Distribution and trafficking of the μ-opioid receptor in enteric neurons of the guinea pig.
The μ-opioid receptor (MOR) is a major regulator of gastrointestinal motility and secretion and mediates opiate-induced bowel dysfunction. Although MOR is of physiological and therapeutic importance to gut function, the cellular and subcellular distribution and regulation of MOR within the enteric nervous system are largely undefined. Herein, we defined the neurochemical coding of MOR-expressing neurons in the guinea pig gut and examined the effects of opioids on MOR trafficking and regulation. MOR expression was restricted to subsets of enteric neurons. In the stomach MOR was mainly localized to nitrergic neurons (∼88%), with some overlap with neuropeptide Y (NPY) and no expression by cholinergic neurons. These neurons are likely to have inhibitory motor and secretomotor functions. MOR was restricted to noncholinergic secretomotor neurons (VIP-positive) of the ileum and distal colon submucosal plexus. MOR was mainly detected in nitrergic neurons of the colon (nitric oxide synthase positive, 87%), with some overlap with choline acetyltransferase (ChAT). No expression of MOR by intrinsic sensory neurons was detected. [d-Ala(2), MePhe(4), Gly(ol)(5)]enkephalin (DAMGO), morphiceptin, and loperamide induced MOR endocytosis in myenteric neurons. After stimulation with DAMGO and morphiceptin, MOR recycled, whereas MOR was retained within endosomes following loperamide treatment. Herkinorin or the δ-opioid receptor agonist [d-Ala(2), d-Leu(5)]enkephalin (DADLE) did not evoke MOR endocytosis. In summary, we have identified the neurochemical coding of MOR-positive enteric neurons and have demonstrated differential trafficking of MOR in these neurons in response to established and putative MOR agonists.


Supplementation with compound polysaccharides contributes to the development and metabolic activity of young rat intestinal microbiota.
Dietary intervention during early life has a significant impact on colonization of the gut microbiota. In addition, some polysaccharides have the potential to selectively stimulate the growth and metabolic activity of intestinal bacteria associated with health and well-being. However, less is known about the effect of polysaccharides on the development of gut microbiota in younger individuals. This study was conducted to investigate the health effects of supplementation with dietary compound polysaccharides (Lycium barbarum polysaccharides (LBP), Poria cocos polysaccharides (PCPs) and Lentinan, 1 : 1 : 1) on the intestinal microecosystem and metabolism of young rats. Male 21-day-old Sprague-Dawley rats received daily intragastric administration of either compound polysaccharides (three dosages, 6 g kg-1, 12 g kg-1 or 24 g kg-1) or saline for 28 consecutive days. 1H-NMR spectroscopy integrated with multi-variate pattern recognition analysis was applied to reveal the metabolism of the host and microflora, while 16S rRNA gene sequencing was used to monitor the dynamic changes in the gut microbiota. The relative concentrations of 35 urinary metabolites and 24 faecal metabolites were significantly changed compared with the control group. 16S rRNA analysis showed that the relative abundances of 4 bacterial genera (Bifidobacterium, Lactobacillus, Allobaculum and Oligella) significantly increased, whereas the relative abundance of 1 bacterial genus (Enterococcus) significantly declined in the compound polysaccharide-treated groups compared with the control group. Meanwhile, dietary compound polysaccharide treatment promoted the functional maturation of the gut bacterial community, characterised by increased basic metabolism (amino acid metabolism and energy metabolism), short chain fatty acid (SCFA)-related metabolism and nucleotide metabolism. These findings suggest that compound polysaccharides may help to promote the colonisation and functional maturation of infant intestinal microbiota and maintain the health of the intestinal microecosystem.


Effects of roughage inclusion and particle size on digestion and ruminal fermentation characteristics of beef steers.
Roughage is fed in finishing diets to promote ruminal health and decrease digestive upset, but the inclusion rate is limited because of the cost per unit of energy and feed management issues. Rumination behavior of cattle may be a means to standardize roughage in beef cattle finishing diets, and increasing the particle size of roughage could modulate the ruminal environment and aid in maintaining ruminal pH. Therefore, this experiment was conducted to determine the effects of corn stalk (CS) inclusion rate and particle size in finishing diets on digestibility, rumination, and ruminal fermentation characteristics of beef steers. Four ruminally cannulated steers were used in a 4 × 4 Latin square experiment. Treatments were arranged as a 2 × 2 factorial with treatments consisting of 5% inclusion of a short-grind roughage (5SG), 10% inclusion of a short-grind roughage (10SG), 5% inclusion of a long-grind roughage (5LG), and 10% inclusion of a long-grind roughage (10LG). Differences in particle size were obtained by grinding corn stalks once (LG) or twice (SG) using a commercial tub grinder equipped with a 7.6-cm screen and quantified using the Penn State Particle Separator (PSPS) to estimate physically effective NDF (peNDF). Each period included 14 d for adaptation and 4 d for diet, fecal, and ruminal fluid collections. Animals were outfitted with rumination monitoring collars to continuously measure rumination activity. The 10LG treatment had a greater ( < 0.01) percentage of large particles (retained on the top 3 sieves of the PSPS) compared to the other treatments. This resulted in a greater ( < 0.01) percentage of estimated peNDF for the 10LG diet compared to the others. Feeding diets containing 5% roughage tended to increase ( ≤ 0.09) DM, NDF, and starch total tract digestibility compared to diets containing 10% roughage. Cattle consuming LG treatments had greater ( < 0.01) rumination time and greater ( < 0.01) ruminal pH than cattle consuming diets containing SG roughage. Cattle receiving the 5% inclusion rate of roughage tended to have greater ( = 0.09) time (h/d) under a ruminal pH of 5.6 and a larger ( = 0.03) area under the threshold compared to cattle receiving the 10% roughage treatments. Overall, feeding a lower inclusion of roughage with a larger particle size may stimulate rumination and aid in ruminal buffering similar to that of a higher inclusion of roughage with a smaller particle size, without negatively impacting digestibility and fermentation.


Outcomes of cesarean sections performed by family physicians and the training they received: a 15-year retrospective study.
Family physicians are the major or sole providers of Cesarean section services in many communities. Approximately 2800 family physicians provide Cesarean section services in communities of all sizes across the country. The outcomes of all Cesarean sections performed at two rural hospitals during a 10- to 15-year period were examined and compared with standard quality-outcome criteria published in the medical literature. Outcome criteria included rates of various surgical complications, use of blood transfusion, infant Apgar scores, and length of postoperative hospital stay. Other descriptive data were examined including patient demographics, operating time, anesthesia type, and choice of incision. Statistical analysis consisted of chi-squares, odds ratios, and stepwise multiple regression. Five hundred sixty-three Cesarean sections were performed by 12 residency-trained family physicians, 68 by general practitioners, 70 by general surgeons, and 9 by obstetrician-gynecologists. Family physicians met or surpassed the referenced standards in all measures examined. The number of Cesarean sections each physician performed while in residency training was also examined. The average number of in-training Cesarean sections was 46, ranging from 25 to 100. The results of this study support the ability of family physicians to provide Cesarean section services based on a wide range of training backgrounds and variable numbers of procedures done in training.


Tyrosine kinase inhibitors can differentially inhibit integrin-dependent and CAM-stimulated neurite outgrowth.
We have used monolayers of parental 3T3 cells and 3T3 cells expressing one of three transfected cell adhesion molecules (CAMs) (NCAM, N-cadherin, and L1) as a culture substrate for rat cerebellar neurons. A number of tyrosine kinase inhibitors have been tested for their ability to inhibit neurite outgrowth over parental 3T3 monolayers which we show to be partly dependent on neuronal integrin receptor function, as compared with neurite outgrowth stimulated by the above three CAMs. Whereas genistein (100 microM), lavendustin A (20 microM), and tyrphostins 34 and 47 (both at 150 microM) had no effect on integrin dependent or CAM stimulated neurite outgrowth, the erbstatin analogue (10-15 micrograms/ml) and tyrphostins 23 and 25 (both at 150 microM) specifically inhibited the response stimulated by all three CAMs. CAM stimulated neurite outgrowth can be accounted for by a G-protein-dependent activation of neuronal calcium channels; experiments with agents that directly activate this pathway localized the erbstatin analogue site of action upstream of the G-protein and calcium channels, whereas tyrphostins have sites of action downstream from calcium channel activation. These data suggest that activation of an erbstatin sensitive tyrosine kinase is an important step upstream of calcium channel activation in the second messenger pathway underlying the neurite outgrowth response stimulated by a variety of CAMs, and that this kinase is not required for integrin-dependent neurite outgrowth.


The formins FHOD1 and INF2 regulate inter- and intra-structural contractility of podosomes.
Podosomes are actin-rich adhesion structures that depend on Arp2/3-complex-based actin nucleation. We now report the identification of the formins FHOD1 and INF2 as novel components and additional actin-based regulators of podosomes in primary human macrophages. FHOD1 surrounds the podosome core and is also present at podosome-connecting cables, whereas INF2 localizes at the podosome cap structure. Using a variety of microscopy-based methods; including a semiautomated podosome reformation assay, measurement of podosome oscillations, FRAP analysis of single podosomes, and structured illumination microscopy, both formins were found to regulate different aspects of podosome-associated contractility, with FHOD1 mediating actomyosin contractility between podosomes, and INF2 regulating contractile events at individual podosomes. Moreover, INF2 was found to be a crucial regulator of podosome de novo formation and size. Collectively, we identify FHOD1 and INF2 as novel regulators of inter- and intra-structural contractility of podosomes. Podosomes thus present as one of the few currently identified structures which depend on the concerted activity of both Arp2/3 complex and specific formins and might serve as a model system for the analysis of complex actin architectures in cells.


Leaf stomatal and epidermal cell development: identification of putative quantitative trait loci in relation to elevated carbon dioxide concentration in poplar.
Genetic variation in stomatal initiation and density, and epidermal cell size and number were examined in a hybrid pedigree of Populus trichocarpa T. & G. and P. deltoides Marsh in both ambient ([aCO2]) and elevated ([eCO2]) concentrations of CO2. We aimed to link anatomical traits with the underlying genetic map of F2 Family 331, composed of 350 markers across 19 linkage groups. Leaf stomatal and epidermal cell traits showed pronounced differences between the original parents. We considered the following traits in the F2 population: stomatal density (SD), stomatal index (SI), epidermal cell area (ECA) and the number of epidermal cells per leaf (ECN). In [eCO2], adaxial SD and SI were reduced in the F2 population, whereas ECA increased and ECN remained unchanged. In [aCO2], four putative quantitative trait loci (QTL) with logarithm of the odds ratio (LOD) scores greater than 2.9 were found for stomatal traits on linkage group B: adaxial SI (LOD scores of 5.4 and 5.2); abaxial SI (LOD score of 3.3); and SD (LOD score of 3.2). These results imply that QTL for SI and SD share linkage group B and are under genetic control. More moderate LOD scores (LOD scores >/= 2.5) suggest QTL for SI on linkage groups A and B and for SD on linkage groups B, D and X with a probable co-locating quantitative trait locus for SI and SD on linkage group D (position 46.3 cM). The QTL in both [aCO2] and [eCO2] for adaxial SD were co-located on linkage group X (LOD scores of 3.5 and 2.6, respectively) indicating a similar response across both treatments. Putative QTL were located on linkage group A (position 89.2 cM) for both leaf size and ECN in [aCO2] and for ECA at almost the same position. The data provide preliminary evidence that leaf stomatal and cell traits are amenable to QTL analysis.


Cutaneous microvascular dysfunction correlates with serum LDL and sLOX-1 receptor concentrations.
The human cutaneous circulation is an accessible and representative regional circulation for investigating mechanisms of microvascular dysfunction, a systemic disease process occurring early in the pathogenesis of atherosclerosis. Elevated concentrations of low-density lipoproteins ([LDL]) are highly atherogenic and independently associated with the severity of coronary atherosclerosis through their actions on the lectin-like oxidized LDL receptors (LOX-1). We hypothesized that cutaneous microvascular dysfunction, as measured by a decrement in endothelial nitric oxide- (NO-) dependent vasodilation during local heating, would be correlated with serum [LDL], oxidized [LDL], and soluble LOX-1 receptors [sLOX-1]. Intradermal microdialysis fibers were placed in the skin of 53 otherwise healthy men and women (aged 52±8 years) whose serum [LDL] ranged from 72 to 233 mg/dL. Skin blood flow was measured by laser Doppler flowmetry over a local forearm skin site as it was heated (42°C) to induce sustained local vasodilation. After flux plateaued, L-NAME was infused to block endothelial NO synthase in order to determine the NO-dependent portion of the vasodilatory response. Data were normalized to maximal cutaneous vascular conductance (CVC). NO-dependent vasodilation was reduced as a linear function of [LDL] (R(2)=0.303, p<0.001), oxidized [LDL] (R(2)=0.214, p<0.001), and [sLOX-1] (R(2)=0.259, p=0.026) but was unrelated to high-density lipoprotein (HDL) concentration (R(2)=0.003, p=0.68). Hypercholesterolemia-induced microvascular dysfunction is related to various LDL markers and involves a reduction in NO-dependent vasodilation that appears to be a progressive process measurable in the skin microcirculation.


Substituting abacavir for hyperlipidemia-associated protease inhibitors in HAART regimens improves fasting lipid profiles, maintains virologic suppression, and simplifies treatment.
Hyperlipidemia secondary to protease inhibitors (PI) may abate by switching to anti-HIV medications without lipid effects. An open-label, randomized pilot study compared changes in fasting lipids and HIV-1 RNA in 104 HIV-infected adults with PI-associated hyperlipidemia (fasting serum total cholesterol >200 mg/dL) who were randomized either to a regimen in which their PI was replaced by abacavir 300 mg twice daily (n = 52) or a regimen in which their PI was continued (n = 52) for 28 weeks. All patients had undetectable viral loads (HIV-1 RNA <50 copies/mL) at baseline and were naive to abacavir and non-nucleoside reverse transcriptase inhibitors. At baseline, the mean total cholesterol was 243 mg/dL, low density lipoprotein (LDL)-cholesterol 149 mg/dL, high density lipoprotein (HDL)-cholesterol 41 mg/dL, and triglycerides 310 mg/dL. Mean CD4+ cell counts were 551 and 531 cells/mm3 in the abacavir-switch and PI-continuation arms, respectively. At week 28, the abacavir-switch arm had significantly greater least square mean reduction from baseline in total cholesterol (-42 vs -10 mg/dL, P < 0.001), LDL-cholesterol (-14 vs +5 mg/dL, P = 0.016), and triglycerides (-134 vs -36 mg/dL, P = 0.019) than the PI-continuation arm, with no differences in HDL-cholesterol (+0.2 vs +1.3 mg/dL, P = 0.583). A higher proportion of patients in the abacavir-switch arm had decreases in protocol-defined total cholesterol and triglyceride toxicity grades, whereas a smaller proportion had increases in these toxicity grades. At week 28, an intent-to treat: missing = failure analysis showed that the abacavir-switch and PI-continuation arms did not differ significantly with respect to proportion of patients maintaining HIV-1 RNA <400 or <50 copies/mL or adjusted mean change from baseline in CD4+ cell count. Two possible abacavir-related hypersensitivity reactions were reported. No significant changes in glucose, insulin, insulin resistance, C-peptide, or waist-to-hip ratios were observed in either treatment arm, nor were differences in these parameters noted between treatments. In hyperlipidemic, antiretroviral-experienced patients with HIV-1 RNA levels <50 copies/mL and CD4+ cell counts >500 cells/mm3, substituting abacavir for hyperlipidemia-associated PIs in combination antiretroviral regimens improves lipid profiles and maintains virologic suppression over a 28-week period, and it simplifies treatment.


Presence and correlates of racial disparities in adherence to colorectal cancer screening guidelines.
We examined the presence and correlates of Black/White racial disparities in adherence to guidelines for colorectal cancer screening (CRCS). The sample included 328 Black and 1827 White patients age 50-75 from 24 VA medical facilities who responded to a mailed survey with phone follow-up (response rate: 73% for Blacks and 89% for Whites). CRCS adherence and race were obtained through surveys and supplemented with administrative data. Logistic regressions estimated the contribution of demographic, health, cognitive, and environmental factors to racial disparities in adherence to CRCS guidelines. In unadjusted analyses, Blacks had slightly lower rates of adherence to CRCS guidelines than Whites (72% versus 77%, p<0.05). This racial disparity in CRCS adherence was explained by race differences in demographic, health, and environmental factors but not by cognitive factors. Tests for interactions revealed that the association of race with adherence varied significantly across levels of income, education, and marital status. In particular, among those who were married with higher levels of education, CRCS adherence was significantly higher for Whites; whereas among those who were unmarried, with low levels of education, adherence was significantly higher for Blacks. We found that disparities in CRCS are greatly attenuated in the VA system and both Whites and Blacks have substantially higher rates of CRCS than the national average. These results point to the success of the VA at implementing CRCS system-wide. Our findings also suggest additional initiatives may be needed for unmarried low income white men and higher income black men.


Formation of shelf stable Pickering high internal phase emulsions (HIPE) through the inclusion of whey protein microgels.
High internal phase emulsions (HIPE) prepared using whey protein microgels (WPMs) as a surfactant were demonstrated to have substantially higher stability than HIPEs prepared using similar loadings of non-gelled whey protein isolate (WPI) or Tween 20. Microgel colloids were prepared from WPI solutions by heat treatment at 85 °C in a narrow pH range (5.8-6.0) to particle sizes of approximately 90, 160 and 350 nm in diameter. ζ-potentials of the WPM increased in negativity with decreasing particle size from -7.4 ± 2.5 down to -21.1 ± 0.9 at 90 nm. All WPMs conferred high stability to corn oil based HIPE when used as an emulsifier. Light microscopy and cryo-scanning electron microscopy showed that both increasing WPM concentration and decreasing WPM particle size produced increasingly smaller and more hexagonally shaped corn oil emulsion droplets; WPI and Tween 20 based HIPE droplets were generally smaller and spherical in shape. The HIPE (75% w/w corn oil) produced with 1% (w/w) WPM as an emulsifier showed stability through 6 months storage at 4 °C at all WPM sizes tested, while the HIPE prepared with 1% (w/w) WPI or Tween 20 exhibited significant creaming. WPM and WPI based HIPE both showed thermal stability at 70 °C and 95 °C while the heating of Tween 20 based HIPE resulted in droplet coalescence and oil-phase separation. HIPE production with WPMs significantly improved the viscoelastic properties of the HIPE, imparting drastic increases in yield stress, critical stress, complex modulus and elastic modulus over HIPE prepared with WPI or Tween 20. The more rigid rheology of the WPM HIPE indicated by these data is likely the primary mechanism driving the improved stability of these emulsions.


Constitutive magnification by the Ybb- chromosome of Drosophila melanogaster.
Ybb- is an rDNA-deficient chromosome of Drosophila that has often been used in magnification experiments to induce high-frequency reversion of bobbed (bb) chromosomes. We observed previously that Ybb- causes ring chromosome loss even when the rings are bb+, suggesting that Ybb- induces magnifying sister chromatid exchanges in bb+ rings. Here we show that the Ybb- chromosome causes low levels of bb magnification in bb+ flies. We refer to the ability of Ybb- to bypass the rDNA deficiency requirement for magnification as 'constitutive' magnification. We have magnified the ribosomal genes on the Ybb- chromosome and analysed the revertant chromosomes using genetic and molecular methods. We find that magnified Ybb- chromosomes also exhibit constitutive magnifier activity. Molecular analysis shows that both type 1 and type 2 intron+ ribosomal gene repeats are associated with magnified Ybb- chromosomes. Type 2 introns have been described previously in the rDNA of both X and Y chromosomes. However, type 1 intervening sequences are thought to be present only in X, but not Y, ribosomal genes. Some of the Ybb- type 1 insertions differ from those present in the rDNA of X chromosomes in that they contain an EcoRI site, and some may be present in tandem arrays. The constitutive magnifier activity of Ybb- may reside either in the structurally unusual ribosomal gene intervening sequences associated with the chromosome, or in the locus on YL that is required for magnification to occur.


Do Homeopathic Pathogenetic Trials generate recognisable and reproducible symptom pictures?: Results from a pilot pathogenetic trial of Ozone 30c.
Homeopathic Pathogenetic Trials (HPTs) are a pillar of homeopathy, a key source of the symptoms characteristic of a particular homeopathic medicine. Homeopaths choose homeopathic medicines by comparing these remedy pictures with the symptoms the patient is presenting. Thus, recognition of these symptom sets underpins the clinical practice of homeopathy. To test whether HPTs generate consistent and recognisable sets of symptoms in consecutive trials. Practising homeopaths, blinded to the homeopathic medicine under investigation, were given the set of symptoms generated during an unpublished HPT and asked to identify the homeopathic medicine used. Ozone, prepared by homeopathic method to the ultramolecular dilution of 30c (10(-60) dilution), was chosen at random from twenty potential medicines. Seven practising homeopaths were asked to make three guesses as to the identity of the remedy. Initially from the full list of possible remedies (N = 2372). Two of the seven homeopaths guessed the identity of the remedy correctly (p < 0.0001). Subsequently, when their choice of possible medicines was restricted to a list of 20, the same two homeopaths selected the correct medicine, however none of the other practising homeopaths did so (p = 0.2). The selection of the correct homeopathic medicine from the unrestricted list (N = 2372 medicines) by two homeopaths is noteworthy given that the homeopathic medicine used during the HPT was diluted well beyond Avogadro's number and would not be expected to produce any detectable or recognisable symptomatology. Possible reasons why the remaining five homeopaths did not guess correctly are discussed. The results show that practising homeopaths may be able to correctly identify a homeopathic medicine from the set of symptoms generated during an HPT. This suggests that such symptom pictures generated by taking an ultramolecular homeopathic medicine are recognisable and specific to the substance taken. Since identification of the remedy was based on past HPT information held in the materia medica, this demonstrates that HPT-generated symptom pictures are reproducible, thus validating the HPT methodology. These promising preliminary findings warrant replication; possible improvements to the trial design to be incorporated in future studies were identified.


Free energy barriers to evaporation of water in hydrophobic confinement.
We use umbrella sampling Monte Carlo and forward and reverse forward flux sampling (FFS) simulation techniques to compute the free energy barriers to evaporation of water confined between two hydrophobic surfaces separated by nanoscopic gaps, as a function of the gap width, at 1 bar and 298 K. The evaporation mechanism for small (1 × 1 nm(2)) surfaces is found to be fundamentally different from that for large (3 × 3 nm(2)) surfaces. In the latter case, the evaporation proceeds via the formation of a gap-spanning tubular cavity. The 1 × 1 nm(2) surfaces, in contrast, are too small to accommodate a stable vapor cavity. Accordingly, the associated free energy barriers correspond to the formation of a critical-sized cavity for sufficiently large confining surfaces, and to complete emptying of the gap region for small confining surfaces. The free energy barriers to evaporation were found to be of O(20kT) for 14 Å gaps, and to increase by approximately ~5kT with every 1 Å increase in the gap width. The entropy contribution to the free energy of evaporation was found to be independent of the gap width.


Immune Activation and HIV-Specific CD8(+) T Cells in Cerebrospinal Fluid of HIV Controllers and Noncontrollers.
The central nervous system (CNS) is an important target of HIV, and cerebrospinal fluid (CSF) can provide a window into host-virus interactions within the CNS. The goal of this study was to determine whether HIV-specific CD8(+) T cells are present in CSF of HIV controllers (HC), who maintain low to undetectable plasma viremia without antiretroviral therapy (ART). CSF and blood were sampled from 11 HC, defined based on plasma viral load (VL) consistently below 2,000 copies/ml without ART. These included nine elite controllers (EC, plasma VL <40 copies/ml) and two viremic controllers (VC, VL 40-2,000 copies/ml). All controllers had CSF VL <40 copies/ml. Three comparison groups were also sampled: six HIV noncontrollers (NC, VL >10,000 copies/ml, no ART); seven individuals with viremia suppressed due to ART (Tx, VL <40 copies/ml); and nine HIV-negative controls. CD4(+) and CD8(+) T cells in CSF and blood were analyzed by flow cytometry to assess expression of CCR5, activation markers CD38 and HLA-DR, and memory/effector markers CD45RA and CCR7. HIV-specific CD8(+) T cells were quantified by major histocompatibility complex class I multimer staining. HIV-specific CD8(+) T cells were detected ex vivo at similar frequencies in CSF of HC and noncontrollers; the highest frequencies were in individuals with CD4 counts below 500 cells/μl. The majority of HIV-specific CD8(+) T cells in CSF were effector memory cells expressing CCR5. Detection of these cells in CSF suggests active surveillance of the CNS compartment by HIV-specific T cells, including in individuals with long-term control of HIV infection in the absence of therapy.


Effect of Structure of Polymers Grafted from Graphene Oxide on the Compatibility of Particles with a Silicone-Based Environment and the Stimuli-Responsive Capabilities of Their Composites.
This study reports the utilization of controlled radical polymerization as a tool for controlling the stimuli-responsive capabilities of graphene oxide (GO) based hybrid systems. Various polymer brushes with controlled molecular weight and narrow molecular weight distribution were grafted from the GO surface by surface-initiated atom transfer radical polymerization (SI-ATRP). The modification of GO with poly(n-butyl methacrylate) (PBMA), poly(glycidyl methacrylate) (PGMA), poly(trimethylsilyloxyethyl methacrylate) (PHEMATMS) and poly(methyl methacrylate) (PMMA) was confirmed by thermogravimetric analysis (TGA) coupled with online Fourier transform infrared spectroscopy (FTIR), transmission electron microscopy (TEM) and X-ray photoelectron spectroscopy (XPS). Various grafting densities of GO-based materials were investigated, and conductivity was elucidated using a four-point probe method. Raman shift and XPS were used to confirm the reduction of surface properties of the GO particles during SI-ATRP. The contact angle measurements indicated the changes in the compatibility of GOs with silicone oil, depending on the structure of the grafted polymer chains. The compatibility of the GOs with poly(dimethylsiloxane) was also investigated using steady shear rheology. The tunability of the electrorheological, as well as the photo-actuation capability, was investigated. It was shown that in addition to the modification of conductivity, the dipole moment of the pendant groups of the grafted polymer chains also plays an important role in the electrorheological (ER) performance. The compatibility of the particles with the polymer matrix, and thus proper particles dispersibility, is the most important factor for the photo-actuation efficiency. The plasticizing effect of the GO-polymer hybrid filler also has a crucial impact on the matrix stiffness and thus the ability to reversibly respond to the external light stimulation.


Sex differences in aging of the human frontal and temporal lobes.
This study investigated effects of age and sex on regional brain structure in humans, focusing on the frontal and temporal lobes. Hemispheric volumes were obtained from magnetic resonance images (MRIs) of 96 young (53 men, 43 women; aged 18-40 years) and 34 older (17 men, 17 women; aged 41-80) healthy volunteers. Images (5 mm axial spin-echo, repetition time of 3000 msec and echo times of 30 and 80 msec) were resliced along the anterior commissure-posterior commissure (AC-PC) axis to standardize for difference in head tilt, and imported into a computer program where borders of the frontal and temporal lobes were delineated. The program calculated regional brain volumes based on slice data from which CSF was segmented out. An age x sex x hemisphere x region interaction indicated that age-related reductions in brain volume were sexually dimorphic, lateralized, and region specific. Greater decrements in brain volume occurred with age in the frontal lobe than in the temporal lobe. Age-related reductions in both regions were greater in men than in women, demonstrating that sexual dimorphisms in human neuroanatomy are not fixed, but continue to change throughout adulthood. The possibility that gonadal hormones play a role in the promotion and/or prevention of neural atrophy with aging is discussed.


Endogenous DNA abasic sites cause cell death in the absence of Apn1, Apn2 and Rad1/Rad10 in Saccharomyces cerevisiae.
In Saccharomyces cerevisiae, mutations in APN1, APN2 and either RAD1 or RAD10 genes are synthetic lethal. In fact, apn1 apn2 rad1 triple mutants can form microcolonies of approximately 300 cells. Expression of Nfo, the bacterial homologue of Apn1, suppresses the lethality. Turning off the expression of Nfo induces G(2)/M cell cycle arrest in an apn1 apn2 rad1 triple mutant. The activation of this checkpoint is RAD9 dependent and allows residual DNA repair. The Mus81/Mms4 complex was identified as one of these back-up repair activities. Furthermore, inactivation of Ntg1, Ntg2 and Ogg1 DNA N-glycosylase/AP lyases in the apn1 apn2 rad1 background delayed lethality, allowing the formation of minicolonies of approximately 10(5) cells. These results demonstrate that, under physiological conditions, endogenous DNA damage causes death in cells deficient in Apn1, Apn2 and Rad1/Rad10 proteins. We propose a model in which endogenous DNA abasic sites are converted into 3'-blocked single-strand breaks (SSBs) by DNA N-glycosylases/AP lyases. Therefore, we suggest that the essential and overlapping function of Apn1, Apn2, Rad1/Rad10 and Mus81/Mms4 is to repair 3'-blocked SSBs using their 3'-phosphodiesterase activity or their 3'-flap endonuclease activity, respectively.


Combined microsurgical and endovascular management of complex intracranial aneurysms.
The disciplines of microneurosurgery and cranial base surgery have reached maturity, and technical advances in the surgical management of aneurysms are limited. Although most aneurysms can be clipped microsurgically or coiled endovascularly, a subset of patients may require a combined approach. A consecutive series of patients with aneurysms in one surgeon's cerebrovascular practice was reviewed retrospectively to analyze strategies for integrating microsurgical and endovascular techniques in the management of complex aneurysms. Between 1997 and 2001, 596 aneurysms in 491 patients were treated microsurgically by the senior author (MTL) at the University of California, San Francisco, and 77 of these patients (96 aneurysms) were managed with a multimodality approach comprising a total of eight different combinations: selective revascularization and aneurysm occlusion (n = 23), endovascular and surgical trapping (n = 1), clipping of the aneurysm after attempted or incomplete coiling (n = 22), coiling after attempted or incomplete clipping (n = 5), clipping of recurrent aneurysm after coiling (n = 6), coiling of recurrent aneurysm after clipping (n = 1), clipping and coiling of multiple remote aneurysms (n = 13), and coiling after previous surgery (n = 6). A total of 96 aneurysms were treated with combined therapy, of which 43% were large or giant in size and 34% had fusiform or dolichoectatic morphology. Complete angiographic obliteration was achieved in 91 aneurysms (95%). Overall, 66 patients (86%) had good outcomes (Glasgow Outcome Scale score of 4 or 5; mean follow-up, 9 mo). The treatment mortality rate was 9.1% (seven patients), and permanent treatment-associated neurological morbidity rate was 5.2% (four patients). Evolving endovascular technologies need to be integrated into the microsurgical management of aneurysms. Multimodality approaches are best used with complex aneurysms in which conventional therapy with a single modality has failed. Revascularization remains a unique surgical contribution to the overall management of aneurysms with which current endovascular techniques cannot be used. Multimodality management should be considered an elegant addition to the therapeutic armamentarium that, through simplification and increased safety, improves the treatment of complex aneurysms beyond what is achievable by performing clipping or coiling alone.


White rice consumption and risk of type 2 diabetes: meta-analysis and systematic review.
To summarise evidence on the association between white rice consumption and risk of type 2 diabetes and to quantify the potential dose-response relation. Meta-analysis of prospective cohort studies. Searches of Medline and Embase databases for articles published up to January 2012 using keywords that included both rice intake and diabetes; further searches of references of included original studies. Included studies were prospective cohort studies that reported risk estimates for type 2 diabetes by rice intake levels. Relative risks were pooled using a random effects model; dose-response relations were evaluated using data from all rice intake categories in each study. Four articles were identified that included seven distinct prospective cohort analyses in Asian and Western populations for this study. A total of 13,284 incident cases of type 2 diabetes were ascertained among 352,384 participants with follow-up periods ranging from 4 to 22 years. Asian (Chinese and Japanese) populations had much higher white rice consumption levels than did Western populations (average intake levels were three to four servings/day versus one to two servings/week). The pooled relative risk was 1.55 (95% confidence interval 1.20 to 2.01) comparing the highest with the lowest category of white rice intake in Asian populations, whereas the corresponding relative risk was 1.12 (0.94 to 1.33) in Western populations (P for interaction=0.038). In the total population, the dose-response meta-analysis indicated that for each serving per day increment of white rice intake, the relative risk of type 2 diabetes was 1.11 (1.08 to 1.14) (P for linear trend<0.001). Higher consumption of white rice is associated with a significantly increased risk of type 2 diabetes, especially in Asian (Chinese and Japanese) populations.


Nuclear gene indicates coat-color polymorphism in mammoths.
By amplifying the melanocortin type 1 receptor from the woolly mammoth, we can report the complete nucleotide sequence of a nuclear-encoded gene from an extinct species. We found two alleles and show that one allele produces a functional protein whereas the other one encodes a protein with strongly reduced activity. This finding suggests that mammoths may have been polymorphic in coat color, with both dark- and light-haired individuals co-occurring.


Action Candidate Driven Clipped Double Q-Learning for Discrete and Continuous Action Tasks.
Double Q-learning is a popular reinforcement learning algorithm in Markov decision process (MDP) problems. Clipped double Q-learning, as an effective variant of double Q-learning, employs the clipped double estimator to approximate the maximum expected action value. Due to the underestimation bias of the clipped double estimator, the performance of clipped Double Q-learning may be degraded in some stochastic environments. In this article, in order to reduce the underestimation bias, we propose an action candidate-based clipped double estimator (AC-CDE) for Double Q-learning. Specifically, we first select a set of elite action candidates with high action values from one set of estimators. Then, among these candidates, we choose the highest valued action from the other set of estimators. Finally, we use the maximum value in the second set of estimators to clip the action value of the chosen action in the first set of estimators and the clipped value is used for approximating the maximum expected action value. Theoretically, the underestimation bias in our clipped Double Q-learning decays monotonically as the number of action candidates decreases. Moreover, the number of action candidates controls the tradeoff between the overestimation and underestimation biases. In addition, we also extend our clipped Double Q-learning to continuous action tasks via approximating the elite continuous action candidates. We empirically verify that our algorithm can more accurately estimate the maximum expected action value on some toy environments and yield good performance on several benchmark problems. Code is available at https://github.com/Jiang-HB/ac_CDQ.


An Expanded Ribosomal Phylogeny of Cyanobacteria Supports a Deep Placement of Plastids.
The phylum Cyanobacteria includes free-living bacteria and plastids, the descendants of cyanobacteria that were engulfed by the ancestral lineage of the major photosynthetic eukaryotic group Archaeplastida. Endosymbiotic events that followed this primary endosymbiosis spread plastids across diverse eukaryotic groups. The remnants of the ancestral cyanobacterial genome present in all modern plastids, enable the placement of plastids within Cyanobacteria using sequence-based phylogenetic analyses. To date, such phylogenetic studies have produced conflicting results and two competing hypotheses: (1) plastids diverge relatively recently in cyanobacterial evolution and are most closely related to nitrogen-fixing cyanobacteria, or (2) plastids diverge early in the evolutionary history of cyanobacteria, before the divergence of most cyanobacterial lineages. Here, we use phylogenetic analysis of ribosomal proteins from an expanded data set of cyanobacterial and representative plastid genomes to infer a deep placement for the divergence of the plastid ancestor lineage. We recover plastids as sister to Gloeomargarita and show that the group diverges from other cyanobacterial groups before Pseudanabaena, a previously unreported placement. The tree topologies and phylogenetic distances in our study have implications for future molecular clock studies that aim to model accurate divergence times, especially with respect to groups containing fossil calibrations. The newly sequenced cyanobacterial groups included here will also enable the use of novel cyanobacterial microfossil calibrations.


Decomposition of Near-Infrared Spectroscopy Signals Using Oblique Subspace Projections: Applications in Brain Hemodynamic Monitoring.
Clinical data is comprised by a large number of synchronously collected biomedical signals that are measured at different locations. Deciphering the interrelationships of these signals can yield important information about their dependence providing some useful clinical diagnostic data. For instance, by computing the coupling between Near-Infrared Spectroscopy signals (NIRS) and systemic variables the status of the hemodynamic regulation mechanisms can be assessed. In this paper we introduce an algorithm for the decomposition of NIRS signals into additive components. The algorithm, SIgnal DEcomposition base on Obliques Subspace Projections (SIDE-ObSP), assumes that the measured NIRS signal is a linear combination of the systemic measurements, following the linear regression model y = Ax + ϵ. SIDE-ObSP decomposes the output such that, each component in the decomposition represents the sole linear influence of one corresponding regressor variable. This decomposition scheme aims at providing a better understanding of the relation between NIRS and systemic variables, and to provide a framework for the clinical interpretation of regression algorithms, thereby, facilitating their introduction into clinical practice. SIDE-ObSP combines oblique subspace projections (ObSP) with the structure of a mean average system in order to define adequate signal subspaces. To guarantee smoothness in the estimated regression parameters, as observed in normal physiological processes, we impose a Tikhonov regularization using a matrix differential operator. We evaluate the performance of SIDE-ObSP by using a synthetic dataset, and present two case studies in the field of cerebral hemodynamics monitoring using NIRS. In addition, we compare the performance of this method with other system identification techniques. In the first case study data from 20 neonates during the first 3 days of life was used, here SIDE-ObSP decoupled the influence of changes in arterial oxygen saturation from the NIRS measurements, facilitating the use of NIRS as a surrogate measure for cerebral blood flow (CBF). The second case study used data from a 3-years old infant under Extra Corporeal Membrane Oxygenation (ECMO), here SIDE-ObSP decomposed cerebral/peripheral tissue oxygenation, as a sum of the partial contributions from different systemic variables, facilitating the comparison between the effects of each systemic variable on the cerebral/peripheral hemodynamics.


Determinants of use of maternal health services in Nigeria--looking beyond individual and household factors.
Utilization of maternal health services is associated with improved maternal and neonatal health outcomes. Considering global and national interests in the Millennium Development Goal and Nigeria's high level of maternal mortality, understanding the factors affecting maternal health use is crucial. Studies on the use of maternal care services have largely overlooked community and other contextual factors. This study examined the determinants of maternal services utilization in Nigeria, with a focus on individual, household, community and state-level factors. Data from the 2005 National HIV/AIDS and Reproductive Health Survey - an interviewer-administered nationally representative survey - were analyzed to identify individual, household and community factors that were significantly associated with utilization of maternal care services among 2148 women who had a baby during the five years preceding the survey. In view of the nested nature of the data, we used multilevel analytic methods and assessed state-level random effects. Approximately three-fifths (60.3%) of the mothers used antenatal services at least once during their most recent pregnancy, while 43.5% had skilled attendants at delivery and 41.2% received postnatal care. There are commonalities and differences in the predictors of the three indicators of maternal health service utilization. Education is the only individual-level variable that is consistently a significant predictor of service utilization, while socio-economic level is a consistent significant predictor at the household level. At the community level, urban residence and community media saturation are consistently strong predictors. In contrast, some factors are significant in predicting one or more of the indicators of use but not for all. These inconsistent predictors include some individual level variables (the woman's age at the birth of the last child, ethnicity, the notion of ideal family size, and approval of family planning), a community-level variable (prevalence of the small family norm in the community), and a state-level variable (ratio of PHC to the population). Factors influencing maternal health services utilization operate at various levels - individual, household, community and state. Depending on the indicator of maternal health services, the relevant determinants vary. Effective interventions to promote maternal health service utilization should target the underlying individual, household, community and policy-level factors. The interventions should reflect the relative roles of the various underlying factors.


Nasal contribution to exhaled nitric oxide during exhalation against resistance or during breath holding.
The concentration of nitric oxide (NO) is increased in the exhaled air of patients with inflammation of the airways, suggesting that this may be a useful measurement to monitor inflammation in diseases such as asthma. However, there have been concerns that exhaled NO may be contaminated by the high concentrations of NO derived from the upper airways, and that this may account for differences in reported values of exhaled NO using different techniques. A study was performed, with argon as a tracer, to determine the extent of nasal contamination of exhaled NO using different expiratory manoeuvres. Exhaled and nasal NO were measured by a chemiluminescence analyser. Argon (4.8%) was delivered continuously to the nose. Gas was sampled from the posterior oropharynx and argon and carbon dioxide were measured by mass spectrometry at the same time as NO. During a single expiration against a low resistance and during breath holding there was no evidence for nasal contamination, whereas during exhalation without resistance argon concentration in the oropharynx was increased from 0.91% (95% CI 0.84% to 0.98%) in ambient air to 1.28% (0.9% to 2.24%, p < 0.0001) during a single breath or 2.37% (2.29% to 2.51%, p < 0.0001) during tidal breathing. Collection of exhaled NO in a reservoir during tidal breathing is likely to be contaminated by NO derived from the nose and this may underestimate any increases in NO derived from the lower respiratory tract in inflammatory diseases. However, with slow expiration against a resistance and created back pressure to close the soft palate, there is no contamination of exhaled air which then reflects concentrations of NO in the lower airways.


Life sciences: radiobiological advanced biostack experiment.
The radiobiological properties of the heavy ions of cosmic radiation were investigated on Spacelab 1 by use of biostacks, monolayers of biological test organisms sandwiched between thin foils of different types of nuclear track detectors. Biostacks were exposed to cosmic radiation at several locations with different shielding environments in the module and on the pallet. Evaluations of the physical and biological components of the experiment to date indicate that in general they survived the spaceflight in good condition. Dosimetric data are presented for the different shielding environments.


Single institutional experience of prevalence and risk factors of thromboembolic events in children with solid tumors.
Children with cancer are long-term survivors and sequelae from thromboembolic events (TEEs) that include postthrombotic syndrome can cause significant morbidity. Prevalence and risk factors in children with solid tumors are not well described despite some recent studies. If risk factors were better defined, it may be possible to institute appropriate strategies to prevent TEEs and sequelae. A single institution study was performed to investigate the prevalence and risk factors of TEEs in pediatric solid tumors; this included a retrospective analysis of children with central nervous system (CNS) and non-CNS solid tumors with and without TEEs. TEEs were observed in 7.16% of analyzed tumors, higher in the non-CNS (10.6%) than in the CNS tumor category (1.9% P <0.0066). Factors associated with significant risk of TEEs are as follows: presence of a mediastinal mass (P = 0.0005), metastatic disease (P = 0.0086), infection (0.0120), central venous access device (CVAD) (P = 0.0167), and steroids as chemotherapy (P = 0.01). In patients with CVADs, a mediastinal mass (P = 0.0024) and the type of CVAD (peripherally inserted central catheters were more significant risk factors compared with Mediport; P < 0.0001) were significant risk factors. There was a 3.5-fold increased risk of TEEs in patients with CVADs with an underlying diagnosis of lymphoma vs. CNS tumors. Patients with non-CNS solid tumors had increased prevalence of TEEs in our study. Risk factors included metastatic disease, presence of a mediastinal mass, CVAD use, infection, and the use of steroids. Our study underscores the need to conduct a prospective study to formulate the use of prophylactic anticoagulation in patients with identified risk factors to prevent TEEs.


Relationship between abuse and neglect in childhood and diabetes in adulthood: differential effects by sex, national longitudinal study of adolescent health.
Few studies have investigated links between child abuse and neglect and diabetes mellitus in nationally representative samples, and none have explored the role of obesity in the relationship. We sought to determine whether child abuse and neglect were associated with diabetes and if so, whether obesity mediated this relationship in a population-representative sample of young adults. We used data from 14,493 participants aged 24 to 34 years from Wave IV of the National Longitudinal Study of Adolescent Health to study associations between self-reported child abuse (sexual, physical, or emotional abuse) and neglect as children and diabetes or prediabetes in young adulthood. We conducted sex-stratified logistic regression analyses to evaluate associations in models before and after the addition of body mass index (BMI) as a covariate. Although the prevalence of diabetes was similar for men and women (7.0% vs 6.7%), men were more likely than women to have prediabetes (36.3% vs 24.6%; omnibus P < .001). Among men, recurrent sexual abuse (≥3 lifetime incidents) was significantly associated with diabetes (OR, 3.66; 95% CI, 1.31-10.24), but not with prediabetes. There was no evidence of mediation by BMI. No forms of child abuse or neglect were associated with diabetes or prediabetes among women. Recurrent sexual abuse is robustly associated with diabetes in young adult men, independently of other forms of child abuse or neglect and BMI. Future research should explore other potential mechanisms for this association to identify avenues for prevention of diabetes among men who have experienced sexual abuse.


Novel rat model for neurocysticercosis using Taenia solium.
Neurocysticercosis is caused by Taenia solium infecting the central nervous system and is the leading cause of acquired epilepsy and convulsive conditions worldwide. Research into the pathophysiology of the disease and appropriate treatment is hindered by lack of cost-effective and physiologically similar animal models. We generated a novel rat neurocysticercosis model using intracranial infection with activated T. solium oncospheres. Holtzman rats were infected in two separate groups: the first group was inoculated extraparenchymally and the second intraparenchymally, with different doses of activated oncospheres. The groups were evaluated at three different ages. Histologic examination of the tissue surrounding T. solium cysticerci was performed. Results indicate that generally infected rats developed cysticerci in the brain tissue after 4 months, and the cysticerci were observed in the parenchymal, ventricle, or submeningeal brain tissue. The route of infection did not have a statistically significant effect on the proportion of rats that developed cysticerci, and there was no dependence on infection dose. However, rat age was crucial to the success of the infection. Epilepsy was observed in 9% of rats with neurocysticercosis. In histologic examination, a layer of collagen tissue, inflammatory infiltrate cells, perivascular infiltrate, angiogenesis, spongy change, and mass effect were observed in the tissue surrounding the cysts. This study presents a suitable animal model for the study of human neurocysticercosis.


15S-Hydroxyeicosatetraenoic acid activates peroxisome proliferator-activated receptor gamma and inhibits proliferation in PC3 prostate carcinoma cells.
15-Lipoxygenase (15-LOX)-2 is expressed in benign prostate secretory cells and benign prostate produces 15S-hydroxyeicosatetraenoic acid (15S-HETE) from exogenous arachidonic acid (AA). In contrast, 15S-LOX-2 and 15S-HETE formation are reduced in prostate carcinoma (Pca). The mechanisms whereby reduced 15-LOX-2 may contribute to Pca development or progression are not known. We investigated the expression of peroxisome proliferator-activated receptor (PPAR) gamma in benign and malignant prostate tissues and the ability of 15S-HETE to activate PPARgamma-dependent transcription and modulate proliferation of the Pca cell line PC3. In contrast to benign prostate and similar to most Pca tissues, 15-LOX-2 mRNA was not detected in PC3 cells, and they did not produce detectable 15-HETE from [14C]AA. By reverse transcription-PCR, PPARgamma mRNA was present in 18 of 18 benign and 9 of 9 tumor specimens. The PPARgamma ligand BRL 49653 and 15S-HETE caused a dose-dependent inhibition of PC3 proliferation in a 14-day soft agar colony-forming assay (IC50 of 3 and 30 microM, respectively). 15S-HETE (10 microM) caused greater inhibition than 10 microM 15R-HETE. At 3 days, BRL 49653 and 15S-HETE caused a slight increase in cells in G0-G1 and a corresponding decrease in cells in S phase. In PC3 cells transiently transfected with a luciferase reporter linked to a PPAR response element, 1 microM BRL 49653 and 10 microM 15S-HETE caused approximately threefold and greater than twofold induction of PPAR-dependent transcription, respectively. By quantitative real-time reverse transcription-PCR and Northern analysis, 3-day treatment with BRL 49653 and 15S-HETE caused a reduction of PPARgamma expression but a marked up-regulation of the PPAR response element containing adipocyte type fatty acid binding protein. These results support the hypothesis that 15-LOX-2-derived 15S-HETE may constitute an endogenous ligand for PPARgamma in the prostate and that loss of this pathway by reduced expression of 15-LOX-2 may contribute to increased proliferation and reduced differentiation in prostate carcinoma.


AIRE deficiency in thymus of 2 patients with Omenn syndrome.
Omenn syndrome is a severe primary immunodeficiency with putative autoimmune manifestations of the skin and gastrointestinal tract. The disease is caused by hypomorphic mutations in recombination-activating genes that impair but do not abolish the process of VDJ recombination, leading to the generation of autoreactive T cells with a highly restricted receptor repertoire. Loss of central tolerance in genetically determined autoimmune diseases, e.g., autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy, is associated with defective expression by medullary thymic epithelial cells of AIRE, the transcription activator that induces thymic expression of tissue-specific antigens. Analysis of AIRE expression in the thymi of 2 Omenn syndrome patients and 1 SCID patient, by real-time RT-PCR and immunohistochemistry, demonstrated a profound reduction in the levels of AIRE mRNA and protein in patients as compared with a normal control subject. Lack of AIRE was associated with normal or even increased levels of keratin and lymphotoxin-beta receptor mRNAs, while mRNAs of the self-antigens insulin, cytochrome P450 1a2, and fatty acid-binding protein were undetectable in thymi from immunodeficiency patients. These results demonstrate that deficiency of AIRE expression is observed in severe immunodeficiencies characterized by abnormal T cell development and suggest that in Omenn syndrome, the few residual T cell clones that develop may escape negative selection and thereafter expand in the periphery, causing massive autoimmune reactions.


[Research on cleaning rate of the C-shaped canal treated by manual or rotary endodontic file combined with ultrasonic rinsing].
To evaluate the cleaning effect of the C-shaped canal treated by manual K file and ProTaper rotary endodontic file combined with ultrasonic cleaning, and find a better cleaning program for the C-shaped root canal. Fifty mandibular second molars were randomly divided into 5 groups: K file group, K file+ultrasonic rinsing group, ProTaper group, ProTaper+ultrasonic rinsing group and the control group. After initial shaping and cleaning, the mandibular second molars were soaked in formalin and stained. Under microscopy, the cleaning rate of necrotic tissue and cutting area were observed and analyzed. The data was processed with SPSS 17.0 software package. The cleaning rates of the treated groups were significantly higher than that of the control group (P<0.05); In each treatment group, the cleaning rate of the apex was significantly lower than that of the crown and central part (P<0.05); The cutting score of ProTaper+ultrasonic cleaning group was lower than that of the other treatment groups; The cutting score of the K file+ultrasonic rinsing group was significantly lower than that of the K file group (P<0.05); The cutting score and cleaning rate were negatively correlated (r=-0.712, P=0.000 ), the linear regression was the cleaning rate =98.325-4.325 × wall cutting score (R=0.454, P<0.05). In the process of shaping and cleaning of C-shaped canal, it is recommended that the ProTaper nickel-titanium rotary endodontic file should be chosen to clean the top of the taproot pipe and combined with ultrasonic rinsing to achieve better results.


Comparison and adaptation.
It has sometimes been suggested that the term adaptation should be reserved for differences with a known genetic basis. We argue that adaptation should be defined by its effects rather than by its causes as any difference between two phenotypic traits (or trait complexes) which increases the inclusive fitness of its carrier. This definition implies that some adaptations may arise by means other than natural selection. It is particularly important to bear this in mind when behavioural traits are considered. Critics of the 'adaptationist programme' have suggested that an important objection to many adaptive explanations is that they rely on ad-hoc arguments concerning the function of previously observed differences. We suggest that this is a less important problem (because evolutionary explanations generally claim some sort of generality and are therefore testable) than the difficulties arising from confounding variables. These are more widespread and more subtle than is generally appreciated. Not all differences between organisms are directly adapted to ecological variation. The form of particular traits usually constrains the form of value that other traits can take, presenting several obstacles to attempts to relate variation in morphological or behavioural characteristics directly to environmental differences. We describe some of the repercussions of differences in body size among vertebrates and ways in which these can be allowed for. In addition, a variety of evolutionary processes can produce non-adaptive differences between organisms. One way of distinguishing between these and adaptations is to investigate adaptive trends in phylogenetically different groups of species.


SARS-CoV-2 spike protein-mediated cell signaling in lung vascular cells.
Currently, the world is suffering from the pandemic of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that uses angiotensin-converting enzyme 2 (ACE2) as a receptor to enter the host cells. So far, 30 million people have been infected with SARS-CoV-2, and nearly 1 million people have died because of COVID-19 worldwide, causing serious health, economical, and sociological problems. However, the mechanism of the effect of SARS-CoV-2 on human host cells has not been defined. The present study reports that the SARS-CoV-2 spike protein alone without the rest of the viral components is sufficient to elicit cell signaling in lung vascular cells. The treatment of human pulmonary artery smooth muscle cells or human pulmonary artery endothelial cells with recombinant SARS-CoV-2 spike protein S1 subunit (Val16 - Gln690) at 10 ng/ml (0.13 nM) caused an activation of MEK phosphorylation. The activation kinetics was transient with a peak at 10 min. The recombinant protein that contains only the ACE2 receptor-binding domain of SARS-CoV-2 spike protein S1 subunit (Arg319 - Phe541), on the other hand, did not cause this activation. Consistent with the activation of cell growth signaling in lung vascular cells by SARS-CoV-2 spike protein, pulmonary vascular walls were found to be thickened in COVID-19 patients. Thus, SARS-CoV-2 spike protein-mediated cell growth signaling may participate in adverse cardiovascular/pulmonary outcomes, and this mechanism may provide new therapeutic targets to combat COVID-19.


The effect of passive smoking and tobacco exposure through breast milk on sudden infant death syndrome.
To examine the relationship between sudden infant death syndrome (SIDS) and smoking during pregnancy; postnatal tobacco smoke exposure from the mother, father, live-in-adults, and day care providers; and postnatal smoke exposure from breast-feeding. Case-control study. Five counties in Southern California. A total of 200 white, African-American, Hispanic, and Asian parents of infants who died of SIDS between 1989 and 1992 were compared with 200 control parents who delivered healthy infants. Case infants were matched to control infants on the basis of birth hospital, birth date, gender, and race. All information was obtained from a detailed telephone interview and validated with medical records. Risk of SIDS associated with passive smoking by the mother, father, live-in adults, and day care providers; smoking in the same room as the infant; total number of cigarettes smoked by all adults; and maternal smoking during the time period of breast-feeding. Conditional logistic regression resulted in overall adjusted odds ratios (ORs) for SIDS associated with passive smoke from the mother of 2.28, the father of 3.46, other live-in adults of 2.18, and all sources of 3.50 (95% confidence interval, 1.81 to 6.75), while simultaneously adjusting for birth weight, sleep position, prenatal care, medical conditions at birth, breast-feeding, and maternal smoking during pregnancy. A dose-response effect was noted for SIDS associated with increasing numbers of cigarettes, as well as total number of smokers. Breast-feeding was protective for SIDS among nonsmokers (OR = 0.37) but not smokers (OR = 1.38), when adjusting for potential confounders. Passive smoking in the same room as the infant increases the risk for SIDS. Physicians should educate new and prospective parents about the risk of tobacco smoke exposure during pregnancy and the first year of the infant's life.


CARBONIC ANHYDRASE ACTIVITY OF INTEGRAL-FUNCTIONAL COMPLEXES OF THYLAKOID MEMBRANES OF SPINACH CHLOROPLASTS.
Isolated thylakoid membranes were disrupted by treatment with nonionic detergents digitonin or dodecyl maltoside. Solubilized polypeptide complexes were separated by native gel charge shift electrophoresis. The position of ATP-synthase complex and its isolated catalytic part (CF1) within gel was determined using the color reaction for ATPase activity. Due to the presence of cytochromes, the red band in unstained gels corresponded to the cytochrome b6f complex. Localization of the cytochrome b6f complex, ATP synthase and coupling CF1 in the native gel was confirmed by their subunit composition determined after SDS-electrophoretic analysis. Carbonic anhydrase (CA) activity in polypeptide zones of PS II, cytochrome b6f complex, and ATP-synthase CF1 was identified in native gels using indicator bromothymol blue. CA activity of isolated CF1 in solution was determined by infrared gas analysis as the rate of bicarbonate dehydration. The water-soluble acetazolamide, an inhibitor of CA, unlike lipophilic ethoxyzolamide inhibited CA activity of CF1 Thus, it was shown for the first time that ATP-synthase has a component which is capable of catalyzing the interconversion of forms of carbonic acid associated with proton exchange. The data obtained suggest the presence of multiple forms of carbonic anhydrase in the thylakoid membranes of spinach chloroplasts and confirm their involvement in the proton transfer to the ATP synthase.


Chloroquine plays a cell-dependent role in the response to treatment of pancreatic adenocarcinoma.
In this study, our aim is to assess the role played by autophagy and its inhibition in the different PDAC cellular compartments, and its involvement in chemo-resistance using primary human pancreatic cancer-derived cells (PCC) and Cancer Associated Fibroblasts (CAF). Autophagy flux, as measured by LC3-I and -II in the presence of Chloroquine, showed a variable level in PCC and CAFs. We found no correlation between autophagy level and degree of tumor differentiation. Association of Chloroquine with gemcitabine, 5FU, oxaliplatin, irinotecan and docetaxel revealed that its effect on survival is cell- and drug-dependent in vitro and in vivo. In addition, we demonstrated that autophagy in CAFs can play an important role in sensitizing PDAC to anticancer treatments since its inhibition increased the resistance of PCCs to gemcitabine. In conclusion, this work clearly shows a heterogeneity in the effect of Chloroquine and highlights a role of CAFs autophagy in sensitizing tumors to treatments. It also reveals that the role of autophagy is more complex than expected in PDAC as well as its sensitivity to treatments.


Outpatient air leak management after lobectomy: a CMS cost analysis.
Air leaks after lobectomy are associated with increased length of stay (LOS) and protracted resource utilization. Portable drainage systems (PDS) allow for outpatient management of air leaks in patients otherwise meeting discharge criteria. We evaluated the safety and cost efficiency of a protocol for outpatient management of air leaks with a PDS. We retrospectively assessed patients who underwent lobectomy for non-small-cell lung cancer at our institution between 2004 and 2014. All patients discharged with a PDS for air leak were included in the analysis. The study group was compared to an internally matched cohort of patients undergoing lobectomy for non-small-cell lung cancer managed without the need for outpatient PDS. Study end points included resource utilization, postoperative complications, and readmission. A total of 739 lobectomies were performed during the study period, 73 (10%) patients with air leaks were discharged with a PDS after fulfilling postoperative milestones. Shorter LOS was observed in the study group (3.88 ± 2.4 versus 5.68 ± 5.7 d, P = 0.014) without significant differences in 30-d readmission (11.7% versus 9.0%, P = 0.615). PDS-related complications occurred in 6.8% of study patients (5/73), and 2.7% (2/73) required overnight readmission. PDSs were used for 8.30 ± 4.5 outpatient days. A CMS-based cost analysis predicted an overall savings of $686.72/patient (4.9% of Medicare reimbursement for a major thoracic procedure), associated with significantly fewer hospital days and resources used. In patients otherwise meeting discharge criteria, outpatient management of air leaks is safe and effective. This strategy is associated with improved efficiency of postoperative care and a modest reduction in hospital costs. This model may be applicable to other thoracic procedures associated with protracted LOS.


Long Path Atmospheric Ozone Absorption in the 9-10-micro Region Observed from a Balloon-Borne Spectrometer.
A balloon-borne spectrometer was used to measure the atmospheric absorption of solar radiation in the 9-10-micro region as a function of altitude. Among the numerous spectra recorded, several were made with very long optical paths above the troposphere obtained from floating altitude (~30 km) while the sun set. When the experimental results are compared with calculated spectra, based on line by line parameters of the nu(3) and nu(1) fundamentals of ordinary ozone, (16)O(3), combined with the Curtis-Godson approximation, large discrepancies are found for the long path spectra. It is shown that the hot bands nu(3), + nu(2), - nu(2), and nu(3), + nu(3), - nu(3), of the (16)O(3), and the nu(3) fundamentals of the isotopic species (16)O(18)O(16)O and (16)O(16)O(18)O, can contribute significant absorption for long paths such as obtained in this experiment. Such long paths also give rise to significant absorptions by the nu(3) - nu(1) and the nu(3) - 2nu(2) degrees bands of CO(2). Including these weak bands in the calculated spectra leads to good agreement with the observed data.


Design of resonance grating coupler.
A new integrated-optic coupler was proposed for coupling a guided wave to a free-space wave propagating vertically from the waveguide surface. The coupler consists of a grating coupler in a cavity formed by two distributed Bragg reflectors, and has a small aperture. The cavity was designed to eliminate both transmission and reflection of the incident guided wave, resulting in 100% radiation by a several-micron aperture. Design consideration was theoretically discussed based on the coupled mode analysis. Predicted performance was simulated and confirmed by the finite difference time domain method.


Transient increases in dendritic spine density contribute to dentate gyrus long-term potentiation.
Dendritic spines are the primary sites for excitatory neurotransmission in the adult brain and exhibit changes in their number and morphology with experience. The relationship between spine formation and synaptic activity has been best characterized along the apical dendrites of pyramidal neurons in the hippocampal CA1 subfield. However, less is known about the structural mechanisms at the spine that mediate plasticity in other hippocampal subfields. The dentate gyrus is the predominant point of entry for synaptic input to the hippocampus, and dentate granule cells differ from CA1 pyramidal neurons in terms of their morphology and biophysical properties. In order to understand the structural mechanisms for plasticity in the dentate gyrus, we measured dendritic spine density in hippocampal slice preparations at different intervals following synaptic stimulation. We observed that transient increases in dendritic spine density are detectable 30 min after induction of long-term potentiation (LTP). By 60 min poststimulation, dendritic spine density has returned to basal levels. Both early LTP and enhancements in dendritic spine density could be blocked by destabilizing actin filaments, but not by inhibitors of transcription or protein synthesis. These results indicate that spine formation is a transient event that is required for dentate gyrus LTP.


Role of the dorsal medial habenula in the regulation of voluntary activity, motor function, hedonic state, and primary reinforcement.
The habenular complex in the epithalamus consists of distinct regions with diverse neuronal populations. Past studies have suggested a role for the habenula in voluntary exercise motivation and reinforcement of intracranial self-stimulation but have not assigned these effects to specific habenula subnuclei. Here, we have developed a genetic model in which neurons of the dorsal medial habenula (dMHb) are developmentally eliminated, via tissue-specific deletion of the transcription factor Pou4f1 (Brn3a). Mice with dMHb lesions perform poorly in motivation-based locomotor behaviors, such as voluntary wheel running and the accelerating rotarod, but show only minor abnormalities in gait and balance and exhibit normal levels of basal locomotion. These mice also show deficits in sucrose preference, but not in the forced swim test, two measures of depression-related phenotypes in rodents. We have also used Cre recombinase-mediated expression of channelrhodopsin-2 and halorhodopsin to activate dMHb neurons or silence their output in freely moving mice, respectively. Optical activation of the dMHb in vivo supports intracranial self-stimulation, showing that dMHb activity is intrinsically reinforcing, whereas optical silencing of dMHb outputs is aversive. Together, our findings demonstrate that the dMHb is involved in exercise motivation and the regulation of hedonic state, and is part of an intrinsic reinforcement circuit.


In silico analysis of usher encoding genes in Klebsiella pneumoniae and characterization of their role in adhesion and colonization.
Chaperone/usher (CU) assembly pathway is used by a wide range of Enterobacteriaceae to assemble adhesive surface structures called pili or fimbriae that play a role in bacteria-host cell interactions. In silico analysis revealed that the genome of Klebsiella pneumoniae LM21 harbors eight chromosomal CU loci belonging to γκп and ϭ clusters. Of these, only two correspond to previously described operons, namely type 1 and type 3-encoding operons. Isogenic usher deletion mutants of K. pneumoniae LM21 were constructed for each locus and their role in adhesion to animal (Intestine 407) and plant (Arabidopsis thaliana) cells, biofilm formation and murine intestinal colonization was investigated. Type 3 pili usher deleted mutant was impaired in all assays, whereas type 1 pili usher deleted mutant only showed attenuation in adhesion to plant cells and in intestinal colonization. The LM21ΔkpjC mutant was impaired in its capacity to adhere to Arabidopsis cells and to colonize the murine intestine, either alone or in co-inoculation experiments. Deletion of LM21kpgC induced a significant decrease in biofilm formation, in adhesion to animal cells and in colonization of the mice intestine. The LM21∆kpaC and LM21∆kpeC mutants were only attenuated in biofilm formation and the adhesion abilities to Arabidopsis cells, respectively. No clear in vitro or in vivo effect was observed for LM21∆kpbC and LM21∆kpdC mutants. The multiplicity of CU loci in K. pneumoniae genome and their specific adhesion pattern probably reflect the ability of the bacteria to adhere to different substrates in its diverse ecological niches.


Schistosoma mansoni and HIV infection in a Ugandan population with high HIV and helminth prevalence.
Recent reports suggest that Schistosoma infection may increase the risk of acquiring human immunodeficiency virus (HIV). We used data from a large cross-sectional study to investigate whether Schistosoma mansoni infection is associated with increased HIV prevalence. We conducted a household survey of residents in island fishing communities in Mukono district, Uganda, between October 2012 and July 2013. HIV status was assessed using rapid test kits. Kato-Katz (KK) stool tests and urine-circulating cathodic antigen (CCA) were used to test for Schistosoma infection. Multivariable logistic regression, allowing for the survey design, was used to investigate the association between S. mansoni infection and HIV infection. Data from 1412 participants aged 13 years and older were analysed (mean age 30.3 years, 45% female). The prevalence of HIV was 17.3%. Using the stool Kato-Katz technique on a single sample, S. mansoni infection was detected in 57.2% (719/1257) of participants; urine CCA was positive in 73.8% (478/650) of those tested. S. mansoni infection was not associated with HIV infection. [KK (aOR = 1.04; 95% CI: 0.74-1.47, P = 0.81), CCA (aOR = 1.53; 95% CI: 0.78-3.00, P = 0.19)]. The median S. mansoni egg count per gram was lower in the HIV-positive participants (P = 0.005). These results add to the evidence that S. mansoni has little effect on HIV transmission, but may influence egg excretion.


Clinical utility of sequential minimal residual disease measurements in the context of risk-based therapy in childhood acute lymphoblastic leukaemia: a prospective study.
The level of minimal residual disease during remission induction is the most important prognostic indicator in patients with acute lymphoblastic leukaemia (ALL). We aimed to establish the clinical significance of minimal residual disease in a prospective trial that used sequential minimal residual disease measurements to guide treatment decisions. Between June 7, 2000, and Oct 24, 2007, 498 assessable patients with newly diagnosed ALL were enrolled in a clinical trial at St Jude Children's Research Hospital. We provisionally classified the risk of relapse as low, standard, or high according to patients' baseline clinical and laboratory features. Final risk assignment to establish treatment intensity was based mainly on minimal residual disease levels measured on days 19 and 46 of remission induction, and on week 7 of maintenance treatment. Additional measurements of minimal residual disease were made on weeks 17, 48, and 120 (end of treatment). The primary aim was to establish the association between event-free survival and patients' minimal residual disease levels during remission induction and sequentially post-remission. This trial was registered at ClinicalTrials.gov, number NCT00137111. Irrespective of the provisional risk classification, 10-year event-free survival was significantly worse for patients with 1% or greater minimal residual disease levels on day 19 compared with patients with lower minimal residual disease levels (69·2%, 95% CI 49·6-82·4, n=36 vs 95·5%, 91·7-97·5, n=244; p<0·001 for the provisional low-risk group and 65·1%, 50·7-76·2, n=56 vs 82·9%, 75·6-88·2, n=142; p=0·01 for the provisional standard-risk group). 12 patients with provisional low-risk ALL and 1% or higher minimal residual disease levels on day 19 but negative minimal residual disease (<0·01%) on day 46 were treated for standard-risk ALL and had a 10-year event-free survival of 88·9% (43·3-98·4). For the 280 provisional low-risk patients, a minimal residual disease level of less than 1% on day 19 predicted a better outcome, irrespective of the minimal residual disease level on day 46. Of provisional standard-risk patients with minimal residual disease of less than 1% on day 19, the 15 with persistent minimal residual disease on day 46 seemed to have an inferior 10-year event-free survival compared with the 126 with negative minimal residual disease (72·7%, 42·5-88·8 vs 84·0%, 76·3-89·4; p=0·06) after receiving the same post-remission treatment for standard-risk ALL. Of patients attaining negative minimal residual disease status after remission induction, minimal residual disease re-emerged in four of 382 studied on week 7, one of 448 at week 17, and one of 437 at week 48; all but one of these six patients died despite additional treatment. By contrast, relapse occurred in only two of the 11 patients who had decreasing minimal residual disease levels between the end of induction and week 7 of maintenance therapy and were treated with chemotherapy alone. Minimal residual disease levels during remission induction treatment have important prognostic and therapeutic implications even in the context of minimal residual disease-guided treatment. Sequential minimal residual disease monitoring after remission induction is warranted for patients with detectable minimal residual disease. National Institutes of Health and American Lebanese Syrian Associated Charities.


Visual Analysis of Large Graphs Using (X,Y)-Clustering and Hybrid Visualizations.
Many different approaches have been proposed for the challenging problem of visually analyzing large networks. Clustering is one of the most promising. In this paper, we propose a new clustering technique whose goal is that of producing both intracluster graphs and intercluster graph with desired topological properties. We formalize this concept in the (X,Y) -clustering framework, where Y is the class that defines the desired topological properties of intracluster graphs and X is the class that defines the desired topological properties of the intercluster graph. By exploiting this approach, hybrid visualization tools can effectively combine different node-link and matrix-based representations, allowing users to interactively explore the graph by expansion/contraction of clusters without loosing their mental map. As a proof of concept, we describe the system Visual Hybrid (X,Y)-clustering (VHYXY) that implements our approach and we present the results of case studies to the visual analysis of social networks.


Factors affecting the quality of life of patients after gastrectomy as assessed using the newly developed PGSAS-45 scale: A nationwide multi-institutional study.
To identify certain clinical factors other than the type of gastrectomy which affect the postoperative quality of life (QOL) of patients after gastrectomy. The postgastrectomy syndrome assessment scale (PGSAS)-45 was designed to assess the severity of symptoms, the living status and the QOL of gastrectomized patients. It consists of 45 items, of which 22 are original items while 23 were retrieved from the SF-8 and Gastrointestinal Symptoms Rating Scale questionnaires with permission. A nationwide surveillance study to validate PGSAS was conducted and 2368 gastric cancer patients who underwent various types of gastrectomy at 52 medical institutions were enrolled. Of these, 1777 patients who underwent total gastrectomy (TG) reconstructed with Roux-Y (n = 393), distal gastrectomy (DG) reconstructed with Billroth-I (n = 909), or DG reconstructed with Roux-Y (n = 475) were evaluated in the current study. The influence of the type of gastrectomy and other clinical factors such as age, sex, duration after surgery, the symptom severity, the degree of weight loss, dietary intake, and the ability for working on the postoperative QOL (i.e., dissatisfaction for daily life subscale, physical component summary and mental component summary of the SF-8) were examined by multiple regression analysis (MRA). In addition, importance of various symptoms such as esophageal reflux, abdominal pain, meal-related distress, indigestion, diarrhea, constipation and dumping on the postoperative living status and QOL were also appraised by MRA. The postoperative QOL were significantly deteriorated in patients who underwent TG compared to those after DG. However, the extent of gastrectomy was not an influential factor on patients' QOL when adjusted by the MRA. Among various clinical factors, the symptom severity, ability for working, and necessity for additional meals were the most influential factors to the postoperative QOL. As for the individual symptoms, meal-related distress, dumping, abdominal pain, and esophageal reflux significantly affected the postoperative QOL in that order, while the influence of indigestion, diarrhea and constipation was insignificant. Several clinical factors such as the symptom severity (especially in meal-related distress and dumping), ability for working and necessity for additional meals were the main factors which affected the patients' well-being after gastrectomy.


Cell-free tumor microparticle vaccines stimulate dendritic cells via cGAS/STING signaling.
Tumor antigens and innate signals are vital considerations in developing new therapeutic or prophylactic antitumor vaccines. The role or requirement of intact tumor cells in the development of an effective tumor vaccine remains incompletely understood. This study reveals the mechanism by which tumor cell-derived microparticles (T-MP) can act as a cell-free tumor vaccine. Vaccinations with T-MPs give rise to prophylactic effects against the challenge of various tumor cell types, while T-MP-loaded dendritic cells (DC) also exhibit therapeutic effects in various tumor models. Such antitumor effects of T-MPs are perhaps attributable to their ability to generate immune signaling and to represent tumor antigens. Mechanically, T-MPs effectively transfer DNA fragments to DCs, leading to type I IFN production through the cGAS/STING-mediated DNA-sensing pathway. In turn, type I IFN promotes DC maturation and presentation of tumor antigens to T cells for antitumor immunity. These findings highlight a novel tumor cell-free vaccine strategy with potential clinical applications.


White Matter Microstructure in Youths With Conduct Disorder: Effects of Sex and Variation in Callous Traits.
Studies using diffusion tensor imaging (DTI) to investigate white matter (WM) microstructure in youths with conduct disorder (CD) have reported disparate findings. We investigated WM alterations in a large sample of youths with CD, and examined the influence of sex and callous-unemotional (CU) traits. DTI data were acquired from 124 youths with CD (59 female) and 174 typically developing (TD) youths (103 female) 9 to 18 years of age. Tract-based spatial statistics tested for effects of diagnosis and sex-by-diagnosis interactions. Associations with CD symptoms, CU traits, a task measuring impulsivity, and the impact of comorbidity, and age- and puberty-related effects were examined. Youths with CD exhibited higher axial diffusivity in the corpus callosum and lower radial diffusivity and mean diffusivity in the anterior thalamic radiation relative to TD youths. Female and male youths with CD exhibited opposite changes in the left hemisphere within the internal capsule, fornix, posterior thalamic radiation, and uncinate fasciculus. Within the CD group, CD symptoms and callous traits exerted opposing influences on corpus callosum axial diffusivity, with callous traits identified as the unique clinical feature predicting higher axial diffusivity and lower radial diffusivity within the corpus callosum and anterior thalamic radiation, respectively. In an exploratory analysis, corpus callosum axial diffusivity partially mediated the association between callous traits and impulsive responses to emotional faces. Results were not influenced by symptoms of comorbid disorders, and no age- or puberty-related interactions were observed. WM alterations within the corpus callosum represent a reliable neuroimaging marker of CD. Sex and callous traits are important factors to consider when examining WM in CD.


DNA detection by integrable electronics.
This paper presents a new electronic methodology to detect DNA hybridization for rapid identification of diseases, as well as food and environmental monitoring on a genetic base. The proposed solution exploits a new (electrical) capacitive measurement circuit, not requiring any prior labeling of the DNA (as it is often the case with the commonly employed optical detection). The sensitivity, the reliability, and the reproducibility of this device have been evaluated by experiments performed with a (non-integrated) prototype implementation, easily integrable in IC and/or micro-fabricated lab-on-a-chip.


Association Between Alendronate Use and Hip Fracture Risk in Older Patients Using Oral Prednisolone.
Oral glucocorticoid treatment increases fracture risk, and evidence is lacking regarding the efficacy of alendronate to protect against hip fracture in older patients using glucocorticoids. To investigate whether alendronate treatment in older patients using oral prednisolone is associated with decreased hip fracture risk and adverse effects. Retrospective cohort study using a national database (N = 433 195) of patients aged 65 years or older undergoing a health evaluation (baseline) at Swedish health care facilities; 1802 patients who were prescribed alendronate after at least 3 months of oral prednisolone treatment (≥5 mg/d) were identified. Propensity score matching was used to select 1802 patients without alendronate use from 6076 patients taking prednisolone with the same dose and treatment time criteria. Follow-up occurred between January 2008 and December 2014. Alendronate vs no alendronate use; no patients had previously taken alendronate at the time of prednisolone initiation. The primary outcome was incident hip fracture. Of the 3604 included patients, the mean age was 79.9 (SD, 7.5) years, and 2524 (70%) were women. After a median follow-up of 1.32 years (interquartile range, 0.57-2.34 years), there were 27 hip fractures in the alendronate group and 73 in the no-alendronate group, corresponding to incidence rates of 9.5 (95% CI, 6.5-13.9) and 27.2 (95% CI, 21.6-34.2) fractures per 1000 person-years, with an absolute rate difference of -17.6 (95% CI, -24.8 to -10.4). The use of alendronate was associated with a lower risk of hip fracture in a multivariable-adjusted Cox model (hazard ratio, 0.35; 95% CI, 0.22-0.54). Alendronate treatment was not associated with increased risk of mild upper gastrointestinal tract symptoms (alendronate vs no alendronate, 15.6 [95% CI, 11.6-21.0] vs 12.9 [95% CI, 9.3-18.0] per 1000 person-years; P = .40) or peptic ulcers (10.9 [95% CI, 7.7-15.5] vs 11.4 [95% CI, 8.0-16.2] per 1000 person-years; P = .86). There were no cases of incident drug-induced osteonecrosis and only 1 case of femoral shaft fracture in each group. Among older patients using medium to high doses of prednisolone, alendronate treatment was associated with a significantly lower risk of hip fracture over a median of 1.32 years. Although the findings are limited by the observational study design and the small number of events, these results support the use of alendronate in this patient group.


Psychological distress and unsatisfied need for psychosocial support in adolescent and young adult cancer patients during the first year following diagnosis.
Identifying at-risk adolescent and young adult (AYA) cancer patients and referring them to age-appropriate psychosocial support services may be instrumental in reducing psychological distress and promoting psychosocial adaptation. The purpose of this study is to identify trajectories of clinically significant levels of distress throughout the first year following diagnosis and to distinguish factors, including supportive care service use, that predict the extent to which AYAs report distress. In this prospective multisite study, 215 AYAs aged 15-39 years were assessed for psychological distress and psychosocial support service use within the first 4 months of diagnosis and again 6 and 12 months later. On the basis of distress scores, respondents were assigned to one of four distress trajectory groups (Resilient, Recovery, Delayed, and Chronic). Multiple logistic regression analyses examined whether demographics, clinical variables, and reports of unsatisfied need for psychosocial support were associated with distress trajectories over 1 year. Twelve percent of AYAs reported clinically significant chronic distress throughout the first 12 months following diagnosis. An additional 15% reported delayed distress. Substantial proportions of AYAs reported that needs for information (57%), counseling (41%), and practical support (39%) remained unsatisfied at 12 months following diagnosis. Not getting counseling needs met, particularly with regard to professional mental health services, was observed to be significantly associated with distress over time. Substantial proportions of AYAs are not utilizing psychosocial support services. Findings suggest the importance of identifying psychologically distressed AYAs and addressing their needs for mental health counseling throughout a continuum of care.


Spectral domain second-harmonic optical coherence tomography.
Optical coherence tomography (OCT) provides micrometer-scale structural imaging by coherent detection of backscattered light. Molecular contrast in OCT has been demonstrated using transient absorption, coherent anti-Stokes Raman scattering, and second-harmonic (SH) generation. The sensitivity of molecular contrast signals can be enhanced by use of Fourier domain techniques. We have constructed a spectrometer-based Fourier domain SH-OCT system for simultaneous acquisition of the fundamental and SH signals. We report a >30 dB increase in SH sensitivity over a similar time domain SH-OCT system and demonstrate contrast between cartilage and bone using collagen as the contrast agent.


Molecular analysis of immunoglobulin genes in diffuse large B-cell lymphomas.
Diffuse large B-cell lymphoma (DLBCL) is a common type of non-Hodgkin's lymphoma (NHL) that is highly heterogeneous from both clinical and histopathologic viewpoints. The immunoglobulin (Ig) heavy (H) chain variable region genes were examined in 71 patients with untreated primary DLBCL. Fifty-eight potentially functional V(H) genes were detected in 53 DLBCL cases; V(H) genes were nonfunctional in 9 cases and were not detected in an additional 9 cases. The use of V(H) gene families by DLBCL tumors was unbiased without overrepresentation of any particular V(H) gene or gene family. Analysis of Ig mutations in comparison to the most closely related germline gene disclosed mutated V(H) genes in all but 1 DLBCL case. More than 2% difference from the most similar germline sequence was detected in 52 potentially functional and the 8 nonfunctional V(H) gene sequences, whereas less than 2% difference from the germline sequence was observed in 3 V(H) gene isolates. Only 3 V(H) gene isolates were unmutated. No correlation was found between V(H) gene use, mutation level, and International Prognostic Index (IPI) or survival. Six of 8 tested tumors showed evidence of ongoing somatic mutations. Evidence for positive or negative antigen selection pressure was observed in 65% of mutated DLBCL cases. Our findings indicate that the etiology and the driving forces for clonal expansion are heterogeneous, which may explain the well-known clinical and pathologic heterogeneity of DLBCL. (Blood. 2000;95:1797-1803)


Mucormycosis with extensive cranial nerve involvement as the first presentation of diabetes mellitus: A case report.
Mucormycosis, a rare fungal infection, mainly affects individuals with diabetes mellitus and those who were immunocompromised and has a high mortality rate. Its most common presentation is similar to that of acute bacterial sinusitis with symptoms of nasal congestion, headache, and fever. The involvement of multiple cranial nerves in mucormycosis was rarely reported in the literature and indicates severe disease. Herein, we report the case of a 56-year-old man who was referred to the ophthalmology outpatient clinic for facial nerve palsy. He was treated with systemic steroids for 10 days with no improvement. On examination, he had a loss of vision and a frozen orbit due to involvement of cranial nerves II, III, IV, V, VI, and VII. An extensive workup revealed a hemoglobin A1C of 10%. However, he was never diagnosed with diabetes mellitus previously and denied any of the classical symptoms of diabetes mellitus. He underwent ethmoidectomy, maxillectomy, and drainage of an intraorbital abscess after appropriate imaging studies. Histopathology confirmed the diagnosis of mucormycosis, and the patient was started on systemic amphotericin B. This case emphasizes the importance of screening for diabetes mellitus. Early recognition of underlying diabetes mellitus in this patient may have prevented the development of mucormycosis along with its devastating complications.


Color stability of ceramic brackets immersed in potentially staining solutions.
To assess the color stability of five types of ceramic brackets after immersion in potentially staining solutions. Ninety brackets were divided into 5 groups (n = 18) according to brackets commercial brands and the solutions in which they were immersed (coffee, red wine, coke and artificial saliva). The brackets assessed were Transcend (3M/Unitek, Monrovia, CA, USA), Radiance (American Orthodontics, Sheboygan, WI, USA), Mystique (GAC International Inc., Bohemia, NY, USA) and Luxi II (Rocky Mountain Orthodontics, Denver, CO, USA). Chromatic changes were analyzed with the aid of a reflectance spectrophotometer and by visual inspection at five specific time intervals. Assessment periods were as received from the manufacturer (T0), 24 hours (T1), 72 hours (T2), as well as 7 days (T3) and 14 days (T4) of immersion in the aforementioned solutions. Results were submitted to statistical analysis with ANOVA and Bonferroni correction, as well as to a multivariate profile analysis for independent and paired samples with significance level set at 5%. The duration of the immersion period influenced color alteration of all tested brackets, even though these changes could not always be visually observed. Different behaviors were observed for each immersion solution; however, brackets immersed in one solution progressed similarly despite minor variations. Staining became more intense over time and all brackets underwent color alterations when immersed in the aforementioned solutions.