The DNA-sensing AIM2 inflammasome controls radiation-induced cell death and tissue injury.
Acute exposure to ionizing radiation induces massive cell death and severe damage to tissues containing actively proliferating cells, including bone marrow and the gastrointestinal tract. However, the cellular and molecular mechanisms underlying this pathology remain controversial. Here, we show that mice deficient in the double-stranded DNA sensor AIM2 are protected from both subtotal body irradiation-induced gastrointestinal syndrome and total body irradiation-induced hematopoietic failure. AIM2 mediates the caspase-1-dependent death of intestinal epithelial cells and bone marrow cells in response to double-strand DNA breaks caused by ionizing radiation and chemotherapeutic agents. Mechanistically, we found that AIM2 senses radiation-induced DNA damage in the nucleus to mediate inflammasome activation and cell death. Our results suggest that AIM2 may be a new therapeutic target for ionizing radiation exposure.


Exploring the alternatives of biological nitrogen fixation.
Most biological nitrogen fixation (BNF) results from the activity of the molybdenum nitrogenase (Mo-nitrogenase, Nif), an oxygen-sensitive metalloenzyme complex found in all known diazotrophs. Two alternative forms of nitrogenase, the vanadium nitrogenase (V-nitrogenase, Vnf) and the iron-only nitrogenase (Fe-only nitrogenase, Anf) have also been identified in the genome of some organisms that encode for Nif. It has been suggested that alternative nitrogenases were responsible for N2-fixation on early Earth because oceans were depleted of bioavailable Mo. Results of recent phylogenetic- and structure-based studies suggest, however, that such an evolutionary path is unlikely, and favor a new model for a stepwise evolution of nitrogenase where the V-nitrogenase and the Fe-only nitrogenase are not the ancestor of the Mo-nitrogenase. Rather, Mo-nitrogenase emerged within the methanogenic archaea and then gave rise to the alternative forms suggesting they arose later in response to the availability of fixed N2 and local environmental factors that influenced metal availability. This review summarizes the current state of knowledge on (1) the biochemistry of these complex systems highlighting the common and specific structural features and catalytic activities of the enzymes, (2) the recent progress in defining the discrete set of genes associated to N2-fixation and the regulatory features that coordinate the differential expression of genes in response to metal availability, and (3) the diverse taxonomic and phylogenic distribution of nitrogenase enzymes and the evolutionary history of BNF from the perspective of metal content and metal availability.


Self-assembly of heptameric nanoparticles derived from tag-functionalized phi29 connectors.
The structure of an induced macromolecular assembly was characterized and found to consist of an ordered heptameric arrangement of recombinant phi29 gp10 connector molecules. Insertion of an N-terminal Strep-II/His(6) tag to the connectors led to the spontaneous formation of large nanoparticles that were distinct from free, wild-type phi29 connectors in both size and symmetry elements. The determination of single-molecule tomograms and image-averaged reconstructions allowed for the stoichiometric and topological characterization of the ordered assemblage, revealing that the nanoparticle is composed of five equatorial connectors arranged with pseudo-5-fold rotational symmetry, capped on its ends by two polar connectors. Additionally, all seven connectors are oriented with their narrower N-terminal necks into the nanoparticle core and wider C-terminal ends out toward the nanoparticle surface, a geometric arrangement accommodated by the shape complementarity of the conical connector profiles. A significant amount of conformational heterogeneity was detected, ranging from changes in overall nanoparticle diameter, to tilting of individual connectors, to variations in connector stoichiometry. Nevertheless, a stable, heptameric nanoparticle was resolved, revealing the significant potential of guided, peptide-mediated supramolecular self-assembly. With this construct, we anticipate the further design of variable N-terminal tags to allow for the generation of nanoparticles with tailored connector stoichiometry and topological arrangements. By modifying the surface-exposed C-terminal ends with application-appropriate moieties, the consistent structure and compact nature of these nanoparticles may prove beneficial in nanotechnological and nanomedical approaches.


A Case of Acute Pancreatitis Associated with Early-Stage Adenocarcinoma of the Gallbladder.
BACKGROUND Gallstones are a common cause of acute pancreatitis. The proposed mechanism by which choledocholithiasis induces pancreatitis is mechanical obstruction of the ampulla leading to the reflux of bile into the pancreatic duct or edema resulting from a gallstone's passage. To our knowledge, there are no previously reported cases of gallbladder adenocarcinoma as a potential cause of acute pancreatitis. Herein, we describe a patient who presented with acute necrotizing pancreatitis, without other associated risk factors, who was found to have a fragmented friable polypoid gallbladder adenocarcinoma. CASE REPORT A 55-year old Hispanic female with prediabetes presented to the Emergency Department with severe epigastric abdominal pain radiating to her back. The patient's clinical presentation, laboratory tests and computed tomography imaging were suggestive of acute necrotizing pancreatitis and a gallbladder lesion concerning for neoplasm. After clinical resolution of her pancreatitis, the patient was brought to the operating room for a cholecystectomy. Final pathology revealed a stage T1aN0 gallbladder adenocarcinoma. CONCLUSIONS We have presented a patient with acute necrotizing pancreatitis in the absence of alcohol abuse, gallstones, biliary sludge, hypertriglyceridemia, hypercalcemia, or hereditary predisposition. Without evidence of other etiologies, we hypothesize that the friable tumor fragments of the gallbladder adenocarcinoma might be the underlying cause of pancreatitis in this patient.


Carbaborane-based alkynylphosphanes and phospholes.
The reaction of 1,2-bis(N,N-dimethylaminochloro-phosphanyl)-1,2-dicarba-closo-dodecaborane(12) and lithiated phenylacetylene gives a five-membered dihydrophosphole derivative with an exocyclic phosphanyl group. This unexpected reaction opens new possibilities for the synthesis of carbaborane-containing phosphorus heterocycles. P,P'-alkynylated 1,2-bis(phosphanyl)-1,2-dicarba-closo-dodecaborane(12)s are obtained from alkynylchlorophosphanes and dilithiated carbaborane. This new class of alkynes can be used for future applications in cyclizations and polymerizations.


Galangin Suppresses Renal Inflammation via the Inhibition of NF-κB, PI3K/AKT and NLRP3 in Uric Acid Treated NRK-52E Tubular Epithelial Cells.
Renal inflammation can result in renal injury. Uric acid (UA) is the final product of purine metabolism in humans and because of the lack of urate oxidase, UA may accumulate in tissues, including kidney, causing inflammation. Galangin was isolated from a traditional Chinese medicine plant and possesses several beneficial effects, working as an anti-oxidant, anti-mutagenic, anti-tumor, anti-inflammatory, anti-microbial, and anti-viral agent. Therefore, this study aimed at investigating the molecular mechanism of galangin in the attenuation of UA induced renal inflammation in normal rat kidney epithelial cells NRK-52E. Our findings suggested that galangin treatment efficiently protected NRK-52E cells against UA induced renal inflammation by decreasing tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-18, prostaglandin E2 (PGE2), and nitric oxide (NO) release, and it inhibited nitric oxide synthase (iNOS), prostaglandin endoperoxide synthase 2 (PTGS2), TNF-α, IL-1β, and IL-18 mRNA expression. In addition, galangin was not exerting any cytotoxicity at the concentrations that were effective against inflammation as assessed by CCK8 assay. Moreover, western blotting showed that galangin treatment effectively inhibited nuclear factor-kappa B (NF-κB), phosphatidylinositol 3 kinase (PI3K)/protein kinase B (AKT) and nucleotide-binding domain- (NOD-) like receptor protein 3 (NLRP3) signaling pathway activation. Taken together, these findings suggested that galangin plays a pivotal role in renal inflammation by suppressing inflammatory responses, which might be closely associated with the inhibition of NLRP3 inflammasome, NF-κB and PI3K/AKT signaling pathway activation.


Mapping female bodily features of attractiveness.
"Beauty is bought by judgment of the eye" (Shakespeare, Love's Labour's Lost), but the bodily features governing this critical biological choice are still debated. Eye movement studies have demonstrated that males sample coarse body regions expanding from the face, the breasts and the midriff, while making female attractiveness judgements with natural vision. However, the visual system ubiquitously extracts diagnostic extra-foveal information in natural conditions, thus the visual information actually used by men is still unknown. We thus used a parametric gaze-contingent design while males rated attractiveness of female front- and back-view bodies. Males used extra-foveal information when available. Critically, when bodily features were only visible through restricted apertures, fixations strongly shifted to the hips, to potentially extract hip-width and curvature, then the breast and face. Our hierarchical mapping suggests that the visual system primary uses hip information to compute the waist-to-hip ratio and the body mass index, the crucial factors in determining sexual attractiveness and mate selection.


Radiant emission characteristics of a nonisothermal spherical cavity.
An equation is derived that relates the emissivity of a spherical cavity to the temperature distribution along the axis normal to the opening. The mathematical formulation of the problem rests on De Vos's method, and is carried out exactly, by means of a suitable serial development. The solution enables one to estimate the influence of the temperature gradient on the radiant emission of the reference spherical blackbody.


Phage display: selecting straws instead of a needle from a haystack.
An increasing number of peptides with specific binding affinity to various protein and even non-protein targets are being discovered from phage display libraries. The power of this method lies in its ability to efficiently and rapidly identify ligands with a desired target property from a large population of phage clones displaying diverse surface peptides. However, the search for the needle in the haystack does not always end successfully. False positive results may appear. Thus instead of specific binders phage with no actual affinity toward the target are recovered due to their propagation advantages or binding to other components of the screening system, such as the solid phase, capturing reagents, contaminants in the target sample or blocking agents, rather than the target. Biopanning experiments on different targets performed in our laboratory revealed some previously identified and many new target-unrelated peptide sequences, which have already been frequently described and published, but not yet recognized as target-unrelated. Distinguishing true binders from false positives is an important step toward phage display selections of greater integrity. This article thoroughly reviews and discusses already identified and new target-unrelated peptides and suggests strategies to avoid their isolation.


Updated parameters and expanded simulation options for a model of the auditory periphery.
A phenomenological model of the auditory periphery in cats was previously developed by Zilany and colleagues [J. Acoust. Soc. Am. 126, 2390-2412 (2009)] to examine the detailed transformation of acoustic signals into the auditory-nerve representation. In this paper, a few issues arising from the responses of the previous version have been addressed. The parameters of the synapse model have been readjusted to better simulate reported physiological discharge rates at saturation for higher characteristic frequencies [Liberman, J. Acoust. Soc. Am. 63, 442-455 (1978)]. This modification also corrects the responses of higher-characteristic frequency (CF) model fibers to low-frequency tones that were erroneously much higher than the responses of low-CF model fibers in the previous version. In addition, an analytical method has been implemented to compute the mean discharge rate and variance from the model's synapse output that takes into account the effects of absolute refractoriness.


Cultural differences in spiritual care: findings of an Israeli oncologic questionnaire examining patient interest in spiritual care.
As professional spiritual care (chaplaincy) is introduced to new cultures worldwide, it bears examining which elements of screening and care are universal and, for those elements showing cultural difference, to study them in each culture. No quantitative spiritual care patient study had previously been done in Israel. Our objectives were twofold: 1) to examine who wants spiritual care in Israel, including demographic and clinical variables, and to compare against other results worldwide to further develop universal screening protocols 2) to see what patients want from spiritual care specifically in the Israeli setting. Self-administered patient questionnaire examining spirituality/religiosity, interest in spiritual care (subdivided by type of care), and key demographic, social, and clinical data. The study setting was an Israeli oncology center at which spiritual care had been recently introduced. Data from 364 oncology patient questionnaires found 41% interest in spiritual care, as compared to 35%-54% in American studies. Having previously been visited by a spiritual caregiver predicted patient interest in further spiritual care (AOR 2.4, 95% CI 1.2-4.6), suggesting that the new service is being well-received. Multivariate stepwise logistic regression analysis identified additional predictors of openness to receiving spiritual care: self-describing as somewhat/very spiritual vs. not spiritual (adjusted odds ratio [AOR] 3.9 and 6.3, 95% CI 1.8-8.6 and 2.6-15.1) or traditional/religious vs. secular (AOR 2.2 and 2.1, 95% CI 1.3-3.6 and 1.1-4.0); and receiving one visit a week or less from family and friends (AOR 5.6, 95% CI 2.1-15.1). These findings are in line with previous American studies, suggesting universality across cultures that could be utilized in screening. Differences in demographic data and medical condition were not significant predictors of patient interest, suggesting a cultural difference, where age and education were predictors in the American context. Levels of interest in explicitly religious or spiritual support such as prayer or addressing religious/spiritual questions were much lower than in other cultures. Results illustrate the demand for and satisfaction with the new Israeli service. The cross-cultural comparison found both culture-dependent and possibly universal predictors of patient interest, and found lower interest in Israel for explicitly religious/spiritual types of support.


First Report of Oleander Leaf Scorch Caused by Xylella fastidiosa in Texas.
Bacterial leaf scorch caused by Xylella fastidiosa has been reported on oleander in California (3) and Florida (4). In June 2002, leaf scorch symptoms including chlorotic mottling of leaves, necrosis on leaf tips or whole leaves, defoliation, and shortened internodes were observed in oleander plants at various locations in Texas, including Galveston, Harlingen, Austin, San Antonio, and El Campo. The symptomatic varieties Calypso, Commandant Barthelemy, Lane Taylor Sealy, Little Red, Mrs. George Roeding, Mrs. Runge, Scarlet Beauty, and Petite Salmon, as well as symptomless varieties, Turner's Shari D and Sugarland from Moody Gardens in Galveston, Texas were sampled. All samples were tested for the presence of X. fastidiosa using enzyme-linked immunosorbent assay (ELISA) and bacterial isolation according to the methods of Huang and Sherald (2). All symptomatic varieties reacted positively in ELISA, and colonies characteristic of X. fastidiosa were isolated from all eight symptomatic varieties 10 to 15 days after incubation at 28°C. The colonies were confirmed to be X. fastidiosa using polymerase chain reaction (PCR) (2). ELISA tests and bacterial isolations from the symptomless Shari D and Sugarland varieties were negative. Membrane entrapment immunofluorescence (MEIF) (1) using the antibody CREC 26 to X. fastidiosa was also done on three of the symptomatic varieties and one asymptomatic variety obtained from Moody Gardens, and fluorescing bacteria were found only in the three symptomatic varieties. Symptomatic samples of Petite Salmon, one pink variety and one red variety obtained from a residential area west of Galveston, and a red oleander in Harlingen, TX, also tested positive with MEIF. Other ELISA-positive samples were obtained from symptomatic oleanders from Austin, San Antonio, and El Campo, TX. The X. fastidiosa bacteria isolated from the variety Lane Taylor Sealy were used to inoculate three red oleander plants by making an 8-cm-long vertical cut into the stem and then in 15 locations injecting approximately 15 μl of a X. fastidiosa suspension (108-9 cells per ml). The cut area was wrapped with Parafilm after inoculation, and the plants were kept at 29°C in a greenhouse. Three healthy red oleanders were inoculated with periwinkle wilt liquid medium for controls. Approximately 3 months after inoculation, chlorotic mottling along the edges of leaves was observed in the oleanders inoculated with X. fastidiosa, and the bacterium was reisolated from symptomatic leaves as described above. No symptoms were observed on the control plants, and bacterial isolation from the control plants was also negative. To our knowledge, this is the first report to show the causal role of X. fastidiosa in oleander leaf scorch and the presence of the disease in different locations in Texas, extending the geographic range of this important bacterial disease. References: (1) R. H. Brlansky et al. Plant Dis. 74:863, 1990. (2) Q. Huang and J. L. Sherald. Curr. Microbiol. 48:73, 2004. (3) A. H. Purcell et al. Phytopathology 89:53, 1999. (4) R. L. Wichman and D. L. Hopkins. Plant Dis. 84:198, 2000.


Knockout of a bacterial-type ATP-binding cassette transporter gene, AtSTAR1, results in increased aluminum sensitivity in Arabidopsis.
ATP-binding cassette (ABC) transporters represent a large family in plants, but the functions of most of these transporters are unknown. Here we report a gene, AtSTAR1, only encoding an ATP-binding domain of a bacterial-type ABC transporter in Arabidopsis (Arabidopsis thaliana). AtSTAR1 is an ortholog of rice (Oryza sativa) OsSTAR1, which has been implicated in aluminum (Al) tolerance. Knockout of AtSTAR1 resulted in increased sensitivity to Al and earlier flowering. Unlike OsSTAR1, AtSTAR1 was expressed in both the roots and shoots and its expression was not induced by Al or other stresses. Investigation of tissue-specific localization of AtSTAR1 through beta-glucuronidase fusion revealed that AtSTAR1 was predominantly expressed at outer cell layers of root tips and developing leaves, whose localization is also different from those of OsSTAR1. However, introduction of OsSTAR1 into atstar1 mutant rescued the sensitivity of atstar1 to Al, indicating that AtSTAR1 has a similar function as OsSTAR1. Furthermore, we found that AtSTAR1 may interact with ALS3, a transmembrane-binding domain in Arabidopsis to form a complex because introduction of OsSTAR1, a functional substitute of AtSTAR1, into als3 mutant resulted in the loss of OsSTAR1 protein. All these findings indicate that AtSTAR1 is involved in the basic detoxification of Al in Arabidopsis.


Anemia is associated with poor outcomes in patients with less severe ischemic stroke.
Anemia is a known predictor of in-hospital mortality among patients with such vascular conditions as acute myocardial infarction, congestive heart failure, and chronic kidney disease. The role of anemia in patients with acute ischemic stroke is less well understood. We sought to examine the association between anemia at hospital admission and the combined outcome of in-hospital mortality and discharge to hospice in patients with acute ischemic stroke. We evaluated data from a retrospective cohort of consecutive ischemic stroke patients presenting within 48 hours of symptom onset at 5 hospitals between 1998 and 2003. Anemia was defined as an admission hematocrit value of <30%. Less severe stroke was defined as an admission National Institutes of Health Stroke Scale score of <10. The outcome was the combined endpoint of in-hospital mortality or discharge to hospice. Among 1306 patients with stroke, anemia was present on admission in 6.4%, and the combined outcome of death or discharge to hospice was present in 10.1%. Anemia was not associated with outcome in patients with severe stroke (anemia, 17.2% [5 of 29] vs no anemia, 28,4% [98 of 345]; P = .20), but was associated with outcome in patients with less severe stroke (anemia, 13.0% [7 of 54] vs no anemia, 2.5% [22 of 878]; P < .0001). After adjustment for stroke severity, admission anemia was independently associated with outcome in patients with less severe stroke (adjusted odds ratio, 4.17; 95% confidence interval, 1.47-11.90), but not in patients with more severe strokes (adjusted odds ratio, 0.82; 95% confidence interval, 0.30-2.22). Our data indicate that anemia is associated with in-hospital mortality or discharge to hospice in patients with less severe ischemic stroke.


Domain structure, localization, and function of DNA polymerase eta, defective in xeroderma pigmentosum variant cells.
DNA polymerase eta carries out translesion synthesis past UV photoproducts and is deficient in xeroderma pigmentosum (XP) variants. We report that poleta is mostly localized uniformly in the nucleus but is associated with replication foci during S phase. Following treatment of cells with UV irradiation or carcinogens, it accumulates at replication foci stalled at DNA damage. The C-terminal third of poleta is not required for polymerase activity. However, the C-terminal 70 aa are needed for nuclear localization and a further 50 aa for relocalization into foci. Poleta truncations lacking these domains fail to correct the defects in XP-variant cells. Furthermore, we have identified mutations in two XP variant patients that leave the polymerase motifs intact but cause loss of the localization domains.


Trends in depressive symptom burden among older adults in the United States from 1998 to 2008.
Diagnosis and treatment of depression has increased over the past decade in the United States. Whether self-reported depressive symptoms among older adults have concomitantly declined is unknown. To examine trends in depressive symptoms among older adults in the US between 1998 and 2008. Serial cross-sectional analysis of six biennial assessments. Health and Retirement Study (HRS), a nationally-representative survey. PATIENTS OR OTHER PARTICIPANTS Adults aged 55 and older (N = 16,184 in 1998). The eight-item Center for Epidemiologic Studies Depression scale (CES-D8) assessed three levels of depressive symptoms (none = 0, elevated = 4+, severe = 6+), adjusting for demographic and clinical characteristics. Having no depressive symptoms increased over the 10-year period from 40.9 % to 47.4 % (prevalence ratio [PR]: 1.16, 95 % CI: 1.13-1.19), with significant increases in those aged ≥ 60 relative to those aged 55-59. There was a 7 % prevalence reduction of elevated symptoms from 15.5 % to 14.2 % (PR: 0.93, 95 % CI: 0.88-0.98), which was most pronounced among those aged 80-84 in whom the prevalence of elevated symptoms declined from 14.3 % to 9.6 %. Prevalence of having severe depressive symptoms increased from 5.8 % to 6.8 % (PR: 1.17, 95 % CI: 1.06-1.28); however, this increase was limited to those aged 55-59, with the probability of severe symptoms increasing from 8.7 % to 11.8 %. No significant changes in severe symptoms were observed for those aged ≥ 60. Overall late-life depressive symptom burden declined significantly from 1998 to 2008. This decrease appeared to be driven primarily by greater reductions in depressive symptoms in the oldest-old, and by an increase in those with no depressive symptoms. These changes in symptom burden were robust to physical, functional, demographic, and economic factors. Future research should examine whether this decrease in depressive symptoms is associated with improved treatment outcomes, and if there have been changes in the treatment received for the various age cohorts.


Distribution and activity of male harbour seals during the mating season
Little is known about male reproductive strategies in aquatically mating pinnipeds. To study the mating patterns of harbour seals, Phoca vitulinaVHF telemetry was used to relate the distribution and behaviour of adult males to the distribution of females during the summer pupping and mating season. Prior to July males occupied large and variable ranges. At the beginning of July, males decreased their mean range size, but continued to spend much of their time in the water where they made characteristic short dives. Acoustic recordings in the presence of several radiotagged males suggested that these short dives were associated with underwater vocal displays. Throughout July, males varied in the geographical areas which they used to perform these displays. Some individuals were found in the water around haul-out sites; others were located on foraging grounds, up to 50 km from pupping sites, and some were consistently located displaying on transit routes between these two areas. This study supports previous suggestions that vocalizations and diving displays may be associated with male mating behaviour, but suggests that males may display over a much wider geographical area than was previously recognized. This system of dispersed but small display territories is suggestive of lekking. However, further research on the distribution of the clumping of displaying males is required to confirm this.


Dermatophyte infections.
Dermatophytes are fungi that require keratin for growth. These fungi can cause superficial infections of the skin, hair, and nails. Dermatophytes are spread by direct contact from other people (anthropophilic organisms), animals (zoophilic organisms), and soil (geophilic organisms), as well as indirectly from fomites. Dermatophyte infections can be readily diagnosed based on the history, physical examination, and potassium hydroxide (KOH) microscopy. Diagnosis occasionally requires Wood's lamp examination and fungal culture or histologic examination. Topical therapy is used for most dermatophyte infections. Cure rates are higher and treatment courses are shorter with topical fungicidal allylamines than with fungistatic azoles. Oral therapy is preferred for tinea capitis, tinea barbae, and onychomycosis. Orally administered griseofulvin remains the standard treatment for tinea capitis. Topical treatment of onychomycosis with ciclopirox nail lacquer has a low cure rate. For onychomycosis, "pulse" oral therapy with the newer imidazoles (itraconazole or fluconazole) or allylamines (terbinafine) is considerably less expensive than continuous treatment but has a somewhat lower mycologic cure rate. The diagnosis of onychomycosis should be confirmed by KOH microscopy, culture, or histologic examination before therapy is initiated, because of the expense, duration, and potential adverse effects of treatment.


Prenatal screening for psychosocial risks in a high risk-population in Peru using the KINDEX interview.
Prenatal stress and other prenatal risk factors (e.g. intimate partner violence) have a negative impact on mother's health, fetal development as well as enduring adverse effects on the neuro-cognitive, behavioral and physical health of the child. Mothers of low socio-economic status and especially those living in crime-ridden areas are even more exposed to a host of risk factors. Societies of extreme violence, poverty and inequalities, often present difficulties to provide adequate mental health care to the most needed populations. The KINDEX, a brief standardized instrument that assesses 11 different risk factors was used by midwives to identify pregnant women at-risk, in a suburban area with one of the highest levels of domestic violence in Lima. The instrument was designed to be used by medical staff to identify high-risk child-bearing women and, based on the results, to refer them to the adequate psychological or social support providers. The aim of this study is to assess the feasibility of psychosocial screening using the KINDEX in a Latin American Country for the first time, and to explore the relationship of the KINDEX with thee major risk areas, maternal psychopathology, perceived stress and traumatic experiences. The study was conducted in cooperation with the gynecological department of a general hospital in a suburban area of Lima. Nine midwives conducted interviews using the KINDEX of ninety-five pregnant women attending the gynecological unit of the hospital. From these, forty pregnant women were re-interviewed by a clinical psychologist using established instruments in order to assess the feasibility of the prenatal assessment in public health settings and the relationship of the KINDEX with maternal perceived stress, psychopathology symptoms and trauma load during pregnancy. We found high rates of risk factors in the examined pregnant women comparable with those found in the general population. Significant correlations were found between the KINDEX sum score and the three risks areas, stress, psychopathology and trauma load as assessed in the Clinical Expert interviews. The different risks assessed by the KINDEX are related to higher levels of stress, psychopathology and trauma load, depending on the risk. The relationship between past adverse experience and current stressors with perceived maternal stress, psychopathology symptoms and traumatic experiences confirm the importance of prenatal assessment for psychosocial risks. The use of KINDEX by midwives providing obstetrical care to pregnant women in urban Peru is feasible and can be used to identify high-risk women and refer them to the adequate mental health or social services for necessary attention and support. Early interventions are essential to mitigating the adverse effects of maternal stress, trauma and psychopathology on the fetus and child.


In vivo NMR imaging and spectroscopic investigation of renal pathology in lean and obese rat kidneys.
Diabetic nephropathy is a major cause of end-stage renal failure. While our understanding of the pathogenesis of nephropathy is incomplete, progressive glomerular injury appears to play a significant role in the decline of renal function. Proton NMR spectroscopy and imaging techniques were used to address changes in renal pathology associated with glomerular mesangial expansion in vivo in kidneys from spontaneously obese and lean (control) littermate Zucker rats. Fully functioning rat kidneys were surgically exposed and externalized for direct NMR signal detection via a coil placed around the organ. High-resolution (78 microns in plane) proton images were obtained at 4.7 T magnetic field strength revealing fine structure within the well-defined cortical and medullary regions. The obese rat kidney images were distinct in appearance from the lean kidney images and exhibited marked cortical expansion as well as increased overall kidney size. Enlargement of mean glomerular diameter was verified histologically in the obese kidneys as compared with the lean kidneys. Proton T1 and T2 relaxation times were determined from the entire kidney using standard spectroscopic techniques, and from specific regions within the kidney from multiple T1- and T-2 weighted images. Additionally, image contrast enhancement resulting from saturation transfer between protons in restricted-mobility environments and mobile water protons within the kidney was investigated in the lean and obese rat kidneys using magnetization-transfer imaging techniques. At the early stage of renal injury examined in this study, diseased and healthy kidneys could not be differentiated on the basis of relaxation times alone. The magnitude of saturation transfer obtained in cortical tissue in the lean and obese kidneys was also not statistically significantly different. However, the magnitude of saturation transfer achieved in the medullary tissue of obese kidneys was statistically significantly less than that achieved in lean kidneys.


The Lck SH3 domain negatively regulates localization to lipid rafts through an interaction with c-Cbl.
Lck is a member of the Src family of protein-tyrosine kinases and is essential for T cell development and function. Lck is localized to the inner surface of the plasma membrane and partitions into lipid rafts via dual acylation on its N terminus. We have tested the role of Lck binding domains in regulating Lck localization to lipid rafts. A form of Lck containing a point mutation inactivating the SH3 domain (W97ALck) was preferentially localized to lipid rafts compared with wild type or SH2 domain-inactive (R154K) Lck when expressed in Lck-deficient J.CaM1 cells. W97ALck incorporated more of the radioiodinated version of palmitic acid, 16-[(125)I]iodohexadecanoic acid. Overexpression of c-Cbl, a ligand of the Lck SH3 domain, depleted Lck from lipid rafts in Jurkat cells. Additionally, Lck localization to lipid rafts was enhanced in c-Cbl-deficient T cells. The association of Lck with c-Cbl in vivo required a functional SH3 domain. These results suggest a model whereby the SH3 domain negatively regulates basal localization of Lck to lipid rafts via association with c-Cbl.


The potential for glycemic control monitoring and screening for diabetes at dental visits using oral blood.
We examined the potential for glycemic control monitoring and screening for diabetes in a dental setting among adults (n = 408) with or at risk for diabetes. In 2013 and 2014, we performed hemoglobin A1c (HbA1c) tests on dried blood samples of gingival crevicular blood and compared these with paired "gold-standard" HbA1c tests with dried finger-stick blood samples in New York City dental clinic patients. We examined differences in sociodemographics and diabetes-related risk and health care characteristics for 3 groups of at-risk patients. About half of the study sample had elevated HbA1c values in the combined prediabetes and diabetes ranges, with approximately one fourth of those in the diabetes range. With a correlation of 0.991 between gingival crevicular and finger-stick blood HbA1c, measures of concurrence between the tests were extremely high for both elevated HbA1c and diabetes-range HbA1c levels. Persons already diagnosed with diabetes and undiagnosed persons aged 45 years or older could especially benefit from HbA1c testing at dental visits. Gingival crevicular blood collected at the dental visit can be used to screen for diabetes and monitor glycemic control for many at-risk patients.


Smaller hippocampal volume following sexual assault in women is associated with post-traumatic stress disorder.
Exposure to sexual assault is a significant risk factor to develop post-traumatic stress disorder (PTSD) in females. The early neurobiological changes leading to the development of PTSD remain understudied and unclear in this population. Participants were 27 adult females recruited within a month following exposure to sexual assault (T1) and 20 age-matched non-exposed controls. Among the victims, 10 participants met (PTSD+) and 15 did not meet (PTSD-) DSM-IV criteria for PTSD 6 months post-trauma (T2). At both visits, hippocampal and amygdala volumes were extracted from magnetic resonance imaging scans, and indices of total diurnal cortisol changes were derived from individual areas under the curve relative to the ground (AUCg). Measures at T1 were compared between groups at T1, measures at T2 between groups at T2, and measures at T1 between groups at T2. At T1, victims had significantly smaller bilateral hippocampal volumes, but not AUCg, than controls. At T2, neither hippocampal volume nor AUCg significantly differed among the groups. However, the PTSD+ group had significantly smaller hippocampal volumes at T1 than the control group, but not compared to the PTSD- group. This study indicates that having smaller hippocampal volumes is a risk factor to develop PTSD in females exposed to sexual assault.


Inhaled corticosteroids for cystic fibrosis.
Reduction of lung inflammation is one of the goals of cystic fibrosis therapy. Inhaled corticosteroids are often used to treat children and adults with cystic fibrosis. The rationale for this is their potential to reduce lung damage arising from inflammation, as well as their effect on symptomatic wheezing. It is important to establish the current level of evidence for the risks and benefits of inhaled corticosteroids, especially in the light of their known adverse effects on growth. This is an update of a previously published review. To assess the effectiveness of taking regular inhaled corticosteroids, compared to not taking them, in children and adults with cystic fibrosis. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register, comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. We requested information from pharmaceutical companies manufacturing inhaled corticosteroids and authors of identified trials.Date of most recent search of the Group's Trials Register: 15 August 2016. Randomised or quasi-randomised trials, published and unpublished, comparing inhaled corticosteroids to placebo or standard treatment in individuals with cystic fibrosis. Two independent authors assessed methodological quality and risk of bias in trials using established criteria and extracted data using standard pro formas. The searches identified 34 citations, of which 26 (representing 13 trials) were eligible for inclusion. These 13 trials reported the use of inhaled corticosteroids in 506 people with cystic fibrosis aged between six and 55 years. One was a withdrawal trial in individuals who were already taking inhaled corticosteroids. Methodological quality and risk of bias were difficult to assess from published information. Many of the risk of bias judgements were unclear due to a lack of available information. Only two trials specified how participants were randomised and less than half of the included trials gave details on how allocation was concealed. Trials were generally judged to have a low risk of bias from blinding, except for two which were open label or did not use a placebo. There were some concerns that a number of trials had not been published in peer-reviewed journals, but the risk of bias from this was unclear. Inclusion criteria varied between trials, as did type and duration of treatment and timing of outcome assessments. Objective measures of airway function were reported in most trials but were often incomplete. Significant benefit has not been conclusively demonstrated. Four trials systematically documented adverse effects and growth was significantly affected in one study using high doses. Evidence from these trials is insufficient to establish whether inhaled corticosteroids are beneficial in cystic fibrosis, but withdrawal in those already taking them has been shown to be safe. There is some evidence they may cause harm in terms of growth. It has not been established whether long-term use is beneficial in reducing lung inflammation, which should improve survival, but it is unlikely this will be proven conclusively in a randomised controlled trial.


Cystic fibrosis gene therapy: successes, failures and hopes for the future.
Cystic fibrosis (CF) is a single-gene disorder with insufficient treatment options and a target organ, the lung that is relatively easily accessible. Thus, it is not surprising that in the early years of gene therapy, CF was at the forefront of this field. Since cloning of the CF gene in 1989, 25 Phase I/II clinical trials involving approximately 420 CF patients have been carried out using a variety of viral and nonviral gene transfer agents. Most early trials focused on the nasal epithelium as a surrogate for the lung to allow for easy access and sampling, and, importantly, to ensure safety. Once an acceptable safety profile had been established, gene transfer agents were administered directly into the lung. Although many of these trials established proof-of-principle for gene transfer in the airways, a gene therapy-based treatment has not yet been developed. Here, we will summarize the key findings of these clinical studies and describe current preclinical and clinical research aimed at further developing gene therapy for CF.


Development of disability in chronic obstructive pulmonary disease: beyond lung function.
COPD is a major cause of disability, but little is known about how disability develops in this condition. The authors analysed data from the Function, Living, Outcomes and Work (FLOW) Study which enrolled 1202 Kaiser Permanente Northern California members with COPD at baseline and re-evaluated 1051 subjects at 2-year follow-up. The authors tested the specific hypothesis that the development of specific non-respiratory impairments (abnormal body composition and muscle strength) and functional limitations (decreased lower extremity function, poor balance, mobility-related dyspnoea, reduced exercise performance and decreased cognitive function) will determine the risk of disability in COPD, after controlling for respiratory impairment (FEV(1) and oxygen saturation). The Valued Life Activities Scale was used to assess disability in terms of a broad range of daily activities. The primary disability outcome measure was defined as an increase in the proportion of activities that cannot be performed of 3.3% or greater from baseline to 2-year follow-up (the estimated minimal important difference). Multivariable logistic regression was used for analysis. Respiratory impairment measures were related to an increased prospective risk of disability (multivariate OR 1.75; 95% CI 1.26 to 2.44 for 1 litre decrement of FEV(1) and OR 1.57 per 5% decrement in oxygen saturation; 95% CI 1.13 to 2.18). Non-respiratory impairment (body composition and lower extremity muscle strength) and functional limitations (lower extremity function, exercise performance, and mobility-related dyspnoea) were all associated with an increased longitudinal risk of disability after controlling for respiratory impairment (p<0.05 in all cases). Non-respiratory impairment and functional limitations were predictive of prospective disability, above-and-beyond sociodemographic characteristics, smoking status and respiratory impairment (area under the receiver operating characteristic curve increased from 0.65 to 0.75; p<0.001). Development of non-respiratory impairment and functional limitations, which reflect the systemic nature of COPD, appear to be critical determinants of disablement. Prevention and treatment of disability require a comprehensive approach to the COPD patient.


Dpysl2 (CRMP2) is required for the migration of facial branchiomotor neurons in the developing zebrafish embryo.
Dihydropyrimidinase-like family proteins (Dpysls) are relevant in several processes during nervous system development; among others, they are involved in axonal growth and cell migration. Dpysl2 (CRMP2) is the most studied member of this family; however, its role in vivo is still being investigated. Our previous studies in zebrafish showed the requirement of Dpysl2 for the proper positioning of caudal primary motor neurons and Rohon-Beard neurons in the spinal cord.In the present study, we show that Dpysl2 is necessary for the proper migration of facial branchiomotor neurons during early development in zebrafish. We generated a dpysl2 knock-out (KO) zebrafish mutant line and used different types of antisense morpholino oligonucleotides (AMO) to analyze the role of Dpysl2 in this process. Both dpysl2 KO mutants and morphants exhibited abnormalities in the migration of these neurons from rhombomers (r) 4 and 5 to 6 and 7. The facial branchiomotor neurons that were expected to be at r6 were still located at r4 and r5 hours after the migration process should have been completed. In addition, mutant phenotypes were rescued by injecting dpysl2 mRNA into the KO embryos. These results indicate that Dpysl2 is involved in the proper migration of facial branchiomotor neurons in developing zebrafish embryos.


Folding and assembly of the large molecular machine Hsp90 studied in single-molecule experiments.
Folding of small proteins often occurs in a two-state manner and is well understood both experimentally and theoretically. However, many proteins are much larger and often populate misfolded states, complicating their folding process significantly. Here we study the complete folding and assembly process of the 1,418 amino acid, dimeric chaperone Hsp90 using single-molecule optical tweezers. Although the isolated C-terminal domain shows two-state folding, we find that the isolated N-terminal as well as the middle domain populate ensembles of fast-forming, misfolded states. These intradomain misfolds slow down folding by an order of magnitude. Modeling folding as a competition between productive and misfolding pathways allows us to fully describe the folding kinetics. Beyond intradomain misfolding, folding of the full-length protein is further slowed by the formation of interdomain misfolds, suggesting that with growing chain lengths, such misfolds will dominate folding kinetics. Interestingly, we find that small stretching forces applied to the chain can accelerate folding by preventing the formation of cross-domain misfolding intermediates by leading the protein along productive pathways to the native state. The same effect is achieved by cotranslational folding at the ribosome in vivo.


Decreased lung function in 7-year-old children with early-life organophosphate exposure.
Organophosphate pesticides are heavily used in agriculture, and adverse associations with respiratory health in occupational settings have been reported. However, most of the evidence comes from studies where there were no biomarkers of exposure and no objective outcome measurement. Non-occupational chronic effects among residents living in agricultural communities are less well described. To evaluate associations between early-life organophosphate exposure and lung function of children living in an agricultural community. Participants were 279 children from the Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS) longitudinal birth cohort. The area under the curve for organophosphate exposure was determined by urinary diethyl and dimethyl dialkylphosphate metabolites of organophosphate pesticides, which were measured five times during childhood (6-60 months). Spirometry was performed at age 7 years. Regression models controlled for maternal smoking during pregnancy, season of birth, particulate matter concentrations with aerodynamic diameter ≤2.5 μm (PM2.5), breast feeding duration, mould and pets at home, distance of home from a highway, food insecurity, maternal education, season of spirometry, sex, height and technician. Childhood diethyl, dimethyl and total dialkylphosphate concentrations were associated with significant decreases in lung function at age 7. Specifically, we found lower FEV1, (L/s) (ß=-0.16, 95% CI -0.30 to -0.02, p=0.03) and FVC (L) (ß=-0.17, 95% CI -0.34 to 0.01, p=0.06) per 10-fold increase of total dialkylphosphate levels. Early-life organophosphate exposure as assessed by dialkylphosphate concentrations was adversely associated with 7-year-old children's lung function.


Crystallization of supercooled fenofibrate studied at ambient and elevated pressures.
In this work, we have performed a detailed investigation on the crystallization tendency of the modeled glass-forming pharmaceutical compound, fenofibrate. To do this, we have employed four different experimental techniques allowing following of the crystallization process. This has included dielectric spectroscopy, optical microscopy, X-ray diffraction and differential scanning calorimetry. From the crystallization kinetic studies carried out at atmospheric pressure, we have determined the temperature dependence of the crystal growth rate and the overall crystallization rate. It was found that the time scale of the molecular motions responsible for α-relaxation correlates much better with the crystal growth rate than with the overall crystallization rate. Experiments carried out under varying thermodynamic conditions while remaining on the same timescale of α-relaxation have demonstrated that the crystallization tendency of the supercooled fenofibrate significantly slows down with increasing pressure. Lastly, we have also shown that the thermodynamic history of reaching crystallization conditions has a substantial impact on its overall progress.


Regulation by glutathione of interleukin-4 activity on cytotoxic T cells.
We have previously shown that cellular glutathione (GSH) regulates the T-cell proliferative activity of interleukin-2 (IL-2). Here, we examined whether and how GSH affects the activity of interleukin-4 (IL-4) on murine cytotoxic T cells. CT.4R, a T-cell line that is responsive to both IL-4 and IL-2, was used as a model. Although GSH alone had little effect on the thymidine incorporation of CT.4R cells, it enhanced the response of CT.4R to IL-4 and increased the level of thymidine incorporation up to more than 60-fold in a concentration-dependent manner. GSH affected the binding of IL-4 to cellular receptors. Scatchard plot analysis showed that GSH treatment did not change the dissociation constant significantly; however, it increased the receptor number from 1173 +/- 126 to 2112 +/- 492 molecules per cell. Internalization and degradation studies of IL-4 showed that the amount of IL-4 internalized and degraded in the GSH-treated cells was about twofold higher than those in the cells without GSH treatment. These results suggest that GSH regulates the binding, internalization, degradation and T-cell proliferative activity of IL-4; alteration of cellular GSH levels may thus affect the growth and replication of cytotoxic T cells through growth stimulating cytokines such as IL-2 and IL-4.


Plant development. Integration of growth and patterning during vascular tissue formation in Arabidopsis.
Coordination of cell division and pattern formation is central to tissue and organ development, particularly in plants where walls prevent cell migration. Auxin and cytokinin are both critical for division and patterning, but it is unknown how these hormones converge upon tissue development. We identify a genetic network that reinforces an early embryonic bias in auxin distribution to create a local, nonresponding cytokinin source within the root vascular tissue. Experimental and theoretical evidence shows that these cells act as a tissue organizer by positioning the domain of oriented cell divisions. We further demonstrate that the auxin-cytokinin interaction acts as a spatial incoherent feed-forward loop, which is essential to generate distinct hormonal response zones, thus establishing a stable pattern within a growing vascular tissue.


Contribution of main causes of death to social inequalities in mortality in the whole population of Scania, Sweden.
To more efficiently reduce social inequalities in mortality, it is important to establish which causes of death contribute the most to socioeconomic mortality differentials. Few studies have investigated which diseases contribute to existing socioeconomic mortality differences in specific age groups and none were in samples of the whole population, where selection bias is minimized. The aim of the present study was to determine which causes of death contribute the most to social inequalities in mortality in each age group in the whole population of Scania, Sweden. Data from LOMAS (Longitudinal Multilevel Analysis in Skåne) were used to estimate 12-year follow-up mortality rates across levels of socioeconomic position (SEP) and workforce participation in 975,938 men and women aged 0 to 80 years, during 1991-2002. The results generally showed increasing absolute mortality differences between those holding manual and non-manual occupations with increasing age, while there were inverted u-shaped associations when using relative inequality measures. Cardiovascular diseases (CVD) contributed to 52% of the male socioeconomic difference in overall mortality, cancer to 18%, external causes to 4% and psychiatric disorders to 3%. The corresponding contributions in women were 55%, 21%, 2% and 3%. Additionally, those outside the workforce (i.e., students, housewives, disability pensioners, and the unemployed) showed a strongly increased risk of future mortality in all age groups compared to those inside the workforce. Even though coronary heart disease (CHD) played a major contributing role to the mortality differences seen, stroke and other types of cardiovascular diseases also made substantial contributions. Furthermore, while the most common types of cancers made substantial contributions to the socioeconomic mortality differences, in some age groups more than half of the differences in cancer mortality could be attributed to rarer cancers. CHD made a major contribution to the socioeconomic differences in overall mortality. However, there were also important contributions from diseases with less well understood mechanistic links with SEP such as stroke and less-common cancers. Thus, an increased understanding of the mechanisms connecting SEP with more rare causes of disease might be important to be able to more successfully intervene on socioeconomic differences in health.


Aberrant GLI1 Activation in DNA Damage Response, Carcinogenesis and Chemoresistance.
The canonical hedgehog (HH) pathway is a multicomponent signaling cascade (HH, protein patched homolog 1 (PTCH1), smoothened (SMO)) that plays a pivotal role during embryonic development through activation of downstream effector molecules, namely glioma-associated oncogene homolog 1 (GLI1), GLI2 and GLI3. Activation of GLIs must be tightly regulated as they modulate target genes which control tissue patterning, stem cell maintenance, and differentiation during development. However, dysregulation or mutations in HH signaling leads to genomic instability (GI) and various cancers, for example, germline mutation in PTCH1 lead to Gorlin syndrome, a condition where patients develop numerous basal cell carcinomas and rarely rhabdomyosarcoma (RMS). Activating mutations in SMO have also been recognized in sporadic cases of medulloblastoma and SMO is overexpressed in many other cancers. Recently, studies in several human cancers have shown that GLI1 expression is independent from HH ligand and canonical intracellular signaling through PTCH and SMO. In fact, this aberrantly regulated GLI1 has been linked to several non-canonical oncogenic growth signals such as Kirsten rat sarcoma viral oncogene homolog (KRAS), avian myelocytomatosis virus oncogene cellular homolog (C-MYC), transforming growth factor β (TGFβ), wingless-type MMTV integration site family (WNT) and β-catenin. Recent studies from our lab and other independent studies demonstrate that aberrantly expressed GLI1 influences the integrity of several DNA damage response and repair signals, and if altered, these networks can contribute to GI and impact tumor response to chemo- and radiation therapies. Furthermore, the ineffectiveness of SMO inhibitors in clinical studies argues for the development of GLI1-specific inhibitors in order to develop effective therapeutic modalities to treat these tumors. In this review, we focus on summarizing current understanding of the molecular, biochemical and cellular basis for aberrant GLI1 expression and discuss GLI1-mediated HH signaling on DNA damage responses, carcinogenesis and chemoresistance.


Low biosorption of PVA coated engineered magnetic nanoparticles in granular sludge assessed by magnetic susceptibility.
When engineered nanoparticles (ENP) enter into wastewater treatment plants (WWTP) their removal from the water phase is driven by the interactions with the biomass in the biological treatment step. While studies focus on the interactions with activated flocculent sludge, investigations on the detailed distribution of ENP in other types of biomass, such as granulated sludge, are needed to assess their potential environmental pollution. This study employed engineered magnetic nanoparticles (EMNP) coated with polyvinyl alcohol (PVA) as model nanoparticles to trace their fate in granular sludge from WWT. For the first time, magnetic susceptibility was used as a simple approach for the in-situ quantification of EMNP with a high precision (error <2%). Compared to other analytical methods, the magnetic susceptibility requires no sample preparation and enabled direct quantification of EMNP in both the aqueous phase and the granular sludge. In batch experiments granular sludge was exposed to EMNP suspensions for 18 h. The results revealed that the removal of EMNP from the water phase (5-35%) and biosorption in the granular sludge were rather low. Less than 2.4% of the initially added EMNP were associated with the biomass. Loosely bounded to the granular sludge, desorption of EMNP occurred. Consequently, the removal of EMNP was mainly driven by physical co-sedimentation with the biomass instead of sorption processes. A mass balance elucidated that the majority of EMNP were stabilized by particulate organic matter in the water phase and can therefore likely be transported further. The magnetic susceptibility enabled tracing EMNP in complex matrices and thus improves the understanding of the general distribution of ENP in technical as well as environmental systems.


A comparison between wolves, Canis lupus, and dogs, Canis familiaris, in showing behaviour towards humans.
Both human and nonhuman primates use imperative pointing to request a desired object from another individual. Gaze alternation often accompanies such pointing gestures, and in species that have no hands this can in itself function as imperative pointing. Dogs have exceptional skills in communicating with humans. The early development of these skills is suggested to have been facilitated by domestication. Adult wolves socialized with humans can use human-provided information to find food in various situations, but it is unclear whether they would use gaze alternation to show their human partner a target location they cannot reach on their own. In our experiment, we tested wolves and dogs in a task where they could indicate an out-of-reach food location to one of two human partners. One partner reacted in a cooperative way and gave the food hidden in the indicated location to the subject whereas the other responded in a competitive way and ate the food herself. Our results suggest that wolves, as well as dogs, use 'showing' behaviours to indicate a food location to a human partner, and that both can adjust their communication to the cooperativeness of their human partners, showing more indicating signals in the presence of the cooperative partner than in the presence of the competitive one. We conclude that wolves and dogs, both kept in packs under the same conditions, can use humans as cooperative partners, and point imperatively in order to receive a desired out-of-reach object. It seems that intensive socialization with humans enables both wolves and dogs to communicate cooperatively about a food location with humans, most probably relying on skills that evolved to promote social coordination within their packs.


Antihypertensive medication use and incident Alzheimer disease: the Cache County Study.
Recent reports suggest that antihypertensive (AH) medications may reduce the risk of dementing illnesses. To examine the relationship of AH medication use with incidence of Alzheimer disease (AD) among the elderly population (aged 65 years and older) of Cache County, Utah, and to examine whether the relationship varies with different classes of AH medications. After an initial (wave 1) multistage assessment (1995 through 1997) to identify prevalent cases of dementia, we used similar methods 3 years later (wave 2) to identify 104 incident cases of AD among the 3308 survivors. At the baseline assessment, we obtained a detailed drug inventory from the study participants. We carried out discrete time survival analyses to examine the association between the use of AH medications (including angiotensin converting enzyme inhibitors, beta-blockers, calcium channel blockers, and diuretics) at baseline with subsequent risk of AD. Use of any AH medication at baseline was associated with lower incidence of AD (adjusted hazard ratio, 0.64; 95% confidence interval, 0.41-0.98). Examination of medication subclasses showed that use of diuretics (adjusted hazard ratio, 0.57; 95% confidence interval, 0.33-0.94), and specifically potassium-sparing diuretics (adjusted hazard ratio, 0.26; 95% confidence interval, 0.08-0.64), was associated with the greatest reduction in risk of AD. Corresponding analysis with a fully examined subsample controlling for blood pressure measurements did not substantially change our findings. These data suggest that AH medications, and specifically potassium-sparing diuretics, are associated with reduced incidence of AD. Because the latter association is a new finding, it requires confirmation in further study.


Evaluation of Bacterial RNA Polymerase Inhibitors in a Staphylococcus aureus-Based Wound Infection Model in SKH1 Mice.
Chronic wounds infected with pathogens such as Staphylococcus aureus represent a worldwide health concern, especially in patients with a compromised immune system. As antimicrobial resistance has become an immense global problem, novel antibiotics are urgently needed. One strategy to overcome this threatening situation is the search for drugs targeting novel binding sites on essential and validated enzymes such as the bacterial RNA polymerase (RNAP). In this work, we describe the establishment of an in vivo wound infection model based on the pathogen S. aureus and hairless Crl:SKH1-Hrhr (SKH1) mice. The model proved to be a valuable preclinical tool to study selected RNAP inhibitors after topical application. While rifampicin showed a reduction in the loss of body weight induced by the bacteria, an acceleration of wound healing kinetics, and a reduced number of colony forming units in the wound, the ureidothiophene-2-carboxylic acid 1 was inactive under in vivo conditions, probably due to strong plasma protein binding. The cocrystal structure of compound 1 with RNAP, that we hereby also present, will be of great value for applying appropriate structural modifications to further optimize the compound, especially in terms of plasma protein binding.


Faster metabolite (1)H transverse relaxation in the elder human brain.
(1)H magnetic resonance spectroscopy (MRS) is unique among imaging modalities because signals from several metabolites are measured during a single examination period. Each metabolite reflects a distinct intracellular process. Furthermore transverse (T2 ) relaxation times probe the viability of the cell microenvironment, e.g., the viscosity of the cellular fluids, the microscopic susceptibility distribution within the cells, and the iron content. In this study, T2s of brain metabolites were measured in the occipital lobe of eighteen young and fourteen elderly subjects at a field strength of 4 tesla. The T2s of N-acetylaspartate, total creatine, and total choline were 23%, 16% and 10% shorter in elderly than in young subjects. The findings of this study suggest that noninvasive detection of T2 provides useful biological information on changes in the cellular microenvironment that take place during aging.


Functional Segregation of the Right Inferior Frontal Gyrus: Evidence From Coactivation-Based Parcellation.
Previous studies helped unraveling the functional architecture of the human cerebral cortex. However, a comprehensive functional segregation of right lateral prefrontal cortex is missing. Here, we delineated cortical clusters in right area 44 and 45 based on their task-constrained whole-brain activation patterns across neuroimaging experiments obtained from a large database. We identified 5 clusters that differed with respect to their coactivation patterns, which were consistent with resting-state functional connectivity patterns of an independent dataset. Two clusters in the posterior inferior frontal gyrus (IFG) were functionally associated with action inhibition and execution, while two anterior clusters were related to reasoning and social cognitive processes. A fifth cluster was associated with spatial attention. Strikingly, the functional organization of the right IFG can thus be characterized by a posterior-to-anterior axis with action-related functions on the posterior and cognition-related functions on the anterior end. We observed further subdivisions along a dorsal-to-ventral axis in posterior IFG between action execution and inhibition, and in anterior IFG between reasoning and social cognition. The different clusters were integrated in distinct large-scale networks for various cognitive processes. These results provide evidence for a general organization of cognitive processes along axes spanning from more automatic to more complex cognitive processes.


Rapid Weight Loss Elicits Harmful Biochemical and Hormonal Responses in Mixed Martial Arts Athletes.
The purpose of this study was to compare biochemical and hormonal responses between mixed martial arts (MMA) competitors with minimal prefight weight loss and those undergoing rapid weight loss (RWL). Blood samples were taken from 17 MMA athletes (Mean± SD; age: 27.4 ±5.3yr; body mass: 76.2 ± 12.4kg; height: 1.71 ± 0.05m and training experience: 39.4 ± 25 months) before and after each match, according to the official events rules. The no rapid weight loss (NWL, n = 12) group weighed in on the day of the event (~30 min prior fight) and athletes declared not having used RWL strategies, while the RWL group (n = 5) weighed in 24 hr before the event and the athletes claimed to have lost 7.4 ± 1.1kg, approximately 10% of their body mass in the week preceding the event. Results showed significant (p < .05) increases following fights, regardless of group, in lactate, glucose, lactate dehydrogenase (LDH), creatinine, and cortisol for all athletes. With regard to group differences, NWL had significantly (p < .05) greater creatinine levels (Mean± SD; pre to post) (NWL= 101.6 ± 15-142.3 ± 22.9μmol/L and RWL= 68.9 ± 10.6-79.5 ± 15.9μmol/L), while RWL had higher LDH (median [interquartile range]; pre to post) (NWL= 211.5[183-236] to 231[203-258]U/L and RWL= 390[370.5-443.5] to 488[463.5-540.5]U/L) and AST (NWL= 30[22-37] to 32[22-41]U/L and 39[32.5-76.5] to 72[38.5-112.5] U/L) values (NWL versus RWL, p < .05). Post hoc analysis showed that AST significantly increased in only the RWL group, while creatinine increased in only the NWL group. The practice of rapid weight loss showed a negative impact on energy availability and increased both muscle damage markers and catabolic expression in MMA fighters.


A Telemedicine Robot System for Assisted and Independent Living.
The emerging demographic trends toward an aging population, demand new ways and solutions to improve the quality of elderly life. These include, prolonged independent living, improved health care, and reduced social isolation. Recent technological advances in the field of assistive robotics bring higher sophistication and various assistive abilities that can help in achieving these goals. In this paper, we present design and validation of a low-cost telepresence robot that can assist the elderly and their professional caregivers, in everyday activities. The developed robot structure and its control objectives were tested in, both, a simulation and experimental environment. On-field experiments were done in a private elderly care center involving elderly persons and caregivers as participants. The goal of the evaluation study was to test the software architecture and the robot capabilities for navigation, as well as the robot manipulator. Moreover, participants' reactions toward a possible adoption of the developed robot system in everyday activities were assessed. The obtained results of the conducted evaluation study are also presented and discussed.


Identification and functional analysis of a novel mutation in the SOX10 gene associated with Waardenburg syndrome type IV.
Waardenburg syndrome type IV (WS4) is a rare genetic disorder, characterized by auditory-pigmentary abnormalities and Hirschsprung disease. Mutations of the EDNRB gene, EDN3 gene, or SOX10 gene are responsible for WS4. In the present study, we reported a case of a Chinese patient with clinical features of WS4. In addition, the three genes mentioned above were sequenced in order to identify whether mutations are responsible for the case. We revealed a novel nonsense mutation, c.1063C>T (p.Q355*), in the last coding exon of SOX10. The same mutation was not found in three unaffected family members or 100 unrelated controls. Then, the function and mechanism of the mutation were investigated in vitro. We found both wild-type (WT) and mutant SOX10 p.Q355* were detected at the expected size and their expression levels are equivalent. The mutant protein also localized in the nucleus and retained the DNA-binding activity as WT counterpart; however, it lost its transactivation capability on the MITF promoter and acted as a dominant-negative repressor impairing function of the WT SOX10.


10-HDA, A Major Fatty Acid of Royal Jelly, Exhibits pH Dependent Growth-Inhibitory Activity Against Different Strains of Paenibacillus larvae.
Paenibacillus larvae (P. larvae) is a bacterial pathogen causing American foulbrood (AFB), the most serious disease of honeybee larvae. The food of young larvae could play an important role in the resistance of larvae against AFB. It contains antibacterial substances produced by honeybees that may inhibit the propagation of the pathogen in larval midguts. In this study, we identified and investigated the antibacterial effects of one of these substances, trans-10-hydroxy-2-decenoic acid (10-HDA), against P. larvae strains including all Enterobacterial Repetitive Intergenic Consensus (ERIC) genotypes. Its inhibitory activities were studied by determining the minimum inhibitory concentrations (MICs). It was found that 10-HDA efficacy increases substantially with decreasing pH; up to 12-fold differences in efficacy were observed between pH = 5.5 and pH = 7.2. P. larvae strains showed different susceptibility to 10-HDA; up to 2.97-fold differences existed among various strains with environmentally important ERIC I and ERIC II genotypes. Germinating spores of the pathogen were generally more susceptible to 10-HDA than vegetative cells. Our findings suggest that 10-HDA could play significant role in conferring antipathogenic activity to larval food in the midguts of young larvae and contribute to the resistance of individual larvae to P. larvae.


Structure discovery in Bayesian networks: an analytical tool for analysing complex animal health data.
Analysing animal health data can be a complex task as the health status of individuals or groups of animals, might depend on many inter-related variables. The objective is to differentiate variables that are directly associated with health status and therefore promising targets for intervention, from variables that are indirectly associated with health status and can therefore at best only affect this indirectly through association with other variables. Bayesian network (BN) modelling is a machine learning technique for empirically identifying associations in complex and high dimensional data, so-called "structure discovery". An introduction to structure discovery using BN modelling is presented, comprising the key assumptions required by the methodology, along with a discussion of advantages and limitations. To demonstrate the various steps required to apply BN structure discovery to animal health data, illustrative analyses of data collected during a previously published study concerned with exposure to bovine viral diarrhoea virus in beef cow-calf herds in Scotland are presented.


Sympathetic modulation of hypercapnic cerebral vasodilation in dogs.
We measured cerebral blood flow using both the radioactive microsphere technique and the cerebral venous outflow technique in dogs anesthetized with chloralase. The effect of sympathetic stimulation on cerebral blood flow was observed during both normocapnia and prolonged hypercapnia using both blood flow techniques. The increase in blood flow with hypercapnia was the same with both methods. During hypercapnia the venous outflow method showed a 38% decrease and microspheres an 18% decrease in cerebral blood flow with sympathetic stimulation. At normal CO2, stimulation caused a decrease in cerebral venous flow: no change was observed with the microsphere method. Analysis of the blood flow patterns to extracerebral tissues and evaluation of extracerebral arterial reference samples failed to prove the existence of axial streaming and subsequent skimming of microspheres within the cephalic circulation. It is concluded that direct electrical stimulation of the sympathetic innervation of the cerebral vessels is capable of reducing cerebral blood flow even during a profound hypercapnic vasodilation.


Inhibitory Effects of Standardized Boesenbergia pandurata Extract and Its Active Compound Panduratin A on Lipopolysaccharide-Induced Periodontal Inflammation and Alveolar Bone Loss in Rats.
Periodontitis, an inflammatory disease of the gingival tissue, triggered by microbial-derived elements, such as lipopolysaccharide (LPS), collapses the periodontal tissues and resorbs the alveolar bone. This study evaluated the inhibitory effects of standardized Boesenbergia pandurata extract (BPE) and panduratin A (PAN) on periodontitis-induced inflammation and alveolar bone loss. Sprague-Dawley rats with LPS-induced periodontitis were orally administered BPE (50 and 200 mg/kg/day) and PAN (20 mg/kg/day) for 8 days. Histological analysis revealed that BPE- and PAN-administered groups showed decreased cell infiltration and alveolar bone resorption. Furthermore, the BPE and PAN significantly alleviated the mRNA and protein expression levels of nuclear factor kappa B (NF-κB), interleukin-1β, matrix metalloproteinase (MMP)-2, and MMP-8. BPE and PAN also inhibited the expression of nuclear factor of activated T cells, cytoplasmic 1, c-Fos, and ostoclastogenesis-related enzymes, including cathepsin K and tartrate-resistant acid phosphatase (ALP). BPE and PAN not only upregulated the osteoblastogenesis-associated markers, such as collagen type I (COL1A1) and ALP, but also increased the ratio of osteoprotegerin to receptor activator of NF-κB ligand. Collectively, BPE and PAN efficiently prevent destruction of periodontal tissues and stimulating the loss of alveolar bone tissues, strongly indicative of their potential as natural antiperiodontitis agents.


Predictive coding of multisensory timing.
The sense of time is foundational for perception and action, yet it frequently departs significantly from physical time. In the paper we review recent progress on temporal contextual effects, multisensory temporal integration, temporal recalibration, and related computational models. We suggest that subjective time arises from minimizing prediction errors and adaptive recalibration, which can be unified in the framework of predictive coding, a framework rooted in Helmholtz's 'perception as inference'.


SF6(-) photodetachment near the adiabatic limit.
High sensitivity photodetachment cross-section measurements of SF6(-) are performed near the adiabatic threshold limit. The extraction of adiabatic detachment energy (ADE) from the high sensitivity measurement of the cross-section change as a function of photon energy is discussed. Below the vertical detachment energy a steep 4 orders of magnitude cross-section drop is observed, with cross sections as low as 2 × 10(-6) Å(2) measured for photon energies below 2 eV. The cross-section is fitted with both the expected spectral shape based on recently calculated Frank-Condon overlaps and a phenomenological threshold function. The resulting 1.7 ± 0.02 eV ADE values are significantly higher than previously recommended experimental ADE values obtained based on kinetics modeling, and possible differences between the experimental approaches are discussed.


Motion sickness during fore-and-aft oscillation: effect of the visual scene.
Repetitive braking and acceleration can cause carsickness, with the extent of sickness depending on the forward view outside the car. It was hypothesized that the visual scene would influence motion sickness caused by low-frequency, low-magnitude fore-and-aft oscillation in the laboratory. There were 120 seated male subjects who were exposed to 30 min of 0.1-Hz fore-and-aft oscillation at an acceleration magnitude of 0.89 m x s(-2) rms (a displacement of +/- 3.18 m). Subjects sat in a cabin with one of six scenes: 1) an internal view of two-dimensional black shapes on a white background; 2) an external view of the same two-dimensional shapes; 3) an external view of six horizontal black lines; 4) a 'real' three-dimensional external view; 5) no view (blindfolded); or 6) an internal collimated view of the two-dimensional shapes. Due to practical constraints, only conditions 1, 2, and 6 were tested in a balanced order. Ratings of motion sickness were obtained at 1-min intervals. Each of the six conditions caused motion sickness, with mean illness ratings that increased similarly over time regardless of viewing condition. The symptoms did not differ significantly between conditions and there was no difference in the risk of reaching an illness rating of 2, 'mild symptoms,' between the six viewing conditions. With a larger number of subjects, a small mean effect of vision might be found with motions having similar frequencies or similar magnitudes to the conditions investigated here. Nevertheless, compared with the large effects of vision with some motions, it is concluded that the visual scene has little effect on sickness caused by pure fore-and-aft oscillation at a frequency of 0.1 Hz and an acceleration magnitude of 0.89 m x s(-2) rms.


Correlation Between Sleep-Time Masseter Muscle Activity and Tooth Wear: An Electromyographic Study.
To assess the correlation between tooth wear and sleep-time masseter muscle activity (sMMA) in a group of healthy young adults who underwent home electromyographic/electrocardiographic (EMG/ECG) recordings with a portable device. A total of 41 healthy volunteers (23 women, 18 men; mean age 28.8 years, range 25 to 40) with good natural dentition underwent a 2-night in-home evaluation with a portable device that allowed a simultaneous sleep-time recording of EMG signals from both masseter muscles and heart rate. The number of sleep bruxism (SB) episodes per sleep hour (SB index), the number of phasic, tonic, and mixed sMMA events per hour, and the total number of sMMA events per night were calculated. All individuals also underwent an assessment of tooth wear on digital casts with the adoption of a six-degree rating scale. Correlations between sMMA variables and tooth wear were assessed using Pearson test. The null hypothesis was that correlation between the two conditions would not be significant. On average, the SB index was 4.5 ± 2.6, while the total number of sleep-time masseter contractions was 97.2 ± 55.2. Of those contractions, almost 60% were phasic. Average tooth wear was 1.5 ± 0.7, with the canines and mandibular incisors showing the highest wear scores. For all pairwise analyses, correlation values were not significant (P values .11 to .69), with r values ranging from 0.064 to 0.253. The null hypothesis of an absence of correlation between tooth wear and sMMA could not be rejected, implying that tooth wear cannot be used as an indicator of ongoing SB or sMMA. Future studies taking into account the multifaceted nature of tooth wear and the complex natural course of sleep phenomena are encouraged to investigate the issue further, at the individual level.


Characterization of the carboxysomal carbonic anhydrase CsoSCA from Halothiobacillus neapolitanus.
In cyanobacteria and many chemolithotrophic bacteria, the CO(2)-fixing enzyme ribulose 1,5-bisphosphate carboxylase/oxygenase (RubisCO) is sequestered into polyhedral protein bodies called carboxysomes. The carboxysome is believed to function as a microcompartment that enhances the catalytic efficacy of RubisCO by providing the enzyme with its substrate, CO(2), through the action of the shell protein CsoSCA, which is a novel carbonic anhydrase. In the work reported here, the biochemical properties of purified, recombinant CsoSCA were studied, and the catalytic characteristics of the carbonic anhydrase for the CO(2) hydration and bicarbonate dehydration reactions were compared with those of intact and ruptured carboxysomes. The low apparent catalytic rates measured for CsoSCA in intact carboxysomes suggest that the protein shell acts as a barrier for the CO(2) that has been produced by CsoSCA through directional dehydration of cytoplasmic bicarbonate. This CO(2) trap provides the sequestered RubisCO with ample substrate for efficient fixation and constitutes a means by which microcompartmentalization enhances the catalytic efficiency of this enzyme.


Antinociceptive activity of the chloroform fraction of Dioclea virgata (Rich.) Amshoff (Fabaceae) in mice.
Acute treatment with the chloroform fraction of Dioclea virgata (Rich.) Amshoff (CFDv) in mice produced decreased ambulation and sedation in the behavioral pharmacological screening. Doses of 125 and 250 mg/kg CFDv decreased latency of sleep onset in the test of sleeping time potentiation. In the open field, animals treated with CFDv reduced ambulation and rearing (250 mg/kg), as well as defecation (125; 250 mg/kg). Regarding the antinociceptive activity, CFDv (125, 250, 500 mg/kg) increased latency to first writhing and decreased the number of writhings induced by acetic acid. In the formalin test, CFDv (250 mg/kg) decreased paw licking time in the first and second phases indicating antinociceptive activity that can be mediated both peripherally and at the central level. CFDv did not affect motor coordination until 120 minutes after treatment. CFDv shows psychopharmacological effects suggestive of CNS-depressant drugs with promising antinociceptive activity.


Shared decision-making conversations and smoking cessation interventions: critical components of low-dose CT lung cancer screening programs.
Lung cancer remains the world's deadliest cancer despite efforts to decrease smoking rates. Lung cancer screening (LCS) with low-dose computed tomography (LDCT) was shown to reduce lung cancer deaths by 20%. Screening with LDCT comes with potential harms including a high rate of false-positive test results, subsequent follow-up procedures, and radiation exposure. For some patients, the potential benefits associated with screening may be outweighed by the harms. The decision to screen must therefore take into consideration patients' risk of developing lung cancer, comorbidities that may prevent diagnostic procedures or curative surgery, and their values and preferences regarding the benefits and harms of screening. A process called shared decision-making (SDM) is recognized as a crucial feature of LCS. SDM is a patient-centered approach where healthcare providers provide best clinical evidence and then work together with patients to discern if the screening process aligns with the patient's values and preferences. Unfortunately, clinician SDM skills are often of poor quality which can lead to patients making uninformed decisions. Decision support tools that help patients make informed decisions and increase SDM on LCS are available. In 2015, the Centers for Medicare & Medicaid Services issued a coverage memo for LCS that contained an unprecedented requirement: an initial patient counseling and SDM visit with the use of at least one decision aid must occur for screening services to be reimbursed. This review focuses on SDM and suggests ways to increase the prevalence and effectiveness of SDM in LCS programs. Stopping smoking greatly reduces a person's risk for developing lung cancer, and smoking cessation messages in LCS guidelines from major medical organizations and interventions in LCS programs are explored. LCS has come of age; so too has SDM as it is an integral part of LCS programs.


Heme oxygenase expression in cultured human trophoblast cells during in vitro differentiation: effects of hypoxia.
Heme oxygenases (HO-1 and HO-2) are responsible for the production of carbon monoxide, a vasodilator. HO is important in controlling placental blood flow and expression can be sensitive to oxygen. We previously reported a reduction in HO-2 expression in placentae obtained from patients with pre-eclampsia or living at high altitude, both associated with placental hypoxia. Thus we hypothesized that HO expression in cultured trophoblasts would be altered by exposure to hypoxia. HO-1 and HO-2 expression was assessed in trophoblast cell cultures following exposure to different oxygen environments. Western blot analyses showed that HO-1 expression in syncytiotrophoblast was significantly lower than in cytotrophoblasts in standard conditions (p < 0.05). There was no difference in HO-1 expression in cytotrophoblasts transferred to 2% O2 for various times. However, exposure of syncytiotrophoblast cultures to hypoxia for 12 h resulted in a significant reduction in HO-1 expression (p < 0.05). HO-2 expression was not affected by exposure to hypoxia in either cytotrophoblast or syncytiotrophoblast cultures. Possible interpretations of these findings are that chronic hypoxia alone is not responsible for reduced HO-2 expression or a much longer exposure to chronic hypoxia (perhaps months) is required. This study also reinforces the complexities of HO regulation by oxygen.


Establishing research priorities for patient safety in emergency medicine: a multidisciplinary consensus panel.
Patient safety in the context of emergency medicine is a relatively new field of study. To date, no broad research agenda for patient safety in emergency medicine has been established. The objective of this study was to establish patient safety-related research priorities for emergency medicine. These priorities would provide a foundation for high-quality research, important direction to both researchers and health-care funders, and an essential step in improving health-care safety and patient outcomes in the high-risk emergency department (ED) setting. A four-phase consensus procedure with a multidisciplinary expert panel was organized to identify, assess, and agree on research priorities for patient safety in emergency medicine. The 19-member panel consisted of clinicians, administrators, and researchers from adult and pediatric emergency medicine, patient safety, pharmacy, and mental health; as well as representatives from patient safety organizations. In phase 1, we developed an initial list of potential research priorities by electronically surveying a purposeful and convenience sample of patient safety experts, ED clinicians, administrators, and researchers from across North America using contact lists from multiple organizations. We used simple content analysis to remove duplication and categorize the research priorities identified by survey respondents. Our expert panel reached consensus on a final list of research priorities through an in-person meeting (phase 3) and two rounds of a modified Delphi process (phases 2 and 4). After phases 1 and 2, 66 unique research priorities were identified for expert panel review. At the end of phase 4, consensus was reached for 15 research priorities. These priorities represent four themes: (1) methods to identify patient safety issues (five priorities), (2) understanding human and environmental factors related to patient safety (four priorities), (3) the patient perspective (one priority), and (4) interventions for improving patient safety (five priorities). This study established expert, consensus-based research priorities for patient safety in emergency medicine. This framework could be used by researchers and health-care funders and represents an essential guiding step towards enhancing quality of care and patient safety in the ED.


A randomized controlled study to evaluate and compare Truview blade with Macintosh blade for laryngoscopy and intubation under general anesthesia.
The Truview EVO2™ laryngoscope is a recently introduced device with a unique blade that provides a magnified laryngeal view at 42° anterior reflected view. It facilitates visualization of the glottis without alignment of oral, pharyngeal, and tracheal axes. We compared the view obtained at laryngoscopy, intubating conditions and hemodynamic parameters of Truview with Macintosh blade. In prospective, randomized and controlled manner, 200 patients of ASA I and II of either sex (20-50 years), presenting for surgery requiring tracheal intubation, were assigned to undergo intubation using a Truview or Macintosh laryngoscope. Visualization of the vocal cord, ease of intubation, time taken for intubation, number of attempts, and hemodynamic parameters were evaluated. Truview provided better results for the laryngeal view using Cormack and Lehane grading, particularly in patients with higher airway Mallampati grading (P < 0.05). The time taken for intubation (33.06±5.6 vs. 23.11±57 seconds) was more with Truview than with Macintosh blade (P < 0.01). The Percentage of Glottic Opening (POGO) score was significantly higher (97.26±8) in Truview as that observed with Macintosh blade (83.70±21.5). Hemodynamic parameters increased after tracheal intubation from pre-intubation value (P < 0.05) in both the groups, but they were comparable amongst the groups. No postoperative adverse events were noted. Tracheal intubation using Truview blade provided consistently improved laryngeal view as compared to Macintosh blade without the need to align the oral, pharyngeal and tracheal axes, with equal attempts for successful intubation and similar changes in hemodynamics. However, the time taken for intubation was more with Truview.


A review on immunohistochemical and histopathologic validation in PET-CT findings with consideration to microRNAs.
This review provides an overview of some of the most recent clinical trials which investigated various types of cancer and other diseases, through the use of PET-CT imaging, highlighting the use of immunohistochemical stains or conventional histopathology for the validation or contradiction of their hypothesis. Furthermore, we investigate a potential new direction of research by analyzing the upcoming role of microRNAs in disease confirmation. An extensive search of MEDLINE/PubMed and SCOPUS electronic databases was made, using the MeSH terms "positron emission tomography computed tomography" and "immunohistochemistry" as well as "SUV" and "immunohistochemistry", restricting the search by clinical trials and time period. Further searches were made for articles regarding Ki-67 and microRNAs in correlation with metabolic PET-CT uptake. Out of all 389 initial search results, 27 original articles were found relevant to the topic. Their contents were synthesized and discussed regarding the matter at hand. No relevant clinical trials involving microRNAs were found. Immunohistochemical and histopathologic results remain widely used and indispensable in modern research, concerning PET-CT validation. Possible candidates for diagnosis confirmation, in future research, may reside in the further development of microRNAs.


Socioeconomic status and lifestyle behaviours in cancer survivors: smoking and physical activity.
Smoking cessation and increased physical activity (pa) have been linked to better outcomes in cancer survivors. We assessed whether socioeconomic factors influence changes in those behaviours after a cancer diagnosis. As part of a cross-sectional study, a diverse group of cancer survivors at the Princess Margaret Cancer Centre (Toronto, ON), completed a questionnaire about past and current lifestyle behaviours and perceptions about the importance of those behaviours with respect to their health. The influence of socioeconomic indicators on smoking status and physical inactivity at 1 year before and after diagnosis were assessed using multivariable logistic regression with adjustment for clinico-demographic factors. Of 1222 participants, 1192 completed the smoking component. Of those respondents, 15% smoked before diagnosis, and 43% of those smokers continued to smoke after. The proportion of survivors who continued to smoke increased with lower education level (p = 0.03). Of the 1106 participants answering pa questions, 39% reported being physically inactive before diagnosis, of whom 82% remained inactive afterward. Survivors with a lower education level were most likely to remain inactive after diagnosis (p = 0.003). Lower education level, household income, and occupation were associated with the perception that pa had no effect or could worsen fatigue and quality of life (p ≤ 0.0001). In cancer survivors, education level was a major modifier of smoking and pa behaviours. Lower socioeconomic status was associated with incorrect perceptions about pa. Targeting at-risk survivors by education level should be evaluated as a strategy in cancer survivorship programs.


Multiple gene genealogies and species recognition in the ectomycorrhizal fungus Paxillus involutus.
Paxillus involutus (basidiomycetes, Boletales) is a common ectomycorrhizal fungus in the Northern Hemisphere. The fungus displays significant variation in phenotypic characters related to morphology, physiology, and ecology. Previous studies have shown that P. involutus contains several intersterility groups and morphological species. In this study, we have used concordance of multiple gene genealogies to identify genetically isolated species of P. involutus. Fragments from five protein coding genes in 50 isolates of P. involutus collected from different hosts and environments in Europe and one location in Canada were analysed using phylogenetic methods. Concordance of the five gene genealogies showed that P. involutus comprises at least four distinct phylogenetic lineages: phylogenetic species I (with nine isolates), II (33 isolates), III (three isolates), and IV (five isolates). The branches separating the four species were long and well supported compared with the species internodes. A low level of shared polymorphisms was observed among the four lineages indicating a long time since the genetic isolation began. Three of the phylospecies corresponded to earlier identified morphological species: I to P. obscurosporus, II to P. involutus s. str., and III to P. validus. The phylogenetic species had an overlapping geographical distribution. Species I and II differed partly in habitat and host preferences.


Clinical Actionability of Multigene Panel Testing for Hereditary Breast and Ovarian Cancer Risk Assessment.
The practice of genetic testing for hereditary breast and/or ovarian cancer (HBOC) is rapidly evolving owing to the recent introduction of multigene panels. While these tests may identify 40% to 50% more individuals with hereditary cancer gene mutations than does testing for BRCA1/2 alone, whether finding such mutations will alter clinical management is unknown. To define the potential clinical effect of multigene panel testing for HBOC in a clinically representative cohort. Observational study of patients seen between 2001 and 2014 in 3 large academic medical centers. We prospectively enrolled 1046 individuals who were appropriate candidates for HBOC evaluation and who lacked BRCA1/2 mutations. We carried out multigene panel testing on all participants, then determined the clinical actionability, if any, of finding non-BRCA1/2 mutations in these and additional comparable individuals. We evaluated the likelihood of (1) a posttest management change and (2) an indication for additional familial testing, considering gene-specific consensus management guidelines, gene-associated cancer risks, and personal and family history. Among 1046 study participants, 40 BRCA1/2-negative patients (3.8%; 95% CI, 2.8%-5.2%) harbored deleterious mutations, most commonly in moderate-risk breast and ovarian cancer genes (CHEK2, ATM, and PALB2) and Lynch syndrome genes. Among these and an additional 23 mutation-positive individuals enrolled from our clinics, most of the mutations (92%) were consistent with the spectrum of cancer(s) observed in the patient or family, suggesting that these results are clinically significant. Among all 63 mutation-positive patients, additional disease-specific screening and/or prevention measures beyond those based on personal and family history alone would be considered for most (33 [52%] of 63; 95% CI, 40.3%-64.2%). Furthermore, additional familial testing would be considered for those with first-degree relatives (42 [72%] of 58; 95% CI, 59.8%-82.2%) based on potential management changes for mutation-positive relatives. This clinical effect was not restricted to a few of the tested genes because most identified genes could change clinical management for some patients. In a clinically representative cohort, multigene panel testing for HBOC risk assessment yielded findings likely to change clinical management for substantially more patients than does BRCA1/2 testing alone. Multigene testing in this setting is likely to alter near-term cancer risk assessment and management recommendations for mutation-affected individuals across a broad spectrum of cancer predisposition genes.