Confinement and activity regulate bacterial motion in porous media.
Understanding how bacteria move in porous media is critical to applications in healthcare, agriculture, environmental remediation, and chemical sensing. Recent work has demonstrated that E. coli, which moves by run-and-tumble dynamics in a homogeneous medium, exhibits a new form of motility when confined in a disordered porous medium: hopping-and-trapping motility, in which cells perform rapid, directed hops punctuated by intervals of slow, undirected trapping. Here, we use direct visualization to shed light on how these processes depend on pore-scale confinement and cellular activity. We find that hopping is determined by pore-scale confinement, and is independent of cellular activity; by contrast, trapping is determined by the competition between pore-scale confinement and cellular activity, as predicted by an entropic trapping model. These results thus help to elucidate the factors that regulate bacterial motion in porous media, and could help aid the development of new models of motility in heterogeneous environments.


PTEN gene expression and mutations in the PIK3CA gene as predictors of clinical benefit to anti-epidermal growth factor receptor antibody therapy in patients with KRAS wild-type metastatic colorectal cancer.
To identify novel genetic markers predictive of clinical benefit from epidermal growth factor receptor-directed antibody therapy in patients with metastatic colorectal cancer. Seventy-six consecutive patients who received cetuximab or panitumumab, either alone or in combination with chemotherapy and with available tumor tissue were included. Tumor tissue was tested by pyrosequencing for mutations at known hot spots in the KRAS, BRAF, PIK3CA, PIK3R1, AKT1, and PTEN genes. PTEN promoter methylation status was analyzed by methylation-specific polymerase chain reaction, and expression was determined by immunohistochemistry (IHC). Forty-four patients had 4 weeks of therapy and were considered for clinical correlates. Consistent with previous studies, KRAS gene mutations were associated with a shorter progression-free survival (PFS) and overall survival (OS). Among the patients with wild-type KRAS, preservation of PTEN expression and PIK3CA wild-type status was associated with improved OS (median OS, 80.4 vs. 32.5 weeks; hazard ratio, 0.33; P = .0008) and a trend toward improved PFS (median PFS, 24.8 vs. 15.2 weeks; hazard ratio, 0.51; P = .06), compared with PTEN-negative or PIK3CA-mutant tumors. PTEN methylation was more common in the metastatic samples than in the primary samples (P = .02). The simultaneous presence of methylation and mutation in the PTEN gene was associated with IHC negativity (P = .026). In addition to KRAS mutation, loss of PTEN expression (by IHC) and PIK3CA mutation is likely to be predictive of a lack of benefit to anti-EGFR therapy in metastatic colorectal cancer. PTEN promoter methylation and mutation status was predictive of PTEN expression and may be used as an alternative means of predicting response to EGFR-targeted therapy.


Two-photon fluorescence excitation spectroscopy by pulse shaping ultrabroad-bandwidth femtosecond laser pulses.
A fast and automated approach to measuring two-photon fluorescence excitation (TPE) spectra of fluorophores with high resolution (~2 nm) by pulse shaping ultrabroad-bandwidth femtosecond laser pulses is demonstrated. Selective excitation in the range of 675-990 nm was achieved by imposing a series of specially designed phase and amplitude masks on the excitation pulses using a pulse shaper. The method eliminates the need for laser tuning and is, thus, suitable for non-laser-expert use. The TPE spectrum of Fluorescein was compared with independent measurements and the spectra of the pH-sensitive dye 8-hydroxypyrene-1,3,6-trisulfonic acid (HPTS) in acidic and basic environments were measured for the first time using this approach.


Transcription and processing of the rodent ID repeat family in germline and somatic cells.
ID elements comprise a rodent SINE (short interspersed DNA repetitive element) family that has amplified by retroposition of a few master genes. In order to understand the important factors of SINE amplification, we investigated the transcription of rat ID elements. Three different size classes of ID transcripts, BC1, BC2 and T3, have been detected in various rat tissues, including brain and testes. We have analysed the nucleotide sequences of testes- and brain-derived ID transcripts isolated by size-fractionation, C-tailing and RACE. Nucleotide sequence variation of testes ID transcripts demonstrated derivation from different loci. However, the transcripts represent a preferred set of ID elements that closely match the subfamily consensus sequences. The small ID transcripts, T3, are not comprised of primary transcripts, but are instead processed polyA-transcripts generated from many different loci. These truncated transcripts would be expected to be retroposition-incompetent forms. Therefore, the amplification of ID elements is likely to be regulated at multiple steps of retroposition, which include transcription and processing. Although brain ID transcripts showed a similar pattern, with the addition of very high levels of transcription from the BC1 locus, we also found evidence that a single locus dominated the production of brain BC2 RNA species. BC1 RNA is highly stable in both germ line and brain cells, based on the low level of detection of the processing product, T3. This stability of BC1 RNA might have been a contributing factor in its role as a master gene for ID amplification.


Developmental Trajectories of Youth Character: A Five-Wave Longitudinal Study of Cub Scouts and Non-Scout Boys.
Youth development programs, such as the Boy Scouts of America, aim to develop positive attributes in youth (e.g., character virtues, prosocial behaviors, and positive civic actions), which are necessary for individuals and societies to flourish. However, few developmental studies have focused on how specific positive attributes develop through participation in programs such as the Boy Scouts of America. As part of the Character and Merit Project, this article examined the developmental trajectories of character and other positive attributes, which are of focal concern of the Boy Scouts of America and the developmental literature. Data were collected from 1398 Scouts (M = 8.59 years, SD = 1.29 years, Range 6.17-11.92 years) and 325 non-Scout boys (M = 9.06 years, SD = 1.43 years, Range 6.20-11.81 years) over five waves of testing across a two-and-half-year period. Latent growth-curve analyses of self-report survey data examined the developmental trajectories of the attributes. Older youth rated themselves lower than younger participants on helpfulness, reverence, thriftiness, and school performance. However, all youth had moderately high self-ratings on all the attributes. Across waves, Scouts' self-ratings increased significantly for cheerfulness, helpfulness, kindness, obedience, trustworthiness, and hopeful future expectations. Non-Scout boys' self-ratings showed no significant change for any attributes except for a significant decrease in religious reverence among non-Scout boys from religious institutions. We discuss implications for positive youth development and for the role of the Boy Scouts of America programming in character development.


Peroxisome proliferator-activated receptor-gamma contributes to the inhibitory effects of Embelin on colon carcinogenesis.
Down-regulation of XIAP (X-linked inhibitor of apoptosis protein) sensitizes colon cancer cells to the anticancer effect of peroxisome proliferator-activated receptor-gamma (PPARgamma) ligands in mice. The aims of this study were to evaluate the effect of embelin (2,5-dihydroxy-3-undecyl-1,4-benzoquinone), an antagonist of XIAP, on colon cancer, with a particular focus on whether PPARgamma is required for embelin to exert its effect. A dominant-negative PPARgamma was used to antagonize endogenous PPARgamma in HCT116 cells. Cells were treated with or without embelin. Cell proliferation, apoptosis, and nuclear factor-kappaB (NF-kappaB) activity were measured. For in vivo studies, 1,2-dimethylhydrazine dihydrochloride (DMH) was s.c. injected to induce colon cancer in PPARgamma(+/+) and PPARgamma(+/-) mice. Mice were fed embelin daily for 10 days before DMH injection, and continued for 30 more weeks. Embelin inhibited proliferation and induced apoptosis in HCT116 cells with marked up-regulation of PPARgamma. In addition, embelin significantly inhibited the expressions of survivin, cyclin D1, and c-Myc. These effects were partially dependent on PPARgamma. PPARgamma(+/-) mice were more susceptible to DMH-induced colon carcinogenesis than PPARgamma(+/+) mice, and embelin significantly reduced the incidence of colon cancer in PPARgamma(+/+) mice but not in PPARgamma(+/-) mice. Embelin inhibited NF-kappaB activity in PPARgamma(+/+) mice but marginally so in PPARgamma(+/-) mice. Thus, reduced expression of PPARgamma significantly sensitizes colonic tissues to the carcinogenic effect of DMH. Embelin inhibits chemical carcinogen-induced colon carcinogenesis, but this effect is partially dependent on the presence of functional PPARgamma, indicating that PPARgamma is a necessary signaling pathway involved in the antitumor activity of normal organisms.


Amplification and deletion of a nod-nif region in the symbiotic plasmid of Rhizobium phaseoli.
One remarkable characteristic of the genomes of some Rhizobium species is the frequent occurrence of rearrangements. In some instances these rearrangements alter the symbiotic properties of the strains. However, no detailed molecular mechanisms have been proposed for the generation of these rearrangements. To understand the mechanisms involved in the formation of rearrangements in the genome of Rhizobium phaseoli, we have designed a system which allows the positive selection for amplification and deletion events. We have applied this system to investigate the stability of the symbiotic plasmid of R. phaseoli. High-frequency amplification events were detected which increase the copy number of a 120-kb region carrying nodulation and nitrogen fixation genes two to eight times. Deletion events that affect the same region were also found, albeit at a lower frequency. Both kinds of rearrangements are generated by recombination between reiterated nitrogenase (nifHDK) operons flanking the 120-kb region.


Customized Probability of Vaginal Delivery With Induction of Labor and Expectant Management in Nulliparous Women at 39 Weeks of Gestation.
To develop models to predict vaginal delivery in low-risk, nulliparous women contemplating elective induction of labor or expectant management at 39 weeks of gestation. We conducted a secondary analysis of a randomized controlled trial of planned elective induction of labor at 39 weeks of gestation compared with expectant management for low-risk nulliparous women. Two groups were included for this analysis: 1) women who were randomized to the induction of labor group and underwent elective induction at 39 0/7-39 4/7 weeks of gestation and 2) women who were randomized to the expectant management group who experienced spontaneous labor or medically indicated delivery (including postterm). Multivariable logistic regression models were developed for each group using patient characteristics that would be available at the time of counseling. Model selection was based on k-fold cross-validation using backward elimination and variables that remained significant at P<.05 were retained. To compare estimated with observed rates, the elective induction of labor model was then applied to each woman in both groups to estimate individualized predicted probabilities of vaginal delivery with elective induction of labor. Of 6,106 women enrolled in the trial, 4,661 met criteria for this analysis. Vaginal delivery occurred in 80.6% of the 2,153 women in the elective induction of labor group and 77.2% of the 2,508 women in the expectant management group (P=.005). The final elective induction of labor model included age, height, weight, and modified Bishop score (area under the receiver operating characteristic curve [AUROC] 0.72, 95% CI 0.70-0.75). The same variables were included in the final expectant management model (AUROC 0.70, 95% CI 0.67-0.72). Across the range of predicted probability deciles derived from the elective induction of labor model, almost all women who underwent elective induction of labor at 39 weeks of gestation had a higher observed chance of vaginal delivery than expectant management. Irrespective of the individual predicted chance of vaginal delivery from elective induction of labor at 39 weeks of gestation, vaginal delivery is generally more frequent if elective induction of labor is undertaken rather than expectant management. These data can be used to counsel nulliparous women regarding their "customized" chances of vaginal delivery as they choose between elective induction of labor or expectant management at 39 weeks of gestation. ClinicalTrials.gov, NCT01990612.


Vocal responses to perturbations in voice auditory feedback in individuals with Parkinson's disease.
One of the most common symptoms of speech deficits in individuals with Parkinson's disease (PD) is significantly reduced vocal loudness and pitch range. The present study investigated whether abnormal vocalizations in individuals with PD are related to sensory processing of voice auditory feedback. Perturbations in loudness or pitch of voice auditory feedback are known to elicit short latency, compensatory responses in voice amplitude or fundamental frequency. Twelve individuals with Parkinson's disease and 13 age- and sex-matched healthy control subjects sustained a vowel sound (/α/) and received unexpected, brief (200 ms) perturbations in voice loudness (±3 or 6 dB) or pitch (±100 cents) auditory feedback. Results showed that, while all subjects produced compensatory responses in their voice amplitude or fundamental frequency, individuals with PD exhibited larger response magnitudes than the control subjects. Furthermore, for loudness-shifted feedback, upward stimuli resulted in shorter response latencies than downward stimuli in the control subjects but not in individuals with PD. The larger response magnitudes in individuals with PD compared with the control subjects suggest that processing of voice auditory feedback is abnormal in PD. Although the precise mechanisms of the voice feedback processing are unknown, results of this study suggest that abnormal voice control in individuals with PD may be related to dysfunctional mechanisms of error detection or correction in sensory feedback processing.


Targeted disruption of otog results in deafness and severe imbalance.
Genes specifically expressed in the inner ear are candidates to underlie hereditary nonsyndromic deafness. The gene Otog has been isolated from a mouse subtractive cDNA cochlear library. It encodes otogelin, an N-glycosylated protein that is present in the acellular membranes covering the six sensory epithelial patches of the inner ear: in the cochlea (the auditory sensory organ), the tectorial membrane (TM) over the organ of Corti; and in the vestibule (the balance sensory organ), the otoconial membranes over the utricular and saccular maculae as well as the cupulae over the cristae ampullares of the three semi-circular canals. These membranes are involved in the mechanotransduction process. Their movement, which is induced by sound in the cochlea or acceleration in the vestibule, results in the deflection of the stereocilia bundle at the apex of the sensory hair cells, which in turn opens the mechanotransduction channels located at the tip of the stereo-cilia. We sought to elucidate the role of otogelin in the auditory and vestibular functions by generating mice with a targeted disruption of Otog. In Otog-/- mice, both the vestibular and the auditory functions were impaired. Histological analysis of these mutants demonstrated that in the vestibule, otogelin is required for the anchoring of the otoconial membranes and cupulae to the neuroepithelia. In the cochlea, ultrastructural analysis of the TM indicated that otogelin is involved in the organization of its fibrillar network. Otogelin is likely to have a role in the resistance of this membrane to sound stimulation. These results support OTOG as a possible candidate gene for a human nonsyndromic form of deafness.


Liposome and lipid bilayer arrays towards biosensing applications.
Sensitive and selective biosensors for high-throughput screening are having an increasing impact in modern medical care. The establishment of robust protein biosensing platforms however remains challenging, especially when membrane proteins are involved. Although this type of proteins is of enormous relevance since they are considered in >60% of the pharmaceutical drug targets, their fragile nature (i.e., the requirement to preserve their natural lipid environment to avoid denaturation and loss of function) puts strong additional prerequisites onto a successful biochip. In this review, the leading approaches to create lipid membrane-based arrays towards the creation of membrane protein biosensing platforms are described. Liposomes assembled in micro- and nanoarrays and the successful set-ups containing functional membrane proteins, as well as the use of liposomes in networks, are discussed in the first part. Then, the complementary approaches to create cell-mimicking supported membrane patches on a substrate in an array format will be addressed. Finally, the progress in assembling free-standing (functional) lipid bilayers over nanopore arrays for ion channel sensing will be reported. This review illustrates the rapid pace by which advances are being made towards the creation of a heterogeneous biochip for the high-throughput screening of membrane proteins for diagnostics, drug screening, or drug discovery purposes.


Echinococcus canadensis G7 (pig strain): an underestimated cause of cystic echinococcosis in Austria.
Anamnesis data of 104 patients with Cystic Echinococcosis were correlated retrospectively with the detected species/strain of Echinococcus. Ninety-two percent (N = 23) of autochthonous Austrian and 33% (N = 9) of patients with former Yugoslavian (YU) origin were infected with E. canadensis G7, the pig strain. All patients originating from Turkey harbored E. granulosus G1, the sheep strain. All E. canadensis G7-infected patients showed small liver cysts (ø 5.9 cm), only one of them an additional lung cyst. The median age at the time of operation of the Austrian patients was 55 years, of the Turkish patients 30 years, and of the former YU patients 23 years in the E. canadensis and 42 years in the E. granulosus-infected patients, respectively. The unexpected high number of E. canadensis G7-infected patients and the immigrants' young age show the importance of E. canadensis as a cause of human Cystic Echinococcosis in Central Europe and accordingly this new species has to be included into future echinococcosis control programs.


The Difficult Ureter: Clinical and Radiographic Characteristics Associated With Upper Urinary Tract Access at the Time of Ureteroscopic Stone Treatment.
To evaluate the association between clinicoradiographic features and need for prestenting (PS) because of inability of the ureter to accommodate the ureteroscope, or ureteral access sheath, at the time of stone treatment. From 2009 to 2013, 120 consecutive nonstented patients underwent ureteroscopic stone treatment with preoperative computerized tomography urogram. Acute stone events with obstruction or infection were excluded. Preoperative radiographic imaging underwent radiologist review. Clinicoradiographic features were characterized, and multivariable logistic regression models were used to identify covariates independently associated with need for PS. Of the 154 renal units treated, 25 (16%) required PS for failed primary access. PS ureters were less likely to have a history of prior ipsilateral ureteral stent (4% vs 31%) or surgery (8% vs 36%; P <.05). Radiographically, PS ureters had a narrower ureteropelvic junction (4 mm vs 5 mm) and were more likely to have <50% ureteral opacification on computerized tomography urogram (32% vs 9%; P <.05). On multivariable analysis, prior ipsilateral ureteral stent (odds ratio [OR] = 0.11) and stone surgery (OR = 0.15) reduced the need for PS; meanwhile, <50% ureteral opacification (OR = 4.41) was independently associated with an increased risk of access failure. We report a 16% incidence of access failure requiring PS at time of ureteroscopy. Clinically, there was an 89% and 85% risk reduction in the need for PS with prior history of ipsilateral ureteral stent or surgery. Radiographically, there was a 4.4-fold increased risk of PS with <50% ureteral opacification. Accordingly, our findings may assist in counseling and operative management of the difficult ureter.


Deprivation of pantothenic acid elicits a movement disorder and azoospermia in a mouse model of pantothenate kinase-associated neurodegeneration.
We asked whether a movement disorder could be elicited by deprivation of pantothenic acid (PA; vitamin B5), the substrate for the enzyme pantothenate kinase 2 (PANK2), which is deficient in the inherited neurological disorder PKAN (pantothenate kinase-associated neurodegeneration formerly called Hallervorden-Spatz syndrome). This study was undertaken because mice made null for Pank2 failed to show the neurological manifestations of the human disease. Wild-type and Pank2 mutant mice were fed pantothenic acid-deficient diets and were monitored for general health, fertility and movement compared with animals on control diets over time. Mice of both genotypes on PA-deficient diets exhibited poor grooming, greying of fur and decreased body weight. With PA deprivation, wild-type mice manifested azoospermia (a phenotype also seen in Pank2 mice) as well as a movement disorder with a low-lying pelvis and slow steps. Rear limbs appeared to drag and occasionally extended into unnatural postures for 16-17 s duration, possibly indicative of dystonia. Movement disruption probably also occurs in PA-deprived Pank2 mutant mice, but they died precipitously before undergoing detailed analysis. Remarkably, restoration of dietary PA led to recovery of general health and grooming, weight gain, reversal of the movement disorder, and reappearance of mature sperm within 4 weeks. This study confirms the primacy of PA metabolism in the mechanism of disease in PKAN. PA deprivation provides a useful phenocopy for PKAN and allows us to test pharmacological and other interventional strategies in the treatment of this devastating disease.


Exploratory double-blind, parallel-group, placebo-controlled study of edaravone (MCI-186) in amyotrophic lateral sclerosis (Japan ALS severity classification: Grade 3, requiring assistance for eating, excretion or ambulation).
Our objective was to explore the efficacy and safety of edaravone in amyotrophic lateral sclerosis (ALS) patients with a Japan ALS severity classification of Grade 3. In a 24-week, double-blind, randomized study, 25 patients who met all of the following criteria were enrolled: Japan ALS severity classification Grade 3; definite, probable, or probable-laboratory supported ALS (El Escorial/revised Airlie House); forced vital capacity (%FVC) ≥60%; duration of disease ≤3 years at consent; and change in the revised ALS functional rating scale (ALSFRS-R) score of -1 to -4 points during the 12-week pre-observation period. Patients received edaravone (n = 13) or placebo (n = 12) for six cycles. The efficacy outcome was change in the ALSFRS-R score. The least-squares mean change in the ALSFRS-R score ± standard error during the 24-week treatment was -6.52 ± 1.78 in the edaravone group and -6.00 ± 1.83 in the placebo group; the difference of -0.52 ± 2.46 was not statistically significant (p = 0.835). Incidence of adverse events was 92.3% (12/13) in the edaravone group and 100.0% (12/12) in the placebo group. There was no intergroup difference in the changes in the ALSFRS-R score. The incidences of adverse events were similar in the two groups.


A novel approach for quantitative assessment of mucosal damage in inflammatory bowel disease.
One of the main reliable histological features to suggest the diagnosis of inflammatory bowel disease is the presence of significant distortion of the crypt architecture indicating the chronic nature of the disease resulting in mucosal damage. This feature has a considerable intra-observer and inter-observer variability leading to significant subjectivity in colonic biopsy assessment. In this paper, we present a novel automated system to assess mucosal damage and architectural distortion in inflammatory bowel disease (IBD). The proposed system relies on advanced image understating and processing techniques to segment digitally acquired images of microscopic biopsies, then, to extract key features to quantify the crypts irregularities in shape and distribution. These features were used as inputs to an artificial intelligent classifier that, after a training phase, can carry out the assessment automatically. The developed system was evaluated using 118 IBD biopsies. 116 out of 118 biopsies were correctly classified as compared to the consensus of three expert pathologists, achieving an overall precision of 98.31%. An automated intelligent system to quantitatively assess inflammatory bowel disease was developed. The proposed system utilized advanced image understanding techniques together with an intelligent classifier to conduct the assessment. The developed system proved to be reliable, robust, and minimizes subjectivity and inter- and intra-observer variability. The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1797721309305023.


For more than love or money: attitudes of student and in-service health workers towards rural service in India.
While international literature on rural retention is expanding, there is a lack of research on relevant strategies from pluralistic healthcare environments such as India, where alternate medicine is an integral component of primary care. In such contexts, there is a constant tug of war in national policy on "Which health worker is needed in rural areas?" and "Who can, realistically, be got there?" In this article, we try to inform this debate by juxtaposing perspectives of three cadres involved in primary care in India-allopathic, ayurvedic and nursing-on rural service. We also identify key incentives for improved rural retention of these cadres. We present qualitative evidence from two states, Uttarakhand and Andhra Pradesh. Eighty-eight in-depth interviews with students and in-service personnel were conducted between January and July 2010. Generic thematic analysis techniques were employed, and the data were organized in a framework that clustered factors linked to rural service as organizational (salary, infrastructure, career) and contextual (housing, children's development, safety). Similar to other studies, we found that both pecuniary and non-pecuniary factors (salary, working conditions, children's education, living conditions and safety) affect career preferences of health workers. For the allopathic cadre, rural primary care jobs commanded little respect; respondents from this cadre aimed to specialize and preferred private sector jobs. Offering preferential admission to specialist courses in exchange for a rural stint appears to be a powerful incentive for this cadre. In contrast, respondents from the Ayurvedic and nursing cadres favored public sector jobs even if this meant rural postings. For these two cadres, better salary, working and rural living conditions can increase recruitment. Rural retention strategies in India have predominantly concentrated on the allopathic cadre. Our study suggests incentivizing rural service for the nursing and Ayurvedic cadres is less challenging in comparison to the allopathic cadre. Hence, there is merit in strengthening rural incentive strategies for these two cadres also. In our study, we have developed a detailed framework of rural retention factors and used this for delineating India-specific recommendations. This framework can be adapted to other similar contexts to facilitate international cross-cadre comparisons.


Plants as green phones: Novel insights into plant-mediated communication between below- and above-ground insects.
Plants can act as vertical communication channels or 'green phones' linking soil-dwelling insects and insects in the aboveground ecosystem. When root-feeding insects attack a plant, the direct defense system of the shoot is activated, leading to an accumulation of phytotoxins in the leaves. The protection of the plant shoot elicited by root damage can impair the survival, growth and development of aboveground insect herbivores, thereby creating plant-based functional links between soil-dwelling insects and insects that develop in the aboveground ecosystem. The interactions between spatially separated insects below- and aboveground are not restricted to root and foliar plant-feeding insects, but can be extended to higher trophic levels such as insect parasitoids. Here we discuss some implications of plants acting as communication channels or 'green phones' between root and foliar-feeding insects and their parasitoids, focusing on recent findings that plants attacked by root-feeding insects are significantly less attractive for the parasitoids of foliar-feeding insects.


Mere categorization and the frog-pond effect.
Zell and Alicke (2009) have shown that comparisons with a few people have a stronger influence on self-evaluations than comparisons with larger samples. One explanation for this effect is that people readily categorize their standing in small groups as "good" or "bad," which supersedes large-sample data. To test this explanation, we created a situation in which students learned that their performance ranked 5th or 6th out of 10 persons on a task. In each experimental session, two groups, each containing 5 people, were created by random assignment. Some students learned that their performance placed them last in one group of 5, and some learned that they were first in the other group of 5. In the other conditions, participants learned only that that they were 5th or 6th in the group of 10. Results showed that being last in the superior group led to lower self-evaluations than being first in the inferior group.


Promoting safety: longer-term responses of three health professional groups to a safety improvement programme.
Patient safety has been addressed since 2002 in the health system of New South Wales, Australia via a Safety Improvement Programme (SIP), which took a system-wide approach. The programme involved two-day courses to educate healthcare professionals to monitor and report incidents and analyse adverse events by conducting root cause analysis (RCA). This paper aims to predict that all professions would favour SIP but that their work and educational histories would result in doctors holding the least and nurses the most positive attitudes. Alternative hypotheses were that doctors' relative power and other professions' team-working skills would advantage the respective groups when conducting RCAs. Responses to a 2005 follow-up questionnaire survey of doctors (n = 53), nurses (209) and allied health staff (59), who had participated in SIP courses, were analysed to compare: their attitudes toward the course; safety skills acquired and applied; perceived benefits of SIP and RCAs; and their experiences conducting RCAs. Significant differences existed between professions' responses with nurses being the most and doctors the least affirming. Allied health responses resembled those of nurses more than those of doctors. The professions' experiences conducting RCAs (number conducted, leadership, barriers encountered, findings implemented) were similar. Observational studies are needed to determine possible professional differences in the conduct of RCAs and any ensuing culture change that this may be eliciting. There is strong professional support for SIPs but less endorsement from doctors, who tend not to prefer the knowledge content and multidisciplinary teaching environment considered optimal for safety improvement education. This is a dilemma that needs to be addressed. Few longer-term SIPs' assessments have been realised and the differences between professional groups have not been well quantified. As a result of this paper, benefits of and barriers to conducting RCAs are now more clearly understood.


Extensive variation, but not local adaptation in an Australian alpine daisy.
Alpine plants often occupy diverse habitats within a similar elevation range, but most research on local adaptation in these plants has focused on elevation gradients. In testing for habitat-related local adaptation, local effects on seed quality and initial plant growth should be considered in designs that encompass multiple populations and habitats. We tested for local adaptation across alpine habitats in a morphologically variable daisy species, Brachyscome decipiens, in the Bogong High Plains in Victoria, Australia. We collected seed from different habitats, controlled for maternal effects through initial seed size estimates, and characterized seedling survival and growth in a field transplant experiment. We found little evidence for local adaptation for survival or plant size, based on three adaptation measures: Home versus Away, Local versus Foreign, and Sympatric versus Allopatric (SA). The SA measure controlled for planting site and population (site-of-origin) effects. There were significant differences due to site-of-origin and planting site effects. An important confounding factor was the size of plants directly after transplantation of seedlings, which had a large impact on subsequent seedling survival and growth. Initial differences in plant width and height influenced subsequent survival across the growing season but in opposing directions: wide plants had higher survival, but tall plants had lower survival. In an additional controlled garden experiment at Cranbourne Royal Botanic Gardens, site-of-origin effects detected in the field experiments disappeared under more benign homogeneous conditions. Although B. decipiens from different source areas varied significantly when grown across a range of alpine habitats, these differences did not translate into a local or habitat-related fitness advantage. This lack of local advantage may signal weak past selection, and/or weak adaptive transgeneration (plasticity) effects.


Patient-reported outcome reference values for patients after kidney transplantation.
Patient-reported outcomes (PROs) are important in managing kidney transplant patients. Although, there are many instruments available to assess PROs, such as health-related quality of life (HRQOL), they are rarely collected in routine nephrology practices. Therefore, the aim of this study was the determination of reference values for physical and psychosocial symptom burden in kidney transplant patients. Patients with a history of kidney transplantation being in aftercare at a nephrological outpatient unit (n = 120) were consecutively recruited, and a computer-based PRO assessment was used to assess their HRQOL reference values. It covered a broad range of clinically relevant physical and psychological symptoms, adherence to immunosuppressants, and disease-specific quality of life. On an average, PROs were assessed 2.9 times per patient, 351 times in total. For PRO monitoring in kidney transplant patients, we consider the 10th/90th percentile as being of particular clinical relevance, as patients exceeding these scores are likely to be in need of additional care. With continuously rising survival rates after kidney transplantation, HRQOL of long-term transplant patients becomes increasingly important, and it is generally accepted that HRQOL improves after successful kidney transplantation. We used a computerized PRO monitoring to determine HRQOL reference values for outpatient kidney transplant patients. Routine PRO monitoring may facilitate the identification of patient issues relevant to treatment, and may contribute to improved symptom and side-effect management. Future studies providing detailed PRO values for stratified patient samples are needed.


Structural modeling and in silico analysis of human superoxide dismutase 2.
Aging in the world population has increased every year. Superoxide dismutase 2 (Mn-SOD or SOD2) protects against oxidative stress, a main factor influencing cellular longevity. Polymorphisms in SOD2 have been associated with the development of neurodegenerative diseases, such as Alzheimer's and Parkinson's disease, as well as psychiatric disorders, such as schizophrenia, depression and bipolar disorder. In this study, all of the described natural variants (S10I, A16V, E66V, G76R, I82T and R156W) of SOD2 were subjected to in silico analysis using eight different algorithms: SNPeffect, PolyPhen-2, PhD-SNP, PMUT, SIFT, SNAP, SNPs&GO and nsSNPAnalyzer. This analysis revealed disparate results for a few of the algorithms. The results showed that, from at least one algorithm, each amino acid substitution appears to harmfully affect the protein. Structural theoretical models were created for variants through comparative modelling performed using the MHOLline server (which includes MODELLER and PROCHECK) and ab initio modelling, using the I-Tasser server. The predicted models were evaluated using TM-align, and the results show that the models were constructed with high accuracy. The RMSD values of the modelled mutants indicated likely pathogenicity for all missense mutations. Structural phylogenetic analysis using ConSurf revealed that human SOD2 is highly conserved. As a result, a human-curated database was generated that enables biologists and clinicians to explore SOD2 nsSNPs, including predictions of their effects and visualisation of the alignment of both the wild-type and mutant structures. The database is freely available at http://bioinfogroup.com/database and will be regularly updated.


Well plate microfluidic system for investigation of dynamic platelet behavior under variable shear loads.
The study of platelet behavior in real-time under controlled shear stress offers insights into the underlying mechanisms of many vascular diseases and enables evaluation of platelet-focused therapeutics. The two most common methods used to study platelet behavior at the vessel wall under uniform shear flow are parallel plate flow chambers and cone-plate viscometers. Typically, these methods are difficult to use, lack experimental flexibility, provide low data content, are low in throughput, and require large reagent volumes. Here, we report a well plate microfluidic (WPM)-based system that offers high throughput, low reagent consumption, and high experimental flexibility in an easy to use well plate format. The system consists of well plates with an integrated array of microfluidic channels, a pneumatic interface, an automated microscope, and software. This WPM system was used to investigate dynamic platelet behavior under shear stress. Multiple channel designs are presented and tested for shear loads with whole blood to determine their applicability to study thrombus formation. Normal physiological shear (0.1-20 dyn/cm(2) ) and pathological shear (20-200 dyn/cm(2) ) devices were used to study platelet behavior in vitro under various shear, matrix coating, and monolayer conditions. The high physiological relevance, low blood consumption, and increased throughput create a valuable technique available to vascular biology researchers. The approach also has extensibility to other research areas including inflammation, cancer biology, and developmental/stem cell research.


Active travel to school: policies and attitudes of school and district leaders.
When promoting active travel to school, it is important to consider school and district policies as well as attitudes of school and district administrators. School principals and district officials in South Carolina participated in the School Travel Survey. Frequency distributions and Chi-squared tests were used to analyze the data. Three hundred fourteen persons responded to the survey (53.2% response rate). Sixty-five percent of district officials reported having a clear position about students walking to school, 80.0% of which were supportive. Seventy-two percent of principals reported having a clear position about walking to school, 67% of which were supportive. These positions were most commonly communicated either orally or through memos or other written documentation rather than through official, written policies or directives. Respondents who personally supported walking to school were more likely to believe that walking to school benefited students' health (Chi-squared = 8.82, df = 1, P = .003) and academic performance (Chi-squared = 14.87, df = 1, P < .0001). Promotion of walking to school should encourage schools and districts to develop official, written directives or policies. Promotional efforts may benefit from linking active travel to academic performance and health.


Vitamin D binding protein sequesters monomeric actin in the circulation of the rat.
Plasma vitamin D binding protein (DBP) may scavenge actin released during cell lysis. We examined the plasma disappearance and tissue appearance of 125I-DBP, 125I-G-actin, and the DBP-G-actin complex after their intravenous administration to rats. The plasma disappearance of DBP and DBP-actin were indistinguishable, with rapid initial (t1/2 = 2.6 h) and slower second (t1/2 = 7 h) slopes. After 125I-G-actin (nanomole) injection, plasma disappearance paralleled that of DBP and DBP-actin. All injected actin was associated with DBP, without evidence of free actin, actin-gelsolin complexes or actin oligomers. Tissue appearances of 125I-apo-DBP (apo) or holo-DBP were similar, with highest accumulations in perfused liver, kidney, and skeletal muscle. Although more complex phenomena (plasma entry of F-actin and intracellular actin binding proteins) would occur in vivo after cell lysis, our results suggest a role for DBP in the sequestration and disposition of actin monomers in the circulation.


D-Tryptophan enhances the reproductive organ-specific expression of the amino acid transporter homolog Dr-SLC38A9 involved in the sexual induction of planarian Dugesia ryukyuensis.
Many animals switch between asexual and sexual reproduction in nature. We previously established a system for the sexual induction of planarian Dugesia ryukyuensis by feeding asexual planarians with minced sexual planarians. We identified DL-tryptophan (Trp) as one of the sex-inducing substances. DL-Trp can induce ovarian development, the first and essential step of sexual induction. D-Trp must act as a principal bioactive compound in terms of ovarian development, because the ovary-inducing activity of D-Trp was 500 times more potent than that of L-Trp. However, how Trp controls sexual induction is still unknown. In this study, qRT-PCR analyses suggested that the putative amino acid transporter gene Dr-SLC38A9 is highly expressed in sexual worms, especially in the yolk glands. In situ hybridization analyses showed that Dr-SLC38A9 is expressed in the ovarian primordia of asexual worms and in the mature ovaries, testes, and yolk glands of sexual worms. In addition, Dr-SLC38A9 RNA interference during sexual induction resulted in the suppression of the development of reproductive organs. These results suggest that Dr-SLC38A9 is involved in the development of these organs. Moreover, we demonstrated that the reproductive organ-specific expression of Dr-SLC38A9 is enhanced by the addition of D-Trp. We propose that D-Trp activates the expression of Dr-SLC38A9 to promote sexual induction in the planarian D. ryukyuensis.


Oral health care for the pregnant patient.
Pregnancy is a unique time in a women's life, accompanied by a variety of physiologic, anatomic and hormonal changes that can affect how oral health care is provided. However, these patients are not medically compromised and should not be denied dental treatment simply because they are pregnant. This article discusses the normal changes associated with pregnant general considerations in the care of pregnant patients, and possible dental complications of pregnancy and their management.


First Report of Clubroot of Eruca sativa Caused by Plasmodiophora brassicae in Brazil.
Eruca sativa Mill. (family Brassicaceae), with its origin in western Asia, is a culinary and pharmacological species cultivated in Europe, Brazil, and other countries. In the United States, it is a minor crop known as arugula or roquette. Clubroot on E. sativa has not been reported in Brazil and has been reported once in the United States in 1914 (1,2,3). On several occasions since 2000, stunted and wilted plants (cv. Rúcula Cultivada) were collected from growers' fields and greenhouses that had been direct-seeded in Vargem Bonita, DF (two fields and one greenhouse) and Quatro Barras, PR (two fields). The infected arugula crops were found in areas where other plants from the genus Brassica were traditionally cultivated. Disease incidence in individual fields varied from 20 to 80%. Diseased plants were severely affected with hypertrophic, malformed roots, and root galls resembling Woronin's description (4). Plasmodia and resting spores in thin sections prepared from root galls were observed with compound and electron microscopes. Pathogenicity tests were conducted on arugula and Brassica pekinensis (Lour.) Rupr. (universal host) with inoculum from naturally infected arugula. The soil of potted test plants at the four-to-five-leaf stage was drenched with a suspension of resting spores. Symptoms identical to those observed on the original plants were produced on all inoculated plants 2 to 3 weeks after inoculation. Control plants remained symptomless. The pathogen was positively identified as Plasmodiophora brassicae Wor. with the combination of macroscopic and microscopic symptoms and signs of the disease and pathogen. P. brassicae was first reported in Brazil in 1965 in the state of São Paulo and in the 1980s in Distrito Federal on several members of the Brassicae. To our knowledge, this is the first report of P. brassicae infecting E. sativa in Brazil. Arugula is a susceptible host and should not be planted on P. brassicae-infested land. References: (1) D. Farr et al. Fungi on Plants and Plant Products in the United States. The American Phytopathological Society, St. Paul, MN. 1989. (2) D. F. Farr et al. Fungal Databases. Systematic Botany and Mycology Laboratory, On-line publication. ARS, USDA, 2003. (3) J. S. Karling. The Plasmodiophorales. Published by J. S. karling, NY. 1942. (4) M. S. Woronin. Plasmodiophora brassicae the Cause of Cabbage Hernia. Phytopathological Classics 4. The American Phytopathological Society, Ithaca, NY, 1934.


Flows, droughts, and aliens: factors affecting the fish assemblage in a Sierra Nevada, California, stream.
The fishes of Martis Creek, in the Sierra Nevada of California (USA), were sampled at four sites annually over 30 years, 1979-2008. This long-term data set was used to examine (1) the persistence and stability of the Martis Creek fish assemblage in the face of environmental stochasticity; (2) whether native and alien fishes responded differently to a natural hydrologic regime (e.g., timing and magnitude of high and low flows); and (3) the importance of various hydrologic and physical habitat variables in explaining the abundances of native and alien fish species through time. Our results showed that fish assemblages were persistent at all sample sites, but individual species exhibited marked interannual variability in density, biomass, and relative abundance. The density and biomass of native fishes generally declined over the period of study, whereas most alien species showed no significant long-term trends. Only alien rainbow trout increased in both density and biomass at all sites over time. Redundancy analysis identified three hydrologic variables (annual 7-day minimum discharge, maximum winter discharge, and number of distinct winter floods) and two habitat variables (percentage of pool habitat and percentage of gravel substrate) that each explained a significant portion of the annual variation in fish assemblage structure. For alien taxa, their proportional contribution to the total fish assemblage was inversely related to mean annual streamflow, one-day maximum discharge in both winter and spring, and the frequency of springtime floods. Results of this study highlight the need for continuous annual monitoring of streams with highly variable flow regimes to evaluate shifts in fish community structure. Apparent successes or failures in stream management may appear differently depending on the time series of available data.


Disseminating research evidence. A controlled trial in continence care.
The dissemination of research evidence from which clinical practice should be based poses many well-documented problems for nurses. This study set out to overcome some of the common barriers to dissemination by providing a research-based clinical handbook for continence care. The impact of the handbook on nurses' knowledge of both urinary and faecal incontinence was tested using an experimental and control group. The experimental group received the handbook while the control group did not. Both groups completed an assessment questionnaire at week 1, prior to the intervention in the experimental group, followed by a second assessment at week 7 after the intervention in the experimental group. Data were collected using semi-structured questionnaires. Statistically significant improvements in knowledge were found for those nurses who received a copy of the handbook, and nurses reported that they found the handbook useful and acceptable as a form of clinical updating. The dissemination of research findings is essential if evidence-based nursing is to become a reality, and this study clearly demonstrates one method by which this can be successfully achieved.


Promoting motor skills in low-income, ethnic children: The Physical Activity in Linguistically Diverse Communities (PALDC) nonrandomized trial.
This study reports the long-term effects of a professional learning program for classroom teachers on fundamental motor skill (FMS) proficiency of primary school students from ethnically diverse backgrounds. A cluster non-randomized trial using a nested cross-sectional design. The study was conducted in 8 primary schools located in disadvantaged and culturally diverse areas in Sydney, Australia. The intervention used an action learning framework, with each school developing and implementing an action plan for enhancing the teaching of FMS in their school. School teams comprised 4-5 teachers and were supported by a member of the research team. The primary outcome was total proficiency score for 7 FMS (run, jump, catch, throw, kick, leap, side gallop). Outcome data were analyzed using mixed effects models. Eight-hundred and sixty-two students (82% response rate) were assessed at baseline in 2006 and 830 (82%) at follow-up in 2010. Compared with students in the control schools, there was a significantly greater increase in total motor skill proficiency among children in the intervention schools at follow-up (adjusted difference=5.2 components, 95%CI [1.65, 8.75]; p=0.01) and in four of the seven motor skills. Training classroom teachers to develop and implement units of work based around individual FMS is a promising strategy for increasing FMS among ethnically diverse children over an extended period of time.


Teamwork, myth or reality: community nurses' experience with general practice attachment.
A survey of 93 community nurses, 48 health visitors, and 45 district nurses was carried out in one area health authority where nurses had been attached to general practice schemes for up to 10 years. The purpose of the study was to determine the nurses' impression of teamwork within their attachment arrangements. Half the group surveyed had either a geographical area or other area health authority responsibilities, or both, in addition to their primary attachment commitment. No structured plan for preparing or evaluating attachment groups had been carried out by the area health authority. Only one third of attached nurses were working from premises shared with other members of the attachment group, and often facilities were poorly designed for teamwork. Health visitors were generally less enthusiastic about attachment and identified more obstacles in developing teamwork than did district nurses. Health visitors also tended to stay with individual attachment groups for shorter periods than did district nurses. Most nurses communicated frequently with attachment group members, but these opportunities were unplanned and usually limited to immediate problems of patient care. In a few attachments patterns of communication and collaboration appeared to be non-existent. Despite the problems identified in this study, most respondents prefer attachment to working solely in a geographical area and value their links the area health authority. Evaluation and positive direction is needed if the primary care team is to develop.


Downregulation of telomerase maintenance-related ACD expression in patients undergoing immunosuppresive therapy following kidney transplantation.
Chronic administration of immunosuppressants has been associated with long-term consequences, including a higher risk of neoplasm development. The processes regulating telomere function exert a major influence on human cancer biology. The present study aimed to assess the effect of immunosuppressive therapy on the expression of genes associated with telomere maintenance and protection in patients following renal transplantation. A total of 51 patients that had undergone kidney transplantation and 54 healthy controls were enrolled in the study. The 51 transplant patients received a three-drug immunosuppressive regimen consisting of cyclosporine A, prednisone and mycophenolate mofetil. In stage 1 of the study, the expression profiles of 123 transcripts, which represented 70 genes, were assessed in peripheral mononuclear blood cells using an oligonucleotide microarray technique in 8 transplant recipients and 4 healthy control subjects. Among the analyzed transcripts, the expression levels of 4 differed significantly between the studied groups; however, only the ACD (adrenocortical dysplasia homolog) gene, encoding the telomere-binding protein POT1-interacting protein 1 (TPP1), was sufficiently specific for telomere homeostasis. The expression of ACD was downregulated in transplant recipients (fold change, 2.11; P=0.006). In stage 2 of the study, reverse transcription-quantitative polymerase chain reaction analysis of ACD, DKC1 and hTERT mRNA was conducted for all transplant patients and control subjects. The results confirmed the downregulation of the ACD gene in patients that had received immunosuppressive therapy (P=0.002). The results of the present study indicate that the downregulation of ACD gene transcription, and thus TPP1 protein expression, may enhance the capacity for cell immortalization, despite normal levels of other key telomere maintenance factors, in patients undergoing immunosuppressive therapy. Furthermore, the results indicate that TPP1 has potential for use as an early clinical marker and/or therapeutic target for cancer in patients following organ transplantation.


NMR studies of DNA structures containing sheared purine•purine and purine•pyrimidine base pairs.
Summary Sheared purine•purine or purine•pyrimidine base pairs are important motifs in nucleic acid structures. They can exist either as tandem base pairs or as a single base pair closing hairpin mini-loops. Presence of such stable motifs greatly increases the structural repertoire of nucleic acid molecules and may play important roles in the contemporary nucleic acid studies. Several RNA crystal structures containing adjacent cross-strand base stacking have been solved. In this review, I will discuss the NMR studies and structural features for DNA molecules containing sheared G•A, A•A, or A•C base pairs. Special attention will be focused on exchangeable proton data, which have turned out to be crucial to the determination of unusual nucleic acid structures. The special features of the partial HIV-1 RT 21-mer act as a good example for correlating the (31)P chemical shifts to the ζ and α torsional angles of the backbone phosphate diesters.


CpG methylation-dependent repression of the human O6-methylguanine-DNA methyltransferase gene linked to chromatin structure alteration.
The mechanism of inactivation of the O6-methylguanine-DNA methyltransferase (MGMT), responsible for repair of mutagenic and cytotoxic O6-alkylguanine, in Mex- tumor cells, is not completely understood. We have examined the role of CpG methylation in the human MGMT promoter in a luciferase (luc) reporter plasmid and associated alteration in chromatin structure. Methylation of 16% CpG sequences in promoter and flanking sequences in the plasmid with HpaII methylase reduced luciferase activity by 10-12-fold, while methylation of all CpG sites, including those in the luc coding sequence, as well as the promoter sequence blocked expression completely. Repression of luc expression due to partial but not complete CpG methylation could be reversed by histone deacetylase inhibitor trichostatin A (TSA). However, 5-azacytidine, which reverses CpG methylation, but not TSA, could reactivate silent MGMT gene in Mex- HeLa MR cells. Furthermore, chromatin immunoprecipitation (ChIP) assay showed reduced level of acetylation of H4 histone bound to the methylated promoter compared with the non-methylated promoter. These results suggest that complete repression of the MGMT gene in Mex- cells requires methylation of CpG sequences in both promoter and neighboring regions of the gene, resulting in inactive, condensed chromatin state of the gene.


Complexity is complicated and so too is comparing complexity metrics-A response to Mikula et al. (2018).
In a recent publication (Pearse et al. 2018b), we explored the macroevolution and macroecology of passerine song using a large citizen science database of bird songs and powerful machine learning tools. Mikula et al. (2018) examine a small subset (<8%) of the data we used, and suggest that our metric of song complexity, the SD of frequency (SDF), does not correlate to other metrics of birdsong complexity, specifically syllable repertoire size and syllable diversity. We comment on the diversity of complexity metrics that exist in the field at present, and, while acknowledging that metrics may differ, outline how this variety allows us to ask more biologically nuanced questions. We see no reason or need for all complexity metrics to be correlated. Since different complexity metrics have been, and will continue to be, used, we outline how metrics could be fairly compared in the future.


A two-step process in the emergence of neurogenesis.
Cnidarians belong to the first phylum differentiating a nervous system, thus providing suitable model systems to trace the origins of neurogenesis. Indeed corals, sea anemones, jellyfish and hydra contract, swim and catch their food thanks to sophisticated nervous systems that share with bilaterians common neurophysiological mechanisms. However, cnidarian neuroanatomies are quite diverse, and reconstructing the urcnidarian nervous system is ambiguous. At least a series of characters recognized in all classes appear plesiomorphic: (1) the three cell types that build cnidarian nervous systems (sensory-motor cells, ganglionic neurons and mechanosensory cells called nematocytes or cnidocytes); (2) an organization of nerve nets and nerve rings [those working as annular central nervous system (CNS)]; (3) a neuronal conduction via neurotransmitters; (4) a larval anterior sensory organ required for metamorphosis; (5) a persisting neurogenesis in adulthood. By contrast, the origin of the larval and adult neural stem cells differs between hydrozoans and other cnidarians; the sensory organs (ocelli, lens-eyes, statocysts) are present in medusae but absent in anthozoans; the electrical neuroid conduction is restricted to hydrozoans. Evo-devo approaches might help reconstruct the neurogenic status of the last common cnidarian ancestor. In fact, recent genomic analyses show that if most components of the postsynaptic density predate metazoan origin, the bilaterian neurogenic gene families originated later, in basal metazoans or as eumetazoan novelties. Striking examples are the ParaHox Gsx, Pax, Six, COUP-TF and Twist-type regulators, which seemingly exert neurogenic functions in cnidarians, including eye differentiation, and support the view of a two-step process in the emergence of neurogenesis.


GFAP is necessary for the integrity of CNS white matter architecture and long-term maintenance of myelination.
To investigate the structural role of glial fibrillary acidic protein (GFAP) in vivo, mice carrying a null mutation in GFAP were generated. In 7/14 mutant animals older than 18 months of age, hydrocephalus associated with white matter loss was detected. Mutant mice displayed abnormal myelination including the presence of actively myelinating oligodendrocytes in adults, nonmyelinated axons in optic nerve, and reduced myelin thickness in spinal cord. White matter was poorly vascularized and the blood-brain barrier was structurally and functionally impaired. Astrocytic structure and function were abnormal, consisting of shortened astrocytic cell processes, decreased septation of white matter, and increased CNS extracellular space. Thus, GFAP expression is essential for normal white matter architecture and blood-brain barrier integrity, and its absence leads to late-onset CNS dysmyelination.


Verbena officinalis essential oil and its component citral as apoptotic-inducing agent in chronic lymphocytic leukemia.
We evaluated the pro-apoptotic activity of Verbena officinalis essential oil and of its main component citral, on lymphocytes collected from normal blood donors and patients with chronic lymphocytic leukemia (CLL). The number of apoptotic cells was greater in CLL patients than in healthy subjects at all different times of incubation (4, 8 and 24 hours) for samples treated with Verbena officinalis essential oil (A) and citral (B) as well vs controls at different concentrations (0.1% and 0.01%). The greater pro-apoptotic ability was shown by both essential oil of Verbena officinalis and citral at lower concentrations (after 4 h A 0.1%: 17.8% vs 37.1%; A 0.01%: 15.8% vs 52%; B 0.1%: 18.4% vs 46.4%; B 0.01%: 15.8% vs 54.2%; after 8 h A 0.1%: 23% vs 38%; A 0.01%: 22.2% vs 55%; B 0.1%: 32% vs 42.2%; B 0.01%: 22% vs 54.3%; after 24 h A 0.1%: 5% vs 20.7%; A 0.01%: 25.8% vs 47.2%; B 0.1%: 18.4% vs 46.4%; B 0.01%: 15.8% vs 54.2%). Patients carrying deletion 17p13 (p53 mutation) showed a reduced ability to undergo apoptosis with respect to patients with other genomic aberrations or normal karyotype. The proapoptotic activity of Verbena officinalis essential oil and citral is thought to be due to a direct procaspase 3 activation. These data further support evidence that indicate natural compounds as a possible lead structure to develop new therapeutic agents.


Lymphoproliferative disorders of the kidney on fine-needle aspiration: cytomorphology and radiographic correlates in 33 cases.
Unless renal lesions present in the setting of widespread lymphoma, biopsy can be indicated to differentiate from metastases, hypovascular renal cell carcinoma, urothelial carcinoma or infection. We review our experience with lymphoproliferative disorders in the kidney diagnosed by fine-needle aspiration (FNA), and focus on clinicopathologic and radiographic features. All cases of non-Hodgkin lymphoma diagnosed on renal FNA at 2 academic institutions between 1989 and 2011 were reviewed. Clinical history, radiographic and cytomorphologic features, and follow-up were assessed. 33 cases were identified, with 15 primary tumors and 18 recurrences/secondary tumors including 1 acute lymphoblastic lymphoma. The majority were aggressive/high-grade lesions (25/33). 25 cases were substantiated by positive flow cytometry results. Most were detected at follow-up/incidentally. 22 cases showed multiple renal and/or retroperitoneal masses or a significant component of adenopathy; others showed a solitary renal mass. Salient radiologic features included hypodense, infiltrative and ill-defined masses. Cytomorphology showed a monotonous population of large atypical lymphoid cells, often with lymphoglandular bodies. Cytologic diagnosis of renal lymphoma requires analysis of morphological, clinical and immunophenotypic information. Helpful features for diagnosis include: multiple masses on computed tomography, a monotonous population of abnormal cells in a background of lymphoglandular bodies and immunophenotyping demonstrating light chain restriction.


Clinical report on longitudinal post-eruptive changes in fluorotic enamel observed in 10 cases over a 2 1/2 year period.
The present longitudinal study was conducted on ten children from age 5-6 years to determine the post-eruptive enamel changes of fluorosed permanent incisors. The children were born and reared in an area of Kenya with a water fluoride level of 14-45 parts per million. The incisors were examined and photographed periodically from the time of eruption over a period of 2 1/2 years. It was noted that the fluorosed incisor was intact as it erupted and then it underwent a variety of changes. In some there was mechanical breakdown (pitting) of the chalky white enamel which occurred rapidly initially and then the breakdown slowed down by 2 years. In others, there was smoothening of the pitted enamel resulting in a translucent appearance. Alternatively there was some degree of patchy staining of the enamel without surface breakdown. Much of the cervical 1/3 of the enamel remained intact even in teeth with severe breakdown. In most cases, these changes were bilaterally symmetrical. The possible reasons for these changes are discussed.


Adolescents' daily face-to-face and computer-mediated communication: Associations with autonomy and closeness to parents and friends.
The amount of time adolescents spend communicating via digital technologies such as smartphones has led to concerns that computer-mediated communication (CMC) is displacing face-to-face (FtF) interactions and disrupting social development. Although many studies have examined CMC in adolescents' relationships with friends, few studies have examined the role of CMC in adolescents' renegotiation of closeness and autonomy with parents. To examine this issue, we administered an online daily diary with 169 U.S. adolescents to estimate the time they spend in CMC and FtF interactions and the number of texts they exchange with friends and parents. On the last day of the survey, we asked adolescents about their emotional closeness to friends and parents and their balance of closeness and volition with parents. Overall, we found more evidence for social stimulation than displacement effects of CMC. Texts and CMC time with friends predicted friend closeness after accounting for FtF time with friends; texts with parents predicted parent closeness after accounting for FtF time with parents. We also found support for our hypothesis that CMC would be associated with greater adolescent volition. CMC time with parents predicted greater volitional dependence (volition plus closeness) whereas texts with friends predicted greater independent decision-making (volition plus distance). We discuss how communication technologies are integrated into U.S. adolescents' relationships with friends and parents and how CMC can facilitate, rather than stifle, adolescents' adjustment of autonomy-relatedness with parents and their construction of emotional closeness with friends. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Adaptive Machine Learning Based Distributed Denial-of-Services Attacks Detection and Mitigation System for SDN-Enabled IoT.
The development of smart network infrastructure of the Internet of Things (IoT) faces the immense threat of sophisticated Distributed Denial-of-Services (DDoS) security attacks. The existing network security solutions of enterprise networks are significantly expensive and unscalable for IoT. The integration of recently developed Software Defined Networking (SDN) reduces a significant amount of computational overhead for IoT network devices and enables additional security measurements. At the prelude stage of SDN-enabled IoT network infrastructure, the sampling based security approach currently results in low accuracy and low DDoS attack detection. In this paper, we propose an Adaptive Machine Learning based SDN-enabled Distributed Denial-of-Services attacks Detection and Mitigation (AMLSDM) framework. The proposed AMLSDM framework develops an SDN-enabled security mechanism for IoT devices with the support of an adaptive machine learning classification model to achieve the successful detection and mitigation of DDoS attacks. The proposed framework utilizes machine learning algorithms in an adaptive multilayered feed-forwarding scheme to successfully detect the DDoS attacks by examining the static features of the inspected network traffic. In the proposed adaptive multilayered feed-forwarding framework, the first layer utilizes Support Vector Machine (SVM), Naive Bayes (NB), Random Forest (RF), k-Nearest Neighbor (kNN), and Logistic Regression (LR) classifiers to build a model for detecting DDoS attacks from the training and testing environment-specific datasets. The output of the first layer passes to an Ensemble Voting (EV) algorithm, which accumulates the performance of the first layer classifiers. In the third layer, the adaptive frameworks measures the real-time live network traffic to detect the DDoS attacks in the network traffic. The proposed framework utilizes a remote SDN controller to mitigate the detected DDoS attacks over Open Flow (OF) switches and reconfigures the network resources for legitimate network hosts. The experimental results show the better performance of the proposed framework as compared to existing state-of-the art solutions in terms of higher accuracy of DDoS detection and low false alarm rate.


Acute forearm compartment syndrome in a newborn caused by reperfusion after spontaneous axillary artery thrombosis.
Acute compartment syndrome of the forearm in newborns is often misdiagnosed and can be disastrous if left untreated. Here, we report a full-term infant of a diabetic mother with underlying heterozygosity for MTHFR C677T and A1298C alleles. A spontaneous thrombosis occurred in the left axillary artery immediately after birth. The patient responded well to anticoagulant (heparin) and thrombolytic (tissue plasminogen activator) agents. After reperfusion of the extremity, acute compartment syndrome developed. Emergent fasciotomy was performed. In this case, effective collaboration between pediatricians and orthopedic surgeons resulted in salvage of the extremity, with good clinical and functional results.


Interaction of the endothelial nitric oxide synthase with the CAT-1 arginine transporter enhances NO release by a mechanism not involving arginine transport.
eNOS (endothelial nitric oxide synthase) catalyses the conversion of L-arginine into L-citrulline and NO. Evidence has been presented previously that eNOS is associated with the CAT (cationic amino acid transporter)-1 arginine transporter in endothelial caveolae, and it has been proposed that eNOS-CAT-1 association facilitates the delivery of extracellular L-arginine to eNOS. Definitive proof of a protein-protein interaction between eNOS and CAT-1 is lacking, however, and it is also unknown whether the two proteins interact directly or via an adaptor protein. In the present study, we raised a polyclonal antibody against CAT-1, and show using reciprocal co-immunoprecipitation protocols that eNOS and CAT-1 do indeed form a complex in BAECs (bovine aortic endothelial cells). In vitro binding assays with GST (glutathione S-transferase)-CAT-1 fusion proteins and eNOS show that the two proteins interact directly and that no single CAT-1 intracellular domain is sufficient to mediate the interaction. Overexpression of CAT-1 in BAECs by adenoviral-mediated gene transfer results in significant increases in both L-arginine uptake and NO production by the cells. However, whereas increased L-arginine transport is reversed completely by the CAT-1 inhibitor, L-lysine, increased NO release is unaltered, suggesting that NO production in this in vitro model is independent of CAT-1-mediated transport. Furthermore, eNOS enzymic activity is increased in lysates of CAT-1-overexpressing cells accompanied by increased phosphorylation of eNOS at Ser-1179 and Ser-635, and decreased association of eNOS with caveolin-1. Taken together, these data suggest that direct interaction of eNOS with CAT-1 enhances NO release by a mechanism not involving arginine transport.


Supramolecular Archimedean cages assembled with 72 hydrogen bonds.
Self-assembly of multiple components into well-defined and predictable structures remains one of the foremost challenges in chemistry. Here, we report on the rational design of a supramolecular cage assembled from 20 ions of three distinct species through 72 hydrogen bonds. The cage is constructed from two kinds of hexagonal molecular tiles, a tris(guanidinium)nitrate cluster and a hexa(4-sulfonatophenyl)benzene, joined at their edges through complementary and metrically matched N-H···O-S hydrogen bonds to form a truncated octahedron, one of the Archimedean polyhedra. The truncated octahedron, with an interior volume of 2200 cubic angstroms, serves as the composite building unit of a body-centered cubic zeolite-like framework, which exhibits an ability to encapsulate a wide range of differently charged species, including organic molecules, transition metal complexes, and "ship-in-a-bottle" nanoclusters not observed otherwise.


Reactions of extracts of Reiter treponeme with syphilitic and non-syphilitic human sera in the single radial haemolysis technique.
A single radial haemolysis (SRH) technique, using Reiter protein or Reiter lysate as the coating antigen, was investigated. Results obtained with syphilitic and presumed non-syphilitic human sera were compared with results obtained in the absorbed fluorescent treponemal antibody test (FTA-ABS), the Reiter protein complement fixation test ( RPCFT ), the Venereal Diseases Research Laboratory Slide test (VDRL) and the Cardiolipin Wasserman reaction ( CWR ). The SRH reaction, with either Reiter antigen, was more sensitive than any of the screening tests ( RPCFT , VDRL and CWR ) for detecting positive syphilitic antibodies. Although the SRH test used almost the same materials as the RPCFT , it was appreciably more sensitive for the detection of the group-specific antibodies in syphilitic human serum.


Reduction of HDL levels lowers plasma PLTP and affects its distribution among lipoproteins in mice.
Phospholipid transfer protein (PLTP) is associated with HDL particles in plasma, where it transfers phospholipids between lipoproteins and remodels HDL particles. Tangier disease patients, with a mutated ABCA1 transporter, have extremely low plasma HDL concentration and reduced PLTP activity levels, a phenotype that is also observed in mice lacking ABCA1. We investigated whether low HDL levels and low PLTP activity are mechanistically related. Firstly, we studied PLTP expression and distribution among lipoproteins in mice lacking ABCA1 (ABCA1(-/-)). Parallel to the strong reduction in PLTP activity in plasma of ABCA1(-/-) mice, decreased PLTP protein levels were observed. Neither PLTP synthesis in liver or macrophages nor the ability of the macrophages to secrete PLTP were impaired in ABCA1(-/-) mice. However, the PLTP activity level in the medium of cultured macrophages was determined by HDL levels in the medium. PLTP was associated with HDL particles in wild type mice, whereas in ABCA1(-/-) mice, PLTP was associated with VLDL and LDL particles. Secondly, we treated different mouse models with varying plasma HDL and PLTP levels (wild type, ABCA1(-/-), apoE(-/-) and PLTPtg mice, overexpressing human PLTP) with a synthetic LXR ligand, and investigated the relationship between LXR-mediated PLTP induction and HDL levels in plasma. Plasma PLTP activity in wild type mice was induced 5.6-fold after LXR activation, whereas in ABCA1(-/-), apoE(-/-) and PLTPtg mice, all having reduced HDL levels, induction of PLTP activity was 2.4- , 3.2- and 2.0-fold, respectively. The less pronounced PLTP induction in these mice compared to wild type mice was not caused by a decreased PLTP gene expression in the liver or macrophages. Our findings indicate that the extent of LXR-mediated PLTP induction depends on plasma HDL levels. In conclusion, we demonstrate that ABCA1 deficiency in mice affects plasma PLTP level and distribution through an indirect effect on HDL metabolism. In addition, we show that the extent of LXR-mediated PLTP induction is HDL-dependent. These findings indicate that plasma HDL level is an important regulator of plasma PLTP and might play a role in the stabilization of PLTP in plasma.


Acute and subacute effects of naturally occurring estrogens on luteinizing hormone secretion in the ovariectomized rat: Part 2.
Acute intravenous administration of the phytoestrogen genistein (G) blocks the gonadotropin-releasing hormone-(GnRH)-induced rise of luteinizing hormone (LH) in ovariectomized rats. The present experiments were performed to determine whether subacute administration of G or the mycoestrogens zearalenone and zearalenol would affect GnRH-induced or progesterone-induced LH secretion in ovariectomized rats. Charles River CD rats were ovariectomized and used 2 to 5 weeks later. Blood samples were obtained either via decapitation or via intraatrial cannulae three days after compounds were injected subcutaneously in sesame oil or corn oil vehicle. LH was measured by RIA. Pretreatment with estradiol benzoate suppressed LH levels at 1200 h, while G had no effect. Challenge with progesterone (8 mg/kg BW, sc) evoked LH release at 1600 h in rats pretreated with estradiol benzoate, but LH levels did not change in rats pretreated with G, zearalenone, or zearalenol. While GnRH-induced LH secretion was preserved in rats pretreated with estradiol, no LH response was detected in rats pretreated with the higher dose of G (8 mg/kg BW) or either dose of zearalenol (0.8 mg/kg BW or 8 mg/kg BW). We conclude that in the ovariectomized rat 1) subacute administration of G, zearalenone, or zearalenol do not inhibit tonic LH secretion, 2) G, zearalenone, and zearalenol do not provide "estrogenic priming" for progesterone-induced LH secretion; however, 3) G and zearalenol do block GnRH-induced LH secretion. The seemingly selective neuroendocrine effects of these naturally-occurring dietary estrogens emphasize that actions of each putative estrogen must be characterized for each "estrogenic" endpoint.


Farnesol signalling in Candida albicans - more than just communication.
Candida albicans is a successful colonizer of the human host, which can, under certain circumstances cause a range of clinically diverse infections. Important virulence-associated traits of the fungus, such as the dimorphic switch and biofilm formation, are controlled by the quorum sensing molecule farnesol. Given the potential of farnesol as a novel antifungal drug, there has been increasing research into the mechanism underlying farnesol sensing and action in C. albicans. However, despite the identification of various factors involved in farnesol signalling, its exact mode of action remains largely unclear. This review provides an overview of the currently known aspects of farnesol production, sensing and action within C. albicans. We also illustrate the characteristic of C. albicans to simultaneously produce and tolerate high farnesol concentrations that are lethal to other microbes. Furthermore, we summarize new literature on the role of farnesol in the interaction of C. albicans with the human host and highlight its action as a potent immunomodulatory molecule.


Potential cross-reactivity between HPV16 L1 protein and sudden death-associated antigens.
In exploring the primary sequence of the human papilloma virus (HPV) 16 major capsid L1 protein for peptide sharing with human proteins, we find that 34 pentamers from the viral capsid protein are shared with human proteins that, when altered, have been linked to short QT syndrome, arrhythmogenic cardiac disorders, cardiovascular diseases and sudden death. In particular, nine out of the 34 viral pentamers are present in a human protein, titin, alterations of which have been linked to cardiac failure and sudden cardiac death. The present data may help evaluate the potential crossreactivity risks in anti-tumor vaccination protocols based on HPV16 L1 protein.


Integrin activation or alpha 9 expression allows retinal pigmented epithelial cell adhesion on Bruch's membrane in wet age-related macular degeneration.
Retinal pigment epithelial cell malfunction is a causative feature of age-related macular degeneration, and transplantation of new retinal pigment epithelial cells is an attractive strategy to prevent further progression and visual loss. However, transplants have shown limited efficacy, mainly because transplanted cells fail to adhere and migrate onto pathological Bruch's membrane. Adhesion to Bruch's membrane is integrin-mediated. Ageing of Bruch's membrane leads to a decline in integrin ligands and, added to this, wet age-related macular degeneration leads to upregulation of anti-adhesive molecules such as tenascin-C. We have therefore investigated whether manipulation of integrin function in retinal pigment epithelial cells can restore their adhesion and migration on wet age-related macular degeneration-damaged Bruch's membrane. Using spontaneously immortalized human retinal pigment epithelial cells (adult retinal pigment epithelium-19), we show that adhesion and migration on the Bruch's membrane components is integrin-dependent and enhanced by integrin-activating agents manganese and TS2/16. These allowed cells to adhere and migrate on low concentrations of ligand, as would be found in aged Bruch's membrane. We next developed a method for stripping cells from Bruch's membrane so that adhesion and migration assays can be performed on its surface. Integrin activation had a moderate effect on enhancing retinal pigmented epithelial cell adhesion and migration on normal human and rat Bruch's membrane. However, on Bruch's membrane prepared from human wet age-related macular degeneration-affected eyes, adhesion was lower and integrin activation had a much greater effect. A candidate molecule for preventing retinal pigmented epithelial interaction with age-related macular degeneration-affected Bruch's membrane is tenascin-C which we confirm is present at high levels in wet age-related macular degeneration membrane. We show that tenascin-C is anti-adhesive for retinal pigmented epithelial cells, but after integrin activation, they can adhere and migrate on it using alphaVbeta3 integrin. Alternatively, we find that transduction of retinal pigmented epithelial cells with alpha9 integrin, a tenascin-C-binding integrin, led to a large increase in alpha9beta1-mediated adhesion and migration on tenascin-C. Both expression of alpha9 integrin and integrin activation greatly enhanced the ability of retinal pigment epithelial cells to adhere to tenascin-rich wet age-related macular degeneration-affected Bruch's membranes. Our results suggest that manipulation of retinal pigment epithelial cell integrins through integrin activating strategies, or expression of new integrins such as alpha9, could be effective in improving the efficacy of retinal pigment epithelial cell transplantation in wet age-related macular degeneration-affected eyes.


Recognition of the core RNA promoter for minus-strand RNA synthesis by the replicases of Brome mosaic virus and Cucumber mosaic virus.
Replication of viral RNA genomes requires the specific interaction between the replicase and the RNA template. Members of the Bromovirus and Cucumovirus genera have a tRNA-like structure at the 3' end of their genomic RNAs that interacts with the replicase and is required for minus-strand synthesis. In Brome mosaic virus (BMV), a stem-loop structure named C (SLC) is present within the tRNA-like region and is required for replicase binding and initiation of RNA synthesis in vitro. We have prepared an enriched replicase fraction from tobacco plants infected with the Fny isolate of Cucumber mosaic virus (Fny-CMV) that will direct synthesis from exogenously added templates. Using this replicase, we demonstrate that the SLC-like structure in Fny-CMV plays a role similar to that of BMV SLC in interacting with the CMV replicase. While the majority of CMV isolates have SLC-like elements similar to that of Fny-CMV, a second group displays sequence or structural features that are distinct but nonetheless recognized by Fny-CMV replicase for RNA synthesis. Both motifs have a 5'CA3' dinucleotide that is invariant in the CMV isolates examined, and mutational analysis indicates that these are critical for interaction with the replicase. In the context of the entire tRNA-like element, both CMV SLC-like motifs are recognized by the BMV replicase. However, neither motif can direct synthesis by the BMV replicase in the absence of other tRNA-like elements, indicating that other features of the CMV tRNA can induce promoter recognition by a heterologous replicase.


Disseminating context-specific access to online knowledge resources within electronic health record systems.
Clinicians' patient care information needs are frequent and largely unmet. Online knowledge resources are available that can help clinicians meet these information needs. Yet, significant barriers limit the use of these resources within the clinical workflow. Infobuttons are clinical decision support tools that use the clinical context (e.g., institution, user, patient) within electronic health record (EHR) systems to anticipate clinicians' questions and provide automated links to relevant information in knowledge resources. This paper describes OpenInfobutton (www.openinfobutton.org): a standards-based, open source Web service that was designed to disseminate infobutton capabilities in multiple EHR systems and healthcare organizations. OpenInfobutton has been successfully integrated with 38 knowledge resources at 5 large healthcare organizations in the United States. We describe the OpenInfobutton architecture, knowledge resource integration, and experiences at five large healthcare organizations.


Sorption and desorption behavior of tributyltin with natural sediments.
Tributyltin (TBT) sorption to four natural sediment samples in artificial seawater was examined under a range of modified pH and salinity conditions. Three of the sediment samples were relatively pristine with regard to TBT contamination, but the fourth was a TBT-contaminated sediment from a commercial marina. Sorption of TBT was described well by linear sorption isotherms, with distribution coefficients ranging from 6.1 to 5210 L/kg depending on the pH and salinity. The sediment organic C content and particle size distribution were important determinants of sorption behavior. The presence of resident TBT in the contaminated marina sediment caused a substantial reduction in further TBT sorption. Desorption of TBT from the marina sediment was described by relatively large observed distribution coefficients ranging from 5100 to 9400 L/kg, suggesting that aging effects may reduce sorption reversibility. Increased artificial seawater salinity generally reduced TBT sorption at pH 4 and 6, but enhanced TBT sorption at pH 8. Regardless of salinity, maximum sorption of TBT was observed at pH 6, which is attributed to an optimal balance between the abundance of cationic TBT+ species and deprotonated surface ligands. Consideration of aqueous TBT speciation along with octanol-water partitioning behavior suggests that hydrophobic partitioning of TBTCl(0) to nonpolar organic matter was important for pH < 6, while partitioning of TBTOH(0) was important at higher pH.


The role of adrenergic receptors in the initiation of vomiting and its gastrointestinal motor correlates.
We investigated the role of adrenergic receptors in the mechanisms of initiation of vomiting and its gastrointestinal (GI) motor correlates. The effects of clonidine, UK-14304, St-91, naphazoline, phenylephrine and isoproterenol were examined for their ability to initiate vomiting and its GI motor correlates. Only the alpha-2 adrenoceptor agonists UK-14304, clonidine, St-91 and naphazoline activated vomiting and its GI motor correlates. Tolerance of vomiting, but not its GI motor correlates, readily developed to all alpha-2 adrenergic receptor agonists but St-91. The responses to UK-14304 or clonidine were blocked by idazoxan, yohimbine, clonidine tolerance or high doses of phenoxybenzamine, but not by propranolol or prazosin. The responses to UK-14304 or clonidine were also blocked by fentanyl, 1-(1-naphthyl) piperazine, methysergide, SCH 22390 or scopolamine, but not by haloperidol, sulpiride, domperidone or naloxone. Adrenoceptor antagonists, clonidine tolerance or sympathetic blockade did not block vomiting or its GI motor correlates activated by apomorphine, CuSO4 or cholecystokinin-octapeptide. We concluded that alpha-2 adrenergic receptors of the chemoreceptive trigger zone can initiate vomiting and its GI motor correlates, but these receptors do not mediate vomiting induced by another chemoreceptive trigger zone stimulant, apomorphine, or stimulation of the GI tract using CuSO4. However, 5-hydroxytryptamine-2 serotonergic, muscarinic cholinergic and opiate receptors within the central nervous system participate in controlling emesis activated by alpha-2 adrenergic agonists. Peripheral adrenergic receptors do not mediate the GI motor correlates of vomiting.


Metabolic activation of phenol by human myeloperoxidase and horseradish peroxidase.
The oxidation of phenol catalyzed by human myeloperoxidase and horseradish peroxidase resulted in extensive binding of phenol-derived metabolites to boiled rat liver protein. This binding paralleled closely the removal of phenol from the incubations and was inhibited from 83 to 99% by the addition of the antioxidants, ascorbate and glutathione, suggesting that metabolism and binding were occurring via a one-electron oxidation pathway. Metabolic studies employing both human myeloperoxidase and horseradish peroxidase resulted in the identification of 4,4'-biphenol and diphenoquinone as the principal identifiable metabolites. The addition of reduced glutathione to incubations containing horseradish peroxidase resulted in the formation of two conjugate species. These conjugate species were identified by fast atom bombardment mass spectrometry to be glutathione conjugates of diphenoquinone. The major gluthathione conjugate was identified as 3-(glutathion-S-yl)-4,4'-biphenol by NMR spectroscopy. These results suggest that the formation of highly reactive species through the peroxidase-mediated metabolism of phenol and other phenolic compounds could play an important role in the hematopoietic toxicity observed during chronic benzene exposure.


Psychometric properties of the OLQ-13 scale to measure Sense of Coherence in a community-dwelling older population.
With the ongoing demographic shift, the quality of life and health promotion among older individuals are becoming increasingly important. Recent research suggests that Sense of Coherence positively affects quality of life. Hence, a valid and reliable measurement of Sense of Coherence is pivotal. The 13-item Orientation to Life Questionnaire (OLQ-13) can be used to measure Sense of Coherence. The purpose of the present study is to assess the psychometric properties, validity, and reliability, of the OLQ-13 in community-dwelling individuals, aged 65 and older. The OLQ-13 scale was administered as part of a healthy aging project for non-institutionalized people aged 65 years and older. Internal consistency and reliability were assessed by means of inter-item and test-halves correlations and Cronbach's alpha. Construct validity was explored using cluster analysis and exploratory factor analysis (n = 703) and tested using confirmatory factor analysis on a separate subset of individuals (n = 658). Item face validity was investigated by means of 12 semi-structured interviews. The reliability and the validity of the OLQ-13 in this population of non-institutionalized individuals aged 65 years and older was ambiguous, at least partly due to the poor performance of two items (b and d), which was confirmed by results from the qualitative part of this study. The psychometric properties of the proposed OLQ-11, obtained by deleting the two items, were better. In particular, the interpretation of exploratory factor solution improved. Whereas the underlying theoretical constructs could not be linked to the exploratory analyses of OLQ-13, this was to some extent possible in OLQ-11. The superior validity of OLQ-11 over OLQ-13 was supported by the better model fit in the confirmatory factor analysis. The present mixed-method study suggests the proposed OLQ-11 as a more suitable instrument for measuring Sense of Coherence than the OLQ-13 in a population of ageing individuals. This study confirms that the validity and reliability of OLQ-13 may differ substantially in different populations.


Molecular signatures of liver dysfunction are distinct in fungal and bacterial infections in mice.
Rationale: The liver is a central organ not only for metabolism but also immune function. Life-threatening infections of both bacterial and fungal origin can affect liver function but it is yet unknown whether molecular changes differ depending on the pathogen. We aimed to determine whether the hepatic host response to bacterial and fungal infections differs in terms of hepatic metabolism and liver function. Methods: We compared murine models of infection, including bacterial peritoneal contamination and infection (PCI), intraperitoneal and systemic C. albicans infection, at 6 and 24 h post-infection, to sham controls. The molecular hepatic host response was investigated by the detection of regulatory modules based on large-scale protein-protein interaction networks and expression data. Topological analysis of these regulatory modules was used to reveal infection-specific biological processes and molecular mechanisms. Intravital microscopy and immunofluorescence microscopy were used to further analyze specific aspects of pathophysiology such as cholestasis. Results: Down-regulation of lipid catabolism and bile acid synthesis was observed after 6 h in all infection groups. Alterations in lipid catabolism were characterized by accumulation of long chain acylcarnitines and defective beta-oxidation, which affected metabolism by 6 h. While PCI led to an accumulation of unconjugated bile acids (BA), C. albicans infection caused accumulation of conjugated BA independent of the route of infection. Hepatic dye clearance and transporter expression revealed reduced hepatic uptake in fungal infections vs. defects in secretion following polybacterial infection. Conclusion: Molecular phenotypes of lipid accumulation and cholestasis allow differentiation between pathogens as well as routes of infection at early stages in mice. Targeted metabolomics could be a useful tool for the profiling of infected/septic patients and the type of pathogen, with subsequent customization and targeting of therapy.


An overview of methods for calculating the burden of disease due to specific risk factors.
There are a number of measures that quantify the public health burden due to specific risk factors for specific diseases. Although these measures are of importance for policymakers, epidemiologists do not often calculate them or may be unfamiliar with some of the issues involved when they do. The primary measure of interest is the attributable fraction (AF), representing the fraction of cases or deaths from a specific disease that would not have occurred in the absence of exposure to a specific risk factor either in the exposed population or the population as a whole. AFs can be multiplied by the total number of cases of a given disease to obtain a "body count"--the absolute number of preventable cases due to a specific risk factor. Two other measures of public health burden, used in conjunction with AFs, are attributable years-of-life-lost and attributable disability-adjusted life-years. We provide an overview of the AF and related measures and discuss some of the specific issues involved in calculating AFs. These issues include calculating the variance of AFs (such as Monte Carlo sensitivity methods), biases arising from some formulas for the AF, sources of data for calculating AFs, dependence of AFs on basic decisions about what exposure-disease associations are causal, and extrapolation from the source population to the target population.