QM/MM study of the stability of dimethyl ether in zeolites H-ZSM-5 and H-Y.
The methanol-to-hydrocarbons (MTH) process transforms C1 carbon sources to higher hydrocarbons, but details of the mechanism that leads to the formation of the first carbon-carbon bond remain unclear. Here, we present a computational investigation of how a crucial intermediate, dimethyl ether (DME), interacts with different zeolite catalysts (H-ZSM-5, H-Y) to gain insight into the initial stages in the MTH process. We use QM/MM computational simulations to model the conversion of methanol to DME in H-ZSM-5, which is a well characterised and important reaction intermediate. We analyse and compare the stability of DME on several acid sites in H-ZSM-5 and H-Y, and show that the more acidic and open "intersection sites" in the H-ZSM-5 framework are able to bond strongest with DME, with complete deprotonation of the acid site occurring. The conversion of methanol to DME in H-ZSM-5 is calculated as requiring a higher activation energy than framework methoxylation, which indicates that a stepwise (indirect) mechanism, through a methoxy intermediate, is the most likely route to DME formation during the initiation of the MTH process.


Virtual electric power wheelchair driving performance of individuals with spastic cerebral palsy.
Upper limb spasticity may impair the use of control interfaces such as joysticks for many individuals with disabilities such as cerebral palsy (CP). The aims of this study were to compare the driving performance of those with CP to that of control participants, to identify the impact of lead time on performance, and to compare two joystick designs, a standard movement sensing joystick and a novel isometric joystick. This study used a repeated-measures design to compare the performance of a group of participants with CP to that of participants without disabilities in a two-dimensional simulated driving task on a computer screen using the two control interfaces. The driving trials used varying "lead times," or the amount of warning time available to make movement decisions and turns. A total of 34 participants with CP and without disability were matched by age and sex into two groups. Participants with CP had lower driving performance in most variables of interest compared with controls. However, surprisingly, reducing lead time also reduced some performance errors, possibly because of more deliberate driving. The isometric joystick outperformed the movement sensing joystick in terms of performance errors but contributed to a prolonged reaction time. The isometric joystick was preferred by participants over the movement sensing joystick in this study and may be a future alternative for individuals with CP for both power mobility and computer access tasks.


Inhibitors of serine/threonine phosphatases enhance phosphorylation of the interferon-gamma receptor while selectively attenuating interferon-gamma-induced gene expression in human peripheral-blood monocytes.
Since many events following ligand-induced receptor clustering are controlled by serine and threonine (Ser/Thr) phosphorylation, we initiated an investigation into the role of Ser/Thr phosphatases in both phosphorylation of the interferon-gamma (IFN-gamma) receptor and IFN gamma-induced gene expression in human peripheral-blood monocytes. Whereas IFN gamma alone did not enhance phosphorylation of the IFN gamma receptor, treatment of monocytes with the Ser/Thr phosphatase inhibitors, okadaic acid and calyculin A, resulted in increased phosphorylation of the IFN gamma receptor. However, when these cells were analysed for IFN gamma-induced IP-10 gene expression, there was profound inhibition. Using three IFN gamma-induced early-response genes, IP-10, the Fc gamma receptor type I (Fc gamma RI) and ISG-54, we found selective sensitivity to pretreatment with okadaic acid and calyculin A. Whereas IFN gamma induction of IP-10 was blocked by both inhibitors, only calyculin A prevented Fc gamma RI-gene expression. Neither inhibitor prevented ISG-54 induction by IFN gamma. IFN-gamma-activated formation of the DNA-binding-protein complex FcRF gamma (which binds to the promoter of the Fc gamma RI gene) remained unaffected by okadaic acid or calyculin A. Therefore these data suggest that Ser/Thr phosphatases have no major part in IFN gamma-initiated signal transduction across the membrane, but selectively control the ultimate transcription of a set of early-response genes.


Recreational scuba divers' aversion to low-frequency underwater sound.
Increasing use of active low-frequency sonar by submarines and ships raises the risk of accidental exposure of recreational divers to low-frequency underwater sound (LFS). This study aimed to characterize the subjective responses of recreational scuba divers to LFS to ascertain the extent to which LFS may impact their enjoyment, comfort, or time spent underwater. Seventeen male and nine female recreational scuba divers participated. Diving was conducted in an acoustically transparent tank located within a larger anechoic pool. Subjects wore scuba gear and were positioned I m below the surface in a prone position. The sound transducer was located 4 m directly below the diver's head. Sound exposures consisted of three signal types (pure tone, 30 Hz hyperbolic sweep up, and 30 Hz hyperbolic sweep down) each presented at six center frequencies from 100 to 500 Hz and six sound pressure levels(SPL) ranging from 130 to 157 dB re 1 microPa. The duration of each sound exposure was 7 s. Subjects responded via an underwater console to rate aversion to LFS on a category-ratio scale, and to indicate the presence or absence of vibration of any body part. Aversion to LFS and the percent incidence of vibration increased as the SPL increased. The percent incidence of vibration decreased linearly with increasing frequency. At the highest SPL the probability that an aversion rating would exceed Very Severe (7 on the category-ratio scale) was predicted to be 19%. There was no significant difference in aversion among signal types. The 100 Hz frequency was the most aversive frequency (P < 0.05). A plot of aversion vs. frequency showed a U-shaped function with minimum aversion at 250 Hz. In conclusion, diver aversion to LFS is dependent upon SPL and center frequency. The highest aversion rating was given for 100 Hz, this frequency corresponded with the greatest probability of detecting vibration. Factors other than vibration seem to account for aversion to the highest frequencies. Our data suggest that LFS exposures up to 145 dB re 1 microPa at frequencies between 100 and 500 Hz will have minimal impact on the recreational diver.


Cutaneous vascular response to exercise and acute hypoxia.
Six normal young men were studied during 50 min of moderate exercise (100-137 W) that included one 15-min (protocol 1) or two 10-min periods of breathing 11-12% O2 (in N2) (protocol 2). Absolute work intensity was kept constant for each subject, but relative severity increased during hypoxia owing to reduction in maximum O2 uptake. Our question was whether hypoxia causes cutaneous vasoconstriction; this in turn should cause a rise in esophageal temperature (Tes) and a shift in the forearm skin blood flow (SkBF)-Tes relationship. In all subjects forearm blood flow (FBF) (venous occlusion plethysmography) rose throughout exercise and Tes tended to stabilize. Neither 10- nor 15-min periods of hypoxia caused systematic changes in FBF or Tes or their relationship to each other. We conclude that hypoxia equivalent to that incurred at 4,500-5,000 m does not significantly alter the short-term regulation of SkBF and body temperature during moderate exercise. Net cutaneous vasoconstriction is not elicited by arterial chemoreflexes under these conditions.


S-Adenosyl-L-methionine-competitive inhibitors of the histone methyltransferase EZH2 induce autophagy and enhance drug sensitivity in cancer cells.
The enhancer of zeste homolog 2 (EZH2) has emerged as a novel anticancer target. Various EZH2 inhibitors have been developed in recent years. Among these, 3-deazaneplanocin A (DZNep) is known to deplete EZH2 protein expression through an indirect pathway. In contrast, GSK343 directly inhibits enzyme activity through an S-adenosyl-L-methionine-competitive pathway. Therefore, we proposed that DZNep and GSK343 may exert differential effects against cancer cells. In this study, we found that GSK343 but not DZNep induced autophagic cell death of cancer cells. Inhibition of EZH2 expression was not required for GSK343-induced autophagy. In addition, GSK343 enhanced the anticancer activity of a multikinase inhibitor, sorafenib, in human hepatocellular carcinoma cells. Our results show that GSK343 is a more potent anticancer agent than DZNep, and for the first time, we show that it acts as an autophagy inducer.


Effect of Ly49 haplotype variance on NK cell function and education.
The class I MHC-specific receptors expressed by murine NK cells exhibit remarkable variation. Specific activating killer Ig-related receptor/Ly49 have major effects on autoimmune and infectious disease induction and outcome in humans and mice. However, these studies are greatly affected by individual background genetics. Furthermore, the educational impact of variable inhibitory KIR/Ly49 gene numbers on NK cell development and the subsequent ability to survey for MHC class I (MHC-I) expression remain unknown. To address these questions, Ly49 congenic mice were generated that maintain a 129-derived Ly49 gene cluster on a C57BL/6 genetic background (B6.Ly49(129) mice), and the in vitro and in vivo NK cell function of these mice was compared with their inbred parental 129S1 and C57BL/6 counterparts. Notably, target cell recognition directed by activating Ly49 receptors was profoundly affected by allelic variation in B6.Ly49(129) congenic cells versus C57BL/6 NK cells. Furthermore, when assessing NK cell function based on education and subsequent recognition of the C57BL/6 MHC-I haplotype by inhibitory Ly49 receptors, B6.Ly49(129) congenic mice exhibited robust NK cell activity, demonstrating efficient NK cell education by the 129S1 Ly49 cluster during development. The responsiveness of NK cells expressing 129S1 Ly49 was shown to be mediated by subsets expressing one or more self-MHC receptors, including Ly49I, Ly49O, Ly49V, and NKG2A. These findings demonstrate that the genetically segregating and diverse MHC-I and Ly49 loci in mice exhibit independent and epistatic effects on NK cell education that can be uncoupled during the intercrossing of inbred strains.


Laparoscopic subtotal gastrectomy for the treatment of advanced gastric cancer: a comparison with open procedure at the beginning of the learning curve.
In the last decades, after some initial concern, laparoscopic subtotal gastrectomy (LSG) is gaining popularity also for the treatment of advanced gastric cancer (AGC). The aim of this study is to compare a single surgeon initial experience on LSG and open subtotal gastrectomy in terms of surgical safety and radicality, postoperative recovery and midterm oncological outcomes. a case control study was conducted matching the first 13 LSG for AGC with 13 open procedures performed by the same surgeon. Operative and pathological data, postoperative parameters and midterm oncological outcomes were analyzed. There was no significant difference in mortality (0%) and morbidity, while the laparoscopic approach allowed lower analgesic consumption and faster bowel movement recovery. Operation time was significantly higher in LSG patients (301.5 vs 232 min, p: 0.023), with an evident learning curve effect. Both groups had a high rate of adequate lymph node harvest, but the number was significantly higher in LSG group (p: 0.033). No significant difference in survival was registered. Multivariate analysis identified age at diagnosis, diffuse-type tumor, pN and LODDS as independent predictors of worse prognosis. LSG can be safely performed for the treatment of AGC, allowing faster postoperative recovery.


A field evaluation of the Hardy TB MODS Kit™ for the rapid phenotypic diagnosis of tuberculosis and multi-drug resistant tuberculosis.
Even though the WHO-endorsed, non-commercial MODS assay offers rapid, reliable TB liquid culture and phenotypic drug susceptibility testing (DST) at lower cost than any other diagnostic, uptake has been patchy. In part this reflects misperceptions about in-house assay quality assurance, but user convenience of one-stop procurement is also important. A commercial MODS kit was developed by Hardy Diagnostics (Santa Maria, CA, USA) with PATH (Seattle, WA, USA) to facilitate procurement, simplify procedures through readymade media, and enhance safety with a sealing silicone plate lid. Here we report the results from a large-scale field evaluation of the MODS kit in a government service laboratory. 2446 sputum samples were cultured in parallel in Lowenstein-Jensen (LJ), conventional MODS and in the MODS kit. MODS kit DST was compared with conventional MODS (direct) DST and proportion method (indirect) DST. 778 samples (31.8%) were Mycobacterium tuberculosis culture-positive. Compared to conventional MODS the sensitivity, specificity, positive, and negative predictive values (95% confidence intervals) of the MODS Kit were 99.3% (98.3-99.8%), 98.3% (97.5-98.8%), 95.8% (94.0-97.1%), and 99.7% (99.3-99.9%). Median (interquartile ranges) time to culture-positivity (and rifampicin and isoniazid DST) was 10 (9-13) days for conventional MODS and 8.5 (7-11) for MODS Kit (p<0.01). Direct rifampicin and isoniazid DST in MODS kit was almost universally concordant with conventional MODS (97.9% agreement, 665/679 evaluable samples) and reference indirect DST (97.9% agreement, 687/702 evaluable samples). MODS kit delivers performance indistinguishable from conventional MODS and offers a convenient, affordable alternative with enhanced safety from the sealing silicone lid. The availability in the marketplace of this platform, which conforms to European standards (CE-marked), readily repurposed for second-line DST in the near future, provides a fresh opportunity for improving equity of access to TB diagnosis and first and second-line DST in settings where the need is greatest.


The molecular relatedness of R factors in enterobacteria of human and animal origin.
The molecular length and DNA homology of R factors isolated from enterobacteria of human and animal origin have been examined. DNA from plasmids of the same compatibility group, whether of human or animal origin is indistinguishable, after allowance has been made for the regions coding for different antibiotic resistances. These results indicate that there is a common pool of R factors in man and ainmals.


Spatial attentional control is not impaired in schizophrenia: Dissociating specific deficits from generalized impairments.
A large literature has established that people with schizophrenia are impaired on tasks that require attentional control. However, evidence is mixed as to whether these impairments are specific deficits (Oltmanns & Neale, 1975) or merely reflect a generalized impairment (Dickinson & Harvey, 2009). Recent evidence also suggests visual attentional control for encoding into working memory may be selectively spared in people with schizophrenia (Gold et al., 2006). The current study used a cued backward masking task to investigate 23 people with schizophrenia and 27 healthy controls. People with schizophrenia were hypothesized to perform better on invalidly cued trials when making a simple identification or location judgment. However, we found schizophrenia impaired performance on both valid and invalid cues to the same degree whether the cue was a stored representation (top-down) or presented at the location of the stimulus (bottom-up). In contrast to a large neuropsychological literature, these findings suggest that people with schizophrenia show no specific spatial attentional control deficit. The errors that they make on such task may be consistent with a generalized impairment.


Physiopathology of H3-receptors and pharmacology of betahistine.
This article reviews published research on the physiology of histamine H3-receptors. The function of this inhibitory autoreceptor, its localisation and influence on histaminergic neurones as well as histamine-controlled processes are presented together with the role of H3-receptors in the vestibular system. In addition to a summary of the properties of the main H3-agonists and -antagonists, the pharmacology of betahistine and its place in the treatment of vertigo are discussed.


[Results of mechanical ventilation in premature infants with respiratory distress syndrome].
This paper reveals the results of synchronized intermittent mandatory ventilation in premature babies over a period of 8 years. Out of 1532 mechanical ventilated newborns 438 were prematures with severe hyaline membrane disease. The incidence of barotraumatic complications (Pneumothorax 1.2%, pulmonary interstitial emphysema 3% and bronchopulmonary dysplasia 3.4%) was relatively low. We discuss this as an effect of using low respirator frequencies guaranteering sufficient emptying time of the lungs.


Bulk properties of aqueous graphene oxide and reduced graphene oxide with surfactants and polymers: adsorption and stability.
A diverse range of molecular surfactants and polymers have been incorporated into aqueous graphene oxide (GO) and reduced graphene oxide (rGO) dispersions in order to understand the complex relationship between surface chemistry, surface forces and interfacial thermodynamics of these materials with typical amphiphiles. Surfactant additives were systematically varied in terms of their charge and hydrophobicity to reveal important structure-function relationships affecting adsorption and interaction with GO and rGO surfaces. Small-angle (and ultra small-angle) neutron scattering was employed to examine and monitor the interactions and self-assembly in each system. Charge was found to be the overriding factor driving adsorption, as cationic surfactants very readily adsorbed to both GO and rGO, whereas anionic surfactants gave little to no evidence of adsorption despite possessing hydrophobic tail-groups. Molecules of neutral charge such as nonionic and zwitterionic surfactants as well as neutral polymers also showed strong affinities for GO and rGO, indicating that dispersion and dipole (induction polarisation) interactions also play a significant role in adsorption with these materials. Modelling the neutron data revealed in many cases a q-2 slope in the low q and ultra low q regions, indicating that scattering was occurring from large, flat surfaces (lamellae or bilayers), suggesting an effective flattening of the sheets in dispersion. The results presented thus help to form a roadmap for the behaviour of GO and rGO with surfactants and polymers, relevant to adsorption, stabilisation, formulation and coating in aqueous environments as adsorbent and functional materials.


Multiple defects in energy metabolism in Alzheimer's disease.
Alzheimer's disease (AD) is the most common form of dementia in old age. Cognitive impairment in AD may be partially due to overall hypometabolism. Indeed, AD is characterized by an early region-specific decline in glucose utilization and by mitochondrial dysfunction, which have deleterious consequences for neurons through increased production of reactive oxygen species (ROS), ATP depletion and activation of cell death processes. In this article, we provide an overview of the alterations on energetic metabolism occurring in AD. First, we resume the evidences that link the 'metabolic syndrome' with increased risk for developing AD and revisit the major changes occurring on both extra-mitochondrial and mitochondrial metabolic pathways, as revealed by imaging studies and biochemical analysis of brain and peripheral samples obtained from AD patients. We also cover the recent findings on cellular and animal models that highlight mitochondrial dysfunction as a fundamental mechanism in AD pathogenesis. Recent evidence posits that mitochondrial abnormalities in this neurodegenerative disorder are associated with changes in mitochondrial dynamics and can be induced by amyloid-beta (Aβ) that progressively accumulates within this organelle, acting as a direct toxin. Furthermore, Aβ induces activation of glutamate N-methyl-D-aspartate receptors (NMDARs) and/or excessive release of calcium from endoplasmic reticulum (ER) that may underlie mitochondrial calcium dyshomeostasis thereby disturbing organelle functioning and, ultimately, damaging neurons. Throughout the review, we further discuss several therapeutic strategies aimed to restore neuronal metabolic function in cellular and animal models of AD, some of which have reached the stage of clinical trials.


Intracortical remodeling in adult rat long bones after fatigue loading.
Intracortical remodeling in the adult skeleton removes and replaces areas of compact bone that have sustained microdamage. Although studies have been performed in animal species in which there is an existing baseline of remodeling activity, laboratory rodents have been considered to have limited suitability as models for cortical bone turnover processes because of a lack of haversian remodeling activity. Supraphysiological cyclic axial loading of the ulna in vivo was used to induce bending with consequent fatigue and microdamage. Right ulnae of adult Sprague-Dawley rats were fatigue-loaded to a prefailure stopping point of 30% decrease in ulnae whole bone stiffness. Ten days after the first loading, left ulnae were fatigued in the same way. Ulnae were harvested immediately to allow comparison of the immediate response of the left ulna to the fatigue loads, and the biological response of the right leg to the fatigue challenge. Histomorphometry and confocal microscopy of basic fuchsin-stained bone sections were used to assess intracortical remodeling activity, microdamage, and osteocyte integrity. Bone microdamage (linear microcracks, as well as patches of diffuse basic fuchsin staining within the cortex) occurred in fatigue-loaded ulnar diaphyses. Ten days after fatigue loading, intracortical resorption was activated in ulnar cortices. Intracortical resorption occurred in preferential association with linear-type microcracks, with microcrack number density reduced almost 40% by 10 days after fatigue. Resorption spaces were also consistently observed within areas of the cortex in which no bone matrix damage could be detected. Confocal microscopy studies showed alterations of osteocyte and canalicular integrity around these resorption spaces. These studies reveal that: (1) rat bone undergoes intracortical remodeling in response to high levels of cyclic strain, which induce microdamage in the cortex; and (2) intracortical resorption is associated both with bone microdamage and with regions of altered osteocyte integrity. From these studies, we conclude that rats can initiate haversian remodeling in long bones in response to fatigue, and that osteocyte death or damage may provide one of the stimuli for this process.


JAMM: a metalloprotease-like zinc site in the proteasome and signalosome.
The JAMM (JAB1/MPN/Mov34 metalloenzyme) motif in Rpn11 and Csn5 underlies isopeptidase activities intrinsic to the proteasome and signalosome, respectively. We show here that the archaebacterial protein AfJAMM possesses the key features of a zinc metalloprotease, yet with a distinct fold. The histidine and aspartic acid of the conserved EX(n)HS/THX(7)SXXD motif coordinate a zinc, whereas the glutamic acid hydrogen-bonds an aqua ligand. By analogy to the active site of thermolysin, we predict that the glutamic acid serves as an acid-base catalyst and the second serine stabilizes a tetrahedral intermediate. Mutagenesis of Csn5 confirms these residues are required for Nedd8 isopeptidase activity. The active site-like architecture specified by the JAMM motif motivates structure-based approaches to the study of JAMM domain proteins and the development of therapeutic proteasome and signalosome inhibitors.


The contribution of physical activity and sedentary behaviours to the growth and development of children and adolescents: implications for overweight and obesity.
The obesity epidemic is a global trend and is of particular concern in children. Recent reports have highlighted the severity of obesity in children by suggesting: "today's generation of children will be the first for over a century for whom life expectancy falls." This review assesses the evidence that identifies the important role of physical activity in the growth, development and physical health of young people, owing to its numerous physical and psychological health benefits. Key issues, such as "does a sedentary lifestyle automatically lead to obesity" and "are levels of physical activity in today's children less than physical activity levels in children from previous generations?", are also discussed.Today's environment enforces an inactive lifestyle that is likely to contribute to a positive energy balance and childhood obesity. Whether a child or adolescent, the evidence is conclusive that physical activity is conducive to a healthy lifestyle and prevention of disease. Habitual physical activity established during the early years may provide the greatest likelihood of impact on mortality and longevity. It is evident that environmental factors need to change if physical activity strategies are to have a significant impact on increasing habitual physical activity levels in children and adolescents. There is also a need for more evidence-based physical activity guidelines for children of all ages. Efforts should be concentrated on facilitating an active lifestyle for children in an attempt to put a stop to the increasing prevalence of obese children.


Illness behavior after severe brain injury: two case reports.
This paper introduces the concept of illness behavior to occupational therapists working with patients with acquired neurological impairments. The paper presents two case reports of patents with unequivocal severe brain trauma who demonstrated help-seeking and dependency behaviors that could not be accounted for by brain damage alone. Incorporating the illness behavior concept in an understanding of the patients' behavior difficulties assisted in the development of an appropriate treatment plan and interventions. This paper emphasizes that severe neurological sequelae and illness behavior may coexist in the same patient. Without an understanding of the personality and environmental factors that may influence recovery, rehabilitative efforts may be less than optimally effective.


The impact of individualized evidence-based decision support on aneurysm patients' decision making, ideals of autonomy, and quality of life.
Patients with an asymptomatic abdominal aneurysm and their surgeon were randomized to receive a general brochure (GB) or an IB presenting survival information and a ranking of the treatment strategies. Before and after receiving the brochure, patients filled out questionnaires on their behavior during the consultation, ideals of patient autonomy, and quality of life. Surgeons answered a short checklist evaluating the consultation. One hundred patients participated, 49 in the intervention, 51 in the control group. The IB group had a better understanding of important issues in the treatment decision, had prepared more questions, and was less satisfied with the duration of the consultation. Their impression that the surgeon perceived them more as a medical problem than a patient with a problem increased. They agreed less with the surgeon's advice and lost some of their belief in "the doctor knows best.'' Beforehand, the IB group had a stronger preference for patient-based decisions, but afterward they displayed more surgeon-based decisions. No effects were seen on patients' quality of life. Individualized evidence-based information stimulated patients' active involvement but in the context of our study led to less patient-based decisions. Patient-made decisions and patient autonomy should, however, not be equated.


Extrathymic Aire-expressing cells support maternal-fetal tolerance.
Healthy pregnancy requires tolerance to fetal alloantigens as well as syngeneic embryonic and placental antigens. Given the importance of the autoimmune regulator (Aire) gene in self-tolerance, we investigated the role of Aire-expressing cells in maternal-fetal tolerance. We report that maternal ablation of Aire-expressing (Aire +) cells during early mouse pregnancy caused intrauterine growth restriction (IUGR) in both allogeneic and syngeneic pregnancies. This phenotype is immune mediated, as IUGR was rescued in Rag1-deficient mice, and involved a memory response, demonstrated by recurrence of severe IUGR in second pregnancies. Single-cell RNA sequencing demonstrated that Aire + cell depletion in pregnancy results in expansion of activated T cells, particularly T follicular helper cells. Unexpectedly, selective ablation of either Aire-expressing medullary thymic epithelial cells or extrathymic Aire-expressing cells (eTACs) mapped the IUGR phenotype exclusively to eTACs. Thus, we report a previously undescribed mechanism for the maintenance of maternal-fetal immune homeostasis and demonstrate that eTACs protect the conceptus from immune-mediated IUGR.


Effect of trypsin inhibitor activity in soya bean on growth performance, protein digestibility and incidence of sub-clinical necrotic enteritis in broiler chicken flocks.
1. The effect of three different levels of dietary trypsin inhibitor activity (achieved by varying the amount of non-toasted full fat soya bean in replacement for toasted full fat soya bean) on the incidence of spontaneously-occurring sub-clinical necrotic enteritis (NE) in broiler chickens was compared. A fourth dietary treatment compared the effect of a diet that used potato protein concentrate as the major protein source. The determined trypsin inhibitor activity increased with the increasing content of non-toasted soya bean: 1·90, 6·21, 8·46 and 3·72 mg/g for the three soya bean diets (0, 100 and 200 g of non-toasted soya bean/kg) and the potato protein diet respectively. 2. Although increasing amounts of the non-toasted full-fat soya bean increased the feed intakes of the birds, there was a marked reduction in protein digestibility, weight gain and feed conversion efficiency. 3. There was a linear increase in sub-clinical NE lesions in the duodenum, jejunum, mid small intestine and ileum with increasing non-toasted soya bean. Caecal Clostridium perfringens counts increased with the increasing dietary content of non-toasted soya bean. Serum α-toxin antibodies were higher in the birds fed the 200 g non-toasted soya bean/kg diet compared with the other diets. 4. The results demonstrated that variation in the amount of non-toasted dietary soya bean not only affects growth performance of broilers but also affects the incidence of sub-clinical necrotic enteritis in the flock. Ensuring the lowest possible trypsin-inhibitor activity in soya bean samples is a valuable tool to improve the health and welfare of birds and in reducing the financial losses from this disease.


[Influence of ippotherapy on primary constipation].
Effective treatment of primary constipation remains one of problematic issues. The disease may be represented individually in the form of functional constipation, and in most of cases it is observed in the form of irritable bowel syndrome or it is conjugated with other functional disorders of bowels. Treatment with combined preparations and means of pluripotential orientation are more and more acknowledged. Ippotherapy is distinguished with its complex action. Aim of the research was to determine influence of the given natural method on dynamics of primary constipation. The research had been held among eleven patients, nine of whom were women and two men. In five cases functional constipation was diagnosed, in six cases - irritable bowel syndrome. Seven patients have been treated with ippotherapy from the very beginning and four of them underwent this treatment after one month of pharmacotherapy. Ippotherapy lasted within five weeks. On a general basis three sessions were held in a week, and after pharmacotherapy - two sessions. Before the beginning of the course of treatment and after its completion patients filled in questionnaires of self-appraisal. Subjective estimation of the dynamics of symptoms was handled in accordance with the method of nonparametric statistics - appraisal criteria had been calculated. All of the examined people have mentioned improvement of health condition after ippotherapy; nine of them have mentioned significant improvement. According to the accurate statistics result of the impact of ippotherapy on all four manifestations of constipation - intervals between defecations have been reduced to the norm, contractions during defecation have reduced, and excrements were of normal consistence and configuration, the sense of fatigue has disappeared. In the case of irritated bowel syndrome according to accurate statistics the episodes with abdominal pains and abdominal swelling have reduced. Iippotherapy was less effective in treatment of postprandial distress syndrome and practically ineffective in case of heartburn. It is important to note that in no cases of ippotherapy no complication of any syndrome or occurrence of new symptoms was revealed. In the process of treatment no procedural discomfort had been observed. Received data confirm manifested positive influence of ippotherapy on the course of functional disorders of bowels, which in case of availability should be considered at the determination of the strategy of management of the given disease.


Gyrodactylus longipes n. sp. (Monogenea: Gyrodactylidae) from farmed gilthead seabream (Sparus aurata L.) from the Mediterranean.
Gyrodactylus longipes n. sp. (Monogenea, Gyrodactylidae) is described from the gills of farmed juvenile gilthead seabream (Sparus aurata L.) from two sites located in Italy and Bosnia-Herzegovina and represents the second species of Gyrodactylus to be described from S. aurata. Gyrodactylus orecchiae Paladini, Cable, Fioravanti, Faria, Di Cave et Shinn, 2009 was the first gyrodactylid to be described from S. aurata, from populations cultured in Albania and Croatia. In the current study, G. longipes was found in a mixed infection with G. orecchiae on fish maintained in Latina Province, Italy, thus extending the reported distribution of the latter throughout the Mediterranean. The morphology of the opisthaptoral hard parts of G. longipes is compared to those of G. orecchiae, using light and scanning electron microscopy. Gyrodactylus longipes is characterised by having larger, elongated ventral bar processes and long, triangular-shaped toe region to their marginal hook sickles which, by comparison, are rhomboid in G. orecchiae. The marginal hook sickles of G. longipes are almost double the size of G. orecchiae which allows for their rapid discrimination from each other in mixed infections. A comparison of the DNA sequence of the ribosomal internal transcribed spacer 1 and 2 regions (ITS1 and ITS2) of G. longipes with the corresponding sequence from G. orecchiae and with those available in GenBank, supports the separate species status of G. longipes. Part of this study necessitated an overview of the existing Gyrodactylus fauna from Italy and Bosnia-Herzegovina; a summary from each country is provided here to assist future investigations.


The impact of early mobility on functional recovery after hip fracture surgery.
To examine the effect of early mobility (EM) on functional recovery after hip fracture surgery, and to investigate the potential factors that delay mobility. In this retrospective observational study, 110 hip fracture patients were divided into two groups according to the days between surgery and mobility referred to as the EM and the delayed mobility groups. Demographic data, perioperative data, functional outcomes, and discharge destination were compared statistically between the groups using univariate analysis and logistic regression analysis. As a sensitivity analysis, the factors associated with the timing of physiotherapy were also assessed. The EM group had significantly better walking ability and Barthel index (p < 0.05), and home discharge rate (p = 0.004). The factors associated with delayed mobility (odds ratio; 95% confidence interval) were delayed postoperative physiotherapy initiation (3.59; 1.76-7.33), days from admission to surgery (1.23; 1.04-1.46), and postoperative CRP (1.14; 1.01-1.29) and hemoglobin level (0.72; 0.54-0.96). Furthermore, patients who received surgery on the day before any holiday were significantly delayed in physiotherapy intervention (p = 0.006). This study demonstrated that EM after hip fracture surgery was associated with improving functional recovery and home discharge rate, and early physiotherapy intervention was associated with EM.


Urinary Pesticide Levels in Children and Adolescents Residing in Two Agricultural Communities in Mexico.
The use of pesticides in agricultural activities has increased significantly during the last decades. Several studies have reported the health damage that results from exposure to pesticides. In Mexico, hundreds of communities depend economically on agricultural activities. The participation of minors in this type of activity and their exposure to pesticides represents a potential public health problem. A cross-sectional study was conducted, in which urine samples (first-morning urine) were taken from children under 15 years of age in both communities. A total of 281 urine samples obtained in both communities were processed for the determination of pesticides with high-performance liquid chromatography together with tandem mass spectrometry. In 100% of the samples, at least two pesticides of the 17 reported in the total samples were detected. The presence of malathion, metoxuron, and glyphosate was remarkable in more than 70% of the cases. Substantial differences were detected regarding the other compounds. It is necessary to carry out long-term studies to determine the damage to health resulting from this constant exposure and to inform the health authorities about the problem in order to implement preventive measures.


Permanent Erb's palsy: a lack of a relationship with obstetrical risk factors.
Our objective was to investigate the association between permanent Erb's palsy and the presence of historic obstetrical risk factors. Cases of documented permanent Erb's palsy from our national registry of children with Erb's palsy were extracted and analyzed for the purpose of this descriptive study. Maternal and neonatal records were reviewed for demographic data, prenatal care, labor characteristics, delivery outcome, and long-term follow-up. Sixty-three infants with permanent Erb's palsy were identified. Seventeen (27.0%) mothers were nulliparous. Mean +/- SD (range) gestational age at delivery and birthweight were 39.9 weeks +/- 1.3 (37-43) and 4501 g +/- 625 (3352-6905), respectively. Maternal and perinatal characteristics of these cases were (n [%]): nondiabetic-56 (89%); weight gain <40 lb-48 (76%); normal labor-57 (91%); 2nd stage <2.0 hr-54 (86%); midpelvic procedure-13 (21%); and shoulder dystocia-59 (94%). There were no statistically significant differences between patients with birthweight >4500 g (n = 26 [41%]) and those with birthweight < or =4500 g (n = 37 [59%]). These data suggest that historic risk factors for neonatal brachial plexus injury may not be associated with permanent Erb's palsy.


[Prognosis of schizophrenia from the viewpoint of patients and relatives. An explorative study].
This study is aimed at exploring what schizophrenic patients and their closest relatives expect the further course of the illness will be like and how it can be influenced. Problem-centered interviews were conducted with 31 schizophrenic patients and their closest relatives at discharge from hospital treatment. The verbatim transcripts of the interviews were analyzed by means of structuring qualitative content analysis. Most frequently, the respondents expected an improvement of the illness or they were unsure whether the actual recovery from psychosis will persist or whether a further relapse will occur. Less frequently, the respondents were sure that this will be the case or that the illness will take a chronic, eventually deteriorating course. The majority was convinced that the course of the illness can be influenced, by psychiatric treatment as well as by the patients themselves. As concerns the social situation in the near future, particularly changes of the occupational status were hoped for. The assessment of the prognosis of the schizophrenic illness by most patients and relatives appears quite realistic. Rather than considering themselves as helpless victims they see opportunities for influencing the further course of the illness. This should have a positive influence on the readiness to use mental health service and to comply with treatment recommendations.


Designing an Alternative, Community Integrated Model of Residential Aged Care for People Living with Dementia: Nominal Group Technique and Thematic Analysis.
Small-scale models of dementia care are a potential solution to deinstitutionalize residential aged care and have been associated with improved resident outcomes, including quality of life and reduced hospitalizations for people living with dementia. This study aimed to generate strategies and ideas on how homes for people living with dementia in a village setting within a suburban community, could be designed and function without external boundaries. In particular, how could residents of the village and members of the surrounding community access and engage safely and equitably so that interpersonal connections might be fostered? Twenty-one participants provided an idea for discussion at three Nominal Group Technique workshops, including people living with dementia, carers or former carers, academics, researchers, and clinicians. Discussion and ranking of ideas were facilitated in each workshop, and qualitative data were analyzed thematically. All three workshops highlighted the importance of a surrounding community invested in the village; education and dementia awareness training for staff, families, services, and the community; and the necessity for adequately and appropriately trained staff. An appropriate mission, vision, and values of the organization providing care were deemed essential to facilitate an inclusive culture that promotes dignity of risk and meaningful activities. These principles can be used to develop an improved model of residential aged care for people living with dementia. In particular, inclusivity, enablement, and dignity of risk are essential principles for residents to live meaningful lives free from stigma in a village without external boundaries.


ACTH- and prolactin-producing pituitary gland microadenoma with biphasic features of atypia and intermediate filament expression.
Herein, we report the case of a 28-year old woman clinically presenting with unclear weight gain over the last years. The patient displayed facial and neck edema in combination with unobtrusive striae distensae. Endocrinological examinations led to the diagnosis of Cushing's disease. Neuroradiological examination revealed an intrasellar tumor mass of 7 mm in diameter. Subsequently, transsphenoidal tumor resection was performed. Histological and immunohistochemical investigations revealed a pituitary gland adenoma showing a biphasic tumor growth pattern with two morphologically different tumor areas producing ACTH and prolactin respectively. Co-expression of ACTH and prolactin is exceedingly rare in pituitary adenoma. To our surprise, both tumor areas exhibited features of atypia consisting in elevated MIB-1 proliferation index in the ACTH-producing portion as well as p53 expression selectively in the prolactin-producing tumor parts. To our knowledge, this is the first case of an ACTH- and prolactin-producing pituitary gland adenoma exhibiting biphasic features of atypia.


Fingerprint Presentation Attack Detector Using Global-Local Model.
The vulnerability of automated fingerprint recognition systems (AFRSs) to presentation attacks (PAs) promotes the vigorous development of PA detection (PAD) technology. However, PAD methods have been limited by information loss and poor generalization ability, resulting in new PA materials and fingerprint sensors. This article thus proposes a global-local model-based PAD (RTK-PAD) method to overcome those limitations to some extent. The proposed method consists of three modules, called: 1) the global module; 2) the local module; and 3) the rethinking module. By adopting the cut-out-based global module, a global spoofness score predicted from nonlocal features of the entire fingerprint images can be achieved. While by using the texture in-painting-based local module, a local spoofness score predicted from fingerprint patches is obtained. The two modules are not independent but connected through our proposed rethinking module by localizing two discriminative patches for the local module based on the global spoofness score. Finally, the fusion spoofness score by averaging the global and local spoofness scores is used for PAD. Our experimental results evaluated on LivDet 2017 show that the proposed RTK-PAD can achieve an average classification error (ACE) of 2.28% and a true detection rate (TDR) of 91.19% when the false detection rate (FDR) equals 1.0%, which significantly outperformed the state-of-the-art methods by ~10% in terms of TDR (91.19% versus 80.74%).


Features of aura in paediatric migraine diagnosed using the ICHD 3 beta criteria.
Background In children and adolescents, the prevalence rate of migraine with aura is 1.6%. Few studies concerning migraine with aura features in paediatric population have been reported. Aim The aim of our study was to investigate clinical features of aura in a retrospective cohort of children with migraine with aura. Furthermore, we studied whether the International Classification of Headache Disorder (ICHD) 3 beta version criteria could efficiently detect migraine with aura in a paediatric population. Results We included 164 patients who experienced aura associated with headache (mean age 9.92 ± 2.64 years). When the ICHD-II criteria were used, a final diagnosis of migraine with typical aura was obtained in 15.3% of patients, probable migraine with typical aura in 13.4%, and typical aura with headache in 61.8%, while in in 9.5% of patients the diagnosis was undetermined. According to ICHD-3 beta, we diagnosed migraine with typical aura in 77.7% of patients, probable migraine with typical aura in 13.4%, and an undetermined diagnosis in 9.5% (less than two attacks). Conclusion Aura features did not depend on age and were similar to those of adults. However, the headache could be difficult to classify if headache duration was considered. In this view, the ICHD-3 beta offers the advantage of not considering headache features, including pain duration, for the diagnosis of migraine with typical aura, thus making this diagnosis easier in children and adolescents.


Successful prophylaxis against experimental streptococcal endocarditis with bacteriostatic antibiotics.
Because bacteriostatic concentrations of vancomycin are effective in prophylaxis against endocarditis due to Streptococcus sanguis in rats, the efficacy of three other bacteriostatic antibiotics was investigated against three different streptococcal species that cause subacute endocarditis in humans: Streptococcus intermedius. S. sanguis, and Streptococcus mitior. Rats were challenged by intravenous injection of 2 x 10(5) colony-forming units of streptococci 24 hr after intracardiac insertion of a transaortic catheter and 30 min after intravenous injection of various doses of clindamycin, erythromycin, and doxycycline. Significant protection was achieved with all three antibiotics, but only clindamycin was fully effective against all three species at doses that simulated serum levels achievable in humans after oral administration. Endocarditis was prevented by antibiotic concentrations in serum far below minimal bactericidal concentrations for these streptococci. Furthermore, serum at the time of bacterial challenge was not bactericidal. Therefore, single doses of nonbactericidal antibiotics prevented endocarditis in rats by mechanisms other than bacterial killing.


[Selective binding of oligodeoxyribonucleotides with Escherichia coli RNA-polymerase and their effect on DNA-dependent RNA synthesis].
It was shown previously, that E. coli RNA polymerase selectively binds certain fractions of oligoribonucleotides with the length greater than or equal to 5 nucleotides from the mixtures of random oligonucleotides of definite length. The data presented demonstrate, that E. coli RNA polymerase from the mixtures of random oligodeoxynucleotides of various length selectively binds oligodeoxynucleotides with the length greater than or equal to 9. The activity of the enzyme correlates with its ability to bind oligodeoxynucleotides. The enzyme which has selectively bound oligodeoxynucleotides, manifests sedimentation position characteristic for E. coli RNA polymerase engaged in transcription. The oligodeoxynucleotides with high affinity to the enzyme act as competitive inhibitors of transcription catalyzed by E. coli RNA polymerase. The data suggest that E. coli RNA polymerase bound oligodeoxynucleotides mimic the nucleotide sequences of the promoter responsible for the binding of the enzyme. It was found that selectively bound oligoribo - and oligodeoxynucleotides do not compete for the site on the enzyme. This property of E. coli RNA polymerase is assumed to play a certain role in the regulation of transcription.


Association between allergic rhinitis and migraine.
Migraine and allergic rhinitis (AR) are two common causes of headache and facial pain that inflammatory mediators with vasoactive function play important roles in both of them. The aim of this research was to determine the prevalence of migraine in AR patients. In a cross-sectional comparative study performed from June to December 2010 in patients with AR sign and symptoms referred to ear, nose, throat (ENT) clinic of a university hospital in Iran-Rasht, 46 patients with positive skin prick test were compared with 60 subject without AR signs and symptoms and with negative skin test. In both the groups, history of migraine according to IHS (International Headache Society ) criteria were investigated. Analysis of data was performed by chi-sqaure and Fisher exact test by using SPSS16. Odds ratio were estimated for determining the chance of migraine in AR. In case group (14 male, 37 female; mean age: 31.17 ± 8.31 years) and control group (23 male, 32 female; mean age: 37.58 ± 12.63 years), the prevalence of migraine was 37% and 5%, respectively. The differences in prevalence of migraine and migraine without aura between cases and controls were significant (P = 0.001). The chance of migraine in AR was 8.227 folds (95% CI: 2.38-28.42). In subjects older than 40 years old, the difference of prevalence of migraine was significant, contrary to subjects younger than 30 years old and between 30 and 39 years old. There is a correlation between migraine especially without aura and AR and this correlation is more powerful with increasing age.


Serotype distribution of Streptococcus mutans a pathogen of dental caries in cardiovascular specimens from Japanese patients.
The involvement of oral bacteria in the pathogenesis of cardiovascular disease has been studied, with Streptococcus mutans, a pathogen of dental caries, detected in cardiovascular lesions at a high frequency. However, no information is available regarding the properties of S. mutans detected in those lesions. Heart valve specimens were collected from 52 patients and atheromatous plaque specimens from 50 patients, all of whom underwent cardiovascular operations, and dental plaque specimens were taken from 41 of those subjects prior to surgery. Furthermore, saliva samples were taken from 73 sets of healthy mothers (n=73) and their healthy children (n=78). Bacterial DNA was extracted from all specimens, then analysed by PCR with S. mutans-specific and serotype-specific primer sets. The detection rates of S. mutans in the heart valve and atheromatous plaque specimens were 63 and 64 %, respectively. Non-c serotypes were identified with a significantly higher frequency in both cardiovascular and dental plaque samples from the subjects who underwent surgery as compared to serotype c, which was detected in 70-75 % of the samples from the healthy subjects. The serotype distribution in cardiovascular patients was significantly different from that in healthy subjects, suggesting that S. mutans serotype may be related to cardiovascular disease.


Comparison of plaque sealing with paclitaxel-eluting stents versus medical therapy for the treatment of moderate nonsignificant saphenous vein graft lesions: the moderate vein graft lesion stenting with the taxus stent and intravascular ultrasound (VELETI) pilot trial.
The presence of moderate saphenous vein graft (SVG) lesions is a major predictor of cardiac events late after coronary artery bypass grafting. We determined the effects of sealing moderate nonsignificant SVG lesions with paclitaxel-eluting stents (PES) on the prevention of SVG atherosclerosis progression. Patients with at least 1 moderate SVG lesion (30% to 60% diameter stenosis) were randomized either to stenting the moderate SVG lesion with a PES (n=30, PES group) or to medical treatment alone (n=27, medical treatment group). Patients had an angiographic and intravascular ultrasound evaluation of the SVG at baseline and at 12-month follow-up. The primary end points were (1) the ultrasound SVG minimal lumen area at follow-up and (2) the changes in ultrasound atheroma volume in an angiographically nondiseased SVG segment. Mean time from coronary artery bypass grafting was 12+/-6 years, and mean low-density lipoprotein cholesterol level was 73+/-31 mg/dL. A total of 70 moderate SVG lesions (39+/-7% diameter stenosis) were evaluated. Significant disease progression occurred in the medical treatment group at the level of the moderate SVG lesion (decrease in minimal lumen area from 6.3+/-3.0 to 5.6+/-3.1 mm(2); P<0.001), leading to a severe flow-limiting lesion or SVG occlusion in 22% of the patients compared with none in the PES group (P=0.014). In the PES group, mean minimal lumen area increased (P<0.001) from 6.1+/-2.2 to 8.6+/-2.9 mm(2) at follow-up (P=0.001 compared with the medical treatment group at 12 months). There were no cases of restenosis or stent thrombosis. No significant atherosclerosis progression occurred at the nonstented SVG segments. At 12-month follow-up, the cumulative incidence of major adverse cardiac events related to the target SVG was 19% in the medical treatment group versus 3% in the PES group (P=0.091). Stenting moderate nonsignificant lesions in old SVGs with PES was associated with a lower rate of SVG disease progression and a trend toward a lower incidence of major adverse cardiac events at 1-year follow-up compared with medical treatment alone, despite very low low-density lipoprotein cholesterol values. This pilot study supports further investigation into the role of plaque sealing in SVGs. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT002289835.


Growth from Birth Through Six Months for Infants of Mothers in the "Women First" Preconception Maternal Nutrition Trial.
To evaluate whether the fetal linear growth effects of maternal nutrition supplementation would be maintained through 6 months postnatal age. The Women First trial was a multicountry, individually randomized clinical trial that compared the impact of maternal nutrition supplementation initiated preconception (Arm 1) vs at ∼11 weeks of gestation (Arm 2), vs no supplement (Arm 3); the intervention was discontinued at delivery. Trial sites were in Democratic Republic of Congo, Guatemala, India, and Pakistan. Analysis includes 2421 infants born to 2408 randomized women. Primary outcome was the trajectory of length-for-age z scores (LAZ) by arm, based on assessments at birth and 1, 3, and 6 months. We fitted longitudinal models on growth from birth to 6 months using generalized estimating equations; maternal intervention effects were evaluated, adjusting for site and baseline maternal covariates. Linear growth for Arms 1 and 2 was statistically greater than for Arm 3 in 3 of the 4 countries, with average pairwise mean differences in LAZ of 0.25 (95% CI 0.15-0.35; P < .001) and 0.19 (95% CI 0.09-0.28; P < .001), respectively. Compared with Arm 3, average overall adjusted relative risks (95% CI) for stunting (LAZ <-2) were lower for Arms 1 and 2: 0.76 (0.66-0.87; P < .001) and 0.77 (0.67-0.88; P < .001), respectively. Improved linear growth in early infancy observed for the 2 intervention arms supports the critical importance of maternal nutrition before conception and in the early phase of gestation. ClinicalTrials.gov: NCT01883193.


Probing Electron-Phonon Interaction through Two-Photon Interference in Resonantly Driven Semiconductor Quantum Dots.
We investigate the temperature dependence of photon coherence properties through two-photon interference (TPI) measurements from a single quantum dot (QD) under resonant excitation. We show that the loss of indistinguishability is related only to the electron-phonon coupling and is not affected by spectral diffusion. Through these measurements and a complementary microscopic theory, we identify two independent separate decoherence processes, both of which are associated with phonons. Below 10 K, we find that the relaxation of the vibrational lattice is the dominant contribution to the loss of TPI visibility. This process is non-Markovian in nature and corresponds to real phonon transitions resulting in a broad phonon sideband in the QD emission spectra. Above 10 K, virtual phonon transitions to higher lying excited states in the QD become the dominant dephasing mechanism, this leads to a broadening of the zero phonon line, and a corresponding rapid decay in the visibility. The microscopic theory we develop provides analytic expressions for the dephasing rates for both virtual phonon scattering and non-Markovian lattice relaxation.


A Comprehensive Review on the Interaction Between the Host GTPase Rab11 and Influenza A Virus.
This year marks the 100th anniversary of one of the deadliest pandemic outbreaks, commonly referred as the Spanish Flu, that was caused by influenza A virus (IAV). Since then, IAV has been in governmental agendas worldwide, and a lot of effort has been put into understanding the pathogen's lifecycle, predict and mitigate the emergence of the strains that provoke yearly epidemics and pandemic events. Despite decades of research and seminal contributions there is still a lot to be investigated. In particular for this review, IAV lifecycle that takes place inside the host cell is not fully understood. Two steps that need clarification include genome transport to budding sites and genome assembly, the latter a complex process challenged by the nature of IAV genome that is divided into eight distinct parts. Assembly of such segmented genome is crucial to form fully infectious viral particles but is also critical for the emergence of viruses with pandemic potential that arise when avian and human IAV strains co-infect a host. The host GTPase Rab11 was separately implicated in both steps, and, interestingly these processes are beginning to emerge as being intimately related. Rab11 was initially proposed to be involved in the budding/release of IAV virions. It was subsequently shown to transport progeny genome, and later proposed to promote assembly of viral genome, but the underlying bridging mechanism the two is far from clear. For simplicity, this Rab11-centric review provides an initial separate account of Rab11 involvement in genome transport and in assembly. IAV genome assembly is a complicated molecular biology process, and therefore earned a dedicated section on how/if the viral genome forms a genomic supramolecular complex. Both topics present intricate challenges, outstanding questions, and unique controversies. At the end of the review, I will explore possible mechanisms intertwining IAV vRNP transport and genome assembly. Importantly, Rab11 has recently emerged as a key factor subverted by evolutionary unrelated viral families (Paramyxo, Bunya, and Orthomyxoviruses, among many others) and bacteria (Salmonella and Shigella) relevant to human health. This review provides a framework to identify common biological principles among the lifecycles of these pathogens.


High-resolution structure of the open NaK channel.
We report the crystal structure of the nonselective cation channel NaK from Bacillus cereus at a resolution of 1.6 A. The structure reveals the intracellular gate in an open state, as opposed to the closed form reported previously, making NaK the only channel for which the three-dimensional structures of both conformations are known. Channel opening follows a conserved mechanism of inner helix bending using a flexible glycine residue, the gating hinge, seen in MthK and most other tetrameric cation channels. Additionally, distinct inter and intrasubunit rearrangements involved in channel gating are seen and characterized for the first time along with inner helix twisting motions. Furthermore, we identify a residue deeper within the cavity of the channel pore, Phe92, which is likely to form a constriction point within the open pore, restricting ion flux through the channel. Mutating this residue to alanine causes a subsequent increase in ion-conduction rates as measured by (86)Rb flux assays. The structures of both the open and closed conformations of the NaK channel correlate well with those of equivalent K(+) channel conformations, namely MthK and KcsA, respectively.


Significance of urinary full-length and ectodomain forms of megalin in patients with type 2 diabetes.
Megalin, an endocytic receptor in proximal tubule cells, is involved in the mechanisms of albuminuria in diabetic nephropathy (DN). To develop efficient novel biomarkers associated with the pathogenesis of DN, we investigated urinary megalin excretion in type 2 diabetes. Sandwich enzyme-linked immunosorbent assay systems were established with monoclonal antibodies against the NH(2) (amino [A]-megalin assay) and COOH (C-megalin assay) termini of megalin to analyze urinary forms of megalin in 68 patients with type 2 diabetes. The A-megalin assay mainly detected a megalin ectodomain form in the soluble urinary fraction, whereas the C-megalin assay identified a full-length form in both soluble and insoluble fractions. Urinary C-megalin levels were significantly high in patients with normoalbuminuria, were elevated in line with increased albuminuria, and showed a better association with estimated glomerular filtration rate (eGFR) (<60 mL/min/1.73 m(2)) than did urinary albumin. In contrast, urinary A-megalin levels were increased in patients with normo- and microalbuminuria but not in those with macroalbuminuria. Urinary C-megalin levels were also positively associated with plasma inorganic phosphate and negatively with hemoglobin levels in those showing no features of bleeding and not taking vitamin D analogs, phosphate binders, or erythropoiesis-stimulating agents. Urinary full-length megalin excretion as measured by the C-megalin assay is well associated with reduced eGFR and linked to the severity of DN, phosphate dysregulation, and anemia, whereas urinary excretion of megalin ectodomain as measured by the A-megalin assay may be associated with distinctive mechanisms of earlier DN in type 2 diabetes.


Extensive Pneumocephalus Secondary to Petrous Bone Cholesteatoma.
Pneumocephalus refers to air inside the cranium; however, otogenic pneumocephalus is rarely reported in the literature. The neurological presentations of pneumocephalus include headache, lethargy, confusion, disorientation, and seizure. Here, we have reported a case of a 42-year-old woman with extensive pneumocephalus and cerebrospinal fluid leak secondary to petrous bone cholesteatoma. She presented to the emergency department with sudden headache and left ear discharge. Physical examination revealed watery otorrhea through a hole in the tympanic membrane. Radiological studies demonstrated extensive soft tissue in the left middle ear and mastoid extending to the internal auditory canal. Free intracranial air was observed, and bony destruction was seen in the cochlea, vestibule, and semicircular canals. The patient was managed surgically via the transotic approach and fully recovered. Although otogenic pneumocephalus is rarely encountered in clinical practice, early diagnosis and urgent management are important to prevent fatal complications.


Meperidine metabolites: identification of N-hydroxynormeperidine and a hydroxy-methoxy derivative of meperidine in biological fluids.
Gas chromatographic and gas chromatographic-mass spectrometric techniques were used to identify non-acidic metabolites of meperidine (N-methyl-4-phenyl-4-carbethoxypiperidine) excreted in human, rat, and guinea pig urine. Following enzymic hydrolysis N-hydroxynormeperidine was identified in the urine of all three species in addition to the expected metabolites normeperidine and meperidine N-oxide. In rat urine the p-hydroxyphenyl metabolite of meperidine was present in appreciable amounts. Also present in small quantity was a new phenolic metabolite of meperidine containing both hydroxyl and O-methoxyl substituents in the phenyl ring of the parent drug. The latter two metabolites were excreted as conjugates in the rat.


Extensive conformational transitions are required to turn on ATP hydrolysis in myosin.
Conventional myosin is representative of biomolecular motors in which the hydrolysis of adenosine triphosphate (ATP) is coupled to large-scale structural transitions both in and remote from the active site. The mechanism that underlies such "mechanochemical coupling," especially the causal relationship between hydrolysis and allosteric structural changes, has remained elusive despite extensive experimental and computational analyses. In this study, using combined quantum mechanical and molecular mechanical simulations and different conformations of the myosin motor domain, we provide evidence to support that regulation of ATP hydrolysis activity is not limited to residues in the immediate environment of the phosphate. Specifically, we illustrate that efficient hydrolysis of ATP depends not only on the proper orientation of the lytic water but also on the structural stability of several nearby residues, especially the Arg238-Glu459 salt bridge (the numbering of residues follows myosin II in Dictyostelium discoideum) and the water molecule that spans this salt bridge and the lytic water. More importantly, by comparing the hydrolysis activities in two motor conformations with very similar active-site (i.e., Switches I and II) configurations, which distinguished this work from our previous study, the results clearly indicate that the ability of these residues to perform crucial electrostatic stabilization relies on the configuration of residues in the nearby N-terminus of the relay helix and the "wedge loop." Without the structural support from those motifs, residues in a closed active site in the post-rigor motor domain undergo subtle structural variations that lead to consistently higher calculated ATP hydrolysis barriers than in the pre-powerstroke state. In other words, starting from the post-rigor state, turning on the ATPase activity requires not only displacement of Switch II to close the active site but also structural transitions in the N-terminus of the relay helix and the "wedge loop," which have been proposed previously to be ultimately coupled to the rotation of the converter subdomain 40 A away.


A methodological paradigm for patient-specific multi-scale CFD simulations: from clinical measurements to parameter estimates for individual analysis.
A new framework for estimation of lumped (for instance, Windkessel) model parameters from uncertain clinical measurements is presented. The ultimate aim is to perform patient-specific haemodynamic analysis. This framework is based on sensitivity analysis tools and the sequential estimation approach of the unscented Kalman filter. Sensitivity analysis and parameter estimation are performed in lumped parameter models, which act as reduced order surrogates of the 3D domain for haemodynamic analysis. While the goal of sensitivity analysis is to assess potential identifiability problems, the unscented Kalman filter estimation leads to parameter estimates based on clinical measurements and modelling assumptions. An application of such analysis and parameter estimation methodology is demonstrated for synthetic and real data. Equality constraints on various physiological parameters are enforced. Since the accuracy of the Windkessel parameter estimates depends on the lumped parameter representativeness, the latter is iteratively improved by running few 3D simulations while simultaneously improving the former. Such a method is applied on a patient-specific aortic coarctation case. Less than 3% and 9% errors between the clinically measured quantities and 3D simulation results for rest and stress are obtained, respectively. Knowledge on how these Windkessel parameters change from rest to stress can thus be learned by such an approach. Lastly, it is demonstrated that the proposed approach is capable of dealing with a wide variety of measurements and cases where the pressure and flow clinical measurements are not taken simultaneously.


'We will eat when I get the grant': negotiating AIDS, poverty and antiretroviral treatment in South Africa.
The maturing HIV epidemic has led to a decline in the health status of many South Africans. One result is an increasing number of AIDS-affected poor who qualify for a government disability grant. Recent research has drawn attention to the unintended conflict that this may present for poor people who might be faced with choosing between maintaining health through antiretroviral treatment and obtaining money through the state grant. While some evidence suggests that most AIDS-affected people would choose antiretroviral treatment over access to a disability grant, other evidence suggests that some would rather die than lose the grant. This paper is a qualitative exploration of ways that AIDS treatment policies and practices and grants for people disabled by AIDS are currently being negotiated by people caught in the double-bind of managing their own health and income. As South Africa continues to broaden its delivery of antiretroviral treatment and AIDS support services, it is important that planners incorporate an understanding of how an HIV or AIDS diagnosis in the context of entrenched poverty may represent both a threat and a means to financial survival. There is a need to consider the 'disinhibiting' effects on HIV prevention and treatment that may result when AIDS support services are aimed at addressing the needs of individuals as opposed to the needs of highly affected communities.


Digital Patient Reported Outcome Measures Platform for Post-COVID-19 Condition and Other Long-Term Conditions: User-Centered Development and Technical Description.
Post-COVID-19 condition (PCC), colloquially known as long COVID, is a multisystem condition characterized by persistent symptoms beyond 4 weeks after the SARS-CoV-2 infection. More than 60 million people with PCC worldwide need prompt assessment, diagnosis, and monitoring, with many requiring specialist help from a multidisciplinary team of health care professionals (HCPs). Consequently, a scalable digital system is required for both people with PCC and HCPs to capture the breadth of symptoms and their impact on health, using patient-reported outcome measures (PROMs) and patient-reported experience measures (PREMs). We aim to develop and implement a novel PCC digital PROM (DPROM) platform for (1) securely collecting PROM and PREM data from people with PCC, (2) enabling users to monitor symptoms longitudinally and assess response to treatment, (3) generating reports for the electronic health records (EHRs), (4) providing summary reports on PCC services based on national requirements, and (5) facilitating the sharing of relevant data with authorized research teams to accelerate our understanding of this new condition and evaluate new strategies to manage PCC. We (1) undertook requirement analysis with people with PCC, HCPs, and researchers to identify the needs of the DPROM platform and determine its required functionalities; (2) designed and developed a clinically useful web portal for staff and a mobile app for patients, with a web-based alternative app to improve patient and staff choice, limit the risk of digital exclusion, and account for variability across services; (3) determined the PROMs and PREMs that PCC services would prefer to use on the platform; and (4) designed the summary report function that can be generated for each user for the EHR and for reporting to national health authorities. A DPROM platform to record PCC symptom profile, condition severity, functional disability, and quality of life, based on the C19-YRS (Yorkshire Rehabilitation Scale) and other PROMs and PREMs, was developed. Individual-level medical information and details on the COVID-19 illness can be captured systematically. The platform generates easy-to-understand scores, radar plots and line graphs for people with PCC to self-monitor their condition and for HCPs to assess the natural course of the condition and the response to interventions. Clinics can configure a suite of PROMs and PREMs based on their local and national service and commissioning requirements and support research studies which require large-scale data collection on PROMs. The DPROM platform enables automatic aggregate data analysis for services to undertake service evaluation and cost-effectiveness analysis. The DPROM platform generated summary report can be uploaded to the EHRs of people with PCC. A multifunctional DPROM platform to assess, grade, and monitor PCC has been developed. Future research will analyze the system's usability in specialist PCC clinical services and other long-term conditions.


Genetic activity at the albino locus in Cattanach's insertion in the mouse.
Cattanach's insertion (Is(In7;X)1Ct or XCt) includes the normal allele at the albino locus (c+), which is subject to inactivation of the X chromosome carrying it, so that XCtX; cc mice have albino and pigmented patches. The X-autosome translocation T(X;16)16H or XT16H leads to preferential inactivation of the other X chromosome in female cells, so that XCtXT16H; cc mice are almost entirely white. However, they grow darker with age, as if reversal of inactivation of the c+ allele were taking place in increasing numbers of melanocytes. To test whether this is dependent only on age or whether it is related to the number of times the animal has moulted, hair was repeatedly plucked from selected areas at the early telogen stage when the follicles are also removed, assuming that the melanocytes or melanoblasts in that region of the skin would be forced to undergo further divisions to colonize the new follicles. The plucked areas grew darker at the same rate as the rest of the coat, suggesting that the progressive reversal of inactivation is dependent only on age. As direct examination of melanocytes in the follicles is difficult, they were examined in the choroid and the retinal pigment epithelium (RPE) of the eye. The frequency of the pigmented cells was lower in the choroid than in the RPE. Since the melanocytes in these structures are different in origin as well as in physical characteristics, it appears that cell type influences either reversal of inactivation, or the frequency with which the influence of the X chromosome extends to the albino locus.


Effects of ablation and activation of Nrf2 on bile acid homeostasis in male mice.
The role of nuclear factor erythroid 2-related factor 2 (Nrf2) in bile acid (BA) homeostasis remains controversial. In this study, activation of Nrf2 was achieved either pharmacologically by CDDO-imidazolide (CDDO-Im) or genetically through a "gene dose-response" model consisting of Nrf2-null, wild-type (WT), Keap1-knockdown (Keap1-KD), and Keap1-hepatocyte knockout (Keap1-HKO) mice. In WT mice, CDDO-Im increased bile flow and decreased hepatic BAs, which was associated with a down-regulation of the canalicular BA efflux transporter Bsep and an increase in biliary BA excretion. In contrast, hepatic Bsep and biliary BA excretion were not altered in Keap1-KD or Keap1-HKO mice, suggesting that Nrf2 is not important for regulating Bsep or BA-dependent bile flow. In contrast, hepatic Mrp2 and Mrp3 were up-regulated by both pharmacological and genetic activations of Nrf2. Furthermore, ileal BA transporters (Asbt and Ostβ) and cholesterol transporters (Abcg5 and Abcg8) were down-regulated by both pharmacological and genetic activations of Nrf2, suggesting a role of Nrf2 in intestinal absorption of BAs and cholesterol. In Nrf2-null mice, CDDO-Im down-regulated hepatic BA uptake transporters (Ntcp, Oatp1a1, and Oatp1b2), leading to a 39-fold increase of serum BAs. To conclude, the present study demonstrates that activation of Nrf2 in mice up-regulates Mrp2 and Mrp3 in the liver and down-regulates BA and cholesterol transporters in the intestine.


Deep TMS H1 Coil treatment for depression: Results from a large post marketing data analysis.
Phase IV study evaluated Deep TMS for major depression in community settings. Data were aggregated from 1753 patients at 21 sites, who received Deep TMS (high frequency or iTBS) using the H1 coil. Outcome measures varied across subjects and included clinician-based scales (HDRS-21) and self-assessment questionnaires (PHQ-9, BDI-II). 1351 patients were included in the analysis, 202 received iTBS. For participants with data from at least 1 scale, 30 sessions of Deep TMS led to 81.6% response and 65.3% remission rate. 20 sessions led to 73.6% response and 58.1% remission rate. iTBS led to 72.4% response and 69.2% remission. Remission rates were highest when assessed with HDRS (72%). In 84% of responders and 80% of remitters, response and remission was sustained in the subsequent assessment. Median number of sessions (days) for onset of sustained response was 16 (21 days) and for sustained remission 17 (23 days). Higher stimulation intensity was associated with superior clinical outcomes. This study shows that beyond its proven efficacy in RCTs, Deep TMS with the H1 coil is effective for treating depression under naturalistic conditions, and the onset of improvement is usually within 20 sessions. However, initial non-responders and non-remitters benefit from extended treatment.


Time to evolve: predicting engineered T cell-associated toxicity with next-generation models.
Despite promising clinical results in a small subset of malignancies, therapies based on engineered chimeric antigen receptor and T-cell receptor T cells are associated with serious adverse events, including cytokine release syndrome and neurotoxicity. These toxicities are sometimes so severe that they significantly hinder the implementation of this therapeutic strategy. For a long time, existing preclinical models failed to predict severe toxicities seen in human clinical trials after engineered T-cell infusion. However, in recent years, there has been a concerted effort to develop models, including humanized mouse models, which can better recapitulate toxicities observed in patients. The Accelerating Development and Improving Access to CAR and TCR-engineered T cell therapy (T2EVOLVE) consortium is a public-private partnership directed at accelerating the preclinical development and increasing access to engineered T-cell therapy for patients with cancer. A key ambition in T2EVOLVE is to design new models and tools with higher predictive value for clinical safety and efficacy, in order to improve and accelerate the selection of lead T-cell products for clinical translation. Herein, we review existing preclinical models that are used to test the safety of engineered T cells. We will also highlight limitations of these models and propose potential measures to improve them.


Revisiting epinephrine in foot surgery.
Anesthetics containing epinephrine have long been thought unsuitable for use in the foot and, particularly, the digits. However, research suggests that epinephrine use is beneficial in the appropriately selected patient. These benefits include a decreased local anesthetic plasma concentration; an increased duration of anesthesia, with a decreased need for additional narcotic use after surgery; decreased development of hemorrhage and postoperative hematoma, without occlusion of vessels; and a lack of complications (in millions of patients reported on in the literature). A retrospective review of more than 150 patients receiving local anesthetics containing epinephrine revealed no complications in the foot and ankle.


Novel crosstalk between Vps26a and Nox4 signaling during neurogenesis.
Despite numerous studies on the molecular switches governing the conversion of stemness to differentiation in embryonic stem cells (ESCs), little is known about the involvement of the retromer complex. Under neural differentiation conditions, Vps26a deficiency (Vps26a-/-) or knockdown suppressed the loss of stemness and subsequent neurogenesis from ESCs or embryonic carcinoma cells, respectively, as evidenced by the long-lasting expression of stemness markers and the slow appearance of neuronal differentiation markers. Interestingly, relatively low reactive oxygen species (ROS) levels were generated during differentiation of Vps26a-/- ESCs, and treatment with an antioxidant or inhibitor of NADPH oxidase (Nox), a family of ROS-generating enzymes, led to restoration of stemness in wild-type cells to the level of Vps26a-/- cells during neurogenesis. Importantly, a novel interaction between Vps26a and Nox4 linked to the activation of ERK1/2 depended highly on ROS levels during neurogenesis, which were strongly suppressed in differentiating Vps26a-/- ESCs. Moreover, inhibition of phosphorylated ERK1/2 (pERK1/2) resulted in decreased ROS and Nox4 levels, indicating the mutual dependency between pERK1/2 and Nox4-derived ROS during neurogenesis. These results suggest that Vps26a regulates stemness by actively cooperating with the Nox4/ROS/ERK1/2 cascade during neurogenesis. Our findings have important implications for understanding the regulation of stemness via crosstalk between the retromer molecule and redox signaling, and may contribute to the development of ESC-based therapeutic strategies for the mass production of target cells.


Treatment of Proximal Humerus Fractures using PHILOS Plate.
Treatment of proximal humerus fractures always holds a dilemma for the treating surgeon. To assess the functional outcome of proximal humerus fractures treated with Proximal Humerus Internal Locking System (PHILOS) plating. Fifty three consecutive patients were treated with PHILOS plating between August 2013 and August 2014. The inclusion criteria were skeletally matured patients with closed fracture proximal humerus with displacement >1 cm and varus angulation of >450. Severely comminuted fractures, open fractures and valgus impacted fractures were excluded from the study. The outcome was assessed using Neer's scoring system. The average age was 54.3±5.8 years. As per the Neers classification system, there were 6 (11.32%) 1-part, 19 (35.85%) 2-part, 17 (32.085) and 11 (20.75%) 3 and 4-part fracture respectively. Average surgical duration was 94±10.2 minutes. Radiological union was seen at 12±4.6 weeks. There were 2 (3.77%) cases of varus collapse. Three (5.66%) cases had screw back out, which was later revised and had a favourable outcome. As per the Neer's scoring system, 7 (13.21%) cases had excellent results, 37 (69.81%) had satisfactory, 6 (11.32%) had unsatisfactory while 3 (05.66%) cases had poor outcomes. PHILOS plating has a good functional outcome. However, proper patient selection, thorough knowledge of the anatomy and biomechanical principles are the pre-requisites for a successful surgery.


Role of simulated repetitive coughing in mucus clearance.
The role of repetitive simulated coughing on the clearance of gel mucus simulant was investigated in vitro, by using a simulated cough machine. The repetition of cough induced a significant increase (p less than 0.01) in mucus simulant clearance (139.3 +/- 78.7 mm) in comparison to a single cough (24.9 +/- 27.5 mm). Moreover, the increase in frequency of the repetitive coughing induced a marked and significant increase in mucus simulant clearance (75.4 +/- 51.1 mm and 139.3 +/- 78.7 mm at 0.1 Hz and 1.6 Hz frequency, respectively). A significant (p less than 0.05) correlation was observed between the percentage increase of clearance and both shear-thinning index (r = 0.62) and the thixotropic index (r = 0.63). These results suggest that the shear-dependent properties of mucus, associated with a repetitive coughing, may increase the efficiency of mucus clearance by air flow mechanisms.


Nicotinic acetylcholine receptor signalling: roles in Alzheimer's disease and amyloid neuroprotection.
Alzheimer's disease (AD), the major contributor to dementia in the elderly, involves accumulation in the brain of extracellular plaques containing the beta-amyloid protein (Abeta) and intracellular neurofibrillary tangles of hyperphosphorylated tau protein. AD is also characterized by a loss of neurons, particularly those expressing nicotinic acetylcholine receptors (nAChRs), thereby leading to a reduction in nAChR numbers. The Abeta(1-42) protein, which is toxic to neurons, is critical to the onset and progression of AD. The discovery of new drug therapies for AD is likely to be accelerated by an improved understanding of the mechanisms whereby Abeta causes neuronal death. We examine the evidence for a role in Abeta(1-42) toxicity of nAChRs; paradoxically, nAChRs can also protect neurons when activated by nicotinic ligands. Abeta peptides and nicotine differentially activate several intracellular signaling pathways, including the phosphatidylinositol 3-kinase/v-akt murine thymoma viral oncogene homolog pathway, the extracellular signal-regulated kinase/mitogen-activated protein kinase, and JAK-2/STAT-3 pathways. These pathways control cell death or survival and the secretion of Abeta peptides. We propose that understanding the differential activation of these pathways by nicotine and/or Abeta(1-42) may offer the prospect of new routes to therapy for AD.


Prognostic and biologic significance of long non-coding RNA profiling in younger adults with cytogenetically normal acute myeloid leukemia.
Long non-coding ribonucleic acids (RNAs) are a novel class of RNA molecules, which are increasingly recognized as important molecular players in solid and hematologic malignancies. Herein we investigated whether long non-coding RNA expression is associated with clinical and molecular features, as well as outcome of younger adults (aged <60 years) with de novo cytogenetically normal acute myeloid leukemia. Whole transcriptome profiling was performed in a training (n=263) and a validation set (n=114). Using the training set, we identified 24 long non-coding RNAs associated with event-free survival. Linear combination of the weighted expression values of these transcripts yielded a prognostic score. In the validation set, patients with high scores had shorter disease-free (P<0.001), overall (P=0.002) and event-free survival (P<0.001) than patients with low scores. In multivariable analyses, long non-coding RNA score status was an independent prognostic marker for disease-free (P=0.01) and event-free survival (P=0.002), and showed a trend for overall survival (P=0.06). Among multiple molecular alterations tested, which are prognostic in cytogenetically normal acute myeloid leukemia, only double CEBPA mutations, NPM1 mutations and FLT3-ITD associated with distinct long non-coding RNA signatures. Correlation of the long non-coding RNA scores with messenger RNA and microRNA expression identified enrichment of genes involved in lymphocyte/leukocyte activation, inflammation and apoptosis in patients with high scores. We conclude that long non-coding RNA profiling provides meaningful prognostic information in younger adults with cytogenetically normal acute myeloid leukemia. In addition, expression of prognostic long non-coding RNAs associates with oncogenic molecular pathways in this disease. clinicaltrials.gov Identifier: 00048958 (CALGB-8461), 00899223 (CALGB-9665), and 00900224 (CALGB-20202).


Effect of early statin treatment in patients with cardiogenic shock complicating acute myocardial infarction.
The benefit of early statin treatment following acute myocardial infarction (MI) complicated with cardiogenic shock (CS) has not been well studied. We sought to assess the effect of early statin therapy in patients with CS complicating acute MI. We studied 553 statin-naive patients with acute MI and CS (Killip class IV) who underwent revascularization therapy between November 2005 and January 2008 at 51 hospitals in the Korea Acute Myocardial Infarction Registry. Patients were divided into 2 groups: those who received statins during hospitalization (n=280) and those who did not (n=273). The influence of statin treatment on a 12-month clinical outcome was examined using a matched-pairs analysis (n=200 in each group) based on the propensity for receiving statin therapy during hospitalization. Before adjustment, patients receiving statin, compared to those not receiving statin, had a more favorable clinical profile, were less likely to suffer procedural complications, and more likely to receive adequate medical therapy. Patients receiving statin had lower unadjusted in-hospital mortality and composite rate of mortality, MI, and repeat revascularization at 12 months, which remained significantly lower after adjustment for patient risk, procedural characteristics, and treatment propensity. In CS patients with acute MI undergoing revascularization therapy, early statin treatment initiated during hospitalization was associated with lower rates of in-hospital death and 12-month adverse cardiac events.


Live imaging of tumor initiation in zebrafish larvae reveals a trophic role for leukocyte-derived PGE₂.
Epidemiology studies and clinical trials have suggested that the use of non-steroidal anti-inflammatory drugs (NSAIDs), including aspirin, can significantly reduce the incidence of and mortality associated with many cancers, and upregulation of the COX2-PGE(2) pathway in tumor microenvironments might drive several aspects of cancer progression. For these reasons, the mechanisms linking COX blockade and cancer prevention have long been an area of active investigation. During carcinogenesis, COX-2 is expressed both by malignant epithelial cells and by tumor-associated stromal cells, including macrophages, but the observation that NSAIDs are most effective in cancer prevention in APC(min/+) mice if the mice are treated from conception suggests that the COX-2/PGE(2) pathway might also be critical at the earliest stages of tumor development. In this study we take advantage of the translucency and genetic tractability of zebrafish larvae to investigate the involvement of inflammatory cells at cancer initiation, when transformed cells first arise in tissues. We previously showed that innate immune cells supply early transformed cells with proliferative cues and, by using complementary pharmacological and genetic experiments, we now show that prostaglandin E(2) (PGE(2)) is the trophic signal required for this expansion of transformed cells. Our in vivo observations at these early stages of cancer initiation provide a potential mechanistic explanation for why long-term use of low doses of NSAIDs, including aspirin, might reduce cancer onset.


Function and expression of CD1d and invariant natural killer T-cell receptor in the cotton rat (Sigmodon hispidus).
The cotton rat (Sigmodon hispidus) belongs to the rodent family of Cricetidae and provides a powerful model to study the pathogenesis of human respiratory viruses and measles virus. Recent studies in other rodent models have suggested a role for invariant natural killer T (iNKT) cells in antiviral immunity and vaccination against respiratory virus infections. Using new experimental tools, we provide the first evidence for a functional CD1d cell molecule (crCD1d) and iNKT T-cell receptor in cotton rats. The crCD1d cDNA sequence was identified and crCD1d transductants showed that monoclonal antibody WTH-2 stains crCD1d as efficiently as mouse or rat CD1d. The expression of crCD1d was clearly weaker for thymocytes and B cells, and higher for T cells, which is different to what is found in murine species. The antigen-presenting capacity of crCD1d was demonstrated with crCD1d-immunoglobulin dimers loaded with the glycolipid PBS57, which bound iNKT T-cell receptors. Evidence for functional cotton rat iNKT cells was provided by detection of interferon-γ and interleukin-4 in cultures of splenocytes stimulated with PBS57 and α-galactosylceramide and by specific staining of about 0·2% of splenocytes with PBS57-loaded crCD1d dimers. Canonical AV14/AJ18 rearrangements were identified and found to contain multiple members of the AV14 (AV11) family. One of them was expressed and found to bind CD1d dimers. In summary, these data provide the first evidence for functional CD1d molecules and iNKT T-cell receptors in cotton rats and provide the tools to analyse them both in the cotton rat model of infectious diseases.


Health Disparities Research Among Small Tribal Populations: Describing Appropriate Criteria for Aggregating Tribal Health Data.
In response to community concerns, we used the Tribal Participatory Research framework in collaboration with 5 American-Indian communities in Washington, Idaho, and Montana to identify the appropriate criteria for aggregating health data on small tribes. Across tribal sites, 10 key informant interviews and 10 focus groups (n = 39) were conducted between July 2012 and April 2013. Using thematic analysis of focus group content, we identified 5 guiding criteria for aggregating tribal health data: geographic proximity, community type, environmental exposures, access to resources and services, and economic development. Preliminary findings were presented to focus group participants for validation at each site, and a culminating workshop with representatives from all 5 tribes verified our final results. Using this approach requires critical assessment of research questions and study designs by investigators and tribal leaders to determine when aggregation or stratification is appropriate and how to group data to yield robust results relevant to local concerns. At project inception, tribal leaders should be consulted regarding the validity of proposed groupings. After regular project updates, they should be consulted again to confirm that findings are appropriately contextualized for dissemination.


Flavodiiron Protein Substitutes for Cyclic Electron Flow without Competing CO2 Assimilation in Rice.
Flavodiiron protein (FLV) mediates photoreduction of O2 to H2O. It is conserved from cyanobacteria to gymnosperms but not in angiosperms. The introduction of a moss (Physcomitrella patens) FLV (PpFLV) gene into Arabidopsis (Arabidopsis thaliana) made photosystem I (PSI) resistant to fluctuating light. Here, we used the same strategy with three rice (Oryza sativa) genotypes. PpFLV in the wild-type rice background functioned as an efficient PSI electron sink and increased resistance to PSI photodamage under fluctuating light. The introduction of PpFLV into the PGR5-RNAi mutant [defective in PROTON GRADIENT REGULATION5 (PGR5)-dependent cyclic electron transport around PSI, CET-PSI], the crr6 mutant [defective in chloroplast NAD(P)H-dehydrogenase-like complex (NDH)-dependent CET-PSI], and the PGR5-RNAi crr6 double mutant (double defective in CET-PSI activity) alleviated PSI photodamage under fluctuating light. Furthermore, PpFLV substituted for the function of PGR5- and NDH-dependent CET-PSI without competing for CO2 assimilation under constant light, as there was no difference in CO2 assimilation per Rubisco content and biomass production was recovered to the wild-type level. Thus, the exogenous FLV system could act not only as a safety valve under fluctuating light, but also generate a proton motive force for balancing the ATP/NADPH production ratio during steady-state photosynthesis.


Control of cell and petal morphogenesis by R2R3 MYB transcription factors.
Petals of animal-pollinated angiosperms have adapted to attract pollinators. Factors influencing pollinator attention include colour and overall size of flowers. Colour is determined by the nature of the pigments, their environment and by the morphology of the petal epidermal cells. Most angiosperms have conical epidermal cells, which enhance the colour intensity and brightness of petal surfaces. The MYB-related transcription factor MIXTA controls the development of conical epidermal cells in petals of Antirrhinum majus. Another gene encoding an R2R3 MYB factor very closely related to MIXTA, AmMYBML2, is also expressed in flowers of A. majus. We have analysed the roles of AmMYBML2 and two MIXTA-related genes, PhMYB1 from Petunia hybrida and AtMYB16 from Arabidopsis thaliana, in petal development. The structural similarity between these genes, their comparable expression patterns and the similarity of the phenotypes they induce when ectopically expressed in tobacco, suggest they share homologous functions closely related to, but distinct from, that of MIXTA. Detailed phenotypic analysis of a phmyb1 mutant confirmed the role of PhMYB1 in the control of cell morphogenesis in the petal epidermis. The phmyb1 mutant showed that epidermal cell shape affects petal presentation, a phenotypic trait also observed following re-examination of mixta mutants. This suggests that the activity of MIXTA-like genes also contributes to petal form, another important factor influencing pollinator attraction.