the family context. SO WHAT? Future research could examine the impact of providing FHH information to different family members as a health promotion strategy.


Molecular defect in siblings with prolidase deficiency and absence or presence of clinical symptoms. A 0.8-kb deletion with breakpoints at the short, direct repeat in the PEPD gene and synthesis of abnormal messenger RNA and inactive polypeptide.
Prolidase deficiency is an autosomal recessive disorder with highly variable symptoms, including mental retardation, skin lesions, and abnormalities of collagenous tissues. In Japanese female siblings with polypeptide negative prolidase deficiency, and with different degrees of severity of skin lesions, we noted an abnormal mRNA with skipping of 192 bp sequence corresponding to exon 14 in lymphoblastoid cells taken from these patients. Transfection and expression analyses using the mutant prolidase cDNA revealed that a mutant protein translated from the abnormal mRNA had an Mr of 49,000 and was enzymatically inactive. A 774-bp deletion, including exon 14 was noted in the prolidase gene. The deletion had termini within short, direct repeats ranging in size of 7 bp (CCACCCT). The "slipped mispairing" mechanism may predominate in the generation of the deletion at this locus. This mutation caused a 192-bp in-frame deletion of prolidase mRNA and was inherited from the consanguineous parents. The same mutation caused a different degree of clinical phenotype of prolidase deficiency in this family, therefore factor(s) not related to the PEPD gene product also contribute to development of the clinical symptoms. Identification of mutations in the PEPD gene from subjects with prolidase deficiency provides further insight into the physiological role and structure-function relationship of this biologically important enzyme.


Binding of the human retrovirus HTLV-III/LAV/ARV/HIV to the CD4 (T4) molecule: conformation dependence, epitope mapping, antibody inhibition, and potential for idiotypic mimicry.
Human immunodeficiency virus (HIV), the retrovirus that causes the acquired immunodeficiency syndrome, is cytopathic for CD4+ T cells and binds to these cells via a complex of the 110,000 m.w. viral-envelope glycoprotein, gp110, and the CD4 molecule. We treated virus with several physical, chemical, and enzymic agents to determine their effect on the capacity of HIV to bind to the CD4+ T cell line, CEM. Reduction and alkylation (but not alkylation alone) and trypsin digestion (but not glycolytic enzyme digestions) of HIV destroyed its capacity to bind. If the tertiary protein structure conferred by disulfide bonding is not disrupted, the tertiary and secondary conformations dependent on noncovalent forces appear to be thermodynamically favored, because treatment with denaturants such as sodium dodecyl sulfate, 8 M urea, alcohol, or heat (56 degrees C or 65 degrees C for 30 min) followed by removal of the denaturants did not affect binding. Irreversible denaturation and loss of binding occurred after heating at 100 degrees C for 10 min. HIV binding to CD4+ T cells was inhibited either by murine monoclonal antibodies to the CD4 molecule or by human polyclonal or murine monoclonal antibodies to the gp110 molecule. On the basis of results of binding inhibition obtained with a panel of alpha-CD4 monoclonal antibodies, the receptor site for virus on the CD4 molecule was mapped to the amino-terminal portion of the molecule. Four candidate alpha-CD4 monoclonal antibodies that were potent inhibitors of virus binding (OKT4A, OKT4D, OKT4F, and Leu-3a) were examined for the possibility that their binding sites (idiotopes) might share structural and conformational similarity with the CD4-binding site on gp110. Polyclonal human or rabbit anti-HIV sera (that reacted with gp110 and inhibited virus binding) did not react with or inhibit the binding of these four alpha-CD4 monoclonal antibodies. Conversely, rabbit anti-idiotypic sera raised against each of the four candidate CD4 monoclonal antibodies did not react with virus or inhibit virus binding to CD4+ T cells. Further search or different approaches may yet yield an idiotype that is a structural and conformational "internal image" of the CD4-binding site of virus.


The Reliance on Vestibular Information During Standing Balance Control Decreases With Severity of Vestibular Dysfunction.
The vestibular system is involved in gaze stabilization and standing balance control. However, it is unclear whether vestibular dysfunction affects both processes to a similar extent. Therefore, the objective of this study was to determine how the reliance on vestibular information during standing balance control is related to gaze stabilization deficits in patients with vestibular dysfunction. Eleven patients with vestibular dysfunction and twelve healthy subjects were included. Gaze stabilization deficits were established by spontaneous nystagmus examination, caloric test, rotational chair test, and head impulse test. Standing balance control was assessed by measuring the body sway (BS) responses to continuous support surface rotations of 0.5° and 1.0° peak-to-peak while subjects had their eyes closed. A balance control model was fitted on the measured BS responses to estimate balance control parameters, including the vestibular weight, which represents the reliance on vestibular information. Using multivariate analysis of variance, balance parameters were compared between patients with vestibular dysfunction and healthy subjects. Robust regression was used to investigate correlations between gaze stabilization and the vestibular weight. Our results showed that the vestibular weight was smaller in patients with vestibular dysfunction than in healthy subjects (F = 7.67, p = 0.011). The vestibular weight during 0.5° peak-to-peak support surface rotations decreased with increasing spontaneous nystagmus eye velocity (ρ = -0.82, p < 0.001). In addition, the vestibular weight during 0.5° and 1.0° peak-to-peak support surface rotations decreased with increasing ocular response bias during rotational chair testing (ρ = -0.72, p = 0.02 and ρ = -0.67, p = 0.04, respectively). These findings suggest that the reliance on vestibular information during standing balance control decreases with the severity of vestibular dysfunction. We conclude that particular gaze stabilization tests may be used to predict the effect of vestibular dysfunction on standing balance control.


The acute care nurse practitioner in collaborative practice.
Nurse-physician relationships remain, for the most part, hierarchical in nature. A hierarchical structure allows the person at the top, most notably the physician, the highest level of authority and power for decision making. Other health care providers are delegated various tasks related to the medical plan of care. One role of nonmedical health care providers, including nurses, is to support the medical plan of care and increase the productivity of physicians. Medical centers have house staff, usually interns and residents, who work collaboratively with the attending physicians in care delivery. At one medical center, a shortage of medical house staff for internal medicine prompted the development and evaluation of an alternative service. The alternative service utilized master prepared, certified nurse practitioners on a nonteaching service to provide care for selected types of medical patients. Physicians consulted with nurse practitioners, but retained decision-making authority concerning patient admission to the service. This paper describes the development and evaluation of an alternative service based on a collaborative practice model and the role of nurse practitioners working under such a model. Discussion includes suggestions for process guideline development for organizations that want to improve collaborative practice relationships between unit nursing staff, nurse practitioners, and physicians.


Long-distance perturbation on Schiff base-counterion interactions by His30 and the extracellular Na+-binding site in Krokinobacter rhodopsin 2.
Krokinobacter rhodopsin 2 (KR2), a light-driven Na+ pump, is a dual-functional protein, pumping protons in the absence of Na+ when K+ or larger alkali metal ions are present. A specific mutation in helix A near the extracellular Na+ binding site, H30A, eliminates its proton pumping ability. We induced structural changes in H30A by altering the alkali metal ion bound at the extracellular binding site, and observed a strong electrostatic interaction between the Schiff base and counterion and torsion around the Schiff base as revealed by solid-state nuclear magnetic resonance (NMR) and Fourier transform infrared (FTIR) spectroscopies. The strong interaction when His30 was absent and no ion bound at the extracellular binding site disabled retinal reisomerization, as was shown with flash-photolysis, forming a small amount of only a K-like intermediate. This revealed why H30A lacks the proton pumping function. Long-distance perturbation of the binding site and Schiff base revealed that a non-transported ion binding at the extracellular site is essential for pumping.


Climate change in our backyards: the reshuffling of North America's winter bird communities.
Much of the recent changes in North American climate have occurred during the winter months, and as result, overwintering birds represent important sentinels of anthropogenic climate change. While there is mounting evidence that bird populations are responding to a warming climate (e.g., poleward shifts) questions remain as to whether these species-specific responses are resulting in community-wide changes. Here, we test the hypothesis that a changing winter climate should favor the formation of winter bird communities dominated by warm-adapted species. To do this, we quantified changes in community composition using a functional index--the Community Temperature Index (CTI)--which measures the balance between low- and high-temperature dwelling species in a community. Using data from Project FeederWatch, an international citizen science program, we quantified spatiotemporal changes in winter bird communities (n = 38 bird species) across eastern North America and tested the influence of changes in winter minimum temperature over a 22-year period. We implemented a jackknife analysis to identify those species most influential in driving changes at the community level and the population dynamics (e.g., extinction or colonization) responsible for these community changes. Since 1990, we found that the winter bird community structure has changed with communities increasingly composed of warm-adapted species. This reshuffling of winter bird communities was strongest in southerly latitudes and driven primarily by local increases in abundance and regional patterns of colonization by southerly birds. CTI tracked patterns of changing winter temperature at different temporal scales ranging from 1 to 35 years. We conclude that a shifting winter climate has provided an opportunity for smaller, southerly distributed species to colonize new regions and promote the formation of unique winter bird assemblages throughout eastern North America.


Interlimb transfer of novel inertial dynamics is asymmetrical.
Mechanisms underlying interlimb transfer of adaptation to visuomotor rotations have recently been explored in depth. However, little data are available regarding interlimb transfer of adaptation to novel inertial dynamics. The present study thus investigated interlimb transfer of dynamics by examining the effect of initial training with one arm on subsequent performance with the other in adaptation to a 1.5-kg mass attached eccentrically to the forearm. Using inverse dynamic analysis, we examined the changes in torque strategies associated with adaptation to the extra mass, and with interlimb transfer of that adaptation. Following initial training with the dominant arm, nondominant arm performance improved substantially in terms of linearity and initial direction control as compared with naïve performance. However, initial training with the nondominant arm had no effect on subsequent performance with the dominant arm. Inverse dynamic analysis revealed that improvements in kinematics were implemented by increasing flexor muscle torques at the elbow to counter load-induced increases in extensor interaction torques as well as increasing flexor muscle torques at the shoulder to counter the extensor actions of elbow muscle torque. Following opposite arm adaptation, the nondominant arm adopted this dynamic strategy early in adaptation. These findings suggest that dominant arm adaptation to novel inertial dynamics leads to information that can be accessed and utilized by the opposite arm controller, but not vice versa. When compared with our previous findings on interlimb transfer of visuomotor rotations, our current findings suggest that adaptations to visuomotor and dynamic transformations are mediated by distinct neural mechanisms.


Small bowel transplantation and chronic rejection alter rat intestinal smooth muscle structure and function.
The purpose of this study was to determine whether morphologic and functional changes in intestinal smooth muscle occur after small bowel transplantation (SBTx) and during chronic rejection. Orthotopic SBTx was performed in syngeneic (ACI-ACI, n = 6) and allogeneic (ACI-Lewis, n = 6) rat strain combinations. The latter received temporary immunosuppression (cyclosporine 15 mg/kg/body weight on postoperative days 0 to 6 once a day, postoperative days 7 to 28 every other day), which led to clinically quiescent chronic rejection of the graft by 90 days after SBTx. At that time structure and function of the jejunal muscularis externa were evaluated with histochemistry, mechanical organ bath, and intracellular electrical recording techniques. Histochemistry showed a 1.5-fold thickening of the intestinal muscularis externa of syngeneic grafts, although contractile properties and intracellular electrical activity were not significantly different from controls. Allogeneic, chronically rejecting grafts showed a threefold increase in the thickness of the muscularis externa as a result of both smooth muscle hyperplasia and hypertrophy. Muscle strips from chronically rejecting grafts generated only 23% of the maximal contractile force generated by controls (bethanechol 300 mumol/L). Median effective concentration and threshold values were not significantly different. Intracellular electrical activity of circular smooth muscle cells revealed a significantly more depolarized resting membrane potential and a reduction in slow wave amplitude compared with controls. Syngeneic SBTx resulted in a significant thickening of the muscularis externa with an apparent adaptation to control in vitro physiologic function. Allogeneic SBTx subject to chronic rejection leads to profound morphologic changes and functional impairments. Changes in muscle structure and function evolve before the clinical signs of graft rejection.


Spontaneous Emergence of Azithromycin Resistance in Independent Lineages of Salmonella Typhi in Northern India.
The emergence and spread of antimicrobial resistance (AMR) pose a major threat to the effective treatment and control of typhoid fever. The ongoing outbreak of extensively drug-resistant Salmonella Typhi (S. Typhi) in Pakistan has left azithromycin as the only remaining broadly efficacious oral antimicrobial for typhoid in South Asia. Ominously, azithromycin-resistant S. Typhi organisms have been subsequently reported in Bangladesh, Pakistan, and Nepal. Here, we aimed to understand the molecular basis of AMR in 66 S. Typhi organisms isolated in a cross-sectional study performed in a suburb of Chandigarh in Northern India using whole-genome sequencing and phylogenetic analysis. We identified 7 S. Typhi organisms with the R717Q mutation in the acrB gene that was recently found to confer resistance to azithromycin in Bangladesh. Six out of the seven azithromycin-resistant S. Typhi isolates also exhibited triple mutations in gyrA (S83F and D87N) and parC (S80I) genes and were resistant to ciprofloxacin. These contemporary ciprofloxacin/azithromycin-resistant isolates were phylogenetically distinct from each other and from those reported from Bangladesh, Pakistan, and Nepal. The independent emergence of azithromycin-resistant typhoid in Northern India reflects an emerging broader problem across South Asia and illustrates the urgent need for the introduction of typhoid conjugate vaccines in the region.


Minimally Invasive Ways of Determining Circadian Rhythms in Humans.
Circadian rhythm exerts a critical role in mammalian health and disease. A malfunctioning circadian clock can be a consequence, as well as the cause of several pathophysiologies. Clinical therapies and research may also be influenced by the clock. Since the most suitable manner of revealing this rhythm in humans is not yet established, we discuss existing methods and seek to determine the most feasible ones.


Atomistic insights into the nanohelix of hydrogenated graphene: formation, characterization and application.
Hydrogenated graphene has been emerging as the cynosure of the subject for numerous studies due to its conductivity, ferromagnetism, and potential for energy storage as well as drug delivery. However, how to find a decent way to overcome the graphene bending barrier and modify graphene from planar structures to 3D structures remains to be further explored. By virtue of molecular mechanics/dynamics simulations, here we present the formation of a carbon nanohelix from a pristine graphene nanoribbon by doping it with hydrogen atoms in a specific pattern. Meanwhile, we quantitatively investigate the effect of the interatomic potential on the process of helical structure formation, thermal stability and mechanical properties of the carbon nanohelix as well as its potential application in molecule packing. The carbon nanohelix portrays an intriguing zigzag strain-stress curve and amazing extensibility under tension as well as relatively limited deformability under compression, which represents its unique signature of mechanical properties to differentiate the carbon nanohelix from the behavior of the carbon nanotube and graphene. These findings lend compelling credence to envision that the carbon nanohelix opens up a viable avenue for nanofabrication and is perceived as a novel nanomaterial for a variety of applications such as electronics, sensors, energy storage, drug delivery and nanocomposites.


Monofilament intraluminal middle cerebral artery occlusion in the mouse.
The rat middle cerebral artery (MCA) occlusion model with an intraluminal filament is well characterized with a two hour period of occlusion in widespread use. The recent availability of transgenic animals has led to an interest in adapting the MCA model in the mouse. To date the model has not been well characterized in the mouse. We performed the present study to compare different durations of MCA occlusion and to validate new functional assessments in this model. The MCA occlusion model (5-0 filament) was used. Swiss-Webster mice, 24-44 g, were randomly assigned to four groups: one hour of occlusion; two hours of occlusion; three hours of occlusion; or permanent occlusion. At 48 hours post-ischemia, the animals were rated on three neurologic function scales, and then the brains were removed for lesion size determination. Overall, there was a significant difference in lesion volume (p < 0.001) between the groups. In the permanent group of mice, the average lesion volume was 78.41 +/- 17.47 mm (n = 12); two and three hours of ischemia produced 51.29 +/- 29.82 mm3 (n = 11) and 54.85 mm3 (n = 13), respectively, significantly different than the one hour group 14.84 +/- 31.34 mm3 (n = 11). All three functional scoring systems found significant overall differences between the four groups with our detailed General and Focal scores producing more robust between group treatment differences and showing correlation coefficients of r = 0.766 and r = 0.788, respectively to infarct volume. The MCA filament occlusion model can be successfully adapted in the mouse with either two or three hour occlusions producing reliable infarcts. New functional scoring systems unique to the mouse appear to add additional information.


Dynamical inference: where phase synchronization and generalized synchronization meet.
Synchronization is a widespread phenomenon that occurs among interacting oscillatory systems. It facilitates their temporal coordination and can lead to the emergence of spontaneous order. The detection of synchronization from the time series of such systems is of great importance for the understanding and prediction of their dynamics, and several methods for doing so have been introduced. However, the common case where the interacting systems have time-variable characteristic frequencies and coupling parameters, and may also be subject to continuous external perturbation and noise, still presents a major challenge. Here we apply recent developments in dynamical Bayesian inference to tackle these problems. In particular, we discuss how to detect phase slips and the existence of deterministic coupling from measured data, and we unify the concepts of phase synchronization and general synchronization. Starting from phase or state observables, we present methods for the detection of both phase and generalized synchronization. The consistency and equivalence of phase and generalized synchronization are further demonstrated, by the analysis of time series from analog electronic simulations of coupled nonautonomous van der Pol oscillators. We demonstrate that the detection methods work equally well on numerically simulated chaotic systems. In all the cases considered, we show that dynamical Bayesian inference can clearly identify noise-induced phase slips and distinguish coherence from intrinsic coupling-induced synchronization.


Comparison of hospital performance in trauma vs emergency and elective general surgery: implications for acute care surgery quality improvement.
As emergency general surgery (EMGS) and trauma care are increasingly being provided by the same personnel with overlapping resources, we postulated that the quality of care provided to EMGS and trauma patients would be similar. We also evaluated the relationship between trauma and elective general surgery (ELGS) care, believing that performance would be similar across these services as it reflects institutional culture. Retrospective cohort study comparing hospital performance in trauma and EMGS care and in trauma and ELGS care. Regression models for mortality and serious morbidity were constructed for trauma, EMGS, and ELGS hospitals contributing to both the National Trauma Data Bank (2007) and American College of Surgeons National Surgical Quality Improvement Program (2005-2008). Forty-six hospitals. Correlations of observed to expected ratios were examined. Outlier status (hospitals with CIs of observed to expected ratios excluding 1.0) was compared using weighted . There was no significant relationship between trauma and EMGS mortality (r=-0.01, P=.94; =-0.10, P=.61) or between trauma and ELGS mortality (r=0.23, P=.12; =0.07, P=.62). There was no significant relationship between trauma and EMGS morbidity (r=0.21, P=.17; =0.04, P=.63) or between trauma and ELGS morbidity (r=0.16, P=.30; =0.11, P=.37). No hospitals were consistently low or high outliers across all 3 groups. Trauma performance improvement programs are well established compared with those for EMGS. Although EMGS patients use similar structures and processes as trauma patients, there is a lack of correlation between the quality of care provided to trauma and EMGS patients; EMGS should be incorporated into trauma performance improvement programs.


Comparisons of Human Immunodeficiency Virus Type 1 Envelope Variants in Blood and Genital Fluids near the Time of Male-to-Female Transmission.
To better understand the transmission of human immunodeficiency virus type 1 (HIV-1), the genetic characteristics of blood and genital viruses from males were compared to those of the imputed founding virus population in their female partners. Initially serodiscordant heterosexual African couples with sequence-confirmed male-to-female HIV-1 transmission and blood and genital specimens collected near the time of transmission were studied. Single viral templates from blood plasma and genital tract RNA and DNA were sequenced across HIV-1 env gp160. Eight of 29 couples examined yielded viral sequences from both tissues. Analysis of these couples' sequences demonstrated, with one exception, that the women's founding viral populations arose from a single viral variant and were CCR5 tropic, even though CXCR4 variants were detected within four males. The median genetic distance of the imputed most recent common ancestor of the women's founder viruses showed that they were closer to the semen viruses than to the blood viruses of their transmitting male partner, but this finding was biased by detection of a greater number of viral clades in the blood. Using multiple assays, the blood and genital viruses were consistently found to be compartmentalized in only two of eight men. No distinct amino acid signatures in the men's viruses were found to link to the women's founders, nor did the women's env sequences have shorter variable loops or fewer N-linked glycosylation sites. The lack of selective factors, except for coreceptor tropism, is consistent with others' findings in male-to-female and high-risk transmissions. The infrequent compartmentalization between the transmitters' blood and semen viruses suggests that cell-free blood virus likely includes HIV-1 sequences representative of those of viruses in semen.IMPORTANCE Mucosal transmissions account for the majority of HIV-1 infections. Identification of the viral characteristics associated with transmission would facilitate vaccine design. This study of HIV strains from transmitting males and their seroconverting female partners found that the males' genital tract viruses were rarely distinct from the blood variants. The imputed founder viruses in women were genetically similar to both the blood and genital tract variants of their male partners, indicating a lack of evidence for genital tract-specific lineages. These findings suggest that targeting vaccine responses to variants found in blood are likely to also protect from genital tract variants.


[A study on medical periodicals published in Turkish in Arabic alphabet-II].
In this article medical periodicals published in Turkish in Arabic alphabet between the year 1849, when the first medical periodical was published, and 1928, when the Latin alphabet was accepted, are introduced. First a general history of medical periodicals is given, then each periodical is introduced with its physical characteristics and contents, such as the publisher, editor, publisher's address, office frequency and duration of the publications, press, measurements, whether it's illustrated or not, number of pages and columns and writer's names are given. Utilizing these data, each periodical is criticized. This study is published in two parts and in the end an alphabetical and chronological list of the periodicals and a list classifying the periodicals, according to their subjects, is given. A general survey of the research is made and conclusions based on the data.


Prenatal retinoid deficiency leads to airway hyperresponsiveness in adult mice.
There is increasing evidence that vitamin A deficiency in utero correlates with abnormal airway smooth muscle (SM) function in postnatal life. The bioactive vitamin A metabolite retinoic acid (RA) is essential for formation of the lung primordium; however, little is known about the impact of early fetal RA deficiency on postnatal lung structure and function. Here, we provide evidence that during murine lung development, endogenous RA has a key role in restricting the airway SM differentiation program during airway formation. Using murine models of pharmacological, genetic, and dietary vitamin A/RA deficiency, we found that disruption of RA signaling during embryonic development consistently resulted in an altered airway SM phenotype with markedly increased expression of SM markers. The aberrant phenotype persisted postnatally regardless of the adult vitamin A status and manifested as structural changes in the bronchial SM and hyperresponsiveness of the airway without evidence of inflammation. Our data reveal a role for endogenous RA signaling in restricting SM differentiation and preventing precocious and excessive SM differentiation when airways are forming.


Parting the Clouds: Three Professionalism Frameworks in Medical Education.
Current controversies in medical education associated with professionalism, including disagreements about curriculum, pedagogy, and assessment, are rooted in part in the differing frameworks that are used to address professionalism. Three dominant frameworks, which have evolved in the medical education community, are described. The oldest framework is virtue based and focuses on the inner habits of the heart, the development of moral character and reasoning, plus humanistic qualities of caring and compassion: The good physician is a person of character. The second framework is behavior based, which emphasizes milestones, competencies, and measurement of observable behaviors: The good physician is a person who consistently demonstrates competence in performing patient care tasks. The third framework is identity formation, with a focus on identity development and socialization into a community of practice: The good physician integrates into his or her identity a set of values and dispositions consonant with the physician community and aspires to a professional identity reflected in the very best physicians. Although each professionalism framework is useful and valid, the field of medical education is currently engaged in several different discourses resulting in misunderstanding and differing recommendations for strategies to facilitate professionalism. In this article, the assumptions and contributions of each framework are described to provide greater insight into the nature of professionalism. By examining each discourse in detail, underlying commonalities and differences can be highlighted to assist educators in more effectively creating professionalism curricula, pedagogy, and assessment.


Multilevel support vector regression analysis to identify condition-specific regulatory networks.
The identification of gene regulatory modules is an important yet challenging problem in computational biology. While many computational methods have been proposed to identify regulatory modules, their initial success is largely compromised by a high rate of false positives, especially when applied to human cancer studies. New strategies are needed for reliable regulatory module identification. We present a new approach, namely multilevel support vector regression (ml-SVR), to systematically identify condition-specific regulatory modules. The approach is built upon a multilevel analysis strategy designed for suppressing false positive predictions. With this strategy, a regulatory module becomes ever more significant as more relevant gene sets are formed at finer levels. At each level, a two-stage support vector regression (SVR) method is utilized to help reduce false positive predictions by integrating binding motif information and gene expression data; a significant analysis procedure is followed to assess the significance of each regulatory module. To evaluate the effectiveness of the proposed strategy, we first compared the ml-SVR approach with other existing methods on simulation data and yeast cell cycle data. The resulting performance shows that the ml-SVR approach outperforms other methods in the identification of both regulators and their target genes. We then applied our method to breast cancer cell line data to identify condition-specific regulatory modules associated with estrogen treatment. Experimental results show that our method can identify biologically meaningful regulatory modules related to estrogen signaling and action in breast cancer. The ml-SVR MATLAB package can be downloaded at http://www.cbil.ece.vt.edu/software.htm.


Interventions for coordination of walking following stroke: systematic review.
Impairments in gait coordination may be a factor in falls and mobility limitations after stroke. Therefore, rehabilitation targeting gait coordination may be an effective way to improve walking post-stroke. This review sought to examine current treatments that target impairments of gait coordination, the theoretical basis on which they are derived and the effects of such interventions. Few high quality RCTs with a low risk of bias specifically targeting and measuring restoration of coordinated gait were found. Consequently, we took a pragmatic approach to describing and quantifying the available evidence and included non-randomised study designs and limited the influence of heterogeneity in experimental design and control comparators by restricting meta-analyses to pre- and post-test comparisons of experimental interventions only. Results show that physiotherapy interventions significantly improved gait function and coordination. Interventions involving repetitive task-specific practice and/or auditory cueing appeared to be the most promising approaches to restore gait coordination. The fact that overall improvements in gait coordination coincided with increased walking speed lends support to the hypothesis that targeting gait coordination gait may be a way of improving overall walking ability post-stroke. However, establishing the mechanism for improved locomotor control requires a better understanding of the nature of both neuroplasticity and coordination deficits in functional tasks after stroke. Future research requires the measurement of impairment, activity and cortical activation in an effort to establish the mechanism by which functional gains are achieved.


Immunolocalization of protease-activated receptor-2 in skin: receptor activation stimulates interleukin-8 secretion by keratinocytes in vitro.
The protease-activated receptor-2 (PAR-2) is a seven transmembrane domain receptor related to the thrombin receptor, which is activated in vitro by cleavage by trypsin. Affinity-purified rabbit IgG raised against a peptide corresponding to the trypsin cleavage site of PAR-2 was used for an immunohistochemical study of skin. The expression of PAR-2 in epidermis was striking, with keratinocytes showing abundant intercellular and cytoplasmic staining. Basal cells showed the strongest staining intensity and the stratum corneum was negative. Staining with control IgG used at the same concentration was consistently negative. The functional expression of PAR-2 by the simian virus transformed human skin keratinocyte cell line SVK14 was demonstrated by Northern blot analysis, flow cytometric analysis and the measurement of intracellular calcium. Treatment of SVK14 with trypsin or a receptor agonist peptide (SLIGKV-NH2) caused a dose-dependent increase in the secretion of the chemokine interleukin-8 (IL-8) in vitro. The effect of the peptide was specific, since control acetylated peptide was without activity. We conclude that PAR-2 is highly expressed by epidermal keratinocytes and receptor activation in vitro leads to increased IL-8 secretion by keratinocytes. These data raise the possibility that PAR-2 may play a role in epidermal homeostasis and inflammatory conditions.


Oncogenic KRAS induces progenitor cell expansion and malignant transformation in zebrafish exocrine pancreas.
Although the cell of origin for pancreatic cancer remains unknown, prior studies have suggested that pancreatic neoplasia may be initiated in progenitor-like cells. To examine the effects of oncogene activation within the pancreatic progenitor pool, we devised a system for real-time visualization of both normal and oncogenic KRAS-expressing pancreatic progenitor cells in living zebrafish embryos. By using BAC transgenes under the regulation of ptf1a regulatory elements, we expressed either extended green fluorescent protein (eGFP) alone or eGFP fused to oncogenic KRAS in developing zebrafish pancreas. After their initial specification, normal eGFP-labeled pancreatic progenitor cells were observed to actively migrate away from the forming endodermal gut tube, and subsequently underwent characteristic exocrine differentiation. In contrast, pancreatic progenitor cells expressing oncogenic KRAS underwent normal specification and migration, but failed to differentiate. This block in differentiation resulted in the abnormal persistence of an undifferentiated progenitor pool, and was associated with the subsequent formation of invasive pancreatic cancer. These tumors showed several features in common with the human disease, including evidence of abnormal Hedgehog pathway activation. These results provide a unique view of the tumor-initiating effects of oncogenic KRAS in a living vertebrate organism, and suggest that zebrafish models of pancreatic cancer may prove useful in advancing our understanding of the human disease.


Age-specific breeding success in a wild mammalian population: selection, constraint, restraint and senescence.
The Selection, Constraint, Restraint and Senescence Hypotheses predict how breeding success should vary with age. The Selection Hypothesis predicts between-individual variation arising from quality differences; the other hypotheses predict within-individual variation due to differing skills or physiological condition (Constraint), residual reproductive lifespan (Restraint), or somatic and reproductive investment (Senescence). Studies tend to focus on either the initial increase in breeding success or later decrease; however, both require consideration when unravelling the underlying evolutionary processes. Additionally, few studies present genetic fitness measures and rarely for both sexes. We therefore test these four hypotheses, which are not mutually exclusive, in a high-density population of European badgers Meles meles. Using an 18-year data set (including 22 microsatellite loci), we show an initial improvement in breeding success with age, followed by a later and steeper rate of reproductive senescence in male than in female badgers. Breeding success was skewed within age-classes, indicating the influence of factors other than age-class. This was partly attributable to selective appearance and disappearance of badgers (Selection Hypothesis). Individuals with a late age of last breeding showed a concave-down relationship between breeding success and experience (Constraint Hypothesis). There was no evidence of abrupt terminal effects; rather, individuals showed a concave-down relationship between breeding success and residual reproductive lifespan (Restraint Hypothesis), with an interaction with age of first breeding only in female badgers. Our results demonstrate the importance of investigating a comprehensive suite of factors in age-specific breeding success analyses, in both sexes, to fully understand evolutionary and population dynamics.


Quantifying the functional rehabilitation of injured football players.
To determine whether quantified, auditable records of functional rehabilitation can be generated using subjective assessments of players' performance in fitness tests routinely used in professional football. Ten sequential test elements grouped into three phases (fitness, ball and match skills, match pace football) were used to monitor players' functional recovery from injury. Physiotherapists subjectively assessed players' performance in each test element using a six point subjective rating scale. Satisfactory performance in each element of the assessment programme added 10% to the injured player's recovery score. Daily recovery scores for injured players were recorded against the time spent in functional rehabilitation. Rehabilitation data for 118 injuries sustained by 55 players over two seasons were recorded. The average time in functional rehabilitation depended on the time spent in pre-functional rehabilitation and the nature and location of injury. Benchmark functional rehabilitation curves (y = mln(x) + c) were developed for thigh (n = 15) and lower leg (n = 8) muscle strains and knee (n = 7) and ankle (n = 9) ligament sprains (R(2) = 0.95-0.98). A structured, quantified rehabilitation programme based on routine fitness and skills exercises and a graded subjective assessment of performance provides an auditable record of a player's functional recovery from a range of lower limb injuries and a transparent exit point from rehabilitation. The proposed method provides a permanent record of the functional rehabilitation of players' injuries and evidence based data to support management's return to play decisions.


Pulsed radiofrequency under ultrasound guidance for persistent stump-neuroma pain.
Limb amputation is a leading cause of pain and disability. Limb amputation can be associated with a myriad of symptoms, including phantom limb sensation, phantom limb pain, and stump pain. Treatment of phantom limb pain and stump pain, remains difficult, therefore optimal management must include a multidisciplinary approach. This case report describes the use of ultrasound for diagnosis and successful management, of persistent stump-neuroma pain, using pulsed radiofrequency ablation.


Immune Responses Regulated by Cannabidiol.
Introduction: Cannabidiol (CBD) as Epidiolex® (GW Pharmaceuticals) was recently approved by the U.S. Food and Drug Administration (FDA) to treat rare forms of epilepsy in patients 2 years of age and older. Together with the increased societal acceptance of recreational cannabis and CBD oil for putative medical use in many states, the exposure to CBD is increasing, even though all of its biological effects are not understood. Once such example is the ability of CBD to be anti-inflammatory and immune suppressive, so the purpose of this review is to summarize effects and mechanisms of CBD in the immune system. It includes a consideration of reports identifying receptors through which CBD acts, since the "CBD receptor," if a single one exists, has not been definitively identified for the myriad immune system effects. The review then provides a summary of in vivo and in vitro effects in the immune system, in autoimmune models, with a focus on experimental autoimmune encephalomyelitis, and ends with identification of knowledge gaps. Conclusion: Overall, the data overwhelmingly support the notion that CBD is immune suppressive and that the mechanisms involve direct suppression of activation of various immune cell types, induction of apoptosis, and promotion of regulatory cells, which, in turn, control other immune cell targets.


SIRT7 represses Myc activity to suppress ER stress and prevent fatty liver disease.
Nonalcoholic fatty liver disease is the most common chronic liver disorder in developed countries. Its pathogenesis is poorly understood, and therapeutic options are limited. Here, we show that SIRT7, an NAD(+)-dependent H3K18Ac deacetylase, functions at chromatin to suppress ER stress and prevent the development of fatty liver disease. SIRT7 is induced upon ER stress and is stabilized at the promoters of ribosomal proteins through its interaction with the transcription factor Myc to silence gene expression and to relieve ER stress. SIRT7-deficient mice develop chronic hepatosteatosis resembling human fatty liver disease. Myc inactivation or pharmacological suppression of ER stress alleviates fatty liver caused by SIRT7 deficiency. Importantly, SIRT7 suppresses ER stress and reverts the fatty liver disease in diet-induced obese mice. Our study identifies SIRT7 as a cofactor of Myc for transcriptional repression and delineates a druggable regulatory branch of the ER stress response that prevents and reverts fatty liver disease.


Anatomical study of truncus arteriousus communis with embryological and surgical considerations.
Twelve specimens of truncus arteriosus communis have been studied anatomically, with special reference to the conal anatomy and to the associated cardiac anomalies which can create additional problems if surgical repair is planned. A wide spectrum of conal morphology has been observed, suggesting that differential conal absorption is a developmental characteristic of truncus arteriousus as well as of transposition complexes. The invariable absence of septation of the ventricular infundibula and semilunar valves, in spite of the variable anatomy of the free wall of the conus, indicates that all types of truncus arteriosus, ontogenetically, should be considered as a single undivided conotruncus. Various types of ventircular septal defect were found: (a) ventricular septal defect with absent crista, in which no remnants of conal septum are present; (b) supracristal ventricular septal defect, in which vestigial conal septum is seen in front of the membranous septum; (c) bulloventricular foramen, associated with univentricular origin of the truncus from the right ventricle. Frequent associated anomalies are underdevelopment of the aortic arch, truncal valve malformations, and obstructive ventricular septal defect. The AV conduction system studied in one case showed an arrangement similar to Fallot's tetralogy with the His bundle and the left bundle-branch in a safe position behind the posteroinferior rim of the defect. The postoperative fate of the frequently abnormal truncal valve and the theoretical indications for total repair for Type IV truncus are also discussed.


Ubiquitination of ATF6 by disease-associated RNF186 promotes the innate receptor-induced unfolded protein response.
Properly balancing microbial responses by the innate immune system through pattern recognition receptors (PRRs) is critical for intestinal immune homeostasis. Ring finger protein 186 (RNF186) genetic variants are associated with inflammatory bowel disease (IBD). However, functions for the E3 ubiquitin ligase RNF186 are incompletely defined. We found that upon stimulation of the PRR nucleotide-binding oligomerization domain containing 2 (NOD2) in human macrophages, RNF186 localized to the ER, formed a complex with ER stress sensors, ubiquitinated the ER stress sensor activating transcription factor 6 (ATF6), and promoted the unfolded protein response (UPR). These events, in turn, led to downstream signaling, cytokine secretion, and antimicrobial pathway induction. Importantly, RNF186-mediated ubiquitination of K152 on ATF6 was required for these outcomes, highlighting a key role for ATF6 ubiquitination in PRR-initiated functions. Human macrophages transfected with the rare RNF186-A64T IBD risk variant and macrophages from common rs6426833 RNF186 IBD risk carriers demonstrated reduced NOD2-induced outcomes, which were restored by rescuing UPR signaling. Mice deficient in RNF186 or ATF6 demonstrated a reduced UPR in colonic tissues, increased weight loss, and less effective clearance of bacteria with dextran sodium sulfate-induced injury and upon oral challenge with Salmonella Typhimurium. Therefore, we identified that RNF186 was required for PRR-induced, UPR-associated signaling leading to key macrophage functions; defined that RNF186-mediated ubiquitination of ATF6 was essential for these functions; and elucidated how RNF186 IBD risk variants modulated these outcomes.


Real-time moment analysis of pulmonary nitrogen washout.
A real-time moment analysis was applied to multibreath nitrogen-washout dynamics of the lung. Because the analysis accounts for breathing pattern variations, subjects could perform the washout with spontaneous breathing. The real-time digital processing of the nitrogen and flow signals incorporates filtering, delay compensation, and corrections for the effects of gas composition and temperature changes. In our study, moment analysis of the multibreath washout was evaluated for 37 subjects: 6 normal nonsmokers, 4 "normal" smokers, 6 asthmatics, 12 with diffuse interstitial disease, and 9 with chronic obstructive pulmonary disease. Moments were computed from end-tidal and breath-averaged nitrogen fractions. The ratio of 1st-to-0th moments was found to yield distinctions among subjects with different degrees of ventilation inhomogeneity, even between normal nonsmokers and "normal" smokers. With minimal computational facilities, this moment analysis not only provides a sensitive index of ventilatory dysfunction, but also a cost-effective tool.


The ubiquitin-specific protease USP15 promotes RIG-I-mediated antiviral signaling by deubiquitylating TRIM25.
Ubiquitylation is an important mechanism for regulating innate immune responses to viral infections. Attachment of lysine 63 (Lys(63))-linked ubiquitin chains to the RNA sensor retinoic acid-inducible gene-I (RIG-I) by the ubiquitin E3 ligase tripartite motif protein 25 (TRIM25) leads to the activation of RIG-I and stimulates production of the antiviral cytokines interferon-α (IFN-α) and IFN-β. Conversely, Lys(48)-linked ubiquitylation of TRIM25 by the linear ubiquitin assembly complex (LUBAC) stimulates the proteasomal degradation of TRIM25, thereby inhibiting the RIG-I signaling pathway. Here, we report that ubiquitin-specific protease 15 (USP15) deubiquitylates TRIM25, preventing the LUBAC-dependent degradation of TRIM25. Through protein purification and mass spectrometry analysis, we identified USP15 as an interaction partner of TRIM25 in human cells. Knockdown of endogenous USP15 by specific small interfering RNA markedly enhanced the ubiquitylation of TRIM25. In contrast, expression of wild-type USP15, but not its catalytically inactive mutant, reduced the Lys(48)-linked ubiquitylation of TRIM25, leading to its stabilization. Furthermore, ectopic expression of USP15 enhanced the TRIM25- and RIG-I-dependent production of type I IFN and suppressed RNA virus replication. In contrast, depletion of USP15 resulted in decreased IFN production and markedly enhanced viral replication. Together, these data identify USP15 as a critical regulator of the TRIM25- and RIG-I-mediated antiviral immune response, thereby highlighting the intricate regulation of innate immune signaling.


Steric and electrostatic effects at the C2 atom substituent influence replication and miscoding of the DNA deamination product deoxyxanthosine and analogs by DNA polymerases.
Deoxyinosine (dI) and deoxyxanthosine (dX) are both formed in DNA at appreciable levels in vivo by deamination of deoxyadenosine (dA) and deoxyguanosine (dG), respectively, and can miscode. Structure-activity relationships for dA pairing have been examined extensively using analogs but relatively few studies have probed the roles of the individual hydrogen-bonding atoms of dG in DNA replication. The replicative bacteriophage T7 DNA polymerase/exonuclease and the translesion DNA polymerase Sulfolobus solfataricus pol IV were used as models to discern the mechanisms of miscoding by DNA polymerases. Removal of the 2-amino group from the template dG (i.e., dI) had little impact on the catalytic efficiency of either polymerase, as judged by either steady-state or pre-steady-state kinetic analysis, although the misincorporation frequency was increased by an order of magnitude. dX was highly miscoding with both polymerases, and incorporation of several bases was observed. The addition of an electronegative fluorine atom at the 2-position of dI lowered the oligonucleotide T(m) and strongly inhibited incorporation of dCTP. The addition of bromine or oxygen (dX) at C2 lowered the T(m) further, strongly inhibited both polymerases, and increased the frequency of misincorporation. Linear activity models show the effects of oxygen (dX) and the halogens at C2 on both DNA polymerases as mainly due to a combination of both steric and electrostatic factors, producing a clash with the paired cytosine O2 atom, as opposed to either bulk or perturbation of purine ring electron density alone.


Curcumin-induced degradation of PKC delta is associated with enhanced dentate NCAM PSA expression and spatial learning in adult and aged Wistar rats.
Polysialylation of the neural cell adhesion molecule (NCAM PSA) is necessary for the consolidation processes of hippocampus-based learning. Previously, we have found inhibition of protein kinase C delta (PKCdelta) to be associated with increased polysialyltransferase (PST) activity, suggesting inhibitors of this kinase might ameliorate cognitive deficits. Using a rottlerin template, a drug previously considered an inhibitor of PKCdelta, we searched the Compounds Available for Purchase (CAP) database with the Accelrys((R)) Catalyst programme for structurally similar molecules and, using the available crystal structure of the phorbol-binding domain of PKCdelta, found that diferuloylmethane (curcumin) docked effectively into the phorbol site. Curcumin increased NCAM PSA expression in cultured neuro-2A neuroblastoma cells and this was inversely related to PKCdelta protein expression. Curcumin did not directly inhibit PKCdelta activity but formed a tight complex with the enzyme. With increasing doses of curcumin, the Tyr(131) residue of PKCdelta, which is known to direct its degradation, became progressively phosphorylated and this was associated with numerous Tyr(131)-phospho-PKCdelta fragments. Chronic administration of curcumin in vivo also increased the frequency of polysialylated cells in the dentate infragranular zone and significantly improved the acquisition and consolidation of a water maze spatial learning paradigm in both adult and aged cohorts of Wistar rats. These results further confirm the role of PKCdelta in regulating PST and NCAM PSA expression and provide evidence that drug modulation of this system enhances the process of memory consolidation.


Correlation between hearing loss and scala media area in guinea pigs with long-standing endolymphatic hydrops.
Histologic analysis of the hydropic and normal guinea pig cochleae was undertaken to assess a potential correlation between the magnitude of endolymphatic hydrops and hearing loss. It was hypothesized that a greater correlation than previously reported might be found by looking at long-standing endolymphatic hydrops and high-frequency range hearing. Surgically induced endolymphatic hydrops in guinea pigs is the most widely used animal model for the study of human Ménière's Disease and recapitulates both endolymphatic hydrops and progressive sensorineural hearing loss. A strong correlation between the magnitude of hydrops and severity of hearing loss has been reported in the human condition, but not in the animal model. Nine albino guinea pigs were each subjected to surgical obstruction of the endolymphatic sac and duct of the right ear. The left ears remained as internal histologic controls. Hearing was assessed from 2 kHz to 32 kHz by auditory brain stem response testing for 16 to 25 weeks after surgery. Histologic morphometry after the animals were killed was used to quantify both turn-specific and weighted overall hydrops. These measures were correlated with hearing loss in each animal at all tested frequencies. A statistically significant correlation between the magnitude of hydrops and the severity of hearing loss was observed for 2 kHz and 16 kHz. These frequencies correlated with both turn-specific hydrops and overall hydrops. However, turn-specific hydrops did not reliably correlate with the magnitude of hearing loss at anatomically appropriate frequency ranges. Where such a correlation did exist, it might well have been simply part of an expression of an overall correlation between hydrops and hearing loss. There may be a greater correlation between hydrops and hearing loss in guinea pigs with long-standing surgically induced hydrops than has previously been reported in animals with less advanced disease. These findings help to validate continued use of the model for hearing loss related to Ménière's Disease, verify the rationale of treatment modalities aimed at reducing hydrops in the human condition, and may indicate that efforts at reducing hydrops in such patients has benefits toward long-term hearing preservation.


Scrub Typhus and the Misconception of Doxycycline Resistance.
Scrub typhus, a neglected infectious disease caused by the obligate intracellular bacterium Orientia tsutsugamushi, is a major cause of fever across the Asia Pacific region with more than a billion people at risk. Treatment with antibiotics such as doxycycline or chloramphenicol is effective for the majority of patients. In the 1990s, reports from northern Thailand raised a troubling observation; some scrub typhus patients responded poorly to doxycycline, which investigators attributed to doxycycline resistance. Despite the controversial nature of these reports, independent verification was neglected, with subsequent studies speculating on the role of doxycycline resistance in contributing to failure of treatment or prophylaxis. In this review, we have outlined the evidence for drug-resistant Orientia tsutsugamushi, assessed the evidence for doxycycline resistance, and highlight more recent findings unsupportive of doxycycline resistance. We conclude that doxycycline resistance is a misconception, with treatment outcome likely to be determined by other bacterial, host, and pharmacological factors.


Evaluation of self-collected glans and rectal swabs from men who have sex with men for detection of Chlamydia trachomatis and Neisseria gonorrhoeae by use of nucleic acid amplification tests.
Self-collected glans and rectal swab specimens from men who have sex with men (MSM) may be appropriate, convenient specimens for testing. We evaluated the use of self-collected swabs for the detection of Chlamydia trachomatis and Neisseria gonorrhoeae by a transcription-mediated amplification test (AC2; Aptima Combo 2; Gen-Probe Inc.) and a strand displacement amplification test (SDA; ProbeTec; Becton Dickinson Co.) in MSM seen at the city sexually transmitted disease clinic in San Francisco, CA. For the glans swab specimen, subjects enrolled early in the study rolled a Dacron swab across the meatus three times (method 1). A slightly more invasive procedure was performed later in the study: the subjects inserted the swab 1/4 in. into the urethra, rotated the swab, and then withdrew the swab (method 2). MSM self-collected a rectal swab specimen and also provided first-catch urine (FCU). Additional rectal swab samples were then obtained by the clinician. For the detection of C. trachomatis and N. gonorrhoeae, all swabs were evaluated by AC2 and SDA, FCU was tested by AC2, and the clinician-collected rectal swabs were cultured. A rectal true-positive (TP) result was defined as a culture-positive result for C. trachomatis or N. gonorrhoeae, two or more positive nucleic acid amplification test (NAAT) results, or a single NAAT-positive result confirmed by an alternate amplification method (the Aptima C. trachomatis or N. gonorrhoeae test). A glans TP result was defined as a positive result for FCU, positive results for both glans specimens (one tested by AC2 and one tested by SDA), or a positive result for a single glans specimen confirmed by an alternate amplification method. The prevalence rates of C. trachomatis and N. gonorrhoeae by testing of FCU were 6.8% (60/882 specimens) and 12.2% (108/882 specimens), respectively. Mixed results were obtained with the glans swab: N. gonorrhoeae detection by AC2 and SDA (method 1) had the best performance (sensitivities, >92%) with samples from a population with a higher prevalence of infection, but their performance for the detection of C. trachomatis was poor and varied by collection method (sensitivities, 56 to 68%). The prevalence rates of C. trachomatis and N. gonorrhoeae in the rectum were 7.3% (66/907 specimens) and 9.4% (83/882 specimens), respectively. The sensitivities of the tests with self-collected and clinician-collected rectal swab specimens were comparable (for C. trachomatis, 41% and 44%, respectively, by SDA and 82% and 71%, respectively, by AC2; for N. gonorrhoeae, 77% and 68%, respectively, by SDA and 84% and 78%, respectively, by AC2). AC2 and SDA were far superior to culture for the detection of C. trachomatis and N. gonorrhoeae in the rectum, with both tests detecting at least twice as many infections. While we found self-collected rectal swabs from MSM to be valid specimens for testing, the sensitivities of the tests with glans swab specimens were disappointing except for those from patients with symptomatic N. gonorrhoeae infections. Self-collected glans swab specimens may not be appropriate for the detection of C. trachomatis or for the detection of N. gonorrhoeae in low-risk or asymptomatic patients by AC2 and SDA, and we would not recommend their use on the basis of our results. Further studies are needed.


Refining developmental coordination disorder subtyping with multivariate statistical methods.
With a large number of potentially relevant clinical indicators penalization and ensemble learning methods are thought to provide better predictive performance than usual linear predictors. However, little is known about how they perform in clinical studies where few cases are available. We used Random Forests and Partial Least Squares Discriminant Analysis to select the most salient impairments in Developmental Coordination Disorder (DCD) and assess patients similarity. We considered a wide-range testing battery for various neuropsychological and visuo-motor impairments which aimed at characterizing subtypes of DCD in a sample of 63 children. Classifiers were optimized on a training sample, and they were used subsequently to rank the 49 items according to a permuted measure of variable importance. In addition, subtyping consistency was assessed with cluster analysis on the training sample. Clustering fitness and predictive accuracy were evaluated on the validation sample. Both classifiers yielded a relevant subset of items impairments that altogether accounted for a sharp discrimination between three DCD subtypes: ideomotor, visual-spatial and constructional, and mixt dyspraxia. The main impairments that were found to characterize the three subtypes were: digital perception, imitations of gestures, digital praxia, lego blocks, visual spatial structuration, visual motor integration, coordination between upper and lower limbs. Classification accuracy was above 90% for all classifiers, and clustering fitness was found to be satisfactory. Random Forests and Partial Least Squares Discriminant Analysis are useful tools to extract salient features from a large pool of correlated binary predictors, but also provide a way to assess individuals proximities in a reduced factor space. Less than 15 neuro-visual, neuro-psychomotor and neuro-psychological tests might be required to provide a sensitive and specific diagnostic of DCD on this particular sample, and isolated markers might be used to refine our understanding of DCD in future studies.


Therapeutic effect of the anti-Fas antibody on arthritis in HTLV-1 tax transgenic mice.
We have recently demonstrated Fas-mediated apoptosis in the synovium, of patients with rheumatoid arthritis (RA) and suggested that it may be one factor responsible for the regression of RA. To examine whether the induction of apoptosis caused by anti-Fas mAb may play a potential role as a new therapeutic strategy for RA, we investigated the effect of anti-Fas mAb (RK-8) on synovitis in an animal model of RA, the human T cell leukemia virus type I (HTLV-1) tax transgenic mice. We report here that administration of anti-Fas mAb into mice intra-articularly improved the paw swelling and arthritis within 48 h. Immunohistochemical study and in vitro culture studies showed that 35% of synovial fibroblasts, 75% of mononuclear cells, and some of polymorphonuclear leukocytes infiltrating in synovium underwent apoptosis by anti-Fas mAb. In situ nick end labeling analysis and electron microscope analysis clearly showed that many cells in synovium were induced apoptosis by anti-Fas mAb administration. However, local administration of anti-Fas mAb did not produce systemic side effects. Results demonstrated that administration of anti-Fas mAb in arthritic joints of the HTLV-1 tax transgenic mice produced improvement of arthritis. These findings suggest that local administration of anti-Fas mAb may represent a useful therapeutic strategy for proliferative synovitis such as RA.


IMCL area density, but not IMCL utilization, is higher in women during moderate-intensity endurance exercise, compared with men.
Women use more fat during endurance exercise as evidenced by a lower respiratory exchange ratio (RER). The contribution of intramyocellular lipid (IMCL) to lipid oxidation during endurance exercise is controversial, and studies investigating sex differences in IMCL utilization have found conflicting results. We determined the effect of sex on net IMCL use during an endurance exercise bout using an ultrastructural evaluation. Men (n = 17) and women (n = 19) completed 90-min cycling at 63% Vo(2peak). Biopsies were taken before and after exercise and fixed for electron microscopy to determine IMCL size, # IMCL/area, IMCL area density, and the % IMCL touching mitochondria. Women had a lower RER and carbohydrate oxidation rate and a higher lipid oxidation rate during exercise (P < 0.05), compared with men. Women had a higher # IMCL/area and IMCL area density (P < 0.05), compared with men. Women, but not men, had a higher % IMCL touching mitochondria postexercise (P = 0.03). Exercise decreased IMCL area density (P = 0.01), due to a decrease in the # IMCL/area (P = 0.02). There was no sex difference in IMCL size or net use. In conclusion, women have higher IMCL area density compared with men, due to an increased # IMCL and not an increased IMCL size, as well as an increased % IMCL touching mitochondria postexercise. Endurance exercise resulted in a net decrease in IMCL density due to decreased number of IMCL, not decreased IMCL size, in both sexes.


Effect of acculturation on variations in having a usual source of care among Asian Americans and non-Hispanic whites in California.
We examined variations in having a usual source of care (USC) among non-Hispanic White and Asian American adults in California. Data were from the 2005 and 2009 California Health Interview Survey. Using a modified Anderson model, we used multiple logistic regression to compare odds of having a USC between non-Hispanic White (n=38554) and Asian American adults (n=7566) and to examine associations with acculturation factors (English proficiency, length of residence, residence in a racially concordant neighborhood) and key enabling (employment, income, insurance) and predisposing (education) factors. Race-related disparities between Asian Americans and non-Hispanic Whites in having a USC were no longer significant after accounting for acculturation factors. Limited English proficiency and short time in the United States (<5 years) were significantly associated with not having a USC for both races. Increasing levels of education and insurance were not associated with better access among Asian Americans. Key differences exist in how Asian American and non-Hispanic White adults access care. Acculturation factors are key drivers of disparities and should be included in access-to-care models with Asians. Insurance and education are differentially significant for Asian Americans and non-Hispanic Whites.


The impact of recent population history on the deleterious mutation load in humans and close evolutionary relatives.
Over the past decade, there has been both great interest and confusion about whether recent demographic events-notably the Out-of-Africa-bottleneck and recent population growth-have led to differences in mutation load among human populations. The confusion can be traced to the use of different summary statistics to measure load, which lead to apparently conflicting results. We argue, however, that when statistics more directly related to load are used, the results of different studies and data sets consistently reveal little or no difference in the load of non-synonymous mutations among human populations. Theory helps to understand why no such differences are seen, as well as to predict in what settings they are to be expected. In particular, as predicted by modeling, there is evidence for changes in the load of recessive loss of function mutations in founder and inbred human populations. Also as predicted, eastern subspecies of gorilla, Neanderthals and Denisovans, who are thought to have undergone reductions in population sizes that exceed the human Out-of-Africa bottleneck in duration and severity, show evidence for increased load of non-synonymous mutations (relative to western subspecies of gorillas and modern humans, respectively). A coherent picture is thus starting to emerge about the effects of demographic history on the mutation load in populations of humans and close evolutionary relatives.


Small and medium-size physician practices use few patient-centered medical home processes.
The patient-centered medical home has become a prominent model for reforming the way health care is delivered to patients. The model offers a robust system of primary care combined with practice innovations and new payment methods. But scant information exists about the extent to which typical US physician practices have implemented this model and its processes of care, or about the factors associated with implementation. In this article we provide the first national data on the use of medical home processes such as chronic disease registries, nurse care managers, and systems to incorporate patient feedback, among 1,344 small and medium-size physician practices. We found that on average, practices used just one-fifth of the patient-centered medical home processes measured as part of this study. We also identify internal capabilities and external incentives associated with the greater use of medical home processes.


Psychometric testing of the Chinese version of the Medical Outcomes Study Social Support Survey among people living with HIV/AIDS in China.
The aim of this study was to assess the psychometric properties of the Chinese (Mandarin) version of the Medical Outcomes Study Social Support Survey (MOS-SSS-CM) among people living with HIV/AIDS (PLWHA) in Mainland China. A cross-sectional study was conducted with a convenience sample of 200 Chinese PLWHA. They completed the MOS-SSS-CM along with the Chinese version of the Beck Depression Inventory Revised (BDI-II) scale, the Zung Self-Rating Anxiety Scale (SAS), the Perceived Stress Scale (PSS-10), and the World Health Organization Quality of Life Brief (WHOQOL-BREF) scale. Internal consistency (Cronbach's α) was 0.97 for the overall MOS-SSS-CM and 0.82-0.91 for the five subscales originally proposed. However, 11 of the 19 items demonstrated unsatisfactory item discriminant validity. An exploratory factor analysis yielded a two-factor solution with tangible and social-emotional dimensions, which demonstrated satisfactory reliability and better discrimination between different subscales than did the original five-factor model. The concurrent validity of the two-factor scale was further confirmed by its significant negative correlations with the BDI-II (r=-0.41, p<0.01); the SAS (r=-0.27, p<0.01); and the PSS-10 (r=-0.30, p<0.01), and significant positive correlation with the WHOQOL-BREF scale (r=0.61, p<0.01). We found a two-factor solution for the MOS-SSS-CM, which demonstrated good reliability and validity when applied to Chinese PLWHA. This was consistent with results from a study of Taiwanese caregivers. Further validation in other populations and disease states is warranted.


Integration of Bioinformatics Resources Reveals the Therapeutic Benefits of Gemcitabine and Cell Cycle Intervention in SMAD4-Deleted Pancreatic Ductal Adenocarcinoma.
Pancreatic ductal adenocarcinoma (PDAC) is the most common and aggressive type of pancreatic cancer. The five-year survival rate of PDAC is very low (less than 8%), which is associated with the late diagnosis, high metastatic potential, and resistance to therapeutic agents. The identification of better prognostic or therapeutic biomarker may have clinical benefits for PDAC treatment. SMAD4, a central mediator of transforming growth factor beta (TGFβ) signaling pathway, is considered a tumor suppressor gene. SMAD4 inactivation is frequently found in PDAC. However, its role in prognosis and therapeutics of PDAC is still unclear. In this study, we applied bioinformatics approaches, and integrated publicly available resources, to investigate the role of SMAD4 gene deletion in PDAC. We found that SMAD4 deletion was associated with poorer disease-free, but not overall, survival in PDAC patients. Cancer hallmark enrichment and pathway analysis suggested that the upregulation of cell cycle-related genes in SMAD4-deleted PDAC. Chemotherapy response profiling of PDAC cell lines and patient-derived organoids revealed that SMAD4-deleted PDAC was sensitive to gemcitabine, the first-line treatment for PDAC, and specific cell cycle-targeting drugs. Taken together, our study provides an insight into the prognostic and therapeutic roles of SMAD4 gene deletion in PDAC, and SMAD4 gene copy numbers may be used as a therapeutic biomarker for PDAC treatment.


Outcomes for whites and blacks at hospitals that disproportionately care for black Medicare beneficiaries.
Hospital care for blacks is concentrated among a small number of hospitals and whether they have worse outcomes across common medical conditions is unknown. We used the 2007 100% Medicare file to calculate 30- and 90-day mortality rates for white and black patients admitted for acute myocardial infarction (AMI), congestive heart failure (CHF), or pneumonia. We ranked all hospitals in the country by their proportion of discharged black patients and identified the top 10 percent of these hospitals as black serving. We examined race-specific adjusted mortality rates and adjusted for differences in hospital characteristics. At 30 days, black-serving hospitals had, compared with nonblack-serving hospitals, similar mortality for AMI, lower mortality for CHF, and higher mortality for pneumonia. At 90 days, mortality was higher at black-serving hospitals for both AMI and pneumonia and comparable for CHF compared with nonblack-serving hospitals. White patients had worse outcomes at black-serving hospitals for two conditions at 30 days and all three conditions at 90 days. Blacks also had worse outcomes at black-serving hospitals. Hospitals with a high proportion of black patients had worse outcomes than other hospitals for both their white and black elderly patients.


Intensive versus Guideline Blood Pressure and Lipid Lowering in Patients with Previous Stroke: Main Results from the Pilot 'Prevention of Decline in Cognition after Stroke Trial' (PODCAST) Randomised Controlled Trial.
Stroke is associated with the development of cognitive impairment and dementia. We assessed the effect of intensive blood pressure (BP) and/or lipid lowering on cognitive outcomes in patients with recent stroke in a pilot trial. In a multicentre, partial-factorial trial, patients with recent stroke, absence of dementia, and systolic BP (SBP) 125-170 mmHg were assigned randomly to at least 6 months of intensive (target SBP <125 mmHg) or guideline (target SBP <140 mmHg) BP lowering. The subset of patients with ischaemic stroke and total cholesterol 3.0-8.0 mmol/l were also assigned randomly to intensive (target LDL-cholesterol <1.3 mmol/l) or guideline (target LDL-c <3.0 mmol/l) lipid lowering. The primary outcome was the Addenbrooke's Cognitive Examination-Revised (ACE-R). We enrolled 83 patients, mean age 74.0 (6.8) years, and median 4.5 months after stroke. The median follow-up was 24 months (range 1-48). Mean BP was significantly reduced with intensive compared to guideline treatment (difference -10·6/-5·5 mmHg; p<0·01), as was total/LDL-cholesterol with intensive lipid lowering compared to guideline (difference -0·54/-0·44 mmol/l; p<0·01). The ACE-R score during treatment did not differ for either treatment comparison; mean difference for BP lowering -3.6 (95% CI -9.7 to 2.4), and lipid lowering 4.4 (95% CI -2.1 to 10.9). However, intensive lipid lowering therapy was significantly associated with improved scores for ACE-R at 6 months, trail making A, modified Rankin Scale and Euro-Qol Visual Analogue Scale. There was no difference in rates of dementia or serious adverse events for either comparison. In patients with recent stroke and normal cognition, intensive BP and lipid lowering were feasible and safe, but did not alter cognition over two years. The association between intensive lipid lowering and improved scores for some secondary outcomes suggests further trials are warranted. ISRCTN ISRCTN85562386.


Cohort profile: the Nordic Antireflux Surgery Cohort (NordASCo).
To describe a newly created all-Nordic cohort of patients with gastro-oesophageal reflux disease (GORD), entitled the Nordic Antireflux Surgery Cohort (NordASCo), which will be used to compare participants having undergone antireflux surgery with those who have not regarding risk of cancers, other diseases and mortality. Included were individuals with a GORD diagnosis recorded in any of the nationwide patient registries in the Nordic countries (Denmark, Finland, Iceland, Norway and Sweden) in 1964-2014 (with various start and end years in different countries). Data regarding cancer, other diseases and mortality were retrieved from the nationwide registries for cancer, patients and causes of death, respectively. The NordASCo includes 945 153 individuals with a diagnosis of GORD. Of these, 48 433 (5.1%) have undergone primary antireflux surgery. Median age at primary antireflux surgery ranged from 47 to 52 years in the different countries. The coding practices of GORD seem to have differed between the Nordic countries. The NordASCo will initially be used to analyse the risk of developing known or potential GORD-related cancers, that is, tumours of the oesophagus, stomach, larynx, pharynx and lung, and to evaluate the mortality in the short-term and long-term perspectives. Additionally, the cohort will be used to evaluate the risk of non-malignant respiratory conditions that might be caused by aspiration of gastric contents.


Trends in the Prevalence of Overweight and Obesity among Chinese Preschool Children from 2006 to 2014.
To examine the trends in the prevalence of overweight and obesity among preschool children from 2006 to 2014. A total of 145,078 children aged 3-6 years from 46 kindergartens finished the annual health examination in Tianjin, China. Height, weight and other information were obtained using standardized methods. Z-scores for weight, height, and BMI were calculated based on the standards for the World Health Organization (WHO) child growth standards. From 2006 to 2014, mean values of height z-scores significantly increased from 0.34 to 0.54, mean values of weight z-scores kept constant, and mean values of BMI z-scores significantly decreased from 0.40 to 0.23. Mean values of height z-scores, weight z-scores, and BMI z-scores slightly decreased among children from 3 to 4 years old, and then increased among children from 4 to 6 years old. Between 2006 and 2014, there were no significant changes in prevalence of overweight (BMI z-scores >2 SD) and obesity (BMI z-scores >3 SD) among 3-4 years children. However, prevalence of obesity (BMI z-scores >2 SD) increased from 8.8% in 2006 to 10.1% in 2010, and then kept stable until 2014 among 5-6 years children. Boys had higher prevalence of obesity than girls. Mean values of BMI z-scores decreased from 2006 to 2014 among Chinese children aged 3-6 years old due to the significant increase of height z-scores. Prevalence of obesity increased from 2006 to 2010, and then kept stable until 2014 among children aged 5-6 years. The prevalence of obesity was higher in boys than in girls.


Stability of the regulatory T cell lineage in vivo.
Tissue maintenance and homeostasis can be achieved through the replacement of dying cells by differentiating precursors or self-renewal of terminally differentiated cells or relies heavily on cellular longevity in poorly regenerating tissues. Regulatory T cells (T(reg) cells) represent an actively dividing cell population with critical function in suppression of lethal immune-mediated inflammation. The plasticity of T(reg) cells has been actively debated because it could factor importantly in protective immunity or autoimmunity. By using inducible labeling and tracking of T(reg) cell fate in vivo, or transfers of highly purified T(reg) cells, we have demonstrated notable stability of this cell population under physiologic and inflammatory conditions. Our results suggest that self-renewal of mature T(reg) cells serves as a major mechanism of maintenance of the T(reg) cell lineage in adult mice.


Different inflammatory phenotypes in adults and children with acute asthma.
Inflammatory phenotypes are recognised in stable adult asthma, but are less well established in childhood and acute asthma. Additionally, Chlamydophila pneumoniae infection as a cause of noneosinophilic asthma is controversial. This study examined the prevalence of inflammatory phenotypes and the presence of current C. pneumoniae infection in adults and children with stable and acute asthma. Adults with stable (n=29) or acute (n=22) asthma, healthy adults (n=11), children with stable (n=49) or acute (n=28) asthma, and healthy children (n=9) underwent clinical assessment and sputum induction. Sputum was assessed for inflammatory cells, and DNA was extracted from sputum cell suspensions and supernatants for C. pneumoniae detection using real-time PCR. The asthma phenotype was predominantly eosinophilic in children with acute asthma (50%) but neutrophilic in adults with acute asthma (82%). Paucigranulocytic asthma was the most common phenotype in both adults and children with stable asthma. C. pneumoniae was not detected in 99% of samples. The pattern of inflammatory phenotypes differs between adults and children, with eosinophilic inflammation being more prevalent in both acute and stable childhood asthma, and neutrophilic inflammation being the dominant pattern of acute asthma in adults. The aetiology of neutrophilic asthma is unknown and is not explained by the presence of current active C. pneumoniae infection.


Brief opportunistic interventions by general practitioners to promote smoking cessation: A conversation analytic study.
Very brief opportunistic interventions for smoking cessation are effective, cost-saving for health systems, and universally recommended in guidelines. However, evidence suggests that clinicians are reluctant to intervene, citing interactional difficulties. Only one UK study has specifically examined smoking discussions, within naturally occurring primary care consultations. However smoking cessation treatment was not available at the time. We examined existing datasets amounting to 519 video-recordings of GP consultations in England for instances of talk about smoking. We used conversation analytic methods to assess patients' responses to doctors asking about smoking, giving advice on smoking, and offering cessation treatment. In 31 recordings it was apparent that the patient smoked, and, in 25/31 consultations, doctors initiated the topic of smoking. They did so by asking about smoking status, commonly during the history-taking phase of the consultation. In many instances, these questions led to active resistance from patients against being placed in a discreditable category, for example by minimising their smoking. This was more pronounced when GPs pursued efforts to quantify the amount smoked. Thereafter, where doctors returned to the topic of smoking, they did so typically by linking smoking to the patient's medical condition, which likewise led to resistance. Guidance recommends that GPs advise on how best to quit smoking where patients are interested in doing so, but this was only evident in a minority of consultations. Where GPs offered support for cessation, they did so using interactional practices that minimised the need for the patient to respond and thereby accept. Interactional difficulties were found to be common in consultations between GPs and people who smoke when GPs actions aligned with some VBA guidelines. Future research should examine when and how advice on how best to quit, and offers of support, should be delivered within primary care consultations.