Pathological aggression in "fierce" mice corrected by human nuclear receptor 2E1.
"Fierce" mice, homozygous for the deletion of nuclear receptor 2E1 (NR2E1), show abnormal brain-eye development and pathological aggression. To evaluate functional equivalency between mouse and human NR2E1, we generated mice transgenic for a genomic clone spanning the human NR2E1 locus and bred these animals to fierce mice deleted for the corresponding mouse gene. In fierce mutants carrying human NR2E1, structural brain defects were eliminated and eye abnormalities ameliorated. Excitingly, behavior in these "rescue" mice was indistinguishable from controls. Because no artificial promoter was used to drive transgene expression, promoter and regulatory elements within the human NR2E1 clone are functional in mouse. Normal behavior in rescue animals suggests that mechanisms underlying the behavioral abnormalities in fierce mice may also be conserved in humans. Our data support the hypothesis that variation at NR2E1 may contribute to human behavioral disorders. Use of this rescue paradigm with other genes will permit the direct evaluation of human genes hypothesized to play a causal role in psychiatric disease but for which evidence is lacking or equivocal.


Jostent covered stent placement for emergency reconstruction of a ruptured internal carotid artery during or after transsphenoidal surgery.
Internal carotid artery (ICA) rupture during transsphenoidal surgery (TSS) is an extremely difficult complication to treat. This study aimed to evaluate the immediate and long-term outcomes of covered stent placement for emergency reconstruction of ruptured ICAs during or after TSS. Seven patients underwent covered stent placement for emergency reconstruction of a ruptured ICA during or after TSS. The safety and effectiveness of covered stent placement for emergency reconstruction of ruptured ICAs were retrospectively analyzed. Pretreatment angiography showed active bleeding in 6 patients (5 intraoperative and 1 postoperative) and a pseudoaneurysm in 1 patient. Of the 6 patients with active bleeding, 5 were treated with a successive operation to control active bleeding. The other patient was treated just after cardiopulmonary resuscitation due to massive nasal bleeding 20 days after revision of TSS. All active bleeding was controlled immediately after covered stent insertion in these 6 patients. One patient showed a gap between the covered stent and ICA wall without active bleeding 30 minutes after glycoprotein IIb/IIIa inhibitor administration due to in-stent thrombosis. The gap was occluded with coil embolization after completion of the temporarily suspended TSS. The seventh patient, whose ICA tear was treated with surgical suture, underwent covered stent placement for a pseudoaneurysm detected on postoperative Day 2. During a mean follow-up period of 46 months (range 12-85 months), all patients had excellent outcomes (modified Rankin Scale score of 0). All the stented ICAs were patent on vascular imaging follow-up at a mean of 34 months (range 12-85 months). Covered stents appear to be a safe and effective option for emergency reconstruction of ruptured ICAs during or after TSS.


Vitamin C restores the contractile response to dobutamine and improves myocardial efficiency in patients with heart failure after anterior myocardial infarction.
Excessive oxidative stress is considered one of the mechanisms of a decrease in contractile force without concomitant reduction in oxygen cost in failing myocardium. We hypothesized that the antioxidant vitamin C may help reverse hyporesponsiveness to beta-adrenergic stimulation and improve myocardial efficiency in patients with heart failure (HF) after myocardial infarction (MI). Nineteen patients with mild to moderate HF due to previous MI (mean left ventricular [LV] ejection fraction 39%) were instrumented with conductance and coronary sinus thermodilution catheters. Left ventricular contractility, expressed as E(es), the slope of end-systolic pressure-volume relationship, and mechanical efficiency, expressed as the ratio of LV stroke work (SW) to myocardial oxygen consumption (MVO2), were measured in response to the intravenous infusion of dobutamine (4 microg/kg per min) before (Dob) and during (Dob + Vit C) the infusion of vitamin C (2.0-g bolus injection and subsequent 50-mg/min infusion through the jugular vein) (vitamin C group, n = 10). The infusion of vitamin C augmented the E(es) response to dobutamine by 20% +/- 8% (Dob 2.1 +/- 0.3, Dob + Vit C 2.5 +/- 0.4 mm Hg/mL, P < .01) and the SW/MVO2 response by 21% +/- 5% (Dob 36% +/- 3%, Dob + Vit C 43% +/- 4%, P < .01). In the control group (n = 9), E(es) and SW/MVO2 were measured in response to dobutamine before (Dob) and during (Dob + vehicle) the infusion of saline. No difference in E(es) or SW/MVO2 was observed between Dob and Dob + vehicle (E(es): Dob 2.1 +/- 0.2, Dob + vehicle 2.1 +/- 0.2 mm Hg/mL per square meter, P = nonsignificant) (SW/MVO2: Dob 35% +/- 4%, Dob + vehicle 33% +/- 4%, P = nonsignificant). The administration of the antioxidant vitamin C enhances the contractile response to dobutamine and improves myocardial efficiency in patients with HF.


The importance of steric zipper on the aggregation of the MVGGVV peptide derived from the amyloid beta peptide.
Amyloid-like fibrils are found in many fatal diseases, such as Alzheimer's disease, Parkinson's disease, type II diabetes mellitus, and prion diseases. Recently, the structural characterization of the MVGGVV peptide from the C-terminal hydrophobic segment of the amyloid-B (AB) peptide has revealed a general feature of amyloid-like fibrils, termed as "steric zipper", which is constituted by a tight side-chain complementation of the opposing B-sheet layers. In this study, several all-atom molecular dynamics simulations with explicit water were conducted to investigate the importance of steric zipper on the aggregation of the MVGGVV peptide. Our results show that the structural stability of the MVGGVV oligomers increases with increasing the number of B-strands. We further proposed that the octameric structure (the SH2-ST4 model in this study) is the possible nucleus seed for MVGGVV protofibril formation. Our results also demonstrated that hydrophobic interaction is the principle driving force to stabilize the adjacent B-strands while the steric zipper involved M1, V2, V5 and V6 is responsible for holding the neighboring B-sheet layers together. Finally, a twisted model of the MVGGVV assembly (SH2-ST50), based on the averaged twisted angle of approximately 11.5 degrees between the adjacent B-strands of the SH2-ST4 model, was proposed. Our results gain insights into the aggregation of the MVGGVV peptide in atomic details and may provide a hint for designing new inhibitors able to prevent the fibril formation of the AB peptide.


Organic thin-film transistors for chemical and biological sensing.
Organic thin-film transistors (OTFTs) show promising applications in various chemical and biological sensors. The advantages of OTFT-based sensors include high sensitivity, low cost, easy fabrication, flexibility and biocompatibility. In this paper, we review the chemical sensors and biosensors based on two types of OTFTs, including organic field-effect transistors (OFETs) and organic electrochemical transistors (OECTs), mainly focusing on the papers published in the past 10 years. Various types of OTFT-based sensors, including pH, ion, glucose, DNA, enzyme, antibody-antigen, cell-based sensors, dopamine sensor, etc., are classified and described in the paper in sequence. The sensing mechanisms and the detection limits of the devices are described in details. It is expected that OTFTs may have more important applications in chemical and biological sensing with the development of organic electronics.


Naturally occurring variation in tadpole morphology and performance linked to predator regime.
Divergent natural selection drives a considerable amount of the phenotypic and genetic variation observed in natural populations. For example, variation in the predator community can generate conflicting selection on behavioral, life-history, morphological, and performance traits. Differences in predator regime can subsequently increase phenotypic and genetic variations in the population and result in the evolution of reproductive barriers (ecological speciation) or phenotypic plasticity. We evaluated morphology and swimming performance in field collected Bronze Frog larvae (Lithobates clamitans) in ponds dominated by predatory fish and those dominated by invertebrate predators. Based on previous experimental findings, we hypothesized that tadpoles from fish-dominated ponds would have small bodies, long tails, and large tail muscles and that these features would facilitate fast-start speed. We also expected to see increased tail fin depth (i.e., the tail-lure morphology) in tadpoles from invertebrate-dominated ponds. Our results support our expectations with respect to morphology in affecting swimming performance of tadpoles in fish-dominated ponds. Furthermore, it is likely that divergent natural selection is playing a role in the diversification on morphology and locomotor performance in this system.


Cancer and the complement cascade.
Despite significant research on the role of inflammation and immunosurveillance in the immunologic microenvironment of tumors, little attention has been given to the oncogenic capabilities of the complement cascade. The recent finding that complement may contribute to tumor growth suggests an insidious relationship between complement and cancer, especially in light of evidence that complement facilitates cellular proliferation and regeneration. We address the hypothesis that complement proteins promote carcinogenesis and suggest mechanisms by which complement can drive the fundamental features of cancer. Evidence shows that this diverse family of innate immune proteins facilitates dysregulation of mitogenic signaling pathways, sustained cellular proliferation, angiogenesis, insensitivity to apoptosis, invasion and migration, and escape from immunosurveillance. Given that the traditionally held functions for the complement system include innate immunity and cancer defense, our review suggests a new way of thinking about the role of complement proteins in neoplasia.


Structure Determination of Mycobacterium tuberculosis Serine Protease Hip1 (Rv2224c).
The Mycobacterium tuberculosis (Mtb) serine protease Hip1 (hydrolase important for pathogenesis; Rv2224c) promotes tuberculosis (TB) pathogenesis by impairing host immune responses through proteolysis of a protein substrate, Mtb GroEL2. The cell surface localization of Hip1 and its immunomodulatory functions make Hip1 a good drug target for new adjunctive immune therapies for TB. Here, we report the crystal structure of Hip1 to a resolution of 2.6 Å and the kinetic studies of the enzyme against model substrates and the protein GroEL2. The structure shows a two-domain protein, one of which contains the catalytic residues that are the signature of a serine protease. Surprisingly, a threonine is located within the active site close enough to hydrogen bond with the catalytic residues Asp463 and His490. Mutation of this residue, Thr466, to alanine established its importance for function. Our studies provide insights into the structure of a member of a novel family of proteases. Knowledge of the Hip1 structure will aid in designing inhibitors that could block Hip1 activity.


Firms, crowds, and innovation.
The purpose of this article is to suggest a (preliminary) taxonomy and research agenda for the topic of "firms, crowds, and innovation" and to provide an introduction to the associated special issue. We specifically discuss how various crowd-related phenomena and practices-for example, crowdsourcing, crowdfunding, user innovation, and peer production-relate to theories of the firm, with particular attention on "sociality" in firms and markets. We first briefly review extant theories of the firm and then discuss three theoretical aspects of sociality related to crowds in the context of strategy, organizations, and innovation: (1) the functions of sociality (sociality as extension of rationality, sociality as sensing and signaling, sociality as matching and identity), (2) the forms of sociality (independent/aggregate and interacting/emergent forms of sociality), and (3) the failures of sociality (misattribution and misapplication). We conclude with an outline of future research directions and introduce the special issue papers and essays.


Predictors of post-traumatic stress disorder following severe injury.
The chronicity and morbidity of established post-traumatic stress disorder (PTSD) has stimulated interest in recognizing and understanding the early development of the disorder. Acute stress disorder, a new diagnosis intended to facilitate early case detection, rests on the occurrence of dissociative reactions. It remains uncertain whether dissociation is a universal or unique early predictor of subsequent PTSD. Traumatic injury is an important and relatively understudied antecedent of PTSD. The objective of this study was to preliminarily identify which previously implicated early reactions and risk factors would apply to the prediction of PTSD following severe traumatic injury. Patients admitted to a regional Level I trauma center following life threatening events who had recall of the incident and did not have signs of traumatic brain injury or recent psychopathology were enrolled. Comprehensive assessments were conducted during hospitalization and after discharge approximately 2 months after the traumatic event. At follow-up, 24% of the available 50 subjects met full criteria for PTSD and an additional 22% met criteria for two of three symptom clusters. Early symptoms of heightened arousal and coping with disengagement were independent predictors of PTSD severity at follow-up. Relationships to initial dissociative reactions and a diagnosis of ASD were not significant. These early predictors found in a setting of severe injury only partially overlap findings from previous PTSD studies.


Characterization of 9p24 risk locus and colorectal adenoma and cancer: gene-environment interaction and meta-analysis.
A potential susceptibility locus for colorectal cancer on chromosome 9p24 (rs719725) was initially identified through a genome-wide association study, though replication attempts have been inconclusive. We genotyped this locus and explored interactions with known risk factors as potential sources of heterogeneity, which may explain the previously inconsistent replication. We included Caucasians with colorectal adenoma or colorectal cancer and controls from 4 studies (total 3,891 cases, 4,490 controls): the Women's Health Initiative (WHI); the Diet, Activity and Lifestyle Study (DALS); a Minnesota population-based case-control study (MinnCCS); and the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO). We used logistic regression to evaluate the association and test for gene-environment interactions. SNP rs719725 was statistically significantly associated with risk of colorectal cancer in WHI (OR per A allele 1.19; 95% CI, 1.01-1.40; P(trend) = 0.04), marginally associated with adenoma risk in PLCO (OR per A allele 1.11; 95% CI, 0.99-1.25; P(trend) = 0.07), and not associated in DALS and MinnCCS. Evaluating for gene-environment interactions yielded no consistent results across the studies. A meta-analysis of 17 studies (including these 4) gave an OR per A allele of 1.07 (95% CI, 1.03-1.12; P(trend) = 0.001). Our results suggest the Aallele for SNP rs719725 at locus 9p24 is positively associated with a small increase in risk for colorectal tumors. Environmental risk factors for colorectal cancer do not appear to explain heterogeneity across studies. If this finding is supported by further replication and functional studies, it may highlight new pathways underlying colorectal neoplasia.


Simplifying the Welfare Quality® assessment protocol for broiler chicken welfare.
Welfare Quality(®) (WQ) assessment protocols place the emphasis on animal-based measures as an indicator for animal welfare. Stakeholders, however, emphasize that a reduction in the time taken to complete the protocol is essential to improve practical applicability. We studied the potential for reduction in time to complete the WQ broiler assessment protocol and present some modifications to the protocol correcting a few errors in the original calculations. Data was used from 180 flocks assessed on-farm and 150 flocks assessed at the slaughter plant. Correlations between variables were calculated, and where correlation was moderate, meaningful and promising (in terms of time reduction), simplification was considered using one variable predicted from another variable. Correlation analysis revealed a promising correlation between severe hock burn and gait scores on-farm. Therefore, prediction of gait scores using hock burn scores was studied further as a possible simplification strategy (strategy 1). Measurements of footpad dermatitis, hock burn, cleanliness and gait score on-farm correlated moderately to highly with slaughter plant measurements of footpad dermatitis and/or hock burn, supporting substitution of on-farm measurements with slaughter plant data. A simplification analysis was performed using footpad dermatitis, hock burn, cleanliness and gait scores measured on-farm predicted from slaughter plant measurements of footpad dermatitis and hock burn (strategy 2). Simplification strategies were compared with the full assessment protocol. Close agreement was found between the full protocol and both simplification strategies although large confidence intervals were found for specificity of the simplified models. It is concluded that the proposed simplification strategies are encouraging; strategy 1 can reduce the time to complete the on-farm assessment by ~1 h (25% to 33% reduction) and strategy 2 can reduce on-farm assessment time by ~2 h (50% to 67% reduction). Both simplification strategies should, however, be validated further, and tested on farms with a wide distribution across the different welfare categories of WQ.


Evaluation of serum cardiac troponin I concentration in Boxers with arrhythmogenic right ventricular cardiomyopathy.
To evaluate serum cardiac troponin I (cTnI) concentrations in Boxers with arrhythmogenic right ventricular cardiomyopathy (ARVC), unaffected (control) Boxers, and control non-Boxers. 10 Boxers with a clinical diagnosis of ARVC defined by > or = 1,000 ventricular premature complexes (VPCs)/24 h on an ambulatory ECG, 10 control Boxers assessed as normal by the presence of < 5 VPCs/24h, and 10 control non-Boxers. Serum was extracted from a blood sample from each dog. Analysis of serum cTnI concentrations was performed. Mean +/- SD serum cTnI concentration was 0.142 +/- 0.05 ng/mL for Boxers with ARVC, 0.079 +/- 0.03 ng/mL for control Boxers, and 0.023 +/- 0.01 ng/mL for control non-Boxers. A significant difference in serum cTnI concentrations was observed among the 3 groups. In the combined Boxer population (ie, Boxers with ARVC and control Boxers), a significant correlation was found between serum cTnI concentration and number of VPCs/24 h (r = 0.78) and between serum cTnI concentration and grade of ventricular arrhythmia (r = 0.77). Compared with clinically normal dogs, Boxers with ARVC had a significant increase in serum cTnI concentration. For Boxers, correlations were found between serum cTnI concentration and number of VPCs/24 h and between concentration and the grade of arrhythmia. Because of the overlap in serum cTnI concentrations in control Boxers and Boxers with ARVC, future studies should evaluate the correlation of serum cTnI concentration with severity of disease in terms of degree of myocardial fibrofatty changes.


The PEX1 ATPase Stabilizes PEX6 and Plays Essential Roles in Peroxisome Biology.
A variety of metabolic pathways are sequestered in peroxisomes, conserved organelles that are essential for human and plant survival. Peroxin (PEX) proteins generate and maintain peroxisomes. The PEX1 ATPase facilitates recycling of the peroxisome matrix protein receptor PEX5 and is the most commonly affected peroxin in human peroxisome biogenesis disorders. Here, we describe the isolation and characterization of, to our knowledge, the first Arabidopsis (Arabidopsis thaliana) pex1 missense alleles: pex1-2 and pex1-3pex1-2 displayed peroxisome-related defects accompanied by reduced PEX1 and PEX6 levels. These pex1-2 defects were exacerbated by growth at high temperature and ameliorated by growth at low temperature or by PEX6 overexpression, suggesting that PEX1 enhances PEX6 stability and vice versa. pex1-3 conferred embryo lethality when homozygous, confirming that PEX1, like several other Arabidopsis peroxins, is essential for embryogenesis. pex1-3 displayed symptoms of peroxisome dysfunction when heterozygous; this semidominance is consistent with PEX1 forming a heterooligomer with PEX6 that is poisoned by pex1-3 subunits. Blocking autophagy partially rescued PEX1/pex1-3 defects, including the restoration of normal peroxisome size, suggesting that increasing peroxisome abundance can compensate for the deficiencies caused by pex1-3 and that the enlarged peroxisomes visible in PEX1/pex1-3 may represent autophagy intermediates. Overexpressing PEX1 in wild-type plants impaired growth, suggesting that excessive PEX1 can be detrimental. Our genetic, molecular, and physiological data support the heterohexamer model of PEX1-PEX6 function in plants.


Liver stiffness measurement among patients with chronic hepatitis B and C: results from a 5-year prospective study.
Liver stiffness measurement (LSM) is widely used to evaluate liver fibrosis, but longitudinal studies are rare. The current study was aimed to monitor LSM during follow-up, and to evaluate the association of LSM data with mortality and liver-related outcomes. We included all patients with chronic viral hepatitis and valid LSM using Fibroscan. Information about liver biopsy, antiviral treatment, and clinical outcome was obtained from medical records and national registers. The study included 845 patients: 597 (71%) with hepatitis C virus (HCV), 235 (28%) with hepatitis B virus (HBV) and 13 (2%) with dual infection. The initial LSM distribution (<7/7-9.9/10-16.9/≥ 17 kPa) was 58%/16%/14%/12%. Among patients with initial LSM values of 7-9.9 kPa, 60% of HCV patients and 83% of HBV patients showed LSM values of <7 kPa at the latest follow-up. Progression rates (defined as >20% and >2 kPa increase, with one measure >7 kPa) were 3.4/100 person years (PY) for HCV and 1.5/100 PY for HBV infected patients. Patients with LSM values of ≥ 17 kPa had the same liver-related complication incidence as patients with biopsy-proven cirrhosis (11.1 versus 12.1/100 PY). Thirteen liver-related deaths occurred among HCV patients (0.6/100 PY), but none among HBV patients. Among patients who died of liver-related causes, all but one had baseline LSM values of ≥ 17 kPa. Overall, patients with LSM values <17 kPa were not associated with adverse outcomes. In contrast, LSM values ≥ 17 kPa were associated with significant risk of liver-related problems. The results of the current study suggest that clinical decisions should not be taken based on a single LSM measurement.


Stem cells and cancer of the stomach and intestine.
Cancer in the 21st century has become the number one cause of death in developed countries. Although much progress has been made in improving patient survival, tumour relapse is one of the important causes of cancer treatment failure. An early observation in the study of cancer was the heterogeneity of tumours. Traditionally, this was explained by a combination of genomic instability of tumours and micro environmental factors leading to diverse phenotypical characteristics. It was assumed that cells in a tumour have an equal capacity to propagate the cancer. This model is currently known as the stochastic model. Recently, the Cancer stem cell model has been proposed to explain the heterogeneity of a tumour and its progression. According to this model, the heterogeneity of tumours is the result of aberrant differentiation of tumour cells into the cells of the tissue the tumour originated from. Tumours were suggested to contain stem cell-like cells, the cancer stem cells or tumour-initiating cells, which are uniquely capable of propagating a tumour much like normal stem cells fuel proliferation and differentiation in normal tissue. In this review we discuss the normal stem cell biology of the stomach and intestine followed by both the stochastic and cancer stem cell models in light of recent findings in the gastric and intestinal systems. The molecular pathways underlying normal and tumourigenic growth have been well studied, and recently the stem cells of the stomach and intestine have been identified. Furthermore, intestinal stem cells were identified as the cells-of-origin of colon cancer upon loss of the tumour suppressor APC. Lastly, several studies have proposed the positive identification of a cancer stem cell of human colon cancer. At the end we compare the cancer stem cell model and the stochastic model. We conclude that clonal evolution of tumour cells resulting from genetic mutations underlies tumour initiation and progression in both cancer models. This implies that at any point during tumour development any tumour cell can revert to a cancer stem cell after having gained a clonal advantage over the original cancer stem cell. Therefore, these models represent two sides of the same coin.


National academy of clinical biochemistry laboratory medicine practice guidelines: recommendations for the use of laboratory tests to support poisoned patients who present to the emergency department.
Exposure to drugs and toxins is a major cause for patients' visits to the emergency department (ED). Recommendations for the use of clinical laboratory tests were prepared by an expert panel of analytical toxicologists and ED physicians specializing in clinical toxicology. These recommendations were posted on the world wide web and presented in open forum at several clinical chemistry and clinical toxicology meetings. A menu of important stat serum and urine toxicology tests was prepared for clinical laboratories who provide clinical toxicology services. For drugs-of-abuse intoxication, most ED physicians do not rely on results of urine drug testing for emergent management decisions. This is in part because immunoassays, although rapid, have limitations in sensitivity and specificity and chromatographic assays, which are more definitive, are more labor-intensive. Ethyl alcohol is widely tested in the ED, and breath testing is a convenient procedure. Determinations made within the ED, however, require oversight by the clinical laboratory. Testing for toxic alcohols is needed, but rapid commercial assays are not available. The laboratory must provide stat assays for acetaminophen, salicylates, co-oximetry, cholinesterase, iron, and some therapeutic drugs, such as lithium and digoxin. Exposure to other heavy metals requires laboratory support for specimen collection but not for emergent testing. Improvements are needed for immunoassays, particularly for amphetamines, benzodiazepines, opioids, and tricyclic antidepressants. Assays for new drugs of abuse must also be developed to meet changing abuse patterns. As no clinical laboratory can provide services to meet all needs, the National Academy of Clinical Biochemistry Committee recommends establishment of regional centers for specialized toxicology testing.


An increase in a circulating inhibitor of Na+,K+-dependent ATPase: a possible link between salt intake and the development of essential hypertension.
1. The plasma's ability to stimulate guinea-pig renal glucose 6-phosphate dehydrogenase (G6PD) in vitro was measured by a cytochemical technique in 23 normotensive subjects and 19 patients with hypertension, all of whom were studied on their normal sodium intake. The ability of plasma to stimulate renal G6PD was significantly (P less than 0.001) increased in the hypertensive patients (mean 195 +/- 52 units/ml) compared with the normotensive subjects (mean 22.2 +/- 5.8 units/ml). In all 42 individuals, there was a significant correlation between diastolic pressure and the ability of plasma to stimulate G6PD (r = 0.69 P less than 0.001). 2. The ability of plasma to stimulate G6PD was greatest in the hypertensive patients with values of plasma renin activity below the normal range. In the normotensive subjects the ability of plasma to stimulate G6PD was significantly greater in the older subjects. 3. As the ability of plasma to stimulate G6PD reflects its ability to inhibit Na+,K+-dependent ATPase, these results suggest that patients with essential hypertension have an increase in a circulating inhibitor of Na+,K+-ATPase. The results support the hypothesis that a rise in a circulating sodium transport inhibitor may, in part, be responsible for the rise in blood pressure in essential hypertension, and may form the link between salt intake, abnormalities of sodium transport and a rise in blood pressure.


Identifying alternatives to old age psychiatry inpatient admission: an application of the balance of care approach to health and social care planning.
Mental health problems in older people are common and costly, posing multiple challenges for commissioners. Against this backdrop, a series of initiatives have sought to shift resources from institutional to community care in the belief that this will save money and concurs with user preferences. However, most of this work has focused on the use of care home beds and general hospital admissions, and relatively little attention has been given to reducing the use of mental health inpatient beds, despite their very high cost. The study employed a 'Balance of Care approach' in three areas of North-West England. This long-standing strategic planning framework identifies people whose needs can be met in more than one setting, and compares the costs and consequences of the possible alternatives in a simulation modelling exercise. Information was collected about a six-month cohort of admissions in 2010/11 (n = 216). The sample was divided into groups of people with similar needs for care, and vignettes were formulated to represent the most prevalent groups. A range of key staff judged the appropriateness of these admissions and suggested alternative care for those considered least appropriate for hospital. A public sector costing approach was used to compare the estimated costs of the recommended care with that people currently receive. The findings suggest that more than a sixth of old age psychiatry inpatient admissions could be more appropriately supported in other settings if enhanced community services were available. Such restructuring could involve the provision of intensive support from Care Home Outreach and Community Mental Health Teams, rather than the development of crisis intervention and home treatment teams as currently advocated. Estimated savings were considerable, suggesting local agencies might release up to £1,300,000 per annum. No obvious trade-off between health and social care costs was predicted. There is considerable potential to change the mix of institutional and community services provided for older people with mental health problems. The conclusions would be strengthened by further studies and the incorporation of evidence about relative outcomes. However, the utility of the approach in challenging established patterns of resource allocation and building local ownership for change is apparent.


Diversity partitioning of stony corals across multiple spatial scales around Zanzibar Island, Tanzania.
The coral reefs of Zanzibar Island (Unguja, Tanzania) encompass a considerable proportion of the global coral-reef diversity and are representative of the western Indian Ocean region. Unfortunately, these reefs have been recently subjected to local and regional disturbances. The objectives of this study were to determine whether there are potentially non-random processes forcing the observed coral diversity patterns, and highlight where and at which spatial scales these processes might be most influential. A hierarchical (nested) sampling design was employed across three spatial scales, ranging from transects (<or=20 m), stations (<100 m), to sites (<1000 m), to examine coral diversity patterns. Two of the four sites, Chumbe and Mnemba, were located within Marine Protected Areas (MPAs), while the other two sites, Changuu and Bawe, were not protected. Additive partitioning of coral diversity was used to separate regional (total) diversity (gamma) into local alpha diversity and among-sample beta diversity components. Individual-based null models were used to identify deviations from random distribution across the three spatial scales. We found that Chumbe and Mnemba had similar diversity components to those predicted by the null models. However, the diversity at Changuu and Bawe was lower than expected at all three spatial scales tested. Consequently, the relative contribution of the among-site diversity component was significantly greater than expected. Applying partitioning analysis for each site separately revealed that the within-transect diversity component in Changuu was significantly lower than the null expectation. The non-random outcome of the partitioning analyses helped to identify the among-sites scale (i.e., 10's of kilometers) and the within-transects scale (i.e., a few meters; especially at Changuu) as spatial boundaries within which to examine the processes that may interact and disproportionately differentiate coral diversity. In light of coral community compositions and diversity patterns we strongly recommend that Bawe be declared a MPA.


Maternal and early life factors of tooth emergence patterns and number of teeth at 1 and 2 years of age.
Various environmental factors have been associated with the timing of eruption of primary dentition, but the evidence to date comes from small studies with limited information on potential risk factors. We aimed to investigate associations between tooth emergence patterns and pre-conception, pregnancy and postnatal influences. Dentition patterns were recorded at ages 1 and 2 years in 2915 children born to women in the Southampton Women's Survey from whom information had been collected on maternal factors before conception and during pregnancy. In mutually adjusted regression models we found that: children were more dentally advanced at ages 1 and 2 years if their mothers had smoked during pregnancy or they were longer at birth; mothers of children whose dental development was advanced at age 2 years tended to have poorer socioeconomic circumstances, and to have reported a slower walking speed pre-pregnancy; and children of mothers of Asian ethnicity had later tooth development than those of white mothers. The findings add to the evidence of environmental impacts on the timing of the eruption of primary dentition in indicating that maternal smoking during pregnancy, socio-economic status and physical activity (assessed by reported walking speed) may influence the child's primary dentition. Early life factors, including size at birth are also associated with dentition patterns, as is maternal ethnicity.


Quantitative cw Overhauser effect dynamic nuclear polarization for the analysis of local water dynamics.
Liquid state Overhauser effect Dynamic Nuclear Polarization (ODNP) has experienced a recent resurgence of interest. The ODNP technique described here relies on the double resonance of electron spin resonance (ESR) at the most common, i.e. X-band (∼10GHz), frequency and ¹H nuclear magnetic resonance (NMR) at ∼15 MHz. It requires only a standard continuous wave (cw) ESR spectrometer with an NMR probe inserted or built into an X-band cavity. We focus on reviewing a new and powerful manifestation of ODNP as a high frequency NMR relaxometry tool that probes dipolar cross relaxation between the electron spins and the ¹H nuclear spins at X-band frequencies. This technique selectively measures the translational mobility of water within a volume extending 0.5-1.5 nm outward from a nitroxide radical spin probe that is attached to a targeted site of a macromolecule. It allows one to study the dynamics of water that hydrates or permeates the surface or interior of proteins, polymers, and lipid membrane vesicles. We begin by reviewing the recent advances that have helped develop ODNP into a tool for mapping the dynamic landscape of hydration water with sub-nanometer locality. In order to bind this work coherently together and to place it in the context of the extensive body of research in the field of NMR relaxometry, we then rephrase the analytical model and extend the description of the ODNP-derived NMR signal enhancements. This extended model highlights several aspects of ODNP data analysis, including the importance of considering all possible effects of microwave sample heating, the need to consider the error associated with various relaxation rates, and the unique ability of ODNP to probe the electron-¹H cross-relaxation process, which is uniquely sensitive to fast (tens of ps) dynamical processes. By implementing the relevant corrections in a stepwise fashion, this paper draws a consensus result from previous ODNP procedures and then shows how such data can be further corrected to yield clear and reproducible saturation of the NMR hyperpolarization process. Finally, drawing on these results, we broadly survey the previous ODNP dynamics literature. We find that the vast number of published, empirical hydration dynamics data can be reproducibly classified into regimes of surface, interfacial, vs. buried water dynamics.


Perspective on Oncogenic Processes at the End of the Beginning of Cancer Genomics.
The Cancer Genome Atlas (TCGA) has catalyzed systematic characterization of diverse genomic alterations underlying human cancers. At this historic junction marking the completion of genomic characterization of over 11,000 tumors from 33 cancer types, we present our current understanding of the molecular processes governing oncogenesis. We illustrate our insights into cancer through synthesis of the findings of the TCGA PanCancer Atlas project on three facets of oncogenesis: (1) somatic driver mutations, germline pathogenic variants, and their interactions in the tumor; (2) the influence of the tumor genome and epigenome on transcriptome and proteome; and (3) the relationship between tumor and the microenvironment, including implications for drugs targeting driver events and immunotherapies. These results will anchor future characterization of rare and common tumor types, primary and relapsed tumors, and cancers across ancestry groups and will guide the deployment of clinical genomic sequencing.


Effects of spaceflight on the murine mandible: Possible factors mediating skeletal changes in non-weight bearing bones of the head.
Spaceflight-induced remodeling of the skull is characterized by greater bone volume, mineral density, and mineral content. To further investigate the effects of spaceflight on other non-weight bearing bones of the head, as well as to gain insight into potential factors mediating the remodeling of the skull, the purpose of the present study was to determine the effects of spaceflight on mandibular bone properties. Female C57BL/6 mice were flown 15d on the STS-131 Space Shuttle mission (n=8) and 13d on the STS-135 mission (n=5) or remained as ground controls (GC). Upon landing, mandibles were collected and analyzed via micro-computed tomography for tissue mineralization, bone volume (BV/TV), and distance from the cemento-enamel junction to the alveolar crest (CEJ-AC). Mandibular mineralization was not different between spaceflight (SF) and GC mice for either the STS-131 or STS-135 missions. Mandibular BV/TV (combined cortical and trabecular bone) was lower in mandibles from SF mice on the STS-131 mission (80.7±0.8%) relative to that of GC (n=8) animals (84.2±1.2%), whereas BV/TV from STS-135 mice was not different from GC animals (n=7). The CEJ-AC distance was shorter in mandibles from STS-131 mice (0.217±0.004mm) compared to GC animals (0.283±0.009mm), indicating an anabolic (or anti-catabolic) effect of spaceflight, while CEJ-AC distance was similar between STS-135 and GC mice. These findings demonstrate that mandibular bones undergo skeletal changes during spaceflight and are susceptible to the effects of weightlessness. However, adaptation of the mandible to spaceflight is dissimilar to that of the cranium, at least in terms of changes in BV/TV.


The post-synaptic density of human postmortem brain tissues: an experimental study paradigm for neuropsychiatric illnesses.
Recent molecular genetics studies have suggested various trans-synaptic processes for pathophysiologic mechanisms of neuropsychiatric illnesses. Examination of pre- and post-synaptic scaffolds in the brains of patients would greatly aid further investigation, yet such an approach in human postmortem tissue has yet to be tested. We have examined three methods using density gradient based purification of synaptosomes followed by detergent extraction (Method 1) and the pH based differential extraction of synaptic membranes (Methods 2 and 3). All three methods separated fractions from human postmortem brains that were highly enriched in typical PSD proteins, almost to the exclusion of pre-synaptic proteins. We examined these fractions using electron microscopy (EM) and verified the integrity of the synaptic membrane and PSD fractions derived from human postmortem brain tissues. We analyzed protein composition of the PSD fractions using two dimensional liquid chromatography tandem mass spectrometry (2D LC-MS/MS) and observed known PSD proteins by mass spectrometry. Immunoprecipitation and immunoblot studies revealed that expected protein-protein interactions and certain posttranscriptional modulations were maintained in PSD fractions. Our results demonstrate that PSD fractions can be isolated from human postmortem brain tissues with a reasonable degree of integrity. This approach may foster novel postmortem brain research paradigms in which the stoichiometry and protein composition of specific microdomains are examined.


Diffractive acoustic elements for laser ultrasonics
Laser ultrasonics is an effective means of generating surface acoustic waves (SAWs). We have shown in previous publications how computer-generated holograms (CGHs) can be used to project optical distributions onto the sample surface. These can be used to control both the frequency content and the spatial distribution of the resulting ultrasound field. In this paper the concept is extended further to produce distributions which themselves act as diffractive acoustic elements (DAEs) for SAWs. It is demonstrated how frequency suppression, multiple foci, and frequency selective focusing of Rayleigh waves may be achieved with these elements. Agreement between the distributions predicted from the designs and those actually measured is excellent.


Types of drinkers and drinking settings: an application of a mathematical model.
US college drinking data and a simple population model of alcohol consumption are used to explore the impact of social and contextual parameters on the distribution of light, moderate and heavy drinkers. Light drinkers become moderate drinkers under social influence, moderate drinkers may change environments and become heavy drinkers. We estimate the drinking reproduction number, R(d) , the average number of individual transitions from light to moderate drinking that result from the introduction of a moderate drinker in a population of light drinkers. Ways of assessing and ranking progression of drinking risks and data-driven definitions of high- and low-risk drinking environments are introduced. Uncertainty and sensitivity analyses, via a novel statistical approach, are conducted to assess R(d) variability and to analyze the role of context on drinking dynamics. Our estimates show R(d) well above the critical value of 1. R(d) estimates correlate positively with the proportion of time spent by moderate drinkers in high-risk drinking environments. R(d) is most sensitive to variations in local social mixing contact rates within low-risk environments. The parameterized model with college data suggests that high residence times of moderate drinkers in low-risk environments maintain heavy drinking. With regard to alcohol consumption in US college students, drinking places, the connectivity (traffic) between drinking venues and the strength of socialization in local environments are important determinants in transitions between light, moderate and heavy drinking as well as in long-term prediction of the drinking dynamics.


Adult cranberry beverage consumers have healthier macronutrient intakes and measures of body composition compared to non-consumers: National Health and Nutrition Examination Survey (NHANES) 2005-2008.
Flavonoids, present in high levels in cranberries, are potent bioactives known for their health-promoting benefits, but cranberry beverages (CB) are not typically recommended as part of a healthy diet. We examine the association between CB consumption with macronutrient intake and weight status. Data for US adults (≥19 years, n = 10,891) were taken from the National Health and Nutrition Examination Survey (NHANES) Survey 2005-2008. Total CB consumption was measured over two non-consecutive 24-h dietary recalls. Linear and logistic regression models adjusting for important covariates were used to examine predicted differences between CB consumers and non-consumers on macronutrient and anthropometric outcomes. Results are weighted to be nationally representative. CB consumers (n = 581) were older (>50 year) non-Hispanic black females. They consumed an average 221 mL (7.5 oz) CB per day. In fully adjusted models CB consumers (vs. non-consumers) had higher carbohydrates and total sugars and lower percent energy from protein and total fat (all p < 0.001), but no difference in total energy. A significantly higher proportion of CB consumers were predicted to be normal weight (BMI < 25 kg/m2; p = 0.001) and had to have lower waist circumferences (p = 0.001). Although there was not a significant trend across level of CB intake, low and middle level CB consumers compared to non-consumers were more likely to be normal weight (p < 0.001) and less likely to be overweight/obese (BMI ≥ 25 kg/m2, p < 0.001). Despite having slightly higher daily macronutrient intakes, CB consumers have more desirable anthropometric measures compared to non-consumers.


Uncoupled cardiac nitric oxide synthase mediates diastolic dysfunction.
Heart failure with preserved ejection fraction is 1 consequence of hypertension and is caused by impaired cardiac diastolic relaxation. Nitric oxide (NO) is a known modulator of cardiac relaxation. Hypertension can lead to a reduction in vascular NO, in part because NO synthase (NOS) becomes uncoupled when oxidative depletion of its cofactor tetrahydrobiopterin (BH(4)) occurs. Similar events may occur in the heart that lead to uncoupled NOS and diastolic dysfunction. In a hypertensive mouse model, diastolic dysfunction was accompanied by cardiac oxidation, a reduction in cardiac BH(4), and uncoupled NOS. Compared with sham-operated animals, male mice with unilateral nephrectomy, with subcutaneous implantation of a controlled-release deoxycorticosterone acetate pellet, and given 1% saline to drink were mildly hypertensive and had diastolic dysfunction in the absence of systolic dysfunction or cardiac hypertrophy. The hypertensive mouse hearts showed increased oxidized biopterins, NOS-dependent superoxide production, reduced NO production, and dephosphorylated phospholamban. Feeding hypertensive mice BH(4) (5 mg/d), but not treating with hydralazine or tetrahydroneopterin, improved cardiac BH(4) stores, phosphorylated phospholamban levels, and diastolic dysfunction. Isolated cardiomyocyte experiments revealed impaired relaxation that was normalized with short-term BH(4) treatment. Targeted cardiac overexpression of angiotensin-converting enzyme also resulted in cardiac oxidation, NOS uncoupling, and diastolic dysfunction in the absence of hypertension. Cardiac oxidation, independently of vascular changes, can lead to uncoupled cardiac NOS and diastolic dysfunction. BH(4) may represent a possible treatment for diastolic dysfunction.


Diffuse traumatic brain injury affects chronic corticosterone function in the rat.
As many as 20-55% of patients with a history of traumatic brain injury (TBI) experience chronic endocrine dysfunction, leading to impaired quality of life, impaired rehabilitation efforts and lowered life expectancy. Endocrine dysfunction after TBI is thought to result from acceleration-deceleration forces to the brain within the skull, creating enduring hypothalamic and pituitary neuropathology, and subsequent hypothalamic-pituitary endocrine (HPE) dysfunction. These experiments were designed to test the hypothesis that a single diffuse TBI results in chronic dysfunction of corticosterone (CORT), a glucocorticoid released in response to stress and testosterone. We used a rodent model of diffuse TBI induced by midline fluid percussion injury (mFPI). At 2months postinjury compared with uninjured control animals, circulating levels of CORT were evaluated at rest, under restraint stress and in response to dexamethasone, a synthetic glucocorticoid commonly used to test HPE axis regulation. Testosterone was evaluated at rest. Further, we assessed changes in injury-induced neuron morphology (Golgi stain), neuropathology (silver stain) and activated astrocytes (GFAP) in the paraventricular nucleus (PVN) of the hypothalamus. Resting plasma CORT levels were decreased at 2months postinjury and there was a blunted CORT increase in response to restraint induced stress. No changes in testosterone were measured. These changes in CORT were observed concomitantly with altered complexity of neuron processes in the PVN over time, devoid of neuropathology or astrocytosis. Results provide evidence that a single moderate diffuse TBI leads to changes in CORT function, which can contribute to the persistence of symptoms related to endocrine dysfunction. Future experiments aim to evaluate additional HP-related hormones and endocrine circuit pathology following diffuse TBI.


Mobile Phones as a Medium of Mental Health Care Service Delivery: Perspectives and Barriers among Patients with Severe Mental Illness.
The use of mobile phone technology to support various components of health care delivery (often referred to as mHealth) is on the rise. Little systematic information, however, is available on user felt needs and barriers to mHealth approaches among people with severe mental illness (SMI). Our objectives were to elicit user needs, preferences, and barriers to using mobile phones for health care service delivery among people with SMI. A cross-sectional study was carried out among 75 subjects with SMI between August 2017 and October 2017. All patients had a minimum illness duration of two years or more and a Global Assessment of Functioning score of less than 70. Information on user perspectives was elicited using a 10-item structured questionnaire, to assess mobile phone usage patterns, felt needs, barriers, and preferences, developed for use in patients with SMI. Majority of the patients reported using mobile phones and were favorably disposed to mHealth approaches. Voice calls (n = 47, 62.7%) were the most preferred mode of service delivery. The most preferred service frequency was twice-weekly (n = 31, 41.3%), followed by once-weekly (n = 22, 29.3%). Majority (n = 47, 62.7%) reported no barriers to mobile phone usage, whereas 14 (18.6%) perceived a lack of necessity of mobile phones as a service delivery medium. Reminders about medication and appointments through mobile phones (n = 35, 46.6%) were the most felt needs, followed by crisis helplines (n = 27, 36.0%) and information about mental health services (n = 22, 29.3%). These findings support the use of mHealth approaches in resource-constrained settings and provide specific inputs to refine the modalities of mHealth service delivery.


Use of a percutaneous transabdominal catheter for management of obstructive urolithiasis in goats, sheep, and potbellied pigs: 69 cases (2000-2014).
OBJECTIVE To evaluate the use of a percutaneous transabdominal catheter (PTC) for urinary bladder drainage in goats, sheep, and potbellied pigs with obstructive urolithiasis. DESIGN Retrospective case series. ANIMALS 43 goats, 10 sheep, and 16 potbellied pigs (all males) with obstructive urolithiasis evaluated at the University of California-Davis Veterinary Medical Teaching Hospital. PROCEDURES Medical records of goats, sheep, and potbellied pigs examined because of obstructive urolithiasis from January 2000 through December 2014 were reviewed. Records of animals for which a standard PTC had been placed into the urinary bladder as part of disease management were selected. Data were collected regarding signalment, complications associated with PTC placement, and duration of PTC placement prior to removal. RESULTS 42 of 43 goats, 5 of 10 sheep, and all potbellied pigs were castrated. Median (range) duration of PTC placement was 2 (1 to 4) days for goats, 1 (1 to 4) day for sheep, and 1 (1 to 3) day for potbellied pigs. Complications associated with PTC placement included blockage of the catheter by urine sediment, perforation of the cecum, and migration of the catheter out of the urinary bladder. CONCLUSIONS AND CLINICAL RELEVANCE Placement of a PTC into the urinary bladder allowed for effective stabilization of goats, sheep, and potbellied pigs with obstructive urolithiasis while acid-base and electrolyte imbalances were corrected. Use of a PTC should be considered for urinary bladder drainage during medical management or prior to surgical management of obstructive urolithiasis for these species.


Comparison of short head-up tilt test with conventional protocol after omission of nonmedicated phase in children and young adults.
Syncope is an important and common clinical condition, and the neurally mediated syncope is the most frequent type of syncope. Tilt testing is considered as a first-line diagnostic test. We conducted the conventional and modified tilt test on 200 subjects in the age range of 5-20 years. In conventional protocol, the patient was tilted for up to 15 min without medication. If syncope did not develop, the patient received 0.1 mg/kg sublingual isosorbide dinitrate. Then, the patient was continued to be tilted for another 15 min. In modified tilt test, before starting the test, the patient received 0.1 mg/kg isosorbide dinitrate sublingually in supine position. Then, the table was tilted for a maximum of 25 min or until the test became positive. In conventional tilt test group 79.13% and in modified tilt test group 87.06% of subjects showed positive results. In conventional tilt test, the mean of response time was 17.67 ± 4.74 min. The mean of the total time of conventional tilt test was 49.81 ± 5.57 min. In modified tilt test, the mean of response time was 7.24 ± 4.83 min. The mean of the total time of modified tilt test was 35.09 ± 7.58 min. Furthermore, the means of both response and total times between two groups were significantly different (P < 0.001). Our study showed that we can save about 15-20 min in total test time which may increase the cooperation and compliance of young patients and decrease their anxiety with this new protocol.


Feedforward attractor targeting for non-linear oscillators using a dual-frequency driving technique.
A feedforward control technique is presented to steer a harmonically driven, non-linear system between attractors in the frequency-amplitude parameter plane of the excitation. The basis of the technique is the temporary addition of a second harmonic component to the driving. To illustrate this approach, it is applied to the Keller-Miksis equation describing the radial dynamics of a single spherical gas bubble placed in an infinite domain of liquid. This model is a second-order, non-linear ordinary differential equation, a non-linear oscillator. With a proper selection of the frequency ratio of the temporary dual-frequency driving and with the appropriate tuning of the excitation amplitudes, the trajectory of the system can be smoothly transformed between specific attractors; for instance, between period-3 and period-5 orbits. The transformation possibilities are discussed and summarized for attractors originating from the subharmonic resonances and the equilibrium state (absence of external driving) of the system.


Posterior fossa craniotomy for trapped fourth ventricle in shunt-treated hydrocephalic children: long-term outcome.
Trapped fourth ventricle (TFV) is a rare late complication of postinfectious or posthemorrhagic hydrocephalus. This entity is distinct from a large fourth ventricle because TFV entails pressure in the fourth ventricle and posterior fossa due to abnormal inflow and outflow of CSF, causing significant symptoms and signs. As TFV is mostly found in children who were born prematurely and have cerebral palsy, diagnosis and treatment options are a true challenge. Between February 1998 and February 2007, 12 children were treated for TFV in Dana Children's Hospital by posterior fossa craniotomy/craniectomy and opening of the TFV into the spinal subarachnoid space. The authors performed a retrospective analysis of relevant data, including pre- and postoperative clinical characteristics, surgical management, and outcome. Thirteen fenestrations of trapped fourth ventricles (FTFVs) were performed in 12 patients. In 6 patients with prominent arachnoid thickening, a stent was left from the opened fourth ventricle into the spinal subarachnoid space. One patient underwent a second FTFV 21 months after the initial procedure. No perioperative complications were encountered. All 12 patients (100%) showed clinical improvement after FTFV. Radiological improvement was seen in only 9 (75%) of the 12 cases. The follow-up period ranged from 2 to 9.5 years (mean 6.11 ± 2.3 years) after FTFV. Fenestration of a TFV via craniotomy is a safe and effective option with a very good long-term outcome and low rate of morbidity.


Cross-helicity in rotating homogeneous shear-stratified turbulence.
We consider homogeneous shear-stratified turbulence in a rotating frame, that exhibits complex nonlinear dynamics. Since the analysis of relative orientation between coupled fluctuating fields helps us to understand turbulence dynamics, we focus on the alignment properties of both the velocity and gravity fields with the potential vorticity gradient. With the help of statistical mechanics, we define a vector field which plays a role in the analogous so-called cross-helicity in magnetohydrodynamics. High-resolution direct numerical simulations of developed homogeneous baroclinic turbulence are performed, and a detailed analysis of probability density functions for cross-helicity is provided. A net preference for positive cross-helicity is shown to be related to a new alignment mechanism. We argue that the analysis of cross-helicity is crucial for understanding the dynamics of buoyancy driven flows.


Use and effectiveness of pegfilgrastim prophylaxis in US clinical practice:a retrospective observational study.
Febrile neutropenia (FN) is a serious complication of myelosuppressive chemotherapy. Clinical practice guidelines recommend routine prophylactic coverage with granulocyte colony-stimulating factor (G-CSF)-such as pegfilgrastim-for most patients receiving chemotherapy with an intermediate to high risk for FN. Patterns of pegfilgrastim prophylaxis during the chemotherapy course and associated FN risks in US clinical practice have not been well characterized. A retrospective cohort design and data from two commercial healthcare claims repositories (01/2010-03/2016) and Medicare Claims Research Identifiable Files (01/2007-09/2015) were employed. Study population included patients who had non-metastatic breast cancer or non-Hodgkin's lymphoma and received intermediate/high-risk regimens. Pegfilgrastim prophylaxis use and FN incidence were ascertained in each chemotherapy cycle, and all cycles were pooled for analyses. Adjusted odds ratios for FN were estimated for patients who did versus did not receive pegfilgrastim prophylaxis in that cycle. Study population included 50,778 commercial patients who received 190,622 cycles of chemotherapy and 71,037 Medicare patients who received 271,944 cycles. In cycle 1, 33% of commercial patients and 28% of Medicare patients did not receive pegfilgrastim prophylaxis, and adjusted odds of FN were 2.6 (95% CI 2.3-2.8) and 1.6 (1.5-1.7), respectively, versus those who received pegfilgrastim prophylaxis. In cycle 2, 28% (commercial) and 26% (Medicare) did not receive pegfilgrastim prophylaxis; corresponding adjusted FN odds were comparably elevated (1.9 [1.6-2.2] and 1.6 [1.5-1.8]). Results in subsequent cycles were similar. Across all cycles, 15% of commercial patients and 23% of Medicare patients did not receive pegfilgrastim prophylaxis despite having FN in a prior cycle, and prior FN increased odds of subsequent FN by 2.1-2.4 times. Notwithstanding clinical practice guidelines, a large minority of patients did not receive G-CSF prophylaxis, and FN incidence was substantially higher among this subset of the population. Appropriate use of pegfilgrastim prophylaxis may reduce patient exposure to this potentially fatal but largely preventable complication of myelosuppressive chemotherapy.


Colloidal heat engines: a review.
Stochastic heat engines can be built using colloidal particles trapped using optical tweezers. Here we review recent experimental realizations of microscopic heat engines. We first revisit the theoretical framework of stochastic thermodynamics that allows to describe the fluctuating behavior of the energy fluxes that occur at mesoscopic scales, and then discuss recent implementations of the colloidal equivalents to the macroscopic Stirling, Carnot and steam engines. These small-scale motors exhibit unique features in terms of power and efficiency fluctuations that have no equivalent in the macroscopic world. We also consider a second pathway for work extraction from colloidal engines operating between active bacterial reservoirs at different temperatures, which could significantly boost the performance of passive heat engines at the mesoscale. Finally, we provide some guidance on how the work extracted from colloidal heat engines can be used to generate net particle or energy currents, proposing a new generation of experiments with colloidal systems.


Allosteric Regulation in the Ligand Binding Domain of Retinoic Acid Receptorγ.
Retinoic acid (RA) plays key roles in cell differentiation and growth arrest through nuclear retinoic acid receptors (RARs), which are ligand-dependent transcription factors. While the main trigger of RAR activation is the binding of RA, phosphorylation of the receptors has also emerged as an important regulatory signal. Phosphorylation of the RARγ N-terminal domain (NTD) is known to play a functional role in neuronal differentiation. In this work, we investigated the phosphorylation of RARγ ligand binding domain (LBD), and present evidence that the phosphorylation status of the LBD affects the phosphorylation of the NTD region. We solved the X-ray structure of a phospho-mimetic mutant of the LBD (RARγ S371E), which we used in molecular dynamics simulations to characterize the consequences of the S371E mutation on the RARγ structural dynamics. Combined with simulations of the wild-type LBD, we show that the conformational equilibria of LBD salt bridges (notably R387-D340) are affected by the S371E mutation, which likely affects the recruitment of the kinase complex that phosphorylates the NTD. The molecular dynamics simulations also showed that a conservative mutation in this salt bridge (R387K) affects the dynamics of the LBD without inducing large conformational changes. Finally, cellular assays showed that the phosphorylation of the NTD of RARγ is differentially regulated by retinoic acid in RARγWT and in the S371N, S371E and R387K mutants. This multidisciplinary work highlights an allosteric coupling between phosphorylations of the LBD and the NTD of RARγ and supports the importance of structural dynamics involving electrostatic interactions in the regulation of RARs activity.


Terbium gallium garnet ceramic Faraday rotator for high-power laser application.
A terbium gallium garnet (TGG) ceramic Faraday rotator (FR) with an isolation ratio of 33 dB was demonstrated at a laser radiation power of 257 W. This FR can be equipped with a large optical aperture by using ceramics technology to prevent laser damage at high-energy pulse operation. The thermal lens of a 257 W laser with a beam diameter of 2.6 mm had a focal length of 9.5 m, which is easily corrected using a spherical lens to suppress the undesirable effects of thermal lensing. The rotation angle of the FR was stabilized by water cooling. The results indicate that the TGG-ceramic-based FR is suitable for high-energy laser systems with high repetition rates.


Species-specific toxicity of ceria nanoparticles to Lactuca plants.
Species-specific differences in the toxicity of manufactured nanoparticles (MNPs) have been reported, but the underlying mechanisms are unknown. We previously found that CeO2 NPs inhibited root elongation of head lettuce, whereas no toxic effect was observed on other plants (such as wheat, cucumber and radish). In this study, interactions between Lactuca plants and three types of CeO2 NPs (lab-synthesized 7 and 25 nm CeO2 NPs, and a commercial CeO2 NPs) were investigated. It was found that CeO2 NPs were toxic to three kinds of Lactuca genus plants and different CeO2 NPs showed different degrees of toxicity. The results of X-ray absorption near edge fine structure indicate that small parts of CeO2 NPs were transformed from Ce(IV) to Ce(III) in roots of the plants that were treated with CeO2 NPs during the seed germination stage. But the high sensitivity of Lactuca plants to the released Ce(3+) ions caused the species-specific phytotoxicity of CeO2 NPs. Differences in sizes and zeta potentials among three types of CeO2 NPs resulted in their different degrees of biotransformation which accounted for the discrepancy in the toxicity to Lactuca plants. This study is among the few, and may indeed the first, that addresses the relation between the physicochemical properties of nanoparticles and its species-specific phytotoxicity.


Apolipoprotein E-epsilon 4 and recurrent genital herpes in individuals co-infected with herpes simplex virus type 2 and HIV.
Apolipoprotein E (APOE) alleles have been associated with the severity of, or susceptibility to, infection by various microbes. We investigated the potential association between the APOE-epsilon 4 allele and the rate of recurrence of genital herpes in patients who were HIV positive and herpes simplex virus type 2 (HSV-2) seropositive. The APOE-epsilon 4 allele was significantly associated with recurrent genital ulceration independent of ethnicity, antiretroviral therapy and CD4 count (OR 8.3; 95% CI 2.4 to 28.5). To our knowledge, this is the first published study to demonstrate this association and suggests that APOE-epsilon 4 may represent a future prognostic marker for symptomatic recurrence of genital herpes in individuals with HIV.


Assessing Electronic Health Literacy in the State of Kuwait: Survey of Internet Users From an Arab State.
The internet and social media have become an important source for health information. In 2017, the State of Kuwait ranked first in mobile subscription penetration in the Arab world; nearly 90% of its population uses the internet. Electronic health (eHealth) literacy is important in populations that have easy and affordable access to internet resources to more effectively manage health conditions as well as improve general population health. The aim of this study was to assess eHealth literacy levels across internet users in Kuwait and identify demographic characteristics that influence eHealth literacy. Furthermore, the study aimed to identify the reasons and type of information that people seek online. Finally, this study examined the utilization of various social media channels for accessing online health information. The social media platforms considered were as follows: WhatsApp, Twitter, Instagram, YouTube, Facebook, and Snapchat. A cross-sectional anonymous Web-based survey was used to collect data about eHealth literacy and related information. The eHealth literacy scale (eHEALS), originally developed by Norman and Skinner, is measured using 8 Likert-type scales. A linear regression model estimates the effect of demographic variables such as age, gender, and education on eHealth literacy while controlling for participants' perceived usefulness and importance of the internet. Participants were also surveyed about their frequency in using social media platforms for seeking health information. Kuwait's composite eHEALS, based on a sample of 386 participants, was 28.63, which is very similar to eHEALS observed among adult populations in other developed countries. Females in Kuwait demonstrated a higher average eHEALS compared with males. Among the social media platforms, the survey results indicated that YouTube is the most frequently used to seek health information, with Facebook being the least frequently used. Internet users in Kuwait appear confident in their ability to search for health-related information online compared with other populations, as indicated by aggregate eHEALS scores. Considering this finding, government and health care organizations should shift more efforts from traditional media toward online health information, focusing on the social media outlets that people in Kuwait find more useful for seeking health information.


Neural basis for categorical boundaries in the primate pre-SMA during relative categorization of time intervals.
Perceptual categorization depends on the assignment of different stimuli to specific groups based, in principle, on the notion of flexible categorical boundaries. To determine the neural basis of categorical boundaries, we record the activity of pre-SMA neurons of monkeys executing an interval categorization task in which the limit between short and long categories changes between blocks of trials within a session. A large population of cells encodes this boundary by reaching a constant peak of activity close to the corresponding subjective limit. Notably, the time at which this peak is reached changes according to the categorical boundary of the current block, predicting the monkeys' categorical decision on a trial-by-trial basis. In addition, pre-SMA cells also represent the category selected by the monkeys and the outcome of the decision. These results suggest that the pre-SMA adaptively encodes subjective duration boundaries between short and long durations and contains crucial neural information to categorize intervals and evaluate the outcome of such perceptual decisions.


Utilization of fermented soybeans paste as flavoring lamination for Turkish dry-cured meat.
The effects of utilizing fermented soybeans paste (miso) as an alternative flavor-coating material for eliminating unpleasant odor of sulphuric and sotolone compounds from cemen in commercial pastirma were investigated. Results showed that miso-pastirma (MP) and commercial pastirma (CP) had higher L* values in comparison with the fresh meat. While no pathogen was detected in all the meat samples, statistically significant stearic acid was increased (P<0.05) and also oleic and arachidic acids were observed in MP. SDS-PAGE patterns indicated that miso had higher impacts on muscle proteins than cemen suggesting that miso can generate proteins and peptides with better technological or nutritional properties. None of the sulphur containing compounds responsible for unpleasant odor was detected in MP. Limonene, 5 esters, beta-pinene and saponins in MP contributed to citrus fruit aroma with smoother, roasty flavor and delicious taste. These findings suggest that miso contain good flavoring molecules for enhancing fruity smell and quality of pastirma. Thus, laminating cured meat with miso can be used as an alternative to cemen for producing healthier pastirma with extended shelf life and better flavor.


Surveillance for waterborne-disease outbreaks--United States, 1997-1998.
Since 1971, CDC and the U.S. Environmental Protection Agency (EPA) have maintained a collaborative surveillance system for collecting and periodically reporting data relating to occurrences and causes of waterborne-disease outbreaks (WBDOs). This summary includes data from January 1997 through December 1998 and a previously unreported outbreak in 1996. The surveillance system includes data regarding outbreaks associated with drinking water and recreational water. State, territorial, and local public health departments are primarily responsible for detecting and investigating WBDOs and voluntarily reporting them to CDC on a standard form. During 1997-1998, a total of 13 states reported 17 outbreaks associated with drinking water. These outbreaks caused an estimated 2,038 persons to become ill. No deaths were reported. The microbe or chemical that caused the outbreak was identified for 12 (70.6%) of the 17 outbreaks; 15 (88.2%) were linked to groundwater sources. Thirty-two outbreaks from 18 states were attributed to recreational water exposure and affected an estimated 2,128 persons. Eighteen (56.3%) of the 32 were outbreaks of gastroenteritis, and 4 (12.5%) were single cases of primary amebic meningoencephalitis caused by Naegleria fowleri, all of which were fatal. The etiologic agent was identified for 29 (90.6%) of the 32 outbreaks, with one death associated with an Escherichia coli O157:H7 outbreak. Ten (55.6%) of the 18 gastroenteritis outbreaks were associated with treated pools or ornamental fountains. Of the eight outbreaks of dermatitis, seven (87.5%) were associated with hot tubs, pools, or springs. Drinking water outbreaks associated with surface water decreased from 31.8% during 1995-1996 to 11.8% during 1997-1998. This reduction could be caused by efforts by the drinking water industry (e.g., Partnership for Safe Water), efforts by public health officials to improve drinking water quality, and improved water treatment after the implementation of EPA's Surface Water Treatment Rule. In contrast, the proportion of outbreaks associated with systems supplied by a groundwater source increased from 59.1% (i.e., 13) during 1995-1996 to 88.2% (i.e., 15) during 1997-1998. Outbreaks caused by parasites increased for both drinking and recreational water. All outbreaks of gastroenteritis attributed to parasites in recreational water were caused by Cryptosporidium, 90% occurred in treated water venues (e.g., swimming pools and decorative fountains), and fecal accidents were usually suspected. The data in this surveillance summary probably underestimate the true incidence of WBDOs because not all WBDOs are recognized, investigated, and reported to CDC or EPA. To estimate the national prevalence of waterborne disease associated with drinking water, CDC and EPA are conducting a series of epidemiologic studies to better quantify the level of waterborne disease associated with drinking water in nonoutbreak conditions. The Information Collection Rule implemented by EPA in collaboration with the drinking water industry helped quantifythe level of pathogens in surface water. Efforts by CDC to address recreational water outbreaks have included meetings with the recreational water industry, focus groups to educate parents on prevention of waterborne disease transmission in recreational water settings, and publications with guidelines for parents and pool operators.


Structural and evolutionary analysis of HLA-D-region products.
The major histocompatibility complex (MHC)--HLA in man and H-2 in mouse--encodes two classes of cell-surface antigens involved in the immune response. The amino acid sequences have been determined for a number of these molecules. Class I antigens, typified by the HLA-ABC antigens, are composed of a 43,000-molecular weight (MW) glycosylated transmembrane polypeptide with three external domains (alpha 1, alpha 2 and alpha 3), of which the one nearest the membrane (alpha 3) is associated with a 12,000-MW nonglycosylated polypeptide, beta 2-microglobulin. The HLA-D-region or class II antigens, DR, DC and SB, are composed of two glycosylated transmembrane polypeptides, of MWs 34,000 (alpha-chain) and 28,000 (beta-chain). Both chains have two external domains which presumably associate with each other, alpha 2, beta 2 being membrane proximal and alpha 1, beta 1 N-terminal and membrane distal. All four membrane-proximal domains (class I alpha 3, beta 2-microglobulin, class II alpha 2 and beta 2) have amino acid sequences that show significant similarities with immunoglobulin constant-region domains. This, together with the similarly placed internal disulphide bonds, suggests they might have an immunoglobulin-like structure (Fig. 1). We have now used computer graphics techniques to predict a detailed three-dimensional structure for the membrane-proximal domains of the class II antigens (alpha 2 and beta 2) based on the known coordinates of immunoglobulin constant domains (Fig. 2). The transmembrane regions of class II antigens have been modelled as two alpha-helices packed together. The proposed structure accounts for conservation of amino acids and leads to evolutionary predictions.


Randomized clinical trial of a phytotherapic compound containing Pimpinella anisum, Foeniculum vulgare, Sambucus nigra, and Cassia augustifolia for chronic constipation.
A phytotherapic compound containing Pimpinella anisum L., Foeniculum vulgare Miller, Sambucus nigra L., and Cassia augustifolia is largely used in Brazil for the treatment of constipation. However, the laxative efficacy of the compound has never been tested in a randomized clinical trial. The aim of this study was to evaluate the efficacy and safety of the product. This randomized, crossover, placebo-controlled, single-blinded trial included 20 patients presenting with chronic constipation according to the criteria of the American Association of Gastroenterology. The order of treatments was counterbalanced across subjects: half of the subjects received the phytotherapic compound for a 5-day period, whereas the other half received placebo for the same period. Both treatment periods were separated by a 9-day washout period followed by the reverse treatment for another 5-day period. The primary endpoint was colonic transit time (CTT), measured radiologically. Secondary endpoints included number of evacuations per day, perception of bowel function, adverse effects, and quality of life. Mean CTT assessed by X ray was 15.7 hours (95%CI 11.1-20.2) in the active treatment period and 42.3 hours (95%CI 33.5-51.1) during the placebo treatment (p < 0.001). Number of evacuations per day increased during the use of active tea; significant differences were observed as of the second day of treatment (p < 0.001). Patient perception of bowel function was improved (p < 0.01), but quality of life did not show significant differences among the study periods. Except for a small reduction in serum potassium levels during the active treatment, no significant differences were observed in terms of adverse effects throughout the study period. The findings of this randomized controlled trial allow to conclude that the phytotherapic compound assessed has laxative efficacy and is a safe alternative option for the treatment of constipation. ClinicalTrial.gov NCT00872430.


Dinophysis acuta in Scottish Coastal Waters and Its Influence on Diarrhetic Shellfish Toxin Profiles.
Diarrhetic shellfish toxins produced by the dinoflagellate genus Dinophysis are a major problem for the shellfish industry worldwide. Separate species of the genus have been associated with the production of different analogues of the okadaic acid group of toxins. To evaluate the spatial and temporal variability of Dinophysis species and toxins in the important shellfish-harvesting region of the Scottish west coast, we analysed data collected from 1996 to 2017 in two contrasting locations: Loch Ewe and the Clyde Sea. Seasonal studies were also undertaken, in Loch Ewe in both 2001 and 2002, and in the Clyde in 2015. Dinophysis acuminata was present throughout the growing season during every year of the study, with blooms typically occurring between May and September at both locations. The appearance of D. acuta was interannually sporadic and, when present, was most abundant in the late summer and autumn. The Clyde field study in 2015 indicated the importance of a temperature front in the formation of a D. acuta bloom. A shift in toxin profiles of common mussels (Mytilus edulis) tested during regulatory monitoring was evident, with a proportional decrease in okadaic acid (OA) and dinophysistoxin-1 (DTX1) and an increase in dinophysistoxin-2 (DTX2) occurring when D. acuta became dominant. Routine enumeration of Dinophysis to species level could provide early warning of potential contamination of shellfish with DTX2 and thus determine the choice of the most suitable kit for effective end-product testing.


Sensorimotor integration for multisegmental frontal plane balance control in humans.
To quantify the contribution of sensory information to multisegmental frontal plane balance control in humans, we developed a feedback control model to account for experimental data. Subjects stood with feet close together on a surface that rotated according to a pseudorandom waveform at three different amplitudes. Experimental frequency-response functions and impulse-response functions were measured to characterize lower body (LB) and upper body (UB) motion evoked during surface rotations while subjects stood with eyes open or closed. The model assumed that corrective torques in LB and UB segments were generated with no time delay from intrinsic musculoskeletal mechanisms and with time delay from sensory feedback mechanisms. It was found that subjects' LB control was primarily based on sensory feedback. Changes in the LB control mechanisms across stimulus amplitude were consistent with the hypothesis that sensory reweighting contributed to amplitude-dependent changes in balance responses whereby subjects decreased reliance on proprioceptive cues that oriented the LB toward the surface and increased reliance on vestibular/visual cues that oriented the LB upright toward earth vertical as stimulus amplitude increased in both eyes open and closed conditions. Sensory reweighting in the LB control system also accounted for most of the amplitude-dependent changes observed in UB responses. In contrast to the LB system, sensory reweighting was not a dominant mechanism of UB control, and UB control was more influenced by intrinsic musculoskeletal mechanisms. The proposed model refines our understanding of sensorimotor integration during balance control by including multisegmental motion and explaining how intersegmental interactions influence frontal plane balance responses.


Wrapping transition and wrapping-mediated interactions for discrete binding along an elastic filament: an exact solution.
The wrapping equilibria of one and two adsorbing cylinders are studied along a semi-flexible filament (polymer) due to the interplay between elastic rigidity and short-range adhesive energy between the cylinder and the filament. We show that statistical mechanics of the system can be solved exactly using a path integral formalism which gives access to the full effect of thermal fluctuations, going thus beyond the usual Gaussian approximations which take into account only the contributions from the minimal energy configuration and small fluctuations about this minimal energy solution. We obtain the free energy of the wrapping-unwrapping transition of the filament around the cylinders as well as the effective interaction between two wrapped cylinders due to thermal fluctuations of the elastic filament. A change of entropy due to wrapping of the filament around the adsorbing cylinders as they move closer together is identified as an additional source of interactions between them. Such entropic wrapping effects should be distinguished from the usual entropic configuration effects in semi-flexible polymers. Our results may be relevant to the problem of adsorption of oriented nano-rods on semi-flexible polymers.


Current cycling, bicycle path use, and willingness to cycle more-findings from a community survey of cycling in southwest sydney, australia.
Encouraging cycling could increase levels of physical activity and health in the community. A population survey of cycling and physical activity was conducted as part of the baseline evaluation of a new intervention research project (Cycling Connecting Communities). A telephone survey of adults (18+) living within 2 kilometers of selected major new bicycle paths in 3 local government areas in south western Sydney, Australia was conducted using a 2-stage sampling method. Multiple logistic regression analyses examined factors associated with riding in the last year, wanting to cycle more, and use of local bicycle paths. With a 65% response rate, 1450 interviews were completed. Having ridden a bicycle in the past year was associated with younger age, being male, having access to a bicycle, and living close to destinations of interest. Two thirds of respondents (65%) wanted to ride more than they currently did. Factors associated with wanting to ride more were having children aged between 5-18 years, having used local bicycle paths, and perceptions of ease of cycling. The study found that there is a latent desire for more cycling among respondents, prompted to some extent by having children of an age (5-18 years) that like cycling, and having a reasonable opportunity to cycle due to local bicycle paths. Being relatively close to destinations of interest increases the likelihood of recent cycling.


Screening for imported diseases in an immigrant population: experience from a teaching hospital in Barcelona, Spain.
The objective of this study was to describe the screening for imported diseases among an immigrant population. This retrospective observational study was of all adult immigrants attended at the Tropical Medicine Unit of the Vall d'Hebron Teaching Hospital from September of 2007 to March of 2010. The screening strategy was adjusted by symptoms, country of origin, and length of residence in Europe. Overall, 927 patients were included. The median age was 34.5 years, and 42.1% of patients were male. A diagnosis was made in 419 (45.2%) patients. The most frequent diagnoses were Chagas disease, anemia, latent tuberculosis infection, intestinal parasitosis, hepatitis B virus (HBV) infection, and human immunodeficiency virus (HIV) infection. After screening, more diseases were identified in immigrants from sub-Saharan Africa (new diagnoses in 56.6% of patients) than patients from other geographic areas. The geographic origin and length of residence in a developed country determine the prevalence of diseases; hence, screening protocols must be based on this information.


The reach and adoption of a coach-led exercise training programme in community football.
To determine the reach and adoption of a coach-led exercise training programme for lower limb injury prevention. Secondary analysis of data from a group-clustered randomised controlled trial. A periodised exercise training warm-up programme was delivered to players during training sessions over an 8-week preseason (weeks 1-8) and 18-week playing season. 1564 community Australian football players. Reach, measured weekly, was the number of players who attended training sessions. Adoption was the number of attending players who completed the programme in full, partially or not at all. Reasons for partial or non-participation were recorded. In week 1, 599 players entered the programme; 55% attended 1 training session and 45% attended > 1 session. By week 12, 1540 players were recruited but training attendance (reach) decreased to <50%. When players attended training, the majority adopted the full programme-ranging from 96% (week 1) to above 80% until week 20. The most common reasons for low adoption were players being injured, too sore, being late for training or choosing their own warm-up. The training programme's reach was highest preseason and halved at the playing season's end. However, when players attended training sessions, their adoption was high and remained close to 70% by season end. For sports injury prevention programmes to be fully effective across a season, attention also needs to be given to (1) encouraging players to attend formal training sessions and (2) considering the possibility of some form of programme delivery outside of formal training.


Unilateral Subcondylar and Condylar Neck Fractures: Randomized Clinical Study.
The aim of the present study was to compare closed treatment with open reduction internal fixation (ORIF) for subcondylar and condylar neck fractures. This randomized prospective study was conducted on thirty patients who visited the Department of Oral and Maxillofacial Surgery, Government Dental College, Srinagar, with condylar fractures. All fractures were displaced; either angulated between 10° and 45° and the ascending ramus was shortened by >2 mm to <15 mm. Patients were divided into two groups after satisfying the inclusion and exclusion criteria - Group I (closed treatment) and Group II (open reduction) (15 implants in each group). In Group I, patients were treated by mandibulo-maxillary fixation using arch bar and elastics for 4 weeks, and in Group II, patients were treated by ORIF using two 1.5-mm miniplates. Follow-up was done at 1 month, 3 months, and 6 months. Our postoperative evaluation included five parameters - maximal interincisal opening, protrusion, lateral excursion on fractured and nonfractured sides, anatomical reduction, and pain and malocclusion. Nonparametric data were compared for statistical significance with Chi square test and parametric data with an independent sample's t-test (P < 0.05). Correct anatomical position of the fragments was achieved significantly more accurately in the operative group in contrast to the closed treatment group. Regarding mouth opening/lateral excursion on fractured and nonfractured sides/protrusion, significant (P < 0.05) differences were observed between both groups (open 39.73/7.50/8.17/7.87 mm vs. closed 36.87/6.07/7.23/7.13 mm). Pain also revealed significant (P = 0.025) difference with less pain in the operative treatment group. Both treatment options for condylar fractures of the mandible yielded acceptable results. However, operative treatment was superior in all objective and subjective functional parameters except occlusion.


Three-dimensional cytoarchitecture of normal and atherosclerotic intima of human aorta.
The three-dimensional cytoarchitecture of normal and atherosclerotic intima of human aorta was studied by light microscopy of consecutive en face preparations (Hautchen preparations) and by scanning electron microscopy. In unaffected intima, a three-dimensional network consisting of cells of variable shape and probably origin was demonstrated. Cellular shape changed from predominantly stellate in the luminal regions of the elastic-hyperplastic layer to elongated spindlelike cells in the musculoelastic layer of the intima. In the surface layers of the fatty streak, cellular contacts were severed, and lipid droplets were often seen between cellular processes. Along with stellate and elongated cells, the fatty streak also had a number of round monocytelike cells. Lipid inclusions were usually detected in stellate and ovoid cells. The integrity of the cellular network was preserved at the marginal zone of the atherosclerotic plaque, while at the slopes and in the central part of the plaque, cells practically lost all contact with each other. Giant stellate cells embedded in crude fibrillar connective tissue matrix were often found there. Disintegration of the cellular network during atherosclerosis is suggested to play an important role in the development of various lesions.


Ara h 2 and Ara h 6 have similar allergenic activity and are substantially redundant.
The moderately homologous (approx. 60%) proteins Ara h 2 and Ara h 6 are the most potent peanut allergens. This study was designed to define the relative individual contributions of Ara h 2 and Ara h 6 to the overall allergenic activity of a crude peanut extract (CPE). Ara h 2 and Ara h 6 were removed from CPE by gel filtration chromatography. Ara h 2.01, Ara h 2.02 and Ara h 6 were further purified (>99%). The potency of each allergen and the ability of these allergens to reconstitute the allergenic activity of CPE depleted of Ara h 2 and Ara h 6 was measured with RBL SX-38 cells sensitized with IgE from sensitized peanut allergic patients. The potency of the native proteins were significantly different (p < 0.0001) although not dramatically so, with a rank order of Ara h 2.01 > Ara h 2.02 > Ara h 6. The addition of either purified Ara h 2 or Ara h 6 independently at their original concentration to CPE depleted of both Ara h 2 and Ara h 6 restored 80-100% of the original CPE allergenic activity. Addition of both Ara h 2 and Ara h 6 consistently completely restored the allergenic activity of CPE. These studies indicate that either Ara h 2 or Ara h 6 independently can account for most of the allergenic activity in a CPE and demonstrate important redundancy in the allergenic activity of these related molecules.


The Rise of Imported Dengue Infections in Victoria, Australia, 2010⁻2016.
Dengue notifications have increased dramatically over the past seven years in Victoria, Australia-a trend which has been seen nationally and reflects increased cases internationally. We reviewed the epidemiology of dengue among Victorian travellers, changes in diagnostic methods and describe the burden placed on local health systems resulting from this disease of public health importance. Cases of dengue notified to the Department of Health and Human Services in Victoria, Australia, between 1 January 2010 and 31 December 2016 were included in this review. Demographic, clinical, diagnostic methods, and risk factor data were examined using descriptive epidemiological analyses. Cases of dengue increased on average by 22% per year, with a total of 2187 cases (5.5 cases/100,000 population) notified over the 7-year reporting period. The most frequently reported country of acquisition was Indonesia (45%) followed by Thailand (14%). The use of multiple diagnostic methods, including the non-structural protein 1 antigen (NS1Ag) detection test, increased over time. The median time between onset of illness and diagnosis diminished from 9 days (IQR: 2⁻15) in 2010 to 4 days (IQR: 2⁻7) in 2016. Proportionally more cases were discharged directly from emergency departments in recent years (10% in 2010 to 28% in 2016, p < 0.001).The increasing incidence of dengue in Australia is reflective of its growing prominence as a travel medicine problem in western countries. For travellers with non-severe dengue, the improved timeliness of dengue diagnostics allows for consideration of best practice ambulatory management approaches as used in endemic areas.


Candida albicans ISW2 Regulates Chlamydospore Suspensor Cell Formation and Virulence In Vivo in a Mouse Model of Disseminated Candidiasis.
Formation of chlamydospores by Candida albicans was an established medical diagnostic test to confirm candidiasis before the molecular era. However, the functional role and pathological relevance of this in vitro morphological transition to pathogenesis in vivo remain unclear. We compared the physical properties of in vitro-induced chlamydospores with those of large C. albicans cells purified by density gradient centrifugation from Candida-infected mouse kidneys. The morphological and physical properties of these cells in kidneys of mice infected intravenously with wild type C. albicans confirmed that chlamydospores can form in infected kidneys. A previously reported chlamydospore-null Δisw2/Δisw2 mutant was used to investigate its role in virulence and chlamydospore induction. Virulence of the Δisw2/Δisw2 mutant strain was reduced 3.4-fold compared to wild type C. albicans or the ISW2 reconstituted strain. Altered host inflammatory reactions to the null mutant further indicate that ISW2 is a virulence factor in C. albicans. ISW2 deletion abolished chlamydospore formation within infected mouse kidneys, whereas the reconstituted strain restored chlamydospore formation in kidneys. Under chlamydospore inducing conditions in vitro, deletion of ISW2 significantly delayed chlamydospore formation, and those late induced chlamydospores lacked associated suspensor cells while attaching laterally to hyphae via novel spore-hypha septa. Our findings establish the induction of chlamydospores by C. albicans during mouse kidney colonization. Our results indicate that ISW2 is not strictly required for chlamydospores formation but is necessary for suspensor cell formation. The importance of ISW2 in chlamydospore morphogenesis and virulence may lead to additional insights into morphological differentiation and pathogenesis of C. albicans in the host microenvironment.