Situational awareness within objective structured clinical examination stations in undergraduate medical training - a literature search.
Medical students may not be able to identify the essential elements of situational awareness (SA) necessary for clinical reasoning. Recent studies suggest that students have little insight into cognitive processing and SA in clinical scenarios. Objective Structured Clinical Examinations (OSCEs) could be used to assess certain elements of situational awareness. The purpose of this paper is to review the literature with a view to identifying whether levels of SA based on Endsley's model can be assessed utilising OSCEs during undergraduate medical training. A systematic search was performed pertaining to SA and OSCEs, to identify studies published between January 1975 (first paper describing an OSCE) and February 2017, in peer reviewed international journals published in English. PUBMED, EMBASE, PsycINFO Ovid and SCOPUS were searched for papers that described the assessment of SA using OSCEs among undergraduate medical students. Key search terms included "objective structured clinical examination", "objective structured clinical assessment" or "OSCE" and "non-technical skills", "sense-making", "clinical reasoning", "perception", "comprehension", "projection", "situation awareness", "situational awareness" and "situation assessment". Boolean operators (AND, OR) were used as conjunctions to narrow the search strategy, resulting in the limitation of papers relevant to the research interest. Areas of interest were elements of SA that can be assessed by these examinations. The initial search of the literature retrieved 1127 publications. Upon removal of duplicates and papers relating to nursing, paramedical disciplines, pharmacy and veterinary education by title, abstract or full text, 11 articles were eligible for inclusion as related to the assessment of elements of SA in undergraduate medical students. Review of the literature suggests that whole-task OSCEs enable the evaluation of SA associated with clinical reasoning skills. If they address the levels of SA, these OSCEs can provide supportive feedback and strengthen educational measures associated with higher diagnostic accuracy and reasoning abilities. Based on the findings, the early exposure of medical students to SA is recommended, utilising OSCEs to evaluate and facilitate SA in dynamic environments.


A CHecklist for statistical Assessment of Medical Papers (the CHAMP statement): explanation and elaboration.
Misuse of statistics in medical and sports science research is common and may lead to detrimental consequences to healthcare. Many authors, editors and peer reviewers of medical papers will not have expert knowledge of statistics or may be unconvinced about the importance of applying correct statistics in medical research. Although there are guidelines on reporting statistics in medical papers, a checklist on the more general and commonly seen aspects of statistics to assess when peer-reviewing an article is needed. In this article, we propose a CHecklist for statistical Assessment of Medical Papers (CHAMP) comprising 30 items related to the design and conduct, data analysis, reporting and presentation, and interpretation of a research paper. While CHAMP is primarily aimed at editors and peer reviewers during the statistical assessment of a medical paper, we believe it will serve as a useful reference to improve authors' and readers' practice in their use of statistics in medical research. We strongly encourage editors and peer reviewers to consult CHAMP when assessing manuscripts for potential publication. Authors also may apply CHAMP to ensure the validity of their statistical approach and reporting of medical research, and readers may consider using CHAMP to enhance their statistical assessment of a paper.


Thermal, Spectroscopic, and Crystallographic Analysis of Mannose-Derived Linear Polyols.
The major diastereomer formed in the Barbier-type metal-mediated allylation of d-mannose has previously been shown to adopt a perfectly linear conformation, both in solid state and in solution, resulting in the formation of hydrogen-bonded networks and subsequent aggregation from aqueous solution upon stirring. Here, a comprehensive study of the solid state structure of both the allylated d-mannose and its racemic form has been conducted. The binary melting point diagram of the system was determined by differential scanning calorimetry analysis, and the obtained results, along with structure determination by single crystal X-ray diffraction, confirmed that allylated mannose forms a true racemate. Further examination by powder X-ray diffraction and CP MAS 13C NMR spectroscopy revealed polymorphism both in the pure enantiomer and in the racemate. In addition, the propargylated and hydrogenated analogues of allylated d-mannose were prepared and subjected to thermal and spectroscopic analyses. The crystal structure of the propargylated compound was successfully determined, showing a linear molecular conformation similar to that found for allylated d-mannose. Both new compounds likewise display aggregation behavior in water, further verifying that the low-energy linear conformation plays a significant role in this unusual behavior of these rodlike mannose derivatives.


UK emissions of the greenhouse gas nitrous oxide.
Signatories of the Kyoto Protocol are obliged to submit annual accounts of their anthropogenic greenhouse gas emissions, which include nitrous oxide (N(2)O). Emissions from the sectors industry (3.8 Gg), energy (14.4 Gg), agriculture (86.8 Gg), wastewater (4.4 Gg), land use, land-use change and forestry (2.1 Gg) can be calculated by multiplying activity data (i.e. amount of fertilizer applied, animal numbers) with simple emission factors (Tier 1 approach), which are generally applied across wide geographical regions. The agricultural sector is the largest anthropogenic source of N(2)O in many countries and responsible for 75 per cent of UK N(2)O emissions. Microbial N(2)O production in nitrogen-fertilized soils (27.6 Gg), nitrogen-enriched waters (24.2 Gg) and manure storage systems (6.4 Gg) dominate agricultural emission budgets. For the agricultural sector, the Tier 1 emission factor approach is too simplistic to reflect local variations in climate, ecosystems and management, and is unable to take into account some of the mitigation strategies applied. This paper reviews deviations of observed emissions from those calculated using the simple emission factor approach for all anthropogenic sectors, briefly discusses the need to adopt specific emission factors that reflect regional variability in climate, soil type and management, and explains how bottom-up emission inventories can be verified by top-down modelling.


Effect of eflorithine on intestinal regeneration.
Patching intestinal defects with adjacent serosal surfaces results in the growth of new intestinal mucosa. Since polyamine biosynthesis is associated with cellular growth and differentiation, it may be important in this regenerative process. Our aim was to determine the effect of eflorithine (difluoromethylornithine), a specific inhibitor of polyamine synthesis, on intestinal regeneration. Forty-eight New Zealand white rabbits had 2 x 5-cm ileal defects patched with adjacent cecal serosal surface. One half of the animals took 2% eflorithine in drinking water postoperatively. Six animals in each group were killed 7, 14, 21, and 28 days after patching. There was no significant difference in neomucosal growth at any time. Villous height, disaccharidase activity, and crypt cell production were significantly lower in the eflorithine-treated animals. Eflorithine-treated animals had significantly lower ornithine decarboxylase activity and polyamine levels. Despite the inhibitory effect of eflorithine on polyamine synthesis and proliferative activity, epithelialization and contraction of the patched defect were not affected. These findings suggest that polyamine synthesis is important in proliferation and differentiation of cells in the neomucosa but does not influence cell migration in intestinal regeneration.


Ethnicity and risk of cardiovascular disease (CVD): 4.8 year follow-up of patients with type 2 diabetes living in Scotland.
Potential differences in cardiovascular risk by ethnicity remain uncertain. We evaluated the association of ethnicity with cardiovascular disease (CVD) incidence in a large cohort of people with type 2 diabetes living in Scotland. Data from Scottish Care Information-Diabetes (SCI-Diabetes) were linked to Scottish Morbidity Records (SMR01) and National Records of Scotland data for mortality for dates between 2005 and 2011. Of 156,991 people with type 2 diabetes with coded ethnicity, 121,535 (77.4%) had no CVD at baseline (White: 114,461; Multiple Ethnic: 2,554; Indian: 797; Other Asian: 319; Pakistani: 2,250; Chinese: 387; African-Caribbean: 301 and Other: 466) and were followed up (mean ± SD: 4.8 ± 2.3 years) for the development of fatal and non-fatal CVD. During follow-up, 16,265 (13.4%) patients developed CVD (ischaemic heart or cerebrovascular diseases). At baseline, Pakistanis were younger and had developed diabetes earlier, had higher HbA1c and longer duration of diabetes, but had lower BP, BMI, creatinine, proportion of smokers and proportion on antihypertensive therapy than whites. The age and sex adjusted HRs for CVD were HR 1.31 (CI 1.17, 1.47), p < 0.001 in Pakistanis and HR 0.66 (CI 0.47, 0.92), p = 0.014 in Chinese compared with whites. Adjusting additionally for an area measure of deprivation, duration of diabetes, conventional CVD and other risk factors, the HR for Pakistanis (HR 1.45 [CI 1.14, 1.85], p = 0.002) was significantly higher, and that for Chinese (HR = 0.58 [CI 0.24, 1.40], p = 0.228) lower, compared with whites. Compared with whites with type 2 diabetes, those of Pakistani ethnicity in Scotland were at increased risk of CVD, whereas Chinese were at lower risk, with these differences unexplained by known risk factors.


The coactivator PGC-1α regulates skeletal muscle oxidative metabolism independently of the nuclear receptor PPARβ/δ in sedentary mice fed a regular chow diet.
Physical activity improves oxidative capacity and exerts therapeutic beneficial effects, particularly in the context of metabolic diseases. The peroxisome proliferator-activated receptor (PPAR) γ coactivator-1α (PGC-1α) and the nuclear receptor PPARβ/δ have both been independently discovered to play a pivotal role in the regulation of oxidative metabolism in skeletal muscle, though their interdependence remains unclear. Hence, our aim was to determine the functional interaction between these two factors in mouse skeletal muscle in vivo. Adult male control mice, PGC-1α muscle-specific transgenic (mTg) mice, PPARβ/δ muscle-specific knockout (mKO) mice and the combination PPARβ/δ mKO + PGC-1α mTg mice were studied under basal conditions and following PPARβ/δ agonist administration and acute exercise. Whole-body metabolism was assessed by indirect calorimetry and blood analysis, while magnetic resonance was used to measure body composition. Quantitative PCR and western blot were used to determine gene expression and intracellular signalling. The proportion of oxidative muscle fibre was determined by NADH staining. Agonist-induced PPARβ/δ activation was only disrupted by PPARβ/δ knockout. We also found that the disruption of the PGC-1α-PPARβ/δ axis did not affect whole-body metabolism under basal conditions. As expected, PGC-1α mTg mice exhibited higher exercise performance, peak oxygen consumption and lower blood lactate levels following exercise, though PPARβ/δ mKO + PGC-1α mTg mice showed a similar phenotype. Similarly, we found that PPARβ/δ was dispensable for PGC-1α-mediated enhancement of an oxidative phenotype in skeletal muscle. Collectively, these results indicate that PPARβ/δ is not an essential partner of PGC-1α in the control of skeletal muscle energy metabolism.


Antidepressant actions of ketamine engage cell-specific translation via eIF4E.
Effective pharmacotherapy for major depressive disorder remains a major challenge, as more than 30% of patients are resistant to the first line of treatment (selective serotonin reuptake inhibitors)1. Sub-anaesthetic doses of ketamine, a non-competitive N-methyl-D-aspartate receptor antagonist2,3, provide rapid and long-lasting antidepressant effects in these patients4-6, but the molecular mechanism of these effects remains unclear7,8. Ketamine has been proposed to exert its antidepressant effects through its metabolite (2R,6R)-hydroxynorketamine ((2R,6R)-HNK)9. The antidepressant effects of ketamine and (2R,6R)-HNK in rodents require activation of the mTORC1 kinase10,11. mTORC1 controls various neuronal functions12, particularly through cap-dependent initiation of mRNA translation via the phosphorylation and inactivation of eukaryotic initiation factor 4E-binding proteins (4E-BPs)13. Here we show that 4E-BP1 and 4E-BP2 are key effectors of the antidepressant activity of ketamine and (2R,6R)-HNK, and that ketamine-induced hippocampal synaptic plasticity depends on 4E-BP2 and, to a lesser extent, 4E-BP1. It has been hypothesized that ketamine activates mTORC1-4E-BP signalling in pyramidal excitatory cells of the cortex8,14. To test this hypothesis, we studied the behavioural response to ketamine and (2R,6R)-HNK in mice lacking 4E-BPs in either excitatory or inhibitory neurons. The antidepressant activity of the drugs is mediated by 4E-BP2 in excitatory neurons, and 4E-BP1 and 4E-BP2 in inhibitory neurons. Notably, genetic deletion of 4E-BP2 in inhibitory neurons induced a reduction in baseline immobility in the forced swim test, mimicking an antidepressant effect. Deletion of 4E-BP2 specifically in inhibitory neurons also prevented the ketamine-induced increase in hippocampal excitatory neurotransmission, and this effect concurred with the inability of ketamine to induce a long-lasting decrease in inhibitory neurotransmission. Overall, our data show that 4E-BPs are central to the antidepressant activity of ketamine.


One-particle-thick, solvent-free, coarse-grained model for biological and biomimetic fluid membranes.
Biological membranes are involved in numerous intriguing biophysical and biological cellular phenomena of different length scales, ranging from nanoscale raft formation, vesiculation, to microscale shape transformations. With extended length and time scales as compared to atomistic simulations, solvent-free coarse-grained membrane models have been exploited in mesoscopic membrane simulations. In this study, we present a one-particle-thick fluid membrane model, where each particle represents a cluster of lipid molecules. The model features an anisotropic interparticle pair potential with the interaction strength weighed by the relative particle orientations. With the anisotropic pair potential, particles can robustly self-assemble into fluid membranes with experimentally relevant bending rigidity. Despite its simple mathematical form, the model is highly tunable. Three potential parameters separately and effectively control diffusivity, bending rigidity, and spontaneous curvature of the model membrane. As demonstrated by selected examples, our model can naturally simulate dynamics of phase separation in multicomponent membranes and the topological change of fluid vesicles.


Structure of the Bacillus subtilis hibernating 100S ribosome reveals the basis for 70S dimerization.
Under stress conditions, such as nutrient deprivation, bacteria enter into a hibernation stage, which is characterized by the appearance of 100S ribosomal particles. In Escherichia coli, dimerization of 70S ribosomes into 100S requires the action of the ribosome modulation factor (RMF) and the hibernation-promoting factor (HPF). Most other bacteria lack RMF and instead contain a long form HPF (LHPF), which is necessary and sufficient for 100S formation. While some structural information exists as to how RMF and HPF mediate formation of E. coli 100S (Ec100S), structural insight into 100S formation by LHPF has so far been lacking. Here we present a cryo-EM structure of the Bacillus subtilis hibernating 100S (Bs100S), revealing that the C-terminal domain (CTD) of the LHPF occupies a site on the 30S platform distinct from RMF Moreover, unlike RMF, the BsHPF-CTD is directly involved in forming the dimer interface, thereby illustrating the divergent mechanisms by which 100S formation is mediated in the majority of bacteria that contain LHPF, compared to some γ-proteobacteria, such as E. coli.


Psychometric properties of the Arabic version of the Activities-Specific Balance Confidence (ABC) scale in ambulatory, community-dwelling, elderly people.
Background: Fear of falling (FOF) is common among elderly individuals and can appear independently of a previous fall. FOF can start a vicious cycle by leading to a sedentary lifestyle and further FOF, with negative physical and mental consequences. The Activities-Specific Balance Confidence (ABC) scale is a popular, theoretically based, reliable and valid tool designed to assess FOF in ambulatory, community-dwelling, elderly people. A balance confidence measurement tool for Arabic-speaking ambulatory, community-dwelling, elderly individuals is lacking. The objective of the present study was to translate and culturally adapt the ABC to Arabic and to determine its psychometric properties in ambulatory, community-dwelling elderly people. Materials and methods: This two-stage exploratory study included a forward and backward translation process and the administration of the Arabic ABC (A-ABC) via face-to-face interviews. In addition, performance-based clinical measures of balance were assessed, and two self-report physical function and disability questionnaires were administered. The study included 60 volunteers (34 women), with a mean age of 74.1±6.23 years, recruited from the Arab population of northern Israel. To determined test-retest reliability, the questionnaire was re-administered to 40 of the 60 participants twice at a 6-8-day interval. Results: One of the 16 A-ABC scale items was modified to adjust for local climate. The main results included high internal consistency (Cronbach's α=0.97), good to excellent structural coherence (corrected item-total correlation: 0.77-0.92); excellent test-retest reliability (ICC=0.98, confidence interval =0.08-3.05); low standard error of measure and low smallest real difference (3.5% and 9.64%, respectively); strong-to-moderate correlations with performance-based clinical measures of balance and self-report physical function and disability questionnaires; and a ceiling effect. A significant difference between genders and between fallers and non-fallers was demonstrated. Conclusions: The A-ABC demonstrated excellent psychometric properties in elderly, Arabic-speaking, independently living individuals and can be used as a balance confidence measurement tool in research and clinical settings.


Blood pressure, renal and metabolic effects of ACTH in normotensive man.
1. The blood pressure, renal and metabolic effects of adrenocorticotropic hormone (ACTH) have been studied in six normotensive subjects and two patients with Addison's disease on maintenance steroid therapy. 2. In normotensive subjects, 5 days ACTH treatment (0.5 mg 12 hourly) was associated with a rise in systolic blood pressure and mean arterial pressure. There was a small rise in diastolic pressure but no consistent change in heart rate. Plasma sodium increased and plasma potassium fell. Serum creatinine and urea concentrations were unchanged. Fluid intake increased and urine output was unchanged but ACTH withdrawal was associated with a diuresis. There was an initial reduction in urinary sodium excretion and a natriuresis after ACTH withdrawal. Plasma volume and body weight rose. 3. ACTH produced increases in plasma cortisol, 11-deoxycortisol, corticosterone, deoxycorticosterone, aldosterone, 17 alpha-hydroxyprogesterone and 17 alpha,20 alpha-dihydroxyprogesterone. Plasma renin concentration fell. 4. Patients with Addison's disease showed no change in blood pressure or in any other metabolic variable studied. 5. The effects of ACTH in man resembled those found in sheep.


Emergent approaches to care coordination in England: exploring the evidence from two national organizations.
For many years, there has been an international concern about the fragmented nature of health and social care services for vulnerable older people and younger adults. This article examines the implementation of two major policies in England designed to ensure frail adults and older people receive services appropriate to their needs. First, care management, which was introduced in 1993 and provided by local government, and second case management, which was introduced in 2005 and provided by primary care through the National Health Service. An analysis of the implementation of the two policies is presented, and data from two national surveys are used to describe similarities and differences between the two approaches in terms of goals, arrangements, service characteristics, and indicators of integration and differentiation within care coordination arrangements. Both were designed to promote the provision of care at home as an alternative to more costly alternatives. Discretion within the policy implementation process has militated against the development of a more differentiated approach to care management in local authorities as compared with case management in primary care trusts and more generally, integration between the two. Future developments within both service settings will be influenced by the introduction of personal budgets.


The Impact of Isolation on Healthcare Worker Contact and Compliance With Infection Control Practices in Nursing Homes.
OBJECTIVETo directly observe healthcare workers in a nursing home setting to measure frequency and duration of resident contact and infection prevention behavior as a factor of isolation practiceDESIGNObservational studySETTING AND PARTICIPANTSHealthcare workers in 8 VA nursing homes in Florida, Maryland, Massachusetts, Michigan, Washington, and TexasMETHODSOver a 15-month period, trained research staff without clinical responsibilities on the units observed nursing home resident room activity for 15-30-minute intervals. Observers recorded time of entry and exit, isolation status, visitor type (staff, visitor, etc), hand hygiene, use of gloves and gowns, and activities performed in the room when visible.RESULTSA total of 999 hours of observation were conducted across 8 VA nursing homes during which 4,325 visits were observed. Residents in isolation received an average of 4.73 visits per hour of observation compared with 4.21 for nonisolation residents (P<.01), a 12.4% increase in visits for residents in isolation. Residents in isolation received an average of 3.53 resident care activities per hour of observation, compared with 2.46 for residents not in isolation (P<.01). For residents in isolation, compliance was 34% for gowns and 58% for gloves. Healthcare worker hand hygiene compliance was 45% versus 44% (P=.79) on entry and 66% versus 55% (P<.01) on exit for isolation and nonisolation rooms, respectively.CONCLUSIONSHealthcare workers visited residents in isolation more frequently, likely because they required greater assistance. Compliance with gowns and gloves for isolation was limited in the nursing home setting. Adherence to hand hygiene also was less than optimal, regardless of isolation status of residents.Infect Control Hosp Epidemiol 2018;39:683-687.


Cognitive interviewing methodology in the development of a pediatric item bank: a patient reported outcomes measurement information system (PROMIS) study.
The evaluation of patient-reported outcomes (PROs) in health care has seen greater use in recent years, and methods to improve the reliability and validity of PRO instruments are advancing. This paper discusses the cognitive interviewing procedures employed by the Patient Reported Outcomes Measurement Information System (PROMIS) pediatrics group for the purpose of developing a dynamic, electronic item bank for field testing with children and adolescents using novel computer technology. The primary objective of this study was to conduct cognitive interviews with children and adolescents to gain feedback on items measuring physical functioning, emotional health, social health, fatigue, pain, and asthma-specific symptoms. A total of 88 cognitive interviews were conducted with 77 children and adolescents across two sites on 318 items. From this initial item bank, 25 items were deleted and 35 were revised and underwent a second round of cognitive interviews. A total of 293 items were retained for field testing. Children as young as 8 years of age were able to comprehend the majority of items, response options, directions, recall period, and identify problems with language that was difficult for them to understand. Cognitive interviews indicated issues with item comprehension on several items which led to alternative wording for these items. Children ages 8-17 years were able to comprehend most item stems and response options in the present study. Field testing with the resulting items and response options is presently being conducted as part of the PROMIS Pediatric Item Bank development process.


Insulin treatment improves the systemic inflammatory reaction to severe trauma.
Determine the effect of insulin on the systemic inflammatory response, pro- and anti-inflammatory cytokines and hepatic acute-phase-response in severely burned pediatric patients. The systemic inflammatory and hepatic acute-phase-response contribute to hypermetabolism, multi-organ failure, and mortality. Insulin has been recently shown to decrease mortality and to prevent the incidence of multi-organ failure in critically ill patients; however, the underlying mechanisms have not been defined. Thirteen thermally injured children received insulin to maintain blood glucose at a range from 120 to 180 mg/dl, 15 children received no insulin with blood glucose levels also at range from 120 to 180 mg/dl and served as controls. Our outcome measures encompassed the effect of insulin on pro-inflammatory mediators, the hepatic acute-phase-response, fat, and the IGF-I system. Insulin administration decreased pro-inflammatory cytokines and proteins, while increasing constitutive-hepatic proteins (P < 0.05). Burned children receiving insulin required significantly less albumin substitution to maintain normal levels compared with control (P < 0.05). Insulin decreased free fatty acids and serum triglycerides when compared with controls (P < 0.05). Serum IGF-I and IGFBP-3 significantly increased with insulin administration (P < 0.05). Insulin attenuates the inflammatory response by decreasing the pro-inflammatory and increasing the anti-inflammatory cascade, thus restoring systemic homeostasis, which has been shown critical for organ function and survival in critically ill patients.


Time-resolved surface plasmon polariton coupled exciton and biexciton emission.
We discuss the coupling between optically excited semiconductor nanocrystals (NC) and thin metal films in both the single and multi-exciton regime. Using time-resolved photoluminescence spectroscopy, we determine the decay dynamics of free space and surface plasmon polariton (SPP) coupled emission. The two dynamics are found to be distinctly different at very small NC-metal separations and at photon energies close to the SPP resonance frequency. A comparison with numerical calculations allow us to conclude that the difference in emission dynamics is associated with the different interactions of parallel and perpendicular dipole emitters with lossy surface waves. Experiments at high excitation densities reveal that the coupling to SPPs and lossy surface waves is identical for excitons and biexcitons.


Effects of the Positive Action program on achievement and discipline: two matched-control comparisons.
This paper reports on the effectiveness of an integrated comprehensive school model for character development, problem behavior prevention, and academic achievement enhancement. The Positive Action program consists of a school curriculum, together with schoolwide climate, family, and community components. As evaluated here, the yearly K-6 curriculum consists of over 140 fifteen-to-twenty-minute lessons per year delivered in school classrooms on an almost daily basis. The program is based on theories of self-concept, learning, behavior, and school ecology. We use a matched control design and school-level achievement and disciplinary data to evaluate program effects on student performance and behavior in two separate school districts. The program improved achievement by 16% in one district and 52% in another, and reduced disciplinary referrals by 78% in one district and 85% in the other. We discuss implications of these replicated findings for the prevention of substance abuse and violence, the improvement of school performance, and the reform of American schools.


Withdrawal from long-term high-dose desipramine therapy. Clinical and biological changes.
Investigation was undertaken on a patient whose long-term intake of desipramine hydrochloride was amongst the highest reported. Desipramine treatment instituted at a daily dosage of 75 mg for depressive equivalents of head, chest, and abdominal pain was increased to 1,000 mg daily over a 12-year interval with minimal side effects. Plasma desipramine level dropped immediately on withdrawal, and urinary metabolite values dropped over the subsequent five days. The electrocardiographic abnormalities of first-degree atrioventricular block and incomplete left bundle branch block rapidly disappeared on cessation of medication. Electroencephalographic changes with symmetrical generalized irregular 5- to 7-cps theta activity and 18- to 28-cps beta activity also improved. Longitudinal polygraphic sleep studies showed prolonged rapid eye movement rebound and increased delta sleep coincident with withdrawal. It took ten days after cessation of desipramine for urinary 3-methoxy-4-hydroxyphenylglycol concentration to increase substantially. Although catecholamines are involved in growth hormone (GH) and cortisol regulation, no abnormalities were found in GH or cortisol levels.


The unique chemistry of Eastern Mediterranean water masses selects for distinct microbial communities by depth.
The waters of the Eastern Mediterranean are characterized by unique physical and chemical properties within separate water masses occupying different depths. Distinct water masses are present throughout the oceans, which drive thermohaline circulation. These water masses may contain specific microbial assemblages. The goal of this study was to examine the effect of physical and geological phenomena on the microbial community of the Eastern Mediterranean water column. Chemical measurements were combined with phospholipid fatty acid (PLFA) analysis and high-throughput 16S rRNA sequencing to characterize the microbial community in the water column at five sites. We demonstrate that the chemistry and microbial community of the water column were stratified into three distinct water masses. The salinity and nutrient concentrations vary between these water masses. Nutrient concentrations increased with depth, and salinity was highest in the intermediate water mass. Our PLFA analysis indicated different lipid classes were abundant in each water mass, suggesting that distinct groups of microbes inhabit these water masses. 16S rRNA gene sequencing confirmed the presence of distinct microbial communities in each water mass. Taxa involved in autotrophic nitrogen cycling were enriched in the intermediate water mass suggesting that microbes in this water mass may be important to the nitrogen cycle of the Eastern Mediterranean. The Eastern Mediterranean also contains numerous active hydrocarbon seeps. We sampled above the North Alex Mud Volcano, in order to test the effect of these geological features on the microbial community in the adjacent water column. The community in the waters overlaying the mud volcano was distinct from other communities collected at similar depths and was enriched in known hydrocarbon degrading taxa. Our results demonstrate that physical phenomena such stratification as well as geological phenomena such as mud volcanoes strongly affect microbial community structure in the Eastern Mediterranean water column.


Dabigatran, rivaroxaban and apixaban vs. high TTR warfarin in atrial fibrillation.
New oral anticoagulants are non-inferior compared with warfarin regarding stroke prevention in atrial fibrillation, with similar or decreased risk of bleeding. However, it is unclear whether high TTR warfarin is as effective and safe as NOACs. Our objective was to investigate efficacy and safety of apixaban, dabigatran or rivaroxaban compared with warfarin in clinical practice. Nationwide retrospective cohort study based on Swedish quality registries. Atrial fibrillation patients initiated on apixaban, dabigatran, rivaroxaban or warfarin between 2013-01-01 and 2015-12-31 were included. Main outcome measures were all-cause stroke and systemic embolism, all-cause stroke, ischemic stroke, hemorrhagic stroke; major bleeding, intracranial bleeding, gastrointestinal bleeding, other bleeding (fatal or requiring hospital care); all-cause mortality; myocardial infarction. The study included 64,382 patients corresponding to 81,176 treatment years. Of these, 37,174 patients were instituted on warfarin, 6574 on dabigatran, 8323 on rivaroxaban and 12,311 on apixaban. In warfarin treated patients, the time in therapeutic range was 71.4%. After propensity score matching, there was no significant difference in risk of stroke or systemic embolism between NOAC and warfarin treated patients. Hazard ratios for major bleeding events were 0.63(95%CI 0.52-0.75) for apixaban, 0.74(0.62-0.87) for dabigatran and 1.06(0.92-1.23) for rivaroxaban, compared with warfarin. This study showed no difference between apixaban, dabigatran, or rivaroxaban compared to high TTR warfarin treatment regarding stroke prevention. However, fewer bleeding events were seen for apixaban and dabigatran, but not for rivaroxaban. Further studies are needed on the comparability of individual NOACs with respect to bleeding risks.


Mortality predictors and effects of antithrombotic therapies in atrial fibrillation: insights from ACTIVE-W.
To assess the risk of death after the occurrence of different types of non-fatal events in patients with atrial fibrillation (AF). Antithrombotic therapies in AF have primarily focused on stroke prevention and bleeding. However, strokes and bleeds differ in severity, and the level of severity may differently impact mortality. We analysed the risk of subsequent mortality after the occurrence of non-fatal vascular and bleeding events in the Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events (ACTIVE)-W trial. In the 3371 patients randomized to vitamin K antagonists and the 3335 patients randomized to clopidogrel plus aspirin in ACTIVE-W, the hazard ratio (HR) and 95% confidence intervals (95% CIs) for subsequent death associated with the occurrence of non-fatal stroke was 5.58 (95% CI 3.84-8.10, P < 0.0001). Both ischaemic (HR 5.29, 95% CI 3.53-7.93, P < 0.0001) and haemorrhagic strokes (HR 7.38, 95% CI 2.74-19.9, P < 0.0001) increased mortality, but transient ischaemic attacks did not. Disabling strokes (Rankin's score > or =3) increased mortality (HR 9.54; 95% CI 6.42-14.2, P< 0.0001), but non-disabling strokes did not. Severe bleeding increased mortality (HR 3.35, 95% CI 2.12-5.27, P < 0.0001), but major bleeding that was not severe according to the study definitions did not. Non-fatal strokes increased mortality in ACTIVE-W, but non-disabling strokes did not. Among major bleeding events, only those also classified as severe increased mortality. Future research should emphasize the prevention of disabling strokes and severe bleeds and place less emphasis on non-disabling stroke or major bleeds that are not severe.


The Immune Mechanisms of Lung Parenchymal Damage in Tuberculosis and the Role of Host-Directed Therapy.
Impaired lung function is common in people with a history of tuberculosis. Host-directed therapy added to tuberculosis treatment may reduce lung damage and result in improved lung function. An understanding of the pathogenesis of pulmonary damage in TB is fundamental to successfully predicting which interventions could be beneficial. In this review, we describe the different features of TB immunopathology that lead to impaired lung function, namely cavities, bronchiectasis, and fibrosis. We discuss the immunological processes that cause lung damage, focusing on studies performed in humans, and using chest radiograph abnormalities as a marker for pulmonary damage. We highlight the roles of matrix metalloproteinases, neutrophils, eicosanoids and cytokines, like tumor necrosis factor-α and interleukin 1β, as well as the role of HIV co-infection. Finally, we focus on various existing drugs that affect one or more of the immunological mediators of lung damage and could therefore play a role as host-directed therapy.


Deletion of CREB-regulated transcription coactivator 1 induces pathological aggression, depression-related behaviors, and neuroplasticity genes dysregulation in mice.
Mood disorders are polygenic disorders in which the alteration of several susceptibility genes results in dysfunctional mood regulation. However, the molecular mechanisms underlying their transcriptional dysregulation are still unclear. The transcription factor cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) and the neurotrophin brain-derived neurotrophic factor (BDNF) have been implicated in rodent models of depression. We previously provided evidence that Bdnf expression critically rely on a potent CREB coactivator called CREB-regulated transcription coactivator 1 (CRTC1). To further evaluate the role of CRTC1 in the brain, we generated a knockout mouse line and analyzed its behavioral and molecular phenotype. We found that mice lacking CRTC1 associate neurobehavioral endophenotypes related to mood disorders. Crtc1(-/-) mice exhibit impulsive aggressiveness, social withdrawal, and decreased sexual motivation, together with increased behavioral despair, anhedonia, and anxiety-related behavior in the novelty-induced hypophagia test. They also present psychomotor retardation as well as increased emotional response to stressful events. Crtc1(-/-) mice have a blunted response to the antidepressant fluoxetine in behavioral despair paradigms, whereas fluoxetine normalizes their aggressiveness and their behavioral response in the novelty-induced hypophagia test. Crtc1(-/-) mice strikingly show, in addition to a reduced dopamine and serotonin turnover in the prefrontal cortex, a concomitant decreased expression of several susceptibility genes involved in neuroplasticity, including Bdnf, its receptor TrkB, the nuclear receptors Nr4a1-3, and several other CREB-regulated genes. Collectively, these findings support a role for the CRTC1-CREB pathway in mood disorders etiology and behavioral response to antidepressants and identify CRTC1 as an essential coactivator of genes involved in mood regulation.


Analysis of a library of macaque nuclear mitochondrial sequences confirms macaque origin of divergent sequences from old oral polio vaccine samples.
Nuclear mtDNA sequences (numts) are a widespread family of paralogs evolving as pseudogenes in chromosomal DNA [Zhang, D. E. & Hewitt, G. M. (1996) TREE 11, 247-251 and Bensasson, D., Zhang, D., Hartl, D. L. & Hewitt, G. M. (2001) TREE 16, 314-321]. When trying to identify the species origin of an unknown DNA sample by way of an mtDNA locus, PCR may amplify both mtDNA and numts. Indeed, occasionally numts dominate confounding attempts at species identification [Bensasson, D., Zhang, D. X. & Hewitt, G. M. (2000) Mol. Biol. Evol. 17, 406-415; Wallace, D. C., et al. (1997) Proc. Natl. Acad. Sci. USA 94, 14900-14905]. Rhesus and cynomolgus macaque mtDNA haplotypes were identified in a study of oral polio vaccine samples dating from the late 1950s [Blancou, P., et al. (2001) Nature (London) 410, 1045-1046]. They were accompanied by a number of putative numts. To confirm that these putative numts were of macaque origin, a library of numts corresponding to a small segment of 12S rDNA locus has been made by using DNA from a Chinese rhesus macaque. A broad distribution was found with up to 30% sequence variation. Phylogenetic analysis showed that the evolutionary trajectories of numts and bona fide mtDNA haplotypes do not overlap with the signal exception of the host species; mtDNA fragments are continually crossing over into the germ line. In the case of divergent mtDNA sequences from old oral polio vaccine samples [Blancou, P., et al. (2001) Nature (London) 410, 1045-1046], all were closely related to numts in the Chinese macaque library.


Hepatitis B vaccine uptake among injecting drug users in England 1998 to 2004: is the prison vaccination programme driving recent improvements?
In 1999, the Department of Health allocated additional funding to Health Authorities in England to expand hepatitis B immunization among injecting drug users (IDUs), with the aim of increasing coverage by 20%. In 2001, a vaccination programme for prison inmates in England was also instigated. Between 1998 and 2004 current IDUs participated in a series of annual unlinked anonymous surveys that recorded vaccine uptake (n = 11 383). The proportion self-reporting vaccine uptake rose significantly from 27% in 1998 to 59% in 2004 [adjusted odds ratio: 3.7 (95% CI 3.2-4.3); increase in uptake of 25% per annum (95% CI 22-27%)]. A second survey, which recruited 852 current IDUs from community settings in 2003/04, found that prisons were the most common source (38%) of vaccine doses, followed by drug services (28%) and general practitioners (17%), with only 14% receiving doses through needle exchanges. These data suggest that the 20% target of improving vaccination coverage has been met, with the prison vaccination programme likely to have made a substantive contribution in recent years. However, prevalence of antibodies to the hepatitis B core antigen was stable (21%) and is currently similar among the vaccinated and unvaccinated. Consideration needs to be given to improving community vaccination provision for IDUs, targeting recent initiates, and determining when surveillance data should indicate reductions in infection so that the effectiveness of the targeted strategy can be assessed.


Eye position effects in oculomotor plasticity and visual localization.
For visual localization to remain accurate across changes of gaze, a signal representing the position of the eye in the orbita is needed to code spatial locations in a reference frame that is independent of retinal displacements. Here we report evidence that the localization of visual objects in space is coded in an extraretinal reference frame. In human subjects, we used outward saccadic adaptation, which can be induced artificially by a systematic displacement of the saccade target. This form of oculomotor plasticity is accompanied by changes in spatial perception, thus highlighting the relevance of saccade metrics for visual localization. We tested the reference frame of outward adaptation for reactive and scanning saccades and visual localization. For scanning saccades, adaptation magnitude was drastically reduced at positions distant from the adapted eye position. Changes in visual localization showed a very similar modulation of eye position. These results suggest that scanning saccade adaptation is encoded in a nonretinotopic reference frame. Eye position effects for reactive saccade adaptation were smaller, and the induced mislocalization did not vary significantly between eye positions. The different modulation of reactive and scanning saccade adaptation supports the idea that oculomotor plasticity can occur at multiple sites in the brain. The findings are also consistent with previous evidence for a stronger influence of scanning saccade adaptation on the visual localization of objects in space.


Using a reproductive life course approach to understand contraceptive method use in Australia.
This paper examines contraceptive method use at different stages of the reproductive life course. Previous research on contraceptive practice in developed countries typically applies age as a proxy for reproductive history. While age is an essential and useful life course measure for understanding contraceptive use, investigations of contraceptive practice should also consider parity and fertility intentions, as they may be more accurate measures of reproductive life course stage. Analysis is based on data collected in the 2005 Household, Income and Labour Dynamics in Australia (HILDA) survey, a nationally representative sample of women of reproductive age (18-44). For women at risk of pregnancy, the most commonly used methods are easily reversed methods such as the oral contraceptive pill (30%) and condom (23%), medium-term methods such as the intrauterine device and implantation (5%) and permanent methods (7% tubal ligation and 9% vasectomy of partner). Logistic regression models are used to investigate the use of four popular contraceptive methods by parity, age and fertility intentions controlling for socio-demographic factors. The main findings indicate that the use of these methods varies substantially by the stage of a woman's reproductive life course: age, parity and fertility intentions are all associated with method use.


Clinical and radiographic comparison of indirect pulp treatment using light-cured calcium silicate and mineral trioxide aggregate in primary molars: A randomized clinical trial.
To clinically and radiographically evaluate the reparative dentin formation in indirect pulp treatment (IPT) using mineral trioxide aggregate (MTA) and light cured calcium silicate (TheraCal) in primary molars over a period of 6 months. A clinical trial on IPT on 43 primary molars in 21 patients between the age of 4-7 years, divided into two groups: 22 teeth in MTA group and 21 in TheraCal group. Measurement of the variation in dentin thickness was done on the digitalized radiograph at baseline, 3 months and 6 months using CorelDRAW X3 software. Statistical analysis using an independent t-test for intragroup and intergroup comparison showed a significant increase in dentin thickness in both the MTA and TheraCal group (intragroup comparison [P < 0.05]). However, intergroup comparison between MTA and TheraCal showed no statistical difference in reparative dentin formation (P > 0.05). Clinically and radiographically, both MTA and TheraCal are good IPT materials. The better handling characteristics and comparable reparative dentin-forming ability of TheraCal make this material an alternative to MTA in pediatric restorative procedures.


TaMOR is essential for root initiation and improvement of root system architecture in wheat.
Optimal root system architecture is beneficial for water-fertilizer use efficiency, stress tolerance and yield improvement of crops. However, because of the complexity of root traits and difficulty in phenotyping deep roots, the study on mechanisms of root development is rarely reported in wheat (Triticum aestivum L.). In this study, we identified that the LBD (LATERAL ORGAN BOUNDARIES DOMAIN) gene TaMOR (MORE ROOT in wheat) determines wheat crown root initiation. The mor mutants exhibited less or even no crown root, dwarfism, less grain number and lodging caused by few roots. The observation of cross sections showed that crown root initiation is inhibited in the mor mutants. Molecular assays revealed that TaMOR interacts with the auxin response factor ARF5 to directly induce the expression of the auxin transporter gene PIN2 (PIN-FORMED 2) in the root base to regulate crown root initiation. In addition, a 159-bp MITE (miniature inverted-repeat transposable element) insertion causing DNA methylation and lower expression of TaMOR-B was identified in TaMOR-B promoter, which is associated with lower root dry weight and shorter plant height. The results bring new light into regulation mechanisms of crown root initiation and offer a new target for the improvement of root system architecture in wheat.


Effect of 1,19-bis(ethylamino)-5,10,15-triazanonadecane on human tumor xenografts.
The polyamine analogue 1,19-bis(ethylamino)-5,10,15-triazanonadecane (BE-4-4-4-4), 5 mg/kg i.p., was given twice daily on days 0-3 and 7-10 (cycle 1) to nude mice with human malignant gliomas (SF-767 and U-87 MG), lung adenocarcinoma (A549), and colon carcinomas (HCT116 and HT29). A second cycle of drug was given to mice with SF-767 and A549 tumors on days 42-45 and 49-52. The maximum animal weight loss varied between 4 and 12%, which was observed 10-15 days following the initiation of treatment, but no overt toxic reactions were noted. The SF-767 brain tumors were extremely responsive to BE-4-4-4-4 alone (3 of 8 complete regressions after 2 cycles); however, the growth of the U-87 MG brain tumor was only slightly inhibited by BE-4-4-4-4 treatment. There was significant inhibition of tumor growth after treatment with one cycle of BE-4-4-4-4 in animals carrying the A549, HCT116, and HT29 tumors. At day 73, the growth of the A549 tumor was inhibited by 78 and 89% following one or two cycles of BE-4-4-4-4, respectively. The mitotic index of A549 tumors was 18 times greater in control mice than in those treated with BE-4-4-4-4 for one or two cycles 99 days after initiation of treatment. 1,3-Bis(2-chloroethyl)-1-nitrosourea (BCNU) was given to mice carrying the U-87 MG or A549 tumors on day 4 (cycle 1) and day 46 (cycle 2) in the maximal tolerated dose of 50 mg/kg for BCNU alone and 40 mg/kg for BCNU plus BE-4-4-4-4. BCNU alone significantly inhibited the growth of U-87 MG tumors but not the growth of A549 tumors. Treatment with the combination of BCNU and BE-4-4-4-4 was significantly better than BCNU alone for A549 tumors and better than BE-4-4-4-4 alone for U87 tumors. However, in both animal groups treated with the combination, there was a significant weight loss, which was not observed for animals treated with either agent alone. These data suggest a role for BE-4-4-4-4 in the treatment of brain, lung, and colon tumors.


Medicaid Expansion Slowed Rates Of Health Decline For Low-Income Adults In Southern States.
Of the fourteen states that have not expanded eligibility for Medicaid, nine are in the southern census region, and two others border that region. Ongoing debate over the merits of Medicaid expansion in these states has focused, in part, on whether the safety net provides sufficient access for uninsured low-income Americans. We analyzed longitudinal survey and vital status data from the twelve-state Southern Community Cohort Study (SCCS) for 15,356 nonelderly adult participants with low incomes, 86 percent of whom were enrolled at community health centers. In difference-in-differences analyses, we compared changes in self-reported health between participants in four expansion and eight nonexpansion states before (2008-13) and after (2015-17) Medicaid expansion. We found that a higher proportion of SCCS participants in expansion states reported increases in Medicaid coverage (a differential change of 7.6 percentage points), a lower proportion experienced a health status decline (-1.8 percentage points), and a higher proportion maintained their baseline health status (1.4 percentage points). The magnitude of estimated reductions in health declines would meaningfully affect a nonexpansion state's health ranking in our sample if that state elected to expand Medicaid. Our results suggest that for low-income adults in the South, Medicaid expansion yielded health benefits-even for those with established access to safety-net care.


Cardiovascular tolerance of intravenous lidocaine in broiler chickens (Gallus gallus domesticus) anesthetized with isoflurane.
To determine the cardiovascular effects of lidocaine infused intravenously (IV) in broiler chickens. Two phase study: Phase 1, randomized up-and-down study to determine effective dose 50 (ED50) for lidocaine; Phase 2, prospective randomized study to determine the cardiovascular effects of lidocaine. Seventeen Ross-708 broiler chickens (Gallus gallus domesticus) [11 chickens (Phase 1) and 6 chickens (Phase 2)], weighing 2.6-4.3 kg. After induction of anesthesia with isoflurane and placement of monitoring equipment including invasive blood pressure, chickens were administered lidocaine IV. During Phase 1, using an up-and-down design, each animal received a variable dose selected based on the response of the previous animal. During Phase 2, each animal was administered 6 mg kg(-1) of lidocaine IV over 2 minutes. Clinically irrelevant cardiovascular effects were defined as a relative decrease of heart rate (HR) and mean blood pressure (MAP) <30% subsequent to IV lidocaine administration. The ED50 was defined as the dose rate that would cause clinically irrelevant cardiovascular depression in 50% of the population. During Phase 1, using an up-and-down study design (n = 11), the ED50 of lidocaine was determined to be 6.30 mg kg(-1) and 6.22 mg kg(-1) (95% confidence interval, 5.30-7.13 mg kg(-1)), when calculated by Dixon's up-and-down method, and logistic regression, respectively. During Phase 2, following infusion of lidocaine (6 mg kg(-1)), no clinically relevant effects on HR or MAP were detected in any animal. Previous reports state that the dose of lidocaine used in birds should be ≤4 mg kg(-1). In this study, 6 mg kg(-1) of lidocaine injected IV was not associated with adverse cardiovascular effects. These results suggest that the dose of 4 mg kg(-1) can be exceeded, at least in chickens, and opens the possibility of other therapeutic uses for lidocaine in birds.


EDEM as an acceptor of terminally misfolded glycoproteins released from calnexin.
Terminally misfolded proteins in the endoplasmic reticulum (ER) are retrotranslocated to the cytoplasm and degraded by proteasomes through a mechanism known as ER-associated degradation (ERAD). EDEM, a postulated Man8B-binding protein, accelerates the degradation of misfolded proteins in the ER. Here, EDEM was shown to interact with calnexin, but not with calreticulin, through its transmembrane region. Both binding of substrates to calnexin and their release from calnexin were required for ERAD to occur. Overexpression of EDEM accelerated ERAD by promoting the release of terminally misfolded proteins from calnexin. Thus, EDEM appeared to function in the ERAD pathway by accepting substrates from calnexin.


Increased survival and prolonged longevity mainly contribute to the temperature-adaptive evolutionary strategy in invasive Bemisia tabaci (Hemiptera: Aleyrodidae) Middle East Asia Minor 1.
With increasing global climate change, analyses of stress-inducing conditions have important significance in ecological adaptation and the biological distribution of species. To reveal the difference in temperature-adaptive strategy between Turpan and Beijing populations of Bemisia tabaci (Gennadius) Middle East Asia Minor 1 (MEAM1) under high-temperature stress conditions, we compared thermal tolerance and life history traits between Beijing and Turpan populations of MEAM1 after exposure to different heat shock treatments for different times. The experimental design reflected the nature of heat stress conditions suffered by MEAM1. The results showed that eggs, red-eyed pupae, and adults of the Turpan population were more heat tolerant than those of the Beijing population under the same stress conditions. Additionally, it was found that longevity and F1 adult survival rate were significantly higher in the Turpan population than in the Beijing population after heat shock stress, but egg number and F1 female ratio were not significantly different between Turpan population and Beijing population. Overall, it was suggested that heat tolerance and longevity traits were the most relevant for climate characteristics and not reproductive traits, and improved heat tolerance and prolonged longevity were important adaptive strategies that helped MEAM1 to survive in harsh high-temperature conditions such as Turpan arid desert climate. The present results provided further insight into the modes of heat tolerance and the ways in which survival and longevity traits respond to environmental selection pressures.


Risk Factors for High-Arched Palate and Posterior Crossbite at the Age of 5 in Children Born Very Preterm: EPIPAGE-2 Cohort Study.
Children born very preterm have an immature sucking reflex at birth and are exposed to neonatal care that can impede proper palate growth. We aimed to describe the frequency of high-arched palate and posterior crossbite at the age of 5 in children born very preterm and to identify their respective risk factors. Our study was based on the data from EPIPAGE-2, a French national prospective cohort study, and included 2,594 children born between 24- and 31-week gestation. Outcomes were high-arched palate and posterior crossbite. Multivariable models estimated by generalized estimation equations with multiple imputation were used to study the association between the potential risk factors studied and each outcome. Overall, 8% of children born very preterm had a high-arched palate and 15% posterior crossbite. The odds of high-arched palate were increased for children with low gestational age (24-29 vs. 30-31 weeks of gestation) [adjusted odds ratio (aOR) 1.76, 95% confidence interval (CI) 1.17, 2.66], thumb-sucking habits at the age of 2 (aOR 1.53, 95% CI 1.03, 2.28), and cerebral palsy (aOR 2.18, 95% CI 1.28, 3.69). The odds of posterior crossbite were increased for children with pacifier-sucking habits at the age of 2 (aOR 1.75, 95% CI 1.30, 2.36). Among very preterm children, low gestational age and cerebral palsy are the specific risk factors for a high-arched palate. High-arched palate and posterior crossbite share non-nutritive sucking habits as a common risk factor. The oro-facial growth of these children should be monitored.


Heterozygous Monocarboxylate Transporter 1 (MCT1, SLC16A1) Deficiency as a Cause of Recurrent Ketoacidosis.
We describe two half-siblings with monocarboxylate transporter 1 (MCT1, SLC16A1) deficiency, a defect on ketone body utilization, that has only recently been identified (van Hasselt et al., N Engl J Med, 371:1900-1907, 2014) as a cause for recurrent ketoacidoses. Our index patient is a boy with non-consanguineous parents who had presented acutely with impaired consciousness and severe metabolic ketoacidosis following a 3-day history of gastroenteritis at age 5 years. A 12.5-year-old half-brother who shared the proband's mother also had a previous history of recurrent ketoacidoses. Results of mutation and enzyme activity analyses in proband samples advocated against methylacetoacetyl-coenzyme A thiolase ("beta-ketothiolase") and succinyl-coenzyme A: 3-oxoacyl coenzyme A transferase (SCOT) deficiencies. A single heterozygous c.982C>T transition in the SLC16A1 gene resulting in a stop mutation (p.Arg328Ter) was detected in both boys. It was shared by their healthy mother and by the proband's half-sister, but was absent in the proband's father. MCT1 deficiency may be more prevalent than is apparent, as clinical manifestations can occur both in individuals with bi- and monoallelic mutations. It may be an important differential diagnosis in recurrent ketoacidosis with or without hypoglycemia, particularly in the absence of any specific metabolic profiles in blood and urine. Early diagnosis may enable improved disease management. Careful identification of potential triggers of metabolic decompensations in individuals even with single heterozygous mutations in the SLC16A1 gene is indicated.


Systems biology-based drug repositioning identifies digoxin as a potential therapy for groups 3 and 4 medulloblastoma.
Medulloblastoma (MB) is the most common malignant brain tumor of childhood. Although outcomes have improved in recent decades, new treatments are still needed to improve survival and reduce treatment-related complications. The MB subtypes groups 3 and 4 represent a particular challenge due to their intragroup heterogeneity, which limits the options for "rational" targeted therapies. Here, we report a systems biology approach to drug repositioning that integrates a nonparametric, bootstrapping-based simulated annealing algorithm and a 3D drug functional network to characterize dysregulated driver signaling networks, thereby identifying potential drug candidates. From more than 1300 drug candidates studied, we identified five members of the cardiac glycoside family as potentially inhibiting the growth of groups 3 and 4 MB and subsequently confirmed this in vitro. Systemic in vivo treatment of orthotopic patient-derived xenograft (PDX) models of groups 3 and 4 MB with digoxin, a member of the cardiac glycoside family approved for the treatment of heart failure, prolonged animal survival at plasma concentrations known to be tolerated in humans. These results demonstrate the power of a systematic drug repositioning method in identifying a potential treatment for MB. Our strategy could potentially be used to accelerate the repositioning of treatments for other human cancers that lack clearly defined rational targets.


Collected world experience about the performance of the snorkel/chimney endovascular technique in the treatment of complex aortic pathologies: the PERICLES registry.
We sought to analyze the collected worldwide experience with use of snorkel/chimney endovascular aneurysm repair (EVAR) for complex abdominal aneurysm treatment. EVAR has largely replaced open surgery worldwide for anatomically suitable aortic aneurysms. Lack of availability of fenestrated and branched devices has encouraged an alternative strategy utilizing parallel or snorkel/chimney grafts (ch-EVAR). Clinical and radiographic information was retrospectively reviewed and analyzed on 517 patients treated by ch-EVAR from 2008 from 2014 by prearranged defined and documented protocols. A total of 119 patients in US centers and 398 in European centers were treated during the study period. US centers preferentially used Zenith stent-grafts (54.2%) and European centers Endurant stent-grafts (62.2%) for the main body component. Overall 898 chimney grafts (49.2% balloon expandable, 39.6% self-expanding covered stents, and 11.2% balloon expandable bare metal stents) were placed in 692 renal arteries, 156 superior mesenteric arteries (SMA), and 50 celiac arteries. At a mean follow-up of 17.1 months (range: 1-70 months), primary patency was 94%, with secondary patency of 95.3%. Overall survival of patients in this high-risk cohort for open repair at latest follow-up was 79%. This global experience represents the largest series in the ch-EVAR literature and demonstrates comparable outcomes to those in published reports of branched/fenestrated devices, suggesting the appropriateness of broader applicability and the need for continued careful surveillance. These results support ch-EVAR as a valid off-the-shelf and immediately available alternative in the treatment of complex abdominal EVAR and provide impetus for the standardization of these techniques in the future.


Paternal Depression in the Postnatal Period and Early Father-Infant Interactions.
Objective. Paternal depressive disorder is associated with adverse effects on child development. One possible mechanism for this is through the effects of the disorder on parenting capacities. The link between paternal depression and father-infant interactions was investigated at three-months postpartum. Design. Major depressive disorder was assessed in N = 192 fathers using a structured clinical interview (SCID). Altogether, 54 fathers met criteria for depression, and 99 fathers were categorized as non-depressed. Observational assessments of face-to-face father-infant interactions were conducted in an infant-seat setting and a floor-mat setting. Associations between paternal depression and father-infant interactions were analyzed. Results. Paternal depression is associated with more withdrawn parental behavior in interactions on the floor-mat. There were few other differences in observed interaction between depressed and non-depressed fathers. Conclusions. Fathers with depression may be more withdrawn, displaying less verbal and behavioral stimulation during interactions with their young infants. They may initiate a pattern of parenting that remains compromised, potentially affecting their children's development.


The Recent Revolution in the Design and Manufacture of Cranial Implants: Modern Advancements and Future Directions.
Large format (i.e., >25 cm) cranioplasty is a challenging procedure not only from a cosmesis standpoint, but also in terms of ensuring that the patient's brain will be well-protected from direct trauma. Until recently, when a patient's own cranial flap was unavailable, these goals were unattainable. Recent advances in implant computer-aided design and 3-dimensional (3-D) printing are leveraging other advances in regenerative medicine. It is now possible to 3-D-print patient-specific implants from a variety of polymer, ceramic, or metal components. A skull template may be used to design the external shape of an implant that will become well integrated in the skull, while also providing beneficial distribution of mechanical force in the event of trauma. Furthermore, an internal pore geometry can be utilized to facilitate the seeding of banked allograft cells. Implants may be cultured in a bioreactor along with recombinant growth factors to produce implants coated with bone progenitor cells and extracellular matrix that appear to the body as a graft, albeit a tissue-engineered graft. The growth factors would be left behind in the bioreactor and the graft would resorb as new host bone invades the space and is remodeled into strong bone. As we describe in this review, such advancements will lead to optimal replacement of cranial defects that are both patient-specific and regenerative.


Emergency department management of acute pain episodes in sickle cell disease.
To characterize the initial management of patients with sickle cell disease and an acute pain episode, to compare these practices with the American Pain Society Guideline for the Management of Acute and Chronic Pain in Sickle-Cell Disease in the emergency department, and to identify factors associated with a delay in receiving an initial analgesic. This was a multicenter retrospective design. Consecutive patients with an emergency department visit in 2004 for an acute pain episode related to sickle cell disease were included. Exclusion criteria included age younger than 18 years. A structured medical record review was used to abstract data, including the following outcome variables: analgesic agent and dose, route, and time to administration of initial analgesic. Additional variables included demographics, triage level, intravenous access, and study site. Mann-Whitney U test or Kruskal-Wallis test and multivariate regression were used to identify differences in time to receiving an initial analgesic between groups. There were 612 patient visits, with 159 unique patients. Median time to administration of an initial analgesic was 90 minutes (25th to 75th interquartile range, 54-159 minutes). During 87% of visits, patients received the recommended agent (morphine or hydromorphone); 92% received the recommended dose, and 55% received the drug by the recommended route (intravenously or subcutaneously). Longer times to administration occurred in female patients (mean difference, 21 minutes; 95% confidence interval = 7 to 36 minutes; p = 0.003) and patients assigned triage level 3, 4, or 5 versus 1 or 2 (mean difference, 45 minutes; 95% confidence interval = 29 to 61 minutes; p = 0.00). Patients from study sites 1 and 2 also experienced longer delays. Patients with an acute painful episode related to sickle cell disease experienced significant delays to administration of an initial analgesic.


Pathological mechanisms in experimental autoimmune myasthenia gravis. II. Passive transfer of experimental autoimmune myasthenia gravis in rats with anti-acetylcholine recepotr antibodies.
Passive transfer of experimental autoimmune myasthenia gravis (EAMG) was achieved using the gamma globulin fraction and purified IgG from sera of rats immunized with Electrophus electricus (eel) acetylcholine receptor (AChR). This demonstrates the critical role of anti-AChR antibodies in impairing neuromuscular transmission in EAMG. Passive transfer of anti-AChR antibodies from rats with chronic EAMG induced signs of the acute phase of EAMG in normal recipient rats, including invasion of the motor end-plate region by mononuclear inflammatory cells. Clinical, eletrophysiological, histological, and biochemical signs of acute EAMG were observed by 24 h after antibody transfer. Recipient rats developed profound weakness and fatigability, and the posture characteristic of EAMG. Striking weight loss was attributable to dehydration. Recipient rats showed large decreases in amplitude of muscle responses to motor nerve stimulation, and repetitive nerve stimulation induced characteristic decrementing responses. End-plate potentials were not detectable in many muscle fibers, and the amplitudes of miniature end-plate potentials were reduced in the others. Passively transferred EAMG more severely affected the forearm muscles than diaphragm muscles, though neuromuscular transmission was impaired and curare sensitivity was increased in both muscles. Some AChR extracted from the muscles of rats with passively transferred EAMG was found to be complexed with antibody, and the total yield of AChR per rat was decreased. The quantitative decrease in AChR approximately paralleled in time the course of clinical and electrophysiological signs. The amount of AChR increased to normal levels and beyond at the time neuromuscular transmission was improving. The excess of AChR extractable from muscle as the serum antibody level decreased probably represented extrajunctional receptors formed in response to functional denervation caused by phagocytosis of the postsynaptic membrane by macrophages. The amount of antibody required to passively transfer EAMG was less than required to bind all AChR molecules in a rat's musculature. The effectiveness of samll amounts of antibody was probably amplified by the activation of complement and by the destruction of large areas of postsynaptic membrane by phagocytic cells. A self-sustaining autoimmune response to AChR was not provoked in animals with passively transferred EAMG.


The Association between Dry Eye Disease and Physical Activity as well as Sedentary Behavior: Results from the Osaka Study.
Purpose. To assess the association of dry eye disease (DED) with physical activity and sedentary behavior. Methods. The cross-sectional survey conducted included Japanese office workers who use visual display terminals (n = 672). DED was assessed according to the Japanese Dry Eye Diagnostic Criteria, and participants were categorized into "definite DED," "probable DED," or "non-DED" groups based on the results of DED examinations. Physical activity and sedentary behavior of participants were assessed using the International Physical Activity Questionnaire (IPAQ), and physical activity level was calculated in metabolic equivalent units per week (MET, min/week). Participants were classified as having a high, moderate, or low level of physical activity. Results. Participants with abnormal tear break-up time (BUT) (≤5 s) were involved in sedentary behavior for significantly longer duration than those with normal BUT (P = 0.035). Non-DED participants (14.5%) tended to have higher levels of physical activity than definite DED participants (2.5%). Participants with definite DED had significantly lower MET scores than those with non-DED (P = 0.025). Conclusions. Our findings suggest that a lower level of physical activity and sedentary behavior are associated with DED; however, longitudinal/intervention studies with large groups of participants are needed to validate these findings.


Survival of cells with bleomycin-induced chromosomal lesions in the cultured lymphocytes of lung cancer patients.
In a previous study of lung cancer, we showed that bleomycin, a radiomimetic agent, induced breaks preferentially on chromosomes 4 and 5. The molecular cytogenetic study reported here, using chromosome painting and G banding, was designed to assess whether the chromatid breaks induced by bleomycin could survive as chromosome-type aberrations after treated lymphocyte populations were allowed to recover in a drug-free medium for one or two cell generations and whether the survival rates of lesions on chromosomes 4 and 5 differed in cases with lung cancer and controls. The findings from 16 cases and 14 controls showed that in samples allowed to recover for 48 h, most aberrations were of the chromosome type. The proportion of chromosome 5 abnormalities surviving as chromosome-type aberrations was significantly higher in the cells of lung cancer cases (13.4%) than in controls (4.6%; P < 0.0001). However, no significant differences in survival of chromosome 4 abnormalities were detected between cases and controls. The proportions of chromosome 5q13-q22 abnormalities were 5.3% in the cases and 0.6% in the controls (P < 0.0001). 5q13-q22 regions encompassed 38.4% of all abnormalities on chromosome 5 in the cases but only 14.5% in the controls. Therefore, the survival rate of chromosome 5 lesions (especially those at 5q13-q22) in lymphocytes might be used as a biomarker to identify populations at high risk for lung cancer.


Retinoic acids and hepatic stellate cells in liver disease.
Quiescent hepatic stellate cells (HSCs) in healthy liver store 80% of total liver retinols and release them depending on the extracellular retinol status. However, HSCs activated by liver injury lose their retinols and produce a considerable amount of extracellular matrix, subsequently leading to liver fibrosis. Emerging evidence suggests that retinols and their metabolites such as retinoic acids (RAs) contribute to liver regeneration, fibrosis and tumor. However, it is not clear yet why HSCs lose retinol, which enzymes are involved in the retinol metabolism of HSCs and what function of retinol metabolites on HSCs upon liver injury. Recently, our group and collaborators have demonstrated that during activation, HSCs not only lose retinols but also metabolize them into RAs by alcohol dehydrogenases and retinaldehyde dehydrogenases. As transcriptional factors, metabolized RAs induce retinoic acid early inducible-1 and suppressor of cytokine signaling 1 in HSCs, which plays an important role in the interaction between HSCs and natural killer cells. In addition, RAs released from HSCs may induce hepatic cannabinoid receptor 1 expression in alcoholic liver steatosis or regulate immune responses upon liver inflammation. The present review summarizes the role of endogenous metabolized RAs on HSCs themselves and on other liver cells including hepatocytes and immune cells. Moreover, the effects of exogenous retinol and RA treatments on HSCs and liver disease are discussed.


Preoperative factors associated with improvements in shoulder function after humeral hemiarthroplasty.
The relationship between the characteristics of the shoulder that can be determined before humeral hemiarthroplasty and the functional improvement after surgery is not known. The goal of this study was to test the hypothesis that the functional outcome of this procedure correlated significantly with factors that are identifiable preoperatively. The study group included seventy-one shoulders in sixty-eight patients undergoing hemiarthroplasty, performed by the same surgeon, for diagnoses other than acute fracture. The mean age of the patients was sixty-one years (range, thirty to eighty-three years). The results were characterized in terms of the change in self-assessed shoulder function and general health status at an average of forty-nine months (range, twenty-four to 142 months) after surgery. The preoperative absence of erosion of the glenoid was associated with greater improvement in shoulder function and level of comfort after hemiarthroplasty (p < 0.001). Shoulders that had not had previous surgery had greater functional improvement than did those that had previous surgery (p = 0.012). Shoulders with an intact rotator cuff showed significantly (p < 0.5) greater improvement in the ability to lift weight above shoulder level after hemiarthroplasty (p <0.5). With regard to diagnoses, shoulders with rheumatoid arthritis, capsulorrhaphy arthropathy, and cuff tear arthropathy had the least functional improvement, whereas those with osteonecrosis (p = 0.0004) and with primary (p = 0.02) and secondary degenerative joint disease (p = 0.03) had the greatest improvement. Patient age and gender did not significantly affect the outcome. These results suggest that the functional improvement following humeral hemiarthroplasty is related to factors that are identifiable before surgery. These data may be of benefit in preoperative discussions with patients who have a shoulder disorder and are considering treatment with hemiarthroplasty.


Altered brain function underlying verbal memory encoding and retrieval in psychotic major depression.
Psychotic major depression (PMD) is associated with deficits in verbal memory as well as other cognitive impairments. This study investigated brain function in individuals with PMD during a verbal declarative memory task. Participants included 16 subjects with PMD, 15 subjects with non-psychotic major depression (NPMD) and 16 healthy controls (HC). Functional magnetic resonance imaging (fMRI) data were acquired while subjects performed verbal memory encoding and retrieval tasks. During the explicit encoding task, subjects semantically categorized words as either "man-made" or "not man-made." For the retrieval task, subjects identified whether words had been presented during the encoding task. Functional MRI data were processed using SPM5 and a group by condition ANOVA. Clusters of activation showing either a significant main effect of group or an interaction of group by condition were further examined using t-tests to identify group differences. During the encoding task, the PMD group showed lower hippocampus, insula, and prefrontal activation compared to HC. During the retrieval task, the PMD group showed lower recognition accuracy and higher prefrontal and parietal cortex activation compared to both HC and NPMD groups. Verbal retrieval deficits in PMD may be associated with deficient hippocampus function during encoding. Increased brain activation during retrieval may reflect an attempt to compensate for encoding deficits.


A new Kv1.2 channelopathy underlying cerebellar ataxia.
A forward genetic screen of mice treated with the mutagen ENU identified a mutant mouse with chronic motor incoordination. This mutant, named Pingu (Pgu), carries a missense mutation, an I402T substitution in the S6 segment of the voltage-gated potassium channel Kcna2. The gene Kcna2 encodes the voltage-gated potassium channel α-subunit Kv1.2, which is abundantly expressed in the large axon terminals of basket cells that make powerful axo-somatic synapses onto Purkinje cells. Patch clamp recordings from cerebellar slices revealed an increased frequency and amplitude of spontaneous GABAergic inhibitory postsynaptic currents and reduced action potential firing frequency in Purkinje cells, suggesting that an increase in GABA release from basket cells is involved in the motor incoordination in Pgu mice. In line with immunochemical analyses showing a significant reduction in the expression of Kv1 channels in the basket cell terminals of Pgu mice, expression of homomeric and heteromeric channels containing the Kv1.2(I402T) α-subunit in cultured CHO cells revealed subtle changes in biophysical properties but a dramatic decrease in the amount of functional Kv1 channels. Pharmacological treatment with acetazolamide or transgenic complementation with wild-type Kcna2 cDNA partially rescued the motor incoordination in Pgu mice. These results suggest that independent of known mutations in Kcna1 encoding Kv1.1, Kcna2 mutations may be important molecular correlates underlying human cerebellar ataxic disease.


Discrete cyclic porphyrin arrays as artificial light-harvesting antenna.
The importance of photosynthesis has driven researchers to seek ways to mimic its fundamental features in simplified systems. The absorption of a photon by light-harvesting (antenna) complexes made up of a large number of protein-embedded pigments initiates photosynthesis. Subsequently the many pigments within the antenna system shuttle that photon via an efficient excitation energy transfer (EET) until it encounters a reaction center. Since the 1995 discovery of the circularly arranged chromophoric assemblies in the crystal structure of light-harvesting antenna complex LH2 of purple bacteria Rps. Acidophila, many designs of light-harvesting antenna systems have focused on cyclic porphyrin wheels that allow for efficient EET. In this Account, we review recent research in our laboratories in the synthesis of covalently and noncovalently linked discrete cyclic porphyrin arrays as models of the photosynthetic light-harvesting antenna complexes. On the basis of the silver(I)-promoted oxidative coupling strategy, we have prepared a series of extremely long yet discrete meso-meso-linked porphyrin arrays and covalently linked large porphyrin rings. We examined the photophysical properties of these molecules using steady-state absorption, fluorescence, fluorescence lifetime, fluorescence anisotropy decay, and transient absorption measurements. Both the pump-power dependence on the femtosecond transient absorption and the transient absorption anisotropy decay profiles are directly related to the EET processes within the porphyrin rings. Within these structures, the exciton-exciton annihilation time and the polarization anisotropy rise time are well-described in terms of the Forster-type incoherent energy hopping model. In noncoordinating solvents such as CHCl(3), meso-pyridine-appended zinc(II) porphyrins and their meso-meso-linked dimers spontaneously assemble to form tetrameric porphyrin squares and porphyrin boxes, respectively. In the latter case, we have demonstrated the rigorous homochiral self-sorting process and efficient EET along these cyclic porphyrin arrays. The meso-cinchomeronimide appended zinc(II) porphyrin forms a cyclic trimer. We have also shown that the corresponding meso-meso-linked diporphyrins undergo high-fidelity self-sorting assembling to form discrete cyclic trimer, tetramer, and pentamer with large association constants through perfect discrimination of enantiomeric and conformational differences of the meso-cinchomeronimide substituents. Collectively, these studies of covalently and noncovalently linked discrete cyclic porphyrin arrays aid in the understanding of the structural requirements for such very fast EET in natural light-harvesting complexes.


Optimization of the expression, purification and polymerase activity reaction conditions of recombinant human PrimPol.
Human PrimPol is a DNA primase/polymerase involved in DNA damage tolerance and prevents nuclear genome instability. PrimPol is also localized to the mitochondria, but its precise function in mitochondrial DNA maintenance has remained elusive. PrimPol works both as a translesion (TLS) polymerase and as the primase that restarts DNA replication after a lesion. However, the observed biochemical activities of PrimPol vary considerably between studies as a result of different reaction conditions used. To reveal the effects of reaction composition on PrimPol DNA polymerase activity, we tested the polymerase activity in the presence of various buffer agents, salt concentrations, pH values and metal cofactors. Additionally, the enzyme stability was analyzed under various conditions. We demonstrate that the reaction buffer with pH 6-6.5, low salt concentrations and 3 mM Mg2+ or 0.3-3 mM Mn2+ cofactor ions supports the highest DNA polymerase activity of human PrimPol in vitro. The DNA polymerase activity of PrimPol was found to be stable after multiple freeze-thaw cycles and prolonged protein incubation on ice. However, rapid heat-inactivation of the enzyme was observed at 37ºC. We also for the first time describe the purification of human PrimPol from a human cell line and compare the benefits of this approach to the expression in Escherichia coli and in Saccharomyces cerevisiae cells. Our results show that active PrimPol can be purified from E. coli and human suspension cell line in high quantities and that the activity of the purified enzyme is similar in both expression systems. Conversely, the yield of full-length protein expressed in S. cerevisiae was considerably lower and this system is therefore not recommended for expression of full-length recombinant human PrimPol.


Enzyme replacement therapy for Fabry disease: a systematic review of available evidence.
Fabry disease is a progressive and life-threatening glycolipid storage disorder affecting both males and females. The primary driver of the disease is the accumulation of glycolipids (globotriaosylceramide [GL-3]) in a variety of cell types, including vascular endothelial cells, a range of renal cell types, cardiomyocytes and neurons, which is caused by deficient activity of the lysosomal enzyme, alpha-galactosidase. The disease typically presents during childhood or adolescence. First manifestations reflect involvement of small nerve fibres of the peripheral and autonomic nervous systems. With age, severe complications involving the kidneys, heart and brain cause considerable morbidity and premature death. Outside the US, enzyme replacement therapy (ERT) with agalsidase alfa 0.2 mg/kg every other week (EOW) and agalsidase beta 1.0 mg/kg EOW is available for the treatment of patients with Fabry disease, while agalsidase beta 1.0 mg/kg EOW is the only approved drug in the US. To analyse the evidence for ERT, a systematic review of the literature was performed to identify prospectively designed randomized, controlled trials (RCTs) and open-label studies on the efficacy of agalsidase alfa and agalsidase beta. MEDLINE and EMBASE databases were searched; inclusion criteria for the systematic review were prospectively designed clinical studies evaluating ERT with quantifiable endpoints: double-blind and open-label studies were eligible. Exclusion criteria were review articles, case reports, case studies, letters to the editor and articles based on registry data (Fabry Outcome Survey or Fabry Registry). In addition, any studies with a retrospective design or data based on post hoc analyses were excluded. The evidence was reviewed with respect to the clinical benefits of ERT at the level of the end organ. A total of 9 RCTs and 23 open-label studies were identified for inclusion. The efficacy of ERT in Fabry disease has been measured against a variety of endpoints, the majority of which were subclinical parameters rather than clinical outcomes. Plasma levels of GL-3 together with accumulation in the kidney, heart and skin were the most commonly studied endpoints, followed by renal endpoints of proteinuria and glomerular filtration rate, whereas cardiac and neurological endpoints were not commonly studied. To date, only one RCT with ERT defined hard clinical outcomes in the form of cardiac, renal or cerebrovascular events, or death as its primary endpoint. The currently available data from prospective RCTs and open-label studies in patients with Fabry disease are more robust for ERT at a dose of 1 mg/kg EOW than a dose of 0.2 mg/kg EOW, although the beneficial effects of ERT with either dose or preparation are variable.


Diagnosis of malaria in the field by fluorescence microscopy of QBC capillary tubes.
The diagnostic performance of commercial capillary tubes containing acridine orange dye (QBC) was compared with the standard diagnosis of malaria by microscopical examination of Giemsa-stained thick blood films (GTS) in remote field conditions. The comparison was conducted among 165 volunteers living in northeastern Irian Jaya, Indonesia, an area having hyperendemic malaria transmission. By GTS, 65 volunteers were positive for malaria, but only 49 were judged positive by QBC. Among the 100 blood films found negative by GTS, 5 were considered positive by QBC. Thus, relative to a GTS standard, the sensitivity and specificity of the QBC was 75% and 95%, respectively. The mean limit of detection for the QBC was approximately 60 parasites per microliter blood, whereas the limit of detection for GTS was 20 parasites per microliter blood. Also, a number of practical difficulties were encountered using the QBC at the field site. The QBC approach to diagnosis of malaria was less sensitive and more inconvenient than GTS under the conditions in remote Irian Jaya.


Influence of yoga on mood states, distress, quality of life and immune outcomes in early stage breast cancer patients undergoing surgery.
Breast cancer patients awaiting surgery experience heightened distress that could affect postoperative outcomes. The aim of our study was to evaluate the effects of yoga intervention on mood states, treatment-related symptoms, quality of life and immune outcomes in breast cancer patients undergoing surgery. Ninety-eight recently diagnosed stage II and III breast cancer patients were recruited for a randomized controlled trial comparing the effects of a yoga program with supportive therapy plus exercise rehabilitation on postoperative outcomes following surgery. Subjects were assessed prior to surgery and four weeks thereafter. Psychometric instruments were used to assess self-reported anxiety, depression, treatment-related distress and quality of life. Blood samples were collected for enumeration of T lymphocyte subsets (CD4 %, CD8 % and natural killer (NK) cell % counts) and serum immunoglobulins (IgG, IgA and IgM). We used analysis of covariance to compare interventions postoperatively. Sixty-nine patients contributed data to the current analysis (yoga n = 33, control n = 36). The results suggest a significant decrease in the state (P = 0.04) and trait (P = 0.004) of anxiety, depression (P = 0.01), symptom severity (P = 0.01), distress (P < 0.01) and improvement in quality of life (P = 0.01) in the yoga group as compared to the controls. There was also a significantly lesser decrease in CD 56% (P = 0.02) and lower levels of serum IgA (P = 0.001) in the yoga group as compared to controls following surgery. The results suggest possible benefits for yoga in reducing postoperative distress and preventing immune suppression following surgery.


Explaining the relation between birth order and intelligence.
Negative associations between birth order and intelligence level have been found in numerous studies. The explanation for this relation is not clear, and several hypotheses have been suggested. One family of hypotheses suggests that the relation is due to more-favorable family interaction and stimulation of low-birth-order children, whereas others claim that the effect is caused by prenatal gestational factors. We show that intelligence quotient (IQ) score levels among nearly 250,000 military conscripts were dependent on social rank in the family and not on birth order as such, providing support for a family interaction explanation.


Knowledge, attitude, and practice among tobacco and alcohol addicts before and after psychological intervention in a de-addiction center at Madhya Pradesh, India.
Tobacco and alcohol addiction has emerged as a major public health issue in most of the regions of the world. It has resulted in enormous disability, disease, and death and acquired the dimension of an epidemic. It is estimated that five million preventable deaths occur every year globally, attributable to tobacco use. The number is expected to double by 2020 if death due to tobacco continues to occur at the same rate. Alcohol, on the other hand, contributes to 25% of all deaths in the age group of 20-39 years. The interventions such as supportive pharmacotherapy, nicotine replacement therapy, counseling, behavioral intervention, psychotherapy, and detoxification therapy are being commonly employed in the management of patients with addiction to tobacco and alcohol. The aim of this study is to compare the knowledge, attitude, and practice (KAP) among tobacco and alcohol addicts before and after psychological intervention in a de-addiction center. This study was a randomized control trial, focusing on psychological interventions practiced in a de-addiction center, Indore, Madhya Pradesh, India. The information on KAP related to tobacco and alcohol was collected at baseline from 83 participants. This was compared with the information collected in the postintervention follow-ups from each participant. Statistical tests for parametric analysis were done using one-way ANOVA with Scheffe's post hoc test, RMANOVA with Mauchly's test for sphericity assumption, and Bonferroni test for comparing the main effects. Nonparametric tests included Pearson's Chi-square test, McNemar's Chi-square test, Spearman's rho, and Kruskal-Wallis test. The statistical significance was fixed at 0.05. The mean KAP score for the study population was highest at the first follow-up followed by the second follow-up for both tobacco and alcohol addiction. The least KAP score was observed at the baseline. Although a significant improvement in the mean KAP score was observed at the first follow-up, subsequent follow-up revealed a reduction in the overall KAP score in the present study. This could be attributed to the fact that following their discharge from the de-addiction center, most of the participants reverted back to their deleterious habits.


Recombinant lactobacilli expressing linoleic acid isomerase can modulate the fatty acid composition of host adipose tissue in mice.
We have previously demonstrated that oral administration of a metabolically active Bifidobacterium breve strain, with ability to form cis-9, trans-11 conjugated linoleic acid (CLA), resulted in modulation of the fatty acid composition of the host, including significantly elevated concentrations of c9, t11 CLA and omega-3 (n-3) fatty acids in liver and adipose tissue. In this study, we investigated whether a recombinant lactobacillus expressing linoleic acid isomerase (responsible for production of t10, c12 CLA) from Propionibacterium acnes (PAI) could influence the fatty acid composition of different tissues in a mouse model. Linoleic-acid-supplemented diets (2 %, w/w) were fed in combination with either a recombinant t10, c12 CLA-producing Lactobacillus paracasei NFBC 338 (Lb338), or an isogenic (vector-containing) control strain, to BALB/c mice for 8 weeks. A third group of mice received linoleic acid alone (2 %, w/w). Tissue fatty acid composition was assessed by GLC at the end of the trial. Ingestion of the strain expressing linoleic acid isomerase was associated with a 4-fold increase (P<0.001) in t10, c12 CLA in adipose tissues of the mice when compared with mice that received the isogenic non-CLA-producing strain. The livers of the mice that received the recombinant CLA-producing Lb338 also contained a 2.5-fold (albeit not significantly) higher concentration of t10, c12 CLA, compared to the control group. These data demonstrate that a single gene (encoding linoleic acid isomerase) expressed in an intestinal microbe can influence the fatty acid composition of host fat.


Predicting the risk of avian influenza A H7N9 infection in live-poultry markets across Asia.
Two epidemic waves of an avian influenza A (H7N9) virus have so far affected China. Most human cases have been attributable to poultry exposure at live-poultry markets, where most positive isolates were sampled. The potential geographic extent of potential re-emerging epidemics is unknown, as are the factors associated with it. Using newly assembled data sets of the locations of 8,943 live-poultry markets in China and maps of environmental correlates, we develop a statistical model that accurately predicts the risk of H7N9 market infection across Asia. Local density of live-poultry markets is the most important predictor of H7N9 infection risk in markets, underscoring their key role in the spatial epidemiology of H7N9, alongside other poultry, land cover and anthropogenic predictor variables. Identification of areas in Asia with high suitability for H7N9 infection enhances our capacity to target biosurveillance and control, helping to restrict the spread of this important disease.