Incidence rate of anemia in inflammatory bowel diseases.
To determine the incidence rate and distribution of anemia types over time from an Inflammatory Bowel Disease (IBD) patient cohort spanning 18 years. Between January 1995 and November 2013, the University Hospital digital databases as well as hard copies of patients' files were reviewed retrospectively. IBD patients with at least one complete blood count (CBC) report were included in this study. We obtained 941 IBD patients' records; 375 (39.9%) patients were diagnosed with Crohn's disease (CD), and 566 (60.1%) patients had ulcerative colitis (UC). Anemia was detected in 548 (58.2%) patients. Female patients were more frequently anemic than male patients (68.4% vs. 49.7%, p=0.001). The frequency of anemia was slightly higher in patients with CD (62.1%) than in patients with UC (55.7%) (p=0.04). The incidence rate of anemia for the entire IBD patient cohort was calculated as 103.45 per 1,000 patient-years. The correlation between the age of the IBD disease and the presence of anemia exhibited a high correlation coefficient of Pearson's r=0.702. This is the first study to report the incidence rate of anemia (103.45 per 1,000 patient-years) in a long-term cohort of IBD patients.


Menopause impacts the relation of plasma adiponectin levels with the metabolic syndrome.
Plasma adiponectin is negatively correlated with metabolic syndrome (MetS) components obesity and insulin sensitivity. Here, we set out to evaluate the effect of menopause on the association of plasma adiponectin with MetS. Data on plasma adiponectin and MetS were available from 2256 individuals participating in the Erasmus Rucphen Family study. Odds ratios for MetS were calculated by logistic regression analysis using plasma adiponectin quartiles. The discriminative accuracy of plasma adiponectin for MetS was determined by calculating the area under the curve (AUC) of receiver operator. Analyses were performed in women and men, pre- and postmenopausal women and younger and older men. Virtually all determinants of MetS differed significantly between groups. Low plasma adiponectin showed the highest risk for MetS in postmenopausal women (odds ratio = 18.6, 95% CI = 7.9-44.0). We observed a high discriminative accuracy of age and plasma adiponectin for MetS not only in postmenopausal women (AUC = 0.76) but also in other subgroups (AUC from 0.67 to 0.87). However, in all groups, the discriminative accuracy of age and body mass index (BMI) for MetS was similar to the discriminative accuracy of age and plasma adiponectin. Low plasma levels of adiponectin are associated with increased prevalence of MetS, especially in postmenopausal women. Age and BMI have similar discriminatory accuracies for presence of MetS when compared with age and plasma adiponectin. Thus, we conclude that the association of plasma adiponectin with MetS is significantly affected by menopause but challenge the additional value of adiponectin for the discriminatory accuracy for presence of MetS.


Gambling Harm as a Global Public Health Concern: A Mixed Method Investigation of Trends in Wales.
Background: Recent research evidence has suggested that gambling is a public health concern. A number of studies report the association between gambling activity and increased instances of various other harms, including substance misuse and psychological disorders. In parallel to alcohol misuse, it is also becoming clear that gambling related harm is more of a continuum of harm, as opposed to traditionally accepted categorisations of gambling behavior: safe and responsible or "problem" and harmful. Previous effective treatment models for alcohol misuse have considered a public health approach to develop interventions. As such, the current research seeks to use a public health approach to both investigate the extent of gambling harm across Wales, and to identify upstream predictors of harm to inform future interventions. Method: A triangulation of data collection methods was utilized across Wales, UK. Two hundred and forty-eight participants completed a quantitative survey relating to gambling behavior and related harm, which included the Problem Severity Gambling Index, the Gambling Commission measure of frequency, The Gambling Motives Questionnaire and the Fast Alcohol Screening tool. Ninety-eight of these participants completed a qualitative subsection. Structured interviews were conducted with 20 individuals from 11 service providers. Semi-structured interviews were conducted for the five case studies of individuals who had previously sought help for gambling. The geographical density and distribution of Licensed Gambling Outlets was also mapped in local areas. Results: The findings provide further evidence of a continuum of gambling related harm. Twenty seven percent of survey participants demonstrate some indicators of risk of gambling harm. Social, cultural and environmental contexts play a role in initiation and maintenance of gambling behavior and the subsequent related harm. Accounts from individuals corroborated the quantitative findings. Conclusions: Findings from this Welsh sample are in line with and add support to the growing international research evidence that gambling harms are a universal issue that cross cultures. It is clear that action is needed by legislators at a policy level and that broadening the focus of intervention to a public health level is necessary to develop effective strategies for harm reduction.


Interleukin 5 deficiency abolishes eosinophilia, airways hyperreactivity, and lung damage in a mouse asthma model.
Airways inflammation is thought to play a central role in the pathogenesis of asthma. However, the precise role that individual inflammatory cells and mediators play in the development of airways hyperreactivity and the morphological changes of the lung during allergic pulmonary inflammation is unknown. In this investigation we have used a mouse model of allergic pulmonary inflammation and interleukin (IL) 5-deficient mice to establish the essential role of this cytokine and eosinophils in the initiation of aeroallergen-induced lung damage and the development of airways hyperreactivity. Sensitization and aerosol challenge of mice with ovalbumin results in airways eosinophilia and extensive lung damage analogous to that seen in asthma. Aeroallergen-challenged mice also display airways hyperreactivity to beta-methacholine. In IL-5-deficient mice, the eosinophilia, lung damage, and airways hyperreactivity normally resulting from aeroallergen challenge were abolished. Reconstitution of IL-5 production with recombinant vaccinia viruses engineered to express this factor completely restored aeroallergen-induced eosinophilia and airways dysfunction. These results indicate that IL-5 and eosinophils are central mediators in the pathogenesis of allergic lung disease.


Protective Effects of Bee Pollen on Multiple Propionic Acid-Induced Biochemical Autistic Features in a Rat Model.
Autism spectrum disorders (ASDs) are neurodevelopmental disorders that clinically presented as impaired social interaction, repetitive behaviors, and weakened communication. The use of bee pollen as a supplement rich in amino acids amino acids, vitamins, lipids, and countless bioactive substances may lead to the relief of oxidative stress, neuroinflammation, glutamate excitotoxicity, and impaired neurochemistry as etiological mechanisms autism. Thirty young male Western albino rats were randomly divided as: Group I-control; Group II, in which autism was induced by the oral administration of 250 mg propionic acid/kg body weight/day for three days followed by orally administered saline until the end of experiment and Group III, the bee pollen-treated group, in which the rats were treated with 250 mg/kg body weight of bee pollen for four weeks before autism was induced as described for Group II. Markers related to oxidative stress, apoptosis, inflammation, glutamate excitotoxicity, and neurochemistry were measured in the brain tissue. Our results indicated that while glutathione serotonin, dopamine, gamma-aminobutyric acid (GABA), GABA/Glutamate ratio, and vitamin C were significantly reduced in propionic acid-treated group (p < 0.05), glutamate, IFN-γ, IL-1A, IL-6, caspase-3, and lipid peroxide levels were significantly elevated (p < 0.05). Bee pollen supplementation demonstrates protective potency presented as amelioration of most of the measured variables with significance range between (p < 0.05)−(p < 0.001).


Activation of p38 mitogen-activated protein kinase in spinal microglia contributes to incision-induced mechanical allodynia.
Recent studies have implicated the activation of stress-activated mitogen-activated protein kinase (MAPK) p38 in spinal microglial cells for development of neuropathic and inflammatory pain. The aim of the present study was to investigate whether phosphorylation of p38 (p-p38) also mediates mechanical allodynia and thermal hyperalgesia induced by plantar incision. After rats received a plantar incision surgery, mechanical allodynia and thermal hyperalgesia were determined by von Frey filaments and radiant heat, respectively, and the number of p-p38 immunoreactive cells in the dorsal horn was quantified to determine p38 activation at different time points after incision. The p38 inhibitor FR167653 was administered intrathecally 30 min before hind paw plantar incision to determine the role of p38 in postoperative pain. A significant increase in number of p-p38 immunoreactive cells was observed in the ipsilateral L4-5 spinal dorsal horn from 1 h to 3 days after the incision. p-p38 was found predominantly in microglia. However, microglial activation (assessed by OX-42 upregulation) was not evident until 3 days after plantar incision. Intrathecal pretreatment of FR167653 attenuated incision-induced mechanical allodynia from 1 h to day 2 and significantly reduced activation of p38 in the dorsal horn 1 day after plantar incision. However, FR167653 only inhibited heat hyperalgesia at an early time point. Plantar incision-induced mechanical allodynia can be prevented by the p38 inhibitor. Our results suggest that p38 activation in spinal microglia play a role in incision-induced mechanical allodynia in rats. Therefore, p38 inhibition may be useful in treating postsurgical pain.


Understanding post-operative temperature drop in cardiac surgery: a mathematical model.
A mathematical model is presented to understand heat transfer processes during the cooling and re-warming of patients during cardiac surgery. Our compartmental model is able to account for many of the qualitative features observed in the cooling of various regions of the body including the central core containing the majority of organs, the rectal region containing the intestines and the outer peripheral region of skin and muscle. In particular, we focus on the issue of afterdrop: a drop in core temperature following patient re-warming, which can lead to serious post-operative complications. Model results for a typical cooling and re-warming procedure during surgery are in qualitative agreement with experimental data in producing the afterdrop effect and the observed dynamical variation in temperature between the core, rectal and peripheral regions. The influence of heat transfer processes and the volume of each compartmental region on the afterdrop effect is discussed. We find that excess fat on the peripheral and rectal regions leads to an increase in the afterdrop effect. Our model predicts that, by allowing constant re-warming after the core temperature has been raised, the afterdrop effect will be reduced.


Effect of Protonation upon Electronic Coupling in the Mixed Valence and Mixed Protonated Complex, [Ni(2,3-pyrazinedithiol)2].
We demonstrate that protonation of a mixed valence molecule, generating a mixed valence mixed protonated (MVMP) state, results in a severe reduction in the electronic coupling intimately connected with electron transfer kinetics. This phenomenon is illustrated by synthesizing a mixed valence molecule, [Ni(2,3-pyrazinedithiol)2], that can be asymmetrically protonated, rendering the MVMP state. We characterize the structural, electronic, vibrational, and magnetic properties of this complex in five different states, including the mixed valence and MVMP states, and then analyze the intervalence charge transfer (IVCT) band to demonstrate a five-fold reduction in electronic coupling upon protonation. We conclude that the reduction in electronic coupling is a result of the asymmetry of the electronic orbitals of the redox sites that results from the asymmetric protonation. This conclusion suggests that many systems designed to link electron and proton transfer will also exhibit a decrease in electronic coupling upon protonation as the strength of the interaction between redox and protonation sites is increased.


The impact of stroke on people living in central Uganda: A descriptive study.
Knowledge about perceived impact of stroke on everyday life as well as rehabilitation needs after stroke in Uganda is necessary to identify and develop rehabilitation interventions. To explore and describe clinical characteristics and functioning during the acute or subacute phase and chronic phase, as well as the impact of stroke on everyday life during the chronic phase in stroke survivors in central Uganda. A cross-sectional observational study was conducted on a consecutively included acute or subacute (n = 58) sample and a chronic (n = 62) sample. Face-to-face interviews were conducted to collect demographic information and clinical characteristics. The Scandinavian Stroke Scale (SSS) was used to collect clinical characteristics, assess neurological impairment and define stroke severity. The Barthel Index was used to assess the level of dependence in activities of daily living. In addition, the Stroke Impact Scale (SIS) 3.0 Uganda version was used to assess the impact of stroke in everyday life as perceived by the individuals in the chronic sample receiving rehabilitation. The mean age of the acute/subacute sample was 49 years and 81% had moderate or severe stroke. The mean age of the chronic rehabilitation group was 53 years and 58% had mild stroke. Time since onset in the acute sample was between 2 days and 3 weeks, and time since onset for the chronic sample varied between 3 months and 3 years. Strength, hand function and participation were the most impacted SIS domains in the chronic sample. People with severe and moderate stroke were more likely to be admitted to Mulago Hospital. The mean age in the study sample was lower than that in high-income countries. Further knowledge is needed regarding the impact of stroke to develop guidelines for stroke rehabilitation interventions feasible in the Ugandan healthcare context in both rural and urban areas.


Sertraline in the prevention of depression.
A group of 480 patients, aged 19-78 with an HRSD score of at least 17 and who met DSM-III criteria for major depressive disorder were studied. Patients were given placebo for a one-week single-blind run-in period, after which sertraline was administered for eight weeks. This was followed by 44 weeks in which patients received sertraline or placebo on a double-blind, randomised basis. Patients were assessed periodically using the 17-item HRSD and the Clinical Global Impression scales. During the entire double-blind period 24 (13.0%) sertraline patients relapsed compared with 48 (45.7%) placebo patients (P less than 0.001). The protective effect of sertraline was maintained throughout the 44 weeks. The study provides evidence that sertraline prevents relapse of the index episode of depression as well as recurrence of further episodes and has few side-effects.


Controlled synthesis of HBsAg in a differentiated human liver carcinoma-derived cell line.
A significant aspect of primary hepatic carcinoma in man is the high positive correlation of hepatocellular carcinoma with infection with hepatitis B virus (HBV)1. Analysis of the relationship between HBV infection and oncogenesis is difficult because natural infection with HBV is limited to man and experimental infection has been achieved only in chimpanzees and gibbons. Furthermore, because HBV has not been successfully propagated in cell culture, basic study of virus-cell interaction of the aetiological agent of one of the most widespread infections of man has been impossible. Recently, however, a cell line (PLC/PRF/5) derived from a human hepatoma biopsy was described which produces the HRV surface antigen (HBsAg) and so provides a tool for the experimental investigation of HBV in viro. We now report the derivation and characterisation of two additional cell lines primary liver carcinomas. In contrast to the PLC/PRF/5 cell line, these cell lines retain the capacity to synthesise many human plasma proteins, including both albumin and alpha-fetoprotein (AFP). One of these lines also produces BHsAg. We also present evidence that HBsAg synthesis and secretion in this cell line are correlated with the growth state of the culture. This finding is in contrast to the continuous HBsAg production found in the PLC/PRF/5 cell line.


The carboxyl-terminal extension of yeast tRNA m5C methyltransferase enhances the catalytic efficiency of the amino-terminal domain.
The human tRNA m(5)C methyltransferase is a potential target for anticancer drugs because it is a novel downstream target of the proto-oncogene myc, mediating Myc-induced cell proliferation. Sequence comparisons of RNA m(5)C methyltransferases indicate that the eukaryotic enzymes possess, in addition to a conserved catalytic domain, a large characteristic carboxyl-terminal extension. To gain insight into the function of this additional domain, the modular architecture of the yeast tRNA m(5)C methyltransferase orthologue, Trm4p, was studied. The yeast enzyme catalyzes the transfer of a methyl group from S-adenosyl-L-methionine to carbon 5 of cytosine at different positions depending on the tRNAs. By limited proteolysis, Trm4p was shown to be composed of two domains that have been separately produced and purified. Here we demonstrate that the aminoterminal domain, encompassing the active site, binds tRNA with similar affinity as the whole enzyme but shows low catalytic efficiency. The carboxyl-terminal domain displays only weak affinity for tRNA. It is not required for m(5)C formation and does not appear to contribute to substrate specificity. However, it enhances considerably the catalytic efficiency of the amino-terminal domain.


Light asymmetry explains the effect of nutrient enrichment on grassland diversity.
One of the most ubiquitous patterns in plant ecology is species loss following nutrient enrichment. A common explanation for this universal pattern is an increase in the size asymmetry of light partitioning (the degree to which large plants receive more light per unit biomass than smaller plants), which accelerates the rates of competitive exclusions. This 'light asymmetry hypothesis' has been confirmed by mathematical models, but has never been tested in natural communities due to the lack of appropriate methodology for measuring the size asymmetry of light partitioning in natural communities. Here, we use a novel approach for quantifying the asymmetry of light competition which is based on measurements of the vertical distribution of light below the canopy. Using our approach, we demonstrate that an increase in light asymmetry is the main mechanism behind the negative effect of nutrient enrichment on species richness. Our results provide a possible explanation for one of the main sources of contemporary species loss in terrestrial plant communities.


Functional cooperation of Dam1, Ipl1, and the inner centromere protein (INCENP)-related protein Sli15 during chromosome segregation.
We have shown previously that Ipl1 and Sli15 are required for chromosome segregation in Saccharomyces cerevisiae. Sli15 associates directly with the Ipl1 protein kinase and these two proteins colocalize to the mitotic spindle. We show here that Sli15 stimulates the in vitro, and likely in vivo, kinase activity of Ipl1, and Sli15 facilitates the association of Ipl1 with the mitotic spindle. The Ipl1-binding and -stimulating activities of Sli15 both reside within a region containing homology to the metazoan inner centromere protein (INCENP). Ipl1 and Sli15 also bind to Dam1, a microtubule-binding protein required for mitotic spindle integrity and kinetochore function. Sli15 and Dam1 are most likely physiological targets of Ipl1 since Ipl1 can phosphorylate both proteins efficiently in vitro, and the in vivo phosphorylation of both proteins is reduced in ipl1 mutants. Some dam1 mutations exacerbate the phenotype of ipl1 and sli15 mutants, thus providing evidence that Dam1 interactions with Ipl1-Sli15 are functionally important in vivo. Similar to Dam1, Ipl1 and Sli15 each bind to microtubules directly in vitro, and they are associated with yeast centromeric DNA in vivo. Given their dual association with microtubules and kinetochores, Ipl1, Sli15, and Dam1 may play crucial roles in regulating chromosome-spindle interactions or in the movement of kinetochores along microtubules.


Brain Pathology in Mucopolysaccharidoses (MPS) Patients with Neurological Forms.
Mucopolysaccharidoses (MPS) are the group of lysosomal storage disorders caused by deficiencies of enzymes involved in the stepwise degradation of glycosaminoglycans. To identify brain pathology common for neurological MPS, we conducted a comprehensive analysis of brain cortex tissues from post-mortem autopsy materials of eight patients affected with MPS I, II, IIIA, IIIC, and IIID, and age-matched controls. Frozen brain tissues were analyzed for the abundance of glycosaminoglycans (heparan, dermatan, and keratan sulfates) by LC-MS/MS, glycosphingolipids by normal phase HPLC, and presence of inflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor superfamily member 10 (TNFSF10) by Western blotting. Fixed tissues were stained for the markers for microgliosis, astrogliosis, misfolded proteins, impaired autophagy, and GM2ganglioside. Our results demonstrate that increase of heparan sulfate, decrease of keratan sulfate, and storage of simple  monosialogangliosides 2 and 3 (GM2 and GM3) as well as the neutralglycosphingolipid, LacCer, together with neuroinflammation and neuronal accumulation of misfolded proteins are the hallmarks of brain pathology in MPS patients. These biomarkers aresimilar to those reported in the corresponding mouse models, suggesting that the pathological mechanism is common for all neurological MPS in humans and mice.


The depressive symptoms of bulimia nervosa.
Standardised measures of mental state were used to compare patients with bulimia nervosa with those with major depressive disorder. The two groups were found to be similar in terms of severity of psychiatric disturbance, as measured by the Montgomery & Asberg Scale and the Present State Examination. Noteworthy symptomatic differences were a greater frequency of obsessional ruminations and anxiety amongst the first group, and a greater frequency of depressed mood, apparent sadness, and suicidal ideation amongst the second. Discriminant function analyses revealed that the two patient groups had a different pattern of symptoms. Examination of the character of the psychiatric symptoms of patients with bulimia nervosa suggests that the anxiety and depressive symptoms are likely to be secondary to the eating disorder itself, rather than of primary significance.


Importance of toxicokinetics for interspecies variation in sensitivity to chemicals.
Interspecies variation in sensitivity to synthetic chemicals can be orders of magnitude large. Species traits causing the variation can be related to toxicokinetics (uptake, distribution, biotransformation, elimination) or toxicodynamics (interaction with biological target sites). We present an approach to systematically measure and model the contribution of uptake, biotransformation, internal distribution, and elimination kinetics toward species sensitivity differences. The aim is to express sensitivity as target tissue specific, internal lethal concentrations. A case study with the pesticides diazinon, imidacloprid, and propiconazole and the aquatic invertebrates Gammarus pulex, Gammarus fossarum, and Lymnaea stagnalis illustrates the approach. L. stagnalis accumulates more pesticides than Gammaridae when measured in whole organisms but less in target tissues such as the nervous system. Toxicokinetics, i.e. biotransformation and distribution, explain the higher tolerance of L. stagnalis to the insecticide diazinon when compared to Gammaridae. L. stagnalis was again more tolerant to the other neurotoxicant imidacloprid; however, the difference in sensitivity could not be explained by toxicokinetics alone, indicating the importance of toxicodynamic differences. Sensitivity to propiconazole was comparable among all species and, when expressed as internal lethal concentrations, falls in the range of baseline toxicity.


Novel roles of nuclear angiotensin receptors and signaling mechanisms.
The renin-angiotensin system (RAS) constitutes an important hormonal system in the physiological regulation of blood pressure. The dysregulation of the RAS is considered a major influence in the development and progression of cardiovascular disease and other pathologies. Indeed, experimental and clinical evidence indicates that blockade of this system with angiotensin-converting enzyme (ACE) inhibitors or angiotensin type 1 receptor (AT1R) antagonists is an effective therapy to attenuate hypertension and diabetic renal injury, and to improve heart failure. Originally defined as a circulating system, multiple tissues express a complete RAS, and compelling evidence now favors an intracellular system involved in cell signaling and function. Within the kidney, intracellular expression of the three predominant ANG receptor subtypes is evident in the nuclear compartment. The ANG type 1 receptor (AT1R) is coupled to the generation of reactive oxygen species (ROS) through the activation of phosphoinositol-3 kinase (PI3K) and PKC. In contrast, both ANG type 2 (AT2R) and ANG-(1-7) (AT7R) receptors stimulate nitric oxide (NO) formation, which may involve nuclear endothelial NO synthase (eNOS). Moreover, blockade of either ACE2-the enzyme that converts ANG II to ANG-(1-7)-or the AT7 receptor exacerbates the ANG II-ROS response on renal nuclei. Finally, in a model of fetal programmed hypertension, the nuclear ROS response to ANG II is enhanced, while both AT2 and AT7 stimulation of NO is attenuated, suggesting that an imbalance in the intracellular RAS may contribute to the development of programming events. We conclude that a functional intracellular or nuclear RAS may have important implications in the therapeutic approaches to cardiovascular disease.


Hemolysis-free blood plasma separation.
Hemolysis, involving the rupture of red blood cells (RBCs) and release of their contents into blood plasma, is a major issue of concern in clinical fields. Hemolysis in vitro can occur as a result of errors in clinical trials; in vivo, hemolysis can be caused by a variety of medical conditions. Blood plasma separation is often the first step in blood-based clinical diagnostic procedures. However, inhibitors released from RBCs due to hemolysis during plasma separation can lead to problems in diagnostic tests such as low sensitivity, selectivity and inaccurate results. In particular, a general lack of simple and reliable blood plasma separation methods has been a major obstacle for microfluidic-based point-of-care (POC) diagnostic devices. Here we present a hemolysis-free microfluidic blood plasma separation platform. A membrane filter was positioned on top of a vertical up-flow channel (filter-in-top configuration) to reduce clogging of RBCs by gravity-assisted cells sedimentation. With this device, separated plasma volume was increased approximately 4-fold (2.4 μL plasma after 20 min with 38% hematocrit human whole blood), and hemoglobin concentration in separated plasma was decreased approximately 90% due to the prevention of RBCs hemolysis, when compared to conventional filter-in-bottom configuration blood plasma separation platforms. On-chip plasma contained ~90% of protein and ~100% of nucleic acids found in off-chip centrifuged plasma, confirming comparable target molecule recovery efficiency. This simple and robust on-chip blood plasma separation device integrates with downstream detection modules to ultimately create sample-to-answer microfluidic POC diagnostics devices.


Escherichia coli O157:H7 induces stronger plant immunity than Salmonella enterica Typhimurium SL1344.
Consumption of fresh produce contaminated with bacterial human pathogens has resulted in various, sometimes deadly, disease outbreaks. In this study, we assessed plant defense responses induced by the fully pathogenic bacteria Escherichia coli O157:H7 and Salmonella enterica serovar Typhimurium SL1344 in both Arabidopsis thaliana and lettuce (Lactuca sativa). Unlike SL1344, O157:H7 induced strong plant immunity at both pre-invasion and post-invasion steps of infection. For instance, O157:H7 triggered stomatal closure even under high relative humidity, an environmental condition that generally weakens plant defenses against bacteria in the field and laboratory conditions. SL1344 instead induced a transient stomatal immunity. We also observed that PR1 gene expression was significantly higher in Arabidopsis leaves infected with O157:H7 compared with SL1344. These results suggest that plants may recognize and respond to some human pathogens more effectively than others. Furthermore, stomatal immunity can diminish the penetration of human pathogens through the leaf epidermis, resulting in low bacterial titers in the plant apoplast and suggesting that additional control measures can be employed to prevent food contamination. The understanding of how plant responses can diminish bacterial contamination is paramount in preventing outbreaks and improving the safety of food supplies.


Survey of premenstrual symptom severity and impairment in Korean adolescents: premenstrual dysphoric disorder, subthreshold premenstrual dysphoric disorder and premenstrual syndrome.
The aims of the study were to examine the prevalence of premenstrual dysphoric disorder (PMDD), subthreshold PMDD and premenstrual syndrome (PMS) among adolescents, and to assess the nature of symptoms and the impact on daily life functions, especially for PMDD and subthreshold PMDD. A cross-sectional survey was conducted among adolescents from an urban area. Participants included 984 girls divided into the following four groups, using a premenstrual symptoms screening tool: PMDD, subthreshold PMDD, moderate/severe PMS and no/mild PMS. An Adolescent Mental Problem Questionnaire, Center for Epidemiological Studies-Depression Scale, revised Children's Manifest Anxiety Scale, and a menstrual information questionnaire were also used. Sixty-three (6.76%) of the subjects met the criteria for PMDD and 58 (6.2%) were subthreshold PMDD. The subthreshold PMDD group included 79.3% who met the symptom criteria for PMDD, but their impairment was moderate, and 21.7% who were falling short by the number of symptoms for PMDD diagnosis, though reporting severe impairment. The symptom intensity and frequency of the subthreshold PMDD subjects were similar to those in subjects with PMDD. In these two groups, 69% had moderate to severe physical symptoms. Psychiatric problems, including depression and anxiety, were higher in the PMDD and subthreshold PMDD groups than in the moderate/severe PMS and no/mild PMS group. In total, 20% of adolescents reported suffering from distressing premenstrual symptoms, and girls with PMDD and subthreshold PMDD were very similar in their symptom severity and characteristics. Prospective daily charting is needed to confirm the accurate diagnosis and management of PMDD.


Hospitalizations for pediatric intoxication: a study from Istanbul.
The objective of this study was to describe the epidemiological features of pediatric patients hospitalized for intoxication. Data were collected from the medical records of children < or =14 years of age, admitted for intoxication in 2005-2007. Of the 2989 admissions, 330 (11%) were intoxication cases; 238 (72.1%) were <5 years old. Pharmaceutic agents were identified in 76.1%. Psychotropics were the most frequently ingested drugs (33.9%), and tricyclic antidepressants were the most common (27.1%). Non-pharmaceutic agents were identified in 79 (23.9%) patients, 54.4% of which were pesticides. The majority of all cases were accidental poisonings (90%), which occurred mostly in children <5 years old (71.5%), mainly by pharmaceutics, followed by self-inflicted intoxications (8.2%), which demonstrated the highest ratio in children >10 years old (6.7%). Intoxications are important especially among children <5 years old. Preventive measures such as implementation of the use of child-proof drug prescription bottles and efforts towards public education may reduce the risks.


Diepoxide-triggered conformational transition of silk fibroin: formation of hydrogels.
Silk fibroin hydrogels with tunable properties could be obtained from aqueous fibroin solutions (4.2 w/v %) in a short period of time. This was achieved by the addition of ethylene glycol diglycidyl ether (EGDE) into the reaction solution. Introduction of EGDE cross-links between the fibroin molecules decreases the mobility of the chains, which triggers the conformational transition from random-coil to β-sheet structure and hence fibroin gelation. Dynamic rheological measurements conducted at 50 °C show the formation of strong to weak hydrogels depending on the pH of the reaction solution. Although EGDE attacks the amino groups of fibroin and forms interstrand cross-links, β-sheets acting as physical cross-links dominate the elasticity of the hydrogels. Mechanical response of low-modulus fibroin hydrogels formed above pH 9.7 is highly nonlinear with strong strain hardening behavior (700%) arising from the alignment of the crystallizable amino acid segments.


Self-assembly and structure of directly imaged inorganic-anion monolayers on a gold nanoparticle.
Cryogenic "trapping" was used to obtain the first TEM images of self-assembled monolayers of inorganic anions on a gold nanoparticle. This unique structural information makes it possible to study the formation of a protecting-ligand shell at an unprecedented level of detail. The protecting ligands are polyoxometalates (POMs; alpha-X(n+)W(12)O(40)((8-n)-), X(n+) = Al(3+) and "2H(+)", and alpha-X(n+)W(11)O(39)((12-n)-), X(n+) = P(5+), Si(4+), and Al(3+)) with large negative charges for association with the gold surface and W atoms (Z = 74) for TEM imaging. The POM-anion shells were obtained by ligand exchange from citrate-protected 13.8 nm gold nanoparticles. Replacement of the organic (citrate) by inorganic (tungsten-oxide) ligand shells results in substantial changes in the surface plasmon resonance (SPR). By correlating cryo-TEM images with changes in the SPR, degrees of surface coverage were reliably quantified by UV-visible spectroscopy. Then, the kinetics and thermodynamics of ligand-shell formation were investigated by systematically varying POM structure and charge. Rates of POM association with the gold surface ("nucleation") are inhibited by the electric-potential barrier of the citrate-stabilized particles, while binding affinities increase linearly with the charges (from 5- to 9-) of structurally different POM anions, suggesting that no single orientation ("lattice matching") is required for monolayer self-assembly. Time-dependent cryo-TEM images reveal that monolayer growth occurs via "islands", a mechanism that points to cation-mediated attraction between bound POMs. Complete ligand shells comprised of 330 molecules of alpha-AlW(11)O(39)(9-) (1) possess small net charges (29e from zeta-potential measurements) and short Debye lengths (kappa(-1) = 1.0 nm), which indicate that approximately 99% of the 2970 K(+) counter cations lie within ca. 1.5 nm (approximately 3 hydrated K(+) ion diameters) from the outer surface of the POM shell. Energetic analysis of the 1.57 +/- 0.04 nm center-to-center distance between molecules of 1 further indicates that K(+) ions reside in the ca. 4.5 A spaces between the bound ligands. These findings reveal an important structural role for counter cations within POM ligand shells on gold nanoparticles, analogous to that for cations in the monolayer walls of hollow POM-macroanion vesicles.


Facilitators, barriers, and components of a culturally tailored afterschool physical activity program in preadolescent African American girls and their mothers.
Traditional physical activity (PA) programs have not been effective in increasing PA in African American girls. Currently, there is limited information regarding the components of PA programs that drive participation in African American girls. The purpose of our investigation was to describe the facilitators, barriers, and components of a culturally tailored afterschool PA program that will potentially inspire the participation of African American mother-daughter dyads. Six focus groups (n=12 mother-daughter dyads; daughters, 7-10 yrs in age) were conducted between March and May 2012. Focus group semi-structured interviews were transcribed, coded, and systematically analyzed using NVivo. Mothers reported a preference for non-traditional (dancing, household chores) types of PA. While daughters preferred to participate in both dance-based and traditional types (walking, riding bikes) of PA. Participants felt that the use of a culturally tailored dance program would be appealing because it highlights the cultural and historical legacy of the African American culture. Mothers wanted programs that would allow them time to spend with their daughters. Top three dance styles that mothers wanted to participate in were African, hip-hop, and Salsa/samba, while daughters reported that they would enjoy participating in hip-hop, African, and jazz. The most common responses given for resources needed for participating in a culturally tailored afterschool dance program were the location of the program, transportation, and childcare for siblings. Our investigation highlights some cultural factors related to facilitators and barriers of PA that should be addressed in designing PA studies for African American girls and their mothers.


UV-inducible DNA repair in the cyanobacteria Anabaena spp.
Strains of the filamentous cyanobacteria Anabaena spp. were capable of very efficient photoreactivation of UV irradiation-induced damage to DNA. Cells were resistant to several hundred joules of UV irradiation per square meter under conditions that allowed photoreactivation, and they also photoreactivated UV-damaged cyanophage efficiently. Reactivation of UV-irradiated cyanophage (Weigle reactivation) also occurred; UV irradiation of host cells greatly enhanced the plaque-forming ability of irradiated phage under nonphotoreactivating conditions. Postirradiation incubation of the host cells under conditions that allowed photoreactivation abolished the ability of the cells to perform Weigle reactivation of cyanophage N-1. Mitomycin C also induced Weigle reactivation of cyanophage N-1, but nalidixic acid did not. The inducible repair system (defined as the ability to perform Weigle reactivation of cyanophages) was relatively slow and inefficient compared with photoreactivation.


Tracheostomy does not improve the outcome of patients requiring prolonged mechanical ventilation: a propensity analysis.
To examine the association between the performance of a tracheostomy and intensive care unit and postintensive care unit mortality, controlling for treatment selection bias and confounding variables. Prospective, observational, cohort study. Twelve French medical or surgical intensive care units. Unselected patients requiring mechanical ventilation for > or =48 hrs enrolled between 1997 and 2004. None. Two models of propensity scores for tracheostomy were built using multivariate logistic regression. After matching on these propensity scores, the association of tracheostomy with outcomes was assessed using multivariate conditional logistic regression. Results obtained with the two models were compared. Of the 2,186 patients included, 177 (8.1%) received a tracheostomy. Both models led to similar results. Tracheostomy did not improve intensive care unit survival (model 1: odds ratio, 0.94; 95% confidence interval, 0.63-1.39; p = .74; model 2: odds ratio, 1.12; 95% confidence interval, 0.75-1.67; p = .59). There was no difference whether tracheostomy was performed early (within 7 days of ventilation) or late (after 7 days of ventilation). In patients discharged free from mechanical ventilation, tracheostomy was associated with increased postintensive care unit mortality when the tracheostomy tube was left in place (model 1: odds ratio, 3.73; 95% confidence interval, 1.41-9.83; p = .008; model 2: odds ratio, 4.63; 95% confidence interval, 1.68-12.72, p = .003). Tracheostomy does not seem to reduce intensive care unit mortality when performed in unselected patients but may represent a burden after intensive care unit discharge.


Effectiveness of training health professionals to provide smoking cessation interventions: systematic review of randomised controlled trials.
To assess the effectiveness of interventions that train healthcare professionals in methods for improving the quality of care delivered to patients who smoke. Systematic literature review. Primary care medical and dental practices in the United States and Canada. Patients were recruited opportunistically. 878 healthcare professionals and 11,228 patients who smoked and were identified in eight randomised controlled trials. In each of these trials healthcare professionals received formal training in smoking cessation, and their performance was compared with that of a control group. Point prevalence rates of abstinence from smoking at six or 12 months in patients who were smokers at baseline. Rates of performance of tasks of smoking cessation by healthcare professionals, including offering counselling, setting dates to stop smoking, giving follow up appointments, distributing self help materials, and recommending nicotine gum. Trials were identified by multiple methods. Data were abstracted according to predetermined criteria by two observers. When possible, meta-analysis was performed using a fixed effects model and the results were subjected to sensitivity analysis. Healthcare professionals who had received training were significantly more likely to perform tasks of smoking cessation than untrained controls. There was a modest increase in the odds of stopping smoking for smokers attending health professionals who had received training compared with patients attending control practitioners (odds ratio 1.35 (95% confidence interval 1.09 to 1.68)). This result was not robust to sensitivity analysis. The effects of training were increased if prompts and reminders were used. There was no definite benefit found for more intensive forms of counselling compared with minimal contact strategies. Training health professionals to provide smoking cessation interventions had a measurable impact on professional performance. A modest, but non-robust, effect on patient outcome was also found, suggesting that training alone is unlikely to be an effective strategy for improving quality of care, unless organisational and other factors are also considered.


Association of PD-L1 expression and PD-L1 gene polymorphism with poor prognosis in lung adenocarcinoma and squamous cell carcinoma.
Programmed cell death 1 receptor (PD-1)/programmed death-1 ligand-1 (PD-L1) interaction has been linked to tumor immune evasion. PD-L1 expression has been indicated in identifying non-small cell lung carcinoma (NSCLC) patients for treatment with anti-PD-1 or anti-PD-L1 therapy. The goal of this study was to evaluate the clinicopathologic values of PD-L1 expression and single-nucleotide polymorphisms (SNPs) in the PD-L1 gene in lung adenocarcinoma (ADC) and squamous cell carcinoma (SqCC). The 147 NSCLC tissues consisted of 84 samples of ADC and 63 samples of SqCC. All tissue microarray paraffin blocks were used for PD-L1 immunohistochemical assays with 22C3, SP263, and SP142 clones. Three SNPs in the PD-L1 gene, rs4143815, rs822336, and rs822337, were genotyped using SNP pyrosequencing. The PD-L1 expression was significantly higher in SqCC than in ADC. Among ADCs, PD-L1 expression was significantly higher in papillary and solid types than in lepidic and acinar types. Statistical associations of the PD-L1 expression with a shorter disease-free survival outcome and lymph node metastasis in the ADCs were found but no associations in SqCCs. Among the three SNPs, the rs4143815 genotype CC was statistically associated with positive 22C3 PD-L1 labeling in NSCLCs. The rs4143815 genotype GG instead showed a trend of shorter survival outcomes but did not reach statistical significance in the ADCs. Our results showed a significantly higher prevalence of positive PD-L1 expression in lung SqCC than in ADC. However, the PD-L1 expression and rs4143815 genotype GG might be useful for the prediction of poor prognosis in lung ADC cases.


Using multiple anchor- and distribution-based estimates to evaluate clinically meaningful change on the Functional Assessment of Cancer Therapy-Biologic Response Modifiers (FACT-BRM) instrument.
The interpretation of health-related quality of life (HRQL) data from clinical trials can be enhanced by understanding the degree of change in HRQL scores that is considered meaningful. Our objectives were to combine distribution-based and two anchor-based approaches to identify minimally important differences (MIDs) for the 27-item Trial Outcome Index (TOI), the seven-item Social Well-Being (SWB) subscale, and the six-item Emotional Well-being (EWB) subscale from the Functional Assessment of Cancer Therapy-Biological Response Modifiers (FACT-BRM) instrument. Distribution-based MIDs were based on the standard error of measurement. Anchor-based approaches utilized patient-reported global rating of change (GRC) and change in physician-reported performance status rating (PSR). Correlations and weighted kappa statistics were used to assess association and agreement between the two anchors. FACT-BRM changes were evaluated for three time periods: baseline to month 1, month 2 to month 3, and month 5 to month 6. Association between GRC and change in PSR was poor. Correlation between the anchors and HRQL change scores was largest at month 1 and decreased through month 6. Combining results from all approaches, the MIDs identified were 5-8 points for the TOI, 2 points for the SWB subscale, and 2-3 points for the EWB subscale. We combined patient-reported estimates, physician-reported estimates, and distribution-based estimates to derive MIDs for HRQL outcomes from the FACT-BRM. These results will enable interpretation of treatment group effects in a clinical trial setting, and they can be used to estimate sample size or power when designing future studies.


Sex differences in disease risk from reported genome-wide association study findings.
Men and women differ in susceptibility to many diseases and in responses to treatment. Recent advances in genome-wide association studies (GWAS) provide a wealth of data for associating genetic profiles with disease risk; however, in general, these data have not been systematically probed for sex differences in gene-disease associations. Incorporating sex into the analysis of GWAS results can elucidate new relationships between single nucleotide polymorphisms (SNPs) and human disease. In this study, we performed a sex-differentiated analysis on significant SNPs from GWAS data of the seven common diseases studied by the Wellcome Trust Case Control Consortium. We employed and compared three methods: logistic regression, Woolf's test of heterogeneity, and a novel statistical metric that we developed called permutation method to assess sex effects (PMASE). After correction for false discovery, PMASE finds SNPs that are significantly associated with disease in only one sex. These sexually dimorphic SNP-disease associations occur in Coronary Artery Disease and Crohn's Disease. GWAS analyses that fail to consider sex-specific effects may miss discovering sexual dimorphism in SNP-disease associations that give new insights into differences in disease mechanism between men and women.


The Unrecognized Epidemic of Electronic Cigarette Burns.
Electronic cigarettes (e-cigarettes) are novel battery-operated devices that deliver nicotine as an inhaled aerosol. They originated from China in 2007 and their use has rapidly increased worldwide in the past decade, yet they remain largely unregulated. Reports of injuries associated with their use have appeared as unusual events in the news media and as case reports in the medical literature. This study was undertaken to explore e-cigarettes as a mechanism of burn injury. Referral records to three burn centers from January 2007 to July 2016 were searched to identify patients with injuries caused by e-cigarettes. Data were gathered from the electronic medical records (EMRs) of patients referred within the most recent 18 months. Thirty patients with burns resulting from e-cigarettes were identified. Twenty-nine were referred within the most recent 18 months. Only one was referred in the preceding 8 years. An explosion was identified by the patient as the inciting event in 26 of the 30 injuries (87%). Explosion of an isolated battery while it was carried on personal attire was reported in 10 cases. Explosion of a fully assembled e-cigarette was described in 16 cases. In seven of these 16 cases, the explosion occurred while the device was idle and carried on personal attire. In the other nine cases, the explosion occurred while the device was being operated. No injury occurred while batteries were charging. The mean age of injured patients was 30 years. The mean size of burn was 4% TBSA. The thighs, hands, and genitalia were the most common sites of injury. Twenty-six patients required hospital admission and nine required surgery. Serious burn injuries from e-cigarettes have recently occurred with greatly increased frequency. The increase in injuries appears out of proportion to the increased popularity of e-cigarettes. The most common pattern of injury is explosion when either the idle device or its batteries are carried on personal attire.


How much data is required for a robust and reliable wastewater characterization?
Water resource recovery facility (WRRF) modeling requires robust and reliable characterization of the wastewater to be treated. Poor characterization can lead to unreliable model predictions, which can have significant economic consequences when models are used to make important facility upgrade/expansion and operational decisions. Current wastewater characterization practice often involves a limited number of relatively short-duration intensive campaigns. On-going work at the Great Lakes Water Authority (GLWA) WRRF, serving 3.1 million residents in Southeast Michigan, provided an opportunity to conduct more detailed wastewater characterization over an annual cycle. The collection system includes a significant combined sewer component, and the WRRF provides primary and secondary treatment (high purity oxygen activated sludge) and phosphorus removal via ferric chloride addition. Detailed wastewater fractionation was conducted weekly over a one-year period. Daily conventional secondary influent and process operational data from that same period were used to evaluate the efficiency of various wastewater characterization strategies on the bioreactor mixed liquor volatile suspended solids (MLVSS) concentration calculated using an International Water Association (IWA) Activated Sludge Model Number 1 (ASM1) with minor modifications. An adaptive strategy consisting of a series of short-duration characterization campaigns, used to assess model fit for its intended purpose and continued until a robust and reliable model result, is recommended. Periods of unusual plant influent and/or operational conditions should be identified, and data from these periods potentially excluded from the analysis. Sufficient data should also be collected to identify periods when poor model structure, rather than wastewater characterization, leads to poor fit of the model to actual data.


Synthetic Polymer with a Structure-Driven Hepatic Deposition and Curative Pharmacological Activity in Hepatic Cells.
Synthetic polymers make strong contributions as tools for delivery of biological drugs and chemotherapeutics. The most praised characteristic of polymers in these applications is complete lack of pharmacological function such as to minimize the side effects within the human body. In contrast, synthetic polymers with curative pharmacological activity are truly rare. Moreover, such activity is typically nonspecific rather than structure-defined. In this work, we present the discovery of poly(ethylacrylic acid) (PEAA) as a polymer with a suit of structure-defined, unexpected, pharmacological, and pharmacokinetic properties not observed in close structural analogues. Specifically, PEAA reveals capacity to bind to albumin with ensuing natural hepatic deposition in vivo and exhibits concurrent inhibitory activity against the hepatitis C virus and inflammation in hepatic cells. Our findings provide a view on synthetic polymers as curative, functional agents and present PEAA as a unique biomedical tool with applications related to health of the human liver.


Length of stay and mortality associated with healthcare-associated urinary tract infections: a multi-state model.
The emergence of antimicrobial resistance is of particular concern with respect to urinary tract infections, since the majority of causative agents are Gram-negative bacteria. Healthcare-associated urinary tract infections (HAUTIs) are frequently associated with instrumentation of the urinary tract, specifically with indwelling catheters. To evaluate the current incidence, mortality, and length of hospital stay associated with HAUTIs. A non-concurrent cohort study design was used, conducted between January 1st, 2010 and June 30th, 2014. All patients admitted to one of the eight participating Australian hospitals and who were hospitalized for more than two days were included. The primary outcome measures were the incidence, mortality, and excess length of stay associated with HAUTIs. From 162,503 patient admissions, 1.73% [95% confidence interval (CI): 1.67-1.80] of admitted patients acquired a HAUTI. Using a multi-state model, the expected extra length of stay due to HAUTI was four days (95% CI: 3.1-5.0 days). Using a Cox regression model, infection significantly reduced the rate of discharge (hazard ratio: 0.78; 95% CI: 0.73-0.83). Women were less likely to die (0.71; 0.66-0.75), whereas older patients were more likely to die (1.40; 1.38-1.43). Death was rarer in a tertiary referral hospital compared to other hospitals, after adjusting for age and sex (0.74; 0.69-0.78). This study is the first to explore the burden of HAUTIs in hospitals using appropriate statistical methods in a developed country. Our study indicates that the incidence of HAUTI, in addition to its associated extra length of stay in hospital, presents a burden to the hospital system. With increasing incidence of UTI due to antimicrobial-resistant organisms, surveillance and interventions to reduce the incidence of HAUTI are required.


Pemphigus vulgaris antigen, a desmoglein type of cadherin, is localized within keratinocyte desmosomes.
Pemphigus vulgaris antigen (PVA) is a member of the desmoglein subfamily of cadherin cell adhesion molecules. Because autoantibodies in this disease cause blisters due to loss of epidermal cell adhesion, and because desmoglein is found in the desmosome cell adhesion junction, we wanted to determine if PVA is also found in desmosomes. By immunofluorescence, PV IgG bound, in a dotted pattern, to the cell surface of cultured human keratinocytes induced to differentiate with calcium, suggesting junctional staining. However, by preembedding, immunogold electron microscopic studies only slight labeling could be detected in desmosomes, presumably because of difficulty in gold penetration of intact desmosomes. We therefore treated the keratinocytes with 0.01% trypsin in 1 mM calcium, conditions known to preserve cadherin antigenicity but that caused slight separation of desmosomes, before immunogold staining. In this case there was extensive labeling of the extracellular part of desmosomes but not of the interdesmosomal cell membrane which was stained with anti-beta 2-microglobulin antibodies. To confirm the specificity of this binding we showed that antibodies raised in rabbits against the extracellular portions of PVA also bound desmosomes in these cultures. In intact mouse epidermis we could also show slight, but specific, immunogold desmosomal labeling with PV IgG. Furthermore, neonatal mice injected with PV IgG affinity purified on PVA showed desmosomal separation with the IgG localized to desmosomal cores. These results indicate that PVA is organized and concentrated within the desmosome where it presumably functions to maintain the integrity of stratifying epithelia.


CD59 costimulation of T cell activation. CD58 dependence and requirement for glycosylation.
In addition to the TCR-CD3 complex, T lymphocytes can be activated via another surface glycoprotein, the CD2 molecule. CD58 is the principal ligand for human CD2; CD59 and CD48 are two additional, low affinity ligands that have been defined for CD2. In this study, we have explored the role of CD59 in T cell activation. We have expressed human rCD58 and rCD59 molecules in Chinese hamster oocytes (CHO), and tested paraformaldehyde-treated transfectants for the ability to promote proliferation of and IL-2 secretion from PBMC and human purified T cells. We have shown that CD59 enhanced CD58-dependent T cell proliferation and IL-2 secretion in the presence of suboptimal concentration of PHA or a submitogenic combination of stimulatory anti-CD2 mAbs, presence of suboptimal concentration of PHA or a submitogenic combination of stimulatory anti-CD2 mAbs, T11-2 + T11-3. CD59-dependent costimulation was dependent on several factors including the level of co-expression of CD58, the ratio of CHO cell transfectants to T cells added in culture, the concentration of mitogen, and also donor-dependent differences. As expected, CD59 costimulation of CD58-dependent T cell proliferation was inhibited by Abs directed against CD59, CD58, and CD2. In our hands, the CD59 molecule itself, in the absence of CD58, was unable to support proliferation alone even in the presence of exogenous recombinant IL-1, IL-2, or IL-6. Finally, the ability of CD59 to enhance CD58-dependent T cell responses was shown to be dependent on N-glycosylation of CD59 at amino acid Asn18.


A parallel quadruplex DNA is bound tightly but unfolded slowly by pif1 helicase.
DNA sequences that can form intramolecular quadruplex structures are found in promoters of proto-oncogenes. Many of these sequences readily fold into parallel quadruplexes. Here we characterize the ability of yeast Pif1 to bind and unfold a parallel quadruplex DNA substrate. We found that Pif1 binds more tightly to the parallel quadruplex DNA than single-stranded DNA or tailed duplexes. However, Pif1 unwinding of duplexes occurs at a much faster rate than unfolding of a parallel intramolecular quadruplex. Pif1 readily unfolds a parallel quadruplex DNA substrate in a multiturnover reaction and also generates some product under single cycle conditions. The rate of ATP hydrolysis by Pif1 is reduced when bound to a parallel quadruplex compared with single-stranded DNA. ATP hydrolysis occurs at a faster rate than quadruplex unfolding, indicating that some ATP hydrolysis events are non-productive during unfolding of intramolecular parallel quadruplex DNA. However, product eventually accumulates at a slow rate.


Three-dimensional object recognition by use of digital holography.
We present a technique for performing three-dimensional (3D) pattern recognition by use of in-line digital holography. The complex amplitude distribution generated by a 3D object at an arbitrary plane located in the Fresnel diffraction region is recorded by phase-shifting interferometry. The digital hologram contains information about the 3D object's shape, location, and orientation. This information allows us to perform 3D pattern-recognition techniques with high discrimination and to measure 3D orientation changes. Experimental results are presented.


Quality of care and service as perceived by adults with developmental disabilities, their parents, and primary caregivers.
How adults with developmental disabilities perceive quality of the care and service they receive was investigated and these perceptions compared with those of their parents and primary caregivers. The sample was 34 adults with developmental disabilities, one of their parents, and their primary caregiver, all from a small Swedish municipality. We adapted Quality From the Patient's Perspective by using simple words and fewer response choices. Results showed it was possible to assess how adults with developmental disabilities evaluated actual care and service conditions. Evaluations of the subjective importance ascribed to these conditions proved too difficult. A high degree of similarity was found in ratings of perceived reality of care and service conditions by the adults with developmental disabilities, their parents, and caregivers.


Isotopic evidence for the Cretaceous-Tertiary impactor and its type.
High-precision mass spectrometric analysis of chromium in sediment samples from the Cretaceous-Tertiary (K-T) boundary coincident with the extinction of numerous organisms on Earth confirms the cosmic origin of the K-T phenomenon. The isotopic composition of chromium in K-T boundary samples from Stevns Klint, Denmark, and Caravaca, Spain, is different from that of Earth and indicates its extraterrestrial source. The chromium isotopic signature is consistent with a carbonaceous chondrite-type impactor. The observed differences in the chromium isotopic composition among various meteorite classes can serve as a diagnostic tool for deciphering the nature of impactors that have collided with Earth during its history.


Assessing drug efficacy against Plasmodium falciparum liver stages in vivo.
Malaria eradication necessitates new tools to fight the evolving and complex Plasmodium pathogens. These tools include prophylactic drugs that eliminate Plasmodium liver stages and consequently prevent clinical disease, decrease transmission, and reduce the propensity for resistance development. Currently, the identification of these drugs relies on in vitro P. falciparum liver stage assays or in vivo causal prophylaxis assays using rodent malaria parasites; there is no method to directly test in vivo liver stage activity of candidate antimalarials against the human malaria-causing parasite P. falciparum. Here, we use a liver-chimeric humanized mouse (FRG huHep) to demonstrate in vivo P. falciparum liver stage development and describe the efficacy of clinically used and candidate antimalarials with prophylactic activity. We show that daily administration of atovaquone-proguanil (ATQ-PG; ATQ, 30 mg/kg, and PG, 10 mg/kg) protects 5 of 5 mice from liver stage infection, consistent with the use in humans as a causal prophylactic drug. Single-dose primaquine (60 mg/kg) has similar activity to that observed in humans, demonstrating the activity of this drug (and its active metabolites) in FRG huHep mice. We also show that DSM265, a selective Plasmodial dihydroorotate dehydrogenase inhibitor with causal prophylactic activity in humans, reduces liver stage burden in FRG huHep mice. Finally, we measured liver stage-to-blood stage transition of the parasite, the ultimate readout of prophylactic activity and measurement of infective capacity of parasites in the liver, to show that ATQ-PG reduces blood stage patency to below the limit of quantitation by quantitative PCR (qPCR). The FRG huHep model, thus, provides a platform for preclinical evaluation of drug candidates for liver stage causal prophylactic activity, pharmacokinetic/pharmacodynamics studies, and biological studies to investigate the mechanism of action of liver stage active antimalarials.


The bipedicled medial plantar flap: Vascular enhancement of a reverse flow Y-V medial plantar flap by the inclusion of a metatarsal artery perforator for the reconstruction of a forefoot defect-A case report.
The pedicled medial plantar (MP) flap is an optimal solution for defects involving the weight-bearing areas of the foot. However, venous congestion is a frequently encountered complication, especially with the reverse-flow variants of the flap, and several strategies have been reported in literature both to prevent and to manage it. In this article, we present the use of a medial plantar flap based distally on the lateral plantar artery with the adjunct of an extra metatarsal perforator from the dorsalis pedis artery as a vascular enhancement to avoid the venous congestion and to improve the overall circulation. This bipedicled flap was successfully advanced to cover a 5 × 3 cm soft-tissue defect located at the level of the first and second metatarsal heads of the right foot resulting from the excision of a squamous cell carcinoma in an 80-year-old male patient with a history of cardiovascular disease. The postoperative course was uneventful. The patient was discharged 7 days after the operation and was able to walk after 6 weeks wearing normal shoes. We believe that preserving plantar metatarsal perforators during the harvesting of an MP flap based distally on the lateral plantar artery may be a precious adjunct as it increases blood supply, especially the venous drainage of the flap.


Cellular immune responses to nine Mycobacterium tuberculosis vaccine candidates following intranasal vaccination.
The identification of Mycobacterium tuberculosis vaccines that elicit a protective immune response in the lungs is important for the development of an effective vaccine against tuberculosis. In this study, a comparison of intranasal (i.n.) and subcutaneous (s.c.) vaccination with the BCG vaccine demonstrated that a single moderate dose delivered intranasally induced a stronger and sustained M. tuberculosis-specific T-cell response in lung parenchyma and cervical lymph nodes of BALB/c mice than vaccine delivered subcutaneously. Both BCG and a multicomponent subunit vaccine composed of nine M. tuberculosis recombinant proteins induced strong antigen-specific T-cell responses in various local and peripheral immune compartments. Among the nine recombinant proteins evaluated, the alanine proline rich antigen (Apa, Rv1860) was highly antigenic following i.n. BCG and immunogenic after vaccination with a combination of the nine recombinant antigens. The Apa-induced responses included induction of both type 1 and type 2 cytokines in the lungs as evaluated by ELISPOT and a multiplexed microsphere-based cytokine immunoassay. Of importance, i.n. subunit vaccination with Apa imparted significant protection in the lungs and spleen of mice against M. tuberculosis challenge. Despite observed differences in the frequencies and location of specific cytokine secreting T cells both BCG vaccination routes afforded comparable levels of protection in our study. Overall, our findings support consideration and further evaluation of an intranasally targeted Apa-based vaccine to prevent tuberculosis.


Physical accessibility in primary health care settings: results from California on-site reviews.
People with disabilities report physical barriers in doctors' offices that affect the quality of care. Whether most or few doctors' offices are accessible is not known. We address this gap with data on 2389 primary care provider facilities. The analysis seeks to describe overall primary care office physical accessibility and identify (1) in which areas offices meet access criteria, (2) which accessibility criteria are most often not met, and (3) whether there are urban/non-urban differences. Reviewers rated medical offices using a 55-item instrument that assessed parking, exterior access, building entrance, interior public spaces, doctor's office interior, and the presence of accessible exam equipment. Five health plans that serve California Medicaid patients conducted reviews of providers signed with their plans. Data from the plans were merged, coded, and a descriptive analysis conducted. An accessible weight scale was present in 3.6% and a height adjustable examination table in 8.4% of the sites. Other high prevalence access barriers were in bathrooms and examination rooms. Parking, exterior access, building access, and interior public spaces generally met the access criteria, except for van accessible parking. These findings provide a base for quantitative expectations about accessibility nationwide, and indicate significant barriers exist. They show it is possible to conduct a large number of accessibility site reviews, providing one model to meet the Affordable Care Act requirement for provider accessibility information. Physical access is important as it may affect the quality of care and willingness of patients to engage in preventive care.


Amphiphilic quaternary ammonium chitosan/sodium alginate multilayer coatings kill fungal cells and inhibit fungal biofilm on dental biomaterials.
Formation of fungal biofilms on health care-related materials causes serious clinical consequences. This study reports a novel fungal repelling strategy to control fungal biofilm formation on denture biomaterials through layer-by-layer self-assembly (LBL). Amphiphilic quaternary ammonium chitosans (CS612) were synthesized and used as the antimicrobial positive layer, and sodium alginate (SA) was chosen as the negative layer to construct LBL multilayers on poly (methyl methacrylate) (PMMA)-based denture materials. The presence of LBL multilayers on denture disc was confirmed and characterized by surface zeta potential, water contact angle, AFM, and FT-IR analyses. The multilayer coatings, especially CS612 as the outmost layer, effectively prevented the fungal initial adhesion and biofilm formation. The Candida cells avoided the multilayer coatings and suspended in broth solution instead of forming biofilms, suggesting that the LBL multilayers had fungal repelling effects. The LBL multilayers were biocompatible toward mammalian cells. In stability tests, after immersion in PBS for 4 weeks under constant shaking and repeated brushing with a denture brush for up to 3000 times, the biofilm-controlling effects of the LBL multilayers were not affected, pointing to a novel long-term strategy in controlling fungal biofilms on denture and other related biomaterials.


Catalytic reaction profile for alcohol oxidation by galactose oxidase.
Galactose oxidase is a remarkable enzyme containing a metalloradical redox cofactor capable of oxidizing a variety of primary alcohols during enzyme turnover. Recent studies using 1-O-methyl alpha-D-galactopyranoside have revealed an unusually large kinetic isotope effect (KIE) for oxidation of the alpha-deuterated alcohol (kH/kD = 22), demonstrating that cleavage of the 6,6'-di[2H]hydroxymethylene C-H bond is fully rate-limiting for oxidation of the canonical substrate. This step is believed to involve hydrogen atom transfer to the tyrosyl phenoxyl in a radical redox mechanism for catalysis [Whittaker, M. M., Ballou, D. P., and Whittaker, J. W. (1998) Biochemistry 37, 8426-8436]. In the work presented here, the enzyme's unusually broad substrate specificity has allowed us to extend these investigations to a homologous series of benzyl alcohol derivatives, in which remote (meta or para) substituents are used to systematically perturb the properties of the hydroxyl group undergoing oxidation. Quantitative structure-activity relationship (QSAR) correlations over the steady state rate data reveal a shift in the character of the transition state for substrate oxidation over this series, reflected in a change in the magnitude of the observed KIE for these reactions. The observed KIE values have been shown to obey a log-linear correlation over the substituent parameter, Hammett sigma. For the relatively difficult to oxidize nitro derivative, the KIE is large (kH/kD = 12.3), implying rate-limiting C-H bond cleavage for the oxidation reaction. This contribution becomes less important for more easily oxidized substrates (e.g., methoxy derivatives) where a much smaller KIE is observed (kH/kD = 3.6). Conversely, the solvent deuterium KIE is vanishingly small for 4-nitrobenzyl alcohol, but becomes significant for the 4-methoxy derivative (kH2O/kD2O = 1.2). These experiments have allowed us to develop a reaction profile for substrate oxidation by galactose oxidase, consisting of three components (hydroxylic proton transfer, electron transfer, and hydrogen atom transfer) comprising a single-step proton-coupled electron transfer mechanism. Each component exhibits a distinct substituent and isotope sensitivity, allowing them to be identified kinetically. The proton transfer component is unique in being sensitive to the isotopic character of the solvent (H2O or D2O), while hydrogen atom transfer (C-H bond cleavage) is independent of solvent composition but is sensitive to substrate labeling. In contrast, electron transfer processes will in general be less sensitive to isotopic substitution. Our results support a mechanism in which initial proton abstraction from a coordinated substrate activates the alcohol toward inner sphere electron transfer to the Cu(II) metal center in an unfavorable redox equilibrium, forming an alkoxy radical which undergoes hydrogen atom abstraction by the tyrosine-cysteine phenoxyl free radical ligand to form the product aldehyde.


RNF126 as a Biomarker of a Poor Prognosis in Invasive Breast Cancer and CHEK1 Inhibitor Efficacy in Breast Cancer Cells.
Purpose: (i) To investigate the expression of the E3 ligase, RNF126, in human invasive breast cancer and its links with breast cancer outcomes; and (ii) to test the hypothesis that RNF126 determines the efficacy of inhibitors targeting the cell-cycle checkpoint kinase, CHEK1.Experimental Design: A retrospective analysis by immunohistochemistry (IHC) compared RNF126 staining in 110 invasive breast cancer and 78 paired adjacent normal tissues with clinicopathologic data. Whether RNF126 controls CHEK1 expression was determined by chromatin immunoprecipitation and a CHEK1 promoter driven luciferase reporter. Staining for these two proteins by IHC using tissue microarrays was also conducted. Cell killing/replication stress induced by CHEK1 inhibition was evaluated in cells, with or without RNF126 knockdown, by MTT/colony formation, replication stress biomarker immunostaining and DNA fiber assays.Results: RNF126 protein expression was elevated in breast cancer tissue samples. RNF126 was associated with a poor clinical outcome after multivariate analysis and was an independent predictor. RNF126 promotes CHEK1 transcript expression. Critically, a strong correlation between RNF126 and CHEK1 proteins was identified in breast cancer tissue and cell lines. The inhibition of CHEK1 induced a greater cell killing and a higher level of replication stress in breast cancer cells expressing RNF126 compared to RNF126 depleted cells.Conclusions: RNF126 protein is highly expressed in invasive breast cancer tissue. The high expression of RNF126 is an independent predictor of a poor prognosis in invasive breast cancer and is considered a potential biomarker of a cancer's responsiveness to CHEK1 inhibitors. CHEK1 inhibition targets breast cancer cells expressing higher levels of RNF126 by enhancing replication stress. Clin Cancer Res; 24(7); 1629-43. ©2018 AACR.


Unusual inferior dislocation of shoulder: reduction by two-step maneuver: a case report.
Dislocation of the shoulder is the commonest of all large joint dislocations. Inferior dislocation constitutes 0.5% of all shoulder dislocations. It characteristically presents with overhead abduction of the arm, the humerus being parallel to the spine of scapula. We present an unusual case of recurrent luxatio erecta in which the arm transformed later into an adducted position resembling the more common anterior shoulder dislocation. Such a case has not been described before in English literature. Closed reduction by the two-step maneuver was successful with a single attempt. MRI revealed posterior labral tear and a Hill-Sachs variant lesion on the superolateral aspect of humeral head. Immobilisation in a chest-arm bandage followed by physiotherapy yielded excellent results. The case is first of its kind; the unusual mechanism, unique radiological findings and alternate method of treatment are discussed.


Dissecting self-renewal in stem cells with RNA interference.
We present an integrated approach to identify genetic mechanisms that control self-renewal in mouse embryonic stem cells. We use short hairpin RNA (shRNA) loss-of-function techniques to downregulate a set of gene products whose expression patterns suggest self-renewal regulatory functions. We focus on transcriptional regulators and identify seven genes for which shRNA-mediated depletion negatively affects self-renewal, including four genes with previously unrecognized roles in self-renewal. Perturbations of these gene products are combined with dynamic, global analyses of gene expression. Our studies suggest specific biological roles for these molecules and reveal the complexity of cell fate regulation in embryonic stem cells.


Nexus between financial development & energy intensity: Two sides of a coin?
This study examines the multidimensional impact of financial development (FD) on consumption energy intensity and production energy intensity. A global sample of 81 economies consisting of three subsamples (29 high income [HIEs], 21 upper middle income [UMEs] and 31 low and lower middle income [LMEs]) from 1997 to 2013 is analyzed by employing several estimators and an inclusive estimation strategy for empirical robustness. Our key findings suggest that: First, FD is broadly found to increase production energy intensity except for the negative effects of financial institutions' efficiency. The results also confirm the long-run relationship. The financial depth and financial access appear to reduce consumption energy intensity, while financial efficiency has the opposite effect. Financial institutions have increasing, while financial markets have decreasing impact on consumption energy intensity in the long run. Second, in the face of an oil price shock, countries with higher levels of FD experience a reduce production energy intensity, while the countries with stronger financial institutions experience a reduction in consumption energy intensity, however, opposite is true in the case of financial markets. Third, the FD appears to decrease production energy intensity in HIEs, while it has increasing effect in UMEs and mixed effects in LMEs. Meanwhile, the FD induces higher consumption energy intensity in LMEs, which is same for the impacts of financial markets in UMEs and HIEs. Lastly, financial institutions appear to reduce consumption energy intensity in UMEs and HIEs. Our findings have profound policy implications in the context of the debate on the role of finance in energy efficiency.


Humeral shortening and inferior subluxation as sequelae of septic arthritis of the shoulder in neonates and infants.
Although humeral shortening as a sequel of septic arthritis of the shoulder in infants has been reported in previous studies, functional disorders of the shoulder resulting from humeral shortening have not yet been clarified. In this study, we retrospectively investigated the long-term outcome of septic arthritis of the shoulder in neonates and infants and examined the relationship between growth disturbance of the humerus and decreased range of motion with respect to glenohumeral joint laxity. We reviewed the cases of fifteen patients (sixteen shoulders) with an age of a few days to 2.6 years at the onset of the disease who were followed from 5.0 to 17.9 years. We noted the initial treatment method and evaluated humeral length and shoulder function at the time of the final follow-up. For the final treatment results, we classified the shoulders with normal findings on radiographs as Grade I, those with humeral head deformity as Grade II, and those with humeral head deformity with inferior subluxation as Grade III. Primary treatment included arthrotomy in ten shoulders. The delay between the onset of the disease and surgery ranged from three to twenty-six days. At the time of the final follow-up, the results were Grade I in five shoulders, Grade II in six shoulders, and Grade III in five shoulders. The mean humeral shortening was 0.1 cm for Grade-I shoulders, 0.9 cm for Grade-II shoulders, and 7.3 cm for Grade-III shoulders. All Grade-III shoulders had >or=3 cm of shortening, and four of the five Grade-III shoulders showed limitation of elevation (abduction of <130 degrees ). None of the Grade-III shoulders had undergone arthrotomy within ten days after the onset of the disease. Inferior subluxation of the humeral head related to shoulder dysfunction resulting from early childhood septic arthritis accompanied humeral shortening of >or=3 cm and was only observed in patients who did not undergo arthrotomy of the shoulder within ten days after the onset of the infection.


Chronic diseases now a leading cause of death in rural India--mortality data from the Andhra Pradesh Rural Health Initiative.
India is undergoing rapid epidemiological transition as a consequence of economic and social change. The pattern of mortality is a key indicator of the consequent health effects but up-to-date, precise, and reliable statistics are few, particularly in rural areas. Deaths occurring in 45 villages (population 180 162) were documented during a 12-month period in 2003-04 by multipurpose primary healthcare workers trained in the use of a verbal autopsy tool. Algorithms were used to define causes of death according to a limited list derived from the international classification of disease version 10. Causes were assigned by two independent physicians with disagreements resolved by a third. A total of 1354 deaths were recorded with verbal autopsies completed for 98%. A specific underlying cause of death was assigned for 82% of all verbal autopsies done. The crude death rate was 7.5/1000 (95% confidence interval, 7.1-7.9). Diseases of the circulatory system were the leading causes of mortality (32%), with similar proportions of deaths attributable to ischaemic heart disease and stroke. Second was injury and external causes of mortality (13%) with one-third of these deaths attributable to deliberate self harm. Third were infectious and parasitic diseases (12%). Tuberculosis and intestinal conditions each caused one-third of deaths within this category. HIV was assigned as the cause for 2% of all deaths. The fourth and fifth leading causes of death were neoplasms (7%) and diseases of the respiratory system (5%). Non-communicable and chronic diseases are the leading causes of death in this part of rural India. The observed pattern of death is unlikely to be unique to these villages and provides new insight into the rapid progression of epidemiological transition in rural India.


High glucose induces antioxidant enzymes in human endothelial cells in culture. Evidence linking hyperglycemia and oxidative stress.
It has been suggested that oxidative stress may play an important role in the pathogenesis of diabetic complications. Hyperglycemia may cause increased production of free radicals, and evidence supports a prominent role for these reactive molecules as mediators of endothelial cell dysfunction in diabetes. It has been demonstrated that active oxygen species induce antioxidant enzyme expression in some tissues, and this phenomenon is considered proof of an existing oxygen-dependent toxicity. In this study, human endothelial cells from umbilical vein, immortalized human endothelial cells, and immortalized human endothelial cells transfected to express high glutathione peroxidase levels were grown in normal and high-glucose conditions. High glucose delayed replication after 7 and 14 days of culture of human endothelial cells, both from umbilical vein and immortalized, while transfected cells were not affected. The activity and the mRNA expression of the antioxidant enzymes CuZn-superoxide-dismutase, Mn-superoxide-dismutase, catalase, and glutathione peroxidase were evaluated after 2, 7, and 14 days of culture. High glucose at days 7 and 14 induced an overexpression of CuZn-superoxide-dismutase, catalase, and glutathione peroxidase in both human endothelial cells from umbilical vein and immortalized human endothelial cells, while in transfected cells it did not. This study demonstrates that high glucose induces an increase in antioxidant enzyme levels in human endothelial cells, suggesting that elevated glucose levels may produce an oxidative stress in the cells.


Visual cues can modulate integration and segregation of objects in auditory scene analysis.
The task of assigning concurrent sounds to different auditory objects is known to depend on temporal and spectral cues. When tones of high and low frequencies are presented in alternation, they can be perceived as a single, integrated melody, or as two parallel, segregated melodic lines, according to the presentation rate and frequency distance between the sounds. At an intermediate distance, in the 'ambiguous' range, both percepts are possible. We conducted an electrophysiological experiment to determine whether an ambiguous sound organization could be modulated toward an integrated or segregated percept by the synchronous presentation of visual cues. Two sets of sounds (one high frequency and one low frequency) were interleaved. To promote integration or segregation, visual stimuli were synchronized to either the within-set frequency pattern or to the across-set intensity pattern. Elicitation of the mismatch negativity (MMN) component of event-related brain potentials was used to index the segregated organization, when no task was performed with the sounds. MMN was elicited only when the visual pattern promoted the segregation of the sounds. The results demonstrate cross-modal effects on auditory object perception in that sound ambiguity was resolved by synchronous presentation of visual stimuli, which promoted either an integrated or segregated perception of the sounds.


Designing Mobile Applications for Emergency Response: Citizens Acting as Human Sensors.
When an emergency occurs, citizens can be a helpful support for the operation centers involved in the response activities. As witnesses to a crisis, they initially can share updated and detailed information about what is going on. Moreover, thanks to the current technological evolution people are able to quickly and easily gather rich information and transmit it through different communication channels. Indeed, modern mobile devices embed several sensors such as GPS receivers, Wi-Fi, accelerometers or cameras that can transform users into well-equipped human sensors. For these reasons, emergency organizations and small and medium enterprises have demonstrated a growing interest in developing smart applications for reporting any exceptional circumstances. In this paper, we present a practical study about this kind of applications for identifying both limitations and common features. Based on a study of relevant existent contributions in this area and our personal direct experience in developing and evaluating emergency management solutions, our aim is to propose several findings about how to design effective and efficient mobile emergency notification applications. For this purpose we have exploited the basic sensors of modern mobile devices and the users' aptitude for using them. The evaluation consists of a practical and a theoretical part. In the practical part, we have simulated a traffic accident as closely as possible to a real scenario, with a victim lying on the ground near a car in the middle of a street. For the theoretical part, we have interviewed some emergency experts for collecting their opinions about the utility of the proposed solution. Results from this evaluation phase confirm the positive impact that EN application have for both operators' and citizens' perspective. Moreover, we collected several findings useful for future design challenges in the same area, as shown in the final redesign of the proposed application.


The potential for health risks from intrusion of contaminants into the distribution system from pressure transients.
The potential for public health risks associated with intrusion of contaminants into water supply distribution systems resulting from transient low or negative pressures is assessed. It is shown that transient pressure events occur in distribution systems; that during these negative pressure events pipeline leaks provide a potential portal for entry of groundwater into treated drinking water; and that faecal indicators and culturable human viruses are present in the soil and water exterior to the distribution system. To date, all observed negative pressure events have been related to power outages or other pump shutdowns. Although there are insufficient data to indicate whether pressure transients are a substantial source of risk to water quality in the distribution system, mitigation techniques can be implemented, principally the maintenance of an effective disinfectant residual throughout the distribution system, leak control, redesign of air relief venting, and more rigorous application of existing engineering standards. Use of high-speed pressure data loggers and surge modelling may have some merit, but more research is needed.


Phylogenetic analysis reveals a correlation between the expansion of very virulent infectious bursal disease virus and reassortment of its genome segment B.
Infectious bursal disease virus (IBDV) is a birnavirus causing immunosuppressive disease in chickens. Emergence of the very virulent form of IBDV (vvIBDV) in the late 1980s dramatically changed the epidemiology of the disease. In this study, we investigated the phylogenetic origins of its genome segments and estimated the time of emergence of their most recent common ancestors. Moreover, with recently developed coalescence techniques, we reconstructed the past population dynamics of vvIBDV and timed the onset of its expansion to the late 1980s. Our analysis suggests that genome segment A of vvIBDV emerged at least 20 years before its expansion, which argues against the hypothesis that mutation of genome segment A is the major contributing factor in the emergence and expansion of vvIBDV. Alternatively, the phylogeny of genome segment B suggests a possible reassortment event estimated to have taken place around the mid-1980s, which seems to coincide with its expansion within approximately 5 years. We therefore hypothesize that the reassortment of genome segment B initiated vvIBDV expansion in the late 1980s, possibly by enhancing the virulence of the virus synergistically with its existing genome segment A. This report reveals the possible mechanisms leading to the emergence and expansion of vvIBDV, which would certainly provide insights into the scope of surveillance and prevention efforts regarding the disease.


A re-randomisation design for clinical trials.
Recruitment to clinical trials is often problematic, with many trials failing to recruit to their target sample size. As a result, patient care may be based on suboptimal evidence from underpowered trials or non-randomised studies. For many conditions patients will require treatment on several occasions, for example, to treat symptoms of an underlying chronic condition (such as migraines, where treatment is required each time a new episode occurs), or until they achieve treatment success (such as fertility, where patients undergo treatment on multiple occasions until they become pregnant). We describe a re-randomisation design for these scenarios, which allows each patient to be independently randomised on multiple occasions. We discuss the circumstances in which this design can be used. The re-randomisation design will give asymptotically unbiased estimates of treatment effect and correct type I error rates under the following conditions: (a) patients are only re-randomised after the follow-up period from their previous randomisation is complete; (b) randomisations for the same patient are performed independently; and (c) the treatment effect is constant across all randomisations. Provided the analysis accounts for correlation between observations from the same patient, this design will typically have higher power than a parallel group trial with an equivalent number of observations. If used appropriately, the re-randomisation design can increase the recruitment rate for clinical trials while still providing an unbiased estimate of treatment effect and correct type I error rates. In many situations, it can increase the power compared to a parallel group design with an equivalent number of observations.


Wellness as fairness.
I argue that distinct conditions of justice lead to diverse wellness outcomes through a series of psychosocial processes. Optimal conditions of justice, suboptimal conditions of justice, vulnerable conditions of injustice, and persisting conditions of injustice lead to thriving, coping, confronting, and suffering, respectively. The processes that mediate between optimal conditions of justice and thriving include the promotion of responsive conditions, the prevention of threats, individual pursuit, and avoidance of comparisons. The mechanisms that mediate between suboptimal conditions of justice and coping include resilience, adaptation, compensation, and downward comparisons. Critical experiences, critical consciousness, critical action, and righteous comparisons mediate between vulnerable conditions of injustice and confrontation with the system. Oppression, internalization, helplessness, and upward comparisons mediate between persisting conditions of injustice and suffering. These psychosocial processes operate within and across personal, interpersonal, organizational and community contexts. Different types of justice are hypothesized to influence well-being within each context. Intrapersonal injustice operates at the personal level, whereas distributive, procedural, relational, and developmental justice impact interpersonal well-being. At the organizational level, distributive, procedural, relational and informational justice influence well-being. Finally, at the community level, distributive, procedural, retributive, and cultural justice support community wellness. Data from a variety of sources support the suggested connections between justice and well-being.


The use of radioactive lysine in studies of protein metabolism; synthesis and utilization of plasma proteins.
Racemic lysine labeled with C(14) in the epsilon carbon position was fed to dogs. The distribution of C(14) in blood and tissue fractions is recorded. In normal dogs sacrificed at 24 hours, approximately one-third of the C(14) was found in the urine, one-third in expired air, and one-third in the body, mostly in protein, predomantly as lysine residues. The rate of C(14) excretion as CO(2), hour by hour, paralleled closely the amount of non-protein C(14) in the blood plasma. The liver, kidney, pancreas, and spleen all have high values for C(14) in 24 hour and 17 day experiments. The gastrointestinal tract is significantly high in the 24 hour experiments. Plasma protein from animals previously fed C(14) containing lysine and thus in turn labeled, was transfused into other dogs and the rate of disappearance of albumin and globulin fractions from the circulation of the recipient dog followed. The results lead to the conclusion that as a whole, plasma proteins are utilized and replaced at a rate of at least 10 per cent per 24 hours. This minimum rate is substantially faster than turnover rates commonly accepted and emphasizes the rôle played by the plasma proteins in the protein economy of the body. The exact rate determination is made uncertain by the lack of knowledge of the magnitude of the amount of protein in solution in extracellular and lymph spaces and its rate of equilibrium with circulating plasma proteins. Evidence from these transfusion studies indicates that plasma globulin is metabolized at a significantly faster rate than plasma albumin. This is confirmed by the observation that following the feeding of labeled lysine to dogs, C(14) is first incorporated in globulin in high concentration but that later it also disappears more rapidly from the globulin fraction. These data suggest that the period of bone marrow maturation of the red cell during which time its related hemoglobin is synthesized does not exceed 3 to 5 days.


Medicaid reimbursement of teaching hospitals.
This paper examines current Medicaid policies on the reimbursement of hospitals' medical education expenses. These policies are of interest because of the pressure on Medicaid programs to reduce expenditures. Data for the paper come mainly from two sources: a survey of Medicaid programs and a survey of teaching hospitals. Teaching hospitals receive a disproportionate share, nearly 70 percent in 1978, of Medicaid short-term hospital payments. Nevertheless, most Medicaid programs either have no explicit policies in this area or have not acted aggressively to limit reimbursement of hospitals' teaching expenses. Revenues from Medicaid are most important to public teaching hospitals. Thus, across-the-board reductions in Medicaid's reimbursement of teaching expenses would most severely affect public institutions, many of which already face cuts in their local government appropriations. Savings to Medicaid would also be short-lived, since teaching hospitals would have the incentive to reduce teaching program size and substitute reimbursable personnel (nurses and staff physicians) for residents.