Simplifying the assessment of the recovery from surgical injury to the lingual nerve.
To determine the sensitivity of conventional sensory assessment in monitoring lingual nerve recovery subsequent to third molar surgery and to evaluate if the assessment methods can be predictive of injury outcome. A prospective case series of 94 patients presenting with lingual nerve injuries evaluated using objective mechanosensory and subjective methods during the recovery period of up to 12 months. The conventional tests were often unable to diagnose the presence of injury due to variability and they were not predictive of outcome. As a result of this study, we are able to identify patients more likely to have permanent rather than temporary lingual nerve injury at four to eight weeks post injury, using patient reported subjective function. The subjective function test also minimises the requirements for specialist training or equipment providing an ideal method for general dental practice. The development of these simple subjective tests may enable us to identify which patients are at risk of permanent lingual nerve injuries in the early post injury phase, thus allowing expeditious therapy when indicated.


Emergencies in Pediatric Palliative Care: A Survey of Ambulance Officers to Understand the Interface between Families and Ambulance Services.
Background: Pediatric palliative care occurs across contexts through the child's illness trajectory, including within the child or young person's community. Interactions with the ambulance service may occur with a child's deterioration, crisis, or when needing transfer, but there is little research on this interaction. Aim: To explore the experiences and attitudes of ambulance officers in managing pediatric patients with palliative care needs. Design: A targeted e-mail survey was sent exploring perceptions of the involvement with these patients including exposure, comfort, resuscitation topics, and supports available. Setting/Participants: Participants were Queensland ambulance officers known to have had an interaction with one of the last 50 pediatric palliative care referrals across Queensland. Results: Twenty-two survey responses were received. Most of the palliative group accessed ambulances for the 13-month study period. Most ambulance officers did not easily identify patients as receiving palliative care. Many participants felt these cases were challenging, confidence levels varied, and staff counselling services were felt to be relevant. Ambulance officers were most likely to use correspondence provided by the family from their usual team as a guide for emergency management. Half of the participants felt patients receiving pediatric palliative care should have a "not for resuscitation" order. Respondents suggested officer support could be improved through increased patient documentation and promotion of existing officer supports. Conclusions: These findings demonstrate challenges experienced by ambulance officers and suggest practical ways in which pediatric palliative care services can better support emergency services.


Physiology and molecular biology of petal senescence.
Petal senescence is reviewed, with the main emphasis on gene expression in relation to physiological functions. Autophagy seems to be the major mechanism for large-scale degradation of macromolecules, but it is still unclear if it contributes to cell death. Depending on the species, petal senescence is controlled by ethylene or is independent of this hormone. EIN3-like (EIL) transcription factors are crucial in ethylene-regulated senescence. The presence of adequate sugar levels in the cell delays senescence and prevents an increase in the levels of EIL mRNA and the subsequent up-regulation of numerous senescence-associated genes. A range of other transcription factors and regulators are differentially expressed in ethylene-sensitive and ethylene-insensitive petal senescence. Ethylene-independent senescence is often delayed by cytokinins, but it is still unknown whether these are natural regulators. A role for caspase-like enzymes or metacaspases has as yet not been established in petal senescence, and a role for proteins released by organelles such as the mitochondrion has not been shown. The synthesis of sugars, amino acids, and fatty acids, and the degradation of nucleic acids, proteins, lipids, fatty acids, and cell wall components are discussed. It is claimed that there is not enough experimental support for the widely held view that a gradual increase in cell leakiness, resulting from gradual plasma membrane degradation, is an important event in petal senescence. Rather, rupture of the vacuolar membrane and subsequent rapid, complete degradation of the plasma membrane seems to occur. This review recommends that more detailed analysis be carried out at the level of cells and organelles rather than at that of whole petals.


Failure to detect hypnozoites in hepatic tissue containing exoerythrocytic schizonts of Plasmodium knowlesi.
Sections of paraffin-embedded rhesus liver containing numerous nearly mature exoerythrocytic schizonts of the non-relapsing malaria parasite, Plasmodium knowlesi, were examined for the presence of hypnozoites by indirect immunofluorescence, employing both homologous and strongly cross-reacting heterologous sera. No hypnozoites or evident hypnozoite equivalents were detected in tissue which, by analogy with results obtained for the relapsing species, P. cynomolgi bastianellii, should have contained 35--50 of the uninucleate forms. These observations are presented as additional evidence in favor of the hypnozoite theory of malarial relapse.


Mouse Serrate-1 (Jagged-1): expression in the developing tooth is regulated by epithelial-mesenchymal interactions and fibroblast growth factor-4.
Serrate-like genes encode transmembrane ligands to Notch receptors and control cell fate decisions during development. In this report, we analyse the regulation of the mouse Serrate-1 gene during embryogenesis. The Serrate-1 gene is expressed from embryonic day 7.5 (E7.5) and expression is often observed at sites of epithelial-mesenchymal interactions, including the developing tooth, where Serrate-1 is first (E11.5) expressed in all cells of the dental epithelium, but not in mesenchyme. A transient upregulation in dental mesenchyme (E12.5-15.5) is correlated with down-regulation of Serrate-1 expression in epithelial cells contacting the mesenchyme, i.e. in the cells destined to become ameloblasts. This expression pattern is reproduced in explants of dental epithelium and mesenchyme in vitro: epithelium induces Serrate-1 expression in mesenchyme, while epithelium in close proximity to this mesenchyme does not express detectable levels of Serrate-1 mRNA, suggesting that down-regulation of Serrate-1 expression in preameloblasts is caused by mesenchyme-derived signals. Finally, regulation of Serrate-1 expression differs from that of Notch genes. The Serrate-1 gene is induced in dental mesenchyme by fibroblast growth factor-4, but not by bone morphogenetic proteins, while the converse is true for Notch genes. This indicates that, at least during tooth development, the expression patterns observed for receptors and ligands in the Notch signaling pathway are generated by different induction mechanisms.


Manual therapy for unsettled, distressed and excessively crying infants: a systematic review and meta-analyses.
To conduct a systematic review and meta-analyses to assess the effect of manual therapy interventions for healthy but unsettled, distressed and excessively crying infants and to provide information to help clinicians and parents inform decisions about care. We reviewed published peer-reviewed primary research articles in the last 26 years from nine databases (Medline Ovid, Embase, Web of Science, Physiotherapy Evidence Database, Osteopathic Medicine Digital Repository , Cochrane (all databases), Index of Chiropractic Literature, Open Access Theses and Dissertations and Cumulative Index to Nursing and Allied Health Literature). Our inclusion criteria were: manual therapy (by regulated or registered professionals) of unsettled, distressed and excessively crying infants who were otherwise healthy and treated in a primary care setting. Outcomes of interest were: crying, feeding, sleep, parent-child relations, parent experience/satisfaction and parent-reported global change. Nineteen studies were selected for full review: seven randomised controlled trials, seven case series, three cohort studies, one service evaluation study and one qualitative study.We found moderate strength evidence for the effectiveness of manual therapy on: reduction in crying time (favourable: -1.27 hours per day (95% CI -2.19 to -0.36)), sleep (inconclusive), parent-child relations (inconclusive) and global improvement (no effect). The risk of reported adverse events was low: seven non-serious events per 1000 infants exposed to manual therapy (n=1308) and 110 per 1000 in those not exposed. Some small benefits were found, but whether these are meaningful to parents remains unclear as does the mechanisms of action. Manual therapy appears relatively safe. CRD42016037353.


Neurobiologic processes in drug reward and addiction.
Neurophysiologic processes underlie the uncontrolled, compulsive behaviors defining the addicted state. These"hard-wired"changes in the brain are considered critical for the transition from casual to addictive drug use. This review of preclinical and clinical (primarily neuroimaging) studies will describe how the delineation between pleasure, reward, and addiction has evolved as our understanding of the biologic mechanisms underlying these processes has progressed. Although the mesolimbic dopaminergic efflux associated with drug reward was previously considered the biologic equivalent of pleasure, dopaminergic activation occurs in the presence of unexpected and novel stimuli (either pleasurable or aversive) and appears to determine the motivational state of wanting or expectation. The persistent release of dopamine during chronic drug use progressively recruits limbic brain regions and the prefrontal cortex, embedding drug cues into the amygdala (through glutaminergic mechanisms) and involving the amygdala, anterior cingulate, orbitofrontal cortex, and dorsolateral prefrontal cortex in the obsessive craving for drugs. The abstinent, addicted brain is subsequently primed to return to drug use when triggered by a single use of drug, contextual drug cues, craving, or stress, with each process defined by a relatively distinct brain region or neural pathway. The compulsive drive toward drug use is complemented by deficits in impulse control and decision making, which are also mediated by the orbitofrontal cortex and anterior cingulate. Within this framework, future targets for pharmacologic treatment are suggested.


Global Rebalancing of Cellular Resources by Pleiotropic Point Mutations Illustrates a Multi-scale Mechanism of Adaptive Evolution.
Pleiotropic regulatory mutations affect diverse cellular processes, posing a challenge to our understanding of genotype-phenotype relationships across multiple biological scales. Adaptive laboratory evolution (ALE) allows for such mutations to be found and characterized in the context of clear selection pressures. Here, several ALE-selected single-mutation variants in RNA polymerase (RNAP) of Escherichia coli are detailed using an integrated multi-scale experimental and computational approach. While these mutations increase cellular growth rates in steady environments, they reduce tolerance to stress and environmental fluctuations. We detail structural changes in the RNAP that rewire the transcriptional machinery to rebalance proteome and energy allocation toward growth and away from several hedging and stress functions. We find that while these mutations occur in diverse locations in the RNAP, they share a common adaptive mechanism. In turn, these findings highlight the resource allocation trade-offs organisms face and suggest how the structure of the regulatory network enhances evolvability.


Probucol suppresses enterocytic accumulation of amyloid-β induced by saturated fat and cholesterol feeding.
Amyloid-β (Aβ) is secreted from lipogenic organs such as intestine and liver as an apolipoprotein of nascent triacylglycerol rich lipoproteins. Chronically elevated plasma Aβ may compromise cerebrovascular integrity and exacerbate amyloidosis--a hallmark feature of Alzheimer's disease (AD). Probucol is a hypocholesterolemic agent that reduces amyloid burden in transgenic amyloid mice, but the mechanisms for this effect are presently unclear. In this study, the effect of Probucol on intestinal lipoprotein-Aβ homeostasis was explored. Wild-type mice were fed a control low-fat diet and enterocytic Aβ was stimulated by high-fat (HF) diet enriched in 10% (w/w) saturated fat and 1% (w/w) cholesterol for the duration of 1 month. Mice treated with Probucol had the drug incorporated into the chow at 1% (w/w). Quantitative immunofluorescence was utilised to determine intestinal apolipoprotein B (apo B) and Aβ abundance. We found apo B in both the perinuclear region of the enterocytes and the lacteals in all groups. However, HF feeding and Probucol treatment increased secretion of apo B into the lacteals without any change in net villi abundance. On the other hand, HF-induced enterocytic perinuclear Aβ was significantly attenuated by Probucol. No significant changes in Aβ were observed within the lacteals. The findings of this study support the notion that Probucol suppresses dietary fat induced stimulation of Aβ biosynthesis and attenuate availability of apo B lipoprotein-Aβ for secretion.


Overexpression of activin-A and -B in malignant mesothelioma - attenuated Smad3 signaling responses and ERK activation promote cell migration and invasive growth.
Activin-A and activin-B, members of the TGF-β superfamily, are regulators of reproductive functions, inflammation and wound healing. These dimeric molecules regulate various cellular activities such as proliferation, migration and suvival. Malignant mesothelioma is an asbestos exposure related tumor affecting mainly pleura and it usually has a dismal prognosis. Here, we demonstrate that both activin-A and -B are abundantly expressed in mesothelioma tumor tissue as well as in cultured primary and established mesothelioma cells. Migratory and invasive mesothelioma cells were also found to have attenuated activation of the Smad2/3 pathway in response to activins. Migration and invasive growth of the cells in three-dimentional matrix was prevented by inhibition of activin activity using a soluble activin receptor 2B (sActR2B-Fc). This was associated with decreased ERK activity. Furthermore, migration and invasive growth was significantly inhibited by blocking ERK phosphorylation. Mesothelioma tumors are locally invasive and our results clearly suggest that acivins have a tumor-promoting function in mesothelioma through increasing expression and switching from canonical Smad3 pathway to non-canonical ERK pathway signaling. Blocking activin activity offers a new therapeutic approach for inhibition of mesothelioma invasive growth.


Effects of AV delay programming on ventricular resynchronisation: role of radionuclide ventriculography.
Optimal atrioventricular delay (AVD) setting for cardiac resynchronisation therapy, i.e. biventricular pacing in patients with heart failure, remains a formidable challenge. Thus, the purpose of this study was to evaluate the effects of different AVD on inter- and intra-ventricular resynchronisation using phase histograms of radionuclide ventriculography (RNV). In 17 consecutive patients (mean age 64 +/- 6 years), RNV was performed 236 +/- 350 days after pacemaker implantation for cardiac resynchronisation therapy. Images were acquired during atrial pacing at 80 bpm and during biventricular pacing with AVD ranging from 80 to 160 ms. Inter-ventricular dyssynchrony was measured by the delay between the mean phase angles of the left and right ventricles. Intra-ventricular dyssynchrony was measured by the standard deviation (SD) of left ventricular phase histograms. Left ventricular (LV) ejection fraction (EF) was inversely correlated to LV dyssynchrony (SD of LV phase histogram, R = -0.82, p < 0.0001). However, the increase in LVEF by biventricular pacing (mean +4.4 +/- 4%) showed only modest correlation to the resulting resynchronisation effect (characterised by a -13 +/- 8 degrees decrease in LV phase histogram SD, R = -0.38, p < 0.0001). RNV is helpful in optimising pacing parameters for resynchronisation therapy. Varying AVD did not have a major impact on intra- or inter-ventricular resynchronisation. Thus, the benefit of AVD-based LVEF optimisation seems to result from atrioventricular resynchronisation.


Metabolism and synthesis of arginine vasopressin in conscious newborn sheep.
Arginine vasopressin (AVP) is an important regulator of cardiovascular homeostasis in the fetus, but its role after birth is unclear. Although infused AVP increases mean arterial pressure (MAP) during the 1st mo after birth, pressor responses are unchanged, suggesting that vascular responsiveness is also unchanged. Alternatively, this could reflect increases in AVP metabolic clearance rate (MCR(AVP)). However, newborn AVP metabolism and synthesis are poorly studied. Therefore, we examined the pressor responses to infused AVP and the pattern of circulating AVP, AVP production rate (PR(AVP)), and MCR(AVP) in conscious newborn sheep (n = 5) at 9-38 days after birth. Basal MAP rose and heart rate (HR) fell during the study period (P < or = 0.02), while circulating AVP was unchanged (P > 0.1), averaging 3.01 +/- 0.86 pg/ml. Infused AVP elicited steady-state responses at 10-40 min, increasing plasma AVP and MAP and decreasing HR (P < 0.001). Although pressor responses were unchanged between 9 and 38 days, the rise in MAP correlated with increases in plasma AVP (R = 0.47, P = 0.02, n = 24). MCR(AVP) was unchanged throughout the 1st mo (P > 0.2), averaging 205 +/- 17 ml.kg(-1).min(-1), and was associated with an elevated PR(AVP), 973 +/- 267 pg.kg(-1).min(-1), which also was unchanged (P > 0.1). After birth, MCR(AVP) and PR(AVP) are elevated, probably accounting for the stable plasma AVP levels. The former is also likely to account for the stable pressor responses to infused AVP during the 1st mo. The reason for the elevated PR(AVP) is unclear but may relate to increases in vascular volume associated with postnatal growth.


Hierarchically structured metal oxide/silica nanofibers by colloid electrospinning.
We present herein a new concept for the preparation of nanofibrous metal oxides based on the simultaneous electrospinning of metal oxide precursors and silica nanoparticles. Precursor fibers are prepared by electrospinning silica nanoparticles (20 nm in diameter) dispersed in an aqueous solution of poly(acrylic acid) and metal salts. Upon calcination in air, the poly(acrylic acid) matrix is removed, the silica nanoparticles are cemented, and nanocrystalline metal oxide particles of 4-14 nm are nucleated at the surface of the silica nanoparticles. The obtained continuous silica fibers act as a structural framework for metal oxide nanoparticles and show improved mechanical integrity compared to the neat metal oxide fibers. The hierarchically nanostructured materials are promising for catalysis applications, as demonstrated by the successful degradation of a model dye in the presence of the fibers.


Association between water consumption from polycarbonate containers and bisphenol A intake during harsh environmental conditions in summer.
With the exception of polycarbonate (PC) baby bottles, little attention has been paid to bisphenol A (BPA) intake from packaged water consumption (PC water dispensers), especially during summer weather conditions. We determined the magnitude and variability of urinary BPA concentrations during summer in 35 healthy individuals largely relying upon PC packaged water to satisfy their potable needs. We used liquid chromatography-tandem mass spectrometry to measure urinary BPA concentrations. A questionnaire was administered in July/August and a spot urine sample was collected on the same day and 7 days after the completion of the interview (without intervention). Linear regression was performed to assess the association of variables, such as water consumption from different sources, on urinary BPA levels for the average of the two urine samples. A significant positive association (p = 0.017) was observed between PC water consumption and urinary BPA levels in females, even after adjusting for covariates in a multivariate regression model. The geometric mean of daily BPA intake back-calculated from urinary BPA data was 118 ng · (kg bw)(-1) · day(-1), nearly double the average intake levels observed in biomonitoring studies worldwide. High urinary BPA levels were partially ascribed to summer's high PC water consumption and weather characteristics (high temperatures, >40 °C; very high UV index values, >8), which could be causing BPA leaching from PC. It is suggested that PC-based water consumption could serve as a proxy for urinary BPA, although the magnitude of its relative contribution to overall daily intake requires further investigation.


Characterization of ERK1 activation site mutants and the effect on recognition by MEK1 and MEK2.
To discern MEK1 and MEK2 specificity for their substrate, extracellular signal-regulated kinase (ERK), site-directed mutagenesis was performed on the amino acid residues flanking the regulatory phosphorylation sites of ERK1. These ERK1 mutants were analyzed for the ability to act as a substrate for MEK1 and MEK2. Based on both phosphorylation and activation analyses, the mutants could be divided into four classes: 1) dramatically decreased phosphorylation and activation, 2) enhanced basal kinase activity, 3) preferentially enhanced phosphorylation of tyrosine and decreased phosphorylation of threonine, and 4) increased threonine phosphorylation with an increase in activation. In general, the residues proximal to the regulatory phosphorylation sites of ERK1 had greater influence on both phosphorylation and activation. This is consistent with the highly specific recognition of the ERK1 regulatory sites by MEK. Mutation of Arg-208 or Thr-207 to an alanine residue significantly altered the relative phosphorylation on Thr-202 and Tyr-204. The Arg-208 to alanine mutant increased the phosphorylation of Tyr-204 approximately 4-fold yet almost completely eliminated the phosphorylation on Thr-202. In contrast, mutation of Gly-199 to alanine resulted in an increased phosphorylation of Thr-202 relative to Tyr-204. This suggests that both Gly-199 and Arg-208 play important roles in determining the relative phosphorylation of Thr-202 and Tyr-204. Our results demonstrate that residues in the phosphorylation lip of ERK play an important role in the recognition and phosphorylation by MEK.


Patient mobility for cardiac problems: a risk-adjusted analysis in Italy.
The Italian National Health System was revised in the last 20 years, introducing new elements such as efficacy, efficiency and competitiveness. Devolution to regional authorities has created a quasi-market system where patients can choose the hospital in which to be treated. Patient mobility therefore becomes an indicator of perceived hospital quality and of financial flows between the regions of Italy. Previous studies analyzed patient mobility in general or by specific disease/diagnosis-related groups but there is a lack of research on the influence of severity of patient condition. The aim of the study was to describe patient mobility, crude and stratified by disease severity, in cardiac surgery units of three health areas (HAs) in Tuscany (Italy). In this retrospective observational study, data was gathered from hospital discharge records obtained from the Tuscan Regional Health Agency, Italy. The three HAs (HA1, HA2, HA3) recorded 25,017 planned hospitalizations in cardiac surgery units in the period 2001-2007. Patients were stratified in four All Patient Refined Diagnosis Related Group (APR-DRG) severity levels. Gandy's nomogram was used to describe how HAs met health care demand and their capacity to attract patients. Cuzick's test was used to identify significant differences in time trends. Raw data showed that the HAs met their own local health care demand. Stratifying by APR-DRG severity, it emerged that capacity to meet local demand remained unchanged for zero-to-minor severity levels, but one HA was less able to meet demand for moderate severity levels or to attract patients from other HAs and Regions of Italy. In fact, HA3 showed a decrease in admissions of local residents. The study highlights important differences between the three HAs that were only revealed by severity stratification: unlike HA3, HA1 and HA2 seemed able to deal with local demand, even after severity stratification. Planners and researchers can benefit from risk stratification data, which provides more elements for correct comparisons and interventions. In the context of patient mobility, the present study is a step in that direction.


Serum magnesium is associated with the risk of dementia.
To determine if serum magnesium levels are associated with the risk of all-cause dementia and Alzheimer disease. Within the prospective population-based Rotterdam Study, we measured serum magnesium levels in 9,569 participants, free from dementia at baseline (1997-2008). Participants were subsequently followed up for incident dementia, determined according to the DSM-III-R criteria, until January 1, 2015. We used Cox proportional hazard regression models to associate quintiles of serum magnesium with incident all-cause dementia. We used the third quintile as a reference group and adjusted for age, sex, Rotterdam Study cohort, educational level, cardiovascular risk factors, kidney function, comorbidities, other electrolytes, and diuretic use. Our study population had a mean age of 64.9 years and 56.6% were women. During a median follow-up of 7.8 years, 823 participants were diagnosed with all-cause dementia. Both low serum magnesium levels (≤0.79 mmol/L) and high serum magnesium levels (≥0.90 mmol/L) were associated with an increased risk of dementia (hazard ratio [HR] 1.32, 95% confidence interval [CI] 1.02-1.69, and HR 1.30, 95% CI 1.02-1.67, respectively). Both low and high serum magnesium levels are associated with an increased risk of all-cause dementia. Our results warrant replication in other population-based studies.


Ultraviolet irradiation effects incorporation of nitrate and nitrite nitrogen into aquatic natural organic matter.
One of the concerns regarding the safety and efficacy of ultraviolet radiation for treatment of drinking water and wastewater is the fate of nitrate, particularly its photolysis to nitrite. In this study, N NMR was used to establish for the first time that UV irradiation effects the incorporation of nitrate and nitrite nitrogen into aquatic natural organic matter (NOM). Irradiation of (15)N-labeled nitrate in aqueous solution with an unfiltered medium pressure mercury lamp resulted in the incorporation of nitrogen into Suwannee River NOM (SRNOM) via nitrosation and other reactions over a range of pH from approximately 3.2 to 8.0, both in the presence and absence of bicarbonate, confirming photonitrosation of the NOM. The major forms of the incorporated label include nitrosophenol, oxime/nitro, pyridine, nitrile, and amide nitrogens. Natural organic matter also catalyzed the reduction of nitrate to ammonia on irradiation. The nitrosophenol and oxime/nitro nitrogens were found to be susceptible to photodegradation on further irradiation when nitrate was removed from the system. At pH 7.5, unfiltered irradiation resulted in the incorporation of (15)N-labeled nitrite into SRNOM in the form of amide, nitrile, and pyridine nitrogen. In the presence of bicarbonate at pH 7.4, Pyrex filtered (cutoff below 290-300 nm) irradiation also effected incorporation of nitrite into SRNOM as amide nitrogen. We speculate that nitrosation of NOM from the UV irradiation of nitrate also leads to production of nitrogen gas and nitrous oxide, a process that may be termed photo-chemodenitrification. Irradiation of SRNOM alone resulted in transformation or loss of naturally abundant heterocyclic nitrogens.


N-acetylcysteine attenuates acute lung injury induced by fat embolism.
Fat embolism syndrome is a clinical issue in subjects with long-bone fracture. It may lead to acute lung injury. The mechanisms and therapeutic regimen remain unclear. The present study was designed to investigate the pathologic and biochemical changes after fat embolization in isolated rat lungs, and to test the effects of posttreatment with N-acetylcysteine (NAC). Prospective, randomized, controlled animal study. University research laboratory. A total of 36 perfused lungs isolated from Sprague-Dawley rats. The isolated lungs were randomly assigned to receive physiologic saline solution (vehicle group), fat embolism (FE group), or FE with NAC posttreatment (FE + NAC group). There were 12 isolated lungs in each group. FE was produced by introduction of corn oil micelles. NAC at a dose 150 mg/kg was given 10 mins after FE. The extent of acute lung injury was evaluated by lung weight change, protein concentration in bronchoalveolar lavage, and exhaled nitric oxide. We also measured the pulmonary arterial pressure and capillary filtration coefficient and determined the nitrate/nitrite, methylguanidine, tumor necrosis factor-alpha, and interleukin-1beta in lung perfusate. Histopathologic changes of the lung were examined and quantified. The levels of neutrophil elastase and myeloperoxidase were determined. The expression of inducible nitric oxide synthase was detected. FE caused acute lung injury as evidenced by the lung weight changes, increases in exhaled nitric oxide and protein concentration in bronchoalveolar lavage, pulmonary hypertension, increased capillary filtration coefficient, and lung pathology. The insult also increased nitrate/nitrite, methylguanidine, tumor necrosis factor-alpha, and interleukin-1beta in lung perfusate, increased neutrophil elastase and myeloperoxidase levels, and upregulated inducible nitric oxide synthase expression. Posttreatment with NAC abrogated these changes induced by FE. FE caused acute lung injury and associated biochemical changes. Posttreatment with NAC was effective to alleviate the pathologic and biochemical changes caused by FE.


Cytomegalovirus Infection May Contribute to the Reduced Immune Function, Growth, Development, and Health of HIV-Exposed, Uninfected African Children.
With increasing access to antiretroviral therapy (ART) in Africa, most children born to HIV-infected mothers are not themselves HIV-infected. These HIV-exposed, uninfected (HEU) children are at increased risk of mortality and have immune, growth, development, and health deficits compared to HIV-unexposed children. HEU children are known to be at higher risk than HIV-unexposed children of acquiring cytomegalovirus (CMV) infection in early life. This risk is largely unaffected by ART and is increased by breastfeeding, which itself is critically important for child health and survival. Early CMV infection, namely in utero or during early infancy, may contribute to reduced growth, altered or impaired immune functions, and sensory and cognitive deficits. We review the evidence that CMV may be responsible for the health impairments of HEU children. There are currently no ideal safe and effective interventions to reduce postnatal CMV infection. If a clinical trial showed proof of the principle that decreasing early CMV infection improved health and development of HEU children, this could provide the impetus needed for the development of better interventions to improve the health of this vulnerable population.


Are maximal inspiratory breathing exercises or incentive spirometry better than early mobilization after cardiopulmonary bypass?
Forty-nine adults who had undergone cardiopulmonary bypass surgery were randomly assigned to one of three exercise programs to determine if either maximal inspiratory breathing exercises or incentive spirometry offered a therapeutic advantage over early mobilization alone. After extubation, the patients started their assigned exercise programs. A physical examination and pulmonary function tests were performed preoperatively, at the start of the exercise program, and 24 and 48 hours after the start of the program. The results showed a significant decrease (approximately 50%) in lung volumes but no airflow obstruction in patients who had coronary artery bypass graft. In those patients who had valve replacement, lung volumes fell, and in addition, mild airflow obstruction occurred. A majority of patients had postoperative pulmonary complications. There were no significant differences among the exercise programs in improving lung volumes and airflow or in preventing postoperative complications. We conclude that maximal inspiratory breathing exercises or incentive spirometry, when used in addition to early mobilization, offers no therapeutic advantage over early mobilization alone after cardiopulmonary bypass surgery.


Computational material flow analysis for thousands of chemicals of emerging concern in European waters.
Knowledge of exposure to a wide range of chemicals, and the spatio-temporal variability thereof, is urgently needed in the context of protecting and restoring aquatic ecosystems. This paper discusses a computational material flow analysis to predict the occurrence of thousands of man-made organic chemicals on a European scale, based on a novel temporally and spatially resolved modelling framework. The goal was to increase understanding of pressures by emerging chemicals and to complement surface water monitoring data. The ambition was to provide a first step towards a "real-life" mixture exposure situation accounting for as many chemicals as possible. Comparison of simulated concentrations and chemical monitoring data for 226 substance/basin combinations showed that the simulated concentrations were accurate on average. For 65% and 90% of substance/basin combinations the error was within one and two orders of magnitude respectively. An analysis of the relative importance of uncertainties revealed that inaccuracies in use volume or use type information contributed most to the error for individual substances. To resolve this, we suggest better registration of use types of industrial chemicals, investigation of presence/absence of industrial chemicals in wastewater and runoff samples and more scientific information exchange.


Laboratory evaluation of adhesive systems.
Adhesive bonding of resin materials to acid-conditioned enamel is a clinically proven technique in preventative, restorative, and orthodontic procedures. Laboratory evaluations of etched-enamel resin bonding have shown excellent bond strengths and the virtual elimination of marginal microleakage. Adhesion to dentin has been more of a challenge. Earlier-generation dentin bonding systems did not yield high bond strengths in the laboratory or prevent marginal microleakage. Newer-generation adhesive systems generally use a dentin conditioner to modify or remove the smear layer and a subsequent application of an adhesive resin bonding agent. Laboratory evaluations of newer systems have shown bond strengths that approach or actually exceed that of etched enamel resin bonding. Bond strengths have improved with the evolution of dentin bonding systems, and microleakage from the cementum/dentin margin has been significantly reduced or prevented with the newer systems. Although laboratory testing of adhesive systems provides a mechanism to screen and compare newly developed systems, clinical trials are essential to document long-term clinical performance.


Murine gut microbiota is defined by host genetics and modulates variation of metabolic traits.
The gastrointestinal tract harbors a complex and diverse microbiota that has an important role in host metabolism. Microbial diversity is influenced by a combination of environmental and host genetic factors and is associated with several polygenic diseases. In this study we combined next-generation sequencing, genetic mapping, and a set of physiological traits of the BXD mouse population to explore genetic factors that explain differences in gut microbiota and its impact on metabolic traits. Molecular profiling of the gut microbiota revealed important quantitative differences in microbial composition among BXD strains. These differences in gut microbial composition are influenced by host-genetics, which is complex and involves many loci. Linkage analysis defined Quantitative Trait Loci (QTLs) restricted to a particular taxon, branch or that influenced the variation of taxa across phyla. Gene expression within the gastrointestinal tract and sequence analysis of the parental genomes in the QTL regions uncovered candidate genes with potential to alter gut immunological profiles and impact the balance between gut microbial communities. A QTL region on Chr 4 that overlaps several interferon genes modulates the population of Bacteroides, and potentially Bacteroidetes and Firmicutes-the predominant BXD gut phyla. Irak4, a signaling molecule in the Toll-like receptor pathways is a candidate for the QTL on Chr15 that modulates Rikenellaceae, whereas Tgfb3, a cytokine modulating the barrier function of the intestine and tolerance to commensal bacteria, overlaps a QTL on Chr 12 that influence Prevotellaceae. Relationships between gut microflora, morphological and metabolic traits were uncovered, some potentially a result of common genetic sources of variation.


Intrarenal platelet consumption in the diffuse proliferative nephritis of systemic lupus erythematosus.
1. Platelet survival and an index of the localization of platelets in the kidney were studied in patients with the proliferative nephritis of systemic lupus erythematosus, either focal or diffuse, and in control subjects. Platelet survival was reduced in patients with proliferative lupus nephritis, more in those with diffuse rather than focal renal involvement. 2. The index of renal platelet localization in patients with diffuse proliferative nephritis suggested an intrarenal platelet consumption not found in other groups. 3. A patient with the classical platelet autoantibody disease, idiopathic thrombocytopenic purpura, also showed reduced platelet survival but localization of platelets was in the spleen rather than the kidney. 4. Intrarenal platelet consumption in diffuse proliferative lupus nephritis may be an epiphenomenon of pre-existing scarring or platelet aggregation secondary to immune complex-formation, which contributes to the progressive sclerosing lesions of this form of nephritis.


Conducting polyfurans by electropolymerization of oligofurans.
Polyfurans have never been established as useful conjugated polymers, as previously they were considered to be inherently unstable and poorly conductive. Here, we show the preparation of stable and conducting polyfuran films by electropolymerization of a series of oligofurans of different chain lengths substituted with alkyl groups. The polyfuran films show good conductivity in the order of 1 S cm-1, good environmental and electrochemical stabilities, very smooth morphologies (roughness 1-5 nm), long effective conjugation lengths, well-defined spectroelectrochemistry and electro-optical switching (in the Vis-NIR region), and have optical band-gaps in the range of 2.2-2.3 eV. A low oxidation potential needed for polymerization of oligofurans (compared to furan) is a key factor in achievement of improved properties of polyfurans reported in this work. DFT calculations and experiments show that polyfurans are much more rigid than polythiophenes, and alkyl substitution does not disturb backbone planarity and conjugation. The obtained properties of polyfuran films are similar or superior to the properties of electrochemically prepared poly(oligothiophene)s under similar conditions.


Modulatory effect of 900 MHz radiation on biochemical and reproductive parameters in rats.
In the present study, the effect of 900 MHz radiation exposure on blood biochemical and reproductive parameters was evaluated in adolescent rats. Male albino Wistar rats (8-10 weeks of age) were exposed to 900 MHz radiation (1hr/day, power density - 146.60 µW/cm2) from a mobile phone for 28 days. On 29th day the animals were euthanized and malondialdehyde (MDA), total antioxidants (TA) levels and Glutathione-S transferase (GST) activity were studied in the blood. Reproductive parameters such as total sperm count, percentage of non-motile sperms, and sperm morphology were determined. Testes sections were stained with H(et)E staining and their cellular integrity was evaluated. Caspase-3 activity in the testes was also determined. MDA concentration was increased but TA levels and GST activity were not found to be different in 900 MHz group compared to controls. Sperm motility was found to be slightly reduced in 900 MHz group. Percentage of abnormal sperm was significantly elevated in 900 MHz group. Additionally, loss of germ cells particularly spermatocytes and spermatids was found in the testes of 900 MHz group. Testes caspase-3 activity was slightly elevated in 900 MHz exposed rats. Chronic 900 MHz exposure induced oxidative damage in the blood and lead to alterations in reproductive parameters in rats (Fig. 4, Ref. 33).


Intermittent v. continuous energy restriction: differential effects on postprandial glucose and lipid metabolism following matched weight loss in overweight/obese participants.
The intermittent energy restriction (IER) approach to weight loss involves short periods of substantial (>70 %) energy restriction (ER) interspersed with normal eating. Studies to date comparing IER to continuous energy restriction (CER) have predominantly measured fasting indices of cardiometabolic risk. This study aimed to compare the effects of IER and CER on postprandial glucose and lipid metabolism following matched weight loss. In all, twenty-seven (thirteen male) overweight/obese participants (46 (sem 3) years, 30·1 (sem 1·0) kg/m2) who were randomised to either an IER intervention (2638 kJ for 2 d/week with an overall ER of 22 (sem 0·3) %, n 15) or a CER intervention (2510 kJ below requirements with overall ER of 23 (sem 0·8) %) completed the study. Postprandial responses to a test meal (over 360 min) and changes in anthropometry (fat mass, fat-free mass, circumferences) were assessed at baseline and upon attainment of 5 % weight loss, following a 7-d period of weight stabilisation. The study found no statistically significant difference in the time to attain a 5 % weight loss between groups (median 59 d (interquartile range (IQR) 41-80) and 73 d (IQR 48-128), respectively, P=0·246), or in body composition (P≥0·437). For postprandial measures, neither diet significantly altered glycaemia (P=0·266), whereas insulinaemia was reduced comparatively (P=0·903). The reduction in C-peptide tended (P=0·057) to be greater following IER (309 128 (sem23 268) to 247781 (sem20 709) pmol×360 min/l) v. CER (297 204 (sem25 112) to 301 655 (sem32 714) pmol×360 min/l). The relative reduction in TAG responses was greater (P=0·045) following IER (106 (sem30) to 68 (sem 15) mmol×360 min/l) compared with CER (117 (sem 43) to 130 (sem 31) mmol×360 min/l). In conclusion, these preliminary findings highlight underlying differences between IER and CER, including a superiority of IER in reducing postprandial lipaemia, which now warrant targeted mechanistic evaluation within larger study cohorts.


Review of Journal of Cardiovascular Magnetic Resonance 2009.
There were 56 articles published in the Journal of Cardiovascular Magnetic Resonance in 2009. The editors were impressed with the high quality of the submissions, of which our acceptance rate was about 40%. In accordance with open-access publishing, the articles go on-line as they are accepted with no collating of the articles into sections or special thematic issues. We have therefore chosen to briefly summarise the papers in this article for quick reference for our readers in broad areas of interest, which we feel will be useful to practitioners of cardiovascular magnetic resonance (CMR). In some cases where it is considered useful, the articles are also put into the wider context with a short narrative and recent CMR references. It has been a privilege to serve as the Editor of the JCMR this past year. I hope that you find the open-access system increases wider reading and citation of your papers, and that you will continue to send your quality manuscripts to JCMR for publication.


The effect of cataract extraction on intraocular pressure.
To examine the current literature covering the long-term effect of cataract extraction on intraocular pressure (IOP). As a result of the high rate of cataract surgery, the impact on IOP continues to be the subject of multiple studies in different populations. Recent publications include those that distinguish patients with open angles from those with more narrow angles, as well as prospective analyses that address the impact of regression to the mean and other types of bias on the effect of postoperative IOP lowering. There are sufficient data to suggest that cataract surgery provides a lowering effect on IOP in the long term. This effect appears to be proportional to preoperative IOP. Eyes with higher preoperative IOP have the greatest average lowering, whereas eyes with IOP in the lower range of statistically normal tend to have an IOP that is unchanged from baseline or even higher following cataract surgery. In patients with narrow angles, the IOP-lowering effect appears to also be proportional to the degree of anterior chamber deepening induced by cataract surgery.


Identification of ω-N-Methyl-4-hydroxytryptamine (Norpsilocin) as a Psilocybe Natural Product.
We report the identification of ω-N-methyl-4-hydroxytryptamine (norpsilocin, 1) from the carpophores of the hallucinogenic mushroom Psilocybe cubensis. The structure was elucidated by 1D and 2D NMR spectroscopy and high-resolution mass spectrometry. Norpsilocin has not previously been reported as a natural product. It likely represents the actual psychotropic agent liberated from its 4-phosphate ester derivative, the known natural product baeocystin. We further present a simple and artifact-free extraction method that prevents dephosphorylation and therefore helps reflect the naturally occurring metabolic profile of Psilocybe mushrooms in subsequent analyses.


DFT calculations as a ligand toolbox for the synthesis of active initiators for ROP of cyclic esters.
New heteroleptic zinc dimeric complexes bearing an aminophenolate ligand of a single-site initiator framework were synthesized and characterized by spectroscopic methods, X-ray analysis, and DFT calculations. The theoretical study, verified by the experimental data, explains the catalytic behaviour in the ROP of lactide in the examined zinc complexes. The presented simple DFT protocol constitutes a valuable method for the qualification of the ancillary ligand to rationally design new complexes to improve their catalytic activity.


Stage-specific IFN-induced and IFN gene expression reveal convergence of type I and type II IFN and highlight their role in both acute and chronic stage of pathogenic SIV infection.
Interferons (IFNs) play a major role in controlling viral infections including HIV/SIV infections. Persistent up-regulation of interferon stimulated genes (ISGs) is associated with chronic immune activation and progression in SIV/HIV infections, but the respective contribution of different IFNs is unclear. We analyzed the expression of IFN genes and ISGs in tissues of SIV infected macaques to understand the respective roles of type I and type II IFNs. Both IFN types were induced in lymph nodes during early stage of primary infection and to some extent in rectal biopsies but not in PBMCs. Induction of Type II IFN expression persisted during the chronic phase, in contrast to undetectable induction of type I IFN expression. Global gene expression analysis with a major focus on ISGs revealed that at both acute and chronic infection phases most differentially expressed ISGs were inducible by both type I and type II IFNs and displayed the highest increases, indicating strong convergence and synergy between type I and type II IFNs. The analysis of functional signatures of ISG expression revealed temporal changes in IFN expression patterns identifying phase-specific ISGs. These results suggest that IFN-γ strongly contribute to shape ISG upregulation in addition to type I IFN.


Midterm Outcomes Following Combined Biceps Tenodesis and Anterior Labral Repair in Active Duty Military Patients Younger Than 35 Years.
Superior labrum anterior-posterior (SLAP) lesions and anterior instability are common causes of shoulder pain and dysfunction among active-duty members of the United States military. However, little data have been published regarding the surgical management of type V SLAP lesions. To compare the outcomes of arthroscopic-assisted subpectoral biceps tenodesis and anterior labral repair with those of arthroscopic SLAP repair (defined as contiguous repair spanning from the superior labrum to the anteroinferior labrum) for type V SLAP tears in active-duty military patients younger than 35 years. Cohort study; Level of evidence, 3. All consecutive patients from January 2010 to December 2015 who underwent arthroscopic SLAP repair or combined biceps tenodesis and anterior labral repair for a type V SLAP lesion with a minimum 5-year follow-up were identified. The decision to perform type V SLAP repair versus combined biceps tenodesis and anterior labral repair was based on the condition of the long head of the biceps tendon (LHBT). Labral repair was performed in patients who had a type V SLAP tear with an otherwise clinically and anatomically healthy LHBT. Combined tenodesis and repair was performed in patients with evidence of LHBT abnormalities. Outcomes including the visual analog scale (VAS) score, the Single Assessment Numeric Evaluation (SANE) score, the American Shoulder and Elbow Surgeons (ASES) shoulder score, the Rowe instability score, and range of motion were collected preoperatively and postoperatively, and scores were compared between the groups. A total of 84 patients met the inclusion criteria for the study. All patients were active-duty service members at the time of surgery. A total of 44 patients underwent arthroscopic type V SLAP repair, and 40 patients underwent anterior labral repair with biceps tenodesis. The mean follow-up was 102.59 ± 20.98 months in the repair group and 94.50 ± 27.11 months in the tenodesis group (P = .1281). There were no significant differences in preoperative range of motion or outcome scores between the groups. Both groups experienced statistically significant improvements in outcome scores postoperatively (P < .0001 for all); however, compared with the repair group, the tenodesis group reported significantly better postoperative VAS (2.52 ± 2.36 vs 1.50 ± 1.91, respectively; P = .0328), SANE (86.82 ± 11.00 vs 93.43 ± 8.81, respectively; P = .0034), and ASES (83.32 ± 15.31 vs 89.90 ± 13.31, respectively; P = .0394) scores. There were no differences in the percentage of patients who achieved the minimal clinically important difference, substantial clinical benefit, and patient acceptable symptom state for the SANE and ASES between the groups. Overall, 34 patients in each group returned to preinjury levels of work (77.3% vs 85.0%, respectively; P = .3677), and 32 patients (72.7%) in the repair group and 33 patients (82.5%) in the tenodesis group returned to preinjury levels of sporting activity (P = .2850). There were no significant differences in the number of failures, revision surgical procedures, or patients discharged from the military between the groups (P = .0923, P = .1602, and P = .2919, respectively). Both arthroscopic-assisted subpectoral biceps tenodesis combined with anterior labral repair and arthroscopic SLAP repair led to statistically and clinically significant increases in outcome scores, marked improvements in pain, and high rates of return to unrestricted active duty in military patients with type V SLAP lesions. The results of this study suggest that biceps tenodesis combined with anterior labral repair produces comparable outcomes to arthroscopic type V SLAP repair in active-duty military patients younger than 35 years.


Heterotopic ossification of the shoulder in patients with traumatic brain injury.
We retrospectively reviewed 10 consecutive patients (11 shoulders) with traumatic brain injury who underwent surgical resection of heterotopic ossification (HO) of the shoulder. Our primary research goal was to determine the change in range of motion (ROM) at the shoulder after resection of heterotopic ossification in patients with traumatic brain injury. Secondary research goals were to determine simple functional outcome gains related to activities of daily living and to determine complications in this patient cohort. Data were collected retrospectively and included measured ROM of the shoulder and observed ability to perform daily activities. The average age of the patients was 33 years (range, 20 -45). Sagittal plane motion (flexion/extension) increased by 85.0°, coronal plane motion (adduction/abduction) increased by 59.1°, and axial plane motion (internal/external rotation) increased by 66.8° (P < .001). Nine patients increased independence with improved functional status (7 patients able to perform all 3 activities of feeding, grooming, and toiletry) (P < .001). Surgical resection of heterotopic ossification of the shoulder is an effective procedure to increase joint mobility and improve function.


Topological-Pattern-Based Recommendation of UMLS Concepts for National Cancer Institute Thesaurus.
The National Cancer Institute Thesaurus (NCIt) is a reference terminology used to support clinical, translational and basic research as well as administrative activities. As medical knowledge evolves, concepts that might be missing from a particular needed subdomain are regularly added to the NCIt. However, terminology development is known to be labor-intensive and error-prone. Therefore, cost-effective semi-automated methods for identifying potentially missing concepts would be useful to terminology curators. Previously, we have developed a structural method leveraging the native term mappings of the Unified Medical Language System to identify potential concepts in several of its source vocabularies to enrich the SNOMED CT. In this paper, we tested an analogous method for NCIt. Concepts from eight UMLS source terminologies were identified as possibilities to enrich NCIt's conceptual content.


Antarctic Moss Biflavonoids Show High Antioxidant and Ultraviolet-Screening Activity.
Ceratodon purpureus is a cosmopolitan moss that survives some of the harshest places on Earth: from frozen Antarctica to hot South Australian deserts. In a study on the survival mechanisms of the species, nine compounds were isolated from Australian and Antarctic C. purpureus. This included five biflavonoids, with complete structural elucidation of 1 and 2 reported here for the first time, as well as an additional four known phenolic compounds. Dispersion-corrected DFT calculations suggested a rotational barrier, leading to atropisomerism, resulting in the presence of diastereomers for compound 2. All isolates absorbed strongly in the ultraviolet (UV) spectrum, e.g., biflavone 1 (UV-A, 315-400 nm), which displayed the strongest radical-scavenging activity, 13% more efficient than the standard rutin; p-coumaric acid and trans-ferulic acid showed the highest UV-B (280-315 nm) absorption. The more complex and abundant 1 and 2 presumably have dual roles as both UV-screening and antioxidant compounds. They are strongly bound to Antarctic moss cell walls as well as located inside the cells of moss from both locations. The combined high stability and photoprotective abilities of these isolates may account for the known resilience of this species to UV-B radiation and its survival in some of the toughest locations in the world.


SLC41A1 is a novel mammalian Mg2+ carrier.
The molecular biology of mammalian magnesium transporters and their interrelations in cellular magnesium homeostasis are largely unknown. Recently, the mouse SLC41A1 protein was suggested to be a candidate magnesium transporter with channel-like properties when overexpressed in Xenopus laevis oocytes. Here, we demonstrate that human SLC41A1 overexpressed in HEK293 cells forms protein complexes and locates to the plasma membrane without, however, giving rise to any detectable magnesium currents during whole cell patch clamp experiments. Nevertheless, in a strain of Salmonella enterica exhibiting disruption of all three distinct magnesium transport systems (CorA, MgtA, and MgtB), overexpression of human SLC41A1 functionally substitutes these transporters and restores the growth of the mutant bacteria at magnesium concentrations otherwise non-permissive for growth. Thus, we have identified human SLC41A1 as being a bona fide magnesium transporter. Most importantly, overexpressed SLC41A1 provide HEK293 cells with an increased magnesium efflux capacity. With outwardly directed Mg(2+) gradients, a SLC41A1-dependent reduction of the free intracellular magnesium concentration accompanied by a significant net decrease of the total cellular magnesium concentration could be observed in such cells. SLC41A1 activity is temperature-sensitive but not sensitive to the only known magnesium channel blocker, cobalt(III) hexaammine. Taken together, these data functionally identify SLC41A1 as a mammalian carrier mediating magnesium efflux.


Relative risk of HIV infection among young men and women in a South African township.
The prevalence of HIV infection in Africa is substantially higher among young women than it is among young men. Biological explanations of this difference have been presented but there has been little exploration of social factors. In this paper we use data from Carletonville, South Africa to explore various social explanations for greater female infection rates. This paper reports on data from a random sample of 507 people between 13 and 24 years old. Subjects were tested for HIV, as well as other sexually transmitted infections (STIs), and answered a behavioural questionnaire. The age-prevalence of HIV infection differs between men and women with considerably higher rates of increase with age among young women. The age of sexual debut did not differ significantly between men and women (15.9 and 16.3 years, respectively) and below the age of 20 years there was no difference in the number or distribution of the number of sexual partners reported by men or women. The risk of infection per partnership was substantially higher among women than among men. Women have sexual partners who are, on average, about five years older than they are with some variation with age. Scaling the age-prevalence curve for men by the age of their sexual partners gives a curve whose shape is indistinguishable from that for women but is about 30% lower for men than for women. In terms of social explanations for HIV rates among women, the data indicates that this difference can be explained by the relative age of sexual partners, but not by other factors explored. In addressing the epidemic among young women it will be essential to deal with the social factors that lead young women to select their partners from older-age cohorts and that shape their sexual networking patterns.


Orthogonal Expression of an Artificial Metalloenzyme for Abiotic Catalysis.
A cytochrome P450 was engineered to selectively incorporate Ir(Me)-deuteroporphyrin IX (Ir(Me)-DPIX), in lieu of heme, in bacterial cells. Cofactor selectivity was altered by introducing mutations within the heme-binding pocket to discriminate the deuteroporphyrin macrocycle, in combination with mutations to the P450 axial cysteine to accommodate a pendant methyl group on the Ir(Me) center. This artificial metalloenzyme was investigated for activity in non-native metallocarbenoid-mediated olefin cyclopropanation reactions and showed enhanced activity for aliphatic and electron-deficient olefins when compared to the native heme enzyme. This work provides a general strategy to augment the chemical functionality of heme enzymes in cells with application towards abiotic catalysis.


A role for Dynlt3 in melanosome movement, distribution, acidity and transfer.
Skin pigmentation is dependent on cellular processes including melanosome biogenesis, transport, maturation and transfer to keratinocytes. However, how the cells finely control these processes in space and time to ensure proper pigmentation remains unclear. Here, we show that a component of the cytoplasmic dynein complex, Dynlt3, is required for efficient melanosome transport, acidity and transfer. In Mus musculus melanocytes with decreased levels of Dynlt3, pigmented melanosomes undergo a more directional motion, leading to their peripheral location in the cell. Stage IV melanosomes are more acidic, but still heavily pigmented, resulting in a less efficient melanosome transfer. Finally, the level of Dynlt3 is dependent on β-catenin activity, revealing a function of the Wnt/β-catenin signalling pathway during melanocyte and skin pigmentation, by coupling the transport, positioning and acidity of melanosomes required for their transfer.


Toxoplasmosis and neuropsychiatric diseases: can serological studies establish a clear relationship?
Toxoplasmosis is a widespread infection, with clinical spectrum ranging from a completely asymptomatic infection to multi-organ involvement. After entering the body, the parasite forms tissue cysts and establishes a chronic infection, involving also the central nervous system (CNS). During the last years, a lot of research has focused on the possible link between exposure to T. gondii and development of neuropsychiatric disorders such as schizophrenia and Parkinson's disease (PD). If a firm association between Toxoplasma infection and neuropsychiatric disorders will be established, this would lead to novel strategies for their prevention and treatment. We will review data from serological and neurodevelopment studies relating infection with T. gondii to such neuropsychiatric diseases.


The results of metal-on-metal hip resurfacing in patients under 30 years of age.
Degenerative hip conditions most commonly affect older patients. However, many cases occur in younger patients. Total hip arthroplasty is the conventional approach; however, hip resurfacing is a viable option. Fifty-three metal-on-metal resurfacings in 46 patients under age 30 were performed. Patients had a variety of etiologies, and were followed clinically and radiographically with mean follow-up of 98.2 months. Clinical scores and x-rays were compared pre-operatively and post-operatively. The last follow-up SF-12 and UCLA scores significantly improved post-operatively (P<0.0001). Range of motion scores also improved (P<0.001), and the mean Harris Hip Score was 88. There were 6 revisions. The Kaplan-Meier survivorship estimate at 8 years was 95%. Metal-on-metal hip resurfacing appears to be an effective procedure for younger patients. Longer-term data are needed for confirmation.


The safety of intravenous dipyridamole thallium myocardial perfusion imaging. Intravenous Dipyridamole Thallium Imaging Study Group.
Clinical data on 3,911 patients were collected from 64 individual investigators to evaluate the safety of intravenous dipyridamole-thallium imaging as an alternative to exercise thallium imaging for the evaluation of coronary artery disease. There were two deaths because of myocardial infarctions, two nonfatal myocardial infarctions, and six cases of acute bronchospasm. Chest pain occurred in 770 patients (19.7%). Headache and dizziness were reported by 476 patients (12.2%) and 460 patients (11.8%), respectively. ST-T changes on the electrocardiogram were seen in 292 patients (7.5%). Use of parenteral aminophylline to treat adverse events associated with intravenous dipyridamole brought complete relief of symptoms in 439 of 454 patients (96.7%). There is a potential for increased risk for serious ischemic events in patients with a history of unstable angina who are administered intravenous dipyridamole. In patients with acutely unstable angina (i.e., continuing chest pain) or in the acute phase of myocardial infarction, use of intravenous dipyridamole in thallium scintigraphy should be avoided. There is also an increased risk for bronchospasm in patients with a history of asthma; acute bronchospasm can be relieved immediately by administration of aminophylline. These results demonstrate that intravenous dipyridamole-thallium scintigraphy is a relatively safe, noninvasive technique for the evaluation of coronary artery disease.


Suitability of commercial barometric pressure sensors to distinguish sitting and standing activities for wearable monitoring.
Despite its medical relevance, accurate recognition of sedentary (sitting and lying) and dynamic activities (e.g. standing and walking) remains challenging using a single wearable device. Currently, trunk-worn wearable systems can differentiate sitting from standing with moderate success, as activity classifiers often rely on inertial signals at the transition period (e.g. from sitting to standing) which contains limited information. Discriminating sitting from standing thus requires additional sources of information such as elevation change. The aim of this study is to demonstrate the suitability of barometric pressure, providing an absolute estimate of elevation, for evaluating sitting and standing periods during daily activities. Three sensors were evaluated in both calm laboratory conditions and a pilot study involving seven healthy subjects performing 322 sitting and standing transitions, both indoor and outdoor, in real-world conditions. The MS5611-BA01 barometric pressure sensor (Measurement Specialties, USA) demonstrated superior performance to counterparts. It discriminates actual sitting and standing transitions from stationary postures with 99.5% accuracy and is also capable to completely dissociate Sit-to-Stand from Stand-to-Sit transitions.


Crystal structure of a defective folding protein.
Maltose-binding protein (MBP or MalE) of Escherichia coli is the periplasmic receptor of the maltose transport system. MalE31, a defective folding mutant of MalE carrying sequence changes Gly 32-->Asp and Ile 33-->Pro, is either degraded or forms inclusion bodies following its export to the periplasmic compartment. We have shown previously that overexpression of FkpA, a heat-shock periplasmic peptidyl-prolyl isomerase with chaperone activity, suppresses MalE31 misfolding. Here, we have exploited this property to characterize the maltose transport activity of MalE31 in whole cells. MalE31 displays defective transport behavior, even though it retains maltose-binding activity comparable with that of the wild-type protein. Because the mutated residues are in a region on the surface of MalE not identified previously as important for maltose transport, we have solved the crystal structure of MalE31 in the maltose-bound state in order to characterize the effects of these changes. The structure was determined by molecular replacement methods and refined to 1.85 A resolution. The conformation of MalE31 closely resembles that of wild-type MalE, with very small displacements of the mutated residues located in the loop connecting the first alpha-helix to the first beta-strand. The structural and functional characterization provides experimental evidence that MalE31 can attain a wild-type folded conformation, and suggest that the mutated sites are probably involved in the interactions with the membrane components of the maltose transport system.


Noninvasive structural and microvascular anatomy of oral mucosae using handheld optical coherence tomography.
In this study, we demonstrated the feasibility of using a handheld optical coherence tomography (OCT) for in vivo visualizations of the microstructural and microvascular features of various oral mucosal types. To scan arbitrary locations of the oral mucosa, a scanning probe was developed, composed of a probe body fabricated by a 3D printer, miniaturized two-axis galvanometer, relay lenses, and reflective prism. With a 3D printing technique, the probe weight and the system volume were greatly reduced, enabling the effective improvement of imaging artifacts from unconscious motion and system complexity. Additionally, in our design, the distal end of the probe can be switched to fit various oral conditions, and the optical parameters of the probe, such as the transverse resolution, working distance, and probe length can be easily varied. The results showed that the epithelium and lamina propria layers, as well as the fungiform papilla and salivary gland, were differentiated. Moreover, various microcirculation features at different mucosal sites were identified that are potentially effective indicators for the diagnosis of premalignant lesions. The demonstrated results indicate that the developed OCT system is a promising tool for noninvasive imaging of oral mucosae.


Laparoscopic excision of lesions suggestive of endometriosis or otherwise atypical in appearance: relationship between visual findings and final histologic diagnosis.
We sought to assess accuracy of visual diagnosis of laparoscopically excised visceral and peritoneal abnormalities suggestive of endometriosis by comparison with final histologic diagnosis. Prospective study of 2005 tissue specimens from 512 patients undergoing laparoscopy for evaluation of pelvic pain was conducted (Canadian Task Force classification II-2). A private practice referral center for treatment of endometriosis. From February 1992 through December 1998, 512 patients underwent laparoscopic excision of endometriosis. In all patients, the primary indication for surgery was pelvic pain with either prior surgical diagnosis or clinical history consistent with endometriosis. All areas of viscera and peritoneum either with typical appearance suggestive of endometriosis or atypical appearance were completely excised and examined histologically. At laparoscopy, all excised lesions were documented in a diagram by the primary surgeon according to anatomic site and visual description and were labeled as either suggestive of endometriosis or otherwise atypical in appearance. The hospital pathology department received entire lesions fixed in formalin and evaluated specimens for presence or absence of endometriosis. Pathologists, who were blinded to the surgeon's suspicion of endometriosis, were provided only the anatomic site of excised tissue. By definition, diagnosis of endometriosis was made when histologic evidence existed of both endometrial glands and stroma. Diagrams detailing appearance, anatomic site, and surgeon's suspicion of endometriosis versus atypical lesions were compared with final histologic diagnosis. The greatest number of patient lesions were excised from cul-de-sac (n = 309). For this site, using visual criteria for diagnosis of endometriosis, positive predictive value was 93.9%, sensitivity was 69.3%, negative predictive value was 41.9%, and specificity was 83.1%. Prevalence was noted to be 79.0% and accuracy was 72.2%. In addition, atypical-appearing tissue not presumed to be endometriosis was confirmed to be endometriosis histologically in 24.3%. In examining tissue specimens from multiple anatomic sites, laparoscopic visual diagnosis of typical endometriosis generally had high positive predictive value. However, both sensitivity and negative predictive value were lower than expected because of atypical lesions subsequently diagnosed as endometriosis. These data suggest that when the surgical objective is complete eradication of endometriosis, the surgeon must be prepared to excise all lesions suggestive of endometriosis and tissue atypical in appearance as in most anatomic sites approximately 25% of atypical specimens proved to be endometriosis.


Utility of cryopreserved hepatocytes suspended in serum to predict hepatic clearance in dogs and monkeys.
An in vitro-in vivo correlation analysis between observed and predicted metabolic clearance in multiple preclinical species including dogs and monkeys constitutes an integral part of prediction for the pharmacokinetics in humans by using liver-derived in vitro preparations. Empirical values of the scaling factor for the extrapolation of metabolic (intrinsic) clearance in the in vitro preparation to that for whole liver were calculated for each preparation of 8 and 5 cryopreserved dog and monkey hepatocytes, respectively, by optimizing the objective function of average fold error between predicted and observed metabolic (intrinsic) clearance for eight and 11 standard compounds for dogs and monkeys, respectively. Thus obtained values of the scaling factor ranged from 5.46 × 10(9) to 19.9 × 10(9) cells/kg body weight with an average of 10.3 × 10(9) cells/kg body weight in dogs, and the value ranged from 2.36 × 10(9) to 4.21 × 10(9) cells/kg body weight with an average of 3.17 × 10(9) cells/kg body weight in monkeys, which were both consistent with biologically calculated values in corresponding species. These results demonstrated the utility of commercially available cryopreserved preparations of dog and monkey hepatocytes for the in vitro-in vivo correlation analyses with the aid of empirically or biologically obtained scaling factors at the early development stage of new drug candidates.


Bias in Contraceptive Provision to Young Women Among Private Health Care Providers in South West Nigeria.
Health care providers' biases regarding the provision of contraceptives to adolescent and young adult women may restrict women's access to contraceptive methods. Two mystery client visits were made to each of 52 private-sector health care facilities and individual providers in South West Nigeria in June 2016. In one visit, the mystery client portrayed an unmarried, nulliparous adolescent, and in the other, the client portrayed a married adult woman with two children. During subsequent in-depth interviews, providers were read vignettes describing hypothetical clients with these same profiles, and were asked how they would interact with each. Descriptive analyses of mystery client interactions were combined with thematic analyses of the interview data. In greater proportions of married-profile visits than of unmarried-profile visits, mystery clients reported that providers had asked about past contraceptive use and method preference; the opposite was true in regard to providers' using side effects to dissuade clients from practicing contraception. In in-depth interviews, providers expressed concerns about fertility loss among unmarried women who used hormonal contraceptives. Providers more commonly recommended condoms, emergency contraception and the pill for unmarried clients, and longer-acting methods for married clients. The restriction of methods was typically explained by providers of various backgrounds in terms of protecting younger, unmarried clients from damaging their fertility. Provider bias in the provision of contraceptives to adolescent and young adult women in South West Nigeria may affect quality of care and method choice. Interventions to reduce provider bias should go beyond technical training to address the underlying sociocultural beliefs that lead providers to impose restrictions that are not based on evidence.


Coordinating unspecified living kidney donation and transplantation across the blood-type barrier in kidney exchange.
This article studies multicenter coordination of unspecified living kidney donation and transplantation across the blood-type barrier in kidney exchange. Important questions are whether such coordination should use domino paired donation or non simultaneous extended altruistic donor chains, what the length of the segments in such chains should be, when they should be terminated, and how much time should be allowed between matching rounds. Furthermore, it is controversial whether the different modalities should be coordinated centrally or locally and independently. Kidney exchange policies are simulated using actual data from the Dutch national kidney exchange program. Sensitivity analysis is performed on the composition of the population, the time unspecified and bridge donors wait before donating to the wait list, the time between matching rounds, and donor renege rates. Central coordination of unspecified donation and transplantation across the blood-type barrier can increase transplants by 10% (PG0.001). Especially highly sensitized and blood type O patients benefit. Sufficient time between matching rounds is essential: three-monthly exchanges result in 31% more transplants than weekly exchanges. Benefits of non simultaneous extended altruistic donor chains are limited in case of low numbers of highly sensitized patients and sufficient unspecified donors. Chains are best terminated when no further segment is part of an optimal exchange within 3 months. There is clear synergy in the central coordination of both unspecified donation and transplantation across the blood-type barrier in kidney exchange. The best configuration of a national program depends on the composition of the patient Y donor population.


Calcium pump, high-affinity Ca2+-ATPase, and other ATPases in dog antrum smooth muscle plasma membrane.
The plasma membrane-enriched fraction from dog antrum smooth muscle is enriched in ATP-dependent azide-insensitive Ca2+ uptake (0.3-0.4 microM Ca2+ required for half-maximal activity), a high-affinity Ca2+-ATPase (Km of 0.3-0.8 microM for Ca2+), a low-affinity Ca2+-ATPase (Km for 250-400 microM for Ca2+), and a Mg2+-ATPase. Studies using membranes washed with EDTA and assay media treated with Chelex 100 showed that the high-affinity Ca2+-ATPase did not depend on contaminating Mg2+. Thus, whereas the ATP-dependent Ca2+ uptake had an absolute requirement for Mg2+, the Ca2+-ATPases did not. Studies using gamma-irradiation showed that the protein responsible for the ATP-dependent Ca2+ uptake was inactivated at significantly lower doses of radiation than the three ATPases. The Ca2+ uptake and the high-affinity Ca2+-ATPase also differed in their inhibition by calmodulin antagonists and 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid. Thus it is unlikely that the high-affinity Ca2+-ATPase by itself is responsible for the ATP-dependent Ca2+ uptake.


Review article: influenza A (H1N1) virus in patients with inflammatory bowel disease.
Infection with influenza A (H1N1)v (swine flu) has caused widespread anxiety, among patients who are potentially immunocompromised, such as those being treated for inflammatory bowel disease. To provide guidance for physicians and their patients on the risk, prevention and management of influenza A (H1N1)v infection. Medline was searched using the following key words: 'swine flu', 'immunosuppression', inflammatory bowel disease', 'recommendations', 'immunization', 'vaccination'. Organizations such as European Centre for Disease Prevention and Control, the Centers for Disease Control and Prevention and the World Health Organization were consulted for recent papers and recommendations regarding immunocompromised patients and influenza A (H1N1)v infection. Pandemic influenza A (H1N1) virus predominantly affects young patients. Those who are immunocompromised because of underlying disease or treatment are considered at higher risk of complications from influenza A (H1N1). They should be offered prevention (vaccination, postexposure prophylaxis) or treatment with antiviral drugs, if affected. Pneumococcal infection is a complication of influenza infection; therefore, pneumococcal vaccination appears advisable. Seasonal influenza vaccination is also recommended. Withdrawal of immunosuppressive treatment appears advisable during severe active infection if possible. Pragmatic advice is the best that can be offered in the current circumstances because of paucity of evidence. Investigation into the impact of influenza A (H1N1)v infection in young people with chronic conditions is needed.


Protein-bound uremic toxins, inflammation and oxidative stress: a cross-sectional study in stage 3-4 chronic kidney disease.
Indoxyl sulfate (IS) and p-cresyl sulfate (PCS) are nephro- and cardiovascular toxins, produced solely by the gut microbiota, which have pro-inflammatory and pro-oxidative properties in vitro. We undertook this study to investigate the associations between IS and PCS and both inflammation and oxidative stress in the chronic kidney disease (CKD) population. In this cross-sectional observational cohort study, participants with stage 3-4 CKD who enrolled in a randomized controlled trial of cardiovascular risk modification underwent baseline measurements of serum total and free IS and PCS (measured by ultraperformance liquid chromotography), inflammatory markers (interferon gamma [IFN-γ], interleukin-6 [IL-6] and tumor necrosis factor-alpha [TNF-α]), antioxidant and oxidative stress markers (plasma glutathione peroxidase [GPx] activity, total antioxidant capacity [TAC] and F2-isoprostanes) and pulse wave velocity (PWV), a marker of arterial stiffness. There were 149 CKD patients (59% male; age 60 ± 10 years; 44% diabetic) with a mean eGFR of 40 ± 9 mL/min/1.73 m(2) (range 25-59). Serum free and total IS were independently associated with serum IL-6, TNF-α and IFN-γ, whereas serum free and total PCS were independently associated with serum IL-6 and PWV. Free IS and PCS were additionally independently associated with serum GPx but not with TAC or F2-isoprostanes. IS and PCS were associated with elevated levels of selected inflammatory markers and an antioxidant in CKD patients. PCS was also associated with increased arterial stiffness. Inflammation and oxidative stress may contribute to the nephro- and cardiovascular toxicities of IS and PCS. Intervention studies targeting production of IS and PCS by dietary manipulation and the subsequent effect on cardiovascular-related outcomes are warranted in the CKD population.


Identification of dredged sediment-derived soils in the alluvial plains of the Leie and the Upper and Sea Scheldt rivers (Belgium) based on physico-chemical soil properties.
An approach was developed to identify surface soils affected by historical dredged sediment disposal in the alluvial plains of the Upper Scheldt, the Sea Scheldt and the Leie river. Dredged sediment-derived soils were identified based on field observations, comparative granulometric analyses and chemical analyses. Criteria developed were based on a comparison between reference data from 102 aerobic soil samples of areas known to be affected by dredged sediment disposal and 104 samples from undisturbed alluvial soils along the studied rivers. A comparative grain size analysis with optical laser diffractometry between the A and C horizon proved useful for the identification of levelled-up sites. The chemical soil characteristics that were most useful in identifying dredged sediment-derived soils were CaCO3, sulfur (S), organic carbon (OC) and phosphorus (P) contents, electrical conductivity (EC), and the C/P and C/S ratios. Criteria for concluding the origin of an investigated soil were specific for the studied area, but the approach presented may provide useful guidelines for developing criteria valid for different regions.


Translocation of liposomes into cancer cells by cell-penetrating peptides penetratin and tat: a kinetic and efficacy study.
Unlike conventional liposomes, sterically stabilized liposomes, with their smaller volume of distribution and reduced clearance, preferentially convey encapsulated drugs into tumor sites. Despite these improvements, intracellular delivery is hampered by the stable drug retention of the liposomes, which diminishes the efficacy of the liposomal drug. To facilitate uptake of liposomal drugs into cells, two cell-penetrating peptides, penetratin (PEN) and TAT, derived from the HIV-1 TAT protein, were studied. In contrast to control peptides, both TAT and PEN enhanced the translocation efficiency of liposomes in proportion to the number of peptides attached to the liposomal surface. A peptide number of as few as five could enhance the intracellular delivery of liposomes. The kinetics of uptake was peptide- and cell-type dependent. Intracellular accumulation of TAT-liposomes increased with incubation time, but PEN-liposomes peaked at 1 h and then declined gradually. After treatment with 1 microg/ml doxorubicin equivalents of liposome for 2 h, TAT increased the doxorubicin uptake of A431 cells by 12-fold. However, the improvement of uptake of liposomal doxorubicin was not reflected by cytotoxicity in vitro or tumor control in vivo. Our results demonstrated that merely adding CPP to a liposome encapsulating anticancer drug was inadequate in improving its antitumor activity. An additional approach to enhance the intracellular release of the encapsulated drug is obviously necessary.


Demographic components of seasonality of pregnancy.
Previous studies of the seasonality of pregnancy and birth have typically been based on monthly numbers or proportions of pregnancies or births (i.e. their distribution throughout the year) without any explicit accounting of the size of the population actually at risk of pregnancy by month. From data on monthly populations at risk and monthly probabilities of pregnancy this paper determines the relative contribution of each component to the monthly distribution of pregnancies. The data come from the National Survey of Family Growth, Cycle III. While there is some seasonality in the size of the at-risk population, it contributes little to the overall monthly variation of pregnancy, which is determined mainly by seasonality of pregnancy probability (fecundability).


Clinical deterioration after intravenous recombinant tissue plasminogen activator treatment: a multicenter transcranial Doppler study.
Patients may experience clinical deterioration (CD) after treatment with intravenous recombinant tissue plasminogen activator (rt-PA). We evaluated the ability of flow findings on transcranial Doppler to predict CD and outcomes on modified Rankin Scale. Patients with acute stroke received intravenous rt-PA within 3 hours of symptom onset at four academic centers. CD was defined as an increase in the National Institutes of Health Stroke Scale (NIHSS) score by 4 points or more within 24 hours. Poor long-term outcome was defined by modified Rankin Scale > or =2 at 3 months. Transcranial Doppler findings were interpreted using the Thrombolysis in Brain Ischemia flow grading system as persistent arterial occlusion, reocclusion, or complete recanalization. Multiple regression analysis was used to identify transcranial Doppler flow as a predictor for CD after controlling for age, sex, baseline NIHSS, hypertension, and glucose. A total of 374 patients received intravenous rt-PA at 142+/-60 minutes (median pretreatment NIHSS score 16 points). At the end of intravenous rt-PA infusion, transcranial Doppler showed persistent arterial occlusion in 219 patients (59%), arterial reocclusion in 54 patients (14%), and complete recanalization in 101 patients (27%). CD occurred in 44 patients: 36 had persistent arterial occlusion or reocclusion (82%), 13 symptomatic intracerebral hemorrhage (29%), and both persistent occlusion/reocclusion and symptomatic intracerebral hemorrhage in 10 patients (23%). After adjustment, patient risk for CD with persistent occlusion was OR 1.7 (95% CI: 0.7 to 4) and with arterial reocclusion 4.9 (95% CI: 1.7 to 13) (P=0.002). Patient risk for poor long-term outcomes with persistent occlusion, partial recanalization, or reocclusion was OR 5.2 (95% CI: 2.7 to 9, P=0.001). Inability to achieve or sustain vessel patency at the end of rt-PA infusion correlates with the likelihood of clinical deterioration and poor long-term outcome. Early arterial reocclusion on transcranial Doppler is highly predictive of CD and poor outcome.


The T-ALL specific t(11;14)(p13;q11) translocation breakpoint cluster region is located near to the Wilms' tumour predisposition locus.
A breakpoint cluster region (T-ALLbcr) has been previously described on 11p13 for T-ALL carrying t(11;14)(p13;q11). One further T-ALL breakpoint is described bringing to 5 out of 6 such translocations which are found to break within a maximum of 6.7 kb on chromosome 11p13. Studies of somatic cell hybrids derived from t(11;14)(p13;q11) T-ALL placed the T-ALLbcr between the genes for catalase (CAT) and the beta-subunit of follicle stimulating hormone (FSHB). This suggested a link between the T-ALLbcr and the Wilms' tumour predisposition locus (WT) since constitutional 11p13 deletions predispose to Wilms' tumour. Utilising somatic cell hybrids from patients with Wilms' tumours and aniridia, we show that while the T-ALLbcr maps distal to the catalase gene at 11p13, it maps outside the shortest region of overlap of a series of 11p13 deletions associated with Wilms'-Aniridia. The data suggest the order of genes at 11p13 to be: centromere-CAT-T-ALLbcr-WT-aniridia-FSHB-telomere. Therefore, the T-ALLbcr must lie very close to but may be distinct from the Wilms' predisposition locus at 11p13.


Mapping and analysis of chromatin state dynamics in nine human cell types.
Chromatin profiling has emerged as a powerful means of genome annotation and detection of regulatory activity. The approach is especially well suited to the characterization of non-coding portions of the genome, which critically contribute to cellular phenotypes yet remain largely uncharted. Here we map nine chromatin marks across nine cell types to systematically characterize regulatory elements, their cell-type specificities and their functional interactions. Focusing on cell-type-specific patterns of promoters and enhancers, we define multicell activity profiles for chromatin state, gene expression, regulatory motif enrichment and regulator expression. We use correlations between these profiles to link enhancers to putative target genes, and predict the cell-type-specific activators and repressors that modulate them. The resulting annotations and regulatory predictions have implications for the interpretation of genome-wide association studies. Top-scoring disease single nucleotide polymorphisms are frequently positioned within enhancer elements specifically active in relevant cell types, and in some cases affect a motif instance for a predicted regulator, thus suggesting a mechanism for the association. Our study presents a general framework for deciphering cis-regulatory connections and their roles in disease.


A Common Genetic Origin for Early Farmers from Mediterranean Cardial and Central European LBK Cultures.
The spread of farming out of the Balkans and into the rest of Europe followed two distinct routes: An initial expansion represented by the Impressa and Cardial traditions, which followed the Northern Mediterranean coastline; and another expansion represented by the LBK (Linearbandkeramik) tradition, which followed the Danube River into Central Europe. Although genomic data now exist from samples representing the second migration, such data have yet to be successfully generated from the initial Mediterranean migration. To address this, we generated the complete genome of a 7,400-year-old Cardial individual (CB13) from Cova Bonica in Vallirana (Barcelona), as well as partial nuclear data from five others excavated from different sites in Spain and Portugal. CB13 clusters with all previously sequenced early European farmers and modern-day Sardinians. Furthermore, our analyses suggest that both Cardial and LBK peoples derived from a common ancient population located in or around the Balkan Peninsula. The Iberian Cardial genome also carries a discernible hunter-gatherer genetic signature that likely was not acquired by admixture with local Iberian foragers. Our results indicate that retrieving ancient genomes from similarly warm Mediterranean environments such as the Near East is technically feasible.


Restricted tissue distribution of Mlsa determinants. Stimulation of Mlsa-reactive T cells by B cells but not by dendritic cells or macrophages.
Evidence was sought on the tissue distribution of Mlsa determinants, a class of cell-associated non-H-2 alloantigens that is highly immunogenic for unprimed T cells. Whereas normal CD4+ T cells and an Mlsa-reactive T hybridoma gave strong responses to Mlsa-positive stimulator populations containing Ig+ B cells, anti-Mlsa responses to B-depleted stimulators were almost undetectable. The B-depleted stimulators tested included Thy-1- spleen cells from mu-suppressed mice (mice treated with anti-mu antibody from birth) and J11d- preparations of spleen dendritic cells (DC) and peritoneal macrophages (M phi) from normal mice. Each of these populations was strongly immunogenic for allo-H-2-reactive T cells. The failure to detect Mlsa determinants on Ig- APC, i.e., M phi and DC, suggests that Mlsa determinants are not typical H-2-associated peptides. The data are more compatible with a model in which Mlsa determinants represent (or form part of) an integral cell membrane molecule expressed largely, and perhaps exclusively, on B cells. T cells might recognize these molecules only in native form, "processed" Mlsa determinants being nonimmunogenic. Consistent with this possibility, no evidence was found that Mlsa-negative B cells could absorb Mlsa determinants from Mlsa-positive B cells in a chimeric environment.


Preferences and patterns of response to public health advice during the COVID-19 pandemic.
With recurring waves of the Covid-19 pandemic, a dilemma facing public health leadership is whether to provide public advice that is medically optimal (e.g., most protective against infection if followed), but unlikely to be adhered to, or advice that is less protective but is more likely to be followed. To provide insight about this dilemma, we examined and quantified public perceptions about the tradeoff between (a) the stand-alone value of health behavior advice, and (b) the advice's adherence likelihood. In a series of studies about preference for public health leadership advice, we asked 1061 participants to choose between (5) strict advice that is medically optimal if adhered to but which is less likely to be broadly followed, and (2) relaxed advice, which is less medically effective but more likely to gain adherence-given varying infection expectancies. Participants' preference was consistent with risk aversion. Offering an informed choice alternative that shifts volition to advice recipients only strengthened risk aversion, but also demonstrated that informed choice was preferred as much or more than the risk-averse strict advice.


ESPERR: learning strong and weak signals in genomic sequence alignments to identify functional elements.
Genomic sequence signals - such as base composition, presence of particular motifs, or evolutionary constraint - have been used effectively to identify functional elements. However, approaches based only on specific signals known to correlate with function can be quite limiting. When training data are available, application of computational learning algorithms to multispecies alignments has the potential to capture broader and more informative sequence and evolutionary patterns that better characterize a class of elements. However, effective exploitation of patterns in multispecies alignments is impeded by the vast number of possible alignment columns and by a limited understanding of which particular strings of columns may characterize a given class. We have developed a computational method, called ESPERR (evolutionary and sequence pattern extraction through reduced representations), which uses training examples to learn encodings of multispecies alignments into reduced forms tailored for the prediction of chosen classes of functional elements. ESPERR produces a greatly improved Regulatory Potential score, which can discriminate regulatory regions from neutral sites with excellent accuracy ( approximately 94%). This score captures strong signals (GC content and conservation), as well as subtler signals (with small contributions from many different alignment patterns) that characterize the regulatory elements in our training set. ESPERR is also effective for predicting other classes of functional elements, as we show for DNaseI hypersensitive sites and highly conserved regions with developmental enhancer activity. Our software, training data, and genome-wide predictions are available from our Web site (http://www.bx.psu.edu/projects/esperr).


Securing recruitment and obtaining informed consent in minority ethnic groups in the UK.
Previous health research has often explicitly excluded individuals from minority ethnic backgrounds due to perceived cultural and communication difficulties, including studies where there might be language/literacy problems in obtaining informed consent. This study addressed these difficulties by developing audio-recorded methods of obtaining informed consent and recording data. This report outlines 1) our experiences with securing recruitment to a qualitative study investigating alternative methods of data collection, and 2) the development of a standardised process for obtaining informed consent from individuals from minority ethnic backgrounds whose main language does not have an agreed written form. Two researchers from South Asian backgrounds recruited adults with Type 2 diabetes whose main language was spoken and not written, to attend a series of focus groups. A screening tool was used at recruitment in order to assess literacy skills in potential participants. Informed consent was obtained using audio-recordings of the patient information and recording patients' verbal consent. Participants' perceptions of this method of obtaining consent were recorded. Recruitment rates were improved by using telephone compared to face-to-face methods. The screening tool was found to be acceptable by all potential participants. Audio-recorded methods of obtaining informed consent were easy to implement and accepted by all participants. Attrition rates differed according to ethnic group. Snowballing techniques only partly improved participation rates. Audio-recorded methods of obtaining informed consent are an acceptable alternative to written consent in study populations where literacy skills are variable. Further exploration of issues relating to attrition is required, and a range of methods may be necessary in order to maximise response and participation rates.