Effect of chronic contractile activity on mRNA stability in skeletal muscle.
Repeated bouts of exercise promote the biogenesis of mitochondria by multiple steps in the gene expression patterning. The role of mRNA stability in controlling the expression of mitochondrial proteins is relatively unexplored. To induce mitochondrial biogenesis, we chronically stimulated (10 Hz; 3 or 6 h/day) rat muscle for 7 days. Chronic contractile activity (CCA) increased the protein expression of PGC-1alpha, c-myc, and mitochondrial transcription factor A (Tfam) by 1.6-, 1.7- and 2.0-fold, respectively. To determine mRNA stability, we incubated total RNA with cytosolic extracts using an in vitro cell-free system. We found that the intrinsic mRNA half-lives (t(1/2)) were variable within control muscle. Peroxisome proliferator-activated receptor-gamma, coactivator-1alpha (PGC-1alpha) and Tfam mRNAs decayed more rapidly (t(1/2) = 22.7 and 31.4 min) than c-myc mRNA (t(1/2) = 99.7 min). Furthermore, CCA resulted in a differential response in degradation kinetics. After CCA, PGC-1alpha and Tfam mRNA half-lives decreased by 48% and 44%, respectively, whereas c-myc mRNA half-life was unchanged. CCA induced an elevation of both the cytosolic RNA-stabilizing human antigen R (HuR) and destabilizing AUF1 (total) by 2.4- and 1.8-fold, respectively. Increases in the p37(AUF1), p40(AUF1), and p45(AUF1) isoforms were most evident. Thus these data indicate that CCA results in accelerated turnover rates of mRNAs encoding important mitochondrial biogenesis regulators in skeletal muscle. This adaptation is likely beneficial in permitting more rapid phenotypic plasticity in response to subsequent contractile activity.


BODIPY-conjugated chitosan nanoparticles as a fluorescent probe.
Recently, development of fluorescent nanoparticle-based probes for various bioimaging applications has attracted great attention. This work aims to develop a new type fluorescent nanoparticle conjugate and evaluate its cytotoxic effects on A549 and BEAS 2B cell lines. Throughout the study, ionically crosslinked chitosan nanoparticles (CNs) were conjugated with carboxylated 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY-COOH). The results of conjugates (BODIPY-CNs) were investigated with regard to their physic-chemical, optical, cytotoxic properties and cellular internalization. The morphology of BODIPY-CNs was found to be spherical in shape and quite uniform having average diameter of 70.25 ± 11.99 nm. Cytotoxicty studies indicated that although BODIPY-COOH itself was quite toxic on both A549- and BEAS 2B-treated cells, CNs increased the cell viability of both cell lines via conjugation to BODIPY-COOH fluorescent molecule up to 67% for A549 and 74% for BEAS 2B cells. These results may suggest a possible utilization of the new fluorescent nanoparticle-based probe for bioimaging in biology and medicine.


Impact of continuous veno-venous hemofiltration on acid-base balance.
Continuous veno-venous hemofiltration (CVVH) appears to have a significant and variable impact on acid-base balance. However, the pathogenesis of these acid-base effects remains poorly understood. The aim of this study was to understand the nature of acid-base changes in critically ill patients with acute renal failure during continuous veno-venous hemofiltration by applying quantitative methods of biophysical analysis (Stewart-Figge methodology). We studied forty patients with ARF receiving CVVH in the intensive care unit. We retrieved the biochemical data from computerized records and conducted quantitative biophysical analysis. We measured serum Na+, K+, Mg2+, Cl-, HCO3-, phosphate, ionized Ca2+, albumin, lactate and arterial blood gases and calculated the following Stewart-Figge variables: Strong Ion Difference apparent (SIDa), Strong Ion Difference Effective (SIDe) and Strong Ion Gap (SIG). Before treatment, patients had mild acidemia (pH: 7.31) secondary to metabolic acidosis (bicarbonate: 19.8 mmol/L and base excess: -5.9 mEq/L). This acidosis was due to increased unmeasured anions (SIG: 12.3 mEq/L), hyperphosphatemia (1.86 mmol/L) and hyperlactatemia (2.08 mmol/L). It was attenuated by the alkalinizing effect of hypoalbuminemia (22.5 g/L). After commencing CVVH, the acidemia was corrected within 24 hours (pH 7.31 vs 7.41, p<0.0001). This correction was associated with a decreased strong ion gap (SIG) (12.3 vs. 8.8 mEq/L, p<0.0001), phosphate concentration (1.86 vs. 1.49 mmol/L, p<0.0001) and serum chloride concentration (102 vs. 98.5 mmol/L, p<0.0001). After 3 days of CVVH, however, patients developed alkalemia (pH: 7.46) secondary to metabolic alkalosis (bicarbonate: 29.8 mmol/L, base excess: 6.7 mEq/L). This alkalemia appeared secondary to a further decrease in SIG to 6.7 mEq/L (p<0.0001) and a further decrease in serum phosphate to 0.77 mmol/L (p<0.0001) in the setting of persistent hypoalbuminemia (21.0 g/L; p=0.56). CVVH corrects metabolic acidosis in acute renal failure patients through its effect on unmeasured anions, phosphate and chloride. Such correction coupled with the effect of hypoalbuminemia, results in the development of a metabolic alkalosis after 72 hours of treatment.


Assessment of Myocardial Function in Kenyan Children With Severe, Acute Malnutrition: The Cardiac Physiology in Malnutrition (CAPMAL) Study.
Mortality among African children hospitalized with severe malnutrition remains high, with sudden, unexpected deaths leading to speculation about potential cardiac causes. Malnutrition is considered high risk for cardiac failure, but evidence is limited. To investigate the role of cardiovascular dysfunction in African children with severe, acute malnutrition (SAM). A prospective, matched case-control study, the Cardiac Physiology in Malnutrition (CAPMAL) study, of 88 children with SAM (exposed) vs 22 severity-matched patients without SAM (unexposed) was conducted between March 7, 2011, and February 20, 2012; data analysis was performed from October 1, 2012, to March 1, 2016. Echocardiographic and electrocardiographic (ECG) recordings (including 7-day Holter monitoring) at admission, day 7, and day 28. Findings in children with (cases) and without (controls) SAM and in marasmus and kwashiorkor phenotypes were compared. Eighty-eight children (52 with marasmus and 36 with kwashiorkor) of the 418 admitted with SAM and 22 severity-matched controls were studied. A total of 63 children (57%) were boys; median age at admission was 19 months (range, 12-39 months). On admission, abnormalities more common in cases vs controls included severe hypokalemia (potassium <2.5 mEq/L) (18 of 81 [22%] vs 0%), hypoalbuminemia (albumin level <3.4 g/dL) (66 of 88 [75%] vs 4 of 22 [18%]), and hypothyroidism (free thyroxine level <0.70 ng/dL or thyrotropin level >4.2 mU/L) (18 of 74 [24%] vs 1 of 21 [5%]) and were associated with typical electrocardiographic changes (T-wave inversion: odds ratio, 7.3; 95% CI, 1.9-28.0; P = .001), which corrected as potassium levels improved. Fourteen children with SAM (16%) but no controls died. Myocardial mass was lower in cases on admission but not by day 7. Results of the Tei Index, a measure of global cardiac function, were within the reference range and similar in cases (median, 0.37; interquartile range [IQR], 0.26-0.45) and controls (median, 0.36; IQR, 0.28-0.42). Echocardiography detected no evidence of cardiac failure among children with SAM, including those receiving intravenous fluids to correct hypovolemia. Cardiac dysfunction was generally associated with comorbidity and typical of hypovolemia, with low cardiac index (median, 4.9 L/min/m2; IQR, 3.9-6.1 L/min/m2), high systemic vascular resistance index (median, 1333 dyne seconds/cm5/m2; IQR, 1133-1752 dyne seconds/cm5/m2), and with few differences between the marasmus and kwashiorkor manifestations of malnutrition. Seven-day continuous ECG Holter monitoring during the high-risk initial refeeding period demonstrated self-limiting significant ventricular arrhythmias in 33 of 55 cases (60%) and 6 of 18 controls (33%) (P = .049); none were temporally related to adverse events, including fatalities. There is little evidence that African children with SAM are at greater risk of cardiac dysfunction or clinically significant arrhythmias than those without SAM or that marasmus and kwashiorkor differed in cardiovascular profile. These findings should prompt a review of current guidelines.


Commitment to school and learning among youth in residential care: The role of mother and father support and parents' divorce.
Commitment to school, commitment to learning, and educational expectations have been shown to contribute to positive outcomes among youth in the general population. However, it is an underexamined phenomenon among youth in care. This study examines the contribution of mother and father support and the moderating role of parents' marital status to commitment to school and learning among youth in residential care settings (RCSs) in Israel. The study was based on the reports of a random cluster sample of 1,409 adolescents (Grades 8 to 12) in 16 educational RCSs for youth from underprivileged backgrounds, who completed structured questionnaires. In line with social capital theories, the findings showed that, after controlling for youth background characteristics and grades at school, both father and mother support were linked positively with youth commitment to school and learning among the whole sample. The findings showed that although there was a positive significant relationship between father support and commitment to school and learning among youth in married-parent families, the link was insignificant among adolescent children of divorced parents. However, the interaction between divorce and mother support was insignificant. These findings highlight the importance of nurturing parent-youth relationships in RCSs and suggest circumstances in which father support is at risk to be less beneficial to youth in RCSs-a risk that should be considered by the care system as a target for prevention and intervention programs. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Fauna of the Kemp Caldera and its upper bathyal hydrothermal vents (South Sandwich Arc, Antarctica).
Faunal assemblages at hydrothermal vents associated with island-arc volcanism are less well known than those at vents on mid-ocean ridges and back-arc spreading centres. This study characterizes chemosynthetic biotopes at active hydrothermal vents discovered at the Kemp Caldera in the South Sandwich Arc. The caldera hosts sulfur and anhydrite vent chimneys in 1375-1487 m depth, which emit sulfide-rich fluids with temperatures up to 212°C, and the microbial community of water samples in the buoyant plume rising from the vents was dominated by sulfur-oxidizing Gammaproteobacteria. A total of 12 macro- and megafaunal taxa depending on hydrothermal activity were collected in these biotopes, of which seven species were known from the East Scotia Ridge (ESR) vents and three species from vents outside the Southern Ocean. Faunal assemblages were dominated by large vesicomyid clams, actinostolid anemones, Sericosura sea spiders and lepetodrilid and cocculinid limpets, but several taxa abundant at nearby ESR hydrothermal vents were rare such as the stalked barnacle Neolepas scotiaensis. Multivariate analysis of fauna at Kemp Caldera and vents in neighbouring areas indicated that the Kemp Caldera is most similar to vent fields in the previously established Southern Ocean vent biogeographic province, showing that the species composition at island-arc hydrothermal vents can be distinct from nearby seafloor-spreading systems. δ 13C and δ 15N isotope values of megafaunal species analysed from the Kemp Caldera were similar to those of the same or related species at other vent fields, but none of the fauna sampled at Kemp Caldera had δ 13C values, indicating nutritional dependence on Epsilonproteobacteria, unlike fauna at other island-arc hydrothermal vents.


Google Scholar, Microsoft Academic, Scopus, Dimensions, Web of Science, and OpenCitations' COCI: a multidisciplinary comparison of coverage via citations.
New sources of citation data have recently become available, such as Microsoft Academic, Dimensions, and the OpenCitations Index of CrossRef open DOI-to-DOI citations (COCI). Although these have been compared to the Web of Science Core Collection (WoS), Scopus, or Google Scholar, there is no systematic evidence of their differences across subject categories. In response, this paper investigates 3,073,351 citations found by these six data sources to 2,515 English-language highly-cited documents published in 2006 from 252 subject categories, expanding and updating the largest previous study. Google Scholar found 88% of all citations, many of which were not found by the other sources, and nearly all citations found by the remaining sources (89-94%). A similar pattern held within most subject categories. Microsoft Academic is the second largest overall (60% of all citations), including 82% of Scopus citations and 86% of WoS citations. In most categories, Microsoft Academic found more citations than Scopus and WoS (182 and 223 subject categories, respectively), but had coverage gaps in some areas, such as Physics and some Humanities categories. After Scopus, Dimensions is fourth largest (54% of all citations), including 84% of Scopus citations and 88% of WoS citations. It found more citations than Scopus in 36 categories, more than WoS in 185, and displays some coverage gaps, especially in the Humanities. Following WoS, COCI is the smallest, with 28% of all citations. Google Scholar is still the most comprehensive source. In many subject categories Microsoft Academic and Dimensions are good alternatives to Scopus and WoS in terms of coverage.


Multicenter feasibility study of bowel preparation with castor oil for colon capsule endoscopy.
Extensive use of laxatives and incomplete excretion rates are problematic for colon capsule endoscopy (CCE). The aim of the present study was to determine the effectiveness of castor oil as a booster. At four Japanese hospitals, 319 examinees undergoing CCE were enrolled retrospectively. Before and after the introduction of castor oil, other preparation reagents were unchanged. Of 319 examinees who underwent CCE, 152 and 167 examinees took regimens with castor oil (between November 2013 and June 2016) and without castor oil (between October 2015 and September 2017), respectively. Capsule excretion rates within its battery life in the groups with and without castor oil were 97% and 81%, respectively (P < 0.0001). Multivariate analysis showed that ages younger than 65 years (adjusted odds ratio [OR], 3.00; P = 0.0048), male gender (adjusted OR, 3.20; P = 0.0051), and use of castor oil (adjusted OR, 6.29; P = 0.0003) were predictors of capsule excretion within its battery life. Small bowel transit time was shorter and total volume of lavage and fluid intake was lower with castor oil than without (P = 0.0154 and 0.0013, respectively). Overall adequate cleansing level ratios with and without castor oil were 74% and 83%, respectively (P = 0.0713). Per-examinee sensitivity for polyps ≥6 mm with and without castor oil was 83% and 85%, respectively, with specificities of 80% and 78%, respectively. Bowel preparation with castor oil was effective for improving capsule excretion rate and reducing liquid loading.


Precocious chondrocyte differentiation disrupts skeletal growth in Kabuki syndrome mice.
Kabuki syndrome 1 (KS1) is a Mendelian disorder of the epigenetic machinery caused by mutations in the gene encoding KMT2D, which methylates lysine 4 on histone H3 (H3K4). KS1 is characterized by intellectual disability, postnatal growth retardation, and distinct craniofacial dysmorphisms. A mouse model (Kmt2d+/βGeo) exhibits features of the human disorder and has provided insight into other phenotypes; however, the mechanistic basis of skeletal abnormalities and growth retardation remains elusive. Using high-resolution micro-CT, we show that Kmt2d+/βGeo mice have shortened long bones and ventral bowing of skulls. In vivo expansion of growth plates within skulls and long bones suggests disrupted endochondral ossification as a common disease mechanism. Stable chondrocyte cell lines harboring inactivating mutations in Kmt2d exhibit precocious differentiation, further supporting this mechanism. A known inducer of chondrogenesis, SOX9, and its targets show markedly increased expression in Kmt2d-/- chondrocytes. By transcriptome profiling, we identify Shox2 as a putative KMT2D target. We propose that decreased KMT2D-mediated H3K4me3 at Shox2 releases Sox9 inhibition and thereby leads to enhanced chondrogenesis, providing a potentially novel and plausible explanation for precocious chondrocyte differentiation. Our findings provide insight into the pathogenesis of growth retardation in KS1 and suggest therapeutic approaches for this and related disorders.


Acute diarrhea: a practical review.
This review provides a practical, simple, and logical approach to the diagnosis and management of patients with acute infectious diarrhea, one of the most common diagnoses in clinical practice. Diarrhea in the immunocompromised host, traveler's diarrhea, and diarrhea in the hospitalized patient are also discussed. Most episodes of acute diarrhea are self-limited, and investigations should be performed only if the results will influence management and outcome. After an adequate history and physical examination, the clinician should be able to classify the acute diarrheal illness, assess the severity, and determine whether investigations are needed. Most patients do not require specific therapy. Therapy should mainly be directed at preventing dehydration. Various home remedies frequently suffice in mild, self-limited diarrhea. However, in large-volume, dehydrating diarrhea, oral rehydration solutions should be used, as they are formulated to stimulate sodium and water absorption. Antidiarrheal agents can be useful in reducing the number of bowel movements and diminishing the magnitude of fluid loss. The most useful agents are opiate derivatives and bismuth subsalicylate. Antibiotic therapy is not required in most patients with acute diarrheal disorders. Guidelines for their use are presented.


Risk assessment and predicting outcomes in patients with depressive symptoms: a review of potential role of peripheral blood based biomarkers.
Depression is one of the major global health challenges and a leading contributor of health related disability and costs. Depression is a heterogeneous disorder and current methods for assessing its severity in clinical practice rely on symptom count, however this approach is unreliable and inconsistent. The clinical evaluation of depressive symptoms is particularly challenging in primary care, where the majority of patients with depression are managed, due to the presence of co-morbidities. Current methods for risk assessment of depression do not accurately predict treatment response or clinical outcomes. Several biological pathways have been implicated in the pathophysiology of depression; however, accurate and predictive biomarkers remain elusive. We conducted a systematic review of the published evidence supporting the use of peripheral biomarkers to predict outcomes in depression, using Medline and Embase. Peripheral biomarkers in depression were found to be statistically significant predictors of mental health outcomes such as treatment response, poor outcome and symptom remission; and physical health outcomes such as increased incidence of cardiovascular events and deaths, and all-cause mortality. However, the available evidence has multiple methodological limitations which must be overcome to make any real clinical progress. Despite extensive research on the relationship of depression with peripheral biomarkers, its translational application in practice remains uncertain. In future, peripheral biomarkers identified with novel techniques and combining multiple biomarkers may have a potential role in depression risk assessment but further research is needed in this area.


PCNA ubiquitination is important, but not essential for translesion DNA synthesis in mammalian cells.
Translesion DNA synthesis (TLS) is a DNA damage tolerance mechanism in which specialized low-fidelity DNA polymerases bypass replication-blocking lesions, and it is usually associated with mutagenesis. In Saccharomyces cerevisiae a key event in TLS is the monoubiquitination of PCNA, which enables recruitment of the specialized polymerases to the damaged site through their ubiquitin-binding domain. In mammals, however, there is a debate on the requirement for ubiquitinated PCNA (PCNA-Ub) in TLS. We show that UV-induced Rpa foci, indicative of single-stranded DNA (ssDNA) regions caused by UV, accumulate faster and disappear more slowly in Pcna(K164R/K164R) cells, which are resistant to PCNA ubiquitination, compared to Pcna(+/+) cells, consistent with a TLS defect. Direct analysis of TLS in these cells, using gapped plasmids with site-specific lesions, showed that TLS is strongly reduced across UV lesions and the cisplatin-induced intrastrand GG crosslink. A similar effect was obtained in cells lacking Rad18, the E3 ubiquitin ligase which monoubiquitinates PCNA. Consistently, cells lacking Usp1, the enzyme that de-ubiquitinates PCNA exhibited increased TLS across a UV lesion and the cisplatin adduct. In contrast, cells lacking the Rad5-homologs Shprh and Hltf, which polyubiquitinate PCNA, exhibited normal TLS. Knocking down the expression of the TLS genes Rev3L, PolH, or Rev1 in Pcna(K164R/K164R) mouse embryo fibroblasts caused each an increased sensitivity to UV radiation, indicating the existence of TLS pathways that are independent of PCNA-Ub. Taken together these results indicate that PCNA-Ub is required for maximal TLS. However, TLS polymerases can be recruited to damaged DNA also in the absence of PCNA-Ub, and perform TLS, albeit at a significantly lower efficiency and altered mutagenic specificity.


Disparities in unmet need for care coordination: the national survey of children's health.
To determine (1) the proportion of parents who report a need for and receipt of effective care coordination for their child, (2) whether unmet care coordination needs differ by children with special health care needs (CSHCN) status and sociodemographic characteristics, and (3) whether having a personal provider or family-centered care mitigates disparities. This study was a cross-sectional analysis of the 2007 National Survey for Children's Health, a nationally representative survey of 91 642 parents. Outcome measures were parent report of need for and lack of effective care coordination. We also examined the effect of parent report of having a personal provider and family-centered care. We conducted weighted bivariate and multivariate analyses. Forty-one percent of parents reported that their child needed care coordination. Among those who needed care coordination, 31% did not receive effective coordination. CSHCN (41%) were more likely than children without special health care needs (26%; P < .001) to have unmet care coordination needs. Latino (40%) and black (37%) children were more likely to have unmet needs than white (27%; P < .001) children. These patterns remained in multivariate analysis. Having a personal provider decreased the odds of having unmet need for care coordination but did not attenuate disparities. Receiving family-centered care mitigated disparities associated with race/ethnicity but not with health status or health insurance. A considerable proportion of parents reported their child needed more care coordination than they received. This was especially true for parents of CSHCN and parents of black and Latino children. Interventions that enhance family-centered care might particularly contribute to reducing racial/ethnic disparities.


Human usage in the native range may determine future genetic structure of an invasion: insights from Acacia pycnantha.
The influence of introduction history and post-introduction dynamics on genetic diversity and structure has been a major research focus in invasion biology. However, genetic diversity and structure in the invasive range can also be affected by human-mediated processes in the native range prior to species introductions, an aspect often neglected in invasion biology. Here we aim to trace the native provenance of the invasive tree Acacia pycnantha by comparing the genetic diversity and structure between populations in the native Australian range and the invasive range in South Africa. This approach also allowed us to explore how human actions altered genetic structure before and after the introduction of A. pycnantha into South Africa. We hypothesized that extensive movement and replanting in A. pycnantha's Australian range prior to its introduction to South Africa might result in highly admixed genotypes in the introduced range, comparable genetic diversity in both ranges, and therefore preclude an accurate determination of native provenance(s) of invasive populations. In the native range Bayesian assignment tests identified three genetic clusters with substantial admixture and could not clearly differentiate previously identified genetic entities, corroborating admixture as a result of replantings within Australia. Assignment tests that included invasive populations from South Africa indicated similar levels of admixture compared to Australian populations and a lack of genetic structure. Invasive populations of A. pycnantha in South Africa are as genetically diverse as native populations, and could not be assigned to particular native range regions. Our results indicate that the genetic structure of A. pycnantha in Australia has been greatly altered through various planting initiatives. Specifically, there is little geographic structure and high levels of admixture. While numerous introduction history scenarios may explain the levels of admixture observed in South Africa, planting records of A. pycnantha in Australia suggest that populations were probably already admixed before propagules were introduced to South Africa. These findings have important implications for the management of invasive A. pycnantha populations in South Africa, especially for classical biological control, and more broadly, for studies that aim to understand the evolutionary dynamics of the invasion process.


Vital statistics of premature and low birthweight infants in Tainan area.
Birth weight and gestational age are strongly associated with perinatal mortality and morbidity. This study was conducted to survey the vital statistics of premature and low birthweight infants in the Tainan area. Between July 1991 and April 1992, fifteen medical institutions were included on a voluntary basis: eight from level I (obstetric specialty clinic), six from level II (regional hospital), and one from level III (tertiary care center). A total of 14,307 deliveries were enrolled, accounting for about 60% of the total delivery for that year in the area. The proportions of delivery among level I, II and III were 52%, 41% and 7%, respectively. The incidence of premature singleton live birth was 4.6%, and the percentages of gestation between 20-27 weeks, 28-31 weeks and 32-37 weeks were 0.2%, 0.6% and 3.8%, respectively. The premature births accounted for 3.5%, 4.8% and 11.3% of live births at the level I, II and III hospitals, respectively. The incidence of low birthweight and very low birthweight singleton live births was 4.4% and 0.5%, respectively. The low birthweight births accounted for 3.5%, 4.5% and 11.1% of live births at the level I, II and III hospitals, respectively. The data revealed that the higher the level of hospital, the higher incidences of premature and low birthweight infant. Teenage mothers (< 20 year of age) had higher low birthweight rate. The risk of having low birthweight infants decreased progressively in mothers of age < 20 (6.3%), 20-24 (5.4%), 25-29 (4.1%) and 30-34 (3.8%), whereas it became higher in mothers older than 35 (4.8%). The incidence of premature and low birthweight births in the Tainan area was low. Teenager or those with maternal age older than 35 year were high risk groups for producing these infants.


Saving the critically injured trauma patient: a retrospective analysis of 1000 uses of intraosseous access.
Intraosseous access (IO) is becoming increasingly accepted in adult populations as an alternative to peripheral vascular access; however, there is still insufficient evidence in large patient groups supporting its use. Retrospective review. This paper reports on the use of IO devices over a 7-year period from August 2006 to August 2013 during combat operations in Afghanistan. A database search of the Joint Theatre Trauma Registry (JTTR) was carried out looking for all the incidences of IO access use during this time. Excel (Microsoft) was used to manage the dataset and perform descriptive statistics on the patient demographics, injuries, treatments and complications that were retrieved. 1014 IO devices were used in 830 adult patients with no major complications. The rate of minor complications, the majority of which were device failure, was 1.38%. 5124 separate infusions of blood products or fluids occurred via IO access, with 36% being of packed red cells. On average, each casualty received 6.95 different infusions of blood products and fluids, and 3.28 separate infusions of drugs through IO access. 32 different drugs were infused to 367 patients via IO, the most frequent being anaesthetic agents. IO access was used in the prehospital environment, during tactical helicopter evacuation and within hospitals. IO access can be used to administer a wide variety of life-saving medications quickly, easily and with low-complication rates. This highlights its valuable role as an alternative method of obtaining vascular access, vital when resuscitating the critically injured trauma patient.


Time-dependent distribution of surface-applied radionuclides and their recovery in maize during the growing season.
The spatial and temporal heterogeneity of field soils influences the fate and behavior of strongly sorbing pollutants and their entry into the food chain. We studied the redistribution of surface-applied 54Mn, 65Zn, 57Co, and 134Cs in the soil profile and their recovery in the aerial parts of maize grown on an untilled agricultural soil during the growing season. Radionuclides were more concentrated in the preferential flow paths (PFP) than in the soil matrix and their concentration decreased with time. The recovery of 54Mn in the aerial plant parts increased between pollen shed and maturity, while the recovery of 65Zn and 57Co did not show any significant difference, and the recovery of 134Cs decreased with time. The amount and distribution of rainfall, and the chemical, physical, and microbiological soil characteristics are the major factors influencing the variation of radionuclide recovery with time.


Diagnosis and management of mild bleeding disorders.
Mild bleeding disorders are a common reason for a referral to a hematologist and these conditions can be challenging to evaluate. Recent research has highlighted that some bleeding symptoms are quite common in the general population and that there is clinical variability in symptom expression among individuals with defined bleeding problems. Moreover, bleeding risks for many bleeding disorders are unknown. This article reviews symptoms and problems that can be considered suspicious of a mild form of bleeding disorder and the diagnostic investigations useful to evaluate these problems. A stepwise approach is presented for the diagnostic evaluation, to allow detection of common and rare coagulation and fibrinolytic defects, and adequate assessments of potential von Willebrand factor and platelet problems. Some common problems in the diagnosis and management of mild bleeding problems are reviewed, including the common failure to establish a diagnosis with testing. An approach is proposed for translation of knowledge to patients who are challenged by mild bleeding problems.


Exercise and a High Fat Diet Synergistically Increase the Pantothenic Acid Requirement in Rats.
It is thought that both exercise and dietary composition increase the utilization of, and thus the requirement for, certain water-soluble vitamins. However, there have been no studies evaluating the combined impacts of exercise and dietary composition on vitamin utilization. In this experiment, rats were fed a pantothenic acid (PaA)-restricted (0.004 g PaA-Ca/kg diet) diet containing 5% (ordinary amount of dietary fat) or 20% fat (high fat), and were forced to swim until exhaustion every other day for 22 d. PaA status was assessed by urinary excretion, which reflects body stores of water-soluble vitamins. The urinary excretion of PaA in rats fed a 5% fat diet was not affected by swimming (5% fat + non-swimming vs. 5% fat + swim; p>0.05). Excretion of PaA was decreased by the high-fat diet (5% fat + non-swim vs. 20% fat + non-swim; p<0.05) and synergistically decreased by exercise (20% fat + non-swim vs. 20% fat + swim; p<0.05). There was a significant interaction between exercise and a high-fat diet. Plasma PaA concentrations showed changes similar to those seen for urinary excretion. The experiment was then repeated using rats fed a PaA-sufficient (0.016 g PaA-Ca/kg diet) diet, and PaA excretion was again synergistically decreased by the combination of exercise and a high-fat diet (p<0.05). These results suggest that the combination of exercise and a high-fat diet synergistically increases the requirement for PaA.


Olanzapine and risperidone disrupt conditioned avoidance responding in phencyclidine-pretreated or amphetamine-pretreated rats by selectively weakening motivational salience of conditioned stimulus.
The rat conditioned avoidance response model is a well-established preclinical behavioral model predictive of antipsychotic efficacy. All clinically approved antipsychotic drugs disrupt conditioned avoidance responding - a feature that distinguishes them from other psychotherapeutics. We previously showed that the typical antipsychotic drug haloperidol disrupts avoidance responding by progressively attenuating the motivational salience of the conditioned stimulus (CS) in normal rats. In this study, using two pharmacological rat models of schizophrenia [e.g. phencyclidine (PCP) or amphetamine sensitization], we examined whether atypicals such as olanzapine or risperidone disrupt avoidance responding through the same behavioral mechanism. Rats were first pretreated with PCP, amphetamine, or saline under one of two different injection schedules for either 1 or 3 weeks. They were then trained to acquire avoidance responding to two types of CS (CS1 and CS2) that differed in their ability to predict the occurrence of the unconditioned stimulus. Finally, rats were tested repeatedly under olanzapine (1.0 mg/kg, subcutaneously) or risperidone (0.33 mg/kg, subcutaneously) daily for 5 or 7 consecutive days. We found that repeated olanzapine or risperidone treatment produced a progressive across-session decline in avoidance responding to both CS1 and CS2. Olanzapine and risperidone disrupted the CS2 (a less salient CS) avoidance to a greater extent than the CS1 avoidance. Pretreatment with PCP and amphetamine did not affect the disruptive effect of olanzapine or risperidone on avoidance responding. On the basis of these findings, we suggest that the atypical drugs olanzapine and risperidone, like the typical drug haloperidol, also disrupt avoidance responding primarily by attenuating the motivational salience of the CS.


Translation and adaption of the interRAI Suite to local requirements in Belgian hospitals.
The interRAI Suite contains comprehensive geriatric assessment tools designed for various healthcare settings. Although each instrument is developed for a particular population, together they form an integrated health evaluation system. The interRAI Acute Care Minimum Data Set (interRAI AC) is tailored for hospitalized older persons. Our aim in this study was to translate and adapt the interRAI AC to the Belgian hospital context, where it can be used together with the interRAI Home Care (HC) and the interRAI Long Term Care Facility (LTCF). A systematic, comprehensive, and rigorous 10-step approach was used to adapt the interRAI AC to local requirements. After linguistic translation by an official translator, five researchers assessed the translation for appropriate hospital jargon. Three researchers double-checked for translation accuracy and proposed additional items. A provisional version was converted into the three official languages of Belgium-Flemish, French, and German. Next, a multidisciplinary panel of nine experts judged item relevance to the Belgian care context and advised which country-specific items should be added. After these suggestions were incorporated into the interRAI AC, hospital staff from nine Flemish hospitals field-tested the tool in their practice. After evaluating field-test results, we compared the interRAI AC with Belgian versions of the interRAI HC and interRAI LTCF. Next, the Flemish, French, and German versions of the Belgian interRAI portfolio were harmonized. Finally, we submitted the Belgian interRAI AC to the interRAI organization for ratification. Eighteen administrative items of the interRAI AC were adapted to the Belgian healthcare context (e.g., usual residence, formal community services prior to admission). Fourteen items assessing the 'informal caregiver', and 17 items, including country-specific items, were added (e.g., advanced directive for euthanasia). The interRAI AC was adapted to local requirements using a meticulous and recursive 10-step approach. As use of the interRAI Suite continues to grow worldwide and as it continues to expand to other care settings and populations, this procedure can guide future translations. This procedure might also be used by others facing similar challenges of complex translation and adaptation situations, where multidimensional instruments are used across multiple care settings in multiple languages.


Progression and treatment of HER2-positive breast cancer.
Approximately 20-30% of breast cancer tumors overexpress or amplify human epidermal growth factor receptor 2 (HER2). The role of this receptor in the progression of HER2+ breast cancer and resistance to certain anticancer monotherapies was investigated. The results of several pre-clinical and clinical trials, with the aim of determining the most safe and effective course of treatment for HER2+ breast cancer, were also thoroughly examined. A thorough search of databases including Pubmed, Springer, and The American Society of Clinical Oncology was performed, and pertinent studies were identified. The most relevant studies were preclinical, phase II, and III clinical trials identifying the function of the HER2 receptor in HER2+ breast cancer progression, as well as studies assessing the efficacy of monotherapy and combination therapy in the treatment of this aggressive form of cancer. The HER2 receptor belongs to a family of receptors that consists of four cell-surface receptors (HER1-4) that share strong homology with the epidermal growth factor receptor (EGFR). All HER receptors interact with specific types of ligands to induce receptor activation, except for HER2, for which no known ligand has yet been identified. HER2 is activated by forming dimers with other HER receptors, and this results in a stronger and more prolonged signal transduction event. When expressed at normal levels, HER2 regulates cell growth, differentiation, and survival. However, under pathological conditions of HER2 overexpression, numerous HER2 heterodimers are formed resulting in aggressive tumor growth. Therefore, the prognosis associated with HER2-positive breast cancer is usually poor. A specific cohort of patients with breast cancer whose tumors test both hormone receptor (estrogen receptor [ER] and progesterone receptor [PR]) and HER2 positive have been found to be resistant to targeted hormone therapy. Studies investigating the etiology of this resistance have found that the cell membrane estrogen receptor communicates with HER2 in promoting the release of ER coactivators that cause the endocrine drug and selective estrogen receptor modulator, tamoxifen, to act as an agonist rather than an antagonist of the hormone estrogen. Thus, research has directed its inquiry toward the development of therapies specifically targeting HER2. The development of trastuzumab, a recombinant monoclonal antibody against HER2, initially proved to be a well-tolerated first line of treatment. However, in the long-term patients, trastuzumab was shown to develop resistance to this monotherapy. Therefore, research on HER2 positive breast cancer has focused on the study of different anti-HER2 combination therapies over the past decade. While the development and approval of the HER2-targeted recombinant monoclonal antibody trastuzumab (Herceptin) has been efficacious in slowing HER2 cancer progression, combining this and other anti-HER2 therapy with either chemotherapy or endocrine therapy has proven more effective in improving overall and progression free survival.


Collective dynamics of processive cytoskeletal motors.
Major cellular processes are supported by various biomolecular motors that usually operate together as teams. We present an overview of the collective dynamics of processive cytokeletal motor proteins based on recent experimental and theoretical investigations. Experimental studies show that multiple motors function with different degrees of cooperativity, ranging from negative to positive. This effect depends on the mechanical properties of individual motors, the geometry of their connections, and the surrounding cellular environment. Theoretical models based on stochastic approaches underline the importance of intermolecular interactions, the properties of single motors, and couplings with cellular medium in predicting the collective dynamics. We discuss several features that specify the cooperativity in motor proteins. Based on this approach a general picture of collective dynamics of motor proteins is formulated, and the future directions and challenges are discussed.


1,25-Dihydroxyvitamin D3 regulation of cardiac myocyte proliferation and hypertrophy.
We previously demonstrated that 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] inhibits myocyte maturation (T. D. O'Connell, D. A. Giacherio, A. K. Jarvis, and R. U. Simpson. Endocrinology 136: 482-488, 1995). To define further the role of 1,25(OH)2D3 in regulating myocardial development, we examined the effects of 1,25(OH)2D3 on proliferation and growth of primary cultures of ventricular myocytes isolated from neonatal rat hearts. When neonatal myocytes were grown in a serum-supplemented medium, cell number approximately doubled, and treating these myocytes with 1,25(OH)2D3 inhibited their proliferation by 56.56% after 4 days. Flow cytometry revealed that 1,25(OH)2D3 reduced the percentage of cells in the S phase of the cell cycle by 31.39% after 4 days. We show for the first time that proliferating cell nuclear antigen protein levels were specifically reduced by 1,25(OH)2D3. Protooncogene c-myc protein levels were also reduced by this hormone. Interestingly, a phorbol ester had a similar effect on myocyte proliferation. Furthermore, 1,25(OH)2D3 increased myocyte protein levels and increased cell size, suggesting that it induces cardiac myocyte hypertrophy. Our findings indicate that 1,25(OH)2D3 and phorbol esters directly regulate myocyte proliferation and induce myocyte hypertrophy. Finally, the data demonstrate that the mechanism by which 1,25(OH)2D3 regulates myocyte proliferation involves blocking entry into the S phase of the cell cycle.


Sampling time after tourniquet removal affects erythrocyte deformability and aggregation measurements.
Venipuncture procedures are widely thought to influence biochemical, hematological or hemorheological measurements. In line with the preparation of the new Guidelines for the standardization of hemorheological measurement, we compared various blood rheological parameters (i.e., red blood cell deformability and aggregation indices) assessed in blood samples obtained after 5, 30, 60 and 90 s following the tourniquet removal and a blood sample obtained without applying a tourniquet (control sample). A slight but significant improvement in red blood cell (RBC) deformability after the removal of tourniquet compared to the control sample was observed. RBC deformability was maximal in the samples obtained 30 s after tourniquet removal and remained slightly higher than the control in the following samples (at 60 and 90 s after tourniquet removal). The aggregation index (AI) decreased with time after tourniquet removal reaching significantly lower values than the control at 90 s after tourniquet removal. This finding was supported by a greater half time for RBC aggregation in the samples obtained 60 and 90 s after tourniquet removal. In conclusion, this study revealed that RBC deformability and aggregation might be significantly altered in the samples obtained after the application and removal of a tourniquet, as a part of the blood sampling procedure. Recommendation "remove the tourniquet at least 5 s prior to the start of blood sampling" may need to be revised.


Increased AKT S473 phosphorylation after mTORC1 inhibition is rictor dependent and does not predict tumor cell response to PI3K/mTOR inhibition.
Mammalian target of rapamycin (mTOR) regulates cellular processes important for progression of human cancer. RAD001 (everolimus), an mTORC1 (mTOR/raptor) inhibitor, has broad antitumor activity in preclinical models and cancer patients. Although most tumor lines are RAD001 sensitive, some are not. Selective mTORC1 inhibition can elicit increased AKT S473 phosphorylation, involving insulin receptor substrate 1, which is suggested to potentially attenuate effects on tumor cell proliferation and viability. Rictor may also play a role because rictor kinase complexes (including mTOR/rictor) regulate AKT S473 phosphorylation. The role of raptor and rictor in the in vitro response of human cancer cells to RAD001 was investigated. Using a large panel of cell lines representing different tumor histotypes, the basal phosphorylation of AKT S473 and some AKT substrates was found to correlate with the antiproliferative response to RAD001. In contrast, increased AKT S473 phosphorylation induced by RAD001 did not correlate. Similar increases in AKT phosphorylation occurred following raptor depletion using siRNA. Strikingly, rictor down-regulation attenuated AKT S473 phosphorylation induced by mTORC1 inhibition. Further analyses showed no relationship between modulation of AKT phosphorylation on S473 and T308 and AKT substrate phosphorylation patterns. Using a dual pan-class I phosphatidylinositol 3-kinase/mTOR catalytic inhibitor (NVP-BEZ235), currently in phase I trials, concomitant targeting of these kinases inhibited AKT S473 phosphorylation, eliciting more profound cellular responses than mTORC1 inhibition alone. However, reduced cell viability could not be predicted from biochemical or cellular responses to mTORC1 inhibitors. These data could have implications for the clinical application of phosphatidylinositol 3-kinase/mTOR inhibitors.


Neuronal population decoding explains the change in signal detection sensitivity caused by task-irrelevant perceptual bias.
Spatiotemporal context in sensory stimulus has profound effects on neural responses and perception, and it sometimes affects task difficulty. Recently reported experimental data suggest that human detection sensitivity to motion in a target stimulus can be enhanced by adding a slow surrounding motion in an orthogonal direction, even though the illusory motion component caused by the surround is not relevant to the task. It is not computationally clear how the task-irrelevant component of motion modulates the subject's sensitivity to motion detection. In this study, we investigated the effects of encoding biases on detection performance by modeling the stochastic neural population activities. We modeled two types of modulation on the population activity profiles caused by a contextual stimulus: one type is identical to the activity evoked by a physical change in the stimulus, and the other is expressed more simply in terms of response gain modulation. For both encoding schemes, the motion detection performance of the ideal observer is enhanced by a task-irrelevant, additive motion component, replicating the properties observed for real subjects. The success of these models suggests that human detection sensitivity can be characterized by a noisy neural encoding that limits the resolution of information transmission in the cortical visual processing pathway. On the other hand, analyses of the neuronal contributions to the task predict that the effective cell populations differ between the two encoding schemes, posing a question concerning the decoding schemes that the nervous system used during illusory states.


Haemopoietic mechanisms in murine allergic upper and lower airway inflammation.
Eosinophil recruitment to the airways, including involvement of haemopoietic eosinophil-basophil progenitors (Eo/B-CFU), is primarily regulated by interleukin-5 (IL-5) and eotaxin. In this study, we investigated the haemopoietic mechanisms in upper and lower airway eosinophilic inflammation. Ovalbumin (OVA) sensitized and challenged BALB/c mice were used to establish isolated upper (UAC), isolated lower (LAC), or combined upper and lower airway (ULAC) inflammation. Airway, blood and bone marrow responses were evaluated in each model. Numbers of airway eosinophils and CD4(+) cells were increased significantly in the nasal mucosa in UAC and ULAC mice, and in the lung tissue in LAC and ULAC groups. Levels of IL-5 and eotaxin were increased significantly in the nasal lavage fluid (NL) in UAC and ULAC mice, and in the bronchoalveolar lavage fluid (BAL) in LAC and ULAC groups. The proportion of IL-5-responsive bone marrow Eo/B-CFU was significantly higher than the control in all treatment groups, but peaked much earlier in the ULAC group. Kinetic studies revealed that IL-5 and eotaxin in NL, BAL and serum peaked between 2 and 12 hr after OVA challenge in ULAC mice, and at 24 hr in UAC mice, related to the timing of maximal progenitor responses. These data support the concept that the systemic mechanisms linking rhinitis to asthma depend on the location and extent of airway allergen exposure.


Mechanism of antifungal activity of terpenoid phenols resembles calcium stress and inhibition of the TOR pathway.
Terpenoid phenols, including carvacrol, are components of oregano and other plant essential oils that exhibit potent antifungal activity against a wide range of pathogens, including Candida albicans, Staphylococcus aureus, and Pseudomonas aeruginosa. To gain a mechanistic view of the cellular response to terpenoid phenols, we used Saccharomyces cerevisiae as a model organism and monitored temporal changes in metabolic activity, cytosolic and vacuolar pH, and Ca(2+) transients. Using a panel of related compounds, we observed dose-dependent Ca(2+) bursts that correlated with antifungal efficacy. Changes in pH were long lasting and followed the Ca(2+) transients. A vma mutant lacking functional vacuolar H(+)-ATPase (V-ATPase) and defective in ion homeostasis was hypersensitive to carvacrol toxicity, consistent with a role for ionic disruptions in mediating cell death. Genomic profiling within 15 min of exposure revealed a robust transcriptional response to carvacrol, closely resembling that of calcium stress. Genes involved in alternate metabolic and energy pathways, stress response, autophagy, and drug efflux were prominently upregulated, whereas repressed genes mediated ribosome biogenesis and RNA metabolism. These responses were strongly reminiscent of the effects of rapamycin, the inhibitor of the TOR pathway of nutrient sensing. The results point to the activation of specific signaling pathways downstream of cellular interaction with carvacrol rather than a nonspecific lesion of membranes, as has been previously proposed.


Do people's world views matter? The why and how.
Over the past decades, personality and social psychologists have extensively investigated the role of self-views in individual functioning. Research on world views, however, has been less well studied due to overly specific conceptualizations, and little research about how and why they impact life outcomes. To answer why and how world views matter, we conducted 7 studies to examine the functions, antecedents, and consequences of generalized beliefs about the world, operationalized as social axioms (Leung et al., 2002). This research focused on 2 axiom factors, namely, social cynicism and reward for application. These axioms were found to explain individual differences in self-views over and above personality traits in Hong Kong and U.S. samples (Study 1) and to explain cultural differences in self-views in addition to self-construals among Mainland Chinese, Hong Kong Chinese, East Asian Canadians, and European Canadians (Study 2). Endorsement of social axioms by participants, their parents, and close friends was collected from Mainland China, Hong Kong, and Canada to infer parental and peer influences on world views (Study 3). World views affected psychological well-being through the mediation of positive self-views across 3 age groups, including children, adolescents, and young adults (Study 4) and over time (Study 5). The mediation of negative self-views was through comparative self-criticism rather than internalized self-criticism (Study 6). Holistic thinking moderated the effect of social cynicism on self-views and psychological well-being (Study 7). These results converge to show that world views as a distal force and self-views as a proximal force matter in people's subjective evaluation of their lives. (PsycINFO Database Record


CYP2B6 Genetic Polymorphisms, Depression, and Viral Suppression in Adults Living with HIV Initiating Efavirenz-Containing Antiretroviral Therapy Regimens in Uganda: Pooled Analysis of Two Prospective Studies.
Single-nucleotide polymorphisms (SNPs) in CYP2B6 have been shown to predict variation in plasma efavirenz concentrations, but associations between these SNPs and efavirenz-mediated depression and viral suppression are less well described. We evaluated three SNPs in CYP2B6 (rs3745274, rs28399499, and rs4803419) in Ugandan persons living with HIV. To define exposure, we used previously published pharmacokinetic modeling data to categorize participants as normal, intermediate, and poor efavirenz metabolizers. Our outcomes were probable depression in the first 2 years after antiretroviral therapy (ART) initiation (mean score of >1.75 on the Hopkins Symptom Depression Checklist) and viral suppression 6 months after ART initiation. We fit generalized estimating equation and modified Poisson regression models adjusted for demographic, clinical, and psychosocial characteristics with or without individuals with depression at the time of ART initiation. Among 242 participants, there were no differences in the pre-ART depression or viral load by efavirenz metabolism strata (p > .05). Participants were classified as normal (32%), intermediate (50%), and poor (18%) metabolizers. Seven percent (56/242) of follow-up visits met criteria for depression. Eighty-five percent (167/202) of participants who completed a 6-month visit achieved viral suppression. CYP2B6 metabolizer strata did not have a statistically significant association with either depression [adjusted risk ratio (aRR) comparing intermediate or poor vs. normal, 1.46; 95% confidence interval (CI), 0.72-2.95] or 6-month viral suppression (aRR, 1.01; 95% CI, 0.88-1.15). However, in analyses restricted to participants without pre-ART depression, poorer CYP2B6 metabolism was associated with increased odds of depression (adjusted odds ratio, 4.11; 95% CI, 1.04-16.20). Efavirenz-metabolizing allele patterns are strongly associated with risk of incident depression. Future work should elucidate further region-specific gene-environment interactions and whether alternate polymorphisms may be associated with efavirenz metabolism.


Characterization of genetic variation in TLR8 in relation to allergic rhinitis.
A previous investigation of all 10 TLR genes for associations with allergic rhinitis (AR) detected a number of significant SNPs in the TLR8 locus. The associations indicated that an accumulation of rare variants could explain the signal. This study therefore searches for rare variants in the TLR8 region and also investigates the reproducibility of previous SNP associations. The TLR8 gene was resequenced in 288 AR patients from Malmö and the data were compared with publically available data. Seven previously AR-associated SNPs from TLR8 were analyzed for AR associations in 422 AR patients and 859 controls from the BAMSE cohort. The associations detected in present and previous studies were compared. Sequencing detected 13 polymorphisms (three promotor and 10 coding) among 288 AR patients. Four of the coding polymorphisms were rare (MAF < 1%) and three of those were novel. Two coding polymorphisms were benign missense mutations and the rest were synonymous. Comparison with 1000Genomes and Exome Aggregation Consortium data revealed no accumulation of rare variants in the AR cases. The AR association tests made using the BAMSE cohort yielded five P-values <0.05. Tests of IgE levels yielded four significant SNP associations to birch pollen. Comparing results between different populations revealed opposing risk alleles, different gender effects, and response to different allergens in the different populations. Rare variants in TLR8 are not associated with AR. Comparison of present and previous association studies reveals contradictory results for common variants. Thus, no associations exist between genetic variation in TLR8 and AR.


Fechner's law in metacognition: A quantitative model of visual working memory confidence.
Although visual working memory (VWM) has been studied extensively, it is unknown how people form confidence judgments about their memories. Peirce (1878) speculated that Fechner's law-which states that sensation is proportional to the logarithm of stimulus intensity-might apply to confidence reports. Based on this idea, we hypothesize that humans map the precision of their VWM contents to a confidence rating through Fechner's law. We incorporate this hypothesis into the best available model of VWM encoding and fit it to data from a delayed-estimation experiment. The model provides an excellent account of human confidence rating distributions as well as the relation between performance and confidence. Moreover, the best-fitting mapping in a model with a highly flexible mapping closely resembles the logarithmic mapping, suggesting that no alternative mapping exists that accounts better for the data than Fechner's law. We propose a neural implementation of the model and find that this model also fits the behavioral data well. Furthermore, we find that jointly fitting memory errors and confidence ratings boosts the power to distinguish previously proposed VWM encoding models by a factor of 5.99 compared to fitting only memory errors. Finally, we show that Fechner's law also accounts for metacognitive judgments in a word recognition memory task, which is a first indication that it may be a general law in metacognition. Our work presents the first model to jointly account for errors and confidence ratings in VWM and could lay the groundwork for understanding the computational mechanisms of metacognition. (PsycINFO Database Record


Relaxed complex scheme suggests novel inhibitors for the lyase activity of DNA polymerase beta.
DNA polymerase beta (pol β), the error-prone polymerase of base excision repair, plays a significant role in chemotherapeutic agent resistance. Its over expression reduces the efficacy of anticancer drug therapies including ionizing radiation, bleomycin, monofunctional alkylating agents and cisplatin. Small-scale studies on different types of cancer showed that pol β is mutated in approximately 30% of tumors. These mutations further lower pol β fidelity in DNA synthesis exposing the genome to serious mutations. These findings suggested pol β as a promising therapeutic target for cancer treatment. More than 60 pol β-inhibitors have been identified so far, however, most of them are either not potent or specific enough to become a drug. Here, we applied the relaxed complex scheme virtual screening (RCSVS) to allow for the full receptor flexibility in filtering the NCI diversity set, DrugBank compounds and a library of ∼ 9000 fragmental compounds for novel pol β inhibitors. In this procedure we screened the set of ∼ 12,500 compounds against an ensemble of 11 dominant-receptor structures representing the essential backbone dynamics of the 8 kDa domain of pol β. Our results predicted new compounds that can bind with higher affinity to the lyase active site compared to pamoic acid (PA), a well-known inhibitor of DNA pol β.


Association between living with children and outcomes from covid-19: OpenSAFELY cohort study of 12 million adults in England.
To investigate whether risk of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and outcomes of coronavirus disease 2019 (covid-19) differed between adults living with and without children during the first two waves of the UK pandemic. Population based cohort study, on behalf of NHS England. Primary care data and pseudonymously linked hospital and intensive care admissions and death records from England, during wave 1 (1 February to 31 August 2020) and wave 2 (1 September to 18 December 2020). Two cohorts of adults (18 years and over) registered at a general practice on 1 February 2020 and 1 September 2020. Adjusted hazard ratios for SARS-CoV-2 infection, covid-19 related admission to hospital or intensive care, or death from covid-19, by presence of children in the household. Among 9 334 392adults aged 65 years and under, during wave 1, living with children was not associated with materially increased risks of recorded SARS-CoV-2 infection, covid-19 related hospital or intensive care admission, or death from covid-19. In wave 2, among adults aged 65 years and under, living with children of any age was associated with an increased risk of recorded SARS-CoV-2 infection (hazard ratio 1.06 (95% confidence interval 1.05 to 1.08) for living with children aged 0-11 years; 1.22 (1.20 to 1.24) for living with children aged 12-18 years) and covid-19 related hospital admission (1.18 (1.06 to 1.31) for living with children aged 0-11; 1.26 (1.12 to 1.40) for living with children aged 12-18). Living with children aged 0-11 was associated with reduced risk of death from both covid-19 and non-covid-19 causes in both waves; living with children of any age was also associated with lower risk of dying from non-covid-19 causes. For adults 65 years and under during wave 2, living with children aged 0-11 years was associated with an increased absolute risk of having SARS-CoV-2 infection recorded of 40-60 per 10 000 people, from 810 to between 850 and 870, and an increase in the number of hospital admissions of 1-5 per 10 000 people, from 160 to between 161 and 165. Living with children aged 12-18 years was associated with an increase of 160-190 per 10 000 in the number of SARS-CoV-2 infections and an increase of 2-6 per 10 000 in the number of hospital admissions. In contrast to wave 1, evidence existed of increased risk of reported SARS-CoV-2 infection and covid-19 outcomes among adults living with children during wave 2. However, this did not translate into a materially increased risk of covid-19 mortality, and absolute increases in risk were small.


A new method for exact three-dimensional reconstructions of diatom frustules.
Exact geometric description, numerical analysis and comparison of microscopic objects such as the frustules of diatoms are of increasing importance in basic research (e.g. functional morphology, taxonomy and biogeochemistry). Similarly, applied research and product development in the fields of lightweight construction and nanotechnology can benefit from machine-readable data of such structures. This paper presents a new method to combine data from scanning electron microscopy and confocal laser scanning microscopy to generate exact three-dimensional models of diatom frustules. We propose a method to obtain a high-quality mesh for subsequent analysis through finite element analysis, for example, for biomechanical research on diatom frustules. A specific lightweight value as a universal tool to describe and compare the biomechanical quality of microscopic objects is introduced. Our approach improves the precision of three-dimensional reconstructions, but the generation of usable finite element meshes from complex three-dimensional data based on microscopic techniques requires either a transformation of grid points into elements or smoothing algorithms. Biomechanical analyses of differently obtained models indicate that more complex three-dimensional reconstructions lead to more realistic results.


Physicians in the USA: Attendance, Beliefs and Patient Interactions.
While much religion-health research depends on social support explanations, little is known about whether religious support is also a part of clinical interactions. How many physicians include religious/spiritual topics in clinical conversations? What characteristics are related to inclusion or avoidance? Using a national sample (n = 1,144), this study provides an overview of religious beliefs and practices of physicians in the USA and their patient interactions. Physician attendance rates are related to the inclusion of religious/spiritual topics, but the religious/spiritual orientation of physicians more closely relates to religious/spiritual patient interactions. Further, some physician specialties have more religious/spiritual physicians than others, providing additional reason to think religious/spiritual patient conversations are not equally distributed throughout the medical landscape.


TRAIL signals, extracellular matrix and vessel remodelling.
The extracellular matrix (ECM) is an essential part of the vasculature, not only providing structural support to the blood vessel wall, but also in its ability to interact with cells to regulate cell phenotype and function including proliferation, migration, differentiation and death - processes important in vascular remodelling. Increasing evidence implicates TNF-related apoptosis-inducing ligand (TRAIL) signalling in the modulation of vascular cell function and remodelling under normal and pathological conditions such as in atherosclerosis. TRAIL can also stimulate synthesis of multiple ECM components within blood vessels. This review explores the relationship between TRAIL signals, the ECM, and its implications in vessel remodelling in cardiovascular disease.


How do polar marine ecosystems respond to rapid climate change?
Climate change will alter marine ecosystems; however, the complexity of the food webs, combined with chronic undersampling, constrains efforts to predict their future and to optimally manage and protect marine resources. Sustained observations at the West Antarctic Peninsula show that in this region, rapid environmental change has coincided with shifts in the food web, from its base up to apex predators. New strategies will be required to gain further insight into how the marine climate system has influenced such changes and how it will do so in the future. Robotic networks, satellites, ships, and instruments mounted on animals and ice will collect data needed to improve numerical models that can then be used to study the future of polar ecosystems as climate change progresses.


Sequence-Based Analysis of Lipid-Related Metabolites in a Multiethnic Study.
Small molecule lipid-related metabolites are important components of fatty acid and steroid metabolism-two important contributors to human health. This study investigated the extent to which rare and common genetic variants spanning the human genome influence the lipid-related metabolome. Sequence data from 1552 European-Americans (EA) and 1872 African-Americans (AA) were analyzed to examine the impact of common and rare variants on the levels of 102 circulating lipid-related metabolites measured by a combination of chromatography and mass spectroscopy. We conducted single variant tests [minor allele frequency (MAF) > 5%, statistical significance P-value ≤ 2.45 × 10-10] and tests aggregating rare variants (MAF ≤ 5%) across multiple genomic motifs, such as coding regions and regulatory domains, and sliding windows. Multiethnic meta-analyses detected 53 lipid-related metabolites-locus pairs, which were inspected for evidence of consistent signal between the two ethnic groups. Thirty-eight lipid-related metabolite-genomic region associations were consistent across ethnicities, among which seven were novel. The regions contain genes that are related to metabolite transport (SLC10A1) and metabolism (SCD, FDX1, UGT2B15, and FADS2). Six of the seven novel findings lie in expression quantitative trait loci affecting the expression levels of 14 surrounding genes in multiple tissues. Imputed expression levels of 10 of the affected genes were associated with four corresponding lipid-related traits in at least one tissue. Our findings offer valuable insight into circulating lipid-related metabolite regulation in a multiethnic population.


Differential effects of Parkinson's disease-associated mutations on stability and folding of DJ-1.
Mutations in the PARK7/DJ-1 gene cause autosomal-recessive Parkinson's disease. In some patients the gene is deleted. The molecular basis of disease in patients with point mutations is less obvious. We have investigated the molecular properties of [L166P]DJ-1 and the novel variant [E64D]DJ-1. When transfected into non-neuronal and neuronal cell lines, steady-state expression levels of [L166P]DJ-1 were dramatically lower than wild-type [WT]DJ-1 and [E64D]DJ-1. Cycloheximide and pulse-chase experiments revealed that the decreased expression levels of [L166P]DJ-1 were because of accelerated protein turnover. Proteasomal degradation was not the major pathway of DJ-1 breakdown because treatment with the proteasome inhibitor MG-132 caused only minimal accumulation of DJ-1, even of the very unstable [L166P]DJ-1 mutant. Because of the structural resemblance of DJ-1 with bacterial cysteine proteases, we considered an autoproteolytic mechanism. However, neither pharmacological inhibition nor site-directed mutagenesis of the putative active site residue Cys-106 stabilized DJ-1. To gain further insight into the structural defects of DJ-1 mutants, human [WT]DJ-1 and both mutants were expressed in Escherichia coli. As in eukaryotic cells, expression levels of [L166P]DJ-1 were dramatically reduced compared with [WT]DJ-1 and [E64D]DJ-1. Circular dichroism spectrometry revealed that the solution structures of [WT]DJ-1 and [E64D]DJ-1 are rich in beta-strand and alpha-helix conformation. Alpha-helices were more susceptible to thermal denaturation than the beta-sheet, and [WT]DJ-1 was more flexible in this regard than [E64D]DJ-1. Thus, structural defects of [E64D]DJ-1 only become apparent upon denaturing conditions, whereas the L166P mutation causes a drastic defect that leads to excessive degradation.


Outcomes in a multi-institutional cohort of patients treated with intraoperative radiation therapy for advanced or recurrent renal cell carcinoma.
This study aimed to analyze outcomes in a multi-institutional cohort of patients with advanced or recurrent renal cell carcinoma (RCC) who were treated with intraoperative radiation therapy (IORT). Between 1985 and 2010, 98 patients received IORT for advanced or locally recurrent RCC at 9 institutions. The median follow-up time for surviving patients was 3.5 years. Overall survival (OS), disease-specific survival (DSS), and disease-free survival (DFS) were estimated with the Kaplan-Meier method. Chained imputation accounted for missing data, and multivariate Cox hazards regression tested significance. IORT was delivered during nephrectomy for advanced disease (28%) or during resection of locally recurrent RCC in the renal fossa (72%). Sixty-nine percent of the patients were male, and the median age was 58 years. At the time of primary resection, the T stages were as follows: 17% T1, 12% T2, 55% T3, and 16% T4. Eighty-seven percent of the patients had a visibly complete resection of tumor. Preoperative or postoperative external beam radiation therapy was administered to 27% and 35% of patients, respectively. The 5-year OS was 37% for advanced disease and 55% for locally recurrent disease. The respective 5-year DSS was 41% and 60%. The respective 5-year DFS was 39% and 52%. Initial nodal involvement (hazard ratio [HR] 2.9-3.6, P<.01), presence of sarcomatoid features (HR 3.7-6.9, P<.05), and higher IORT dose (HR 1.3, P<.001) were statistically significantly associated with decreased survival. Adjuvant systemic therapy was associated with decreased DSS (HR 2.4, P=.03). For locally recurrent tumors, positive margin status (HR 2.6, P=.01) was associated with decreased OS. We report the largest known cohort of patients with RCC managed by IORT and have identified several factors associated with survival. The outcomes for patients receiving IORT in the setting of local recurrence compare favorably to similar cohorts treated by local resection alone suggesting the potential for improved DFS with IORT.


Enhanced glucosinolates in root exudates of Brassica rapa ssp. rapa mediated by salicylic acid and methyl jasmonate.
Elicitation studies with salicylic acid (SA) and methyl jasmonate (MJ) inducing a targeted rhizosecretion of high levels of anticarcinogenic glucosinolates in Brassica rapa ssp. rapa plants were conducted. Elicitor applications not only led to an accumulation of individual indole glucosinolates and the aromatic 2-phenylethyl glucosinolate in the turnip organs but also in turnip root exudates. This indicates an extended systemic response, which comprises the phyllosphere with all aboveground plant organs and the rhizosphere including the belowground root system and also root exudates. Both elicitor applications induced a doubling in 2-phenylethyl glucosinolate in root exudates, whereas application of MJ enhanced rhizosecreted indole glucosinolates up to 4-fold. In addition, the time course study revealed that maximal elicitation was observed on the 10th day of SA and MJ treatment. This study may provide an essential contribution using these glucosinolates as bioactive additives in functional foods and nutraceuticals.


VX-166: a novel potent small molecule caspase inhibitor as a potential therapy for sepsis.
Prevention of lymphocyte apoptosis by caspase inhibition has been proposed as a novel treatment approach in sepsis. However, it has not been clearly demonstrated that caspase inhibitors improve survival in sepsis models when dosed post-insult. Also, there are concerns that caspase inhibitors might suppress the immune response. Here we characterize VX-166, a broad caspase inhibitor, as a novel potential treatment for sepsis. VX-166 was studied in a number of enzymatic and cellular assays. The compound was then tested in a murine model of endotoxic shock (lipopolysaccharide (LPS), 20 mg/kg IV) and a 10 d rat model of polymicrobial sepsis by caecal ligation and puncture (CLP). VX-166 showed potent anti-apoptotic activity in vitro and inhibited the release of interleukin (IL)-1beta and IL-18. In the LPS model, VX-166 administered 0, 4, 8 and 12 h post-LPS significantly improved survival in a dose-dependent fashion (P < 0.0028). In the CLP model, VX-166 continuously administered by mini-osmotic pump significantly improved survival when dosed 3 h after insult, (40% to 92%, P = 0.009). When dosed 8 h post-CLP, VX-166 improved survival from 40% to 66% (P = 0.19). Mode of action studies in the CLP model confirmed that VX-166 significantly inhibited thymic atrophy and lymphocyte apoptosis as determined by flow cytometry (P < 0.01). VX-166 reduced plasma endotoxin levels (P < 0.05), suggesting an improved clearance of bacteria from the bloodstream. Release of IL-1beta in vivo or T-cell activation in vitro were moderately affected. Our studies enhance the case for the use of caspase inhibitors in sepsis. VX-166 itself has promise as a therapy for the treatment of sepsis in man.


Design modifications of the uncemented Furlong hip stem result in minor early subsidence but do not affect further stability: a randomized controlled RSA study with 5-year follow-up.
Even small design modifications of uncemented hip stems may alter the postoperative 3-D migration pattern. The Furlong Active is an uncemented femoral stem which, in terms of design, is based on its precursor-the well-proven Furlong HAC-but has undergone several design changes. The collar has been removed on the Active stem along with the lateral fin; it is shorter and has more rounded edges in the proximal part. We compared the migration patterns of the uncemented Furlong HAC stem and the modified Furlong Active stem in a randomized, controlled trial over 5 years using radiostereometry (RSA). 50 patients with primary osteoarthritis were randomized to receive either the HAC stem or the Active stem. The patients underwent repeated RSA examinations (postoperatively, at 3 months, and after 1, 2, and 5 years) and conventional radiography, and they also filled out hip-specific questionnaires. During the first 3 months, the collarless Active stem subsided to a greater extent than the collar-fitted HAC stem (0.99 mm vs. 0.31 mm, p=0.05). There were, however, no other differences in movement measured by RSA or in clinical outcome between the 2 stems. After 3 months, both stem types had stabilized and almost no further migration was seen. The Active stem showed no signs of unfavorable migration. Our results suggest that the osseointegration is not compromised by the new design features.


Contemporary radiosurgery of cerebral cavernous malformations: Part 2. Treatment outcome for hemispheric lesions.
OBJECTIVEThe role of radiosurgery (RS) in treating superficial cavernous malformations (CMs) is insufficiently studied in part because of the disappointing results of early experimental attempts as compared to the mostly safe and effective microsurgery. Nonetheless, because of lesion- or treatment-specific factors, a therapeutic alternative may be required. In this study, the authors aimed to assess the safety of RS in treating superficial CMs and to analyze its long-term effect on hemorrhage rates and epilepsy control.METHODSThe authors conducted a retrospective analysis of 96 patients with 109 CMs located in the cerebral or cerebellar hemispheres and treated with RS between 1995 and 2014. A median of 15 Gy (range 10-25 Gy) was given to the 50% prescription isodose level, lesion volume was 604 mm3 (4-8300 mm3), and the prescription isodose volume was 638.5 mm3 (4-9500 mm3). Outcomes were compared to those of 206 deep-seated lesions reported on in another study. Ninety-five patients had available follow-up, which was a median of 7 years (1-21 years). Median patient age was 42 years (0.5-77) at presentation and 45 (3-80) at treatment. Seventy-one CMs presented with symptomatic hemorrhage, and 52 caused seizures.RESULTSIn the nonhemorrhagic group (37 lesions), one bleed occurred during the follow-up period, for an annual bleed rate of 0.4% per lesion. The lifetime annual bleed rate of CMs having a single hemorrhage prior to treatment was 2.5%. The rebleed rate in the single-bleed group decreased from 1.8% within the first 2 years after RS to 0.7% thereafter. The pretreatment rebleed rate for lesions having multiple bleeds prior to RS was 14.15%, which fell to 3.85% for the first 2 years after RS and declined to 1.3% thereafter. Multivariate analysis showed younger age, deep lesion location, and multiple pretreatment hemorrhages as significant predictors of posttreatment hemorrhage.Pretreatment hemorrhages led to permanent deficits in 41.4% of the cases with a single bleed and in 46.1% of cases with multiple bleeds. Only mild (modified Rankin Scale score 1) and a low rate of permanent neurological deficits were caused either by posttreatment hemorrhages (4.3%) or by radiation (2%).The rate of improvement in epilepsy was 84.9% after RS in patients with at least one seizure prior to treatment, not depending on the presence of hemorrhage or the time interval between presentation and treatment. Favorable outcome occurred in 81% of patients whose seizures were not controlled with antiepileptic medication prior to RS.CONCLUSIONSRadiosurgery for superficial CMs is safe and appears to be effective, offering a real treatment alternative to surgery for selected patients. Given their relatively benign natural history, superficial CMs require further study to verify the long-term benefit of RS over the lesions' natural history.


Time outdoors and physical activity as predictors of incident myopia in childhood: a prospective cohort study.
Time spent in "sports/outdoor activity" has shown a negative association with incident myopia during childhood. We investigated the association of incident myopia with time spent outdoors and physical activity separately. Participants in the Avon Longitudinal Study of Parents and Children (ALSPAC) were assessed by noncycloplegic autorefraction at ages 7, 10, 11, 12, and 15 years, and classified as myopic (≤-1 diopters) or as emmetropic/hyperopic (≥-0.25 diopters) at each visit (N = 4,837-7,747). Physical activity at age 11 years was measured objectively using an accelerometer, worn for 1 week. Time spent outdoors was assessed via a parental questionnaire administered when children were aged 8-9 years. Variables associated with incident myopia were examined using Cox regression. In analyses using all available data, both time spent outdoors and physical activity were associated with incident myopia, with time outdoors having the larger effect. The results were similar for analyses restricted to children classified as either nonmyopic or emmetropic/hyperopic at age 11 years. Thus, for children nonmyopic at age 11, the hazard ratio (95% confidence interval, CI) for incident myopia was 0.66 (0.47-0.93) for a high versus low amount of time spent outdoors, and 0.87 (0.76-0.99) per unit standard deviation above average increase in moderate/vigorous physical activity. Time spent outdoors was predictive of incident myopia independently of physical activity level. The greater association observed for time outdoors suggests that the previously reported link between "sports/outdoor activity" and incident myopia is due mainly to its capture of information relating to time outdoors rather than physical activity.


In vitro killing of Candida albicans by fatty acids and monoglycerides.
The susceptibility of Candida albicans to several fatty acids and their 1-monoglycerides was tested with a short inactivation time, and ultrathin sections were studied by transmission electron microscopy (TEM) after treatment with capric acid. The results show that capric acid, a 10-carbon saturated fatty acid, causes the fastest and most effective killing of all three strains of C. albicans tested, leaving the cytoplasm disorganized and shrunken because of a disrupted or disintegrated plasma membrane. Lauric acid, a 12-carbon saturated fatty acid, was the most active at lower concentrations and after a longer incubation time.


Alcohol use and change over time in firearm safety among families with young children.
Improperly stored firearms pose a clear health risk to children. Previous research concurrently links alcohol use with lower levels of firearm safety. The objectives of this study were to assess (1) how families move from unsafe to safer firearm storage practices and (2) how parental drinking was associated with moving away from unsafe firearm storage practices. This study used data from the Early Childhood Longitudinal Study-Birth Cohort, 2003 when children were two years old and again when they were four years old. Parents were asked about firearm storage practices, alcohol consumption, and information to measure other confounding variables. Their responses were used to identify families who engaged in unsafe firearm storage practices (n = 650) during the initial testing period and to assess how alcohol consumption and other variables were associated with moving to safer firearm storage practices at the second testing period. Families grew more likely to adopt safer firearm storage practices as their children aged, compared with continuing unsafe practices. Multivariate logistic regressions indicated that parental drinking, however, reduced the likelihood that parents moved to safer storage practices, controlling for covariates. Other families- and community-level variables, in particular, family structure, were also associated with the likelihood of moving to safer firearm storage behaviors. Families with higher levels of alcohol use may need additional assistance in addressing firearm safety. The findings call for future research to better understand how physicians can counsel at-risk families to help them store firearms more securely.


Biological concepts in human sodium channel epilepsies and their relevance in clinical practice.
Voltage-gated sodium channels (SCNs) share similar amino acid sequence, structure, and function. Genetic variants in the four human brain-expressed SCN genes SCN1A/2A/3A/8A have been associated with heterogeneous epilepsy phenotypes and neurodevelopmental disorders. To better understand the biology of seizure susceptibility in SCN-related epilepsies, our aim was to determine similarities and differences between sodium channel disorders, allowing us to develop a broader perspective on precision treatment than on an individual gene level alone. We analyzed genotype-phenotype correlations in large SCN-patient cohorts and applied variant constraint analysis to identify severe sodium channel disease. We examined temporal patterns of human SCN expression and correlated functional data from in vitro studies with clinical phenotypes across different sodium channel disorders. Comparing 865 epilepsy patients (504 SCN1A, 140 SCN2A, 171 SCN8A, four SCN3A, 46 copy number variation [CNV] cases) and analysis of 114 functional studies allowed us to identify common patterns of presentation. All four epilepsy-associated SCN genes demonstrated significant constraint in both protein truncating and missense variation when compared to other SCN genes. We observed that age at seizure onset is related to SCN gene expression over time. Individuals with gain-of-function SCN2A/3A/8A missense variants or CNV duplications share similar characteristics, most frequently present with early onset epilepsy (<3 months), and demonstrate good response to sodium channel blockers (SCBs). Direct comparison of corresponding SCN variants across different SCN subtypes illustrates that the functional effects of variants in corresponding channel locations are similar; however, their clinical manifestation differs, depending on their role in different types of neurons in which they are expressed. Variant function and location within one channel can serve as a surrogate for variant effects across related sodium channels. Taking a broader view on precision treatment suggests that in those patients with a suspected underlying genetic epilepsy presenting with neonatal or early onset seizures (<3 months), SCBs should be considered.


Interferon-independent and -induced regulation of Epstein-Barr virus EBNA-1 gene transcription in Burkitt lymphoma.
Replication of the Epstein-Barr virus (EBV) genome within latently infected cells is dependent on the EBV EBNA-1 protein. The objective of this study was to identify transcriptional regulatory proteins that mediate EBNA-1 expression via the viral promoter Qp, which is active in EBV-associated tumors such as Burkitt lymphoma and nasopharyngeal carcinoma. Results of a yeast one-hybrid screen suggested that a subset of the interferon regulatory factor (IRF) family may regulate EBNA-1 transcription by targeting an essential cis-regulatory element of Qp, QRE-2. Further investigation indicated that the transcriptional activator IRF-1 and the closely related IRF-2, a repressor of interferon-induced gene expression, are both capable of activating Qp. However, the major QRE-2-specific binding activity detected within extracts of Burkitt lymphoma cells was attributed to IRF-2, suggesting that interferon-independent activation of Qp is largely mediated by IRF-2 in these cells. We observed no effect of gamma interferon on Qp activity in transfection assays, whereas we observed a moderate but significant repression of Qp activity in response to alpha interferon, possibly mediated by either the interferon consensus sequence binding protein or IRF-7, a novel alpha interferon-inducible factor identified in this study. Since expression of IRF-1 and IRF-2 is increased in response to interferons, the Qp activity observed in the presence of interferon likely represented an equilibrium between IRF factors that activate and those that repress gene expression in response to interferon. Thus, by usurping both IRF-1 and its transcriptional antagonist IRF-2 to activate Qp, EBV has evolved not only a mechanism to constitutively express EBNA-1 but also one which may sustain EBNA-1 expression in the face of the antiviral effects of interferon.


Dermoscopy vs. reflectance confocal microscopy for the diagnosis of lentigo maligna.
Several dermoscopic and in vivo reflectance confocal microscopy (RCM) diagnostic criteria of lentigo maligna (LM)/lentigo maligna melanoma (LMM) have been identified. However, no study compared the diagnostic accuracy of these techniques. We evaluated the diagnostic accuracy of dermoscopy and RCM for LM/LMM using a holistic assessment of the images. A total of 223 facial lesions were evaluated by 21 experts. Diagnostic accuracy of the clinical, dermoscopic and RCM examination was compared. Interinvestigator variability and confidence level in the diagnosis were also evaluated. Overall diagnostic accuracy of the two imaging techniques was good (area under the curve of the sROC function: 0.89). RCM was more sensitive (80%, vs. 61%) and less specific (81% vs. 92%) than dermoscopy for LM/LMM. In particular, RCM showed a higher sensitivity for hypomelanotic and recurrent LM/LMM. RCM had a higher interinvestigator agreement and a higher confidence level in the diagnosis than dermoscopy. Reflectance confocal microscopy and dermoscopy are both useful techniques for the diagnosis of facial lesions and in particular LM/LMM. RCM is particularly suitable for the identification of hypomelanotic and recurrent LM/LMM.


Foreign body ingestion in children presenting to a tertiary paediatric centre in South Africa: A retrospective analysis focusing on battery ingestion.
Ingestion of foreign bodies remains a frequent reason for presentation to paediatric emergency departments worldwide. Among the variety of objects ingested, button batteries are particularly harmful owing to their electrochemical properties, which can cause extensive injuries if not diagnosed and treated rapidly. International trends show an increasing incidence of button battery ingestion, leading to concern that this pattern may be occurring in South Africa. Limited local data on paediatric foreign body ingestion have been published. To assess battery ingestion rates in a tertiary paediatric hospital. We hypothesised that the incidence has increased, in keeping with international trends. Secondary objectives included describing admission rates, requirements for anaesthesia and surgery, and promoting awareness of the problems associated with battery ingestion. We performed a retrospective, descriptive analysis of the Red Cross War Memorial Children's Hospital trauma database, including all children under 13 years of age seen between 1 January 2010 and 31 December 2015 with suspected ingestion of a foreign body. The ward admissions database was then examined to find additional cases in which children were admitted directly. After exclusion of duplicate records, cases were classified by type of foreign body, management, requirement for admission, anaesthesia and surgery. Descriptive statistics were used to analyse the data in comparison with previous studies published from this database. Patient age and gender patterns matched the literature, with a peak incidence in children under 2 years of age. Over the 6-year period, 180 patients presented with food foreign bodies, whereas 497 objects were classified as non-food. After exclusion of misdiagnosed cases, the remaining 462 objects were dominated by coins (44.2%). Batteries were the causative agent in 4.8% (22/462). Although the subtypes of batteries were not reliably recorded, button batteries accounted for at least 64% (14/22). Most children who ingested batteries presented early, but more required admission, anaesthesia and surgery than children who ingested other forms of foreign body. The study demonstrated that the local incidence of button battery ingestion may be increasing, although data are still limited.Admission, anaesthesia and surgery rates for batteries were higher in this cohort than for all other foreign bodies. As button batteries can mimic coins, with much more dire consequences on ingestion, our ability to expedite diagnosis and management hinges on a high index of suspicion. It is imperative to increase awareness among healthcare workers and parents.


Transcutaneous angioplasty of experimental aortic coarctation.
A dilatable form of juxtaductal aortic coarctation was surgically created in 29 newborn lambs. Of the 17 long-term survivors, four lambs served as controls and 13 underwent transcutaneous balloon dilation angioplasty with either polyvinylchloride or polyethylene catheters after 7--10 weeks of recovery. During growth before dilation, there was little change in the systolic gradient across the coarctation (36.6-35.3 mm Hg) despite an increase in animal weight from 3.8 to 19.3 kg. This systolic gradient remained constant in undilated lambs throughout a 6-month follow-up. Dilation produced an immediate 65% increase in the diameter of the coarctation and a 68% decrease in the systolic gradient across the coarctation site. Successful dilation required very high (6--8 atmospheres) dilating pressures. This gradient relief persisted throughout a follow-up of up to 1 year. Although no late sequelae could be attributed to the angioplasty, one lamb suffered an anterior aortic tear (associated with a difficult postdilation wire passage across the dilation site), which resulted in fatal intrathoracic hemorrhage. Cross pathologic inspection demonstrated intimal and medial tears in successfully dilated lambs in the first 3 days after dilation; on late pathologic examination, the intima appeared completely healed, without evidence of aneurysm or accelerated atheroma formation, within 2 months. These results, in conjunction with previous human in vitro studies, support the hypothesis that human aortic coarctation may be a dilatable lesion, although the safe limits and optimal protocols for dilating human coarctations are not known.


Effect of presurgical incisor extrusion on stability of anterior open bite malocclusion treated with orthognathic surgery.
The records of 40 nongrowing open bite patients treated with orthodontics and maxillary surgery were divided into two groups and evaluated. The extrusion group (n = 19) included those patients who had presurgical maxillary incisor extrusion of at least 1.5 mm. In the nonextrusion group (n = 21), the maxillary incisors were maintained or intruded prior to surgery. Statistical analysis showed no relationship between presurgical extrusion of the maxillary incisors and the stability of open bite correction; the maxillary incisors were generally stable long term in both groups. Overbite decreased a mean of -0.97 mm in the extrusion group and -0.67 mm in the nonextrusion group during the mean 5-year 10-month follow-up period after appliance removal. Twenty-five percent (10 of 40, 5 from each group) of the sample had no incisal overlap long term. These findings suggest that a moderate amount of presurgical incisor extrusion or lack of extrusion are stable long term and have little influence on posttreatment stability of open bites. The decrease in overbite observed after treatment may result from the influence of various dental, skeletal, and soft tissue factors rather than from any single factor.


Wide-cross whole-genome radiation hybrid mapping of the cotton (Gossypium barbadense L.) genome.
Whole-genome radiation hybrid mapping has been applied extensively to human and certain animal species, but little to plants. We recently demonstrated an alternative mapping approach in cotton (Gossypium hirsutum L.), based on segmentation by 5-krad gamma-irradiation and derivation of wide-cross whole-genome radiation hybrids (WWRHs). However, limitations observed at the 5-krad level suggested that higher doses might be advantageous. Here, we describe the development of an improved second-generation WWRH panel after higher dose irradiation and compare the resulting map to the 5-krad map. The genome of G. hirsutum (n = 26) was used to rescue the radiation-segmented genome of G. barbadense (n = 26) introduced via 8- and 12-krad gamma-irradiated pollen. Viable seedlings were not recovered after 12-krad irradiation, but 8-krad irradiation permitted plant recovery and construction of a 92-member WWRH mapping panel. Assessment of 31 SSR marker loci from four chromosomes revealed that the 8-krad panel has a marker retention frequency of ca. 76%, which is approximately equivalent to the rate of loss in a low-dose animal radiation hybrid panel. Retention frequencies of loci did not depart significantly from independence when compared between the A and D subgenomes, or according to positions along individual chromosomes. WWRH maps of chromosomes 10 and 17 were generated by the maximum likelihood RHMAP program and the general retention model. The resulting maps bolster evidence that WWRH mapping complements traditional linkage mapping and works in cotton, and that the 8-krad panel complements the 5-krad panel by offering higher rates of chromosome breakages, lower marker retention frequency, and more retention patterns.