Comparative analysis of the recently discovered hAT transposon TcBuster in human cells.
Transposons are useful tools for creating transgenic organisms, insertional mutagenesis, and genome engineering. TcBuster, a novel hAT-family transposon system derived from the red flour beetle Tribolium castaneum, was shown to be highly active in previous studies in insect embryoes. We tested TcBuster for its activity in human embryonic kidney 293 (HEK-293) cells. Excision footprints obtained from HEK-293 cells contained small insertions and deletions consistent with a hAT-type repair mechanism of hairpin formation and non-homologous end-joining. Genome-wide analysis of 23,417 piggyBac, 30,303 Sleeping Beauty, and 27,985 TcBuster integrations in HEK-293 cells revealed a uniquely different integration pattern when compared to other transposon systems with regards to genomic elements. TcBuster experimental conditions were optimized to assay TcBuster activity in HEK-293 cells by colony assay selection for a neomycin-containing transposon. Increasing transposon plasmid increased the number of colonies, whereas gene transfer activity dependent on codon-optimized transposase plasmid peaked at 100 ng with decreased colonies at the highest doses of transposase DNA. Expression of the related human proteins Buster1, Buster3, and SCAND3 in HEK-293 cells did not result in genomic integration of the TcBuster transposon. TcBuster, Tol2, and piggyBac were compared directly at different ratios of transposon to transposase and found to be approximately comparable while having their own ratio preferences. TcBuster was found to be highly active in mammalian HEK-293 cells and represents a promising tool for mammalian genome engineering.


Targeted muscle reinnervation in oncologic amputees: Early experience of a novel institutional protocol.
We describe a multidisciplinary approach for comprehensive care of amputees with concurrent targeted muscle reinnervation (TMR) at the time of amputation. Our TMR cohort was compared to a cross-sectional sample of unselected oncologic amputees not treated at our institution (N = 58). Patient-Reported Outcomes Measurement Information System (NRS, PROMIS) were used to assess postamputation pain. Thirty-one patients underwent amputation with concurrent TMR during the study; 27 patients completed pain surveys; 15 had greater than 1 year follow-up (mean follow-up 14.7 months). Neuroma symptoms occurred significantly less frequently and with less intensity among the TMR cohort. Mean differences for PROMIS pain intensity, behavior, and interference for phantom limb pain (PLP) were 5.855 (95%CI 1.159-10.55; P = .015), 5.896 (95%CI 0.492-11.30; P = .033), and 7.435 (95%CI 1.797-13.07; P = .011) respectively, with lower scores for TMR cohort. For residual limb pain, PROMIS pain intensity, behavior, and interference mean differences were 5.477 (95%CI 0.528-10.42; P = .031), 6.195 (95%CI 0.705-11.69; P = .028), and 6.816 (95%CI 1.438-12.2; P = .014), respectively. Fifty-six percent took opioids before amputation compared to 22% at 1 year postoperatively. Multidisciplinary care of amputees including concurrent amputation and TMR, multimodal postoperative pain management, amputee-centered rehabilitation, and peer support demonstrates reduced incidence and severity of neuroma and PLP.


Associations between β-blockers and psychiatric and behavioural outcomes: A population-based cohort study of 1.4 million individuals in Sweden.
β-blockers are widely used for treating cardiac conditions and are suggested for the treatment of anxiety and aggression, although research is conflicting and limited by methodological problems. In addition, β-blockers have been associated with precipitating other psychiatric disorders and suicidal behaviour, but findings are mixed. We aimed to examine associations between β-blockers and psychiatric and behavioural outcomes in a large population-based cohort in Sweden. We conducted a population-based longitudinal cohort study using Swedish nationwide high-quality healthcare, mortality, and crime registers. We included 1,400,766 individuals aged 15 years or older who had collected β-blocker prescriptions and followed them for 8 years between 2006 and 2013. We linked register data on dispensed β-blocker prescriptions with main outcomes, hospitalisations for psychiatric disorders (not including self-injurious behaviour or suicide attempts), suicidal behaviour (including deaths from suicide), and charges of violent crime. We applied within-individual Cox proportional hazards regression to compare periods on treatment with periods off treatment within each individual in order to reduce possible confounding by indication, as this model inherently adjusts for all stable confounders (e.g., genetics and health history). We also adjusted for age as a time-varying covariate. In further analyses, we adjusted by stated indications, prevalent users, cardiac severity, psychiatric and crime history, individual β-blockers, β-blocker selectivity and solubility, and use of other medications. In the cohort, 86.8% (n = 1,215,247) were 50 years and over, and 52.2% (n = 731,322) were women. During the study period, 6.9% (n = 96,801) of the β-blocker users were hospitalised for a psychiatric disorder, 0.7% (n = 9,960) presented with suicidal behaviour, and 0.7% (n = 9,405) were charged with a violent crime. There was heterogeneity in the direction of results; within-individual analyses showed that periods of β-blocker treatment were associated with reduced hazards of psychiatric hospitalisations (hazard ratio [HR]: 0.92, 95% confidence interval [CI]: 0.91 to 0.93, p < 0.001), charges of violent crime (HR: 0.87, 95% CI: 0.81 to 0.93, p < 0.001), and increased hazards of suicidal behaviour (HR: 1.08, 95% CI: 1.02 to 1.15, p = 0.012). After stratifying by diagnosis, reduced associations with psychiatric hospitalisations during β-blocker treatment were mainly driven by lower hospitalisation rates due to depressive (HR: 0.92, 95% CI: 0.89 to 0.96, p < 0.001) and psychotic disorders (HR: 0.89, 95% CI: 0.85 to 0.93, p < 0.001). Reduced associations with violent charges remained in most sensitivity analyses, while associations with psychiatric hospitalisations and suicidal behaviour were inconsistent. Limitations include that the within-individual model does not account for confounders that could change during treatment, unless measured and adjusted for in the model. In this population-wide study, we found no consistent links between β-blockers and psychiatric outcomes. However, β-blockers were associated with reductions in violence, which remained in sensitivity analyses. The use of β-blockers to manage aggression and violence could be investigated further.


Catalytic asymmetric Tamura cycloadditions involving nitroalkenes.
The first examples of asymmetric Tamura cycloaddition reactions involving singly activated alkenes are reported. Homophthalic anhydride reacts with α-methyl nitrosytrenes in the presence of an alkaloid-based catalyst to generate fused bicyclic aromatic ketone products with three new stereocentres (which are susceptible to subsequent equilibration) in 12-99% ee. An unusual equilibration process which occurs in methanolic medium in the absence of a recognisable base via proton transfer at the α-carbon of an ester was investigated experimentally and computationally.


Rib fractures in the elderly.
We sought to ascertain the extent to which advanced age influences the morbidity and mortality after rib fractures (fxs), to define the relationship between number of rib fractures and morbidity and mortality, and to evaluate the influence of analgesic technique on outcome. A retrospective cohort study involving all 277 patients > or = 65 years old with rib fxs admitted to a Level I trauma center over 10 years was undertaken. The control group consisted of 187 randomly selected patients, 18 to 64 years old, with rib fxs admitted over the same time period. Outcomes included pulmonary complications, number of ventilator days, length of intensive care unit and hospital stay (LOS), disposition, and mortality. The specific analgesic technique used was also examined. The two groups had similar mean number of rib fxs (3.6 elderly vs. 4.0 young), mean chest Abbreviated Injury Scores (3.0 vs. 3.0), and mean Injury Severity Score (20.7 vs. 21.4). However, mean number of ventilator days (4.3 vs. 3.1), intensive care unit days (6.1 vs. 4.0), and LOS (15.4 vs. 10.7 days) were longer for the elderly patients. Pneumonia occurred in 31% of elderly versus 17% of young (p < 0.01) and mortality was 22% for the elderly versus 10% for the young (p < 0.01). Mortality and pneumonia rates increased as the number of rib fxs increased with and odds ratio for death of 1.19 and for pneumonia of 1.16 per each additional rib fracture (p < 0.001). The use of epidural analgesia in the elderly (LOS >2 days) was associated with a 10% mortality versus 16% without the use of an epidural (p = 0.28). In the younger group (LOS >2 days), mortality with and without the use of an epidural was 0% and 5%, respectively. Elderly patients who sustain blunt chest trauma with rib fxs have twice the mortality and thoracic morbidity of younger patients with similar injuries. For each additional rib fracture in the elderly, mortality increases by 19% and the risk of pneumonia by 27%. As the number of rib fractures increases, there is a significant increase in morbidity and mortality in both groups, but with different patterns for each group. Further prospective study is needed to determine the utility of epidural analgesia in this population.


Effectiveness of a varied assemblage of seed dispersers of a fleshy-fruited plant.
Disperser effectiveness is the number of new plants resulting from the activity of one disperser relative to other dispersers or to nondispersed seeds. Effectiveness remains largely uninvestigated due to the complexity of its measurement. We measured the effectiveness of seed dispersers (Larus michahellis, Turdus merula, and Oryctolagus cuniculus) of the shrub Corema album (Empetraceae) using a simulation model of the recruitment process that was parameterized with field data of seed dispersal, predation, and seedling emergence and validated with independent data on seedling density. The model allows tracking the fate of seeds dispersed by each animal and estimating, for the first time, disperser effectiveness as seedlings per square meter contributed by each disperser. It also allows quantifying the relative importance of different recruitment processes in determining the quantity and spatial distribution of recruitment. Larus michahellis was the most effective disperser in two of the three habitats studied, contributing 3-125 times more than the other two species, whose lower effectiveness depended mostly on deposition patterns (T. merula) or deleterious effects on seedling emergence (O. cuniculus). The dependence of the plant on each disperser differed between habitats and was the greatest in sparse scrub, where recruitment depended almost exclusively on gulls (90%). Quantity and quality of dispersal were not correlated; quality was a better predictor of disperser effectiveness. Seedling emergence was the most crucial process in determining both the spatial pattern of recruitment among microhabitats (99.8% of variance explained) and the quantity of recruitment within microhabitats (43-83%). A sensitivity analysis showed that increasing seed dispersal improved the recruitment for all dispersers when there was no competition for fruits. However, with limited fruits, increased dispersal of lower quality dispersers reduced overall recruitment. Our results show important differences in effectiveness among dispersers and illustrate the different influences of the components of effectiveness, which varied depending not only on the disperser but also on the circumstances (e.g., type of habitat).


Improvements in exercise performance: effects of carbohydrate feedings and diet.
In an effort to determine the effects of carbohydrate (CHO) feedings immediately before exercise in both the fasted and fed state, 10 well-trained male cyclists [maximum O2 consumption (VO2 max), 4.35 +/- 0.11 l/min)] performed 45 min of cycling at 77% VO2 max followed by a 15-min performance ride on an isokinetic cycle ergometer. After a 12-h fast, subjects ingested 45 g of liquid carbohydrate (LCHO), solid carbohydrate confectionery bar (SCHO), or placebo (P) 5 min before exercise. An additional trial was performed in which a high-CHO meal (200 g) taken 4 h before exercise was combined with a confectionery bar feeding (M + SCHO) immediately before the activity. At 10 min of exercise, serum glucose values were elevated by 18 and 24% during SCHO and LCHO, respectively, compared with P. At 0 and 45 min no significant differences were observed in muscle glycogen concentration or total use between the four trials. Total work produced during the final 15 min of exercise was significantly greater (P less than 0.05) during M + SCHO (194,735 +/- 9,448 N X m), compared with all other trials and significantly greater (P less than 0.05) during LCHO and SCHO (175,204 +/- 11,780 and 176,013 +/- 10,465 N X m, respectively) than trial P (159,143 +/- 11,407 N X m). These results suggest that, under conditions when CHO stores are less than optimal, exercise performance is enhanced with the ingestion of 45 g of CHO 5 min before 1 h of intense cycling.(ABSTRACT TRUNCATED AT 250 WORDS)


Polyelectrolyte vectors for gene delivery: influence of cationic polymer on biophysical properties of complexes formed with DNA.
Cationic polymer/DNA complexes are widely used for gene delivery, although the influence of the cationic polymer on the biophysical properties of the resulting complex is poorly understood. Here, several series of cationic polymers have been used to evaluate the influence of structural parameters on properties of DNA complexes. Parameters studied included the length of side chain, charge type (primary versus tertiary and quaternary), polymer molecular weight, and charge spacing along the polymer backbone. Cationic polymers with short side chains (such as polyvinylamine) formed small complexes, resistant to destabilization by polyanions, with low surface charge, limited transfection activity, and efficient intranuclear transcription. Conversely, cationic polymers with long side chains (e.g., poly[methacryloyl-Gly-Gly-NH-(CH(2))(6)-NH(2))] showed inefficient complex formation, high positive surface charge, and better transfection activity. The effects of molecular weight varied between polymers, for example, low molecular weight poly(L-lysine) produced relatively small complexes, whereas low molecular weight poly[2-(trimethylammonio)ethyl methacrylate chloride] produced large aggregates. Polymers containing quaternary ammonium groups showed efficient complex formation but poor transfection. Finally, spreading charges widely on the polymer structure inhibited their ability to condense DNA. In summary, to achieve small, stable complexes, the use of cationic polymers with short side chains bearing primary amino groups is suggested.


Pneumonia prevention in intubated patients given sucralfate versus proton-pump inhibitors and/or histamine II receptor blockers.
Ventilator-associated pneumonia (VAP) is a common cause of infectious morbidity and mortality in the intensive care unit (ICU). The type of stress-ulcer prophylaxis (SUP) given to ventilated patients may, in part, be responsible. We observed an increase in VAP as ventilator bundle compliance increased and a decrease in VAP when bundle compliance decreased. We reasoned that SUP which raises gastric pH such as proton-pump inhibitors (PPIs) and histamine II (H2) receptor antagonists as opposed to SUP which does not raise pH such as sucralfate (S) may be responsible and also may alter the causative bacteria. This is a single-center retrospective cohort analysis of all intubated, adult surgical patients admitted to the surgical ICU between January and June during the 3-y period 2012-2014. Demographics, APACHE II, Injury Severity Score, VAP occurrence, culprit bacteria, ventilator days, and ICU days were recorded based on the type of SUP given. There were 45 instances of VAP in the 504 study patients, 33 in the PPI/H2 group, and 12 in the S group (P < 0.01). VAP per 1000 ventilator days were 10.2 for PPI/H2 and 3.7 for S (P < 0.01). Culprit bacteria were mostly Pseudomonas, gram-negative bacilli, and methicillin-resistant Staphylococcus aureus in PPI/H2 patients (n = 29) compared with oropharyngeal flora in S patients (n = 6; P < 0.001). There was a substantial difference in VAP occurrence and in the culprit bacteria between S and PPI/H2 treated patients due perhaps to gastric alkalization.


Enhancement of in vitro proliferation and bioactivity of human anterior cruciate ligament fibroblasts using an in situ tissue isolation method and basic fibroblast growth factor culture conditions: A pilot analysis.
Previous studies have reported poor proliferation and bioactivity of human anterior cruciate ligament fibroblasts (hACLFs) after injury. As hACLFs are one of the most significant and indispensable source of seed cells in constructing tissue-engineered ligament, enhancing hACLF proliferation would offer favorable cellular-biological ability and induce the extracellular matrix secretion of hACLFs after loading on multiple types of scaffolds. Enhancing the bioactivity of hACLFs would improve tissue repair and functional recovery after tissue-engineered ligament transplantation. This study compared cells prepared by collagenase digestion and the in situ culture of tissue pieces and investigated the effect of basic fibroblast growth factor (bFGF) on hACLFs. Six adult patients participated in this study. Of these patients, tissues from three were compared after culture establishment through collagenase digestion or in situ tissue isolation. hACLF phenotypic characteristics were assessed, and the effect of bFGF on hACLF cultures was observed. hACLFs cultured with and without bFGF served as the experimental and control groups, respectively. Cell Counting Kit-8 was used to detect proliferation. The expression of ligament-related genes and proteins was evaluated by immunofluorescence staining, real-time polymerase chain reaction (PCR) assays, and Western blot assays. The morphology of hACLFs isolated using the two methods differed after the 2nd passage. The proliferation of cells obtained by in situ culture was higher than that of cells obtained by collagenase digestion. hACLFs cultured with bFGF after the 3rd passage exhibited a higher proliferation rate than the controls. Immunofluorescence staining, real-time PCR, and Western blot analysis showed a significant increase in ligament-related gene and protein expression in the hACLFs cultured with bFGF. The in situ isolation of tissue pieces enhanced hACLF proliferation in vitro, and the hACLFs exhibited phenotypic characteristics of fibroblasts. hACLFs cultured with bFGF exhibited increased hACLF bioactivity.


Tubal sterilization in the United States, 1994-1996.
Although the number and rate of tubal sterilizations, the settings in which they are performed and the characteristics of women obtaining sterilization procedures provide important information on contraceptive practice and trends in the United States, such data have not been collected and tabulated for manyyears. Information on tubal sterilizations from the National Hospital Discharge Survey and the National Survey of Ambulatory Surgery was analyzed to estimate the number and characteristics of women having a tubal sterilization procedure in the United States during the period 1994-1996 and the resulting rates of tubal sterilization. These results were compared with those of previous studies to examine trends in clinical setting, in the timing of the procedure and in patient characteristics. In 1994-1996, more than two million tubal sterilizations were performed, for an average annual rate of 1 1.5 per 1,000 women; half were performed postpartum and half were interval procedures (i. e., were unrelated by timing to a pregnancy). All postpartum procedures were performed during inpatient hospital stays, while 96% of interval procedures were outpatient procedures. Postpartum sterilization rates were higher than interval sterilization rates among women 20-29 years of age; interval sterilization procedures were more common than postpartum procedures at ages 35-49. Sterilization rates were highest in the South. For postpartum procedures, private insurance was the expectedprimary source of payment for 48% and Medicaid was expected to pay for 41 %; for interval sterilization procedures, private insurance was the expected primary source of payment for 68% and Medicaid for 24%. Outpatient tubal sterilizations andprocedures using laparoscopy have increased substantially since the last comprehensive analysis of tubal sterilization in 1987, an indication of the effect of technical advances on the provision of this service. Continued surveillance of both inpatient and outpatient procedures is necessary to monitor the role of tubal sterilization in contraceptive practice.


Interaction of Klebsiella oxytoca and Burkholderia cepacia in dual-species batch cultures and biofilms as a function of growth rate and substrate concentration.
Dual-species microbial interactions have been extensively reported for batch and continuous culture environments. However, little research has been performed on dual-species interaction in a biofilm. This research examined the effects of growth rate and substrate concentration on dual-species population densities in batch and biofilm reactors. In addition, the feasibility of using batch reactor kinetics to describe dual-species biofilm interactions was explored. The scope of the research was directed toward creating a dual-species biofilm for the biodegradation of trichloroethylene, but the findings are a significant contribution to the study of dual-species interactions in general. The two bacterial species used were Burkholderia cepacia PR1-pTOM(31c), an aerobic organism capable of constitutively mineralizing trichloroethylene (TCE), and Klebsiella oxytoca, a highly mucoid, facultative anaerobic organism. The substrate concentrations used were different dilutions of a nutrient-rich medium resulting in dissolved organic carbon (DOC) concentrations on the order of 30, 70, and 700 mg/L. Presented herein are single- and dual-species population densities and growth rates for these two organisms grown in batch and continuous-flow biofilm reactors. In batch reactors, planktonic growth rates predicted dual-species planktonic species dominance, with the faster-growing organism (K. oxytoca) outcompeting the slower-growing organism (B. cepacia). In a dual-species biofilm, however, dual-species planktonic growth rates did not predict which organism would have the higher dual-species biofilm population density. The relative fraction of each organism in a dual-species biofilm did correlate with substrate concentration, with B. cepacia having a greater proportional density in the dual-species culture with K. oxytoca at low (30 and 70 mg/L DOC) substrate concentrations and K. oxytoca having a greater dual-species population density at a high (700 mg/L DOC) substrate concentration. Results from this research demonstrate the effectiveness of using substrate concentration to control population density in this dual-species biofilm.


Lec1A Chinese hamster ovary cell mutants appear to arise from a structural alteration in N-acetylglucosaminyltransferase I.
The biochemical and kinetic properties of UDP-GlcNAc:alpha-D-mannoside (GlcNAc to Man alpha 1,3) beta 1,2-N-acetylglucosaminyltransferase I (GlcNAc-TI) have been investigated in the Chinese hamster ovary glycosylation mutant Lec1A. Previous studies showed that, whereas Lec1A cells synthesize complex carbohydrates at levels consistent with partial GlcNAc-TI action, no GlcNAc-TI activity was detected in Lec1A cell-free extracts (Stanley, P., and Chaney, W. (1985) Mol. Cell. Biol. 5, 1204-1211). It is now reported that, under altered reaction conditions, GlcNAc-TI activity can be measured in Lec1A cell extracts. The GlcNAc-TI enzyme in Lec1A.2C has a pH optimum of 7.5 (compared with 6.25 for the parental enzyme) and apparent Km values for Man5GlcNAc2Asn and UDP-GlcNAc that are, respectively, 21- and 44-fold higher than the apparent Km values of GlcNAc-TI from parental Chinese hamster ovary cells. Two independent Lec1A mutants possess GlcNAc-TI activities with similarly altered biochemical and kinetic properties. In fact, under optimal assay conditions for each cell line, the level of GlcNAc-TI in Lec1A extracts is equal to that of parental Chinese hamster ovary cell extracts. Interestingly, the two glycosylation sites of the G glycoprotein of vesicular stomatitis virus are processed quite differently in Lec1A cells. The glycopeptide nearest the carboxyl-terminal appears to be a preferred substrate for the Lec1A GlcNAc-TI activity. The combined data suggest that the Lec1A mutation affects the gene that codes for GlcNAc-TI, giving rise to a structurally altered glycosyltransferase with different biochemical properties.


Phenylalanine ammonia-lyase and cell wall peroxidase are cooperatively involved in the extensive formation of ferulate network in cell walls of developing rice shoots.
The relationship between the formation of cell wall-bound ferulic acid (FA) and diferulic acid (DFA) and the change in activities of phenylalanine ammonia-lyase (PAL) and cell wall-bound peroxidase (CW-PRX) was studied in rice shoots. The length and the fresh mass of shoots increased during the growth period from day 4 to 6, while coleoptiles ceased elongation growth on day 5. The amounts of FA and DFA isomers as well as cell wall polysaccharides continued to increase during the whole period. The activities of PAL and CW-PRX greatly increased in the same manner during the period. There were close correlations between the PAL activity and ferulate content or between the CW-PRX activity and DFA content. The expression levels of investigated genes for PAL and putative CW-PRX showed good accordance with the activities of these enzymes. These results suggest that increases in PAL and CW-PRX activities are cooperatively involved in the formation of ferulate network in cell walls of rice shoots and that investigated genes may be, at least in part, associated with the enzyme activities. The substantial increase in such network probably causes the maturation of cell walls and thus the cessation of elongation growth of coleoptiles.


Effects of calcium antagonists and vasodilators on arterial myosin phosphorylation and actin-myosin interactions.
The mechanism of action of many direct-acting vascular smooth muscle relaxant agents is undefined. Moreover, an additional intracellular locus of action for some Ca++ entry blockers has been proposed. We have examined the potential for direct action by some of these agents at the level of smooth muscle contractile proteins by quantitating changes in Ca++-dependent superprecipitation of native arterial actomyosin. Moreover, inasmuch as previous research has linked phosphorylation of the 20,000 dalton myosin light chain to Ca++-dependent regulation of contraction, effects on myosin phosphorylation also were quantitated. Whereas the standard calmodulin antagonist W-7 inhibited both parameters by approximately 50% at 10(-4) M, diazoxide, hydralazine, 3-isobutyl-1-methylxanthine, papaverine, propranolol, nifedipine, nitrendipine, sodium nitroprusside and verapamil did not significantly inhibit either parameter at equimolar concentrations. Cyclandelate significantly delayed the onset of superprecipitation, but did not affect the extent of superprecipitation or myosin phosphorylation. The Ca++ antagonists felodipine and diltiazem inhibited superprecipitation by approximately 25%. However, unlike W-7, or felodipine, diltiazem did not concomitantly inhibit myosin phosphorylation. Inhibition of superprecipitation by diltiazem was apparent at a concentration of 10(-6) M, was manifest by a rightward shift in the pCa relationship and could be attenuated by exogenous calmodulin. These results show that most vasodilators do not have direct effects on smooth muscle contractile protein function. However, diltiazem may inhibit Ca++-dependent arterial actin-myosin interactions by a mechanism which is independent of regulation of myosin light chain phosphorylation.


Lipidomics Provides Novel Insights into Understanding the Bee Pollen Lipids Transepithelial Transport and Metabolism in Human Intestinal Cells.
Bee pollen (BP) shows profound gut-protecting potentials. BP lipids (BPLs) mainly composed by phospholipids and polyunsaturated fatty acids might be one of the important contributors, while how BPL exerts gut-protecting effects and is transported through intestinal cell monolayers need to be investigated. Here, we exploited a strategy that combines an UPLC-Q-exactive orbitrap/MS-based lipidomics approach with a human intestinal cell (Caco-2) monolayer transport model, to determine the transepithelial transportation of BPL from Camellia sinensis L. (BPL-Cs), in pathological conditions. The results showed that BPL-Cs protected Caco-2 cells against dextran sulfate sodium (DSS)-induced intestinal barrier dysfunction by improving cell viability, maintaining membrane integrity, increasing tight junctions (ZO-1 and Claudin-1), and eliciting the expressions of antioxidative-related genes (NQO1, Nrf2, Txnrd1, and GSTA1). Lipidomics analysis revealed that DSS suppressed the transport and uptake of most of BPL-Cs including glycerophospholipids, sphingomyelins, and glycosylsphingolipids. Pretreatment with BPL-Cs significantly regulated glycerophospholipid and sphingolipid metabolisms, potentially involved in building permeability barriers and alleviating intestinal oxidative stress. Finally, eight classes of lipids were identified as the potential biomarkers for evaluating DSS-induced Caco-2 cell dysfunctions and BPL-intervened modulation. These findings shed light on the development of BPL as gastrointestinal protective food supplements in the future.


Noise figure measurements on Nd and Yb doped double-clad fiber amplifiers.
We present comparative noise figure measurements on neodymium and ytterbium doped double-clad fiber amplifiers. While the neodymium doped amplifier showed the quantum-limited noise figure of 3 dB, the ytterbium doped amplifier exhibited excess noise due to its three-level system. We compared optical and electrical methods with respect to the accuracy and the suitability for high power measurements.


[Auditory provoked potentials in children with neonatal risk for hypoacusia].
Auditory evoked potentials of the brain stem (AEPBS) provide a simple noninvasive method of evaluating hearing function and have been widely used for early detection of hypoacusis in children. Between April 1992 and May 1994, a study was done of 400 Mexican children who presented at least one neonatal risk factor for hearing impairment. The average age of the children studied was 6.6 months and their average gestational age at birth was 35.1 weeks. Just over half of them (51%) had been treated with amikacin. The study found 1427 risk factors (3.5 per child), the most common ones being exposure to ototoxic substances, hyperbilirubinemia, and birthweight of less that 1500 g. In 27% of the children, peripheral auditory changes were found, and 13% did not respond to auditory stimuli. Low birthweight and young gestational age at birth, high serum concentration of bilirubin, sepsis, subependymal or intraventricular hemorrhage, mechanical ventilation, and exposure to ototoxic substances were significantly associated with the presence of severe or profound hypoacusis.


A comprehensive approach for the patient with Clostridium difficile infection.
During the last decade there have been many changes and advances in the research on Clostridium difficile infection (CDI). We have improved diagnostic and therapeutic tools and, at the same time, we have learned that the CDI implies, especially in the most vulnerable patients, an important morbidity. CDI has traditionally been undervalued and it is widely dispersed in hospitals. Surely, there is inertness in its management and there are also broad areas of improvement. If we add to this the high cost of the new drugs and the practical difficulties to implement the faecal microbiota transplant, we realize that we may not be taking full advantage of all the opportunities to improve patient's outcomes. The implementation of policies that favour the supervision of all CDI cases by an expert in infectious diseases will contribute to a better global management of this important disease.


Learning and interactivity in solving a transformation problem.
Outside the psychologist's laboratory, thinking proceeds on the basis of a great deal of interaction with artefacts that are recruited to augment problem-solving skills. The role of interactivity in problem solving was investigated using a river-crossing problem. In Experiment 1A, participants completed the same problem twice, once in a low interactivity condition, and once in a high interactivity condition (with order counterbalanced across participants). Learning, as gauged in terms of latency to completion, was much more pronounced when the high interactivity condition was experienced second. When participants first completed the task in the high interactivity condition, transfer to the low interactivity condition during the second attempt was limited; Experiment 1B replicated this pattern of results. Participants thus showed greater facility to transfer their experience of completing the problem from a low to a high interactivity condition. Experiment 2 was designed to determine the amount of learning in a low and high interactivity condition; in this experiment participants completed the problem twice, but level of interactivity was manipulated between subjects. Learning was evident in both the low and high interactivity groups, but latency per move was significantly faster in the high interactivity group, in both presentations. So-called problem isomorphs instantiated in different task ecologies draw upon different skills and abilities; a distributed cognition analysis may provide a fruitful perspective on learning and transfer.


The social structure of microbial community involved in colonization resistance.
It is well established that host-associated microbial communities can interfere with the colonization and establishment of microbes of foreign origins, a phenomenon often referred to as bacterial interference or colonization resistance. However, due to the complexity of the indigenous microbiota, it has been extremely difficult to elucidate the community colonization resistance mechanisms and identify the bacterial species involved. In a recent study, we have established an in vitro mice oral microbial community (O-mix) and demonstrated its colonization resistance against an Escherichia coli strain of mice gut origin. In this study, we further analyzed the community structure of the O-mix by using a dilution/regrowth approach and identified the bacterial species involved in colonization resistance against E. coli. Our results revealed that, within the O-mix there were three different types of bacterial species forming unique social structure. They act as 'Sensor', 'Mediator' and 'Killer', respectively, and have coordinated roles in initiating the antagonistic action and preventing the integration of E. coli. The functional role of each identified bacterial species was further confirmed by E. coli-specific responsiveness of the synthetic communities composed of different combination of the identified players. The study reveals for the first time the sophisticated structural and functional organization of a colonization resistance pathway within a microbial community. Furthermore, our results emphasize the importance of 'Facilitation' or positive interactions in the development of community-level functions, such as colonization resistance.


Fistulas in ano: endoanal ultrasonographic assessment assists decision making for surgery.
Eighteen patients with a clinical impression of a complex fistula in ano, had anal endosonography to delineate the anatomy of the fistula track and identify associated areas of sepsis. The clinical impression of a complex fistula was refuted by endosonography and subsequent surgical exploration in two cases. Horseshoe tracks were identified in nine (50%) patients and fluid collections, not evident on clinical examination were identified in eight (45%) patients. Accurate identification of the internal opening with a 7 MHz transducer was possible in two (11%) cases. External sphincter damage was evident in four (22%) patients. Surgical findings matched endosonographic appearances in all but one case (94%). Anal endosonography is an accurate and minimally invasive method of delineating the relation of fistula tracks to the anal sphincters and identifying deep areas of sepsis in relation to such fistulas.


Predictors of successful smoking cessation following advice from nurses in general practice.
At follow-up of 751 subjects receiving a brief nurse-administered anti-smoking intervention in general practice, 135 subjects (18%) reported stopping smoking, of whom 44 (6%) reported sustained cessation for one year. The demographic, social and attitudinal characteristics of these subjects were compared with 616 subjects who continued to smoke. The most important predictors of cessation were intention to stop (OR 5.1, 95% CI 2.1-12.0), personal rating of likelihood of cessation (OR 4.9, 95% CI 2.8-8.5), nurse rating of likelihood of cessation (OR 4.0, 95% CI 2.2-7.4), and smoking habit of partner (1.9, 95% CI 1.3-2.9). As practice nurses are able to distinguish likely quitters from those who are not motivated and less likely to succeed, it is important to decide whether it is more cost effective to target support at the motivated or to spend more time encouraging less motivated. The most challenging, but possibly the most rewarding, task is to try to reduce the high proportion of new ex-smokers who relapse. Although 41.1% (95% CI 28.1, 58.0) of those expressing a definite intention to stop smoking gave up, only 17.9% (95% CI 8.9, 30.4) achieved sustained cessation. However, as sustained cessation is strongly predicted by social variables, such as marital status and time spent in the company of smokers, preventing relapse may not be easy to achieve through medical intervention alone.


A Broad Set of Chromatin Factors Influences Splicing.
Several studies propose an influence of chromatin on pre-mRNA splicing, but it is still unclear how widespread and how direct this phenomenon is. We find here that when assembled in vivo, the U2 snRNP co-purifies with a subset of chromatin-proteins, including histones and remodeling complexes like SWI/SNF. Yet, an unbiased RNAi screen revealed that the outcome of splicing is influenced by a much larger variety of chromatin factors not all associating with the spliceosome. The availability of this broad range of chromatin factors impacting splicing further unveiled their very context specific effect, resulting in either inclusion or skipping, depending on the exon under scrutiny. Finally, a direct assessment of the impact of chromatin on splicing using an in vitro co-transcriptional splicing assay with pre-mRNAs transcribed from a nucleosomal template, demonstrated that chromatin impacts nascent pre-mRNP in their competence for splicing. Altogether, our data show that numerous chromatin factors associated or not with the spliceosome can affect the outcome of splicing, possibly as a function of the local chromatin environment that by default interferes with the efficiency of splicing.


Doppler-free nonlinear absorption in ethylene by use of continuous-wave cavity ringdown spectroscopy.
We report what we believe to be the first systematic study of Doppler-free, nonlinear absorption by use of cavity ringdown spectroscopy. We have developed a variant of cavity ringdown spectroscopy for the mid-infrared region between 9 and 11 microm, exploiting the intracavity power buildup that is possible with continuous-wave lasers. The infrared source consists of a continuous-wave CO2 laser with 1-mW tunable infrared sidebands that couple into a high-finesse stable resonator. We tune the sideband frequencies to observe a saturated, Doppler-free Lamb dip in the nu7, 11(1,10) <-- 11(2,10) rovibrational transition of ethylene (C2H4). Power studies of the Lamb dip are presented to examine the intracavity effects of saturation on the Lamb-dip linewidth, the peak depth, and the broadband absorption.


Deciphering the Structural Effects of Activating EGFR Somatic Mutations with Molecular Dynamics Simulation.
Numerous somatic mutations occurring in the epidermal growth factor receptor (EGFR) family (ErbB) of receptor tyrosine kinases (RTK) have been reported from cancer patients, although relatively few have been tested and shown to cause functional changes in ErbBs. The ErbB receptors are dimerized and activated upon ligand binding, and dynamic conformational changes of the receptors are inherent for induction of downstream signaling. For two mutations shown experimentally to alter EGFR function, A702V and the Δ746ELREA750 deletion mutation, we illustrate in the following protocol how molecular dynamics (MD) simulations can probe the (1) conformational stability of the mutant tyrosine kinase structure in comparison with wild-type EGFR; (2) structural consequences and conformational transitions and their relationship to observed functional changes; (3) effects of mutations on the strength of binding ATP as well as for binding between the kinase domains in the activated asymmetric dimer; and (4) effects of the mutations on key interactions within the EGFR binding site associated with the activated enzyme. The protocol provides a detailed step-by-step procedure as well as guidance that can be more generally useful for investigation of protein structures using MD simulations as a means to probe structural dynamics and the relationship to biological function.


Metabolism of the glutathione-acrolein adduct, S-(2-aldehydo-ethyl)glutathione, by rat liver alcohol and aldehyde dehydrogenase.
The oxidative and reductive metabolism of the acrolein-glutathione adduct, S-(2,aldehydo-ethyl)glutathione, by rat liver aldehyde dehydrogenase (ALDH) and alcohol dehydrogenase (ADH) was characterized. The glutathione-acrolein adduct is oxidized to the respective acid by two different forms of ALDH contained in rat liver cytosol which are distinct from two forms of ALDH present in the mitochondria also capable of oxidizing the aldehyde moiety of the adduct. Extensive kinetic characterization (Km, Vmax and V/K parameters) of the ALDH enzymes suggest that the glutathione-acrolein adduct is oxidized most efficiently by one form of mitochondrial ALDH which is 3.5 to 175 times more active (based on V/K comparisons) than the other forms of mitochondrial and cytosolic ALDH evaluated. The glutathione-acrolein adduct is also subject to reductive metabolism by rat liver ALH. However, the Km value (877 microM) for reduction of the adduct suggests that this would be a minor pathway of metabolism. Collectively, these results indicate that the glutathione-acrolein adduct formed after exposure to acrolein, or as a result of allyl alcohol oxidation and cyclophosphamide metabolism, can be oxidized by hepatic ALDH or ADH, respectively. However, the kinetic parameters for these pathways suggest that micromolar concentrations of this adduct may accumulate before these enzyme systems mediate significant oxidative or reductive pathways of detoxification. The proposition that the glutathione-acrolein adduct may play a role in acrolein-mediated hepatotoxicity is discussed.


Inflammatory Pseudotumors of the Skull Base: Meta-Analysis.
To describe the presentation, treatment, and outcome of inflammatory pseudotumors (IPs) of the skull base. English-language articles in PubMed, Web of Science, and EMBASE from earliest available through April 2014. Articles were identified using a keyword search for "inflammatory pseudotumor," "inflammatory myofibroblastoma," or "plasma cell granuloma," including a keyword localizing to the skull base. One hundred papers with 157 cases met inclusion criteria. History, tumor site, initial and subsequent treatment, outcomes, and complications were extracted. Student t test, z test, and analysis of variance were used to analyze demographics, symptoms, sites involved, and outcomes. Odds ratios for site versus initial treatment were calculated. At diagnosis, average patient age was 41 years. Approximately 70% of lesions primarily involved the anterior skull base, 29% the lateral skull base, and 1.2% the occiput. The most common initial treatments were steroids (44%), surgery (28%), and surgery with steroids (16%). Anterior lesions were 55.8 times more likely than lateral lesions to be treated initially with steroids (CI, 14.7-212). Seventy-six percent of patients had stable or resolved symptoms after a single course of treatment. Diagnosis of skull base IP requires ruling out other aggressive pathologies, such as malignancy and infection, and maintaining a high index of suspicion. Surgery is favored for lesions that can be removed in toto with minimal morbidity, as well as steroids for those sites where anatomy limits complete resection, such as within the orbit, cavernous sinus, or brain. An option for larger lesions involving vital anatomy is debulking, followed by postoperative steroids.


Emotional contagion and trait empathy in prosocial behavior in young people: the contribution of autonomic (facial feedback) and balanced emotional empathy scale (BEES) measures.
The present research investigated first the facial feedback measured by EMG (electromyography) during decisions to engage in prosocial-helping behaviors and secondly the relation between this psychophysiological correlate and emotional empathy trait in young people. Thirty young subjects were invited to choose to adopt or not a prosocial behavior in response to social interactions. An increased zygomatic and corrugator muscle activity was found in response to prosocial interventions. Moreover, a significant positive correlation was found between empathic profile and the EMG modulation. These results highlight the role of emotions and empathy in prosocial behavior, induced by an "emotional contagion effect."


A metasynthesis: mothering other-than-normal children.
The author used Noblit and Hare's 1988 comparative method of synthesizing qualitative studies to address the need for collective knowledge development related to mothering other-than-normal children. Twelve studies were included in a metasynthesis for a total sample of 79. The nature of the child's disability, demographics, and methodology used varied widely. Initially, 13 common themes were extracted using reciprocal translation. Further analysis revealed 4 steps common to the mothering experience under which themes were categorized. Suggestions for application to practice include keeping in mind qualities of a supportive health professional from the mothers' perspective, encouraging mothers to challenge societal definitions of normalcy, and recognizing the significance of hope in fueling maternal caregiving.


The use of isolated lung cells in in vitro pulmonary toxicology: studies of DNA damage, apoptosis and alteration of gene expression.
Isolated lung cells constitute a valuable system for studying mechanisms involved in chemically induced toxicity in the lung. Different lung cells isolated from various species may be studied. Bronchiolar Clara and alveolar type 2 cells produce important lung-specific proteins, hold a major role in the metabolism of xenobiotics and serve as progenitor cells for other lung cell types. They are possible target cells in lung carcinogenesis. Alveolar macrophages play an important role in lung defence and in inflammatory responses. In the present study we have characterised chemically induced DNA damage, apoptosis, changes in cell cycle progression, transformation and alterations in gene expression in these specific lung cells isolated from rat, rabbit and human. Major differences between the cell types and the various species in the induction of DNA damage by chemicals were found, as measured by the 32P-postlabelling and alkaline filter elution techniques. Benzo(a)pyrene and hydrogen fluoride were found to induce apoptosis in the isolated cells as measured by microscopical analysis and flow cytometry. The function of various important tissue- or cell type specific proteins (CYP 2B1, Clara cell protein) and/or cellular signal transduction pathways constitute important targets that may be affected by exposure to toxic compounds. Using immunological and molecular techniques the differential expression of specific proteins/RNAs and their activity can be studied. Among other proteins, c/ebp is involved in the regulation of transcription at the end of signal pathways. The protein is differentially expressed in rat lung cells and thus could be suitable for studying differential toxic effects in various lung cells. In humans, bronchoalveolar lavage (BAL) fluid from human volunteers can be readily obtained and examined after exposure to different chemical compounds. An increase in the percentage of CD3-positive cells (T-lymphocytes) was found after exposure to hydrogen fluoride. The number of certain cell types and cytokines may be used to estimate the degree of inflammatory reaction. In conclusion, the use of in vitro data including the use of specific, primary human lung cell types may contribute considerably to the quality of risk assessment, together with in vivo data from animals and man.


Accelerometer validity and placement for detection of changes in physical activity in dogs under controlled conditions on a treadmill.
The objective of the research was to determine the optimal location and method of attachment for accelerometer-based motion sensors, and to validate their ability to differentiate rest and increases in speed in healthy dogs moving on a treadmill. Two accelerometers were placed on a harness between the scapulae of dogs with one in a pouch and one directly attached to the harness. Two additional accelerometers were placed (pouched and not pouched) ventrally on the dog's collar. Data were recorded in 1s epochs with dogs moving in stages lasting 3 min each on a treadmill: (1) at rest, lateral recumbency, (2) treadmill at 0% slope, 3 km/h, (3) treadmill at 0% slope, 5 km/h, (4) treadmill at 0% slope, 7 km/h, (5) treadmill at 5% slope, 5 km/h, and (6) treadmill at 5% slope, 7 km/h. Only the harness with the accelerometer in a pouch along the dorsal midline yielded statistically significant increases (P<0.05) in vector magnitude as walking speed of the dogs increased (5-7 km/h) while on the treadmill. Statistically significant increases in vector magnitude were detected in the dogs as the walking speed increased from 5 to 7 km/h, however, changes in vector magnitude were not detected when activity intensity was increased as a result of walking up a 5% grade. Accelerometers are a valid and objective tool able to discriminate between and monitor different levels of activity in dogs in terms of speed of movement but not in energy expenditure that occurs with movement up hill.


Technology observed: attitudes of a wary public.
Our analysis of the interviews with a sample of the California public about a range of their attitudes toward technology shows that a modification of our understanding of the collective state of mind on this subject is in order. The current assessment of the public as largely, and somewhat vacantly, enamored with science and technology does not hold. Nor does a picture of a public generally hostile and alienated by technology. Neither panglossian optimism nor prophecies of doom can be supported by these interviews. Rather a more mixed picture emerges. Out of that picture, a potential public can be isolated, whose mood it behooves science policy-makers to watch. This group tends to associate a number of related conditions with technological development; moreover, it is likely to make assessments on those relationships so perceived. To the degree this group has "antitechnological" feelings, these feelings are clearly linked to the group's awareness that the social consequences of technology can produce conditions which threaten important values. The particular distribution of age and political identification suggests that those who are young and who identify themselves as "liberal" form the core of potential opposition to technological development and that such opposition is at least in part a function of different value preferences. The associations between political identification and attitudes about technology, distrust of decision-making, and concern for environmental impacts all make this point. In short, "technological dissent" cannot be written off as antiintellectual and without foundation. It is, in fact, preeminently sensible. What the alignments visible within the potential public portend for the future is not clear, although they do not allow us to accept an inference drawn from past studies-that because the young retain confidence in scientists and engineers all is well for the general climate of science and technology. We can only speculate whether, as these younger people grow older, they will carry their uneasiness about technology with them. Were they to do so, and were this group to be joined by still younger people who also hold these wary attitudes, the context of scientific and technological work could become much more fraught with political controversy. Another point emerging from our interpretation is how very crucial to continued free scientific inquiry is the distinction between scientific work and technological activities apparently now made by a sizable portion of the public. Should this distinction become lost, perhaps through continual merging of science's role with technology's by the popular press, attitudes now mainly associated with technology could spill over to scientific research as well. Yet our data also provide evidence of the successes of the scientific and technological communities. They have become such a critical part of life that people are seriously concerned with their future development. The opportunity is present for both communities to find ways of responding to the situation so that thoughtful action can be taken to implement technology for the benefit of the commonweal.


Mutation of genes controlling mRNA metabolism and protein synthesis predisposes to neurodevelopmental disorders.
Brain development is a tightly controlled process that depends upon differentiation and function of neurons to allow for the formation of functional neural networks. Mutation of genes encoding structural proteins is well recognized as causal for neurodevelopmental disorders (NDDs). Recent studies have shown that aberrant gene expression can also lead to disorders of neural development. Here we summarize recent evidence implicating in the aetiology of NDDs mutation of factors acting at the level of mRNA splicing, mRNA nuclear export, translation and mRNA degradation. This highlights the importance of these fundamental processes for human health and affords new strategies and targets for therapeutic intervention.


Gamma Knife Radiosurgery for Vestibular Schwannomas and Quality of Life Evaluation.
Further investigation is needed to look at the impact of vestibular schwannoma (VS) on the health-related quality of life (QOL) of participants who undergo Gamma Knife® radiosurgery (GKRS). Investigators compared the QOL for VS participants to reported US population norms in order to evaluate disease burden and long-term QOL several years after GKRS. This cross-sectional study surveyed participants to assess hearing status, tinnitus, imbalance, vertigo, as well as the Short-Form 36-item Health Questionnaire (SF-36). The data were normalized, age adjusted, and functional status was correlated to determine clinically significant differences. A total of 353 participants who underwent GKRS between 1997 and 2007 were included in this study with a median postoperative period of 5 years. SF-36 scores were very similar to population norms, and age-adjusted scores for participants followed the US population curve. Frequent vertigo and balance problems had the largest statistically and clinically significant effect on physical and mental component summary scores followed by nonuseful hearing in the tumor ear. Participants reported a good long-term QOL that was very similar to the QOL of US population norms. Of the common VS symptoms, vertigo had the greatest impact on QOL followed by imbalance and then hearing loss.


Association between objectively measured static standing and low back pain - a cross-sectional study among blue-collar workers.
This study aims to investigate the cross-sectional association between objectively measured total time and temporal patterns of static standing (short bouts: 0-5 min; moderate bouts: >5-10 min; and long bouts: >10 min) during work and leisure and low back pain (LBP) among 698 blue-collar workers. Workers reported LBP on a 0-10 scale. The association between time spent on static standing and LBP was tested with linear regression. A positive association with LBP intensity was found for long bouts of static standing (β = 0.27) during total day (work + leisure), and total static standing time at leisure (β = 0.12). No significant associations were found for static standing during work and LBP intensity. These findings indicate that particularly long bouts of static standing over the entire day contribute to LBP in blue-collar workers. Practitioner Summary: The association between LBP and static standing time was investigated. This study indicates that prolonged time standing during total day and standing during leisure are positively associated with LBP among blue-collar workers. Therefore, practitioners should consider long periods of standing as a potential risk factor for LBP.


Application of circularly polarized laser radiation for sensing of crystal clouds.
The application of circularly polarized laser radiation and measurement of the fourth Stokes parameter of scattered radiation considerably reduce the probability of obtaining ambiguous results for radiation depolarization in laser sensing of crystal clouds. The uncertainty arises when cloud particles appear partially oriented by their large diameters along a certain azimuth direction. Approximately in 30% of all cases, the measured depolarization depends noticeably on the orientation of the lidar reference plane with respect to the particle orientation direction. In this case, the corridor of the most probable depolarization values is about 0.1-0.15, but in individual cases, it can be noticeably wider. The present article considers theoretical aspects of this phenomenon and configuration of a lidar capable of measuring the fourth Stokes parameter together with an algorithm of lidar signal processing in the presence of optically thin cloudiness when molecular scattering cannot be neglected. It is demonstrated that the element ?44 of the normalized backscattering phase matrix (BSPM) can be measured. Results of measurements are independent of the presence or absence of azimuthal particle orientation. For sensing in the zenith or nadir, this element characterizes the degree of horizontal orientation of long particle diameters under the action of aerodynamic forces arising during free fall of particles.


Gender differences in coronary plaque composition by coronary computed tomography angiography.
Coronary computed tomography angiography allows the differentiation of non-calcified (NCAP), calcified (CAP), and mixed coronary artery plaques (MCAP). Although males are thought to have a higher prevalence of atherosclerosis for a given age, there are currently few data regarding age-adjusted sex differences in plaque morphology and composition. We studied 1015 consecutive asymptomatic South Korean patients (49+/-10 years, 64% men) who underwent 64-slice coronary computed tomography angiography during a routine health evaluation. Coronary plaque characteristics were analyzed on a per-segment basis according to the modified AHA classification. Plaques with more than 50% calcified tissue were classified as CAP, plaques with less than 50% calcified tissue were classified as MCAP, and plaques without calcium were classified as NCAP. Multiple regression analysis was used to describe the cross-sectional association between sex and plaque-type burden (>or=2 affected segments) after adjustment for age and other cardiovascular risk factors. There was a greater prevalence of coronary plaque among men (13 vs. 4%, P<0.001). Males were more likely to have an increased burden of CAP (4 vs. 1%, P = 0.01) and MCAP (5 vs. 1%, P<0.001), whereas the burden of NCAP was similar across sex (2 vs. 1%, P = 0.28). After multivariable adjustment, men have six to seven times greater odds of having an increased burden of CAP and MCAP, whereas no sex difference was observed in the burden of NCAP. In this population of asymptomatic middle-aged Korean individuals, males had a significantly greater burden of MCAP and CAP. Future studies will determine whether these differences contribute to the accelerated cardiovascular risk observed in men.


Objective confirmation of subjective measures of human well-being: evidence from the U.S.A.
A huge research literature, across the behavioral and social sciences, uses information on individuals' subjective well-being. These are responses to questions--asked by survey interviewers or medical personnel--such as, "How happy do you feel on a scale from 1 to 4?" Yet there is little scientific evidence that such data are meaningful. This study examines a 2005-2008 Behavioral Risk Factor Surveillance System random sample of 1.3 million U.S. citizens. Life satisfaction in each U.S. state is measured. Across America, people's answers trace out the same pattern of quality of life as previously estimated, from solely nonsubjective data, in one branch of economics (so-called "compensating differentials" neoclassical theory, originally from Adam Smith). There is a state-by-state match (r = 0.6, P < 0.001) between subjective and objective well-being. This result has some potential to help to unify disciplines.


Public's attitudes on participation in a biobank for research: an Italian survey.
The creation of biobanks depends upon people's willingness to donate their samples for research purposes and to agree to sample storage. Moreover, biobanks are a public good that requires active participation by all interested stakeholders at every stage of development. Therefore, knowing public's attitudes towards participation in a biobank and biobank management is important and deserves investigation. A survey was conducted among family members of patients attending the outpatient department of our institute for a geriatric or neurological visit, documenting their willingness to participate in a biobank and their views on the legal-ethical aspects of biobank management. Information regarding subjects' attitudes on biomedical research in general and genetic research in particular was also collected. Participants' data on biobanks were compared with data previously collected from the Italian ethics committees (ECs) to evaluate the extent to which lay people and ethics committees share views and concerns regarding biobanks. One hundred forty-five subjects took part in the survey. The willingness to give biological samples for the constitution of a biobank set up for research purposes was declared by 86% of subjects and was modulated by subjects' education. People in favour of providing biological samples for a biobank expressed a more positive view on biomedical research than did people who were not in favour; attitude towards genetic research in dementia was the strongest predictor of participation. Different from ECs that prefer specific consent (52%) and do not choose the option of broad consent (8%) for samples collection in a biobank, participants show a clear preference for broad consent (57%), followed by partially restricted consent (16%), specific consent (15%), and multi-layered consent (12%). Almost all of the subjects available to contribute to a biobank desire to receive both individual research results and research results of general value, while around fifty per cent of ECs require results communication. Family members showed willingness to participate in a biobank for research and expressed a view on the ethical aspects of a biobank management that differ on several issues from the Italian ECs' opinion. Laypersons' views should be taken into account in developing biobank regulations.


Dyadic interventions for community-dwelling people with dementia and their family caregivers: a systematic review.
In this review, we study the effects of dyadic psychosocial interventions focused on community-dwelling people with dementia and their family caregivers, and the relationship of the effects with intervention components of programs. A search from January 2005 to January 2012 led to 613 hits, which we reviewed against our inclusion criteria. We added studies from 1992 to 2005 reviewed by Smits et al. (Smits, C. H. M., De Lange, J., Droes, R.-M., Meiland, F., Vernooij-Dassen, M. and Pot, A. M. (2007). Effects of combined intervention programs for people with dementia living at home and their caregivers: a systematic review. International Journal of Geriatric Psychiatry, 22, 1181–1193). We assessed the methodological quality of 41 programs with the Cochrane criteria and two items of the Oxford Centre of Evidence-based Medicine guidelines. Studies of moderate to high quality concerning 20 different dyadic psychosocial programs for people with dementia and caregivers were included. Nineteen of these programs show significant effects on the patient with dementia, the caregiver, or both. Due to differences in the programs and the studies, this study does not provide an unequivocal answer about which programs are most effective. Programs with intervention components that actively train one or more specific functional domains for the person with dementia and/or the caregiver seem to have a beneficial impact on that domain, although there are exceptions. Reasons can be found in the program itself, the implementation of the program, and the study design. Dyadic psychosocial programs are effective, but the outcomes for the person with dementia and the caregiver vary. More attention is needed for matching the targeted functional domains, intervention components, and delivery characteristics of a program with the needs of the person with dementia and the family caregiver.


Saccharomyces cerevisiae Apl2p, a homologue of the mammalian clathrin AP beta subunit, plays a role in clathrin-dependent Golgi functions.
Clathrin-coated vesicles mediate selective intracellular protein traffic from the plasma membrane and the trans-Golgi network. At these sites, clathrin-associated protein (AP) complexes have been implicated in both clathrin coat assembly and collection of cargo into nascent vesicles. We have found a gene on yeast chromosome XI that encodes a homologue of the mammalian AP beta subunits. Disruptions of this gene, APl2, and a previously identified beta homologue, APl1, have been engineered in cells expressing wild-type (CHC1) or temperature sensitive (chc1-ts) alleles of the clathrin heavy chain gene. APl1 or APl2 disruptions (apl1 delta or apl2 delta) yield no discernable phenotypes in CHC1 strains, indicating that the Apl proteins are not essential for clathrin function. However, the apl2 delta, but not the apl1 delta, allele enhances the growth and alpha-factor pheromone maturation defects of chc1-ts cells. Disruption of APl2 also partially suppresses the vacuolar sorting defect that occurs in chc1-ts cells immediately after imposition of the non-permissive temperature. These Golgi-specific effects of apl2 delta in chc1-ts cells provide evidence that Apl2p is a component of an AP complex that interacts with clathrin at the Golgi apparatus.


Association of tumor necrosis factor-alpha 308G/A polymorphism with recurrent miscarriages in women.
Recurrent miscarriage (RM) is the most common pregnancy loss in the first trimester affecting approximately 0.5-2% of women. It is a heterogeneous condition and remains an enigma as the underlying cause is still difficult to track down. This study was aimed to investigate the distribution of tumor necrosis factor-alpha (TNF-α) 308G/A polymorphism and its association with RM in females. The comparative picture was also demonstrated by comparing genotyping results with healthy control women having no history of miscarriage. This clinical study was conducted among 115 women aged 21-44 years with history of recurrence of miscarriage. The samples were collected from women attending the outpatient departments of various hospitals, nursing homes, and infertility clinics of this region. In the present study, 111 fertile healthy women aged 24-46 years with at least one live birth and no history of miscarriage were also included. Mean age of women with RM was found to be 28 ± 5.6 years by recall method, whereas it was found to be 30 ± 7.4 in context to healthy women with no history of pregnancy loss. In the present study, 66% of women with RM had homozygous wild type genotype (GG) while 30% and 4% of women had heterozygous (GA) and homozygous mutant genotype (AA), respectively. Among control group, 79%, 16%, and 5% of women showed GG, GA, and AA genotype, respectively. The current study supports the concept of TNF-α 308G/A variant in particular with reproductive failure, GG and GA alleles showing 1-fold risk association with RM (odds ratio: 1.86 and 1.43, respectively).


Contemporary art in medicine: the Cleveland Clinic art collection.
Fine art is good medicine. It comforts, elevates the spirit, and affirms life and hope. Art in the healthcare setting, combined with outstanding care and service, creates an environment that encourages healing and supports the work of medical professionals. As one of the world's great medical centers, Cleveland Clinic has always included the arts in its healing environment. The four founders and subsequent leadership encouraged artistic and musical expression by employees. Distinguished artworks have long hung on the walls. In 1983, an Aesthetics Committee was officially formed at Cleveland Clinic to address issues of art and design in Cleveland Clinic facilities.


Semi-automated positional analysis using laser scanning microscopy of cells transfected in a regenerating newt limb.
Limb regeneration in urodele amphibians such as the newt is a key system for investigating the positional identity of cells. The regenerate arises locally from blastemal cells, mesenchymal progenitors that normally give rise to structures distal to the amputation plane but which can be respecified (proximalized) by treatment with retinoic acid (RA) such that proximal structures are formed. To establish an assay for positional identity, cells of distal and RA-treated distal blastemas are labeled by transfection with an alkaline phosphatase marker gene using particle bombardment (biolistics). After grafting the distal blastema to a proximal stump, a context known as intercalary regeneration, the proximodistal distribution of labeled cells in the resulting regenerate is an index of positional identity. We use enzyme-labeled fluorescence (ELF) in conjunction with laser scanning microscopy to detect transfected cells within a section of the entire regenerate. A semi-automated analysis of the positional distribution of marked cells along the proximal-distal axis demonstrates that cells from both distal and RA-treated blastemas contribute to the regenerate. This procedure provides an efficient and accurate tool for positional analysis of transfected cells, and should be applicable for studying genes that play a role in specifying cell position during morphogenesis.


EGO-1 is related to RNA-directed RNA polymerase and functions in germ-line development and RNA interference in C. elegans.
Cell-fate determination requires that cells choose between alternative developmental pathways. For example, germ cells in the nematode worm Caenorhabditis elegans choose between mitotic and meiotic division, and between oogenesis and spermatogenesis. Germ-line mitosis depends on a somatic signal that is mediated by a Notch-type signaling pathway. The ego-1 gene was originally identified on the basis of genetic interactions with the receptor in this pathway and was also shown to be required for oogenesis. Here, we provide more insight into the role of ego-1 in germ-line development. We have determined the ego-1 gene structure and the molecular basis of ego-1 alleles. Putative ego-1 null mutants had multiple, previously unreported defects in germ-line development. The ego-1 transcript was found predominantly in the germ line. The predicted EGO-1 protein was found to be related to the tomato RNA-directed RNA polymerase (RdRP) and to Neurospora crassa QDE-1, two proteins implicated in post-transcriptional gene silencing (PTGS). For a number of germ-line-expressed genes, ego-1 mutants were resistant to a form of PTGS called RNA interference. The ego-1 gene is the first example of a gene encoding an RdRP-related protein with an essential developmental function. The ego-1 gene is also required for a robust response to RNA interference by certain genes. Hence, a protein required for germ-line development in C. elegans may be a component of the RNA interference/PTGS machinery.


Preparation of the lactate oxidase apoenzyme and studies on the binding of flavin mononucleotide to the apoenzyme.
1. Lactate oxidase from Mycobacterium smegmatis is completely resolved into free flavin and apoenzyme by treatment with acid (NH4)2SO4. 2. Reconstitution involves rapid binding of FMN, but the recovery of enzyme activity was slower and appeared to be biphasic. 3. The preparation of the holoenzyme obtained differs from the native enzyme in specific activity, extinction coefficients and mobility on disc-gel electrophoresis. 4. Dialysis of this reconstituted enzyme in 0.1 M-sodium phosphate buffer, pH 7.0, at 0 degrees C for 1 week yields a preparation which closely resembles the native enzyme.


Recognition by pregnancy serums of non-HL-A alloantigens selectively expressed on B lymphocytes.
A group of alloantibodies are found in pregnancy sera which react with antigens present on B lymphocytes and monocytes but are not detectable on the vast majority of unstimulated T cells. This specificity distinguishes them from HL-A antibodies which react with both cell types. They were readily recognized through indirect fluorescent antibody analysis by employing the combination of B-cell lymphoid lines and normal peripheral blood T cells. Different sera gave a variety of patterns of reactivity with a panel of 11 lymphoid lines. Similar differential patterns were also observed with normal B cells from different individuals particularly after concentrating the B cells. The antibodies were also cytotoxic to B cells and this procedure gave parallel results to the fluorescence method. The pattern of reactions obtained indicated a very heterogeneous system similar to that for HL-A. Special study of certain of the sera provided evidence that the lymphocyte-defined determinants of the mixed lymphocyte reaction system were involved. For convenience the term HL-B has been employed for these antigens.


Phonological skills in predominantly English-speaking, predominantly Spanish-speaking, and Spanish-English bilingual children.
There is a paucity of information detailing the phonological skills of Spanish-English bilingual children and comparing that information to information concerning the phonological skills of predominantly English-speaking (PE) and predominantly Spanish-speaking (PS) children. The purpose of this study was to examine the relationship between amount of output (i.e., percentage of time each language was spoken) in each language and phonological skills in Spanish-English bilingual children and PE and PS children. Fifteen typically developing children, ranging in age from 5;0 (years;months) to 5;5 (mean = 5;2), participated in the study. The participants consisted of 5 PE speakers, 5 PS speakers, and 5 bilingual (Spanish-English) speakers. A single-word assessment was used to gather information on phonological skills (consonant accuracy, type and frequency of substitutions, frequency of occurrence of phonological patterns [e.g., cluster reduction], accuracy of syllable types [e.g., CV, CVC, CCV, etc.]), and type and rate of cross-linguistic effects. The results indicated that there was no significant correlation between amount of output in each language and phonological skills either in the Spanish skills of PS children and Spanish-English bilingual speakers or in the English skills of PE children and Spanish-English bilingual speakers. In addition, there was no significant difference in segmental accuracy, syllabic accuracy, or percentage of occurrence of phonological patterns between either the Spanish skills of PS children and Spanish-English bilingual speakers or the English skills of PE children and Spanish-English bilingual speakers. Finally, the children showed a limited number of cross-linguistic effects. Results from this study indicate no link between parent estimates of language output and phonological skill and demonstrate that Spanish-English bilingual children will have commensurate, although not identical, phonological skills as compared to age-matched PS and PE children.


Phase-matched sum frequency generation in strained silicon waveguides using their second-order nonlinear optical susceptibility.
Using analysis and numerical simulation, we have investigated near-infrared and mid-infrared second-harmonic generation (SHG) and sum frequency generation (SFG) in crystal silicon (SOI) waveguides that possess a strong second-order nonlinear susceptibility by virtue of a Si(3)N(4) straining layer applied directly to the top surface of the waveguide. This layer induces anisotropic compressive strain in the waveguide core. Using the technique of TE/TM mode birefringence, we have derived waveguide geometries for both slab and strip channel waveguides that offer perfect phase matching of three lightwaves for SHG/SFG along a uniform waveguide, thereby offering the prospect of efficient wavelength conversion in monolithic silicon photonics.


D-enantiomeric peptides that eradicate wild-type and multidrug-resistant biofilms and protect against lethal Pseudomonas aeruginosa infections.
In many infections, bacteria form surface-associated communities known as biofilms that are substantially more resistant to antibiotics than their planktonic counterparts. Based on the design features of active antibiofilm peptides, we made a series of related 12-amino acid L-, D- and retro-inverso derivatives. Specific D-enantiomeric peptides were the most potent at inhibiting biofilm development and eradicating preformed biofilms of seven species of wild-type and multiply antibiotic-resistant Gram-negative pathogens. Moreover, these peptides showed strong synergy with conventional antibiotics, reducing the antibiotic concentrations required for complete biofilm inhibition by up to 64-fold. As shown previously for 1018, these D-amino acid peptides targeted the intracellular stringent response signal (p)ppGpp. The most potent peptides DJK-5 and DJK-6 protected invertebrates from lethal Pseudomonas aeruginosa infections and were considerably more active than a previously described L-amino acid peptide 1018. Thus, the protease-resistant peptides produced here were more effective both in vitro and in vivo.


Thalidomide for inflammatory bowel disease: Systematic review.
Thalidomide is an immunomodulatory drug used in the experimental treatment of refractory Crohn disease and ulcerative colitis. We aimed to review the existing evidence on the efficacy and safety of thalidomide in the treatment of inflammatory bowel diseases. CENTRAL, MEDLINE, LILACS, POPLINE, CINHAL, and Web of Science were searched in March 2016. Manual search included conference and reference lists. All types of studies, except single case reports, were included. Outcomes evaluated were: induction of remission; maintenance of remission; steroid reduction; effect on penetrating Crohn disease; endoscopic remission; adverse events. The research strategies retrieved 722 papers. Two randomized controlled trials and 29 uncontrolled studies for a total of 489 patients matched the inclusion criteria. Thalidomide induced a clinical response in 296/427 (69.3%) patients. Clinical remission was achieved in 220/427 (51.5%) cases. Maintenance of remission was reported in 128/160 (80.0%) patients at 6 months and in 96/133 (72.2%) at 12 months. Reduction in steroid dosage was reported in 109/152 (71.7%) patients. Fistulas improved in 49/81 (60.5%) cases and closed in 28/81 (34.6%). Endoscopic improvement was observed in 46/66 (69.7%) and complete mucosal healing in 35/66 (53.0%) patients. Cumulative incidence of total adverse events and of those leading to drug suspension was 75.6 and 19.7/1000 patient-months, respectively. Neurological disturbances accounted for 341/530 (64.3%) adverse events and were the most frequent cause of drug withdrawal. Existing evidence suggests that thalidomide may be a valid treatment option for patients with inflammatory bowel diseases refractory to other first- and second-line treatments.


"No man is an island": Effects of interpersonal proximity on spatial attention.
While it is generally acknowledged that another person's presence can influence how we behave within our environment, our understanding of the mechanisms underlying this influence is limited. Three experiments investigated the effect of social presence on the lateral distribution of spatial attention. Shifts in spatial attention were measured using line bisection, while participants sat in each other's personal space. An attentional withdrawal was observed, whereby attention moved away from the other person when the same task was using turn-taking (Experiment 1) and independent responding (Experiment 2) paradigms. When participant pairs engaged in different tasks (Experiment 3), attentional withdrawal was no longer observed. Our results strongly suggest that the influence of interpersonal proximity on attention merits greater consideration than it has received from researchers investigating social effects on cognition.


Longitudinal study based on a safety registry for malaria patients treated with artenimol-piperaquine in six European countries.
European travellers to endemic countries are at risk of malaria and may be affected by a different range of co-morbidities than natives of endemic regions. The safety profile, especially cardiac issues, of artenimol (previously dihydroartemisinin)-piperaquine (APQ) Eurartesim® during treatment of uncomplicated imported falciparum malaria is not adequately described due to the lack of longitudinal studies in this population. The present study was conducted to partially fill this gap. Participants were recruited through Health Care Provider's safety registry in 15 centres across 6 European countries in the period 2013-2016. Adverse events (AE) were collected, with a special focus on cardiovascular safety by including electrocardiogram QT intervals evaluated after correction with either Bazett's (QTcB) or Fridericia's (QTcF) methods, at baseline and after treatment. QTcB and/or QTcF prolongation were defined by a value > 450 ms for males and children and > 470 ms for females. Among 294 participants, 30.3% were women, 13.7% of Caucasian origin, 13.5% were current smoker, 13.6% current alcohol consumer and 42.2% declared at least one illness history. The mean (SD) age and body mass index were 39.8 years old (13.2) and 25.9 kg/m2 (4.7). Among them, 75 reported a total of 129 AE (27 serious), 46 being suspected to be related to APQ (11 serious) and mostly labelled as due to haematological, gastrointestinal, or infection. Women and Non-African participants had significantly (p < 0.05) more AEs. Among AEs, 21 were due to cardiotoxicity (7.1%), mostly QT prolongation, while 6 were due to neurotoxicity (2.0%), mostly dizziness. Using QTcF correction, QT prolongation was observed in 17/143 participants (11.9%), only 2 of them reporting QTcF > 500 ms (milliseconds) but no clinical symptoms. Using QTcB correction increases of > 60 ms were present in 9 participants (6.3%). A trend towards increased prolongation was observed in those over 65 years of age but only a few subjects were in this group. No new safety signal was reported. The overall efficacy rate was 255/257 (99.2%). APQ appears as an effective and well-tolerated drug for treatment of malaria in patients recruited in European countries. AEs and QT prolongation were in the range of those obtained in larger cohorts from endemic countries. Trial registration This study has been registered in EU Post-Authorization Studies Register as EUPAS6942.


A meta-analysis of the incidence of non-AIDS cancers in HIV-infected individuals.
To estimate summary standardized incidence ratios (SIRs) of non-AIDS cancers among HIV-infected individuals compared with general population rates overall and stratified by gender, AIDS, and highly active antiretroviral therapy (HAART) era. A meta-analysis using SIRs from 18 studies of non-AIDS cancer in HIV-infected individuals. SIRs for non-AIDS cancers in HIV-infected individuals and 95% confidence limits (CLs) were abstracted from each study. Random effects meta-analyses were used to estimate summary SIRs. Modifications by gender, AIDS, and HAART era were estimated with meta-regression. Four thousand seven hundred ninety-seven non-AIDS cancers occurred among 625,716 HIV-infected individuals. SIRs for several cancers were elevated. In particular, cancers associated with infections, such as anal (SIR = 28; 95% CL 21 to 35), liver (SIR = 5.6; 95% CL 4.0 to 7.7), and Hodgkin lymphoma (SIR = 11; 95% CL 8.8 to 15) and smoking, such as lung (SIR = 2.6; 95% CL 2.1 to 3.1), kidney (SIR = 1.7; 95% CL 1.3 to 2.2), and laryngeal (SIR = 1.5; 95% CL 1.1 to 2.0). AIDS was associated with greater SIRs for Hodgkin lymphoma, leukemia, lung, brain, and all non-AIDS cancers combined. HIV-infected individuals may be at an increased risk of developing non-AIDS cancers, particularly those associated with infections and smoking. An association with advanced immune suppression was suggested for certain cancers.


Single and multiple photoionisation of H2S by 40-250 eV photons.
Multi-electron coincidence measurements on photoionisation of H(2)S have been carried out at photon energies from 40 to 250 eV. They quantify molecular field effects on the Auger process in detail and are in good agreement with the existing theory. Spectra of core-valence double ionisation of H(2)S are presented and partially analysed. Auger decays from the core-valence states produce triply charged product spectra with unexplained and surprising intensity distributions. Triple ionisation by the double Auger process from 2p hole states shows little effect of the molecular field splitting, but includes a substantial contribution from cascade processes, some involving dissociation in intermediate states. The onset of triple ionisation at the molecular geometry is determined as 61 ± 0.5 eV.


Promoting mHealth in Nursing Practice in China.
The purpose of this project was to reveal the status quo of mHealth application in clinical settings in China, especially in reducing patient falls and pressure ulcers and discuss how patient safety could be enhanced in the context of global collaboration on patient safety. The literature search resulted in a total of 290 articles. A steady increase is witnessed in the field of mHealth, especially after the year 2010. Personal digital assistant and electronic cart are the two main devices used in mobile nursing workstation. mHealth was mainly focused on two clinical areas, nursing practice (60.69%) and nursing management (25.86%). mHealth has begun to change the way of nursing process in prevention of adverse nurse events with an encouraging results in reducing the rate of pressure ulcer and falls. Healthcare educators should fully recognize the characteristics of mHealth and enhance a clinical informatics component in the curricula.


TMEM106B protects C9ORF72 expansion carriers against frontotemporal dementia.
Variants in transmembrane protein 106 B (TMEM106B) modify the disease penetrance of frontotemporal dementia (FTD) in carriers of progranulin (GRN) mutations. We investigated whether TMEM106B is also a genetic modifier of disease in carriers of chromosome 9 open reading frame 72 (C9ORF72) expansions. We assessed the genotype of 325 C9ORF72 expansion carriers (cohort 1), 586 FTD patients lacking C9ORF72 expansions [with or without motor neuron disease (MND); cohort 2], and a total of 1,302 controls for TMEM106B variants (rs3173615 and rs1990622) using MassArray iPLEX and Taqman genotyping assays. For our primary analysis, we focused on functional variant rs3173615, and employed a recessive genotypic model. In cohort 1, patients with C9ORF72 expansions showed a significantly reduced frequency of carriers homozygous for the minor allele as compared to controls [11.9 vs. 19.1 %, odds ratio (OR) 0.57, p = 0.014; same direction as carriers of GRN mutations]. The strongest evidence was provided by FTD patients (OR 0.33, p = 0.009) followed by FTD/MND patients (OR 0.38, p = 0.017), whereas no significant difference was observed in MND patients (OR 0.85, p = 0.55). In cohort 2, the frequency of carriers homozygous for the minor allele was not significantly reduced in patients as compared to controls (OR 0.77, p = 0.079); however, a significant reduction was observed when focusing on those patients with frontotemporal lobar degeneration and TAR DNA-binding protein 43 inclusions (FTLD-TDP; OR 0.26, p < 0.001). Our study identifies TMEM106B as the first genetic factor modifying disease presentation in C9ORF72 expansion carriers. Homozygosity for the minor allele protects carriers from developing FTD, but not from developing MND; similar effects are seen in FTLD-TDP patients with yet unknown genetic causes. These new findings show that the protective effects of TMEM106B are not confined to carriers of GRN mutations and might be relevant for prognostic testing, and as a promising therapeutic target for the entire spectrum of FTLD-TDP.


The CSS-12: Development and Validation of a Short-Form Version of the Cyberchondria Severity Scale.
Cyberchondria is defined as an increase in anxiety about one's health status as a result of excessive online searches. McElroy and Shevlin (2014) developed the first multidimensional, self-report measure of this construct-the Cyberchondria Severity Scale (CSS). The CSS consists of 33 items which can be summed to form a total score, and/or 5 subscale scores. The aim of the present study was to develop a short-form version of the CSS, removing the "Mistrust" subscale. Participants were undergraduate students from two UK universities (N = 661, 73% female, Mage = 22.19 years, SD = 5.88). Students completed the CSS, Short Health Anxiety Inventory (SHAI) and Generalized Anxiety Disorder Assessment (GAD-7). Twelve items were chosen for retention in the short form based on an exploratory factor analysis. These items corresponded to the four factors previously identified in the 33-item scale (minus the "Mistrust" subscale). Confirmatory factor analysis was used to validate the structure of the CSS-12. Confirmatory bifactor modeling indicated that the majority of item covariance was accounted for by a general cyberchondria factor. Construct validity was assessed by examining associations with the SHAI and GAD-7, with stronger correlations observed between the CSS-12 and the SHAI (compared with the GAD-7). The CSS-12 is a brief, reliable, and valid measure of worry/anxiety attributable to excessive online health research.


Analysis of the reversibility of chronic liver allograft rejection implications for a staging schema.
In contrast to all other vascularized organ allografts, chronic rejection (CR) of the liver is potentially reversible. We therefore studied demographic, perioperative, biochemical, and histologic features associated with reversibility or progression to graft failure. Using very stringent clinical and histological criteria, we identified a subgroup of 23 of 916 patients receiving primary liver allografts with CR from the Liver Transplantation Database. Of these, 13 experienced graft failure as a result of CR, and 10 patients recovered to normal histology or liver injury test results. Male-to-female sex mismatch (p = 0.07), younger recipient age (p = 0.09), younger donor age (p = 0.06), white-to-white race match (p = 0.09), primary diagnosis of biliary atresia (p = 0.02), and cold ischemia time of more than 12 hours (p = 0.02) were associated with graft failure. Patients who eventually recovered from CR were more likely to have acute rejection within the first 2 weeks (70% vs 23%; p = 0.04), had a higher number of acute rejection episodes (p = 0.08), and were more likely to have been treated with OKT3 (90% vs 46%, p = 0.07). Although overlap existed in the histopathologic findings between the patients whose grafts failed and those who recovered, those patients who developed bile duct loss in more than 50% of the portal tracts (p < 0.01), severe (bridging) perivenular fibrosis (p = 0.05), and the presence of foam cell clusters (p = 0.06) were more likely to require retransplantation. In contrast to other solid organ allografts, CR of the liver is not an irreversible process. These findings can be used to understand the evolution of CR and to design a biologically correct and clinically relevant staging system.


Transmyocardial laser therapy: a strategic approach.
Coronary artery bypass and percutaneous intervention have become the established methods of coronary revascularization in treating angina pectoris. Subsets of angina patients, however, are not amenable to either of these procedures. Transmyocardial laser revascularization (TMR) has been developed as a potential treatment to address such patients, and clinical research to date illustrates the success of TMR for this patient group. Although the symptoms of ischemic heart disease manifest themselves in a variety of ways, the best results with TMR are seen in patients with severe angina rather than in patients with silent ischemia or congestive heart failure. Potential TMR patients receive diagnostic tests to determine if and where the therapy should be applied. A recent cardiac catheterization is required to document the status of and the coronary-system suitability for the planned intervention. It is not appropriate to assume that a patient with nonbypassable, noninterventional coronary artery disease has to be relegated to medical therapy only. Additionally, echocardiography demonstrates the status of cardiac valves and segmental wall motion activity. This knowledge allows the surgeon to determine the sequence of surgery and if abnormalities are present. Once the decision to use TMR use has been made, there are 2 approaches--sole therapy or adjunctive therapy. TMR is not to be substituted for a feasible bypass graft, but the best time to make this decision may well be during the surgery itself, because grafts that appear surgically feasible on an angiogram may be less feasible after the chest has been opened. The decision to perform sole-therapy TMR in the absence of bypassable vessels clearly must be made before opening the chest. Whether to use cardiopulmonary bypass (CPB) and the sequence in which to perform TMR and bypass grafts are based on surgeon preference. The advantage of performing TMR on CPB is that channels can quickly be lased without pause. A potential advantage of performing TMR before bypass grafts is that "channel leak" (bleeding) can be minimized by the conclusion of the surgery. Complete revascularization has become technically more difficult because of the increasing use of percutaneous approaches and because patients are being referred for coronary artery bypass grafting much later in the course of their coronary disease progression than before. TMR may well be a viable alternative to bypassing a heavily diseased, previously intervened, small-diameter coronary artery. Thus, a model in which myocardial perfusion is considered within the context of the natural circulation can be conceived as an alternative to a model in which circulation is altered by interventional, surgical, and/or transmyocardial methods. TMR has been shown to be effective in accomplishing a complete revascularization when the restoration of circulation to ischemic territories with interventional therapy, bypass surgery, or a combination of both has been ineffective. We recommend that interested users follow this "complete revascularization strategy" algorithm for all ischemic vessels being considered for interventional or surgical treatment. Running each diseased vessel through this thought process will ensure that available treatment options are considered in the optimization of a patient's outcome. The use of TMR for angina relief has evolved into a clinically proven technology that has enabled physicians to address difficult revascularization cases with a therapy that is safe and effective.


Recommended cognitive outcomes in preclinical Alzheimer's disease: Consensus statement from the European Prevention of Alzheimer's Dementia project.
The Horizon 2020/IMI European Prevention of Alzheimer's Dementia (EPAD) project will undertake large-scale proof-of-concept trials in predementia Alzheimer's disease (AD). Within EPAD, the monitoring of cognitive trajectories in the preclinical period will constitute a central outcome measure; however, there are currently no clear guidelines as to how this should be achieved as most measures have been developed for the period around dementia diagnosis. The EPAD Scientific Advisory Group for Clinical and Cognitive Outcomes identified appropriate cognitive measures based on a literature search covering both cognitive correlates of preclinical brain changes from imaging studies and cognitive changes observed over time in nondementia population cohorts developing incident dementia. These measures were evaluated according to the following criteria: validity, coherence with biomarker changes, psychometric properties, cross-cultural suitability, availability of alternative forms, and normative data limited practice effects. The resulting consensus statement provides recommendations for both future drug trials and research into preclinical Alzheimer's disease.