Family and carer smoking control programmes for reducing children's exposure to environmental tobacco smoke.
Children's exposure to other people's cigarette smoke (environmental tobacco smoke, or ETS) is associated with a range of adverse health outcomes for children. Parental smoking is a common source of children's exposure to ETS. Older children are also at risk of exposure to ETS in child care or educational settings. Preventing exposure to cigarette smoke in infancy and childhood has significant potential to improve children's health worldwide. To determine the effectiveness of interventions aiming to reduce exposure of children to ETS. We searched the Cochrane Tobacco Addiction Group Specialized Register and conducted additional searches of the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, PsycINFO, EMBASE, CINAHL, ERIC, and The Social Science Citation Index & Science Citation Index (Web of Knowledge). Date of the most recent search: September 2013. Controlled trials with or without random allocation. Interventions must have addressed participants (parents and other family members, child care workers and teachers) involved with the care and education of infants and young children (aged 0 to 12 years). All mechanisms for reduction of children's ETS exposure, and smoking prevention, cessation, and control programmes were included. These include health promotion, social-behavioural therapies, technology, education, and clinical interventions. Two authors independently assessed studies and extracted data. Due to heterogeneity of methodologies and outcome measures, no summary measures were possible and results were synthesised narratively. Fifty-seven studies met the inclusion criteria. Seven studies were judged to be at low risk of bias, 27 studies were judged to have unclear overall risk of bias and 23 studies were judged to have high risk of bias. Seven interventions were targeted at populations or community settings, 23 studies were conducted in the 'well child' healthcare setting and 24 in the 'ill child' healthcare setting. Two further studies conducted in paediatric clinics did not make clear whether the visits were to well or ill children, and another included both well and ill child visits. Thirty-six studies were from North America, 14 were in other high income countries and seven studies were from low- or middle-income countries. In only 14 of the 57 studies was there a statistically significant intervention effect for child ETS exposure reduction. Of these 14 studies, six used objective measures of children's ETS exposure. Eight of the studies had a high risk of bias, four had unclear risk of bias and two had a low risk of bias. The studies showing a significant effect used a range of interventions: seven used intensive counselling or motivational interviewing; a further study used telephone counselling; one used a school-based strategy; one used picture books; two used educational home visits; one used brief intervention and one study did not describe the intervention. Of the 42 studies that did not show a significant reduction in child ETS exposure, 14 used more intensive counselling or motivational interviewing, nine used brief advice or counselling, six used feedback of a biological measure of children's ETS exposure, one used feedback of maternal cotinine, two used telephone smoking cessation advice or support, eight used educational home visits, one used group sessions, one used an information kit and letter, one used a booklet and no smoking sign, and one used a school-based policy and health promotion. In 32 of the 57 studies, there was reduction of ETS exposure for children in the study irrespective of assignment to intervention and comparison groups. One study did not aim to reduce children's tobacco smoke exposure, but rather aimed to reduce symptoms of asthma, and found a significant reduction in symptoms in the group exposed to motivational interviewing. We found little evidence of difference in effectiveness of interventions between the well infant, child respiratory illness, and other child illness settings as contexts for parental smoking cessation interventions. While brief counselling interventions have been identified as successful for adults when delivered by physicians, this cannot be extrapolated to adults as parents in child health settings. Although several interventions, including parental education and counselling programmes, have been used to try to reduce children's tobacco smoke exposure, their effectiveness has not been clearly demonstrated. The review was unable to determine if any one intervention reduced parental smoking and child exposure more effectively than others, although seven studies were identified that reported motivational interviewing or intensive counselling provided in clinical settings was effective.


Clinical and Subclinical Femoral Vascular Complications after Deployment of two Different Vascular Closure Devices or Manual Compression in the Setting of Coronary Intervention.
In the past two decades vascular closure devices (VCD) have been increasingly utilized as an alternative to manual compression after percutaneous femoral artery access. However, there is a lack of data confirming a significant reduction of vascular complication in a routine interventional setting. Systematic assessment of puncture sites with ultrasound was hardly performed. 620 consecutive patients undergoing elective or urgent percutaneous coronary intervention were randomly allocated to either Angioseal (AS; n = 210), or Starclose (SC; n = 196) or manual compression (MC; n = 214). As an adjunct to clinical evaluation vascular ultrasonography was used to assess the safety of each hemostatic method in terms of major and minor vascular complications. The efficacy of VCDs was assessed by achievement of puncture site hemostasis. No major complications needing transfusion or vascular surgery were observed. Furthermore, the overall incidence of clinical and subclinical minor complications was similar among the three groups. There was no differences in the occurrence of pseudoaneurysmata (AS = 10; SC = 6; MC = 10), arteriovenous fistula (AS = 1; SC = 4; MC = 2) and large hematoma (AS = 11; SC = 10; MC = 14). The choice of access site treatment had no impact in the duration of hospital stay (AS = 6.7; SC = 7.4; MS = 6.4 days). In the setting of routine coronary intervention AS and SC provide a similar efficacy and safety as manual compression. Subclinical vascular injuries are rare and not related to VCD use.


Triplet Tellurophene-Based Semiconducting Polymer Nanoparticles for Near-Infrared-Mediated Cancer Theranostics.
Semiconducting polymer (SP) nanoparticles (NPs) have recently emerged as one of the most promising agents for photoacoustic imaging (PAI)-guided photothermal/photodynamic therapy (PTT/PDT). Herein, a triplet tellurophene-based SP (PNDI-2T) was synthesized with efficient tin-free direct heteroarylation polycondensation. The PNDI-2T NPs display remarkable near-infrared absorption and low cytotoxicity. In addition, PNDI-2T NPs can generate abundant reactive oxygen species (ROS) since tellurophene facilitates the intersystem crossing to generate triplet excited states. Remarkably, PNDI-2T NPs present a high photothermal conversion efficiency (η = 45%) and a high ROS yield (ΦΔ = 38.7%) under 808 nm laser irradiation. Furthermore, we showed that PNDI-2T NPs could be excellent PAI-guided PTT/PDT agents for cancer theranostics. This study provides a new route to developing highly efficient and low cytotoxic agents for PAI-guided PTT/PDT.


Shorter Ends, Faster End? Leukocyte Telomere Length and Mortality Among Older Taiwanese.
Recent studies have found mixed results regarding the association between leukocyte telomere length (LTL)--thought to be a marker of cellular aging--and all-cause mortality. Some studies have reported a significant inverse relationship, but others have not, perhaps in part owing to insufficient power. We examine the relationship using data from a nationally representative sample of older Taiwanese (54+ in 2000), which is larger (n = 942) than most previous studies, and which includes comprehensive information on potential confounders including white blood cell distribution and inflammatory markers. Results from a Cox hazards model demonstrate a small, but significant, association between LTL and mortality that is independent of age, sex, and lifestyle factors. White blood cell distribution, especially the proportion of neutrophils, is an important predictor of LTL; however, the association between LTL and mortality changes little controlling for white blood cell distribution. In contrast, the association between LTL and mortality weakens considerably (by 48%) after adjustment for inflammatory markers and homocysteine. Our results suggest that the relationship between short telomeres and mortality is tied to inflammation and homocysteine. Longitudinal studies are needed to explore bidirectional influences resulting from the fact that inflammation leads to shorter leukocyte telomeres, which in turn results in senescence, which exacerbates inflammation.


Abusive head trauma: judicial admissions highlight violent and repetitive shaking.
Confessions are uncommon in abusive head trauma (AHT) cases, and there is debate over whether shaking alone can cause the injuries characteristic of AHT. The objective of this article is to correlate legal statements by perpetrators with medical documentation to offer insights into the mechanism of injury. In this retrospective observational study we examined forensic evidence from 112 cases referred for AHT over a 7-year period. We compared 29 cases in which a perpetrator confessed to violence toward the child with 83 cases in which there was no confession. Inclusion criteria were subdural hematoma (SDH) on computed tomography and perpetrator admission of a causal relationship between the violence inflicted and the child's symptoms. Groups were compared by using Student's t test for age and Fisher's exact test for gender, death, fractures, retinal hemorrhages, ecchymoses, symptoms, and SDH patterns. All medical records from birth to diagnosis, imaging studies, and written investigation reports were reviewed. All confessions came from forensic investigations. There was no statistically significant difference between the 2 groups for any of the variables studied. Shaking was described as extremely violent (100%) and was repeated (55%) from 2 to 30 times (mean: 10) because it stopped the infant's crying (62.5%). Impact was uncommon (24%). No correlation was found between repeated shaking and SDH densities. This unique forensic case series confirms the violence of shaking. The high frequency of habitual AHT is a strong argument for reporting suspected cases to judicial authorities and helps to explain the difficulty in dating the injuries.


Light Emitting Diode (LED) Phototherapy versus Conventional Phototherapy in Neonatal Hyperbilirubinemia: A Single Blinded Randomized Control Trial from Coastal India.
Neonatal hyperbilirubinemia is a common problem with potentiality to cause irreversible brain damage. Reduction of serum bilirubin level is essential to minimize such damage. Compact fluorescent tubes, halogen bulbs, fiber optic blankets, and LEDs are commonly used light sources for phototherapy with varying efficacies. This study aimed at evaluating the effect of LED versus conventional phototherapy on (a) rate of reduction in total serum bilirubin levels, (b) effect on urinary lumirubin excretion, and (c) comparing side effects of phototherapies among neonates with hyperbilirubinemia. In this randomized control trial, 166 neonates ≥ 35 weeks of age requiring phototherapy were recruited and further divided into 2 groups [LED (83) and conventional (83)] by using computer generated random numbers. Serial total serum bilirubin levels and random urinary lumirubin levels were collected and side effects of phototherapy were noted. Rate of fall in total serum bilirubin levels (TSB, μmol/L/hour) and random urinary lumirubin levels were computed. Data were collected using a pretested proforma. Analysis was done with Statistical Package for Social Sciences (SPSS) version 11.5. Independent sample "t" test and Chi-square tests were used with p value of <0.05 being significant. Significant difference was documented in mean rate of decrease of TSB (μmol/L/hour) in LED group (5.3 ± 2.91) when compared to conventional group (3.76 ± 2.39) (p <0.001). A significant increase in mean random urinary lumirubin levels (arbitrary units) was observed in LED group (129.01 ± 33.18) when compared to conventional group (114.44 ± 44.84) (p = 0.021). Side effects were minimal and comparable in both groups. This study concludes the rates of decrease in total serum bilirubin levels and increase in urinary lumirubin levels were significant with LED when compared with conventional phototherapy, implying LED to be more efficacious.


Effect of lysophosphatidic acid acyltransferase-beta inhibition in acute leukemia.
Phosphatidic acid (PA) is an important component of mammalian target of rapamycin (mTOR) signaling and in the recruitment of Raf to the cell membrane. PA can be produced by several mechanisms, including by a series of lysophosphatidic acid acyl transferases (LPAATs). LPAAT-beta is an isoform that is overexpressed in some human cancers and its inhibition has been investigated as a potential targeted cancer therapy. We report that LPAAT-protein and enzyme activity in acute leukemia cell lines and blasts from patient samples are equivalent to levels in normal mononuclear cells. Treatment with the LPAAT-beta inhibitor CT-32228 (Cell Therapeutics, Seattle, WA) uniformly induces apoptosis in multiple leukemia cell lines. In patient samples, however, apoptosis was variably induced by CT-32228 and appeared to be related to the degree of cellular proliferation. The growth inhibitory effect of CT-32228 on normal hematopoietic progenitors was more pronounced in cells induced to proliferate by growth factors. These data suggest that CT-32228 may have potential in the treatment of acute leukemias, but that efficacy is more directly related to the degree of cell proliferation rather than to the level of LPAAT-beta expression or activity.


Overview of systematic reviews assessing the evidence for shorter versus longer duration antibiotic treatment for bacterial infections in secondary care.
Our objective was to assess the clinical effectiveness of shorter versus longer duration antibiotics for treatment of bacterial infections in adults and children in secondary care settings, using the evidence from published systematic reviews. We conducted electronic searches in MEDLINE, Embase, Cochrane, and Cinahl. Our primary outcome was clinical resolution. The quality of included reviews was assessed using the AMSTAR criteria, and the quality of the evidence was rated using the GRADE criteria. We included 6 systematic reviews (n = 3,162). Four reviews were rated high quality, and two of moderate quality. In adults, there was no difference between shorter versus longer duration in clinical resolution rates for peritonitis (RR 1.03, 95% CI 0.98 to 1.09, I2 = 0%), ventilator-associated pneumonia (RR 0.93; 95% CI 0.81 to 1.08, I2 = 24%), or acute pyelonephritis and septic UTI (clinical failure: RR 1.00, 95% CI 0.46 to 2.18). The quality of the evidence was very low to moderate. In children, there was no difference in clinical resolution rates for pneumonia (RR 0.98, 95% CI 0.91 to 1.04, I2 = 48%), pyelonephritis (RR 0.95, 95% CI 0.88 to 1.04) and confirmed bacterial meningitis (RR 1.02, 95% CI 0.93 to 1.11, I2 = 0%). The quality of the evidence was low to moderate. In conclusion, there is currently a limited body of evidence to clearly assess the clinical benefits of shorter versus longer duration antibiotics in secondary care. High quality trials assessing strategies to shorten antibiotic treatment duration for bacterial infections in secondary care settings should now be a priority.


Tele-education as method of medical education.
Development of computer networks and introduction and application of new technologies in all aspects of human activity needs to be followed by universities in their transformation on how to approach scientific, research, and education teaching curricula. Development and increased use of distance learning (DL) over the past decade have clearly shown the potential and efficiency of information technology applied in education. Use of information technology in medical education is where medical informatics takes its place as important scientific discipline which ensures benefit from IT in teaching and learning process involved. Definition of telemedicine as "use of technologies based on health care delivered on distance" covers areas such as electronic health, tele-health (eHealth), telematics, but also tele-education. Web based medical education today is offered in different forms--from online lectures, online exams, web based continuous education programs, use of electronic libraries, online medical and scientific databases etc. Department of Medical Informatics of Medical Faculty of University of Sarajevo has taken many steps to introduce distance learning in medical curricula--from organising professional--scientific events (congresses, workshop etc), organizing first tele-exam at the faculty and among first at the university, to offering online lectures and online education material at the Department's website (www.unsa-medinfo.org). Distance learning in medical education, as well as telemedicine, significantly influence health care in general and are shaping the future model of medical practice. Basic computer and networks skills must be a part of all future medical curricula. The impact of technical equipment on patient-doctor relationship must be taken into account, and doctors have to be trained and prepared for diagnosing or consulting patients by use of IT. Telemedicine requires special approach in certain medical fields--tele-consultation, tele-surgery, tele-radiology and other specific telemedicine applications should be introduced to the curricula. Telemedicine and distance learning are best suited for medical education and doctor-to-doctor consultation--first contact between doctor and a patient should stay face-to-face when possible. In this paper, we present the results of the project Introduction and Implementation of Distance Learning at the Medical Faculty of University of Sarajevo and compare it with the following expected outcomes: development and integration of information technology in medical education; creation of flexible infrastructure which will enable access to e-learning to all students and teaching staff; improvement of digital literacy of academic population; ensuring high educational standards to students and teaching staff; helping medical staffto develop "life-long learning" approach in work and education.


Effects of Bathing Habits on Postoperative Wound Complications Following Sacrococcygeal Pilonidal Sinus Surgery: A Retrospective Analysis of 67 Adolescent Patients.
Sacrococcygeal pilonidal sinus disease generally affects young people and impacts their quality of life. Few published studies assessing the characteristics of the disease in the adolescent population exist. In this paper, the authors aim to evaluate the effects of bathing habits on wound complications in adolescent patients following Karydakis flap surgery for sacrococcygeal pilonidal sinus. The medical records of 79 adolescent patients who underwent sacrococcygeal pilonidal sinus surgery between January 2014 and December 2017 at the Surgery Clinic of Malatya State Hospital (Malatya, Turkey) were evaluated retrospectively. Following exclusion, 67 patients were evaluated for demographics, body mass index (BMI), previous abscess formation, bathing frequency, number of sinus pits, and postoperative wound infection and dehiscence. The total follow-up time for the 67 patients was 90 days. The BMIs of patients with previous abscess formation were significantly higher (P = .029). In the cases with abscess, the number of pilonidal sinus pits was significantly higher (P = .039) There was a statistically significant difference between postoperative complication rates according to the number of baths per week. Wound infection rates were found to be higher in patients who bathed more than twice weekly during the 28 days after surgery (P = .005). No statistical significance was observed in complication rates from days 28 to 90 after the surgery between those who bathed twice weekly and more than twice weekly (P > .05). Postoperative wound complications in adolescent patients treated with Karydakis flap surgery for sacrococcygeal pilonidal sinus are more frequent in those who bathe more than twice weekly during the first 28 days postoperatively.


Intra-operative cerebral microembolisation during primary hybrid total hip arthroplasty compared with primary hip resurfacing.
Fat embolism during total joint arthroplasty or intramedullary procedures is well documented and is infrequently fatal. Considerable morbidity is associated with fat embolism syndrome, and post operative cognitive dysfunction is frequently seen, yet the exact pathophysiology remains unclear. Intraoperative cerebral microemboli can be detected using transcranial Doppler ultrasound and moreover the presence of a patent foramen ovale (PFO) may be examined for using a validated technique employing this modality. Persistent patent foramen ovale may act as a conduit for embolic material to traverse from the venous to the systemic circulation and consequently affect cerebral function. We wished to 1) investigate the incidence of cerebral microembolisation during primary hybrid total hip arthroplasty and compare this with hip resurfacing, 2) examine the influence of patent foramen ovale on cerebral microembolisation and 3)assess the influence of cerebral microemboli on the outcome of patients undergoing these procedures. We prospectively compared 12 patients undergoing hip resurfacing with 12 patients undergoing hybrid total hip replacement (THR) for the incidence and load of intraoperative cerebral microemboli, using transcranial Doppler. All patients were tested for the presence of a patent foramen ovale using a validated technique. Outcome was assessed using the WOMAC, Harris Hip Score, Oxford Hip Score and EuroQoL quality of life measure. No patient in the hip resurfacing group demonstrated intra-operative cerebral microembolisation. Five patients in the THR group showed transcranial Doppler evidence of microemobli during the procedure. With the small numbers of patients available, there was not a significant difference in microemboli load between the groups (p = 0.09). There was no significant difference between the groups regarding the incidence of PFO (p = 0.78). There was no significant relationship between the incidence and total microemboli load and the incidence of PFO (p = 0.56). There was no significant difference in outcome at six months between patients who demonstrated microemboli and those who did not. The incidence of cerebral microembolisation during hip resurfacing appears to be very low. Although our study demonstrated cerebral microemboli in a significant proportion of patients undergoing primary hybrid THR, the numbers of microemboli were low and the presence of a patent foramen ovale did not influence microemboli incidence or load. Finally, patients who demonstrated cerebral microemboli did not have a worse outcome than patients who did not.


Interviewer effects in a cohort study. Results from the Massachusetts Women's Health Study.
Although interviewer error is widely recognized as an important source of variation in epidemiologic investigations, scant published information exists documenting the impact of interviewer variation on study findings. Using data from the Massachusetts Women's Health Study, a population-based cohort study of 2,569 middle-aged women (1982-1987), the authors evaluated interviewer variation in responses to different types of questions, and assessed the impact of interviewer variation on inferences derived from study data. Respondent sociodemographic and lifestyle characteristics were similar for the four study interviewers at the first follow-up. No interviewer variation was detected for questions concerning recall of specific events, but responses to questions regarding recall of subjective or personal information or those which required further probing did differ significantly by interviewer. Adjustment for interviewer effects had no impact on the conclusions obtained from one analysis of predictors of depression, despite significant interviewer variation in the outcome and predictor variables, but it did change conclusions from an analysis of the impact of support networks on psychological symptoms, wherein the interviewer variable was strongly related to the outcome after data were controlled for predictor variables. Given these findings, examination of data for interviewer effects is advisable despite incorporation of quality control measures in a study's design.


Psychotherapy with a Narcissistic Patient Using Kohut's Self Psychology Model.
According to Kohut's self psychology model, narcissistic psychopathology is a result of parental lack of empathy during development. Consequently, the individual does not develop full capacity to regulate self esteem. The narcissistic adult, according to Kohut's concepts, vacillates between an irrational overestimation of the self and irrational feelings of inferiority, and relies on others to regulate his self esteem and give him a sense of value. In treatment, Kohut recommends helping the patient develop these missing functions. Kohut proposes that the therapist should empathically experience the world from the patient's point of view (temporary indwelling) so that the patient feels understood. Interpretations are used when they can help the patient understand his sometimes intense feelings about any empathic failure on the part of the therapist, and understand why he (the patient) needs to restore solidity and comfort after being injured by any failed empathic (self object) ties. As insight develops, the patient begins to understand why he might experience these apparently small empathic failures so deeply.In this article, therapy with a narcissistic patient is approached from the point of view of Kohut's self psychology theory, and the successes and problems that were encountered with this approach are described and discussed.


A de novo missense mutation (R1623Q) of the SCN5A gene in a Japanese girl with sporadic long QT sydrome. Mutations in brief no. 140. Online.
Two missense mutations and a nine-nucleotide deletion of the cardiac sodium channel (SCN5A) gene have been shown to cause long QT syndrome (LQTS) in several familial cases. We identified a novel missense mutation (R1623Q) of the SCN5A gene in a Japanese girl with sporadic LQTS. We used polymerase chain reaction, single-strand conformation polymorphism analysis and DNA sequence analysis to identify a mutation of the SCN5A gene in the patient. A single nucleotide substitution of guanine to adenine, in codon 1612, changed the coding sense of the SCN5A from arginine to glutamine (R1623Q) in the S4 segment of domain IV which is a highly conserved region of the SCN5A. This mutation was not identified in the unaffected biological parents and brother of the patient, and 100 normal, unrelated individuals. This finding is the first evidence of a de nova mutation in SCN5A associated with LQTS.


Simulation of an erbium-doped chalcogenide micro-disk mid-infrared laser source.
The feasibility of mid-infrared (MIR) lasing in erbium-doped gallium lanthanum sulfide (GLS) micro-disks was examined. Lasing condition at 4.5 µm signal using 800 nm pump source was simulated using rate equations, mode propagation and transfer matrix formulation. Cavity quality (Q) factors of 1.48 × 10(4) and 1.53 × 10(6) were assumed at the pump and signal wavelengths, respectively, based on state-of-the-art chalcogenide micro-disk resonator parameters. With an 80 µm disk diameter and an active erbium concentration of 2.8 × 10(20) cm(-3), lasing was shown to be possible with a maximum slope efficiency of 1.26 × 10(-4) and associated pump threshold of 0.5 mW.


Sea-ice algal phenology in a warmer Arctic.
The Arctic sea-ice decline is among the most emblematic manifestations of climate change and is occurring before we understand its ecological consequences. We investigated future changes in algal productivity combining a biogeochemical model for sympagic algae with sea-ice drivers from an ensemble of 18 CMIP5 climate models. Model projections indicate quasi-linear physical changes along latitudes but markedly nonlinear response of sympagic algae, with distinct latitudinal patterns. While snow cover thinning explains the advancement of algal blooms below 66°N, narrowing of the biological time windows yields small changes in the 66°N to 74°N band, and shifting of the ice seasons toward more favorable photoperiods drives the increase in algal production above 74°N. These diverse latitudinal responses indicate that the impact of declining sea ice on Arctic sympagic production is both large and complex, with consequent trophic and phenological cascades expected in the rest of the food web.


Fortification of flour with folic acid.
After randomized, controlled trials established that consumption of folic acid before pregnancy and during the early weeks of gestation reduces the risk of a neural tube defect (NTD)-affected pregnancy, the United States Public Health Service recommended in 1992 that all women capable of becoming pregnant consume 400 microg folic acid daily. In 1998, folic acid fortification of all enriched cereal grain product flour was fully implemented in the United States and Canada. To provide guidance on national fortification of wheat and maize flours to prevent 50 to 70% of the estimated 300,000 NTD-affected pregnancies worldwide. An expert workgroup reviewed the latest evidence of effectiveness of folic acid flour fortification and the safety of folic acid. Recent estimates show that in the United States and Canada, the additional intake of about 100 to 150 microg/day of folic acid through food fortification has been effective in reducing the prevalence of NTDs at birth and increasing blood folate concentrations in both countries. Most potential adverse effects associated with folic acid are associated with extra supplement use not mandatory fortification. Fortification of wheat flour has a proven record of prevention in other developed countries. In 2009, 51 countries had regulations written for mandatory wheat flour fortification programs that included folic acid. NTDs remain an important cause of perinatal mortality and infantile paralysis worldwide. Mandatory fortification of flour with folic acid has proved to be one of the most successful public health interventions in reducing the prevalence of NTD-affected pregnancies. Most developing countries have few, if any, common sources of folic acid, unlike many developed countries, which have folic acid available from ready-to-eat cereals and supplements. Expanding the number of developed and developing countries with folic acid flour fortification has tremendous potential to safely eliminate most folic acid-preventable NTDs.


Preferred EEG brain states at stimulus onset in normal ageing: Explorations in a fixed interstimulus interval Go/NoGo task.
Some 40 years ago, Erol Başar began an interesting line of brain dynamics research on the phase of oscillatory EEG activity. Stimuli presented at a fixed interstimulus interval (ISI) were reported to produce a "preferred phase angle" at stimulus onset in the ongoing EEG oscillations, so that cortical negativity occurred more often than expected. Our previous work has confirmed this phenomenon in young adults, and linked it to enhancements in stimulus-elicited ERP components and behaviour. The present study sought evidence for this phenomenon in older adults. Twenty healthy independent-living participants (5 males) aged 59.8 to 74.8 years (M = 68.2) completed a fixed ISI equiprobable auditory oddball task. EEG phases in four traditional bands were computed separately for each artefact-free Go and NoGo trial. These were used to group accepted trials according to the phase quartile at stimulus onset in each band, forming 16 mean ERPs for each participant at each phase quartile/band combination, separately for Go and NoGo. The 32 mean ERPs were decomposed by separate Principal Component Analyses, and the N1 and P3 components were examined as a function of EEG phase at stimulus onset in each band. Differential preferential occurrence of phase states was found in all bands, generally confirming prior results in young adults despite important age differences in both EEG spectra and ERP morphology. Substantial effects on N1 and P3 components, as well as prestimulus CNVs, are discussed. The stability of this phenomenon across age indicates its important role in perception and cognition.


Quantification of Campylobacter on the surface and in the muscle of chicken legs at retail.
The objective of this study was to determine the prevalence and numbers of Campylobacter on the skin and in the muscle of chicken legs at retail to examine the external and internal contamination for an exposure assessment. Furthermore, the study assessed seasonal influence on Campylobacter contamination in chicken legs. Of the 140 examined skin samples, 66% were positive, and the internal contamination of 115 sampled chicken legs was 27%. The enumeration of Campylobacter on the surface of positive chicken legs revealed a median of 2.4 log CFU/g of skin, and the quantification of Campylobacter in the muscle gave results mainly under the detection limit of the most-probable-number method (<0.3 MPN Campylobacter per g). The external contamination was significantly higher than the internal. In both skin and muscle samples, Campylobacter jejuni had a much higher incidence than Campylobacter coli. However, with regard to the specification of Campylobacter on the surface of chicken legs, C. coli was isolated at higher colony counts than C. jejuni. During the 1-year study, two peaks of Campylobacter contamination occurred, one in the early springtime (February and March, 100 and 90%, respectively) and the second during the warmer months in the summer (July and August, both 90%). Furthermore, a positive correlation between prevalence and numbers of Campylobacter on chicken legs was observed.


Acetylation accumulates PFKFB3 in cytoplasm to promote glycolysis and protects cells from cisplatin-induced apoptosis.
Enhanced glycolysis in cancer cells has been linked to cell protection from DNA damaging signals, although the mechanism is largely unknown. The 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) catalyzes the generation of fructose-2,6-bisphosphate, a potent allosteric stimulator of glycolysis. Intriguingly, among the four members of PFKFB family, PFKFB3 is uniquely localized in the nucleus, although the reason remains unclear. Here we show that chemotherapeutic agent cisplatin promotes glycolysis, which is suppressed by PFKFB3 deletion. Mechanistically, cisplatin induces PFKFB3 acetylation at lysine 472 (K472), which impairs activity of the nuclear localization signal (NLS) and accumulates PFKFB3 in the cytoplasm. Cytoplasmic accumulation of PFKFB3 facilitates its phosphorylation by AMPK, leading to PFKFB3 activation and enhanced glycolysis. Inhibition of PFKFB3 sensitizes tumor to cisplatin treatment in a xenograft model. Our findings reveal a mechanism for cells to stimulate glycolysis to protect from DNA damage and potentially suggest a therapeutic strategy to sensitize tumor cells to genotoxic agents by targeting PFKFB3.


Delivering Hospital-Based Pediatric Palliative Care: The Symptoms, Interventions, and Outcomes for Children With Cancer in Bangladesh.
The majority of pediatric cancer deaths occur in low- and middle-income countries (LMICs). Pediatric palliative care (PPC) focuses on relieving physical, psychosocial, and spiritual suffering throughout the continuum of cancer care and is considered integral to cancer care for children in all settings. There is limited evidence from LMICs about the characteristics, symptoms, and outcomes of children with cancer who receive PPC, which is needed to define the global need and guide the development of these services. This retrospective review of clinical records of children who received PPC was conducted during a pilot project (January 2014-August 2015) that implemented a PPC team at a tertiary hospital in Dhaka, Bangladesh. Clinical data on diagnosis, symptoms, treatment status, deaths, and key palliative care interventions were collected and analyzed using descriptive statistics. There were 200 children who received PPC during the pilot project. The most common diagnoses were acute lymphoblastic leukemia (62%) and acute myeloid leukemia (11%). Psychosocial support for children (n = 305; 53%) and management of physical symptoms (n = 181; 31%) were the most common types of interventions provided. The most frequently recorded symptoms were pain (n = 60; 30%), skin wounds (n = 16; 8%), and weakness (n = 9; 5%). The most common medications prescribed were morphine (n = 32) and paracetamol (n = 21). A hospital-based PPC service addresses pain and symptom concerns as well as psychosocial needs for children with cancer and their families in a setting where resources are limited. Health care facilities should incorporate palliative care into the care of children with cancer to address the needs of children and their families.


An epitope-based approach of HLA-matched platelets for transfusion: a noninferiority crossover randomized trial.
Platelet transfusion refractoriness results in adverse outcomes and increased health care costs. Managing refractoriness resulting from HLA alloimmunization necessitates the use of HLA antigen-matched platelets but requires a large platelet donor pool and does not guarantee full matching. We report the first randomized, double-blind, noninferiority, crossover trial comparing HLA epitope-matched (HEM) platelets with HLA standard antigen-matched (HSM) platelet transfusions. Alloimmunized, platelet-refractory, thrombocytopenic patients with aplastic anemia, myelodysplastic syndrome, or acute myeloid leukemia were eligible. HEM platelets were selected using HLAMatchMaker epitope (specifically eplet) matching. Patients received up to 8 prophylactic HEM and HSM transfusions provided in random order. The primary outcome was 1-hour posttransfusion platelet count increment (PCI). Forty-nine patients were randomized at 14 UK hospitals. For intention to treat, numbers of evaluable transfusions were 107 and 112 for HEM and HSM methods, respectively. Unadjusted mean PCIs for HEM and HSM methods were 23.9 (standard deviation [SD], 15) and 23.5 (SD, 14.1), respectively (adjusted mean difference, -0.1; 95% confidence interval [CI], -2.9 to 2.8). Because the lower limit of the 95% CI was not greater than the predefined noninferiority limit, the HEM approach was declared noninferior to the HSM approach. There were no differences in secondary outcomes of platelet counts, transfusion requirements, and bleeding events. Adequate 1-hour PCI was more frequently observed, with a mean number of 3.2 epitope mismatches, compared with 5.5 epitope mismatches for inadequate 1-hour increments. For every additional epitope mismatch, the likelihood of an adequate PCI decreased by 15%. Epitope-matched platelets should be considered to support HLA alloimmunized patients. This trial was registered at www.isrctn.com as #ISRCTN23996532.


Post myocardial infarction of the left ventricle: the course ahead seen by cardiac MRI.
In the last decades, cardiac magnetic resonance imaging (MRI) has gained acceptance in cardiology community as an accurate and reproducible diagnostic imaging modality in patients with ischemic heart disease (IHD). In particular, in patients with acute myocardial infarction (MI) cardiac MRI study allows a comprehensive assessment of the pattern of ischemic injury in term of reversible and irreversible damage, myocardial hemorrhage and microvascular obstruction (MVO). Myocardial salvage index, derived by quantification of myocardium (area) at risk and infarction, has become a promising surrogate end-point increasingly used in clinical trials testing novel or adjunctive reperfusion strategies. Early post-infarction, the accurate and reproducible quantification of myocardial necrosis, along with the characterization of ischemic myocardial damage in its diverse components, provides important information to predict post-infarction left ventricular (LV) remodeling, being useful for patients stratification and management. Considering its non-invasive nature, cardiac MRI suits well for investigating the time course of infarct healing and the changes occurring in peri-infarcted (adjacent) and remote myocardium, which ultimately promote the geometrical, morphological and functional abnormalities of the entire left ventricle (global LV remodeling). The current review will focus on the cardiac MRI utility for a comprehensive evaluation of patients with acute and chronic IHD with particular regard to post-infarction remodeling.


Semantic Interference through Multiple Distractors in Picture Naming in People with Aphasia.
When we refer to an object or concept by its name, activation of semantic and categorical information is necessary to retrieve the correct lexical representation. Whereas in neurotypical individuals it is well established that semantic context can interfere with or facilitate lexical retrieval, these effects are much less studied in people with lesions to the language network and impairment at different steps of lexical-semantic processing. Here, we applied a novel picture naming paradigm, where multiple categorically related and unrelated words were presented as distractors before a to-be-named target picture. Using eye tracking, we investigated preferential fixation on the cohort members versus nonmembers. Thereby, we can judge the impact of explicit acknowledgment of the category and its effect on semantic interference. We found that, in contrast to neurotypical participants [van Scherpenberg, C., Abdel Rahman, R., & Obrig, H. A novel multiword paradigm for investigating semantic context effects in language production. PLoS One, 15, e0230439, 2020], participants suffering from mild to moderate aphasia did not show a fixation preference on category members but still showed a large interference effect of ∼35 msec, confirming the implicit mechanism of categorical interference. However, preferential fixation on the categorically related cohort words correlated with clinical tests regarding nonverbal semantic abilities and integrity of the anterior temporal lobe. This highlights the role of supramodal semantics for explicit recognition of a semantic category, while semantic interference is triggered if the threshold of lexical cohort activation is reached. Confirming psycholinguistic evidence, the demonstration of a large and persistent interference effect through implicit lexico-semantic activation is important to understand deficits in people with a lesion in thelanguage network, potentially relevant for individualized intervention aiming at improving naming skills.


An automated microfluidic gene-editing platform for deciphering cancer genes.
Gene-editing techniques such as RNA-guided endonuclease systems are becoming increasingly popular for phenotypic screening. Such screens are normally conducted in arrayed or pooled formats. There has been considerable interest in recent years to find new technological methods for conducting these gene-editing assays. We report here the first digital microfluidic method that can automate arrayed gene-editing in mammalian cells. Specifically, this method was useful in culturing lung cancer cells for up to six days, as well as implementing automated gene transfection and knockout procedures. In addition, a standardized imaging pipeline to analyse fluorescently labelled cells was also designed and implemented during these procedures. A gene editing assay for interrogating the MAPK/ERK pathway was performed to show the utility of our platform and to determine the effects of knocking out the RAF1 gene in lung cancer cells. In addition to gene knockout, we also treated the cells with an inhibitor, Sorafenib Tosylate, to determine the effects of enzymatic inhibition. The combination of enzymatic inhibition and guide targeting on device resulted in lower drug concentrations for achieving half-inhibitory effects (IC50) compared to cells treated only with the inhibitor, confirming that lung cancer cells are being successfully edited on the device. We propose that this system will be useful for other types of gene-editing assays and applications related to personalized medicine.


Epstein-Barr virus: silent companion or causative agent of chronic liver disease?
The Epstein-Barr virus (EBV) has an important and multifaceted role in liver pathology. As a member of the herpes virus family, EBV establishes a persistent infection in more than 90% of adults. Besides acute hepatitis during primary infection, many clinical syndromes of interest for the hepatologist are associated with EBV infection. The role of EBV in the evolution of chronic hepatitis from hepatotropic viruses is considered. Chronic EBV-associated hepatitis is suspected in immunocompetent adults with compatible serology, suggestive histology and detection of the viral genome in the liver and/or increase of specific circulating cytotoxic T-lymphocytes. EBV is the main cause of post-transplant lymphoproliferative disorders which occur in up to 30% of cases. EBV-driven lymphoproliferative diseases are also recognized in non-immunocompromised patients and liver is involved in up to a third of the cases. Directly implicated in the pathogenesis of different tumors, EBV has a disputable role in hepatocellular carcinoma carcinogenesis. Further research is required in order to establish or reject the role of EBV in human liver cancer. This paper attempts to discuss the range of EBV-associated chronic liver diseases in immunocompetent patients, from mild, self-limiting mononuclear hepatitis to liver cancer.


Gut-mediated and HLA-B27-associated arthritis: an emphasis on ankylosing spondylitis and Crohn's disease with a proposal for the use of new treatment.
Ankylosing spondylitis (AS) and Crohn's disease (CD), especially when associated with spondylitis are interrelated conditions included within the categories of spondyloarthropathic disease entities. They share some common clinical, genetic, and microbiological findings. An extensive amount of studies which have been carried out by various independent groups throughout the world have shown that Klebsiella pneumoniae microorganisms could be suggested as the most likely etiopathogenetic triggers for AS and CD based on the molecular mimicry mechanism and the existence of the evidence for immunological, microbiological, and molecular link between Klebsiella and self antigens. It is proposed that the use of low starch diet in conjunction with the currently used treatment might help in the eradication of Klebsiella microbes from the bowel and could result in the stoppage and alleviation of the disease process in patients with AS and/or CD.


Pancreaticobiliary and duodenal perforations after periampullary endoscopic procedures: diagnosis and management.
To review our experience with management of pancreaticobiliary and duodenal (PB/D) perforations after periampullary endoscopic interventions. Although pancreaticobiliary and duodenal perforations after periampullary endoscopic procedures are rare, their management has not been well described. Individuals who experienced pancreaticobiliary and duodenal perforations. Comorbidities, interventions performed, mechanism/site of perforation, management, and hospital morbidity/mortality. Seventy-five perforations (0.6%) occurred in 12,427 procedures; 20 perforations (27%) occurred during biliary stricture dilatation, 18 (24%) during diagnostic endoscopic retrograde cholangiopancreatography, and 15 (20%) during management of choledocholithiasis. Perforations were caused by guidewire insertion in 24 patients (32%), sphincterotomy in 11 (15%), passage of the endoscope in 8 (11%), or stent migration in 7 (9%) and were identified during the index procedure in 45 patients (60%). Delayed presentations included pain in 33 patients (44%), leukocytosis in 26 (35%), and/or fever in 13 (17%) and were diagnosed using computed tomography in 19 patients (25%) and abdominal radiography in 10 (13%); 9 cases (12%) were diagnosed more than 24 hours after the procedure. Indications for operative treatment were gaping duodenal perforations and perforations in patients with surgically altered anatomy. Indications for nonoperative management included contained bile duct perforations and focal duodenal perforations. Management was nonoperative in 53 patients (71%) and operative in 22 (29%). Patients with duodenal perforations, higher American Society of Anesthesia status (P<.01 each), and older age (mean +/- SEM, 65 +/- 4 vs 55 +/- 2 years; P = .02) were more likely to require operative management. Hospital stay (mean +/- SEM, 16 +/- 4 vs 4 +/- 1 days; P<.05) and mortality (13% vs 4%; P<.05) were greater in operative patients (P<.05 each). Most (70%) pancreaticobiliary and duodenal perforations secondary to periampullary endoscopic interventions can be managed nonoperatively. Most biliary perforations can be managed nonoperatively; a requirement for operative treatment increases the mortality rate.


Demand for weight loss counseling after copayment elimination.
Overweight and obesity are public health issues in the United States, and veterans have a higher rate of overweight and obesity than the general population. Our objective was to examine whether copayment elimination increased use of a weight loss clinic by veterans. We examined clinic use by 44,411 new patients seen in a Veterans Affairs (VA) MOVE! weight management clinic before the copayment elimination and clinic use by 64,398 new patients seen in the year after copayment elimination. We examined clinic use via mixed-effects models for patients who were already exempt from copayment and patients who were newly exempt from copayment. We used 2 outcomes before and after copayment elimination: 1) the ratio of number of clinic visits by new users with the mean number of MOVE! clinic visits by all users, and 2) the number of clinic visits by each new user in the 6 months after their first visit. All models were adjusted for patient and clinic factors. Among newly exempt patients, the clinic-standardized rate of new use increased by 2.2% after the copayment was eliminated but increased 12% among already exempt veterans. This finding was confirmed in adjusted analyses. Analysis of number of clinic visits adjusted for patient and clinic factors also found that exempt and nonexempt veterans had similar numbers of repeat clinic visits. We saw an unexpected larger increase in demand among veterans who receive all VA care for free. These results suggest that VA should not assume that copayment reductions for selective preventive services will motivate patient change and achieve intended system-level outcomes.


Pygopus and legless provide essential transcriptional coactivator functions to armadillo/beta-catenin.
Wnt signaling controls important aspects of animal development, and its deregulation has been causally linked to cancer. Transduction of Wnt signals entails the association of beta-catenin with nuclear TCF DNA binding proteins and the subsequent activation of target genes. The transcriptional activity of Armadillo (Arm, the Drosophila beta-catenin homolog) largely depends on two recently discovered components, Legless (Lgs) and Pygopus (Pygo). Lgs functions as an adaptor between Arm/beta-catenin and Pygo, but different mechanisms have been proposed as to how Arm/beta-catenin is controlled by Lgs and Pygo. Although Lgs and Pygo were originally thought to serve as nuclear cofactors for Arm/beta-catenin to enhance its transactivation capacity, a recent analysis argued that they function instead to target Arm/beta-catenin to the nucleus. Here, we used genetic assays in cultured cells and in vivo to discriminate between the two paradigms. Regardless of the measures taken to maintain the nuclear presence of Arm/beta-catenin, a transcriptional-activation function of Pygo could not be bypassed. Our findings therefore indicate that Arm/beta-catenin depends on Lgs and Pygo primarily for its transcriptional output rather than for its nuclear import.


Effects of low-intensity non-coherent light therapy on the inflammatory process in the calcaneal tendon of ovariectomized rats.
The aim of this experimental study was to investigate the effects of low-intensity light-emitting diode (LED) phototherapy on the inflammatory process in the calcaneal tendon of ovariectomized rats (OVX) through the involvement of the inflammatory mediators interleukin (IL)-6, IL-10, and tumor necrosis factor-alpha (TNF-α). Thirty-five female Wistar rats were divided into 4 groups: 3 groups of OVX rats totaling 30 rats (untreated OVX rats [OVX injury group], treated OVX rats [OVX LED group], and control OVX rats; subgroups existed based on the sampling times, which were 3, 7, and 14 days) and 1 group of non-OVX rats (not OVX; n = 5). Tendon injury was induced by trauma using a 208-g mass placed at 20 cm from the right tendon of each animal with energy of 0.70 J. The animals were treated 12 h after tendonitis with LED therapy and every 48 h thereafter until euthanasia (at 3, 7, or 14 days). The tendons were dissected and stored in liquid nitrogen at -196 °C, thawed only at the time of immunoenzymatic testing (ELISA). Groups treated with LED showed a decrease in the number of pro-inflammatory cells, IL-6, and TNF-α (p <0.05), and an increase in IL-10 (p < 0.05) when compared to the not OVX group (p < 0.05). It was concluded that low-intensity LED treatment using the parameters and wavelength of 945 nm in the time periods studied reduced the release of IL-6 and TNF-α and increased the release of IL-10, thereby improving the inflammatory response in OVX rats.


Multiple Grammars and the Logic of Learnability in Second Language Acquisition.
The core notion of modern Universal Grammar is that language ability requires abstract representation in terms of hierarchy, movement operations, abstract features on words, and fixed mapping to meaning. These mental structures are a step toward integrating representational knowledge of all kinds into a larger model of cognitive psychology. Examining first and second language at once provides clues as to how abstractly we should represent this knowledge. The abstract nature of grammar allows both the formulation of many grammars and the possibility that a rule of one grammar could apply to another grammar. We argue that every language contains Multiple Grammars which may reflect different language families. We develop numerous examples of how the same abstract rules can apply in various languages and develop a theory of how language modules (case-marking, topicalization, and quantification) interact to predict L2 acquisition paths. In particular we show in depth how Germanic Verb-second operations, based on Verb-final structure, can apply in English. The argument is built around how and where V2 from German can apply in English, seeking to explain the crucial contrast: "nothing" yelled out Bill/(*)"nothing" yelled Bill out in terms of the necessary abstractness of the V2 rule.


Preclinical evaluation of Mab CC188 for ovarian cancer imaging.
Cancer stem cells (CSCs) have been successfully isolated from solid tumors and are believed to be initiating cells of primary, metastatic and recurrent tumors. Imaging and therapeutic reagents targeted to CSCs have potential to detect subclinical tumors and completely eradicate the disease. Previously, we have demonstrated that Mab CC188 binds to colon cancer CD133- and CD133+ (CSCs) cells. In this study, we examined the reactivity of Mab CC188 to ovarian cancer cells including CD133+ cells and primary tumor tissues using immunofluorescence staining methods and tissue microarray technique. We also explored the feasibility of using NIR dye-labeled Mab CC188 probe to image ovarian tumors in vivo. Mab CC188 stains both CD133- and CD133+ cells of ovarian cancer. Tissue microarray analysis reveals that 75% (92/123) of ovarian cancer cases are positively stained with Mab CC188. Weak positive (±), positive (+), strong positive (++) and very strong positive (+++) stains are 14.8, 3.7, 11 and 24.4%, respectively. In contrast, Mab CC188 staining is low in normal cells and tissues. In vivo study show that significant amounts of the probe accumulates in the excretion organs in the early period postinjection. At 24 hr, the imaging probes have largely accumulates in the tumor, while the intensity of the imaging probe decreases in the liver. The tumor uptake was still evident at 120-hr postinjection. Our work suggests that Mab CC188-based imaging and therapeutic reagents are capable of detecting early stage ovarian tumors and effectively treating the tumor.


The effect of changing plantarflexion resistive moment of an articulated ankle-foot orthosis on ankle and knee joint angles and moments while walking in patients post stroke.
The adjustment of plantarflexion resistive moment of an articulated ankle-foot orthosis is considered important in patients post stroke, but the evidence is still limited. Therefore, the aim of this study was to investigate the effect of changing the plantarflexion resistive moment of an articulated ankle-foot orthosis on ankle and knee joint angles and moments in patients post stroke. Gait analysis was performed on 10 subjects post stroke under four different plantarflexion resistive moment conditions using a newly designed articulated ankle-foot orthosis. Data were recorded using a Bertec split-belt instrumented treadmill in a 3-dimensional motion analysis laboratory. The ankle and knee sagittal joint angles and moments were significantly affected by the amount of plantarflexion resistive moment of the ankle-foot orthosis. Increasing the plantarflexion resistive moment of the ankle-foot orthosis induced significant decreases both in the peak ankle plantarflexion angle (P<0.01) and the peak knee extension angle (P<0.05). Also, the increase induced significant increases in the internal dorsiflexion moment of the ankle joint (P<0.01) and significantly decreased the internal flexion moment of the knee joint (P<0.01). These results suggest an important link between the kinematic/kinetic parameters of the lower-limb joints and the plantarflexion resistive moment of an articulated ankle-foot orthosis. A future study should be performed to clarify their relationship further so that the practitioners may be able to use these parameters as objective data to determine an optimal plantarflexion resistive moment of an articulated ankle-foot orthosis for improved orthotic care in individual patients.


Use of land facets to plan for climate change: conserving the arenas, not the actors.
Even under the most optimistic scenarios, during the next century human-caused climate change will threaten many wild populations and species. The most useful conservation response is to enlarge and link protected areas to support range shifts by plants and animals. To prioritize land for reserves and linkages, some scientists attempt to chain together four highly uncertain models (emission scenarios, global air-ocean circulation, regional circulation, and biotic response). This approach has high risk of error propagation and compounding and produces outputs at a coarser scale than conservation decisions. Instead, we advocate identifying land facets-recurring landscape units with uniform topographic and soil attributes-and designing reserves and linkages for diversity and interspersion of these units. This coarse-filter approach would conserve the arenas of biological activity, rather than the temporary occupants of those arenas. Integrative, context-sensitive variables, such as insolation and topographic wetness, are useful for defining land facets. Classification procedures such as k-means or fuzzy clustering are a good way to define land facets because they can analyze millions of pixels and are insensitive to case order. In regions lacking useful soil maps, river systems or riparian plants can indicate important facets. Conservation planners should set higher representation targets for rare and distinctive facets. High interspersion of land facets can promote ecological processes, evolutionary interaction, and range shift. Relevant studies suggest land-facet diversity is a good surrogate for today's biodiversity, but fails to conserve some species. To minimize such failures, a reserve design based on land facets should complement, rather than replace, other approaches. Designs based on land facets are not biased toward data-rich areas and can be applied where no maps of land cover exist.


A Pak1-PP2A-ERM signaling axis mediates F-actin rearrangement and degranulation in mast cells.
Mast cells coordinate allergy and allergic asthma and are crucial cellular targets in therapeutic approaches to inflammatory disease. Allergens cross-link immunoglobulin E bound at high-affinity receptors on the mast cell's surface, causing release of preformed cytoplasmic granules containing inflammatory molecules, including histamine, a principal effector of fatal septic shock. Both p21 activated kinase 1 (Pak1) and protein phosphatase 2A (PP2A) modulate mast cell degranulation, but the molecular mechanisms underpinning these observations and their potential interactions in common or disparate pathways are unknown. In this study, we use genetic and other approaches to show that Pak1's kinase-dependent interaction with PP2A potentiates PP2A's subunit assembly and activation. PP2A then dephosphorylates threonine 567 of Ezrin/Radixin/Moesin (ERM) molecules that have been shown to couple F-actin to the plasma membrane in other cell systems. In our study, the activity of this Pak1-PP2A-ERM axis correlates with impaired systemic histamine release in Pak1(-/-) mice and defective F-actin rearrangement and impaired degranulation in Ezrin disrupted (Mx1Cre(+)Ezrin(flox/flox)) primary mast cells. This heretofore unknown mechanism of mast cell degranulation provides novel therapeutic targets in allergy and asthma and may inform studies of kinase regulation of cytoskeletal dynamics in other cell lineages.


Relationships Among Adverse Events, Disease Characteristics, and Demographics in Treatment of Postherpetic Neuralgia With Gastroretentive Gabapentin.
To characterize risk factors for occurrence of adverse events (AEs) and treatment discontinuations due to AEs for improving safety and tolerability of treatment of postherpetic neuralgia (PHN). Patients with PHN (n=556) received 1800 mg once-daily gastroretentive gabapentin (G-GR) in 2 phase 3 and 1 phase 4 study. Safety assessments included the incidence and severity of AEs and analysis of discontinuations due to AEs. Multivariable, logistic regression analyses examined predictors of AE reporting and discontinuations due to AEs. In total, 53.2% of patients reported any AE, and 12.9% discontinued because of AEs. Both AE incidence and treatment discontinuations decreased rapidly during the 2-week titration to sustained, low levels. The probability to report any AE was 0.6 for females versus 0.4 for males, whereas there were no differences in probabilities for age (less than 75 vs. 75 y and older) and race (nonwhite vs. white). Consistent with this, only female sex was a significant (P=0.0006) predictor of AE reporting. Experiencing moderate (P≤0.0001) or severe (P=0.0006) AEs, but not patient demographics, was predictive of treatment discontinuations. The probability of discontinuation due to moderate AEs was 0.4 and 0.5 for severe AEs. The tolerability of G-GR was not affected by patient age, but was affected by AE severity. Although being female was predictive of reporting AEs, it did not influence treatment discontinuation. Given that PHN is a disease for which the risk and duration of PHN increases with age and with being female, G-GR appears to be a well-suited treatment option for PHN.


Unpacking the Black Box: A Formative Research Approach to the Development of Theory-Driven, Evidence-Based, and Culturally Safe Text Messages in Mobile Health Interventions.
Mobile-cellular subscriptions have increased steadily over the past decade. The accessibility of SMS messages over existing mobile networks is high and has almost universal availability even on older and unsophisticated mobile phones and in geographic settings where wireless coverage is weak. There is intensive exploration of this inexpensive mobile telecommunication technology to improve health services and promote behavior change among vulnerable populations. However, a neglected area of research is the documentation and critical analysis of the formative research process required in the development and refinement of effective SMS messages. The objective of this qualitative research study was to identify major factors that may impact on the effectiveness of evidence-based SMS messages designed to reduce health inequities in hypertension management in low resource settings, including Aboriginal populations in high-income countries and rural populations in low-income countries. Specifically, we were interested in uncovering the range of mediators that impact on appropriate message content transmission and, ultimately, on health behavior improvements in a range of these sociocultural settings. Collaborative qualitative research with Canadian Aboriginal and Tanzanian participants was conducted to deconstruct the content and transmission of evidence-based health information contained in SMS messages in the context of an international research project designed to address health inequalities in hypertension, and to develop a grounded theory of the major factors that mediate the effectiveness of this communication. We also examined the interrelationship of these mediators with the three essential conditions of the behavior system of the Behavioral Change Wheel model (capability, opportunity, and motivation) and cultural safety. Four focus groups with a total of 45 participants were conducted. Our grounded theory research revealed how discrepancies develop between the evidence-based text message created by researchers and the message received by the recipient in mobile health interventions. These discrepancies were primarily generated by six mediators of meaning in SMS messages: (1) negative or non-affirming framing of advocacies, (2) fear- or stress-inducing content, (3) oppressive or authoritarian content, (4) incongruity with cultural and traditional practices, (5) disconnect with the reality of the social determinants of health and the diversity of cultures within a population, and (6) lack of clarity and/or practicality of content. These 6 mediators of meaning provide the basis for sound strategies for message development because they impact directly on the target populations' capability, opportunity, and motivation for behavior change. The quality of text messages impacts significantly on the effectiveness of a mobile health intervention. Our research underscores the urgent need for interventions to incorporate and evaluate the quality of SMS messages and to examine the mediators of meaning within each targeted cultural and demographic group. Reporting on this aspect of mobile health intervention research will allow researchers to move away from the current black box of SMS text message development, thus improving the transparency of the process as well as the quality of the outcomes.


Modeling the complexities of water, hygiene, and health in Limpopo Province, South Africa.
Researchers have long studied the causes and prevention strategies of poor household water quality and early childhood diarrhea using intervention-control trials. Although the results of such trails can lead to useful information, they do not capture the complexity of this natural/engineered/social system. We report on the development of an agent-based model (ABM) to study such a system in Limpopo, South Africa. The study is based on four years of field data collection to accurately capture essential elements of the communities and their water contamination chain. An extensive analysis of those elements explored behaviors including water collection and treatment frequency as well as biofilm buildup in water storage containers, source water quality, and water container types. Results indicate that interventions must be optimally implemented in order to see significant reductions in early childhood diarrhea (ECD). Household boiling frequency, source water quality, water container type, and the biofilm layer contribution were deemed to have significant impacts on ECD. Furthermore, concurrently implemented highly effective interventions were shown to reduce diarrhea rates to very low levels even when other, less important practices were suboptimal. This technique can be used by a variety of stakeholders when designing interventions to reduce ECD incidences in similar settings.


Sonochemical/hydration-dehydration synthesis of Pt-TiO2 NPs/decorated carbon nanotubes with enhanced photocatalytic hydrogen production activity.
Modified Pt-TiO2 NPs/decorated carbon nanotubes were synthesized utilizing sonochemical/hydration-dehydration techniques. Pt was loaded on TiO2 by a photodeposition method keeping in mind the end goal to achieve electron-hole pair separation and promote the surface reaction. The morphological and basic properties of Pt-TiO2/fCNTs were investigated by field emission scanning electron microscopy (FESEM), high resolution transmission electron microscopy (HRTEM), powder X-ray diffraction (XRD), UV-vis diffuse reflectance spectroscopy (DRS), photoluminescence (PL) and Raman spectroscopy. The selected area electron diffraction (SAED) patterns of Pt-TiO2/fCNTs were obtained utilizing TEM-based energy dispersive X-ray spectroscopy (EDXS) analysis. It was found that the TiO2 nanoparticles were uniformly distributed on the fCNTs, and the Pt particles were decorated on the surface of TiO2/fCNTs. The photocatalytic hydrogen production activity of the Pt(0.5%)-TiO2/fCNTs(0.5%) nanoparticle composites was investigated using a sacrificial agent methanol solution. Pt-loaded TiO2 demonstrated a hydrogen evolution rate around 20 times that of TiO2/fCNTs(0.5%) (fSWCNTs, fMWCNTs). When compared with platinized TiO2 in methanol, which was utilized as a control material, Pt-TiO2/fCNTs demonstrated an almost 2-fold increment in hydrogen generation.


Efficiency of prostacyclin in the treatment of protamine-mediated right ventricular failure and acute pulmonary hypertension.
Protamine is used after cardiopulmonary bypass was stopped in order to reverse the anticoagulant effects of heparin administered during open-heart operations. Adverse hemodynamic responses to protamine are common, ranging from minor perturbations to cardiovascular collapse. The aim of the present study was to investigate whether a prostacyclin is effective in the treatment of protamine-mediated acute pulmonary hypertension and right ventricular failure in the perioperative period of isolated coronary artery bypass grafting (CABG) operations. In sixty-eight (1.78%) of 3800 patients who underwent isolated CABG, acute pulmonary hypertension and right ventricular failure developed during or following the protamine infusion. These 68 patients were included in the study and were randomized into two groups. Thirty-eight of the patients received prostaglandin I(2) (PGI(2)), norepinephrine and dopamine (PGI(2) group), whereas 30 patients received nitroglycerin, norepinephrine and dopamine (control group). Hemodynamic data were recorded before and after the above drug combinations. The mean value of left ventricle ejection fraction significantly increased (p < 0.05) and mean values of central venous pressure, pulmonary artery systolic and diastolic pressure, pulmonary capillary wedge pressure and pulmonary vascular resistance significantly decreased (p < 0.05) in the PGI(2) group. The mean value of pulmonary capillary wedge pressure significantly decreased (p < 0.05) and the mean value of central venous pressure significantly increased (p < 0.05) in the control group. In conclusion, prostacyclin (PGI(2)) is effective in the treatment of protamine-mediated acute pulmonary hypertension and right ventricular failure in the perioperative period in isolated CABG operations. This finding may be an important contribution to the treatment of severe protamine complications during open-heart operations.


Tumour promoting and suppressing roles of the atypical MAP kinase signalling pathway ERK3/4-MK5.
Perturbed action of signal transduction pathways, including the mitogen-activated protein (MAP) kinase pathways, is one of the hallmarks of many cancers. While the implication of the typical MAP kinase pathways ERK1/2-MEK1/2, p38MAPK and JNK is well established, recent findings illustrate that the atypical MAP kinase ERK3/4-MK5 may also be involved in tumorigenic processes. Remarkably, the ERK3/4-MK5 pathway seems to possess anti-oncogenic as well as pro-oncogenic properties in cell culture and aninal models. This review summarizes the mutations in the genes encoding ERK3, ERK4 and MK5 that have been detected in different cancers, reports aberrant expression levels of these proteins in human tumours, and discusses the mechanisms by which this pathway can induce senescence, stimulate angiogenesis and invasiveness.


GASS: genome structural annotation for Eukaryotes based on species similarity.
With the development of high-throughput sequencing techniques, more and more genomes were sequenced and assembled. However, annotating a genome's structure rapidly and expressly remains challenging. Current eukaryotic genome annotations require various, abundant supporting data, such as: species-specific and cross-species protein sequences, ESTs, cDNA and RNA-Seq data. Collecting those data and merging their analytical results to achieve a consistent complete annotation is a complex, time and cost consuming task. In our study, we proposed a fast and easy-to-use computational tool: GASS (Genome Annotation based on Species Similarity). It annotates a eukaryotic genome based on only the annotations from another similar species. With aligning the exons' sequences of an annotated similar species to the un-annotated genome, GASS detects the optimal transcript annotations with a shortest-path model. In our study, GASS was used to achieve the rhesus annotations based on the human annotations. The produced annotations were evaluated by comparing them to the two existing rhesus annotation databases (RefSeq and Ensembl) directly and being aligned with three RNA-Seq data of rhesus. The experiment results showed that more than 65% RefSeq exons and splicing junctions were exactly found by GASS. GASS's sensitivity was higher than RefSeq's, and was close to Ensembl's. GASS had higher specificities than Ensembl at gene, transcript, exon and splicing junction levels. We also found the mis-assemblies of rheMac3 genome, which led to the 2 bp shifts in annotating position on exons' boundary and then the incomplete splicing canonical sites in Refseq annotations. These detections were further supported by various data sources. GASS quickly produces structural genome annotations in sufficient abundance and accuracy. With simple and rapid running of GASS, small labs can create quick views of genome annotations for an un-annotated species, without the necessity to create, collect, analyze and synthesize extra various data sources, or wait several months for the annotations from professional organizations. GASS can be applied to many study occasions, such as the analysis of RNA-Seq datasets from the unannotated species whose genome drafts are available but the annotations are not.


Pulmonary epithelial integrity in children: relationship to ambient ozone exposure and swimming pool attendance.
Airway irritants such as ozone are known to impair lung function and induce airway inflammation. Clara cell protein (CC16) is a small anti-inflammatory protein secreted by the nonciliated bronchiolar Clara cells. CC16 in serum has been proposed as a noninvasive and sensitive marker of lung epithelial injury. In this study, we used lung function and serum CC16 concentration to examine the pulmonary responses to ambient O3 exposure and swimming pool attendance. The measurements were made on 57 children 10-11 years of age before and after outdoor exercise for 2 hr. Individual O3 exposure was estimated as the total exposure dose between 0700 hr until the second blood sample was obtained (mean O3 concentration/m3 times symbol hours). The maximal 1-hr value was 118 microg/m3 (59 ppb), and the individual exposure dose ranged between 352 and 914 microg/m3hr. These O3 levels did not cause any significant changes in mean serum CC16 concentrations before or after outdoor exercise, nor was any decrease in lung function detected. However, children who regularly visited chlorinated indoor swimming pools had significantly lower CC16 levels in serum than did nonswimming children both before and after exercise (respectively, 57 +/- 2.4 and 53 +/- 1.7 microg/L vs. 8.2 +/- 2.8 and 8.0 +/- 2.6 microg/L; p < 0.002). These results indicate that repeated exposure to chlorination by-products in the air of indoor swimming pools has adverse effects on the Clara cell function in children. A possible relation between such damage to Clara cells and pulmonary morbidity (e.g., asthma) should be further investigated.


Granulocyte-macrophage colony-stimulating factor modulates the excitation-response coupling sequence in human neutrophils.
We have investigated the effects of granulocyte-macrophage (GM) CSF on two biochemical responses thought to play internal signaling roles in the neutrophils, namely the increase in the concentration of free calcium and the changes in the internal pH. The changes in the right-angle light scatter of the cell suspensions were also examined. GM-CSF was found not to affect the resting levels of calcium or the internal pH of the cells. However, pre-incubation of the neutrophils with the growth factor resulted in an increase in the magnitude of the calcium transients that follow the stimulation of the cells with chemotactic factors as well as a profound depression of the cell alkalinization that is induced by fMet-Leu-Phe, leukotriene B4, and platelet-activating factor, as well as by phorbol esters. The rapid cytoplasmic acidification elicited by these agents was apparently magnified. GM-CSF did not directly affect the Na+/H+ antiport as GM-CSF-treated cells were as capable as untreated cells of recovering from an acid load. The right-angle light scatter responses of the cells to the chemotactic factors were found not to be affected by GM-CSF. These results provide an initial description of the effects of GM-CSF on the cellular physiology of the neutrophils and insights into the mechanism of action of this factor as well as into the excitation-response coupling sequence activated by chemotactic factors.


Affinity and kinetic analysis of L-selectin (CD62L) binding to glycosylation-dependent cell-adhesion molecule-1.
The selectin family of cell adhesion molecules mediates the tethering and rolling of leukocytes on blood vessel endothelium. It has been postulated that the molecular basis of this highly dynamic adhesion is the low affinity and rapid kinetics of selectin interactions. However, affinity and kinetic analyses of monomeric selectins binding their natural ligands have not previously been reported. Leukocyte selectin (L-selectin, CD62L) binds preferentially to O-linked carbohydrates present on a small number of mucin-like glycoproteins, such as glycosylation-dependent cell adhesion molecule-1 (GlyCAM-1), expressed in high endothelial venules. GlyCAM-1 is a soluble secreted protein which, following binding to CD62L, stimulates beta2-integrin-mediated adhesion of lymphocytes. Using surface plasmon resonance, we show that a soluble monomeric form of CD62L binds to purified immobilized GlyCAM-1 with a dissociation constant (Kd) of 108 microM. CD62L dissociates from GlyCAM-1 with a very fast dissociation rate constant (>/=10 s-1) which agrees well with the reported dissociation rate constant of CD62L-mediated leukocyte tethers. The calculated association rate constant is >/=10(5) M-1 s-1. At concentrations just above its mean serum level (approximately 1.5 microg/ml or approximately 30 nM), GlyCAM-1 binds multivalently to immobilized CD62L. It follows that soluble GlyCAM-1 may cross-link CD62L when it binds to cells, suggesting a mechanism for signal transduction.


Estimating the harms of nicotine-containing products using the MCDA approach.
An international expert panel convened by the Independent Scientific Committee on Drugs developed a multi-criteria decision analysis model of the relative importance of different types of harm related to the use of nicotine-containing products. The group defined 12 products and 14 harm criteria. Seven criteria represented harms to the user, and the other seven indicated harms to others. The group scored all the products on each criterion for their average harm worldwide using a scale with 100 defined as the most harmful product on a given criterion, and a score of zero defined as no harm. The group also assessed relative weights for all the criteria to indicate their relative importance. Weighted averages of the scores provided a single, overall score for each product. Cigarettes (overall weighted score of 100) emerged as the most harmful product, with small cigars in second place (overall weighted score of 64). After a substantial gap to the third-place product, pipes (scoring 21), all remaining products scored 15 points or less. Cigarettes are the nicotine product causing by far the most harm to users and others in the world today. Attempts to switch to non-combusted sources of nicotine should be encouraged as the harms from these products are much lower.


Germ cell transplantation in an azoospermic Klinefelter bull.
Germ cell transplantation is a technique that transfers donor testicular cells into recipient testes. A population of germ cells can colonize the recipient testis, initiate spermatogenesis, and produce sperm capable of fertilization. In the present study, a nonmosaic Klinefelter bull was used as a germ cell recipient. The donor cell suspension was introduced into the rete testis using ultrasound-guided puncture. A pulsatile administration of GnRH was performed to stimulate spermatogenesis. The molecular approach to detect donor cells was done by a quantitative polymerase chain reaction with allele discrimination based on a genetic mutation between donor and recipient. Therefore, a known genetic mutation, associated with coat-color phenotype, was used to calculate the ratio of donor to recipient cells in the biopsy specimens and ejaculates for 10 mo. After slaughtering, meiotic preparations were performed. The injected germ cells did not undergo spermatogenesis. Six months after germ cell transplantation, the donor cells were rejected, which indicates that the donor cells could not incorporate in the testis. The hormone stimulation showed that the testosterone-producing Leydig cells were functionally intact. Despite subfertility therapy, neither the recipient nor the donor cells underwent spermatogenesis. Therefore, nonmosaic Klinefelter bulls are not suitable as germ cell recipients. Future germ cell recipients in cattle could be mosaic Klinefelters, interspecies hybrids, bulls with Sertoli cell-only syndrome, or bulls with disrupted germ cell migration caused by RNA interference.


A biomimetic 3D model of hypoxia-driven cancer progression.
The fate of tumors depends both on the cancer cells' intrinsic characteristics and on the environmental conditions where the tumors reside and grow. Engineered in vitro models have led to significant advances in cancer research, allowing the investigation of cells in physiological environments and the study of disease mechanisms and processes with enhanced relevance. Here we present a biomimetic cancer model based on a collagen matrix synthesized through a biologically inspired process. We compared in this environment the responses of two breast tumor lineages characterized by different molecular patterns and opposite clinical behaviors: MCF-7 that belong to the luminal A subtype connected to an indolent course, and basal-like MDA-MB-231 connected to high-grade and aggressive disease. Cancer cells in the biomimetic matrix recreate a hypoxic environment that affects their growth dynamics and phenotypic features. Hypoxia induces apoptosis and the selection of aggressive cells that acquire expression signatures associated with glycolysis, angiogenesis, cell-matrix interaction, epithelial to mesenchymal transition and metastatic ability. In response to hypoxia MDA-MB-231 migrate on the collagen fibrils and undergo cellular senescence, while MCF-7 do not exhibit these behaviors. Our biomimetic model mimics the evolution of tumors with different grade of aggressiveness fostered by a hypoxic niche and provides a relevant technology to dissect the events involved in cancer progression.


Relationship between muscle hardness estimated by the indentation method and muscle contractile level.
The purpose of this study was to investigate the relationship between muscle contractile level and hardness by the indentation method. Eleven healthy male subjects were involved in this study. The subjects put their arms horizontally on a table. The subjects were instructed to keep the isometric contractile force constant at three elbow angles. The indentation depth and reaction force of the biceps brachii muscle were measured, and electromyogram (EMG) were done. First, EMGs before and during the indentation were compared. The EMGs showed no significant increase during the indentation. The indentation did not affect muscle activities. Next, the force indentation depth curves were approximated with the non-linear Voigt model by the least square method, and the indices of the elasticity and the viscosity were estimated. Then the relationship between the indices and the contractile levels were investigated. The contractile level was the force normalized by that in the maximum voluntary contraction. The elastic indices increased almost linearly as the contractile levels increased. The relationships at different elbow angles did not show significant differences. However, the characteristics of the viscous indices varied depending on the subjects.


Evolutionary divergence times in the Annonaceae: evidence of a late Miocene origin of Pseuduvaria in Sundaland with subsequent diversification in New Guinea.
Phylogenetic analyses of the Annonaceae consistently identify four clades: a basal clade consisting of Anaxagorea, and a small 'ambavioid' clade that is sister to two main clades, the 'long branch clade' (LBC) and 'short branch clade' (SBC). Divergence times in the family have previously been estimated using non-parametric rate smoothing (NPRS) and penalized likelihood (PL). Here we use an uncorrelated lognormal (UCLD) relaxed molecular clock in BEAST to estimate diversification times of the main clades within the family with a focus on the Asian genus Pseuduvaria within the SBC. Two fossil calibration points are applied, including the first use of the recently discovered Annonaceae fossil Futabanthus. The taxonomy and morphology of Pseuduvaria have been well documented, although no previous dating or biogeographical studies have been undertaken. Ancestral areas at internal nodes within Pseuduvaria are determined using dispersal-vicariance analysis (DIVA) and weighted ancestral area analysis (WAAA). The divergence times of the main clades within the Annonaceae were found to deviate slightly from previous estimates that used different calibration points and dating methods. In particular, our estimate for the SBC crown (55.2-26.9 Mya) is much younger than previous estimates (62.5-53.1 +/- 3.6 Mya and ca. 58.76 Mya). Early diversification of Pseuduvaria was estimated to have occurred 15-8 Mya, possibly associated with the 'mid-Miocene climatic optimum.' Pseuduvaria is inferred to have originated in Sundaland in the late Miocene, ca. 8 Mya; subsequent migration events were predominantly eastwards towards New Guinea and Australia, although several migratory reversals are also postulated. Speciation of Pseuduvaria within New Guinea may have occurred after ca. 6.5 Mya, possibly coinciding with the formation of the Central Range orogeny from ca. 8 Mya. Our divergence time estimates within the Annonaceae are likely to be more precise as we used a UCLD clock model and calibrated the phylogeny using new fossil evidence. Pseuduvaria is shown to have dispersed from Sundaland after the late Miocene. The present-day paleotropical distribution of Pseuduvaria may have been achieved by long-distance dispersal, and speciation events might be explained by global climatic oscillations, sea level fluctuations, and tectonic activity.


A molecular beacon, bead-based assay for the detection of nucleic acids by flow cytometry.
Molecular beacons are dual-labelled probes that are typically used in real-time PCR assays, but have also been conjugated with solid matrices for use in microarrays or biosensors. We have developed a fluid array system using microsphere-conjugated molecular beacons and the flow cytometer for the specific, multiplexed detection of unlabelled nucleic acids in solution. For this array system, molecular beacons were conjugated with microspheres using a biotin-streptavidin linkage. A bridged conjugation method using streptavidin increased the signal-to-noise ratio, allowing for further discrimination of target quantitation. Using beads of different sizes and molecular beacons in two fluorophore colours, synthetic nucleic acid control sequences were specifically detected for three respiratory pathogens, including the SARS coronavirus in proof-of-concept experiments. Considering that routine flow cytometers are able to detect up to four fluorescent channels, this novel assay may allow for the specific multiplex detection of a nucleic acid panel in a single tube.


Compound-specific hydrogen isotope analysis of fluorine-, chlorine-, bromine- and iodine-bearing organics using gas chromatography-chromium-based high-temperature conversion (Cr/HTC) isotope ratio mass spectrometry.
The conventional high-temperature conversion (HTC) approach towards hydrogen compound-specific isotope analysis (CSIA) of halogen-bearing (F, Cl, Br, I) organics suffers from incomplete H2 yields and associated hydrogen isotope fractionation due to generation of HF, HCl, HBr, and HI byproducts. Moreover, the traditional off-line combustion of highly halogenated compounds results in incomplete recovery of water as an intermediary compound for hydrogen isotope ratio mass spectrometry (IRMS), and hence also leads to isotope fractionation. This study presents an optimized chromium-based high-temperature conversion (Cr/HTC) approach for hydrogen CSIA of various fluorinated, chlorinated, brominated and iodinated organic compounds. The Cr/HTC approach is fast, economical, and not affected by low H2 yields and associated isotope fractionation. The performance of the modified gas chromatography/chromium-based high-temperature conversion (GC-Cr/HTC) system was monitored and optimized using an ion trap mass spectrometer. Quantitative conversion of organic hydrogen into H2 analyte gas was achieved for all halogen-bearing compounds. The corresponding accuracy of CSIA was validated using (i) manual dual-inlet (DI)-IRMS after off-line conversion into H2 , and (ii) elemental analyzer (EA)-Cr/HTC-IRMS (on-line conversion). The overall hydrogen isotope analysis of F-, Cl-, Br- and I-bearing organics via GC-Cr/HTC-IRMS achieved a precision σ ≤ 3 mUr and an accuracy within ±5 mUr along the VSMOW-SLAP scale compared with the measured isotope compositions resulting from both validation methods, off-line and on-line. The same analytical performance as for single-compound GC-Cr/HTC-IRMS was achieved compound-specifically for mixtures of halogenated organics following GC separation to baseline resolution. GC-Cr/HTC technology can be implemented in existing analytical equipment using commercially available materials to provide a versatile tool for hydrogen CSIA of halogenated and non-halogenated organics. Copyright © 2017 John Wiley & Sons, Ltd.


Toxicological evaluation of nail polish waste discarded in the environment.
Nail polish has been widely used around the world. However, the hazards of nail polishes discarded in the environment are still poorly investigated. Thus, the toxicogenetic effects of solubilized (SE) and leached (LE) extracts from nail polishes were investigated, simulating their disposal on water and landfill, respectively, and identifying their physicochemical properties and chemical constituents. Organic compounds and metals were detected in both extracts. SE and LE only induced mutagenic effects in TA98 Salmonella strain in the presence and absence of exogenous metabolic activation. Although both extracts did not significantly increase the frequency of micronucleated HepG2 cells, the cell viability was affected by 24-h exposure. No DNA damage was observed in gonad fish cells (RTG-2) exposed to both extracts; however, the highest SE and LE concentrations induced significant lethal and sublethal effects on zebrafish early-life stages during 96-h exposure. Based on our findings, it can be concluded that if nail polishes enter aquatic systems, it may cause negative impacts to the environment.


Cracking the chromatin code: precise rule of nucleosome positioning.
Various aspects of packaging DNA in eukaryotic cells are outlined in physical rather than biological terms. The informational and physical nature of packaging instructions encoded in DNA sequences is discussed with the emphasis on signal processing difficulties--very low signal-to-noise ratio and high degeneracy of the nucleosome positioning signal. As the author has been contributing to the field from its very onset in 1980, the review is mostly focused at the works of the author and his colleagues. The leading concept of the overview is the role of deformational properties of DNA in the nucleosome positioning. The target of the studies is to derive the DNA bendability matrix describing where along the DNA various dinucleotide elements should be positioned, to facilitate its bending in the nucleosome. Three different approaches are described leading to derivation of the DNA deformability sequence pattern, which is a simplified linear presentation of the bendability matrix. All three approaches converge to the same unique sequence motif CGRAAATTTYCG or, in binary form, YRRRRRYYYYYR, both representing the chromatin code.


[Identification and functional analysis of a KCNA5 mutation responsible for idiopathic atrial fibrillation].
To investigate the molecular mechanism of idiopathic atrial fibrillation (AF) associated with KCNA5 mutation. The clinical data and blood samples from 130 unrelated subjects with idiopathic AF were collected and evaluated in contrast to 200 healthy individuals. The coding exons and the flanking introns of KCNA5 gene were amplified by polymerase chain reaction and sequenced using the di-deoxynucleotide chain termination approach to identify potential mutations. Multiple alignment of the KCNA5 encoded protein sequences across species was performed. The KCNA5 gene was cloned and the corresponding mutant was acquired by site directed mutagenesis. The recombinant plasmid expressing or tracing KCNA5 was constructed and transfected into COS-7 cells with Lipofectamine, respectively. The effects of mutated KCNA5 gene on the electrophysiological characteristics and subcellular location of encoded ion channel were explored by patch-clamp and confocal microscope, respectively. A heterozygous missense KCNA5 mutation, c.1580C > T was identified in 1 of 130 idiopathic AF patients. Namely, the triplet substitution of ATG for ACG at codon 527, predicting the conversion of threonine into methionine at amino acid residue 527 (T527M), was detected. Functional analysis revealed that KCNA5 T527M mutation exerted predominant negative effect on the currents but no effect on the subcellular location of encoded ion channel. The heterozygous KCNA5 T527M mutation identified in 1 idiopathic AF patient exerts predominant negative effect on the currents of encoded ion channel, thereby conducting to idiopathic AF.


Epidermal growth factor receptor relocalization and kinase activity are necessary for directional migration of keratinocytes in DC electric fields.
Human keratinocytes migrate towards the negative pole in DC electric fields of physiological strength. This directional migration is promoted by epidermal growth factor (EGF). To investigate how EGF and its receptor (EGFR) regulate this directionality, we first examined the effect of protein tyrosine kinase inhibitors, including PD158780, a specific inhibitor for EGFR, on this response. At low concentrations, PD158780 inhibited keratinocyte migration directionality, but not the rate of migration; at higher concentrations, it reduced the migration rate as well. The less specific inhibitors, genistein, lavendustin A and tyrphostin B46, reduced the migration rate, but did not affect migration directionality. These data suggest that inhibition of EGFR kinase activity alone reduces directed motility, and inhibition of multiple tyrosine kinases, including EGFR, reduces the cell migration rate. EGFR redistribution also correlates with directional migration. EGFR concentrated on the cathodal face of the cell as early as 5 minutes after exposure to electric fields. PD158780 abolished EGFR localization to the cathodal face. These data suggest that EGFR kinase activity and redistribution in the plasma membrane are required for the directional migration of keratinocytes in DC electric fields. This study provides the first insights into the mechanisms of directed cell migration in electric fields.