Nonrandom distribution of Burkholderia pseudomallei clones in relation to geographical location and virulence.
Burkholderia pseudomallei is a soil-dwelling saprophyte and the causative agent of melioidosis, a life-threatening human infection. Most cases are reported from northeast Thailand and northern Australia. Using multilocus sequence typing (MLST), we have compared (i) soil and invasive isolates from northeast Thailand and (ii) invasive isolates from Thailand and Australia. A total of 266 Thai B. pseudomallei isolates were characterized (83 soil and 183 invasive). These corresponded to 123 sequence types (STs), the most abundant being ST70 (n=21), ST167 (n=15), ST54 (n=12), and ST58 (n=11). Two clusters of related STs (clonal complexes) were identified; the larger clonal complex (CC48) did not conform to a simple pattern of radial expansion from an assumed ancestor, while a second (CC70) corresponded to a simple radial expansion from ST70. Despite the large number of STs, overall nucleotide diversity was low. Of the Thai isolates, those isolated from patients with melioidosis were overrepresented in the 10 largest clones (P<0.0001). There was a significant difference in the classification index between environmental and disease isolates (P<0.001), confirming that genotypes were not distributed randomly between the two samples. MLST profiles for 158 isolates from Australia (mainly disease associated) contained a number of STs (96) similar to that seen with the Thai invasive isolates, but no ST was found in both populations. There were also differences in diversity and allele frequency distribution between the two populations. This analysis reveals strong genetic differentiation on the basis of geographical isolation and a significant differentiation on the basis of virulence potential.


Dynamic expression of tRNA-derived small RNAs define cellular states.
Transfer RNA (tRNA)-derived small RNAs (tsRNAs) have recently emerged as important regulators of protein translation and shown to have diverse biological functions. However, the underlying cellular and molecular mechanisms of tsRNA function in the context of dynamic cell-state transitions remain unclear. Expression analysis of tsRNAs in distinct heterologous cell and tissue models of stem vs. differentiated states revealed a differentiation-dependent enrichment of 5'-tsRNAs. We report the identification of a set of 5'-tsRNAs that is upregulated in differentiating mouse embryonic stem cells (mESCs). Notably, interactome studies with differentially enriched 5'-tsRNAs revealed a switch in their association with "effector" RNPs and "target" mRNAs in different cell states. We demonstrate that specific 5'-tsRNAs can preferentially interact with the RNA-binding protein, Igf2bp1, in the RA-induced differentiated state. This association influences the transcript stability and thereby translation of the pluripotency-promoting factor, c-Myc, thus providing a mechanistic basis for how 5'-tsRNAs can modulate stem cell states in mESCs. Together our study highlights the role of 5'-tsRNAs in defining distinct cell states.


A mobile/web app for long distance caregivers of older adults: functional requirements and design implications from a user centered design process.
Recent trends of population aging and globalization have required an increasing number of individuals to act as long distance caregivers (LDCs) to aging family members. Information technology solutions may ease the burden placed on LDCs by providing remote monitoring, easier access to information and enhanced communication. While some technology tools have been introduced, the information and technology needs of LDCs in particular are not well understood. Consequently, a needs assessment was performed by using video conferencing software to conduct semi-structured interviews with 10 LDCs. Interviews were enriched through the use of stimulus materials that included the demonstration of a prototype LDC health management web/mobile app. Responses were recorded, transcribed and then analyzed. Subjects indicated that information regarding medication regimens and adherence, calendaring, and cognitive health were most needed. Participants also described needs for video calling, activity data regarding sleep and physical exercise, asynchronous communication, photo sharing, journaling, access to online health resources, real-time monitoring, an overall summary of health, and feedback/suggestions to help them improve as caregivers. In addition, all respondents estimated their usage of a LDC health management website would be at least once per week, with half indicating a desire to access the website from a smartphone. These findings are being used to inform the design of a LDC health management website to promote the meaningful involvement of distant family members in the care of older adults.


Biochemical, genetic, and epidemiologic characterization of Haemophilus influenzae biogroup aegyptius (Haemophilus aegyptius) strains associated with Brazilian purpuric fever.
Brazilian purpuric fever (BPF) is a recently recognized fulminant pediatric disease characterized by fever, with rapid progression to purpura, hypotensive shock, and death. BPF is usually preceded by purulent conjunctivitis that has resolved before the onset of fever. Both the conjunctivitis and BPF are caused by Haemophilus influenzae biogroup aegyptius (formerly called H. aegyptius). Isolates from 15 BPF cases, mainly from blood or hemorrhagic cerebrospinal fluid, case-associated isolates from 42 persons in towns where BPF cases occurred, and control strains from 32 persons in towns without BPF cases were characterized biochemically, genetically, and epidemiologically. Results indicated that a single clone was responsible for all BPF cases identified in six Brazilian towns from 1984 through 1986. All of 15 (100%) case strains were the same clone as was 1 of 32 (3%) control strains (P = less than 10(-8). Isolates of the clone were preferentially intrarelated by DNA hybridization (99% relatedness, hydroxyapatite method at 60 and 75 degrees C) and were separable from other H. influenzae biogroup aegyptius strains (approximately 90% relatedness at 60 degrees C and 82% relatedness at 75 degrees C). All isolates of the BPF clone and no other strains contained a 24-megadalton plasmid of restriction endonuclease type 3031, were of a single multilocus enzyme mobility type, were of a single sodium dodecyl sulfate-polyacrylamide gel electrophoresis type, and were in one of two ribosomal DNA restriction patterns. All BPF clone isolates reacted with monoclonal antibodies produced from a case strain; only 3 of 62 (5%) other strains reacted with this monoclonal antibody. Ninety percent of BPF clone strains and 27% of other strains were relatively resistant to sulfamethoxazole-trimethoprim.


Perspectives on HIV Pre- and Post-Exposure Prophylaxes (PrEP and PEP) Among Female and Male Sex Workers in Mombasa, Kenya: Implications for Integrating Biomedical Prevention into Sexual Health Services.
Pre- and post-exposure prophylaxes (PrEP and PEP) can reduce the risk of HIV acquisition, yet often are inaccessible to and underutilized by most-vulnerable populations, including sex workers in sub-Saharan Africa. Based on in-depth interviews with 21 female and 23 male HIV-negative sex workers in Mombasa, Kenya, we found that awareness and knowledge of PrEP and PEP were low, although willingness to use both was high. Participants felt PrEP would be empowering and give added protection against infection, although some expressed concerns about side effects. Despite PEP's availability, few knew about it and even fewer had used it, but most who had would use it again. Sex workers valued confidentiality, privacy, trustworthiness, and convenient location in health services and wanted thorough HIV/STI assessments. These findings suggest the importance of situating PrEP and PEP within sex worker-friendly health services and conducting outreach to promote these biomedical prevention methods for Kenyan sex workers.


Cerebrospinal Fluid Ceruloplasmin, Haptoglobin, and Vascular Endothelial Growth Factor Are Associated with Neurocognitive Impairment in Adults with HIV Infection.
Dysregulated iron transport and a compromised blood-brain barrier are implicated in HIV-associated neurocognitive disorders (HAND). We quantified the levels of proteins involved in iron transport and/or angiogenesis-ceruloplasmin, haptoglobin, and vascular endothelial growth factor (VEGF)-as well as biomarkers of neuroinflammation, in cerebrospinal fluid (CSF) from 405 individuals with HIV infection and comprehensive neuropsychiatric assessments. Associations with HAND [defined by a Global Deficit Score (GDS) ≥ 0.5, GDS as a continuous measure (cGDS), or by Frascati criteria] were evaluated for the highest versus lowest tertile of each biomarker, adjusting for potential confounders. Higher CSF VEGF was associated with GDS-defined impairment [odds ratio (OR) 2.17, p = 0.006] and cGDS in unadjusted analyses and remained associated with GDS impairment after adjustment (p = 0.018). GDS impairment was also associated with higher CSF ceruloplasmin (p = 0.047) and with higher ceruloplasmin and haptoglobin in persons with minimal comorbidities (ORs 2.37 and 2.13, respectively; both p = 0.043). In persons with minimal comorbidities, higher ceruloplasmin and haptoglobin were associated with HAND by Frascati criteria (both p < 0.05), and higher ceruloplasmin predicted worse impairment (higher cGDS values, p < 0.01). In the subgroup with undetectable viral load and minimal comorbidity, CSF ceruloplasmin and haptoglobin were strongly associated with GDS impairment (ORs 5.57 and 2.96, respectively; both p < 0.01) and HAND (both p < 0.01). Concurrently measured CSF IL-6 and TNF-α were only weakly correlated to these three biomarkers. Higher CSF ceruloplasmin, haptoglobin, and VEGF are associated with a significantly greater likelihood of HAND, suggesting that interventions aimed at disordered iron transport and angiogenesis may be beneficial in this disorder.


E-learning to Improve Healthcare Professionals' Attitudes and Practices on Breastfeeding.
Breastfeeding training has a crucial role in increasing healthcare professionals' attitudes and in improving professional support for breastfeeding. The collaboration between the Italian National Institute of Health, UNICEF, and the Local Health Authority of Milan has led to the development of an online course on lactation and infant feeding practices. To assess if the course was effective in improving healthcare professionals' attitudes and practices (APs). We conducted a prestudy-poststudy, comparing users' APs before (T0) and after (T1) the course through a 20-item questionnaire. Changes in APs were analyzed using paired t-test. Lower mean differences indicated more positive attitudes and more frequent professional practices favoring breastfeeding. Statistical analysis was carried out using SPSS version 15.0. The course had 26,009 registrants and was successfully completed by 91.3% of users. The dropout rate was 8.7%. The final cohort was composed of 15,004 participants. The course improved attitudes, while minor changes were observed on practices (p < 0.05). Mean total attitude scores were 2.4 at T0 and 1.9 at T1, while mean total practice scores were 2.2 and 2.1, respectively. The main effects regarded the use of medications during breastfeeding (3.02 ± 1.29 at T0 and 1.88 ± 1.08 at T1) and the self-reported compliance with the International Code of Marketing of Breast Milk Substitutes (2.29 ± 1.24 at T0, 2.03 ± 1.21 at T1). The noninteractive, high-coverage e-learning approach seems to be a useful tool for improving awareness and positive attitudes toward breastfeeding among healthcare professionals.


Birth weight, stress, and the metabolic syndrome in adult life.
There is now widespread agreement that small size at birth is associated with an increased risk of the metabolic syndrome (glucose intolerance, high blood pressure, and dyslipidemia) and related pathologies, including cardiovascular disease in later life. Evidence is emerging that suggests that programming of hormonal systems in response to an adverse fetal environment may be one of the mechanisms underlying these long-term consequences of growth restriction in early life. In particular, alterations in neuroendocrine responses to stress may be important. Recent research suggests that increased adrenocortical and sympathoadrenal responses are associated with small size at birth. Epidemiological studies show that such physiological alterations in these neuroendocrine systems may have potent effects on risk of cardiovascular disease through their influence on risk factors, such as plasma glucose and lipid concentrations and blood pressure.


Predicting Wolbachia potential to knock down dengue virus transmission.
Releasing mosquitoes infected with the intracellular bacteria Wolbachia is a candidate strategy for dengue control that has recently advanced to field-testing. A critical next step is to evaluate the impact of this strategy on dengue epidemiology. A recent study by Ferguson and colleagues presents a mathematical framework to predict the likely effect of mosquitoes carrying Wolbachia on dengue virus transmission. Fitting the mathematical model to empirical data obtained with Wolbachia-infected mosquitoes experimentally challenged with viremic blood from dengue patients indicates that dengue virus transmission could be reduced by a degree that would have a significant impact on public health.


Pulse distortion in single-mode fibers. 3: Chirped pulses.
The theory of pulse distortion in single-mode fibers is extended to include laser sources that suffer a linear wavelength sweep (chirp) during the duration of the pulse. The transmitted pulse is expressed as a Fourier integral whose spectral function is given by an analytical expression in closed form. The rms width of the transmitted pulse is also expressed in closed form. Numerical examples illustrate the influence of the chirp on the shape and rms width of the pulse. A somewhat paradoxical situation exists. A given input pulse can be made arbitrarily short by a sufficiently large amount of chirping, and, after a given fiber length, this chirped pulse returns to its original width. But at this particular distance an unchirped pulse would be only [equiation] times longer. Thus chirping can improve the rate of data transmission by only 40%.


Epidemiology of vertigo.
Epidemiological findings on the distribution, determinants and outcome of vertigo can be used for clinical decision making and can help understand the underlying causes of vestibular diseases. This article gives an overview of the epidemiology of the vestibular symptom vertigo and of four specific vestibular disorders: benign paroxysmal positional vertigo, migrainous vertigo, Menière's disease and vestibular neuritis. Based on a neurotologic survey of the general population, 1-year prevalence estimates for vertigo were 4.9%, for migrainous vertigo 0.89% and for benign paroxysmal positional vertigo 1.6%. Diagnostic positional manoeuvres and treatments for benign paroxysmal positional vertigo, however, are still not being done by most doctors. The female preponderance among patients with benign paroxysmal positional vertigo and migrainous vertigo may be linked to migraine but is not fully understood. A recently reported prevalence of Menière's disease of 0.51% is much higher than previous estimates. Follow-up studies have shown benign paroxysmal positional vertigo recurrence rates of 50% at 5 years and a persistence of dizziness related to anxiety in almost a third of patients 1 year after vestibular neuritis. The epidemiology of vertigo and vestibular disorders is still an underdeveloped field. Recent studies have underscored the impact of vertigo at the population level, but its determinants and outcome are not well known yet.


Secretion and Endocytosis in Pollen Tubes: Models of Tip Growth in the Spot Light.
Pollen tube tip growth is a widely used model ideally suited to study cellular processes underlying polarized cell expansion. Local secretion supplying material for plasma membrane (PM) and cell wall extension is essential for this process. Cell wall biogenesis requires fusion of secretory vesicles with the PM at an about 10× higher rate than PM extension. Excess material is therefore incorporated into the PM, which needs to be reinternalized through endocytosis. The classical model of tip growth proposes that exocytosis occurs at the apex and that newly incorporated PM material is transported to adjacent lateral regions, where excess material is endocytically recycled. This model was recently challenged based on studies indicating that lateral exocytosis may be balanced by apical endocytosis. This review provides an overview of published data pertaining to exocytosis, endocytosis and vesicular trafficking in pollen tubes. Its key aim is to present classical and alternative models of tip growth in the light of available experimental data. By necessity, the review focusses on pollen tubes of angiosperm models (Nicotiana tabacum, Arabidopsis, Lilium longiflorum), which have been studied far more extensively and grow much faster than structurally strikingly different gymnosperm pollen tubes. Only major transport pathways are considered, which substantially contribute to the mass-flow of membrane material at the pollen tube tip. Growth oscillation, which may be displayed in particular by fast-growing pollen tubes, are not discussed as their influence on the spatial organization of apical membrane traffic is not understood.


Long non-coding RNA regulation of liver cancer stem cell self-renewal offers new therapeutic targeting opportunities.
Long non-coding RNAs (lncRNA) are critical regulators of gene expression, and can reprogram the transcriptome to modulate cellular processes involved in cellular growth and differentiation, and thereby contribute to tumorigenesis. In addition to effects on tumor cell growth, survival and cell signaling, lncRNA can modulate cancer stem cell (CSC) behavior, including the expression of pluripotency factors. The identification of lncRNA that are mechanistically linked to cancer stem cell self-renewal and differentiation, or aberrant signaling pathways associated with tumor growth or progression, offer new opportunities for therapeutic intervention.


Factorial structure of a short version of the Center for Epidemiologic Studies Depression Scale.
To investigate the factor structure of a ten-item version of the Center for Epidemiologic Studies Depression Scale (CESD-10). Two hundred and thirty-one Chinese persons aged 60-92 were individually interviewed with the CESD-10. The data were subject to confirmatory factor analysis testing several competing models. The one-factor model hypothesizes that all ten items are loaded on a single factor. In the two-factor model, positive affect items are loaded on one factor, and the remaining items on the other. The three-factor model distinguishes between positive affect, depressed affect, and somatic symptoms. The three-factor model was the best fitting model, with a comparative fit index of 0.95 and a standardized root mean square residual of 0.06. Depressed affect and somatic symptoms were highly correlated, and both were moderately correlated with positive affect. Nonetheless, all three factors appeared to tap a common underlying construct of depression-when a higher-order construct of depression was allowed to explain the intercorrelations of the three factors, depressed affect loaded at 0.88, somatic symptoms loaded at 0.92, and positive affect loaded at 0.51, on the higher-order construct. The data provided support for the factorial validity of the CESD-10.


An ER protein functionally couples neutral lipid metabolism on lipid droplets to membrane lipid synthesis in the ER.
Eukaryotic cells store neutral lipids such as triacylglycerol (TAG) in lipid droplets (LDs). Here, we have addressed how LDs are functionally linked to the endoplasmic reticulum (ER). We show that, in S. cerevisiae, LD growth is sustained by LD-localized enzymes. When LDs grow in early stationary phase, the diacylglycerol acyl-transferase Dga1p moves from the ER to LDs and is responsible for all TAG synthesis from diacylglycerol (DAG). During LD breakdown in early exponential phase, an ER membrane protein (Ice2p) facilitates TAG utilization for membrane-lipid synthesis. Ice2p has a cytosolic domain with affinity for LDs and is required for the efficient utilization of LD-derived DAG in the ER. Ice2p breaks a futile cycle on LDs between TAG degradation and synthesis, promoting the rapid relocalization of Dga1p to the ER. Our results show that Ice2p functionally links LDs with the ER and explain how cells switch neutral lipid metabolism from storage to consumption.


The postoperative analgesic effect of morphine and paracetamol in the patients undergoing laparotomy, using PCA method.
postoperative pain increases the activity of the sympathetic system, causes hypermetabolic conditions, retains salt and water, increases glucose, fatty acid lactate and oxygen consumption, weakens the immunity system which delays wound healing. Our object was comparison of the analgesic effect of morphine and paracetamol in the patients undergoing laparotomy, using PCA method. Seventy patients who had undergone laparotomy were studied using double blind randomized clinical trial (35 patients received morphine and 35 paracetamol) in the Shahid Rajaee Center and Velayat Hospital (Qazvin, Iran). People using opioids, painkillers and sedatives regularly and in large doses and patients with a history of lung or liver problems did not participate in this project. The parameters of the severity of pain and nausea (VAS), hemodynamic changes (BP and HR), pruritus, arterial oxygen desaturation and patient satisfaction (VAS) of both groups were measured by a third party (trained colleague). The data was analyzed using SPSS 16 statistical software then descriptive results were extracted and ultimately the groups were compared using the following statistical tests: student's T-test, chi 2 and Fisher's exact test (P<0.05). The mean age of the participants was 45±12.5 years. Women constituted 24.3% of the patients and men 75.7%. The average pain severity for morphine and paracetamol groups (VAS) was 5.3±2.2and 6.37±1.7 after2 hours and reached 1.91±1.3 and 2.49±1.3 after 8 hours (after the operation) respectively. There was a significant difference between the groups after 2 and 4 hours in terms of pain severity (after 2 hours P=0.007 and after 4 hours P=0.047). However there was no significant difference between the average pain severity of the studied groups (after 6 hours P=0.4 and 8 hours P=0.08). After 8 hours, the average nausea severity was the minimum in both groups being 1.71±1.6 and 1.43±1.1 in morphine and paracetamol groups respectively. Nausea severity was higher after 2 hours in paracetamol group. In morphine group, it was higher after 4, 6 and 8 hours. Difference between the groups was not significant. The average satisfaction level (VAS) for morphine and paracetamol groups reached from 5.29±2.3 and 4.2±2.4 after 2 hours, to 7.94±1.8 and 7.69±2.1 after 8 hours (after the operation), respectively. The average satisfaction level of patients was higher in morphine group in 2,4,6 and 8 hours and except for, after 4 hours (P=0.01), the satisfaction difference between both groups was not significant in other hours (P=0.06 after 2 hours, P=0.6 after 6 hours and P=0.5 after 8 hours) Morphine seems to be more effective at 2 and 4 hours, but after 4 hours they have similar effects, the satisfaction difference between both groups was not significant in the patients.


Thermodynamics of triple helix formation: spectrophotometric studies on the d(A)10.2d(T)10 and d(C+3T4C+3).d(G3A4G3).d(C3T4C3) triple helices.
We have stabilized the d(A)10.2d(T)10 and d(C+LT4C+3).d(G3A4G3).d(C3T4C3) triple helices with either NaCl or MgCl2 at pH 5.5. UV mixing curves demonstrate a 1:2 stoichiometry of purine to pyrimidine strands under the appropriate conditions of pH and ionic strength. Circular dichroic titrations suggest a possible sequence-independent spectral signature for triplex formation. Thermal denaturation profiles indicate the initial loss of the third strand followed by dissociation of the underlying duplex with increasing temperature. Depending on the base sequence and ionic conditions, the binding affinity of the third strand for the duplex at 25 degrees C is two to five orders of magnitude lower than that of the two strands forming the duplex. Thermodynamic parameters for triplex formation were determined for both sequences in the presence of 50 mM MgCl2 and/or 2.0 M NaCl. Hoogsteen base pairs are 0.22-0.64 kcal/mole less stable than Watson-Crick base pairs, depending on ionic conditions and base composition. C+.G and T.A Hoogsteen base pairs appear to have similar stability in the presence of Mg2+ ions at low pH.


Syrian Civil-War-Related Intraocular Foreign Body Injuries: A Four-Year Retrospective Analysis.
To analyze the data of patients who underwent vitreoretinal surgery due to intraocular foreign body (IOFB) injuries that occurred in the Syrian civil war. Seventy-eight eyes of 78 patients who underwent vitreoretinal surgery due to IOFB injuries that occurred during the Syrian civil war were analyzed. Forty-four eyes (56.4%) had traumatic cataract, 44 (56.4%) had retinal tears, 42 (53.8%) had vitreous hemorrhage, 18 (23%) had retinal detachment, 12 (15.3%) had endophthalmitis, and eight eyes had hyphema (10.2%). IOFBs consisted of metal in 62 eyes (79.4%), stone in eight eyes (10.2%), organic material in four eyes (5.1%), and glass in four eyes (5.1%). Approximately 86% of the eyes had initial VAs of 4/200 or worse. However, VAs improved in 64 eyes (82%) after the surgeries. Despite delays in treatment and the severity of injuries, 82% (64/78) of the eyes had an improvement in VA after the surgeries.


Multiple sclerosis increases the risk of venous thromboembolism: a nationwide cohort analysis.
The purpose of this study was to evaluate the effects of multiple sclerosis (MS) on the risk of venous thromboembolism (VTE) development. We identified patients diagnosed with MS in Taiwan between 1998 and 2010 using the National Health Insurance Research Database and the Catastrophic Illness Patient Database (RCIPD). Each MS patient was frequency matched to 4 controls according to age, sex and the year of MS registration to the RCIPD. Patients with a history of VTE and incomplete information of age and sex were excluded. All patients were followed up from the index year until VTE diagnosis, loss to follow-up or the end of 2010. We calculated the hazard ratios (HRs) and 95% confidence intervals (CIs) of VTE in the MS and comparison cohorts using Cox proportional hazards regression models. We followed up 1238 MS patients and 4952 comparison patients for approximately 6437 and 27 595 person-years, respectively. After adjusting for age, sex and comorbidities, the MS patients exhibited a 6·87-fold increased risk of VTE compared with the control patients. Women with MS were associated with an 11·1-fold increased risk of VTE development compared with the non-MS women (95% CI: 2·70-45·5). The MS patients aged < 50 years exhibited a 14·8-fold increased risk of developing VTE compared with age-matched patients in the comparison cohort (95% CI: 2·99-73·4). The risk of VTE development increased with the duration of hospitalization stay. MS patients are associated with significantly greater risk of developing VTE compared with non-MS patients.


Updated UK Recommendations for HER2 assessment in breast cancer.
Human epidermal growth factor receptor 2 (HER2) overexpression is present in approximately 15% of early invasive breast cancers, and is an important predictive and prognostic marker. The substantial benefits achieved with anti-HER2 targeted therapies in patients with HER2-positive breast cancer have emphasised the need for accurate assessment of HER2 status. Current data indicate that HER2 test accuracy improved following previous publication of guidelines and the implementation of an external quality assessment scheme with a decline in false-positive and false-negative rates. This paper provides an update of the guidelines for HER2 testing in the UK. The aim is to further improve the analytical validity and clinical utility of HER2 testing by providing guidelines of test performance parameters, and recommendations on the postanalytical interpretation of test results. HER2 status should be determined in all newly diagnosed and recurrent breast cancers. Testing involves immunohistochemistry with >10% complete strong membrane staining defining a positive status. In situ hybridisation, either fluorescent or bright field chromogenic, is used either upfront or in immunohistochemistry borderline cases to detect the presence of HER2 gene amplification. Situations where repeat HER2 testing is advised are outlined and the impact of genetic heterogeneity is discussed. Strict quality control and external quality assurance of validated assays are essential. Testing laboratories should perform ongoing competency assessment and proficiency tests and ensure the reliability and accuracy of the assay. Pathologists, oncologists and surgeons involved in test interpretation and clinical use should adhere to published guidelines and maintain accurate performance and consistent interpretation of test results.


Increasing independence in autism spectrum disorders: a review of three focused interventions.
The features of autism that inhibit the independent demonstration of skills, as well as three effective interventions for increasing independence, are explored in this review article. Independent performance may prove difficult for individuals with autism spectrum disorders (ASD) due to the core deficits of the disability, as well as executive function deficits that impact initiation and generalization. These difficulties, coupled with intervention strategies that encourage over-reliance on adult support, contribute to poor long term outcomes for adults with ASD in employment, housing, and relationship development. Self-monitoring, video modeling, and individual work systems each emphasize a shift in stimulus control from continuous adult management to an alternative stimulus and have proven successful in addressing executive function deficits and increasing independence.


Yoga for low back pain: a systematic review of randomized clinical trials.
It has been suggested that yoga has a positive effect on low back pain and function. The objective of this systematic review was to assess the effectiveness of yoga as a treatment option for low back pain. Seven databases were searched from their inception to March 2011. Randomized clinical trials were considered if they investigated yoga in patients with low back pain and if they assessed pain as an outcome measure. The selection of studies, data extraction and validation were performed independently by two reviewers. Seven randomized controlled clinical trials (RCTs) met the inclusion criteria. Their methodological quality ranged between 2 and 4 on the Jadad scale. Five RCTs suggested that yoga leads to a significantly greater reduction in low back pain than usual care, education or conventional therapeutic exercises. Two RCTs showed no between-group differences. It is concluded that yoga has the potential to alleviate low back pain. However, any definitive claims should be treated with caution.


A 10-year follow-up study on suicidal mortality after 1999 Taiwan earthquake.
The long-term impact of natural disasters on suicide in general population and survivors remains uncertain. The present report examined the direction and the length of the influence of an earthquake over suicide across age groups. We used an interrupted time-series design with non-equivalent no-treatment group to evaluate post-earthquake changes in suicide rates by the standardized mortality ratio. The time trend changes in suicide rates before and after the earthquake were similar for males and females but different between senior and junior age groups. Gender-specific relative ratios were 0.85 (95%CI: 0.81-0.90) for males and 0.79 (95% CI: 0.72-0.86) for females. Age-gender-stratified relative ratios were 0.61 (95% CI: 0.53-0.70) and 0.69 (95% CI: 0.64-0.75) for males and females aged less than 45 years, respectively. Although the overall suicide mortality increased after the earthquake, the relative suicide risk ratio decreased 31-39% for those aged less than 45 years, which persisted for nearly 10 years after earthquake. Our study demonstrated that a severe earthquake resulted in a significant decrease in standardized suicide mortality ratios in exposed areas for 10 years compared to unexposed area, particularly in a younger population.


Molecular barcoding of aquatic oligochaetes: implications for biomonitoring.
Aquatic oligochaetes are well recognized bioindicators of quality of sediments and water in watercourses and lakes. However, the difficult taxonomic determination based on morphological features compromises their more common use in eco-diagnostic analyses. To overcome this limitation, we investigated molecular barcodes as identification tool for broad range of taxa of aquatic oligochaetes. We report 185 COI and 52 ITS2 rDNA sequences for specimens collected in Switzerland and belonging to the families Naididae, Lumbriculidae, Enchytraeidae and Lumbricidae. Phylogenetic analyses allowed distinguishing 41 lineages separated by more than 10 % divergence in COI sequences. The lineage distinction was confirmed by Automatic Barcode Gap Discovery (ABGD) method and by ITS2 data. Our results showed that morphological identification underestimates the oligochaete diversity. Only 26 of the lineages could be assigned to morphospecies, of which seven were sequenced for the first time. Several cryptic species were detected within common morphospecies. Many juvenile specimens that could not be assigned morphologically have found their home after genetic analysis. Our study showed that COI barcodes performed very well as species identifiers in aquatic oligochaetes. Their easy amplification and good taxonomic resolution might help promoting aquatic oligochaetes as bioindicators for next generation environmental DNA biomonitoring of aquatic ecosystems.


The kinetics of dimethylhydroxypyridinone interactions with iron(iii) and the catalysis of iron(iii) ligand exchange reactions: implications for bacterial iron transport and combination chelation therapies.
Many microbes acquire environmental Fe by secreting organic chelators, siderophores, which possess the characteristics of a high and specific binding affinity for iron(iii) that results in the formation of thermodynamically stable, and kinetically inert iron(iii) complexes. Mechanisms to overcome the kinetic inertness include the labilization of iron(iii) by means of ternary complex formation with small chelators. This study describes a kinetic investigation of the labilization of iron(iii) between two stable binding sites, the prototypical siderophore ferrioxamine B and EDTA, by the bidentate siderophore mimic, 1,2-dimethyl-3-hydroxy-4-pyridinone (L1, H(DMHP)). The proposed mechanism is substantiated by investigating the iron(iii) exchange reaction between ferrioxamine B and H(DMHP) to form Fe(DMHP)3, as well as the iron(iii) exchange from Fe(DMHP)3 to EDTA. It is also shown that H(DMHP) is a more effective catalyst for the iron(iii) exchange reaction than bidentate hydroxamate chelators reported previously, supporting the hypothesis that chelator structure and iron(iii) affinity influence low denticity ligand facilitated catalysis of iron(iii) exchange reactions. The results are also discussed in the context of the design and use of combination chelator therapies in the treatment of Fe overload in humans.


Purified cardiomyocytes from bone marrow mesenchymal stem cells produce stable intracardiac grafts in mice.
We have previously isolated cardiomyogenic cells from murine bone marrow (CMG cells). Regenerated cardiomyocytes are important candidates for cell transplantation, but as they are stem cell derived, they can be contaminated with various cell types, thereby requiring characterization and purification. Our objectives were to increase the efficiency of cell transplantation and to protect the recipients from possible adverse effects using an efficient and effective purification process as well as to characterize regenerated cardiomyocytes. Noncardiomyocytes were eliminated from a mixture of stem-cell-derived cells using a fluorescence-activated cell sorter to specifically isolate CMG cells transfected with a recombinant plasmid containing enhanced green fluorescent protein (EGFP) cDNA under the control of the myosin light chain-2v (MLC-2v) promoter. Gene expression and the action potential were investigated, and purified cells were transplanted into the heart of adult mice. Six percent to 24% of transfected CMG cells expressed EGFP after differentiation was induced, and a strong EGFP-positive fraction was selected. All the sorted cells began spontaneous beating after 3 weeks. These cells expressed cardiomyocyte-specific genes such as alpha-skeletal actin, beta-myosin heavy chain, MLC-2v, and CaV1.2 and incorporated bromodeoxyuridine for 5 days. The isolated EGFP-positive cells were expanded for 5 days and then transplanted into the left ventricle of adult mouse hearts. The transplanted cells survived for at least 3 months and were oriented in parallel to the cardiomyocytes of the recipient heart. The purification and transplantation of differentiated cardiomyocytes from adult stem cells provides a viable model of tissue engineering for the treatment of heart failure.


Murine lymphokine-activated killer (LAK) cells: phenotypic characterization of the precursor and effector cells.
Murine and human lymphocytes incubated in recombinant interleukin 2 (RIL 2) generate a population of cytotoxic cells (lymphokine-activated killer cells [LAK]), which are able to lyse a wide array of fresh tumor cells but do not lyse fresh normal cells. Intravenous administration of these cells with the concomitant administration of RIL 2 can eliminate established pulmonary and hepatic metastases in mice. To characterize the cell that has in vitro LAK activity, we subdivided murine lymphocytes by lysing select subpopulations with the use of complement and antibodies against lymphocyte surface markers or by fluorescence-activated cell sorting. Thy-1.2-negative splenocytes were found to generate near normal amounts of LAK activity after RIL 2 incubation. Small and inconsistent LAK cell activity was generated from Thy-1.2-positive splenocytes. Ia-positive and surface immunoglobulin-positive splenocytes had little or no LAK precursor capability and did not appear to be necessary for LAK activation. Treatment of splenocytes with anti-asialo GM1 (anti-ASGM1) heterosera and complement markedly decreased their ability to generate LAK activity. At the effector stage, cytotoxic cells were of the Thy-1.2-positive, Ia-negative phenotype. Ia-depleted cells were separated into subpopulations bearing or not bearing the gamma Fc receptor (gamma FcR). The majority of cytotoxicity resided in gamma FcR-positive cells. Thus the precursors of murine LAK cells are "null" lymphocytes bearing neither T nor B cell surface markers but develop the Thy-1.2 cell surface marker in vitro, in association with the development of lytic activity for fresh tumor cells after stimulation by RIL 2.


Gaming control using a wearable and wireless EEG-based brain-computer interface device with novel dry foam-based sensors.
A brain-computer interface (BCI) is a communication system that can help users interact with the outside environment by translating brain signals into machine commands. The use of electroencephalographic (EEG) signals has become the most common approach for a BCI because of their usability and strong reliability. Many EEG-based BCI devices have been developed with traditional wet- or micro-electro-mechanical-system (MEMS)-type EEG sensors. However, those traditional sensors have uncomfortable disadvantage and require conductive gel and skin preparation on the part of the user. Therefore, acquiring the EEG signals in a comfortable and convenient manner is an important factor that should be incorporated into a novel BCI device. In the present study, a wearable, wireless and portable EEG-based BCI device with dry foam-based EEG sensors was developed and was demonstrated using a gaming control application. The dry EEG sensors operated without conductive gel; however, they were able to provide good conductivity and were able to acquire EEG signals effectively by adapting to irregular skin surfaces and by maintaining proper skin-sensor impedance on the forehead site. We have also demonstrated a real-time cognitive stage detection application of gaming control using the proposed portable device. The results of the present study indicate that using this portable EEG-based BCI device to conveniently and effectively control the outside world provides an approach for researching rehabilitation engineering.


Maternal dietary protein deficiency decreases amino acid concentrations in fetal plasma and allantoic fluid of pigs.
This study was conducted to test the hypothesis that maternal dietary protein deficiency decreases amino acid availability to the fetus, thereby contributing to retarded fetal growth. Primiparous gilts selected genetically for low or high plasma total cholesterol concentrations (low line and high line, respectively) were mated, and then fed 1.8 kg/d of isocaloric diets containing 13% or 0.5% crude protein. At d 40 or 60 of gestation, they were hysterectomized, and maternal and fetal blood samples as well as amniotic and allantoic fluids were obtained for analyses of amino acids, ammonia and urea. Dietary protein restriction decreased (P < 0.05) the following: 1) maternal plasma concentrations of urea at d 40 and 60 of gestation; 2) fetal plasma concentrations of alanine, arginine, branched-chain amino acids (BCAA), glutamine, glycine, lysine, ornithine, proline, taurine, threonine and urea at d 60 of gestation; 3) amniotic and allantoic fluid concentrations of urea at d 40 and 60 of gestation; and 4) allantoic fluid concentrations of alanine, arginine, BCAA, citrulline, cystine, glycine, histidine, methionine, proline, serine, taurine, threonine and tyrosine at d 40 of gestation, in gilts of both genetic lines. At d 60 of gestation, protein deficiency decreased (P < 0.05) allantoic fluid concentrations of arginine, cystine, glycine, taurine and tyrosine in low line gilts and of cystine, glutamine, ornithine, serine, taurine and tyrosine in high line gilts. Low line and high line gilts also differed remarkably in allantoic fluid concentrations of arginine, glutamine, ornithine and ammonia at d 40 and 60 of gestation. Our results suggest the following: 1) protein-deficient gilts maintain maternal plasma concentrations of amino acids by mobilizing maternal protein stores and decreasing oxidation of amino acids during the first half of gestation; 2) protein deficiency may impair placental transport of amino acids from the maternal to the fetal blood; and 3) low line and high line gilts differ in fetal amino acid metabolism. Decreases in concentrations of the essential and nonessential amino acids in the fetus may be a mechanism whereby maternal dietary protein restriction results in fetal growth retardation.


Factors associated with the decline in under-five diarrhea mortality in India: a LiST analysis.
India has achieved 86% reduction in the number of under-five diarrheal deaths from 1980 to 2015. Nonetheless diarrhea is still among the leading causes of under-five deaths. The aim of this analysis was to study the contribution of factors that led to decline in diarrheal deaths in the country and the effect of scaling up of intervention packages to address the remaining diarrheal deaths. We assessed the attribution of different factors and intervention packages such as direct diarrhea case management interventions, nutritional factors and WASH interventions which contributed to diarrhea specific under-five mortality reduction (DSMR) during 1980 to 2015 using the Lives Saved Tool (LiST). The potential impact of scaling up different packages of interventions to achieve universal coverage levels by year 2030 on reducing the number of remaining diarrheal deaths were estimated. The major factors associated with DSMR reduction in under-fives during 1980 to 2015, were increase in ORS use, reduction in stunting prevalence, improved sanitation, changes in age appropriate breastfeeding practices, increase in the vitamin-A supplementation and persistent diarrhea treatment. ORS use and reduction in stunting were the two key interventions, each accounting for around 32% of the lives saved during this period. Scaling up the direct diarrhea case management interventions from the current coverage levels in 2015 to achieve universal coverage levels by 2030 can save around 82 000 additional lives. If the universal targets for nutritional factors and WASH interventions can be achieved, an additional 23 675 lives can potentially be saved. While it is crucial to improve the coverage and equity in ORS use, an integrated approach to promote nutrition, WASH and direct diarrhea interventions is likely to yield the highest impact on reducing the remaining diarrheal deaths in under-five children.


Impairment of gastric ulcer healing by alendronate, a nitrogen-containing bisphosphonate, in rats.
Bisphosphonates such as alendronate have been developed as antiresorptive agents capable of treating diseases related to bone remodeling. In the present study, we examined the effect of alendronate on the healing of acetic acid-induced gastric ulcers in rats and investigated the mechanism involved in this action both in vivo and in vitro using the rat gastric epithelial cell line (RGM1). Acetic acid-induced gastric ulcers healed spontaneously, with up-regulation of COX-2/prostaglandin E2 production as well as expression of vascular endothelium-derived growth factor (VEGF) and basic fibroblast growth factor (bFGF) in ulcerated mucosa. The healing of ulcers was impaired by indomethacin (2 mg/kg, s.c.) or alendronate (60 mg/kg, p.o.) given once daily for 7 days, starting 3 days after acid application. Indomethacin, but not alendronate, inhibited mucosal prostaglandin E2 production. Alendronate as well as indomethacin decreased the protein expression of both VEGF and bFGF in ulcerated mucosa, resulting in a reduction of angiogenesis in the ulcer base. Supplementation of recombinant bFGF significantly reverted the delay in ulcer healing caused by alendronate. On the other hand, the size of cell-free areas in RGM1 cells in vitro decreased with time after wound induction, and this process was promoted by epidermal growth factor (EGF; 10 ng/ml). Co-incubation with alendronate (1 mM) did not affect the spontaneous healing but significantly suppressed the accelerated wound healing caused by EGF. These results suggest that alendronate impairs the healing of gastric ulcers in rats, and this effect may be related to down-regulation of VEGF and bFGF, the important growth factors for vascularization/granulation, as well as suppression of the stimulatory action of EGF on epithelial proliferation/migration.


Ultrahigh-speed optical coherence tomography utilizing all-optical 40 MHz swept-source.
We present an ultrahigh-speed optical coherence tomography (OCT) based on an all-optical swept-source with an A-scan rate of 40 MHz. The inertia-free swept-source, which has its output power of 41.2 mW and tuning range of 40 nm and high scan linearity in wavenumber with Pearson's correlation coefficients r of 0.9996, consists of a supercontinuum laser, an optical band-pass filter, a linearly chirped fiber Bragg grating, an erbium-doped fiber amplifier, and two buffer stages. With sensitivity of 87 dB, high-speed OCT imaging of biological tissue in vivo is also demonstrated.


Genomic modulators of the immune response.
Our understanding of immunity has historically been informed by studying heritable mutations in both the adaptive and innate immune responses, including primary immunodeficiency and autoimmune diseases. Recent advances achieved through the application of genomic and epigenomic approaches are reshaping the study of immune dysfunction and opening up new avenues for therapeutic interventions. Moreover, applying genomic techniques to resolve functionally important genetic variation between individuals is providing new insights into immune function in health. This review describes progress in the study of rare variants and primary immunodeficiency diseases arising from whole-exome sequencing (WES), and discusses the application, success, and challenges of applying genome-wide association studies (GWAS) to disorders of immune function and how they may inform more rational use of therapeutics. In addition, the application of expression quantitative-trait mapping to immune phenotypes, progress in understanding MHC disease associations, and insights into epigenetic mechanisms at the interface of immunity and the environment are reviewed.


[Methodologic function of the concept of health in the evaluation of the goal of "health for all by the year 2000"].
This paper makes a socio-historical analysis of the determinants of health on the basis of the different ideas that are held about it. It examines the methodological and practical part played by these different ideas in the past and in the present, and the conclusion is reached that health is a sociobiological process historically determined. With the foregoing definition as a starting point, the author reviews the validity of primary care as a "key" strategy for attaining the goal of health for all by the year 2000.


Idiopathic esophageal ulceration in patients infected with human immunodeficiency virus.
Esophageal disease is a common and important cause of morbidity and mortality in patients with human immunodeficiency virus (HIV) infection. The etiology of HIV-related esophageal ulceration varies. After all known etiologies are excluded, a subgroup of patients remains with esophageal ulceration known as idiopathic esophageal ulceration (IEU). Establishing a diagnosis of IEU is critical and precludes unnecessary treatment with antiviral, antifungal, or antibiotic agents. A review of the current literature indicates that there are no prospective, placebo-controlled, randomized, double-blind trials on the specific treatment of IEU. Several preliminary reports suggest that corticosteroids and thalidomide may be effective. The incidence and natural history of IEU are incompletely known. It is important to establish that any potential therapeutic agents employed to treat IEU do not increase viral replication or provide viral protection. There is a need for well-designed, placebo-controlled, prospective studies to assess the risks and benefits of corticosteroids, thalidomide, and other agents in the treatment of idiopathic esophageal ulceration.


Does on-field sprinting performance in young soccer players depend on how fast they can run or how fast they do run?
The aim of this study was to examine the impact of maximal sprinting speed (MSS) on the peak speed attained during soccer matches. Time-motion analysis of running activity was collected from 14 highly trained young male outfield footballers (8 wide midfielders [WM] and 6 central defenders [CD], 173.2 ± 0.06 m, 60.8 ± 8.1 kg, 16.7 ± 0.7 years) during 14 different friendly international club level matches. The 2 fastest players (a WM and a CD) were compared with the slower players who played in the same position. Each player's MSS was determined using the fastest 10-m split time during an electronically timed 40-m sprint. Game speed was recorded via portable global positioning systems. Faster players reached higher absolute peak running speeds in games than did their slower counterparts regardless of the playing position, with large to very large effect sizes and qualitative indications of "almost certain" and "very likely" positive effects associated with being fast. None of the players reached their MSS during the matches; however, the fastest CD attained a lower percentage of his MSS compared to both, his slower CD counterparts and the fastest WM. Given the higher peak speeds reached in games by the fastest players, and the fact that all players (irrespective of their MSS) used a high percentage of their MSS, these preliminary results provide direct support to the hypothesis that MSS can impact on what a player can do in actual playing conditions. Our results also indicate that playing position has an important role in influencing the expression of MSS.


Ultrafast dynamics of hydrogen bond exchange in aqueous ionic solutions.
The structural and dynamical properties of aqueous ionic solutions influence a wide range of natural and biological processes. In these solutions, water has the opportunity to form hydrogen bonds with other water molecules and anions. Knowing the time scale with which these configurations interconvert represents a key factor to understanding the influence of molecular scale heterogeneity on chemical events in aqueous ionic solutions. We have used ultrafast IR spectroscopy and Car-Parrinello molecular dynamics (CPMD) simulations to investigate the hydrogen bond (H-bond) structural dynamics in aqueous 6 M sodium perchlorate (NaClO4) solution. We have measured the H-bond exchange dynamics between spectrally distinct water-water and water-anion H-bond configurations with 2DIR spectroscopy and the orientational relaxation dynamics of water molecules in different H-bond configurations with polarization-selective IR pump-probe experiments. The experimental H-bond exchange time correlates strongly with the experimental orientational relaxation time of water molecules. This agrees with prior observations in water and aqueous halide solutions, and has been interpreted within the context of an orientational jump model for the H-bond exchange. The CPMD simulations performed on aqueous 6 M NaClO4 solution clearly demonstrate that water molecules organize into two radially and angularly distinct structural subshells within the first solvation shell of the perchlorate anion, with one subshell possessing the majority of the water molecules that donate H-bonds to perchlorate anions and the other subshell possessing predominantly water molecules that donate two H-bonds to other water molecules. Due to the high ionic concentration used in the simulations, essentially all water molecules reside in the first ionic solvation shells. The CPMD simulations also demonstrate that the molecular exchange between these two structurally distinct subshells proceeds more slowly than the H-bond exchange between the two spectrally distinct H-bond configurations. We interpret this to indicate that orientational motions predominantly dictate the rate of H-bond exchange, while translational diffusion must occur to complete the molecular exchange between the two structurally distinct subshells around the perchlorate anions. The 2DIR measurements observe the H-bond exchange between the two spectrally distinct H-bond configurations, but the lifetime of the hydroxyl stretch precludes the observation of the slower molecular exchange. Our 2DIR experiments and CPMD simulations demonstrate that orientational motions predominantly equilibrate water molecules within their local solvation subshells, but the full molecular equilibration within the first solvation shell around the perchlorate anion necessitates translational motion.


Validation of the Arabic version of the MADRS scale among Lebanese patients with depression.
To use the Arabic version of the MADRS in Lebanese depressed patients, check its validity and reproducibility compared to other versions of the questionnaire and assess risk factors affecting the total MADRS score. This case-control study, performed between September 2016 and January 2017, included 200 patients (100 patients, 100 controls). The questionnaire included two parts, the first one concerning the socio-demographic characteristics another one that included the Montgomery-Asberg Depression Rating Scale (MADRS) questions, which was translated from English to Arabic through an initial translation and back translation process. The MADRS scale items converged over a solution of one factor that had an Eigenvalue over 1, explaining a total of 83.90% of the variance. A Kaiser-Meyer-Olkin measure of sampling adequacy of 0.953 was found, with a significant Bartlett's test of sphericity (P<0.001). A stepwise linear regression, using the total MADRS score as continuous variable, showed that a university level of education would significantly decrease the total MADRS score by 20 points (beta=-20.02, CI: from -26.337 to -13.709, P<0.001). Unemployment was significantly more associated with an increase in the total MADRS score level by 10.23 points (beta=10.23, CI: 3.944-16.526, P=0.002). This study shows that the Arabic version of the MADRS has promising psychometric properties, and thus it is a good tool to use for the diagnosis of patients with depression. Based on this study, health care professionals and researchers can readily use the MADRS questionnaire to estimate the overall severity of depression among psychiatric patients in Lebanon.


Using local lexicalized rules to identify heart disease risk factors in clinical notes.
Heart disease is the leading cause of death globally and a significant part of the human population lives with it. A number of risk factors have been recognized as contributing to the disease, including obesity, coronary artery disease (CAD), hypertension, hyperlipidemia, diabetes, smoking, and family history of premature CAD. This paper describes and evaluates a methodology to extract mentions of such risk factors from diabetic clinical notes, which was a task of the i2b2/UTHealth 2014 Challenge in Natural Language Processing for Clinical Data. The methodology is knowledge-driven and the system implements local lexicalized rules (based on syntactical patterns observed in notes) combined with manually constructed dictionaries that characterize the domain. A part of the task was also to detect the time interval in which the risk factors were present in a patient. The system was applied to an evaluation set of 514 unseen notes and achieved a micro-average F-score of 88% (with 86% precision and 90% recall). While the identification of CAD family history, medication and some of the related disease factors (e.g. hypertension, diabetes, hyperlipidemia) showed quite good results, the identification of CAD-specific indicators proved to be more challenging (F-score of 74%). Overall, the results are encouraging and suggested that automated text mining methods can be used to process clinical notes to identify risk factors and monitor progression of heart disease on a large-scale, providing necessary data for clinical and epidemiological studies.


Zbasic: A Purification Tag for Selective Ion-Exchange Recovery.
A positively charged protein domain, denoted Zbasic, can be used as a general purification tag for purification of recombinantly produced target proteins by cation-exchange chromatography. The Zbasic domain is constructed from the Protein A-derived Z-domain, and engineered to be highly charged, which allows selective capture on a cation exchanger at physiological pH values. Moreover, Zbasic is selective also under denaturing conditions and can be used for purification of proteins solubilized from inclusion bodies. Zbasic can then be used as a flexible linker to the cation-exchanger resin, and thereby allows solid-phase refolding of the target protein.Herein, protocols for purification of soluble Zbasic-tagged fusion proteins , as well as for integrated purification and solid-phase refolding of insoluble fusion proteins , are described. In addition, a procedure for enzymatic tag removal and recovery of native target protein is outlined.


Glucocorticoid therapy in giant cell arteritis: duration and adverse outcomes.
To evaluate the course of glucocorticoid (GC) therapy and associated adverse events in a population-based cohort of patients with giant cell arteritis (GCA). We identified 125 Olmsted County residents with GCA diagnosed between 1950 and 1991 and obtained followup information on the 120 patients who were diagnosed antemortem and agreed to participate in this study. Clinical variables, GC doses, and GC adverse events on each patient were recorded. The relationship between GC therapy and the development of adverse events was studied by the Cox and Anderson-Gill proportional hazards models. All patients were treated with GCs and responded rapidly (median initial dosage 60 mg prednisone/day). The dosage was later reduced according to the treating physicians' judgment. The median duration required to reach 7.5 mg/day was 6.5 months and the median duration required to reach 5 mg/day was 7.5 months. Relapses or recurrences occurred in 57 patients. For the 87 patients followed to discontinuation of GC therapy and permanent remission of GCA (median of 22 months), the total median dose of prednisone was 6.47 gm. Adverse events associated with GCs were recorded in 103 (86%) patients and 2 or more events occurred in 70 patients (58%). Age and higher cumulative dose of GCs were associated with the development of adverse GC side effects. GCs are therapeutically effective in GCA and the prednisone dosage was reduced to physiologic levels in three-fourths of the patients within 1 year. However, most patients developed serious adverse side effects related to GCs, indicating that less toxic therapeutic measures are needed.


Analysis of factors important for the occurrence of Campylobacter in Danish broiler flocks.
For more than a decade human campylobacteriosis has been the leading zoonosis in many developed countries. Consumption of poultry or poultry products has been identified as the primary source of infection in humans. This study was conducted to identify risk factors for the occurrence of Campylobacter in Danish broiler flocks. The study was based on a large data set consisting of Campylobacter positive status for nearly 6000 broiler flocks and 43 explanatory variables. Data were obtained from the Danish Campylobacter surveillance programme in poultry and from the responses to a standardized questionnaire answered via interviews with broiler farm owners. Two hundred and forty broiler farms, comprising 539 broiler houses, were included in the study and their Campylobacter status was followed over a 2-year period (1999-2000). The large number of observations made it possible to carry out a multivariate analysis including all 43 variables. A multivariate analysis was conducted using a generalized linear model, and the correlations between the houses from the same farms were accounted for by adding a variance structure to the model. The procedures for analyses included backward elimination, forward selection and expanding of the number of observations used in the variance analysis along with the reduction of the number of parameters in the model. The unit of analysis was 'broiler house', meaning that all results from a broiler house were aggregated into one prevalence figure (number of positive flocks/total number of flocks delivered over the 2-year period). The following factors were found to be significantly associated with the occurrence of Campylobacter in the broiler flocks: old broiler houses, late introduction of whole wheat in the feed, relatively high broiler age at slaughter, improper rodent control, large number of chimneys on the broiler house, farm located in an area with a high density of cattle farms, having more than one broiler house on the farm, and improper storage of wheat. This large-scale study confirms several risk factors identified in previous studies. The results concerning chimneys may be explained by the easier access that flies have to the broiler houses, which seems in agreement with recent Danish studies on the significance of fly-screens to reduce Campylobacter in broiler flocks. The results of this study may be used in identification of effective interventions aimed at controlling Campylobacter in Danish broiler flocks.


Stimulation of endothelial progenitor cells by microRNA-31a-5p to induce endothelialization in an aneurysm neck after coil embolization by modulating the Axin1-mediated β-catenin/vascular endothelial growth factor pathway.
Emerging evidence shows that frequent recurrence of intracranial aneurysms (IAs) after endovascular coiling is attributable to the lack of endothelialization across the aneurysm neck. Recently, much attention has been given to the role of microRNAs (miRs) in vascular disease, although their contributory role to IA is poorly understood. Adult male Sprague-Dawley rats were subjected to microsurgery to create a coiled embolization aneurysm model, and were injected with miR-31a-5p agomir or a negative control agomir via the tail vein at a dose of 10 mg/kg per week for 4 weeks after IA induction. H & E staining, scanning electron microscopy, and flow cytometry were performed to evaluate the effects of miR-31a-5p agomir on endothelialization and the number of circulating endothelial progenitor cells (EPCs). The effects of miR-31a-5p on the viability and functioning of EPCs were also determined using Cell Counting Kit-8, wound-healing assay, and tube formation assays. The authors tested the ability of miR-31a-5p to promote EPC-induced endothelialization in a model of coiled embolization aneurysm. miR-31a-5p agomir improved endothelialization and elevated the number of circulating EPCs in the peripheral blood compared to a negative control agomir-treated group. In addition, the number of vWF- and KDR-positive cells in the aneurysm neck was increased in the miR-31a-5p agomir-treated group. Furthermore, upregulation of miR-31a-5p promoted EPC proliferation, migration, and tube formation and enhanced the expression of the proangiogenic factor vascular endothelial growth factor in vitro. Mechanistically, miR-31a-5p directly targeted the 3' untranslated region (3'UTR) of Axin1 messenger RNA and repressed its expression. Besides, miR-31a-5p exerted its effect on EPCs by regulating the Axin1-mediated Wnt/β-catenin pathway. Collectively, these results indicate that miR-31a-5p is an important regulator of EPC mobilization and endothelialization and may have a positive effect on aneurysm repair.


Diet and exercise orthogonally alter the gut microbiome and reveal independent associations with anxiety and cognition.
The ingestion of a high-fat diet (HFD) and the resulting obese state can exert a multitude of stressors on the individual including anxiety and cognitive dysfunction. Though many studies have shown that exercise can alleviate the negative consequences of a HFD using metabolic readouts such as insulin and glucose, a paucity of well-controlled rodent studies have been published on HFD and exercise interactions with regard to behavioral outcomes. This is a critical issue since some individuals assume that HFD-induced behavioral problems such as anxiety and cognitive dysfunction can simply be exercised away. To investigate this, we analyzed mice fed a normal diet (ND), ND with exercise, HFD diet, or HFD with exercise. We found that mice on a HFD had robust anxiety phenotypes but this was not rescued by exercise. Conversely, exercise increased cognitive abilities but this was not impacted by the HFD. Given the importance of the gut microbiome in shaping the host state, we used 16S rRNA hypervariable tag sequencing to profile our cohorts and found that HFD massively reshaped the gut microbial community in agreement with numerous published studies. However, exercise alone also caused massive shifts in the gut microbiome at nearly the same magnitude as diet but these changes were surprisingly orthogonal. Additionally, specific bacterial abundances were directly proportional to measures of anxiety or cognition. Thus, behavioral domains and the gut microbiome are both impacted by diet and exercise but in unrelated ways. These data have important implications for obesity research aimed at modifications of the gut microbiome and suggest that specific gut microbes could be used as a biomarker for anxiety or cognition or perhaps even targeted for therapy.


Outcomes after diagnosis of mild cognitive impairment in a large autopsy series.
To determine clinical and neuropathological outcomes following a clinical diagnosis of mild cognitive impairment (MCI). Data were drawn from a large autopsy series (N = 1,337) of individuals followed longitudinally from normal or MCI status to death, derived from 4 Alzheimer Disease (AD) Centers in the United States. Mean follow-up was 7.9 years. Of the 874 individuals ever diagnosed with MCI, final clinical diagnoses were varied: 39.2% died with an MCI diagnosis, 46.8% with a dementia diagnosis, and 13.9% with a diagnosis of intact cognition. The latter group had pathological features resembling those with a final clinical diagnosis of MCI. In terms of non-AD pathologies, both primary age-related tauopathy (p < 0.05) and brain arteriolosclerosis pathology (p < 0.001) were more severe in MCI than cognitively intact controls. Among the group that remained MCI until death, mixed AD neuropathologic changes (ADNC; ≥1 comorbid pathology) were more frequent than "pure" ADNC pathology (55% vs 22%); suspected non-Alzheimer pathology comprised the remaining 22% of cases. A majority (74%) of subjects who died with MCI were without "high"-level ADNC, Lewy body disease, or hippocampal sclerosis pathologies; this group was enriched in cerebrovascular pathologies. Subjects who died with dementia and were without severe neurodegenerative pathologies tended to have cerebrovascular pathology and carry the MCI diagnosis for a longer interval. MCI diagnosis usually was associated with comorbid neuropathologies; less than one-quarter of MCI cases showed "pure" AD at autopsy. Ann Neurol 2017;81:549-559.


Dendritic cell interactions with NK cells from different tissues.
In recent years, it has been realized that innate lymphocytes do not act in isolation but potentiate their efficiency by interacting with each other, resulting even in the regulation of adaptive immune response. One such cross-talk exists between dendritic cells (DCs) and natural killer (NK) cells. Here, we summarize recent studies on which subsets of these two innate immune components participate in this interaction, how it influences immune responses, and to which extent similar stimuli are integrated by DCs and NK cells during innate immunity. We suggest that this cross-talk should be harnessed by activating both of these innate leucocyte populations with new adjuvant formulations for immunotherapies.


Cervical cancer prevention and the Millennium Development Goals.
The advent of new technologies such as the human papillomavirus (HPV) vaccine and HPV DNA tests--along with new insights into the appropriate use of low-resource technologies such as visual inspection of the cervix and treatment of cervical lesions with cryotherapy--have increased optimism about the potential for effective disease control in low-resource settings. Nevertheless, it is also important to ask ourselves how new health initiatives contribute, or fail to contribute, to major global undertakings such as achievement of the Millennium Development Goals (MDGs). While reproductive health in general, and cervical cancer prevention in particular, are not explicitly mentioned among the MDGs, they are implied; and it is certain that women cannot contribute to sustainable development without good health. The question is, in what ways do scaled-up cervical cancer prevention activities, including introduction of the new HPV vaccines and increased access to precancer screening and treatment, contribute to attainment of the MDGs?


Multiview Bayesian Correlated Component Analysis.
Correlated component analysis as proposed by Dmochowski, Sajda, Dias, and Parra (2012) is a tool for investigating brain process similarity in the responses to multiple views of a given stimulus. Correlated components are identified under the assumption that the involved spatial networks are identical. Here we propose a hierarchical probabilistic model that can infer the level of universality in such multiview data, from completely unrelated representations, corresponding to canonical correlation analysis, to identical representations as in correlated component analysis. This new model, which we denote Bayesian correlated component analysis, evaluates favorably against three relevant algorithms in simulated data. A well-established benchmark EEG data set is used to further validate the new model and infer the variability of spatial representations across multiple subjects.


Virtual endoscopy: a promising new technology.
Growing evidence shows that early detection of cancer can substantially reduce mortality, necessitating screening programs that encourage patient compliance. Radiology is already established as a screening tool, as in mammography for breast cancer and ultrasonography for congenital anomalies. Advanced processing of helical computed tomographic data sets permits three-dimensional and virtual endoscopic models. Such models are noninvasive and require minimal patient preparation, making them ideal for screening. Virtual endoscopy has been used to evaluate the colon, bronchi, stomach, blood vessels, bladder, kidney, larynx, and paranasal sinuses. The most promising role for virtual endoscopy is in screening patients for colorectal cancer. The technique has also been used to evaluate the tracheobronchial tree for bronchogenic carcinoma. Three-dimensional and virtual endoscopy can screen, diagnose, evaluate and assist determination of surgical approach, and provide surveillance of certain malignancies.


Molecular Models for the Core Components of the Flagellar Type-III Secretion Complex.
We show that by using a combination of computational methods, consistent three-dimensional molecular models can be proposed for the core proteins of the type-III secretion system. We employed a variety of approaches to reconcile disparate, and sometimes inconsistent, data sources into a coherent picture that for most of the proteins indicated a unique solution to the constraints. The range of difficulty spanned from the trivial (FliQ) to the difficult (FlhA and FliP). The uncertainties encountered with FlhA were largely the result of the greater number of helix packing possibilities allowed in a large protein, however, for FliP, there remains an uncertainty in how to reconcile the large displacement predicted between its two main helical hairpins and their ability to sit together happily across the bacterial membrane. As there is still no high resolution structural information on any of these proteins, we hope our predicted models may be of some use in aiding the interpretation of electron microscope images and in rationalising mutation data and experiments.


Microinjection of a monoclonal antibody against SPN antigen, now identified by peptide sequences as the NuMA protein, induces micronuclei in PtK2 cells.
Several high molecular mass proteins which relocate from the interphase nucleus to the spindle poles during mitosis have been defined by antibodies. Microinjection experiments have shown that at least the antigen defined by SPN antibody plays a functional role during mitosis. Recently the cDNA sequence for human NuMA antigen was established and epitopes for antibodies to centrophilin, and to 1F1 and 1H1 antigens were found to be included in the NuMA protein. Here we show that immunoprecipitated SPN antigen reacts with an autoimmune human NuMA serum. In addition three peptides derived from immunoprecipitated human SPN by cyanogen bromide cleavage and covering more than fifty amino acids show a perfect fit with the sequence predicted for NuMA protein. Thus SPN antigen and NuMA are the same protein. Injection of SPN-3 antibody into interphase or mitotic PtK2 cells results in cells with micronuclei. For cells injected in prophase, prometaphase or metaphase 90%, 78% and 77% display defective cytokinesis or yield daughter cells with micronuclei. In contrast only 16% of cells injected in anaphase are abnormal. Thus SPN/NuMA antigen may be required during early, but not during later, stages of mitosis. Surprising parallels are seen between the effects of microinjecting SPN-3 antibody and treatment with colcemid and taxol of PtK2 and HeLa cells. Our results identify an important role during mitosis for the SPN/NuMA antigen.


Nonparametric Detection of Nonlinearly Mixed Pixels and Endmember Estimation in Hyperspectral Images.
Mixing phenomena in hyperspectral images depend on a variety of factors, such as the resolution of observation devices, the properties of materials, and how these materials interact with incident light in the scene. Different parametric and nonparametric models have been considered to address hyperspectral unmixing problems. The simplest one is the linear mixing model. Nevertheless, it has been recognized that the mixing phenomena can also be nonlinear. The corresponding nonlinear analysis techniques are necessarily more challenging and complex than those employed for linear unmixing. Within this context, it makes sense to detect the nonlinearly mixed pixels in an image prior to its analysis, and then employ the simplest possible unmixing technique to analyze each pixel. In this paper, we propose a technique for detecting nonlinearly mixed pixels. The detection approach is based on the comparison of the reconstruction errors using both a Gaussian process regression model and a linear regression model. The two errors are combined into a detection statistics for which a probability density function can be reasonably approximated. We also propose an iterative endmember extraction algorithm to be employed in combination with the detection algorithm. The proposed detect-then-unmix strategy, which consists of extracting endmembers, detecting nonlinearly mixed pixels and unmixing, is tested with synthetic and real images.


Phylogenomics and historical biogeography of the monocot order Liliales: out of Australia and through Antarctica.
We present the first phylogenomic analysis of relationships among all ten families of Liliales, based on 75 plastid genes from 35 species in 29 genera, and 97 additional plastomes stratified across angiosperm lineages. We used a supermatrix approach to extend our analysis to 58 of 64 genera of Liliales, and calibrated the resulting phylogeny against 17 fossil dates to produce a new timeline for monocot evolution. Liliales diverged from other monocots 124 Mya and began splitting into separate families 113 Mya. Our data support an Australian origin for Liliales, with close relationships between three pairs of lineages (Corsiaceae/Campynemataceae, Philesiaceae/Ripogonaceae, tribes Alstroemerieae/Luzuriageae) in South America and Australia or New Zealand reflecting teleconnections of these areas via Antarctica. Long-distance dispersal (LDD) across the Pacific and Tasman Sea led to re-invasion of New Zealand by two lineages (Luzuriaga, Ripogonum); LDD allowed Campynemanthe to colonize New Caledonia after its submergence until 37 Mya. LDD permitted Colchicaceae to invade East Asia and Africa from Australia, and re-invade Africa from Australia. Periodic desert greening permitted Gloriosa and Iphigenia to colonize Southeast Asia overland from Africa, and Androcymbium-Colchicum to invade the Mediterranean from South Africa. Melanthiaceae and Liliaceae crossed the Bering land-bridge several times from the Miocene to the Pleistocene.


Oral parafunctions and association with symptoms of temporomandibular disorders in Japanese university students.
We examined whether oral parafunctions are associated with symptoms of temporomandibular disorders (TMD) in 3557 Japanese university students, aged between 18 and 26 years. Participants completed a questionnaire regarding various oral parafunctions and subjective symptoms related to TMD, and underwent a dental examination. The prevalence of temporomandibular joint (TMJ) noise, TMJ pain and impaired mouth opening was 41.7, 16.0 and 16.3%, respectively. The most prevalent parafunction was sleeping on one side (60.2%), followed by supporting the jaw by leaning on the palm of the hand (44.8%). Mean age, decayed, missing and filled teeth, and number of teeth were not significantly different between TMD positive and negative groups according to unpaired t-test. The chi-squared test revealed that the ratio of females was significantly higher among students with TMD than without TMD. Multiple logistic regression models adjusted for age and gender demonstrated that chewing on one side caused an increased risk of TMJ noise [odds ratio (OR) = 1.52, P < 0.001], TMJ pain (OR = 1.54, P < 0.001), and impaired mouth opening (OR = 2.00, P < 0.001). Tooth clenching also increased the risk of TMJ noise (OR = 1.86, P < 0.001), TMJ pain (OR = 1.79, P = 0.001) and impaired mouth opening (OR = 1.88, P < 0.001). Further prospective cohort studies, including other potential risk factors, are required to clarify these relationships.


Evaluating longitudinal markers under two-phase study designs.
Little attention has been given to the design of efficient studies to evaluate longitudinal biomarkers. Measuring longitudinal markers on an entire cohort is cost prohibitive and, especially for rare outcomes such as cancer, may be infeasible. Thus, methods for evaluation of longitudinal biomarkers using efficient and cost-effective study designs are needed. Case cohort (CCH) and nested case-control (NCC) studies allow investigators to evaluate biomarkers rigorously and at reduced cost, with only a small loss in precision. In this article, we develop estimators of several measures to evaluate the accuracy and discrimination of predicted risk under CCH and NCC study designs. We use double inverse probability weighting (DIPW) to account for censoring and sampling bias in estimation and inference procedures. We study the asymptotic properties of the proposed estimators. To facilitate inference using two-phase longitudinal data, we develop valid resampling-based variance estimation procedures under CCH and NCC. We evaluate the performance of our estimators under CCH and NCC using simulation studies and illustrate them on a NCC study within the hepatitis C antiviral long-term treatment against cirrhosis (HALT-C) clinical trial. Our estimators and inference procedures perform well under CCH and NCC, provided that the sample size at the time of prediction (effective sample size) is reasonable. These methods are widely applicable, efficient, and cost-effective and can be easily adapted to other study designs used to evaluate prediction rules in a longitudinal setting.


Comparison of 4 Pediatric Intraosseous Access Devices: A Randomized Simulation Study.
Obtaining intravascular access can be challenging or even impossible in several clinical situations. As an alternative, medications and fluids can be administered via the intraosseous (IO) route, which is a well-tolerated and established alternative, especially in the emergency setting. Seventy-five novice physicians participated in this randomized simulation study. After a single educational session and 6 months without any clinical application, participants were asked to identify the correct puncture site and obtain IO access using 3 widely used mechanical devices (BIG Pediatric, Arrow EZ-IO, NIO Pediatric) and a manual device (Jamshidi needle) on a pediatric manikin and turkey bone, respectively. Sixty-eight participants correctly identified the puncture site and performed IO cannulations. First placement attempt success rate was similar with mechanical devices (NIO Pediatric, 100%; Arrow EZ-IO, 97%; and BIG Pediatric, 90%), whereas was only 43% using the manual Jamshidi device. Also, procedure time was much faster using mechanical devices (ranging between 18 and 23 seconds) compared with the manual Jamshidi device (34 seconds). Although the efficacy of devices was demonstrated in simulated environment in novice users, further studies are needed to assess the efficacy and safety of devices in clinical comparative settings. With more experienced users, the success rate may differ considerably as compared with naive users.


Climate projections for glacier change modelling over the Himalayas.
Glaciers are of key importance to freshwater supplies in the Himalayan region. Their growth or decline is among other factors determined by an interaction of 2-m air temperature (TAS) and precipitation rate (PR) and thereof derived positive degree days (PDD) and snow and ice accumulation (SAC). To investigate determining factors in climate projections, we use a model ensemble consisting of 36 CMIP5 general circulation models (GCMs) and 13 regional climate models (RCMs) of two Asian CORDEX domains for two different representative concentration pathways (RCP4.5 and RCP8.5). First, we downsize the ensemble in respect to the models' ability to correctly reproduce dominant circulation patterns (i.e., the Indian summer monsoon [ISM] and western disturbances [WDs]) as well as elevation-dependent trend signals in winter. Within this evaluation, a newly produced data set for the Indus, Ganges and Brahmaputra catchments is used as observational data. The reanalyses WFDEI, ERA-Interim, NCEP/NCAR and JRA-55 are used to further account for observational uncertainty. In a next step, remaining TAS and PR data are bias corrected applying a new bias adjustment method, scale distribution mapping, and subsequently PDD and SAC computed. Finally, we identify and quantify projected climate change effects. Until the end of the century, the ensemble indicates a rise of PDD, especially during summer and for lower altitudes. Also TAS is rising, though the highest increases are shown for higher altitudes and between December and April (DJFMA). PRs connected to the ISM are projected to robustly increase, while signals for PR changes during DJFMA show a higher level of uncertainty and spatial heterogeneity. However, a robust decline in solid precipitation is projected over our research domain, with the exception of a small area in the high mountain Indus catchment where no clear signal emerges.


Age-mediated changes in the gastrointestinal tract.
Physiological functions of the two extreme ends of the age spectrum, children (<18 y old) and older adults (aged 65 y and over), differ from healthy young adults. This consequently affects the pharmacokinetic profiles of administered drugs, which, in turn, impacts upon clinical practice and drug therapy. The gastrointestinal milieu acts as a distinct and vital organ regulating the dissolution, absorption and metabolism of orally ingested drugs. Age-mediated alteration in the physiology and function of the gut can reshape the pharmacokinetics of certain drugs. However, our understanding of this topic is limited. This article references the gut physiology of healthy adults to capture the available evidence in the literature on the extent and nature of the changes in childhood and older age. The gut, as an organ, is examined with regards to the effect of age on luminal fluid, microbiota, transit and motility, and the intestinal mucosa. Whilst drastic developmental changes were observed in certain aspects of the gastrointestinal environment, the examination reveals significant gaps in our knowledge in the physiology and function of the developing or ageing gut. The revelation of the unknown paves the way towards a better characterization of the human gastrointestinal tract for optimized drug therapy in children and older adults.


Oxidative stress during 1-lung ventilation.
Resuming 2-lung ventilation from 1-lung ventilation might induce a re-expansion and reoxygenation effect. The oxidative stress during 1-lung ventilation/2-lung ventilation has not been studied, although severe complications, such as re-expansion pulmonary edema, were reported. Reactive oxygen species production and total antioxidant status assay levels were measured in this study during 1-lung ventilation/2-lung ventilation. The effects on extravascular lung water, cardiac output, and intrathoracic blood volume were also studied by using the Pulsion PiCCO system. Twenty patients undergoing 1-lung ventilation/2-lung ventilation (>60 minutes) for video-assisted thoracoscopic surgery with minimal lung injuries were included in this study. Reactive oxygen species production was measured by means of lucigenin (detecting superoxide mainly) and luminol (detecting H2O2 and HOCl mainly) chemiluminescence. Reactive oxygen species production, total antioxidant status assay (by using the Randox TAS kit), extravascular lung water, cardiac output, and intrathoracic blood volume values were measured before 1-lung ventilation (T1), before resuming 2-lung ventilation (T2), 5 minutes after 2-lung ventilation (T3), and 30 minutes after 2-lung ventilation (T4). One-lung ventilation time was 118 +/- 33 minutes. Lucigenin chemiluminescence (but not luminol chemiluminescence) increased significantly at T3 and T4. Total antioxidant status decreased nonsignificantly. Extravascular lung water, intrathoracic blood volume, and permeability index values changed nonsignificantly after 2-lung ventilation. Cardiac output increased significantly at T4, and there is a negative correlation between cardiac output and extravascular lung water (r = -0.431, P < .005). Resuming 2-lung ventilation induces a massive superoxide production. Comparable extravascular lung water and intrathoracic blood volume and a nonsignificant decrease of total antioxidant status indicate adequate antioxidant capacity to counteract it. Severe oxidative injuries after 1-lung ventilation/2-lung ventilation should be considered in patients without adequate antioxidative capacity, such as those with cancer and trauma.


Differential expression of IDA (INFLORESCENCE DEFICIENT IN ABSCISSION)-like genes in Nicotiana benthamiana during corolla abscission, stem growth and water stress.
IDA (INFLORESCENCE DEFICIENT IN ABSCISSION)-like signaling peptides and the associated HAE (HAESA)-like family of receptor kinases were originally reported in the model plant Arabidopsis thaliana (Arabidopsis) to be deeply involved in the regulation of abscission. Actually, IDA peptides, as cell-to-cell communication elements, appear to be implicated in many developmental processes that rely on cell separation events, and even in the responses to abiotic stresses. However, the knowledge related to the molecular machinery regulating abscission in economically important crops is scarce. In this work, we determined the conservation and phylogeny of the IDA-like and HAE-like gene families in relevant species of the Solanaceae family and analyzed the expression of these genes in the allopolyploid Nicotiana benthamiana, in order to identify members involved in abscission, stem growth and in the response to drought conditions. The phylogenetic relationships among the IDA-like members of the Solanaceae studied, grouped the two pairs of NbenIDA1 and NbenIDA2 protein homeologs with the Arabidopsis prepropeptides related to abscission. Analysis of promoter regions searching for regulatory elements showed that these two pairs of homeologs contained both hormonal and drought response elements, although NbenIDA2A lacked the hormonal regulatory elements. Expression analyses showed that the pair of NbenIDA1 homeologs were upregulated during corolla abscission. NbenIDA1 and NbenIDA2 pairs showed tissue differential expression under water stress conditions, since NbenIDA1 homeologs were highly expressed in stressed leaves while NbenIDA2 homeologs, especially NbenIDA2B, were highly expressed in stressed roots. In non-stressed active growing plants, nodes and internodes were the tissues with the highest expression levels of all members of the IDA-like family and their putative HAE-like receptors. Our results suggest that the pair of NbenIDA1 homeologs are involved in the natural process of corolla abscission while both pairs of NbenIDA1 and NbenIDA2 homeologs are implicated in the response to water stress. The data also suggest that IDA peptides may be important during stem growth and development. These results provide additional evidence that the functional module formed by IDA peptides and its receptor kinases, as defined in Arabidopsis, may also be conserved in Solanaceae.


Influence of different collagenase solvents and timing of their delivery on porcine islet isolation.
Methods to minimize the effect of cold ischaemia on porcine islet isolation were investigated. Forty pancreata were randomized to intraductal collagenase delivery in University of Wisconsin solution (UW) or Hanks balanced salt solution (HBSS) (control) both before and after 65 min of cold pancreas storage. Collagenase was also administered in a specially designed cold storage solution (University of Leicester solution, ULEIC), before cold storage. Median islet yield was significantly greater if the pancreas was distended with collagenase in either UW (21524 islet equivalents (IEQ) per g) or ULEIC (19814 IEQ/g) before cold storage, compared with that after distension with HBSS (6924 IEQ/g) following cold storage (P < 0.05). Islet fragmentation, islet purification and glucose-stimulated insulin release were not significantly different after collagenase delivery in either UW or ULEIC compared with those after administration in HBSS. It is concluded that porcine islet yields can be improved significantly by intraductal collagenase administration in either UW or ULEIC immediately after excision of the pancreas.


Androgen dependent mechanisms of pro-angiogenic networks in placental and tumor development.
The placenta and tumors share important characteristics, including a requirement to establish effective angiogenesis. In the case of the placenta, optimal angiogenesis is required to sustain the blood flow required to maintain a successful pregnancy, whereas in tumors establishing new blood supplies is considered a key step in supporting metastases. Therefore the development of novel angiogenesis inhibitors has been an area of active research in oncology. A subset of the molecular processes regulating angiogenesis are well understood in the context of both early placentation and tumorigenesis. In this review we focus on the well-established role of androgen regulation of angiogenesis in cancer and relate these mechanisms to placental angiogenesis. The physiological actions of androgens are mediated by the androgen receptor (AR), a ligand dependent transcription factor. Androgens and the AR are essential for normal male embryonic development, puberty and lifelong health. Defects in androgen signalling are associated with a diverse range of clinical disorders in men and women including disorders of sex development (DSD), polycystic ovary syndrome in women and many cancers. We summarize the diverse molecular mechanisms of androgen regulation of angiogenesis and infer the potential significance of these pathways to normal and pathogenic placental function. Finally, we offer potential research applications of androgen-targeting molecules developed to treat cancer as investigative tools to help further delineate the role of androgen signalling in placental function and maternal and offspring health in animal models.


The role of self-organization in the promotion of resilience in maltreated children.
The dynamic nature of resilience necessitates that children from high-risk backgrounds who are functioning adaptively despite experiences of adversity must be examined over time. In the current investigation, the adaptation of school-age maltreated and nonmaltreated socioeconomically disadvantaged children was examined over 3 consecutive years. In accord with predictions, a higher percentage of nonmaltreated children than of maltreated children were found to be resilient. Moreover, a higher percentage of maltreated than of nonmaltreated children were shown to exhibit functioning consistently in the low adaptive range. Differential predictors of resilience were found in maltreated and nonmaltreated children. Specifically, for maltreated children, positive self-esteem, ego resilience, and ego overcontrol predicted resilient functioning, whereas relationship features were more influential for nonmaltreated children. These findings are discussed in relation to the unfolding of resilient self-organizational strivings in maltreated and nonmaltreated children.


The effect of prone versus supine positioning of Goettingen minipigs on lung density as viewed by computed tomography.
Minipigs are frequently used for scientific research as they are easy to handle and the dimensions of their vascular system do not change after 20 months of age. Although surgical interventions under anaesthesia are often performed in the supine position the effects of this positioning on lung functionality in minipigs have not been systematically described. This study aimed to analyse the influence of supine positioning on the macrostructure of the lung and the pulmonary density by the use of computed tomography imaging in pre-adult Göttingen minipigs. Twelve pre-adult female minipigs were used in the study and lung density was investigated in both the prone and the supine positions. The time between the scans in prone and supine positions was less than 5 minutes (296 ± 6 sec). In the prone position lung density did not differ between the dorsal and ventral part of the lung (-641 ± 72 Hounsfield units [HU]). However in the supine position there was a ventrodorsal gradient of decreasing density (ventral part of the lung: -497 ± 106 HU, dorsal part of the lung: -723 ± 51 HU). The changes in lung density were not accompanied by changes in lung volume (829 ± 191 ml). These results suggest an influence of the body position on the ventilation/perfusion (V(A)/Q) matching of the lung which could possibly result in lowered lung oxygenation as well as in an increased heart activity in the supine position. Additionally, due to the steep course of the vena cava caudalis from the caval foramen in the diaphragm across to the heart (in contrast to the more shallow course in the prone position) the activity of the heart necessary to pump the venous blood to the right atrium has to be higher in the supine position than in the prone position. In pigs the capacity of the heart to increase frequency is limited due to a diastolic/systolic (D/S) ratio <1. Supine positioning may possibly increase their risk of cardiovascular complications.