Respiratory infections precede adult-onset asthma.
Respiratory infections in early life are associated with an increased risk of developing asthma but there is little evidence on the role of infections for onset of asthma in adults. The objective of this study was to assess the relation of the occurrence of respiratory infections in the past 12 months to adult-onset asthma in a population-based incident case-control study of adults 21-63 years of age. We recruited all new clinically diagnosed cases of asthma (n = 521) during a 2.5-year study period and randomly selected controls (n = 932) in a geographically defined area in South Finland. Information on respiratory infections was collected by a self-administered questionnaire. The diagnosis of asthma was based on symptoms and reversible airflow obstruction in lung function measurements. The risk of asthma onset was strongly increased in subjects who had experienced in the preceding 12 months lower respiratory tract infections (including acute bronchitis and pneumonia) with an adjusted odds ratio (OR) 7.18 (95% confidence interval [CI] 5.16-9.99), or upper respiratory tract infections (including common cold, sinusitis, tonsillitis, and otitis media) with an adjusted OR 2.26 (95% CI 1.72-2.97). Individuals with personal atopy and/or parental atopy were more susceptible to the effects of respiratory infections on asthma onset than non-atopic persons. This study provides new evidence that recently experienced respiratory infections are a strong determinant for adult-onset asthma. Reducing such infections might prevent onset of asthma in adulthood, especially in individuals with atopy or hereditary propensity to it.


Outpatient percutaneous renal biopsy in adult patients.
To study the safety and efficacy of performing percutaneous renal biopsy in the outpatient department compared to the traditional inpatient policy, we studied 44 consecutive patients with proteinuria and other urinary sediment abnormalities, at King Fahd Hospital of the University, Al-Khobar, Saudi Arabia, during the period from September 2004 to August 2006. The patients were divided into two groups: group I, in whom kidney biopsy was performed and followed by 1-day hospital admission; and group II, in whom renal biopsy was performed in the outpatient department and followed by 6 hours' observation period and then by regular outpatient visits. All biopsies were performed with the use of real-time ultrasound and automated biopsy needle. Patients with a history of a bleeding diathesis or abnormal coagulation profile and those receiving warfarin, heparin, aspirin, or nonsteroidal anti-inflammatory drugs were excluded from the study. Only minor biopsy-related complications such as gross hematuria, perinephric hematoma that resolved without the need for blood transfusion or surgical intervention occurred in three (13.6%) patients in group I and in two (9.1%) patients in group II. The complications were apparent within 6 hours in all but one patient (97.7%). Overall, hematuria was identified in 52% of patients at < or = 2 hours, 85% at < or = 4 hours, and 97.7% at < or =6 hours. The 24-hour hematocrit levels were not significantly different between the study groups. One (4.5%) patient from group II had a small perinephric hematoma, which was detected by ultrasound examination at 24 hours but not at 6 hours post biopsy period.; it resolved spontaneously without intervention. We conclude that in selected patients, same-day discharge after 6 hours of renal biopsy may be given safely without increased risk of complications.


3-Aryl-2-(3'-substituted-1',2',4'-oxadiazol-5'-yl)tropane analogues of cocaine: affinities at the cocaine binding site at the dopamine, serotonin, and norepinephrine transporters.
Previous studies have shown that 3 beta-(substituted phenyl)tropan-2 beta-carboxylic acid esters possess high affinity for the cocaine binding site on the dopamine transporter both in vitro and in vivo and inhibit dopamine uptake in vitro. Since 1,2,4-oxadiazoles are excellent bioisosteres of ester groups, we have prepared several 3 beta-(substituted phenyl)-2 beta-(3-substituted 1',2',4'-oxadiazol-5'-yl)tropanes (5b-h) and all four stereoisomers of (1R,5S)-3 phenyl-2-(3-methyl-1',2',4'-oxadiazol-5'-yl)tropane (5a and 6-8). The 3 alpha-phenyl-2-alpha-(3'-methyl-1',2',4'-oxadiazole) isomer 7 was prepared from a stereoselective addition of phenyllithium to (1R,5S)-2-(3'-methyl-1',2',4'-oxadiazol-5-yl)-8-methyl-8- azabicyclo[3.2.1]oct-2-ene (11). The binding affinities for 5a-h and 6-8 at the dopamine, serotonin, and norepinephrine transporters were obtained. In general these bioisosteres showed potencies for the dopamine transporter similar to those of their parent esters. 3 beta-(4'-Chlorophenyl)-2 beta-(3'-phenyl-1',2',4'-oxadiazol-5'-yl)tropane (5d) was the most potent analogue with an IC50 of 1.62nM. However, 3 beta-(4'-chlorophenyl)-2 beta-(3'-methoxyphenyl-1',2'4'- oxadiazol-5'-yl)tropane (5e) with an IC50 of 1.81 nM was the most selective analogue for the dopamine transporter showing NE/DA and 5-HT/DA ratios of 461 and 186, respectively. The cis- and trans-3 alpha-phenyl-2-(3'-methyl-1',2',4'-oxadiazol-5'-yl)tropanes (7 and 8), which exist in a boat conformation, have IC50 values only slightly greater than that of the 3 beta,2 beta-isomer (5a) which possesses the cocaine stereochemistry.


Unravelling the pathophysiology of complex regional pain syndrome: focus on sympathetically maintained pain.
1. In diseases such as complex regional pain syndrome (CRPS), where neuropathic pain is the primary concern, traditional pain classifications and lesion descriptors are of limited value. To obtain better treatment outcomes for patients, the underlying pathophysiological mechanisms of neuropathic pain need to be elucidated and analysed so that therapeutic targets can be identified and specific treatments developed. 2. In the present review, we examine the current literature on sympathetically maintained pain (SMP), a subset of neuropathic pain, within the context of CRPS. Evidence from both human and animal studies is presented and discussed in terms of its support for the existence of SMP and the mechanistic information it provides. 3. We discuss three current hypotheses that propose both a site and method for sympathetic-sensory coupling: (i) direct coupling between sympathetic and sensory neurons in the dorsal root ganglion; (ii) chemical coupling between sympathetic and nociceptive neuron terminals in skin; and (iii) the development of a-adrenoceptor-mediated supersensitivity in nociceptive fibres in skin in association with the release of inflammatory mediators. 4. Finally, we propose a new hypothesis that integrates the mechanisms of chemical coupling and a-adrenoceptor-mediated supersensitivity. This hypothesis is based on previously unpublished data from our laboratory showing that a histological substrate suitable for sympathetic-sensory coupling exists in normal subjects. In the diseased state, the nociceptive fibres implicated in this substrate may be activated by both endogenous and exogenous noradrenaline. The mediating a-adrenoceptors may be expressed on the nociceptive fibres or on closely associated support cells.


T cell activation and anergy to islet cell antigen in type I diabetes.
Early exposure to cow milk proteins was linked to the development of type I diabetes by consistent epidemiology, and by feeding and tolerization studies in diabetes-prone rodents. Dietary BSA was suggested as the culprit because patients and relevant rodents have elevated anti-BSA Abs that precipitate the recently cloned protein, p69, from beta cell lysates. A total of 68 of 78 children with recent onset diabetes had BSA-reactive T cells at the time of diagnosis. Here we 1) map the fine specificity of these T cells, 2) delineate a homologous peptide sequence near the N-terminus of p69, and 3) demonstrate T cell recognition of this p69 sequence (T cell epitope p69, Tep69) by patient T cells. The Tep69 sequence is conserved in p69 of patients and diabetes-prone rodents. Whereas BSA triggers T cell proliferation, recombinant p69 and a synthetic Tep69 peptide induce early stages of T cell activation (IL-2R transcription) but insufficient IL-2 production and thus anergy. Exogenous IL-2 overrides anergy and allows proliferative expansion of p69-responsive T cells. In mixing experiments, p69 and Tep69 peptide prevented proliferative responses to BSA even at 100-fold smaller concentrations. These findings imply that high-affinity self-peptide triggers anergy, whereas low-affinity mimicry Ag triggers proliferative expansion of these T cells. This implies a disease model in which mimicry Ag would rescue autoreactive cells from ablation by self-Ag.


Human molybdopterin synthase gene: genomic structure and mutations in molybdenum cofactor deficiency type B.
Biosynthesis of the molybdenum cofactor (MoCo) can be divided into (1) the formation of a precursor and (2) the latter's subsequent conversion, by molybdopterin synthase, into the organic moiety of MoCo. These two steps are reflected by the complementation groups A and B and the two formally distinguished types of MoCo deficiency that have an identical phenotype. Both types of MoCo deficiency result in a pleiotropic loss of all molybdoenzyme activities and cause severe neurological damage. MOCS1 is defective in patients with group A deficiency and has been shown to encode two enzymes for early synthesis via a bicistronic transcript with two consecutive open reading frames (ORFs). MOCS2 encodes the small and large subunits of molybdopterin synthase via a single transcript with two overlapping reading frames. This gene was mapped to 5q and comprises seven exons. The coding sequence and all splice site-junction sequences were screened for mutations, in MoCo-deficient patients in whom a previous search for MOCS1 mutations had been negative. In seven of the eight patients whom we investigated, we identified MOCS2 mutations that, by their nature, are most likely responsible for the deficiency. Three different frameshift mutations were observed, with one of them found on 7 of 14 identified alleles. Furthermore, a start-codon mutation and a missense mutation of a highly conserved amino acid residue were found. The locations of the mutations confirm the functional role of both ORFs. One of the patients with identified MOCS2 mutations had been classified as type B, in complementation studies. These findings support the hypothetical mechanism, for both forms of MoCo deficiency, that formerly had been established by cell-culture experiments.


Purine analogs inhibit nerve growth factor-promoted neurite outgrowth by sympathetic and sensory neurons.
Past studies have shown that purine analogs block certain, but not all, responses of cultured rat PC12 pheochromocytoma cells to nerve growth factor (NGF). In the present work, newborn rat sympathetic and sensory neurons were exposed to NGF in the presence or absence of the purine analogs 6-thioguanine and 2-aminopurine. These compounds reversibly suppressed NGF-dependent neurite outgrowth by the neurons and did so at concentrations comparable to those effective on PC12 cells. In contrast to their effects on neurites, neither compound significantly blocked NGF-promoted neuronal survival. Similar effects were seen with cultures of chick embryo sympathetic ganglia. These findings show that purine analog effects on NGF responses can be extended to mammalian and avian neurons. Moreover, the differential effects of the analogs on neurite outgrowth and survival indicate that these 2 actions of NGF can be dissected from one another and may represent different mechanistic pathways.


Exploring the directionality in the relationship between descriptive and injunctive parental and peer norms and snacking behavior in a three-year-cross-lagged study.
People's eating behavior is assumed to be influenced by what other people do (perceived descriptive norms) and what others approve of (perceived injunctive norms). It has been suggested that adolescents are more susceptible to peer norms than parental norms, because they experience a strong need for group acceptance that leads to conforming to peer group norms. The current study examined changes in snacking behavior and four types of social norms (i.e., parental and peer descriptive and injunctive norms) that promoted fruit and vegetable intake among adolescents. This study was the first to examine whether snacking behavior also influenced norm perceptions by testing the directionality of these associations. The study consisted of 819 participants (M [SD] age = 11.19 [1.36]; 46.1% boys), collected at three time points (T1 = 2016, T2 = 2017 and T3 = 2018) during the MyMovez project. Self-reported frequency of snack consumption, perceived parental and peer descriptive and injunctive norms were assessed. The primary analysis consisted of a series of cross-lagged autoregressive models specified in a structural equation modeling framework. Model comparisons testing the descriptive and injunctive norms in separate models and in an additional combined model revealed evidence for bi-directional associations between norms and snacking behavior. Descriptive peer and parent norms were not found to have an effect on subsequent snacking behaviors. Perceived injunctive parental norms were positively associated with healthy snack food intake and negatively associated with unhealthy snack intake (forward direction). Injunctive peer norms were negatively associated with healthy snack food intake. In addition, higher unhealthy snack food intake was negatively associated with the perception of descriptive and injunctive parental norms 1 year later (reversed direction). We did not find peer norms to be more closely associated with changes in snacking behaviors compared to parental norms. Parents expecting their children to snack healthy had a positive influence on healthy snacking behavior whereas only acting as a healthy role model did not. Future research should address the possible interaction between descriptive and injunctive norms. Research should also take into account the bi-directional relations between eating behaviors and normative perceptions.


Mitochondrial acclimation potential to ocean acidification and warming of Polar cod (Boreogadus saida) and Atlantic cod (Gadus morhua).
Ocean acidification and warming are happening fast in the Arctic but little is known about the effects of ocean acidification and warming on the physiological performance and survival of Arctic fish. In this study we investigated the metabolic background of performance through analyses of cardiac mitochondrial function in response to control and elevated water temperatures and PCO2 of two gadoid fish species, Polar cod (Boreogadus saida), an endemic Arctic species, and Atlantic cod (Gadus morhua), which is a temperate to cold eurytherm and currently expanding into Arctic waters in the wake of ocean warming. We studied their responses to the above-mentioned drivers and their acclimation potential through analysing the cardiac mitochondrial function in permeabilised cardiac muscle fibres after 4 months of incubation at different temperatures (Polar cod: 0, 3, 6, 8 °C and Atlantic cod: 3, 8, 12, 16 °C), combined with exposure to present (400μatm) and year 2100 (1170μatm) levels of CO2. OXPHOS, proton leak and ATP production efficiency in Polar cod were similar in the groups acclimated at 400μatm and 1170μatm of CO2, while incubation at 8 °C evoked increased proton leak resulting in decreased ATP production efficiency and decreased Complex IV capacity. In contrast, OXPHOS of Atlantic cod increased with temperature without compromising the ATP production efficiency, whereas the combination of high temperature and high PCO2 depressed OXPHOS and ATP production efficiency. Polar cod mitochondrial efficiency decreased at 8 °C while Atlantic cod mitochondria were more resilient to elevated temperature; however, this resilience was constrained by high PCO2. In line with its lower habitat temperature and higher degree of stenothermy, Polar cod has a lower acclimation potential to warming than Atlantic cod.


"It's a Dog's Life": Culture, Empathy, Gender, and Domestic Violence Predict Animal Abuse in Adolescents-Implications for Societal Health.
Whereas the majority of previous research conducted on animal abuse has been in environments where animal abuse is rarely evidenced, the current study investigated the ramifications of animal abuse in an environment wherein the national culture creates an ethos of the "social acceptability" of animal abuse in society. Two survey studies were conducted with adolescent participants, to investigate the role played by several factors in the prediction of animal abuse in this age group. In Study 1, with samples from two different national cultures (101 from Germany and 169 from Romania; 143 boys/135 girls; age 13 to 17), animal abuse was negatively associated with affective empathy and national culture; more frequent animal abuse was found in Romania. Affective empathy fully mediated the association between gender and animal abuse. Specifically, girls were found to be higher in affective empathy; in turn, participants who were higher in affective empathy committed less animal abuse. Witnessing animal abuse was also predictive of engaging in animal abuse, but not independent of national culture. In Study 2, 15-year-old males ( n = 21) and females ( n = 39) took part, 29 from rural and 31 from urban locations in Romania. Rural adolescents were more likely to abuse animals and had higher exposure to domestic violence, which (in turn) was associated with more animal abuse. The implications of these findings in a society where animal abuse is encouraged and enacted on a national scale are discussed.


Hydrolysis of thionopeptides by the aminopeptidase from Aeromonas proteolytica: insight into substrate binding.
A series of L-leucine aniline analogues were synthesized that contained either a carbonyl or thiocarbonyl as a part of the amide bond. Additionally, the para-position on the phenyl ring of several substrates was altered with various electron-withdrawing or donating groups. The kinetic constants K(m) and k(cat) were determined for the hydrolysis of each of these compounds in the presence of the aminopeptidase from Aeromonas proteolytica (AAP) containing either Zn(II) or Cd(II). The dizinc(II) form of AAP ([ZnZn(AAP)]) was able to cleave both carbonyl and thiocarbonyl containing peptide substrates with similar efficiency. However, the dicadmium(II) form of AAP ([CdCd(AAP)]) was unable to cleave any of the carbonyl-containing compounds tested but was able to cleave the thionopeptide substrates. This is consistent with the borderline hard/soft nature of Zn(II) vs Cd(II). The trends observed in the K(m) values suggest that the oxygen atom of the amide bond directly interacts with the dinuclear active site of AAP. Heterodimetallic forms of AAP that contained one atom of Zn(II) and one of Cd(II) (i.e., [CdZn(AAP)] and [ZnCd(AAP)]) were also prepared. The K(m) values for the thionopeptides substrates are the smallest when Cd(II) is in the first metal binding site, suggesting that substrate binds to the first metal binding site. 1-Phenyl-2-thiourea (PTU) and urea (PU) were also examined to determine the differences between thionopeptide and peptide binding to AAP. PTU and PU were found to be competitive inhibitors of AAP with inhibition constants of 0.24 and 4.6 mM, respectively. The electronic absorption and EPR spectra of [CoCo(AAP)], [CoZn(AAP)], and [ZnCo(AAP)] were recorded in the absence and presence of both PU and PTU. Spectral changes were observed for PTU binding to [CoCo(AAP)] and [CoZn(AAP)] but not for [ZnCo(AAP)], while no spectral changes were observed for any of the Co(II)-substituted forms of AAP upon the addition of PU. These data indicate that carbonyl binding occurs only at the first metal binding site. In light of the data presented herein, the substrate binding step in the proposed mechanism of AAP catalyzed peptide hydrolysis can be further refined.


Integrated Cancer Treatment in the Course of Metastatic Pancreatic Cancer: Complete Resolution in 2 Cases.
Pancreatic cancer (PC) has a very low average survival, but its prognosis is further reduced in the case of metastatic spread. Medical therapy in these cases is the only applicable methodology in the international guidelines. During anticancer treatments, common side effects are nausea, vomiting, arthralgia, neuropathy, and alopecia as well as a myelosuppressive effect. The toxicity of various drugs not only affects the quality of life of the patient, but often its severity requires a reduction in if not the termination of drug administration. Scientific studies have shown that a combined use of chemotherapy and certain natural substances, in the form of standardized extracts, can lead to an enhancement of the action of the chemotherapy. Here, we describe 2 cases of metastatic PC. The first case concerns the integrated treatment of a patient with cancer of the pancreas tail with metastatic involvement ab initio of peripancreatic lymph nodes and liver parenchyma, with numerous secondary lesions greater than 9.5 cm. The second case concerns the integrated treatment of a patient with cancer of the pancreatic body with metastatic involvement of the liver parenchyma, with a small secondary lesion. In both cases, an integrated cancer treatment approach, combining chemotherapy with natural remedies, extracts, and hyperthermia, induced a notable remission of primary and metastatic lesions.


A childhood obesity prevention programme in Barcelona (POIBA Project): Study protocol of the intervention.
Childhood obesity preventive interventions should promote a healthy diet and physical activity at home and school. This study aims to describe a school-based childhood obesity preventive programme (POIBA Project) targeting 8-to-12- year-olds. Evaluation study of a school-based intervention with a pre-post quasi-experimental design and a comparison group. Schools from disadvantaged neighbourhoods are oversampled. The intervention consists of 9 sessions, including 58 activities of a total duration between 9 and 13 hours, and the booster intervention of 2 sessions with 8 activities lasting 3 or 4 hours. They are multilevel (individual, family and school) and multicomponent (classroom, physical activity and family). Data are collected through anthropometric measurements, physical fitness tests and lifestyle surveys before and after the intervention and the booster intervention. In the intervention group, families complete two questionnaires about their children's eating habits and physical activity. The outcome variable is the cumulative incidence rate of obesity, obtained from body mass index values and body fat assessed by triceps skinfold thickness. The independent variables are socio-demographic, contextual, eating habits, food frequency, intensity of physical activity and use of new technologies. It is essential to implement preventive interventions at early ages and to follow its effects over time. Interventions involving diet and physical activity are the most common, being the most effective setting the school. The POIBA Project intervenes in both the school and family setting and focuses on the most disadvantaged groups, in which obesity is most pronounced and difficult to prevent.


A mammalian oocyte-specific linker histone gene H1oo: homology with the genes for the oocyte-specific cleavage stage histone (cs-H1) of sea urchin and the B4/H1M histone of the frog.
Oocytes and early embryos of multiple (non-mammalian) species lack the somatic form of the linker histone H1. To the best of our knowledge, a mammalian oocyte-specific linker (H1) histone(s) has not, as yet, been reported. We have uncovered the cDNA in question in the course of a differential screening (suppression subtractive hybridization (SSH)) project. Elucidation of the full-length sequence of this novel 1.2 kb cDNA led to the identification of a 912 bp open reading frame. The latter encoded a novel 34 kDa linker histone protein comprised of 304 amino acids, tentatively named H1oo. Amino acid BLAST analysis revealed that H1oo displayed the highest sequence homology to the oocyte-specific B4 histone of the frog, the respective central globular (putative DNA binding) domains displaying 54% identity. Substantial homology to the cs-H1 protein of the sea urchin oocyte was also apparent. While most oocytic mRNAs corresponding to somatic linker histones are not polyadenylated (and remain untranslated), the mRNAs of (non-mammalian) oocyte-specific linker histones and of mammalian H1oo, are polyadenylated, a process driven by the consensus signal sequence, AAUAAA, detected in the 3'-untranslated region of the H1oo cDNA. Our data suggest that the mouse oocyte-specific linker histone H1oo (1) constitutes a novel mammalian homolog of the oocyte-specific linker histone B4 of the frog and of the cs-H1 linker histone of the sea urchin; (2) is expressed as early as the GV (PI) stage oocyte, persisting into the MII stage oocyte, the oocytic polar bodies, and the two-cell embryo, extinction becoming apparent at the four- to eight-cell embryonic stage; and (3) may play a key role in the control of gene expression during oogenesis and early embryogenesis, presumably through the perturbation of chromatin structure.


Unique Presentations of Burkholderia gladioli Infections in Several Strains of Immunocompromised Mice.
Four strains of experimentally naïve mice (NOD. Cg-Prkdc scid Il2rg tm1Wjl /SzJ [NSG], NOD. Cg- Rag1 tm1Mom Il2rg tm1Wjl /SzJ [NRG], B6.129S(Cg)-Stat1 tm1Dlv/J [STAT1 -/-], and B6.129S7- Ifngr1 tm1Agt/J[IFNγR -/-] housed in a barrier facility developed unusual and seemingly unrelated clinical signs. Young NSG/NRG mice (n = 49, mean age = 4 ± 0.4 mo) exhibited nonspecific clinical signs of moderate-to-severe lethargy, hunched posture, decreased body condition, and pallor. In contrast to the NSG/NRG mice, the STAT1-/- and IFNγ R-/- mice (n = 5) developed large subcutaneous abscesses on the head and neck. These mice were euthanized, and samples were collected for culture. NSG/NRG mice had moderate-markedly enlarged livers (20 of 49, 40%) and spleens (17 of 49, 35%). The livers contained multiple, variably-sized, tan regions throughout all lobes. Histology revealed necrotizing hepatitis (13 of 17, 77%), splenic and hepatic extramedullary hematopoiesis (17 of 17, 100%), glomerular histiocytosis (6 of 17, 35%), and metritis (6 of 11, 55%) with perivascular inflammation, suggesting hematogenous spread Differentials for these lesions included mouse hepatitis virus, ectromelia virus, Pseudomonas aeruginosa, Salmonella spp., and Clostridium piliforme. Burkholderia gladioli was cultured from liver lesions and subcutaneous abscesses and confirmed with 16S ribosomal RNA sequencing. After completing systematic testing of the environment, failure of the water autoclave cycle was suspected as the cause of the outbreak. To address the situation, individually ventilated racks were sanitized and new breeders were purchased; these actions dramatically reduced B. gladioli infections. The current literature contains few reports of B. gladioli infections in immunocompromised mice, and its typical presentation is torticollis and rolling. B. gladioli infection is a potential differential for subcutaneous abscesses, hepatitis, and splenomegaly in immunocompromised mice. Careful monitoring of sterilization techniques is essential to prevent such infections in a barrier facility.


Specific IgE to allergens in cord blood is associated with maternal immunity to Toxoplasma gondii and rubella virus.
Various studies have found reduced prevalences of atopic sensitization and atopic diseases in children previously exposed to infections or living conditions with a high microbial burden, such as the farming environment. We sought to determine the relationships of cord blood immunoglobulin E (IgE) with maternal health conditions before and during pregnancy. Pregnant women living in rural areas in five European countries were recruited in the third trimester of pregnancy. Information on maternal health during pregnancy was collected from maternity records and by questionnaires (n = 497). Specific IgE for inhalant and food allergens was assessed in cord blood and peripheral blood samples of the mothers. Inverse associations of cord blood IgE to seasonal allergens with positive maternal records for Toxoplasma gondii (adjusted odds ratio = 0.37 [0.17-0.81]) and rubella virus (adjusted odds ratio = 0.35 [0.13-0.96]) were found. The previously described effect of prenatal farm exposure on IgE to seasonal allergens was partly confounded by a positive maternal record for T. gondii. The number of maternal siblings, maternal contact to cats during pregnancy or during her first year of life, predicted a positive maternal record for T. gondii. Maternal immunity to T. gondii and rubella may impact on atopic sensitization in the fetus. A positive T. gondii record explained the previously identified effect of prenatal farm exposure on IgE to seasonal allergens only to a minor extent.


Runaway sexual selection leads to good genes.
Mate choice and sexual displays are widespread in nature, but their evolutionary benefits remain controversial. Theory predicts these traits can be favored by runaway sexual selection, in which preference and display reinforce one another due to genetic correlation; or by good genes benefits, in which mate choice is advantageous because extreme displays indicate a well-adapted genotype. However, these hypotheses are not mutually exclusive, and the adaptive benefits underlying mate choice can themselves evolve. In particular, examining how and why sexual displays become indicators of good genes is challenging in natural systems. Here, we use experimental evolution in "digital organisms" to demonstrate the origins of condition-dependent indicator displays following their spread due to a runaway process. Surprisingly, handicap-like costs are not necessary for displays to become indicators of male viability. Instead, a pleiotropic genetic architecture underlies both displays and viability. Runaway sexual selection and good genes benefits should thus be viewed as interacting mechanisms that reinforce one another.


[A numerical analysis of the effects of the lower-limb prosthetic socket on muscle atrophy of the residual limb].
Muscle atrophy of the residual limb after lower-limb amputation is a disadvantage of amputees' rehabilitation. To investigate the biomechanics mechanism of muscle atrophy of the residual limb, we built a finite element model of a residual limb including muscle, skeletons and main vessels based on magnetic resonance images of a trans-femoral amputee, and studied the biomechanics effects of the socket of the lower-limb prosthesis on the soft tissue and vessels in the residual limb. It was found that the descending branch of the lateral femoral circumflex artery suffered the most serious constriction due to the extrusion, while that of the deep femoral artery was comparatively light. Besides, the degree of the constriction of the descending branch of the lateral femoral circumflex vein, femoral vein and deep femoral vein decreased in turn, and that of the great saphenous vein was serious. The stress-strain in the anterior femoral muscle group were highest, while the stress concentration of the inferior muscle group was observed at the end of the thighbone, and other biomechanical indicators at the inferior region were also high. This study validated that the extrusion of the socket on the vessels could cause muscle atrophy to some degree, and provided theoretical references for learning the mechanism of muscle atrophy in residual limb and its effective preventive measures.


Heterospecific eavesdropping in ant-following birds of the Neotropics is a learned behaviour.
Animals eavesdrop on other species to obtain information about their environments. Heterospecific eavesdropping can yield tangible fitness benefits by providing valuable information about food resources and predator presence. The ability to eavesdrop may therefore be under strong selection, although extensive research on alarm-calling in avian mixed-species flocks has found only limited evidence that close association with another species could select for innate signal recognition. Nevertheless, very little is known about the evolution of eavesdropping behaviour and the mechanism of heterospecific signal recognition, particularly in other ecological contexts, such as foraging. To understand whether heterospecific eavesdropping was an innate or learned behaviour in a foraging context, we studied heterospecific signal recognition in ant-following birds of the Neotropics, which eavesdrop on vocalizations of obligate ant-following species to locate and recruit to swarms of the army ant Eciton burchellii, a profitable food resource. We used a playback experiment to compare recruitment of ant-following birds to vocalizations of two obligate species at a mainland site (where both species are present) and a nearby island site (where one species remains whereas the other went extinct approx. 40 years ago). We found that ant-following birds recruited strongly to playbacks of the obligate species present at both island and mainland sites, but the island birds did not recruit to playbacks of the absent obligate species. Our results strongly suggest that (i) ant-following birds learn to recognize heterospecific vocalizations from ecological experience and (ii) island birds no longer recognize the locally extinct obligate species after eight generations of absence from the island. Although learning appears to be the mechanism of heterospecific signal recognition in ant-following birds, more experimental tests are needed to fully understand the evolution of eavesdropping behaviour.


RNAs are packaged into human cytomegalovirus virions in proportion to their intracellular concentration.
The assembly of human cytomegalovirus (HCMV) virions is a complex process and involves the incorporation of viral transcripts. These RNAs are delivered to the newly infected cells and have the potential to be translated in the absence of HCMV gene expression. We have quantified the relative amount of RNAs in HCMV virions and infected cells with real-time reverse transcription-PCR and observed that viral and cellular RNAs are packaged in proportion to the amount of RNA within the cell at the time of assembly. To determine whether cis elements influenced RNA packaging, we constructed a recombinant HCMV mutant virus that expressed the yellow fluorescence protein (YFP) gene fused to the virion RNA UL21.5. We also constructed a mutant virus in which the UL21.5 transcription unit was replaced with the YFP gene. YFP RNA was incorporated into both viruses, indicating that RNA is incorporated in the absence of a virus-specific signal motif. Furthermore, with in situ hybridization, packaged transcripts were observed throughout the cytoplasm of the infected cells, including the site of virus assembly. Several proteins that nonspecifically interact with RNA, including the tegument protein pp28, were found within HCMV virions. These studies demonstrate that both viral and cellular RNAs are nonspecifically incorporated into HCMV, potentially through interactions with several virion proteins.


Effects of Nitrate Application on Amaranthus powellii Wats. : III. Optimal Allocation of Leaf Nitrogen for Photosynthesis and Stomatal Conductance.
Optimal allocation of leaf nitrogen maximizes daily CO(2) assimilation for a given leaf nitrogen concentration. According to the hypothesis of optimization, this condition occurs when the partial derivative of assimilation rate with respect to leaf nitrogen concentration is constant. This hypothesis predicts a linear increase of assimilation rate with leaf nitrogen concentration under constant conditions. Plants of Amaranthus powellii Wats. were grown at 1, 5, 10, or 45 millimolar nitrate to obtain leaves with different nitrogen concentrations. Assimilation rate at 340 microbar CO(2)/bar, stomatal conductance, CO(2)- and light-saturated net photosynthetic rate, the initial slope of the CO(2) response of photosynthesis, ribulose-1,5'-bisphosphate carboxylase activity, and phosphoenolpyruvate carboxylase activity were linearly related to estimated or actual leaf nitrogen concentration. The data are consistent with the optimal use of leaf nitrogen. This hypothesis and the hypothesis of optimal stomatal conductance were combined to determine the relationship between conductance and leaf nitrogen concentration. The slope of conductance versus leaf nitrogen concentration was not significantly different than the slope predicted by the combination of the two hypotheses. Stomatal conductance was linearly related to leaf nitrogen in the field and the slope decreased with lower xylem pressure potentials in a manner consistent with the hypotheses. Finally, apparent maximum stomatal aperture of isolated abaxial epidermal strips was linearly related to leaf nitrogen suggesting stomatal conductance and assimilation rate are controlled in parallel by leaf nitrogen concentration or some factor correlated with leaf nitrogen.


Occurrence of phthalates in aquatic environment and their removal during wastewater treatment processes: a review.
Phthalates are plasticizers and are concerned environmental endocrine-disrupting compounds. Due to their extensive usage in plastic manufacturing and personal care products as well as the potential to leach out from these products, phthalates have been detected in various aquatic environments including drinking water, groundwater, surface water, and wastewater. The primary source of their environmental occurrence is the discharge of phthalate-laden wastewater and sludge. This review focuses on recent knowledge on the occurrence of phthalate in different aquatic environments and their fate in conventional and advanced wastewater treatment processes. This review also summarizes recent advances in biological removal and degradation mechanisms of phthalates, identifies knowledge gaps, and suggests future research directions.


Repeated aerosol-vapor JP-8 jet fuel exposure affects neurobehavior and neurotransmitter levels in a rat model.
Four groups of Fischer Brown Norway hybrid rats were exposed for 5, 10, 15, or 20 d to aerosolized-vapor jet propulsion fuel 8 (JP-8) compared to freely moving (5 and 10-d exposures) or sham-confined controls (15 and 20-d exposures). Behavioral testing utilized the U.S. Environmental Protection Agency Functional Observational Battery. Exploratory ethological factor analysis identified three salient factors (central nervous system [CNS] excitability, autonomic 1, and autonomic 2) for use in profiling JP-8 exposure in future studies. The factors were used as dependent variables in general linear modeling. Exposed animals were found to engage in more rearing and hyperaroused behavior compared to controls, replicating prior JP-8 exposure findings. Exposed animals also showed increasing but rapidly decelerating stool output (autonomic 1), and a significant increasing linear trend for urine output (autonomic 2). No significant trends were noted for either of the control groups for the autonomic factors. Rats from each of the groups for each of the time frames were randomly selected for tissue assay from seven brain regions for neurotransmitter levels. Hippocampal DOPAC was significantly elevated after 4-wk JP-8 exposure compared to both control groups, suggesting increased dopamine release and metabolism. Findings indicate that behavioral changes do not appear to manifest until wk 3 and 4 of exposure, suggesting the need for longitudinal studies to determine if these behaviors occur due to cumulative exposure, or due to behavioral sensitization related to repeated exposure to aerosolized-vapor JP-8.


Sustained Malaria Control Over an 8-Year Period in Papua New Guinea: The Challenge of Low-Density Asymptomatic Plasmodium Infections.
The scale-up of effective malaria control in the last decade has resulted in a substantial decline in the incidence of clinical malaria in many countries. The effects on the proportions of asymptomatic and submicroscopic infections and on transmission potential are yet poorly understood. In Papua New Guinea, vector control has been intensified since 2008, and improved diagnosis and treatment was introduced in 2012. Cross-sectional surveys were conducted in Madang Province in 2006 (with 1280 survey participants), 2010 (with 2117 participants), and 2014 (with 2516 participants). Infections were quantified by highly sensitive quantitative polymerase chain reaction (PCR) analysis, and gametocytes were quantified by reverse-transcription qPCR analysis. Plasmodium falciparum prevalence determined by qPCR decreased from 42% in 2006 to 9% in 2014. The P. vivax prevalence decreased from 42% in 2006 to 13% in 2010 but then increased to 20% in 2014. Parasite densities decreased 5-fold from 2006 to 2010; 72% of P. falciparum and 87% of P. vivax infections were submicroscopic in 2014. Gametocyte density and positivity correlated closely with parasitemia, and population gametocyte prevalence decreased 3-fold for P. falciparum and 29% for P. vivax from 2010 to 2014. Sustained control has resulted in reduced malaria transmission potential, but an increasing proportion of gametocyte carriers are asymptomatic and submicroscopic and represent a challenge to malaria control.


Testing methods to mitigate Caribbean yellow-band disease on Orbicella faveolata.
Outbreaks of coral diseases continue to reduce global coral populations. In the Caribbean, yellow band is a severe and wide-spread disease that commonly affects corals of the Orbicella spp. complex, significantly impeding coral reproduction, and hindering the natural recovery of Orbicella spp. Caribbean yellow-band disease (CYBD) lesions may be severe, and often result in the complete loss of coral tissue. The slow spread of CYBD, however, provides an opportunity to test methods to mitigate the disease. Here we report the results of in situ experiments, conducted within Buck Island Reef National Monument in St. Croix, USVI, to test the effectiveness of three techniques to minimize disease impact on Orbicella faveolata: (1) shading, (2) aspirating, and (3) chiseling a "firebreak" to isolate the lesion. Neither shading nor aspirating the diseased tissue significantly reduced CYBD tissue loss. However, chiseling reduced the rate and amount of tissue lost by 31%. While 30-40% of the chiseled lesions appeared to be free of disease signs 12-16 months after treatment, success significantly and steadily declined over 23 months, indicating a possible lack of long-term viability of the technique. The results of this study demonstrate that creating a "firebreak" between diseased and healthy-appearing tissue slows the spread of the disease and may prolong the life of O. faveolata colonies. The firebreak method yielded the best results of all the techniques tested, and also required the least amount of effort and resources. However, we do not recommend that this treatment alone be used for long-term disease mitigation. Rather, we propose that modifications of this and other treatment options be sought. The results also highlight the need for extended monitoring of CYBD after any treatment, due to the slow but variable rate and pattern of tissue loss in this disease.


Cardioprotective Potential of Plant-Derived Molecules: A Scientific and Medicinal Approach.
Since the beginning of human civilization, plants have been used in alleviating the human distress and it was recorded for about thousands of years ago that the plants are being used for medicinal purposes. Natural bioactive compounds called phytochemicals are obtained from medicinal plants, vegetables, and fruits, which functions to combat against various ailments. There is dire need to explore the plant biodiversity for its medicinal and pharmacological potentials. Different databases such as Google scholar, Medline, PubMed, and the Directory of Open Access Journals were searched to find the articles describing the cardioprotective function of medicinal plants. Various substances from a variety of plant species are used for the treatment of cardiovascular abnormalities. The cardioprotective plants contain a variety of bioactive compounds, including diosgenin, isoflavones, sulforaphane, carotinized, catechin, and quercetin, have been proved to enhance cardioprotection, hence reducing the risk of cardiac abnormalities. The present review article provides the data on the use of medicinal plants particularly against cardiac diseases and to explore the molecules/phytoconstituents as plant secondary metabolites for their cardioprotective potential.


[Monitoring and non pharmacologic measures during a pandemic virus (H1N1) 2009 in Spain].
Nonpharmacological public health measures are used to reduce exposure of susceptible persons to an infectious agent. Its use is recommended at the start of a pandemic, when the transmission begins, and the characteristics of the new virus are unknown. The National Plan for Preparedness and Response to Pandemic Influenza included the application of these measures, recommending the establishment of an Advisory Committee for implementation, with a multidisciplinary composition. The mandate at this Committee is to analyze the epidemiological and social context in confronting the pandemic and to propose public health measures according to their evolution. This article describes isolation, quarantine and closure of schools measures, aiming to reduce the spread of the virus in the population. It also reviews the epidemiological parameters that help to understand the impact of its implementation. The public health measures reviewed in this paper reduce transmission of the virus, and they have to be considered in response to an influenza pandemic. The impact on health will depend on how quickly they are taken and how people accept and follow them. Response plans should recommend its use, depending on the severity and characteristics of the new pandemic virus. The data analysis should be considered as part of the response, because the information collection and analysis will be key to advising health authorities on what measures should be adopted.


Rates of microfilarial production by Onchocerca volvulus are not cumulatively reduced by multiple ivermectin treatments.
Regular distribution of ivermectin reduces onchocerciasis transmission and morbidity by killing, within humans, the microfilarial stage of the parasite (microfilaricidal effect). In addition, ivermectin exerts a so-called embryostatic effect by which microfilarial production by the adult female worm becomes suppressed during a number of weeks after treatment. To assess the overall effect of ivermectin on onchocerciasis transmission and evaluate the likelihood of local elimination of the infection it is important to estimate the magnitude of the anti-fertility effect over the course of a treatment programme. Estimates of the effect of repeated drug treatments on the production of microfilariae by adult Onchocerca volvulus were obtained by developing a model that was fitted to data collected from three hyperendemic communities in Guatemala, where eligible residents received ivermectin twice per year for two and a half years. The data consist of microfilarial load measurements in the skin, collected just before each six-monthly treatment during the programme. The model that is developed describes the dynamics of an individual host's expected microfilarial load over the 30-month study period. We adopt a Bayesian approach and use Markov chain Monte Carlo (McMC) techniques to fit the model to the data. Combining estimates from the three villages, average microfilarial production in the first six months post-treatment was reduced by ~64% of its pre-treatment level, regardless of values chosen for the pre-ivermectin fertility rate within plausible ranges. Increased adult worm death rate after treatment (to mimic removal of macrofilariae via nodulectomy during the programme) resulted in a smaller estimated magnitude of the embryostatic effect (rate of microfilarial production was reduced by ~58% of pre-ivermectin value). After subsequent treatments, the rate of microfilarial production appeared to be similarly decreased. The data and analyses therefore do not support the hypothesis of a cumulative effect of multiple ivermectin treatments on microfilarial production by female worms.


Noise-assisted binary information transmission in vertical cavity surface emitting lasers.
The response of a polarization-bistable vertical cavity surface emitting laser to a small amplitude, pseudorandom binary signal is experimentally studied. A high-contrast output is obtained when the optimum amount of noise is added to the system. The quality of the transmission, measured by the bit-error rate, exhibits a resonantlike behavior as a function of the input noise. We analyze possible applications of this transmission scheme to optical communications and compare it with those used in a standard amplitude modulation scheme.


Performance of endovenous foam sclerotherapy in the USA for the treatment of venous disorders: ACP/SVM/AVF/SIR quality improvement guidelines.
This report summarizes the findings of the consensus panel based on the results of the comprehensive questionnaire of US American College of Phlebology annual congress attendees and results of the systematic meta-analysis of the literature and provides quality improvement guidelines for the use of endovenous foam sclerotherapy (EFS) for the treatment of venous disorders, as well as identifies areas of needed research. Based on the above data, quality improvement guidelines were developed and reviewed by the ten US consensus panel members and approved by their respective societies. EFS is effective for the treatment of truncal and tributary varicose veins, both as primary treatment and for treatment of recurrence. It may improve the signs and symptoms associated with varicose veins including pain and swelling. EFS is contraindicated in patients who have experienced an allergic reaction to previous treatment with foam or liquid sclerosant, and in patients with acute venous thrombosis events secondary to EFS. These guidelines for the use of EFS in the treatment of venous disorders provide an initial framework for the safe and efficacious use of this therapy, and the impetus to promote the evaluation of the questions remaining regarding the use of EFS through well-designed randomized and cohort studies.


Predictors of transfusion of packed red blood cells in coronary artery bypass grafting surgery.
Finding predictors of blood transfusion may facilitate the most efficient approach for the use of blood bank services in coronary artery bypass grafting procedures. The aim of this retrospective study is to identify preoperative and intraoperative patient characteristics predicting the need for blood transfusion during or after CABG in our local cardiac surgical service. 435 patients undergoing isolated first-time CABG were reviewed for their preoperative and intraoperative variables and analyzed postoperative data. Patients were 255 males and 180 females, with mean age 62.01 ± 10.13 years. Regression logistic analysis was used for identifying the strongest perioperative predictors of blood transfusion. Blood transfusion was used in 263 patients (60.5%). The mean number of transfused blood products units per patient was 2.27 ± 3.07 (0-23) units. The total number of transfused units of blood products was 983. Univariate analysis identified age >65 years, weight <70 Kg, body mass index <25 Kg/m2, hemoglobin <13mg/dL, hematocrit < 40% and ejection fraction <50%, use of cardiopulmonary bypass (CPB), not using an internal thoracic artery as a bypass, and multiple bypasses as significant predictors. The strongest predictors using multivariate analysis were hematocrit < 40% (OR 2.58; CI 1.62-4.15; P<0.001), CPB use (OR 2.00; CI 1.27-3.17; P=0.003) and multiple bypasses (OR 2.31; CI 1.31-4.08; P=0.036). The identification of these risk factors leads to better identification of patients with a greater probability of using blood, allocation blood bank resources and cost-effectiveness use of blood products.


Relationship problems and the DSM:needed improvements and suggested solutions.
Relational problems are clinically significant behavioral or psychological syndromes or patterns that occur between or among individuals and that are associated with present distress or disability or with a significant increased risk of suffering death, pain, disability, or an important loss of freedom. Relational problems (e.g., partner relational problems, partner abuse, child maltreatment) are included as Axis I disorders in the DSM-IV as V-codes (i.e., "Other conditions that may be a focus of clinical attention"). However, there are no criteria provided in the DSM-IV for these codes. In this article, we briefly review literature that incontrovertibly documents both relational problems' syndromes/patterns and their serious sequelae. We then review a series of studies that provide evidence of content validity and inter-rater agreement for criteria to determine presence versus absence of relational problems. The most studied subset of relational problem criteria, those for partner and child maltreatment, have been shown to have remarkably high levels of reliability when disseminated broadly in the field (kappa = .66-.89), at agreement levels never reached by DSM diagnoses for individuals. We conclude by arguing that science, service, families, individuals, and the DSM itself, would be well served to include diagnostic criteria for relational problems and to consider the various options for placement of relational problems/processes in the DSM-V.


Structure of rhomboid protease in complex with β-lactam inhibitors defines the S2' cavity.
Rhomboids are evolutionarily conserved serine proteases that cleave transmembrane proteins within the membrane. The increasing number of known rhomboid functions in prokaryotes and eukaryotes makes them attractive drug targets. Here, we describe structures of the Escherichia coli rhomboid GlpG in complex with β-lactam inhibitors. The inhibitors form a single bond to the catalytic serine and the carbonyl oxygen of the inhibitor faces away from the oxyanion hole. The hydrophobic N-substituent of β-lactam inhibitors points into a cavity within the enzyme, providing a structural explanation for the specificity of β-lactams on rhomboid proteases. This same cavity probably represents the S2' substrate binding site of GlpG. We suggest that the structural changes in β-lactam inhibitor binding reflect the state of the enzyme at an initial stage of substrate binding to the active site. The structural insights from these enzyme-inhibitor complexes provide a starting point for structure-based design for rhomboid inhibitors.


Nitric oxide impairs Ca2+ activation and slows cross-bridge cycling kinetics in skeletal muscle.
The effects of the nitric oxide (NO) donor spermine NONOate (Sp-NO, 1.0 mM) on cross-bridge recruitment and cross-bridge cycling kinetics were studied in permeabilized rabbit psoas muscle fibers. Fibers were activated at various Ca2+ concentrations (pCa, negative logarithm of Ca2+ concentration), and the pCa at which force was maximal (pCa 4.0) and approximately 50% of maximal (pCa50 5.6) were determined. Fiber stiffness was determined using 1-kHz sinusoidal length perturbations, and the fraction of cross bridges in the force-generating state was estimated by the ratio of stiffness during maximal (pCa 4.0) and submaximal (pCa 5.6) Ca2+ activation to stiffness during rigor (at pCa 4.0). Cross-bridge cycling kinetics were evaluated by measuring the rate constant for force redevelopment after quick release (by 15% of optimal fiber length, L(o)) and restretch of the fiber to L(o). Exposing fibers to Sp-NO for 10 min reduced force and the fraction of cross bridges in the force-generating state at maximal and submaximal (pCa50) Ca2+ activation. However, the effects of Sp-NO were more pronounced during submaximal Ca2+ activation. Sp-NO also reduced the rate constant for force redevelopment but only during submaximal Ca2+ activation. We conclude that Sp-NO reduces Ca2+ sensitivity by decreasing the number of cross bridges in the strongly bound state and also impairs cross-bridge cycling kinetics during submaximal activation.


Sources of cell-to-cell variability in canonical nuclear factor-κB (NF-κB) signaling pathway inferred from single cell dynamic images.
The canonical nuclear factor-κB (NF-κB) signaling pathway controls a gene network important in the cellular inflammatory response. Upon activation, NF-κB/RelA is released from cytoplasmic inhibitors, from where it translocates into the nucleus, subsequently activating negative feedback loops producing either monophasic or damped oscillatory nucleo-cytoplasmic dynamics. Although the population behavior of the NF-κB pathway has been extensively modeled, the sources of cell-to-cell variability are not well understood. We describe an integrated experimental-computational analysis of NF-κB/RelA translocation in a validated cell model exhibiting monophasic dynamics. Quantitative measures of cellular geometry and total cytoplasmic concentration and translocated RelA amounts were used as priors in Bayesian inference to estimate biophysically realistic parameter values based on dynamic live cell imaging studies of enhanced GFP-tagged RelA in stable transfectants. Bayesian inference was performed on multiple cells simultaneously, assuming identical reaction rate parameters, whereas cellular geometry and initial and total NF-κB concentration-related parameters were cell-specific. A subpopulation of cells exhibiting distinct kinetic profiles was identified that corresponded to differences in the IκBα translation rate. We conclude that cellular geometry, initial and total NF-κB concentration, IκBα translation, and IκBα degradation rates account for distinct cell-to-cell differences in canonical NF-κB translocation dynamics.


Whole blood gene expression profiles in insulin resistant Latinos with the metabolic syndrome.
Although insulin resistance in skeletal muscle is well-characterized, the role of circulating whole blood in the metabolic syndrome phenotype is not well understood. We set out to test the hypothesis that genes involved in inflammation, insulin signaling and mitochondrial function would be altered in expression in the whole blood of individuals with metabolic syndrome. We further wanted to examine whether similar relationships that we have found previously in skeletal muscle exist in peripheral whole blood cells. All subjects (n=184) were Latino descent from the Arizona Insulin Resistance registry. Subjects were classified based on the metabolic syndrome phenotype according to the National Cholesterol Education Program's Adult Treatment Panel III. Of the 184 Latino subjects in the study, 74 were classified with the metabolic syndrome and 110 were without. Whole blood gene expression profiling was performed using the Agilent 4x44K Whole Human Genome Microarray. Whole blood microarray analysis identified 1,432 probes that were altered in expression ≥ 1.2 fold and P<0.05 after Benjamini-Hochberg in the metabolic syndrome subjects. KEGG pathway analysis revealed significant enrichment for pathways including ribosome, oxidative phosphorylation and MAPK signaling (all Benjamini-Hochberg P<0.05). Whole blood mRNA expression changes observed in the microarray data were confirmed by quantitative RT-PCR. Transcription factor binding motif enrichment analysis revealed E2F1, ELK1, NF-kappaB, STAT1 and STAT3 significantly enriched after Bonferroni correction (all P<0.05). The results of the present study demonstrate that whole blood is a useful tissue for studying the metabolic syndrome and its underlying insulin resistance although the relationship between blood and skeletal muscle differs.


Energy landscapes, supergraphs, and "folding funnels" in spin systems.
Dynamical connectivity graphs, which describe dynamical transition rates between local energy minima of a system, can be displayed against the background of a disconnectivity graph which represents the energy landscape of the system. The resulting supergraph describes both dynamics and statics of the system in a unified coarse-grained sense. We give examples of the supergraphs for several two-dimensional spin and protein-related systems. We demonstrate that disordered ferromagnets have supergraphs akin to those of model proteins whereas spin glasses behave like random sequences of amino acids that fold badly.


Quantifying behavior to understand the brain.
Over the past years, numerous methods have emerged to automate the quantification of animal behavior at a resolution not previously imaginable. This has opened up a new field of computational ethology and will, in the near future, make it possible to quantify in near completeness what an animal is doing as it navigates its environment. The importance of improving the techniques with which we characterize behavior is reflected in the emerging recognition that understanding behavior is an essential (or even prerequisite) step to pursuing neuroscience questions. The use of these methods, however, is not limited to studying behavior in the wild or in strictly ethological settings. Modern tools for behavioral quantification can be applied to the full gamut of approaches that have historically been used to link brain to behavior, from psychophysics to cognitive tasks, augmenting those measurements with rich descriptions of how animals navigate those tasks. Here we review recent technical advances in quantifying behavior, particularly in methods for tracking animal motion and characterizing the structure of those dynamics. We discuss open challenges that remain for behavioral quantification and highlight promising future directions, with a strong emphasis on emerging approaches in deep learning, the core technology that has enabled the markedly rapid pace of progress of this field. We then discuss how quantitative descriptions of behavior can be leveraged to connect brain activity with animal movements, with the ultimate goal of resolving the relationship between neural circuits, cognitive processes and behavior.


Color-based grouping and inhibition in visual search: evidence from a probe detection analysis of preview search.
In four experiments, we examined selection processes in visual search using a probe detection task to measure the allocation of attention. Under preview search conditions, probes were harder to detect on old relative to new distractors (Experiment 1). This cannot be attributed solely to low-level sensory factors (Experiment 2). In addition, probe detection was sensitive to color-based grouping of old distractors and to color similarity between old distractors (Experiments 3 and 4). These effects were dissociated when the color of the old distractors changed but probe detection effects remained. Collectively, the data indicate both group-based suppression of distractors and the separate inhibition of distractor features in search.


Anterior "cheek" electrodes are comparable to sphenoidal electrodes for the identification of ictal activity.
Sphenoidal electrodes are used to localize epileptiform activity originating in the temporal lobe during complex partial seizures. Sphenoidal electrodes, however, are semi-invasive and uncomfortable to the patient. We compared skin electrodes placed on the cheek ("cheek electrodes") with sphenoidal electrodes for the detection of the side and site of complex partial seizure onset. In a masked, randomized comparison of single ictal recordings in 22 patients, there were no significant differences between sphenoidal and cheek electrode montages in detecting the side or site of ictal onset (P < 0.01). Signal/noise ratios for interictal spikes were a mean 16.5% greater at sphenoidal sites compared to cheek sites (paired t test, t = 2.4, P < 0.05). This difference, however, did not influence the detection of rhythmical ictal activity in cheek and sphenoidal montages in our study, nor the assignment of side, site or time of seizure onset by unbiased readers. Recordings from cheek electrodes are comparable to those from sphenoidal electrodes and are useful for localizing ictal activity.


Induction of apoptosis by ethanol extract of Citrus unshiu Markovich peel in human bladder cancer T24 cells through ROS-mediated inactivation of the PI3K/Akt pathway.
Citrus unshiu peel has been used to prevent and treat various diseases in traditional East-Asian medicine including in Korea. Extracts of C. unshiu peel are known to have various pharmacological effects including antioxidant, anti-inflammatory, and antibacterial properties. Although the possibility of their anti-cancer activity has recently been reported, the exact mechanisms in human cancer cells have not been sufficiently studied. In this study, the inhibitory effect of ethanol extract of C. unshiu peel (EECU) on the growth of human bladder cancer T24 cells was evaluated and the underlying mechanism was investigated. The present study demonstrated that the suppression of T24 cell viability by EECU is associated with apoptosis induction. EECU-induced apoptosis was found to correlate with an activation of caspase-8, -9, and -3 in concomitance with a decrease in the expression of the inhibitor of apoptosis family of proteins and an increase in the Bax:Bcl-2 ratio accompanied by the proteolytic degradation of poly(ADP-ribose) polymerase. EECU also increased the generation of reactive oxygen species (ROS), collapse of mitochondrial membrane potential, and cytochrome c release to the cytosol, along with a truncation of Bid. In addition, EECU inactivated phosphatidylinositol 3-kinase (PI3K) as well as Akt, a downstream molecular target of PI3K, and LY294002, a specific PI3K inhibitor significantly enhanced EECU-induced apoptosis and cell viability reduction. However, N-acetyl cysteine, a general ROS scavenger, completely reversed the EECU-induced dephosphorylation of PI3K and Akt, as well as cell apoptosis. Taken together, these findings suggest that EECU inhibits T24 cell proliferation by activating intrinsic and extrinsic apoptosis pathways through a ROS-mediated inactivation of the PI3K/Akt pathway.


Health education for patients with acute coronary syndrome and type 2 diabetes mellitus: an umbrella review of systematic reviews and meta-analyses.
This umbrella review aimed to identify the current evidence on health education-related interventions for patients with acute coronary syndrome (ACS) or type two diabetes mellitus (T2DM); identify the educational content, delivery methods, intensity, duration and setting required. The purpose was to provide recommendations for educational interventions for high-risk patients with both ACS and T2DM. Umbrella review of systematic reviews and meta-analyses. Inpatient and postdischarge settings. Patients with ACS and T2DM. CINAHL, Cochrane Library, Joanna Briggs Institute, Journals@Ovid, EMBase, Medline, PubMed and Web of Science databases from January 2000 through May 2016. Clinical outcomes (such as glycated haemoglobin), behavioural outcomes (such as smoking), psychosocial outcomes (such as anxiety) and medical service use. Fifty-one eligible reviews (15 for ACS and 36 for T2DM) consisting of 1324 relevant studies involving 2 88 057 patients (15 papers did not provide the total sample); 30 (58.8%) reviews were rated as high quality. Nurses only and multidisciplinary teams were the most frequent professionals to provide education, and most educational interventions were delivered postdischarge. Face-to-face sessions were the most common delivery formats, and many education sessions were also delivered by telephone or via web contact. The frequency of educational sessions was weekly or monthly, and an average of 3.7 topics was covered per education session. Psychoeducational interventions were generally effective at reducing smoking and admissions for patients with ACS. Culturally appropriate health education, self-management educational interventions, group medical visits and psychoeducational interventions were generally effective for patients with T2DM. Results indicate that there is a body of current evidence about the efficacy of health education, its content and delivery methods for patients with ACS or T2DM. These results provide recommendations about the content for, and approach to, health education intervention for these high-risk patients.


March Madness 2011: for whom the bell tolls?
The American Heart Association has developed 12 recommendations for preparticipation screening of high school and college athletes, but the application of these recommendations across the US is inconsistent. A recent clinical study suggests that the incidence and prevalence of sudden athletic death (SAD) is greater than previously believed. Currently, diagnostic screening is considered too expensive and is delivered sporadically. Logic dictates that the medical community must become more involved in reducing the incidence and prevalence of SAD through an improved preparticipation screening process. An effective screening process must be able to reproducibly predict and prevent potential risk using the most effective resources and keeping the cost-benefit ratio at a minimum. The most effective use of our resources will limit the potential of liability for institutions and physicians and, hopefully, eliminate episodes of SAD.


Identification of a phytase gene in barley (Hordeum vulgare L.).
Endogenous phytase plays a crucial role in phytate degradation and is thus closely related to nutrient efficiency in barley products. The understanding of genetic information of phytase in barley can provide a useful tool for breeding new barley varieties with high phytase activity. Quantitative trait loci (QTL) analysis for phytase activity was conducted using a doubled haploid population. Phytase protein was purified and identified by the LC-ESI MS/MS Shotgun method. Purple acid phosphatase (PAP) gene was sequenced and the position was compared with the QTL controlling phytase activity. A major QTL for phytase activity was mapped to chromosome 5 H in barley. The gene controlling phytase activity in the region was named as mqPhy. The gene HvPAP a was mapped to the same position as mqPhy, supporting the colinearity between HvPAP a and mqPhy. It is the first report on QTLs for phytase activity and the results showed that HvPAP a, which shares a same position with the QTL, is a major phytase gene in barley grains.


Neonatal maternal separation predisposes adult rats to colonic barrier dysfunction in response to mild stress.
Intestinal dysfunction is related to stress and early life events, but the mechanisms are largely unknown. Our aim was to determine whether early trauma predisposes adult rats to intestinal mucosal dysfunction in response to stress. Neonatal Sprague-Dawley rats were individually separated from their mothers for 3 h/day at 4-21 days of age. Between days 80 and 90, separated and control rats were subjected to mild acute stress (30-min water avoidance) or sham stress. Mucosal barrier function and ion transport were assessed in colonic tissues mounted in Ussing chambers. Mild stress increased short-circuit current, conductance, and transepithelial transport of macromolecules in separated rats, while having minimal effects in controls. Pretreatment of the separated rats with a corticotropin-releasing hormone (CRH) antagonist, the peptide alpha-helical CRH(9-41) injected intraperitoneally 20 min before stress, abolished the stress-induced mucosal changes. Our results indicate that neonatal trauma can induce phenotypic changes in adulthood, including enhanced vulnerability of the gut mucosa to stress via mechanisms involving peripherally located CRH receptors.


Giant aneurysm in a left coronary artery fistula: diagnostic cardiovascular imaging and treatment considerations.
Congenital coronary artery fistula complicated with giant coronary artery aneurysm is a very rare condition. In this case report, we present a 65-year-old woman, referred to us with a continuous heart murmur, occasional atypical chest pain and few episodes of fainting. A giant aneurysm and a coronary-pulmonary fistula were diagnosed using multiple cardiovascular imaging modalities to provide a sufficient anatomical picture. The patient was considered at high risk of sudden death from aneurysm rupture and received surgical treatment. Subsequent histopathological examination revealed a true aneurysm with severe wall calcifications, ulcerations and large areas with marked thinning of the wall. The postoperative course was uneventful.


Predictive factors of better outcomes by monotherapy of an antivascular endothelial growth factor drug, ranibizumab, for diabetic macular edema in clinical practice.
Intravitreal ranibizumab (IVR) has been approved for treating diabetic macular edema (DME), and is used in daily clinical practice. However, the treatment efficacies of IVR monotherapy in real-world clinical settings are not well known.The medical records of 56 eyes from 38 patients who received their first IVR for DME between April 2014 and March 2015, and were retreated with IVR monotherapy as needed with no rescue treatment, such as laser photocoagulation, were retrospectively reviewed. The clinical course, best-corrected visual acuity (BCVA), and fundus findings at baseline, before the initial IVR injection, and at 12 months, were evaluated.Twenty-five eyes from 25 patients (16 men; mean age 68.7 ± 9.8 years) who received IVR in the first eye, or unilaterally, without any other treatments during follow-up were included. After 12 months, mean central retinal thickness (CRT), which includes edema, was reduced (P = .003), although mean BCVA remained unchanged. There was a negative correlation between individual changes in BCVA (r = -0.57; P = .003) and CRT (r = -0.60; P = .002) at 12 months compared with baseline values. BCVA changes were greater in individuals with a history of pan-retinal photocoagulation at baseline (P = .026). After adjusting for age and sex, CRT improvement >100 μm at 12 months was associated with a greater CRT at baseline (OR 0.87 per 10 μm [95% CI 0.72-0.97]; P = .018) according to logistic regression analyses; however, better BCVA and CRT at 12 months were associated with a better BCVA (r = 0.77; P < .001) and lower CRT (r = 0.41; P = .039) at baseline, respectively, according to linear regression analyses.IVR monotherapy suppressed DME, and the effects varied according to baseline conditions. Eyes that had poorer BCVA or greater CRT, or a history of pan-retinal photocoagulation at baseline, demonstrated greater improvement with IVR monotherapy. In contrast, to achieve better outcome values, DME eyes should be treated before the BCVA and CRT deteriorate. These findings advance our understanding of the optimal use of IVR for DME in daily clinical practice, although further study is warranted.


Alcoholic hepatitis: appropriate indication for liver transplantation?
The majority of liver transplantation centers have required patients with alcohol-induced liver disease to demonstrate a period of abstinence (generally 6 months' duration) to qualify for transplant listing. This requirement has excluded patients with alcoholic hepatitis from transplant consideration. Since 2011, several studies have examined the outcomes of patients undergoing liver transplantation with brief abstinence as a lifesaving intervention for alcoholic hepatitis. This review includes each of the recent studies and discusses their implications for general transplant practice. A Medical Literature Analysis and Retrieval System search revealed five published studies - three prospective and two retrospective - pertaining to liver transplantation for alcoholic hepatitis. Among patients with medication-nonresponsive alcoholic hepatitis, those who underwent transplantation had superior survival. Liver recipients with alcoholic hepatitis had comparable survival to those with 6 or more months of abstinence. Their relapse rates were not statistically different in the short term over those transplanted with longer abstinence, although some patients in each prospective cohort relapsed to drinking despite narrow inclusion criteria and extensive pretransplant staff reviews and posttransplant surveillance. Liver transplantation is a reasonable treatment consideration for highly selective cases of alcoholic hepatitis. Further research is needed to refine inclusion criteria, address posttransplant relapse prevention interventions, and monitor long-term outcomes.


Glucagon and the colon.
The effect of glucagon on human colonic myoelectrical activity is described. By means of intraluminal, serosal, and surface electrodes, recordings from all areas of the large bowel have been obtained. Glucagon inhibited both electrical and pressure rhythms in all subjects tested. Evidence is produced to suggest a direct action on colonic smooth muscle. A controlled trial using glucagon during routine barium enema examinations suggests that it may prove to be useful for hypotonic examinations of the colon where painful spasm is present.


Serology of rabbit haemorrhagic disease virus in wild rabbits before and after release of the virus in New Zealand.
Rabbit haemorrhagic disease virus (RHDV) was illegally released in New Zealand in August 1997. The initial release and spread of the virus was conducted by landholders in an effort to reduce costs associated with more conventional control methods (poisoning and shooting). Serum was collected from wild rabbits throughout the Otago region prior to the release and from 13 sites in the months following the first epizootic. Following the occurrence of the first RHDV epizootic on 13 pastoral farming properties a range of survival rates was found. The major factor influencing the survival rate was found to be the method of release, with widespread use of carrot or oat baits containing RHDV resulting in poor kills. Widespread use of baits also resulted in higher levels of antibody in surviving adult rabbits with a higher proportion of adult females surviving the epizootic, compared with properties where the disease was allowed to spread naturally. A correlation was found between survival rate and the percentage of surviving adults with high levels of antibody. These results suggest that poor kill rates are not due to poor spread of the virus, that the large-scale use of baits resulted in protective immunisation and that rabbit control should in the future be achieved through establishing naturally spreading epidemics rather than widespread use of baits.


Effect of slice thickness on detectability in breast CT using a prewhitened matched filter and simulated mass lesions.
Dedicated breast CT (bCT) is an emerging technology with the potential to improve the detection of breast cancer in screening and diagnostic capacities. Typically, the 3D volume reconstructed from the scanner is displayed as sectional images. The purpose of this study was to evaluate the effect of section thickness on the detectability of simulated masses using a prewhitened matched filter (PWMF) as a model observer. A breast CT scanner has been designed and fabricated in the authors' laboratory with more than 200 women imaged in IRB-approved phase I and phase II trials to date. Of these, 151 bilateral data sets were selected on the basis of low artifact content, sufficient breast coverage, and excluding cases with breast implants. BIRADS breast density ratings were available for 144 of these patients. Spherical mass lesions of diameter 1, 2, 3, 5, 11, and 15 mm were mathematically generated and embedded at random locations within the parenchymal region of each bCT volume. Microcalcifications were not simulated in this study. For each viewing plane (sagittal, axial, and coronal) and section thickness (ranging from 0.3 to 44 mm), section images of the breast parenchyma containing the lesion were generated from the reconstructed bCT data sets by averaging voxels over the length of the section. Using signal known exactly (SKE) model observer methodology, receiver operating characteristic (ROC) curve analysis was performed on each generated projected image using a PWMF based model observer. ROC curves were generated for each breast data set, and the area under the ROC curve (AUC) was evaluated as well as the sensitivity at 95% specificity. For all lesion sizes, performance rises modestly to a peak before falling off substantially as section thickness increases over the range of the study. We find that the optimal section thickness tracks the size of the lesion to be detected linearly with a small positive offset and slopes ranging from 0.27 to 0.44. No significant differences were observed between left and right breasts. Performance measures are negatively correlated with measures of breast density, with an average correlation coefficient of -0.48 for the BIRADS breast density score and -0.81 for the proportion of glandular tissue in the breast interior. This study shows quantitatively how PWMF detection performance of a known lesion size is influenced by section thickness in dedicated breast CT. While the optimal section thickness is tuned to the size of the lesion being detected, overall performance is more robust for thin section images compared to thicker images.


Enrichment activities in the medical school psychiatry programme - could this be a key to engaging medical students in psychiatry? A study from a high secure forensic psychiatric UK hospital.
The majority of research studies on medical student attitudes toward psychiatry focus on influencing factors and the medical school experience. This study evaluates the effectiveness of a one-day visit to a high secure forensic psychiatric unit on medical students' attitudes towards psychiatry and also assesses career intentions and the factors influencing these. Change in attitudes and career intention were measured by administering a questionnaire, which included the 30-item Attitudes Toward Psychiatry (ATP-30) survey, at the start (time 1) and end (time 2) of the one-day visit. Qualitative data on factors influencing career choice was also gathered. Evaluation of 284 responses revealed a significant increase in positive attitude towards psychiatry from time 1 to time 2 in the sample as a whole. The most influential factor on consideration of psychiatry as a career across all groups was the medical school clinical placement. For those that tended away from choosing psychiatry as a career, patient prognosis was important. Poor recruitment in psychiatry in the UK is already established which will doubtless be compounded by controversies surrounding the proposed new junior doctors' contract. Now more than ever, the need to inspire and motivate those at medical school encountering psychiatry is crucial. Our findings add to the body of evidence that the medical school clinical attachment is fundamental in shaping attitudes. However, these results also show that a well-planned visit to a specialised psychiatric unit outside of traditional placements can have a significant impact on students' attitudes toward psychiatry and mental illness in general. There is limited literature in the UK on enrichment activities within the psychiatry medical school curriculum. We propose that developing opportunities for enrichment activities within psychiatry could increase the scope of how we engage students in this fascinating field of medicine.


Strength of forelimb lateralization predicts motor errors in an insect.
Lateralized behaviours are widespread in both vertebrates and invertebrates, suggesting that lateralization is advantageous. Yet evidence demonstrating proximate or ultimate advantages remains scarce, particularly in invertebrates or in species with individual-level lateralization. Desert locusts (Schistocerca gregaria) are biased in the forelimb they use to perform targeted reaching across a gap. The forelimb and strength of this bias differed among individuals, indicative of individual-level lateralization. Here we show that strongly biased locusts perform better during gap-crossing, making fewer errors with their preferred forelimb. The number of targeting errors locusts make negatively correlates with the strength of forelimb lateralization. This provides evidence that stronger lateralization confers an advantage in terms of improved motor control in an invertebrate with individual-level lateralization.


Analysis of competition performance in dressage and show jumping of Dutch Warmblood horses.
Most Warmblood horse studbooks aim to improve the performance in dressage and show jumping. The Dutch Royal Warmblood Studbook (KWPN) includes the highest score achieved in competition by a horse to evaluate its genetic ability of performance. However, the records collected during competition are associated with some aspects that might affect the quality of the genetic evaluation based on these records. These aspects include the influence of rider, censoring and preselection of the data. The aim of this study was to quantify the impact of rider effect, censoring and preselection on the genetic analysis of competition data of dressage and show jumping of KWPN. Different models including rider effect were evaluated. To assess the impact of censoring, genetic parameters were estimated in data sets that differed in the degree of censoring. The effect of preselection on variance components was analysed by defining a binary trait (sport-status) depending on whether the horse has a competition record or not. This trait was included in a bivariate model with the competition trait and used all horses registered by KWPN since 1984. Results showed that performance in competition for dressage and show jumping is a heritable trait (h2 ~ 0.11-0.13) and that it is important to account for the effect of rider in the genetic analysis. Censoring had a small effect on the genetic parameter for highest performance achieved by the horse. A moderate heritability obtained for sport-status indicates that preselection has a genetic basis, but the effect on genetic parameters was relatively small.


Posttraumatic stress disorder in the National Comorbidity Survey.
Data were obtained on the general population epidemiology of DSM-III-R posttraumatic stress disorder (PTSD), including information on estimated life-time prevalence, the kinds of traumas most often associated with PTSD, sociodemographic correlates, the comorbidity of PTSD with other lifetime psychiatric disorders, and the duration of an index episode. Modified versions of the DSM-III-R PTSD module from the Diagnostic Interview Schedule and of the Composite International Diagnostic Interview were administered to a representative national sample of 5877 persons aged 15 to 54 years in the part II subsample of the National Comorbidity Survey. The estimated lifetime prevalence of PTSD is 7.8%. Prevalence is elevated among women and the previously married. The traumas most commonly associated with PTSD are combat exposure and witnessing among men and rape and sexual molestation among women. Posttraumatic stress disorder is strongly comorbid with other lifetime DSM-III-R disorders. Survival analysis shows that more than one third of people with an index episode of PTSD fail to recover even after many years. Posttraumatic stress disorder is more prevalent than previously believed, and is often persistent. Progress in estimating age-at-onset distributions, cohort effects, and the conditional probabilities of PTSD from different types of trauma will require future epidemiologic studies to assess PTSD for all lifetime traumas rather than for only a small number of retrospectively reported "most serious" traumas.


Effect of PEG Grafting Density and Hydrodynamic Volume on Gold Nanoparticle-Cell Interactions: An Investigation on Cell Cycle, Apoptosis, and DNA Damage.
In this study, interactions of polyethylene glycol (PEG)-coated gold nanoparticles (AuNPs) with cells were investigated with particular focus on the relationship between the PEG layer properties (conformation, grafting density, and hydrodynamic volume) and cell cycle arrest, apoptosis, and DNA damage. Steric hindrance and PEG hydrodynamic volume controlled the protein adsorption, whereas the AuNP core size and PEG hydrodynamic volume were primary factors for cell uptake and viability. At all PEG grafting densities, the particles caused significant cell cycle arrest and DNA damage against CaCo2 and PC3 cells without apoptosis. However, at a particular PEG grafting density (∼0.65 chains/nm(2)), none of these severe damages were observed on 3T3 cells indicating discriminating behavior of the healthy (3T3) and cancer (PC3 and CaCo2) cells. It was concluded that the PEG grafting density and hydrodynamic volume, tuned with the PEG concentration and AuNP size, played an important role in particle-cell interactions.


Virtual worlds as a tool to facilitate weight management for young people.
Childhood obesity is a serious problem in the UK, with around 20% of children aged 10-11 being overweight or obese. Lifestyle interventions can be effective, but there is limited evidence of their effectiveness in delivering sustained weight loss. The present research explored potential of web-based, 3-dimensional virtual worlds (VWs) for facilitation of weight-management, well-being and patient and public involvement (PPI) for young people. Attendees of a weight management camp took part in induction sessions for use of the VW of Second Life. All participants successfully learned how to interact with one another and navigate the virtual environment. Participant appraisals of Second Life were varied. Some found it complicated and difficult to use, and some found it fun and the majority stated that they would choose to use VWs again. There is considerable potential for use of VWs to promote weight management, and Second Life or a similar VW could be used to deliver this. Potential barriers include members of the target sample having limited access to computers with necessary system requirements for running VWs, and that some may find VW-based educational experiences unappealing or challenging to navigate. For some however, VWs may provide a useful mode for provision of education, PPI and support relating to weight management.


Imetelstat, a telomerase inhibitor, differentially affects normal and malignant megakaryopoiesis.
Imetelstat (GRN163L) is a specific telomerase inhibitor that has demonstrated clinical activity in patients with myeloproliferative neoplasms (MPN) and in patients with solid tumors. The antitumor effects were associated with the development of thrombocytopenia, one of the common side effects observed in patients treated with imetelstat. The events underlying these adverse effects are not apparent. In this report, we investigated the potential mechanisms that account for imetelstat's beneficial effects in MPN patients and the manner by which imetelstat treatment leads to a reduction in platelet numbers. Using a well-established system of ex vivo megakaryopoiesis, we demonstrated that imetelestat treatment affects normal megakaryocyte (MK) development by exclusively delaying maturation of MK precursor cells. By contrast, additional stages along MPN MK development were affected by imetelstat resulting in reduced numbers of assayable colony-forming unit MK and impaired MK maturation. In addition, treatment with imetelstat inhibited the secretion of fibrogenic growth factors by malignant but not by normal MK. Our results indicate that the delay observed in normal MK maturation may account for imetelstat-induced thrombocytopenia, while the more global effects of imetelstat on several stages along the hierarchy of MPN megakaryopoiesis may be responsible for the favorable clinical outcomes reported in MPN patients.


Predictors of response to anti-TNF-alpha therapy among patients with rheumatoid arthritis: results from the British Society for Rheumatology Biologics Register.
Anti-tumour necrosis factor-alpha (TNF-alpha) therapies represent an important advancement in therapy for rheumatoid arthritis (RA). However, there remains a proportion of patients who do not improve despite therapy. These drugs are expensive and have the potential of serious toxicity. Therefore, it would be ideal to predict the patients who will respond, so that the use of these drugs can be targetted. To identify the clinical factors present at the start of anti-TNF-alpha therapy that are associated with response at 6 months in patients with RA. The British Society for Rheumatology (BSR) Biologics Register collects detailed data on all patients with a rheumatic disease receiving biologic therapy in the UK. We studied all patients with RA who had started etanercept (ETA) or infliximab (INF) and had achieved a minimum 6 months follow-up by 1 October, 2004. The disease status at the baseline and at 6 months was assessed using the Disease Activity Score (DAS28). The response was classified according to the European League against Rheumatism (EULAR) improvement criteria. The effect of baseline characteristics on response was studied using multivariate ordinal logistic regression. 2879 patients were included in this analysis (1267 ETA, 1612 INF). At the start of therapy, the mean age was 55 yrs, disease duration 14 yrs, baseline DAS28 6.7 and health assessment questionnaire (HAQ) 2.1. In all, 28% of ETA and 86% of INF patients were receiving methotrexate. After 6 months, 18% had a good EULAR response, of whom 9% were considered to be in remission and 50% had a moderate response. There was no overall difference in response rate between the two anti-TNF-alpha therapies. A higher baseline HAQ score correlated with a lower response rate while a better response was associated with the current use of NSAIDs and the use of methotrexate (MTX), although the latter only reached statistical significance with ETA [OR 1.82 (95% CI 1.38-2.40)]. There was a lower response rate among current smokers, particularly in patients receiving INF [OR 0.77 (95% CI 0.60-0.99)]. Age, disease duration, rheumatoid factor and the previous number of disease-modifying antirheumatic drugs (DMARDs) did not predict response to either drug. However, females were less likely to achieve remission. These data support an improved outcome among patients receiving MTX in combination with anti-TNF-alpha therapies. However, the most disabled patients were less likely to respond, despite concurrent MTX. The benefits of NSAIDs may reflect the relative absence of comorbidities in patients who can tolerate these drugs or the continuing presence of reversible inflammatory symptoms. The association of smoking and poor outcome with INF is a novel finding and may reflect alterations in pharmacokinetics. The inability of other baseline disease characteristics to predict the outcome suggests that other factors, including potential genetic differences in drug metabolism, may be influencing the response to anti-TNF-alpha therapies.


Identification and characterization of the human Set1B histone H3-Lys4 methyltransferase complex.
We previously identified a mammalian Set1A complex analogous to the yeast Set1/COMPASS histone H3-Lys4 methyltransferase complex (Lee, J.-H., and Skalnik, D. G. (2005) J. Biol. Chem. 280, 41725-41731). Data base analysis indicates that human Set1A protein shares 39% identity with an uncharacterized SET domain protein, KIAA1076, hereafter denoted Set1B. Immunoprecipitation and mass spectrometry reveal that Set1B associates with a approximately 450 kDa complex that contains all five non-catalytic components of the Set1A complex, including CFP1, Rbbp5, Ash2, Wdr5, and Wdr82. These data reveal two human protein complexes that differ only in the identity of the catalytic histone methyltransferase. In vitro assays demonstrate that the Set1B complex is a histone methyltransferase that produces trimethylated histone H3 at Lys(4). Both Set1A and Set1B are widely expressed. Inducible expression of the carboxyl terminus of either Set1A or Set1B decreases steady-state levels of both endogenous Set1A and Set1B protein, but does not alter the expression of the non-catalytic components of the Set1 complexes. A 123-amino acid fragment upstream of the Set1A SET domain is necessary for interaction with CFP1, Ash2, Rbbp5, and Wdr5. This protein domain is also required to mediate feedback inhibition of Set1A and Set1B expression, which is a consequence of reduced Set1A and Set1B stability when not associated with the methyltransferase complex. Confocal microscopy reveals that Set1A and Set1B each localize to a largely non-overlapping set of euchromatic nuclear speckles, suggesting that Set1A and Set1B each bind to a unique set of target genes and thus make non-redundant contributions to the epigenetic control of chromatin structure and gene expression.


Participatory Design of an Electronic Cross-Facility Health Record (ECHR) System for Pediatric Palliative Care: A Think-Aloud Study.
Pediatric palliative care (PPC) patients experience years of multisectoral and professional care. An electronic cross-facility health record (ECHR) system can support the immediate exchange of information among PPC professionals. Based on a needs assessment, a prototype ECHR system was developed. To evaluate potential users' perspective regarding the system, a qualitative observational study was conducted consisting of a concurrent think-aloud session and a semi-structured qualitative interview. Twenty PPC professionals (nurses, physicians) from specialized outpatient PPC teams, a PPC unit, and medical offices rated the ECHR system as a helpful tool to improve the exchange and collection of information, communication between PPC professionals, and treatment planning. From the user's point of view, the basic logic of the ECHR system should be further adapted to improve the interaction of data remirrored from patient records of outpatient and inpatient care with those entered via the system. The users wished for further functions (text search) and content (information on therapies). Some content, such as the treatment process, needs to be further adapted. The developed ECHR system needs to be more specific in some features by offering all available information; while for other features, be less specific to offer a quick overview. The ability to share information promptly and automatically was seen as a tremendous improvement to the quality of care for PPC patients.