Angiotensin-(1-7) enhances LTP in the hippocampus through the G-protein-coupled receptor Mas.
The renin-angiotensin system not only plays a critical role in blood pressure control but is also involved in learning and memory mechanisms. In addition to angiotensin (Ang) II, Ang-(1-7) may also have important biological activities in the brain. Here, we show for the first time that Ang-(1-7) enhances long-term potentiation (LTP) in the CA1 region of the hippocampus. Our studies with AT1 receptor antagonists and selective Ang-(1-7) receptor antagonists demonstrate the existence of a distinct Ang-(1-7) receptor in the brain, the G-protein-coupled receptor Mas, encoded by the Mas protooncogene. We also show that the genetic deletion of this receptor abolishes the Ang-(1-7)-induced enhancement of LTP. Thus, we firstly demonstrate that Ang-(1-7) influences the induction of LTP in limbic structures implicating its distinct function in learning and memory mechanisms; secondly, we have identified Mas as a functional receptor for Ang-(1-7) in the brain.


Real-time cross-sectional echocardiographic imaging and measurement of the patent ductus arteriosus in infants and children.
While echocardiography has been used to noninvasively document indirect effects on the heart of left-to-right shunting through a patent ductus arteriosus, no noninvasive technique has been developed to image the duct itself. In this study, 35 sequential studies were performed on 28 patients with a mechanical sector scanner to image the distal pulmonary artery and its bifurcation by scanning along the axis of the right ventricular outflow tract. Cross-sectional imaging, just superior to the take-off of the right pulmonary artery, provided visualization of the patent ductus as a distal continuation of the pulmonary artery connecting to the descending aorta. Ductal visualization by cross-sectional echo was validated by saline echo contrast observations of right-to-left and left-to-right shunting through the duct in 14 patients, by surgical observations in 11, angiographic observations in 13 and autopsy observations in three. Angiographic size of the ductus arteriosus, whether constricted or widely patent, tortuous or straight, was predicted correctly and echo/angiographic correlations for smallest inner ductal dimension were excellent (r = 0.97). This study provides a method for and validates the direct imaging of the ductus arteriosus and suggests that cross-sectional echocardiography can accurately predict ductal contour and quantitative ductal cross-sectional size noninvasively.


Nitric oxide and nitroxides can act as efficient scavengers of protein-derived free radicals.
Nitric oxide ((*)NO) may act as either a pro-oxidant or an antioxidant in biological systems. Although (*)NO and nitroxide radicals react slowly with most molecules, they react at near diffusion-controlled rates with other radicals and may therefore be efficient protective agents. This study assessed the ability of (*)NO and nitroxides to intercept specific protein-derived radicals and compared the efficacy of these species. Three protein radical systems were investigated as follows: BSA-derived radicals generated via radical transfer from H(2)O(2)-activated horseradish peroxidase, radicals formed on myoglobin via reaction with H(2)O(2), and carbon-centered radicals formed from amino acid hydroperoxides on exposure to Fe(2+)-EDTA. In each case, radicals were generated in the absence or presence of (*)NO or nitroxides of different size and charge. Concentration-dependent loss of the protein radicals was detected by electron paramagnetic resonance with both (*)NO and nitroxides and time-dependent consumption of (*)NO using an (*)NO electrode. The protein oxidation product dityrosine was significantly reduced by (*)NO and nitroxides, and 3,4-dihydroxyphenylalanine levels were reduced by nitroxides but not (*)NO. Overall, these studies demonstrate that (*)NO and nitroxides are efficient near-stoichiometric scavengers of protein radicals and, hence, are potential protective agents against protein oxidation reactions and resulting damage. These reactions show little dependence on nitroxide structure or charge.


Hoeflea anabaenae sp. nov., an epiphytic symbiont that attaches to the heterocysts of a strain of Anabaena.
The heterotrophic, epiphytic, symbiotic bacterial strain WH2K(T) was previously isolated from a two-member culture in which it was attached to the heterocysts of a strain of Anabaena (SSM-00). Analysis of its 16S rRNA gene sequence demonstrated that the symbiont was most closely related to the type strain of Hoeflea marina (96.9 % similarity), which belongs to the family Phyllobacteriaceae within the order Rhizobiales of the class Alphaproteobacteria. A polyphasic taxonomic study was performed on strain WH2K(T), which consisted of irregular rods (2-5 µm long, 0.2 µm wide) that appeared to be narrower at one pole. Optimal growth was obtained in complex media with 15 g sea salts l(-1), at 18-34 °C (30 °C optimum) and at pH 6.0-8.0 (optimum pH 6.5). Unknown growth requirements were provided by small amounts of yeast extract but not by standard vitamin and trace metal solutions. Of the substrates tested, WH2K(T) was able to utilize only acetate, pyruvate, malate and fumarate. Growth was observed only under aerobic and microaerobic conditions, and nitrate was not reduced. No photosynthetic pigments were detected under any of the growth conditions tested. The predominant fatty acids were a summed feature that comprises C(18 : 1)ω7c, C(18 : 1)ω9t, C(18 : 1)ω12t or any combination of these (64.0 %) and an unidentified fatty acid of equivalent chain length 17.603 (13.5 %). The polar lipid profile consisted of diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, phosphatidylmonomethylethanolamine, phosphatidylcholine, phosphoglycolipid, unknown lipids and an unidentified aminolipid. The only respiratory ubiquinone detected was Q-10. The DNA G+C content of the strain was 58.1 mol%. The organism can form a site-specific attached symbiotic relationship with a species of Anabaena. Based on phylogenetic and phenotypic evidence, it is proposed that strain WH2K(T) be classified within a novel species of the genus Hoeflea, for which the name Hoeflea anabaenae sp. nov. is proposed. The type strain is WH2K(T) ( = CCUG 56626(T) = NRRL B-59520(T)).


Transmission of leprosy within households.
As part of the leprosy control program, population follow-up studies were carried out during 1962 to 1970 in Gudiyatham Taluk, an administrative unit in South India (population: 400,000). More than 97% of the 23,285 contacts from 5,088 families having a leprosy patient were clinically examined using accepted methodology and confirmed as having or not having leprosy. New cases developing among household contacts of leprosy (secondary attack rates) were determined and studied in relation to characteristics of the index case and that of contacts. The secondary attack rate is defined as the number of new cases discovered in the contacts of leprosy patients per 1,000 person-years, which is equivalent to observing 1,000 persons per year. Nearly two-thirds of all new cases were of the tuberculoid type of leprosy and another one-sixth of indeterminate type. Lepromatous and borderline cases each constituted about ten percent of the total new cases. The total secondary attack rate was 6.8 per 1,000 person-years. Compared to an annual incidence rate of 0.8 per 1,000 in the total population, this incidence rate among the contacts is nearly ten times higher. Such enhanced risks are observed clearly and consistently when studied by the number of patients within a family for both sexes and in various age-groups. The rate for females (6.3 per 1,000 person-year) though less, was not significantly different from that of males (7.1 per 1,000 person-year). The differences observed between males and females for each type of leprosy were also not statistically significant. The risks for children (less than 15 years) are significantly higher than those for adults. Among boys, the maximum risk was observed in the age-group 5-14 years, whereas for females the risk is highest in the age-group 5-9 years, dropping down significantly after that. Furthermore, it was observed that significant differences existed between children and adults only in males but not in females. The secondary attack rates almost doubled when there were multiple index cases in the family. Regardless of the number of index cases, the male-female differences were not statistically significant. Attack rates were significantly enhanced when there was a bacilliferous type of leprosy (lepromatous or borderline) in the family. This was true for the specific attack rates of each type of leprosy too. However, a significantly higher proportion of lepromatous and borderline types is also seen when there is a bacilliferous type of leprosy present. The study reiterates the differences in susceptibility to leprosy among males and females, especially during younger ages. Further immunological studies are necessary to determine the differences in host responses in males and females that produce such a characteristic sex-ratio in prevalence of leprosy. There is still a great need to obtain more data on incidence rates both in general population and among contacts on the basis of prospective observation using acceptable statistical technics in design and analysis.


TGF-β regulated leukemia cell susceptibility against NK targeting through the down-regulation of the CD48 expression.
Transforming growth factor-β (TGF-β) is known to function as a dual role regulatory cytokine for being either a suppresser or promoter during tumor initiation and progression. In solid tumors, TGF-β secreted from tumor microenvironment acts as a suppresser against host immunity, like natural killer (NK) cells, to favor tumor evasion. However, besides solid tumors, the underlying mechanism of how TGF-β regulates leukemogenesis, tumor progression, immunoediting, and NK function is still not clear in detail. In this study, we found that TGF-β induced leukemia MEG-01 and U937 cells to become less sensitive to NK-92MI targeting by down-regulating CD48, a ligand for NK activating receptor 2B4, but not down-regulating other tumor-associated carbohydrate antigens (TACAs). In CD48-knockdown cells, cells responding to NK-92MI targeting displayed a phenotype of less NK susceptibility and cell conjugation. On the other hand, when NK cells were treated with TGF-β, TGF-β suppressed NK recognition, degranulation, and killing activity in time-dependent manner by regulating ICAM-1 binding capacity instead of affecting expressions of activating and inhibitory receptors. Taken together, both leukemia cells and immune NK cells could be regulated by TGF-β through suppressing leukemia cell surface CD48 to escape from host surveillance and down-regulating NK cell surface ICAM-1 binding activity to impair NK functions, respectively. Our results suggested that TGF-β had effect in leukemia similar to that observed in solid tumors but through different regulatory mechanism.


Researchers' attitudes to the 3Rs-An upturned hierarchy?
Animal use in biomedical research is generally justified by its potential benefits to the health of humans, or other animals, or the environment. However, ethical acceptability also requires scientists to limit harm to animals in their research. Training in laboratory animal science (LAS) helps scientists to do this by promoting best practice and the 3Rs. This study evaluated scientists' awareness and application of the 3Rs, and their approach to other ethical issues in animal research. It was based on an online survey of participants in LAS courses held in eight venues in four European countries: Portugal (Porto, Braga), Germany (Munich, Heidelberg), Switzerland (Basel, Lausanne, Zurich), and Denmark (Copenhagen). The survey questions were designed to assess general attitudes to animal use in biomedical research, Replacement alternatives, Reduction and Refinement conflicts, and harm-benefit analysis. The survey was conducted twice: immediately before the course ('BC', N = 310) and as a follow-up six months after the course ('AC', N = 127). While courses do appear to raise awareness of the 3Rs, they had no measurable effect on the existing low level of belief that animal experimentation can be fully replaced by non-animal methods. Most researchers acknowledged ethical issues with their work and reported that they discussed these with their peers. The level of an animal's welfare, and especially the prevention of pain, was regarded as the most pressing ethical issue, and as more important than the number of animals used or the use of animals as such. Refinement was considered more feasible than Replacement, as well as more urgent, and was also favoured over Reduction. Respondents in the survey reversed the 'hierarchy' of the 3Rs proposed by their architects, Russell and Burch, prioritizing Refinement over Reduction, and Reduction over Replacement. This ordering may conflict with the expectations of the public and regulators.


Remote control of charge transport and chiral induction along a DNA-metallohelicate.
Herein we present a new strategy to achieve chiral induction and redox switching along the backbone of metallohelicate architectures, wherein a DNA duplex directs the handedness and charge transport properties of a metal-organic assembly more than 60 bonds away (a distance of >10 nm). The quantitative and site-specific binding of copper(i) ions to DNA-templated coordination sites imparts enhanced thermodynamic stability to the assembly, while the DNA duplex transfers its natural right-handed helicity to the proximal and distal metal centers of the helicates. When copper(ii) ions are employed instead of copper(i) ions, spontaneous DNA-mediated reduction occurs, which we propose is followed by a slower change in coordination environment (from pentacoordinate CuII to tetrahedral CuI) to generate copper(i) helicates. We demonstrate that the reduction of the adjacent and distal bis-phenanthroline sites is dependent on their proximity to DNA guanine bases (which act as the electron source). The kinetics of helical charge transport can thus be tuned based on guanine-CuII separation, resulting in a sequence- and distance-dependent redox switch that transfers electronic information from DNA to multiple linearly-arranged metal centers.


Mesorhizobium loti increases root-specific expression of a calcium-binding protein homologue identified by promoter tagging in Lotus japonicus.
A promoter tagging program in the legume Lotus japonicus was initiated to identify plant genes involved in the nitrogen-fixing symbiosis between legumes and rhizobia. Seven transformed plant lines expressing the promoterless reporter gene uidA (beta-glucuronidase; GUS) specifically in roots and/or nodules were identified. Four of these expressed GUS in the roots only after inoculation with nodule-forming Mesorhizobium loti. In one line (T90), GUS activity was found in the root epidermis, including root hairs. During seedling growth, GUS expression gradually became focused in developing nodules and disappeared from root tissue. No GUS activity was detected when a non-nodulating mutant of M. loti was used to inoculate the plants. The T-DNA insertion in this plant line was located 1.3 kb upstream of a putative coding sequence with strong homology to calcium-binding proteins. Four motifs were identified, which were very similar to the "EF hands" in calmodulin-related proteins, each binding one Ca2+. We have named the gene LjCbp1 (calcium-binding protein). Northern (RNA) analyses showed that this gene is expressed specifically in roots of L. japonicus. Expression was reduced in roots inoculated with non-nodulating M. loti mutants and in progeny homozygous for the T-DNA insertion, suggesting a link between the T-DNA insertion and this gene.


Similarities and differences in the dental tissue proportions of the deciduous and permanent canines of Early and Middle Pleistocene human populations.
The two- and three-dimensional assessment of dental tissues has become routine in human taxonomic studies throughout the years. Nonetheless, most of our knowledge of the variability of the enamel and dentine dimensions of the human evolutionary lineage comes from the study of permanent dentition, and particularly from molars. This leads to a biased view of the variability of these features. Due to their early formation and rapid development, the deciduous teeth allow more simplified inferences regarding the processes involved in the dental tissue development of each group. Therefore, their study could be very valuable in dental palaeohistology. In this research, we have explored the dental tissue proportions of the deciduous canines belonging to some human samples of the Early and Middle Pleistocene. The purpose of this was to discuss the meaning of the similarities and differences observed in their histological pattern, as well as to evaluate the degree of covariance with that observed in the permanent dentition of these populations. Our results show that, although there are some similarities in the dental tissue proportions between the deciduous and permanent canines of the study samples, the two dental classes do not provide a similar or comparable pictures of the dental tissue pattern present in the dentition of fossil hominins. Future works on the dental tissue patterns of the anterior and posterior dentition, including deciduous teeth, of fossil samples, may help to shed light on this hypothesis.


A Comparison of Heart Rate Training Load and Perceptual Effort Between Masters and Young Cyclists
Due to age-related changes in the psychobiological state of masters athletes, this brief report aimed to compare training load responses using heart rate (HR) and ratings of perceived exertion (RPE) during standardized training sessions between masters and young cyclists. Masters (n = 10; 55.6 [5.0] y) and young (n = 8; 25.9 [3.0] y) cyclists performed separate endurance and high-intensity interval training sessions. Endurance intensity was set at 95% of ventilatory threshold 2 for 1 hour. High-intensity interval training consisted of 6 × 30-second intervals at 175% peak power output with 4.5-minute rest between intervals. HR was monitored continuously and RPE collected at standardized time periods during each session. Banister training impulse and summated-HR-zones training loads were also calculated. Despite a significantly lower mean HR in masters cyclists during endurance (P = .04; d = 1.06 [±0.8], moderate) and high-intensity interval training (P = .01; d = 1.34 [±0.8], large), no significant differences were noted (P > .05) when responses were determined relative to maximum HR or converted to training impulse and summated-HR-zone loads. Furthermore, no interaction or between-group differences were evident for RPE across either session (P > .05). HR and RPE values were comparable between masters and young cyclists when relative HR responses and HR training load models are used. This finding suggests HR and RPE methods used to monitor or prescribe training load can be used interchangeably between masters and young athletes irrespective of chronological age.


Unique organization of Leptospira interrogans rRNA genes.
We cloned Sau3AI fragments containing the rRNA genes for Leptospira interrogans serovar canicola strain Moulton in the BamHI site of lambda EMBL3 bacteriophage DNA. Physical maps of the fragments were constructed, and the locations of the rRNA genes were determined by Southern blot hybridization and S1 protection. Each fragment of the 23S or the 16S rRNA gene contained at least one copy of the 23S or the 16S sequence. Genomic hybridization showed that there were two genes for the 23S rRNA and the 16S rRNA but only one gene for the 5S rRNA on the chromosome of L. interrogans. The results revealed the important fact that each rRNA gene is located far from the other rRNA genes. Our findings, accordingly, also suggest that these rRNA genes are expressed independently in this organism.


Achieving clinical equality in an influenza pandemic: patent realities.
A twenty-first century novel influenza A (H1N1) pandemic is currently unfolding, and the eventual scope of this public health crisis is not clear. In addition, ongoing surveillance of the avian influenza A (H5N1) virus reveals outbreaks of human-to-human transmission of the virus, with significant mortality. Effective pandemic management depends on pharmaceutical intervention with two different clinical objectives: the generation of an immune response to specific viral strains (vaccination) and the reduction of viral replication in an infected individual (antiviral administration). The ability to offer pharmaceutical interventions for a public health crisis depends on three factors: development, capacity, and access. Pharmaceutical measures must be developed, capacity must be established, and access must be ensured. The article discusses the three nodes of patenting that influence the availability of pharmaceutical countermeasures in an influenza pandemic. Identification of the causative influenza virus is the first step in pandemic management and precedes vaccine design, and the virus and its RNA sequence are both knowledge assets and inputs for vaccine design. Vaccine development, therefore, will be influenced by any patents on the genetic sequences or proteins of the pandemic virus, as well as on novel methods for vaccine production, the actual vaccine or adjuvant technology, all of which are relevant to the assembly of a working vaccine on short notice. Pharmaceutical treatment of influenza infection during a pandemic could also rely on use of patented antiviral drugs, whose efficacy may be revealed as the pandemic unfolds. Unlike vaccines, these are not generally developed de novo for a pandemic, but their availability could be dependent on the exercise of patent rights by market incumbents. Patent rights could control capacity, which may determine access. Pandemic planning must consider how patenting can influence development, capacity and access to pharmaceutical interventions. The national and international public health authorities are slowly integrating intellectual property considerations into pandemic planning. Further integration will anticipate the emergence of patent claims, identify any relevant patents, encourage access norms, and consider the use of legal mechanisms that could alleviate patent-mediated obstacles to the availability of critical products and methods that may be patented. Pandemic management must also co-exist with existing efforts to control seasonal influenza outbreaks. The article analyzes the intersection of patent nodes relevant to vaccine development and to antiviral distribution during a global influenza pandemic, identifying where such patents may facilitate or inhibit the availability of pharmaceutical countermeasures, and offers preliminary observations on the emerging novel H1N1 pandemic. The goal of international clinical equality is essential for the eradication of an influenza pandemic, and strategies for its achievement can also be applied to other diseases.


A muscarinic cholinergic antagonist and a dopamine agonist rapidly increase ZENK mRNA expression in the form-deprived chicken retina.
Increases in the expression of the immediate early gene ZENK in the retina, measured by changes in the levels of mRNA and protein immunoreactivity, are amongst the most rapid responses so far measured to conditions that decrease the rate of eye growth in chickens. Our aim was to determine whether atropine, a muscarinic cholinergic antagonist, and 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene hydrobromide, a dopamine agonist, which are known to block excessive eye growth, produce similar changes in ZENK expression. Form-deprivation resulted in significant down-regulation of the expression of retinal ZENK mRNA within 1 h of fitting the diffusers, whereas removal of the diffusers from the eyes of chickens that had developed form-deprivation myopia resulted in significant up-regulation of retinal ZENK expression within 1 h. When atropine (10 microL of 25 mM solution) and 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene hydrobromide (10 microL of a 10 mM solution) were injected intravitreally, just prior to fitting the diffusers, the down-regulation of retinal ZENK mRNA caused by form-deprivation was reversed. This resulted in levels of ZENK mRNA higher than in control or contralateral control eyes. The doses were chosen because they are known to block the excessive axial elongation induced by form-deprivation, without affecting the growth of control eyes. Neither agent had any effect on retinal ZENK expression within this time period when injected into control eyes. These results suggest that both muscarinic acetylcholine antagonists and dopamine agonists act early in the signal cascade controlling eye growth, possibly within the retina itself.


pH-dependent molecular dynamics of vesicular stomatitis virus glycoprotein G.
Vesicular stomatitis virus glycoprotein G (VSV-G) belongs to a new class of viral fusion proteins (Class III). The structure of VSV-G has been solved in two different conformations and fusion is known to be triggered by low pH. To investigate Class III fusion mechanisms, molecular dynamics simulations were performed on the VSV-G prefusion structure in two different protonation states: at physiological pH (pH 7) and low pH present in the endosome (pH 5). Domain IV containing the fusion loops, which need to interact with the target membrane, exhibits the highest mobility. Energetic analyses revealed weakened interaction between Domain IV and the protein core at pH 5, which can be attributed to two pairs of structurally neighboring conserved and differentially protonated residues in the Domain IV-core interface. Energetic calculations also demonstrated that the interaction between the subunits in the core of the trimeric VSV-G is strengthened at pH 5, mainly due to newly formed interactions between the C-terminal loop of Domain II and the N-terminus of the adjacent subunit. A pair of interacting residues in this interface that is affected by differential protonation was shown to be the main effectors of this phenomenon. The results of this study thus enhance the mechanistic understanding of the effects of protonation changes in VSV-G.


Deep sequencing uncovers commonality in small RNA profiles between transgene-induced and naturally occurring RNA silencing of chalcone synthase-A gene in petunia.
Introduction of a transgene that transcribes RNA homologous to an endogenous gene in the plant genome can induce silencing of both genes, a phenomenon termed cosuppression. Cosuppression was first discovered in transgenic petunia plants transformed with the CHS-A gene encoding chalcone synthase, in which nonpigmented sectors in flowers or completely white flowers are produced. Some of the flower-color patterns observed in transgenic petunias having CHS-A cosuppression resemble those in existing nontransgenic varieties. Although the mechanism by which white sectors are generated in nontransgenic petunia is known to be due to RNA silencing of the CHS-A gene as in cosuppression, whether the same trigger(s) and/or pattern of RNA degradation are involved in these phenomena has not been known. Here, we addressed this question using deep-sequencing and bioinformatic analyses of small RNAs. We analyzed short interfering RNAs (siRNAs) produced in nonpigmented sectors of petal tissues in transgenic petunia plants that have CHS-A cosuppression and a nontransgenic petunia variety Red Star, that has naturally occurring CHS-A RNA silencing. In both silencing systems, 21-nt and 22-nt siRNAs were the most and the second-most abundant size classes, respectively. CHS-A siRNA production was confined to exon 2, indicating that RNA degradation through the RNA silencing pathway occurred in this exon. Common siRNAs were detected in cosuppression and naturally occurring RNA silencing, and their ranks based on the number of siRNAs in these plants were correlated with each other. Noticeably, highly abundant siRNAs were common in these systems. Phased siRNAs were detected in multiple phases at multiple sites, and some of the ends of the regions that produced phased siRNAs were conserved. The features of siRNA production found to be common to cosuppression and naturally occurring silencing of the CHS-A gene indicate mechanistic similarities between these silencing systems especially in the biosynthetic processes of siRNAs including cleavage of CHS-A transcripts and subsequent production of secondary siRNAs in exon 2. The data also suggest that these events occurred at multiple sites, which can be a feature of these silencing phenomena.


Towards an intelligent wheelchair system for users with cerebral palsy.
This paper describes and evaluates an intelligent wheelchair, adapted for users with cognitive disabilities and mobility impairment. The study focuses on patients with cerebral palsy, one of the most common disorders affecting muscle control and coordination, thereby impairing movement. The wheelchair concept is an assistive device that allows the user to select arbitrary local destinations through a tactile screen interface. The device incorporates an automatic navigation system that drives the vehicle, avoiding obstacles even in unknown and dynamic scenarios. It provides the user with a high degree of autonomy, independent from a particular environment, i.e., not restricted to predefined conditions. To evaluate the rehabilitation device, a study was carried out with four subjects with cognitive impairments, between 11 and 16 years of age. They were first trained so as to get acquainted with the tactile interface and then were recruited to drive the wheelchair. Based on the experience with the subjects, an extensive evaluation of the intelligent wheelchair was provided from two perspectives: 1) based on the technical performance of the entire system and its components and 2) based on the behavior of the user (execution analysis, activity analysis, and competence analysis). The results indicated that the intelligent wheelchair effectively provided mobility and autonomy to the target population.


The epidemiological impact of the NHS COVID-19 app.
The COVID-19 pandemic has seen the emergence of digital contact tracing to help to prevent the spread of the disease. A mobile phone app records proximity events between app users, and when a user tests positive for COVID-19, their recent contacts can be notified instantly. Theoretical evidence has supported this new public health intervention1-6, but its epidemiological impact has remained uncertain7. Here we investigate the impact of the National Health Service (NHS) COVID-19 app for England and Wales, from its launch on 24 September 2020 to the end of December 2020. It was used regularly by approximately 16.5 million users (28% of the total population), and sent approximately 1.7 million exposure notifications: 4.2 per index case consenting to contact tracing. We estimated that the fraction of individuals notified by the app who subsequently showed symptoms and tested positive (the secondary attack rate (SAR)) was 6%, similar to the SAR for manually traced close contacts. We estimated the number of cases averted by the app using two complementary approaches: modelling based on the notifications and SAR gave an estimate of 284,000 (central 95% range of sensitivity analyses 108,000-450,000), and statistical comparison of matched neighbouring local authorities gave an estimate of 594,000 (95% confidence interval 317,000-914,000). Approximately one case was averted for each case consenting to notification of their contacts. We estimated that for every percentage point increase in app uptake, the number of cases could be reduced by 0.8% (using modelling) or 2.3% (using statistical analysis). These findings support the continued development and deployment of such apps in populations that are awaiting full protection from vaccines.


An alternative mitophagy pathway mediated by Rab9 protects the heart against ischemia.
Energy stress, such as ischemia, induces mitochondrial damage and death in the heart. Degradation of damaged mitochondria by mitophagy is essential for the maintenance of healthy mitochondria and survival. Here, we show that mitophagy during myocardial ischemia was mediated predominantly through autophagy characterized by Rab9-associated autophagosomes, rather than the well-characterized form of autophagy that is dependent on the autophagy-related 7 (Atg) conjugation system and LC3. This form of mitophagy played an essential role in protecting the heart against ischemia and was mediated by a protein complex consisting of unc-51 like kinase 1 (Ulk1), Rab9, receptor-interacting serine/thronine protein kinase 1 (Rip1), and dynamin-related protein 1 (Drp1). This complex allowed the recruitment of trans-Golgi membranes associated with Rab9 to damaged mitochondria through S179 phosphorylation of Rab9 by Ulk1 and S616 phosphorylation of Drp1 by Rip1. Knockin of Rab9 (S179A) abolished mitophagy and exacerbated the injury in response to myocardial ischemia, without affecting conventional autophagy. Mitophagy mediated through the Ulk1/Rab9/Rip1/Drp1 pathway protected the heart against ischemia by maintaining healthy mitochondria.


Segmenting lung fields in serial chest radiographs using both population-based and patient-specific shape statistics.
This paper presents a new deformable model using both population-based and patient-specific shape statistics to segment lung fields from serial chest radiographs. There are two novelties in the proposed deformable model. First, a modified scale invariant feature transform (SIFT) local descriptor, which is more distinctive than the general intensity and gradient features, is used to characterize the image features in the vicinity of each pixel. Second, the deformable contour is constrained by both population-based and patient-specific shape statistics, and it yields more robust and accurate segmentation of lung fields for serial chest radiographs. In particular, for segmenting the initial time-point images, the population-based shape statistics is used to constrain the deformable contour; as more subsequent images of the same patient are acquired, the patient-specific shape statistics online collected from the previous segmentation results gradually takes more roles. Thus, this patient-specific shape statistics is updated each time when a new segmentation result is obtained, and it is further used to refine the segmentation results of all the available time-point images. Experimental results show that the proposed method is more robust and accurate than other active shape models in segmenting the lung fields from serial chest radiographs.


Comprehensive detection of human terminal oligo-pyrimidine (TOP) genes and analysis of their characteristics.
Although the knowledge accumulated on the transcriptional regulations of eukaryotes is significant, the knowledge on their translational regulations remains limited. Thus, we performed a comprehensive detection of terminal oligo-pyrimidine (TOP), which is one of the well-characterized cis-regulatory motifs for translational controls located immediately downstream of the transcriptional start sites of mRNAs. Utilizing our precise 5'-end information of the full-length cDNAs, we could screen 1645 candidate TOP genes by position specific matrix search. Among them, not only 75 out of 78 ribosomal protein genes but also eight previously identified non-ribosomal-protein TOP genes were included. We further experimentally validated the translational activities of 83 TOP candidate genes. Clear translational regulations exerted on the stimulation of 12-O-tetradecanoyl-1-phorbol-13-acetate for at least 41 of them was observed, indicating that there should be a few hundreds of human genes which are subjected to regulation at translation levels via TOPs. Our result suggests that TOP genes code not only formerly characterized ribosomal proteins and translation-related proteins but also a wider variety of proteins, such as lysosome-related proteins and metabolism-related proteins, playing pivotal roles in gene expression controls in the majority of cellular mRNAs.


Situational determinants of cardiovascular and emotional reactivity in high and low hostile men.
Various epidemiologic studies have found that high scores on the Cook and Medley Hostility (Ho) scale are associated with increased risk of coronary heart disease (CHD), severity of atherosclerosis, and all-cause mortality. One plausible biological mechanism suspected of contributing to increased risk of CHD is sympathetic nervous system-mediated hyperresponsivity to environmental stressors. The present study evaluated cardiovascular reactivity among young men with high versus low Ho scores during performance of an anagram task with or without harassment. Compared to performing the task alone, harassment led to increased cardiovascular arousal that was more pronounced for the high Ho subjects than the low Ho subjects. Moreover, harassment produced increases in self-rated anger, irritation, and tension, but it was only among those subjects with high Ho scores that increased anger and irritation were associated with enhanced cardiovascular arousal. While suggesting a role for anger- and irritation-induced cardiovascular arousal in pathogenesis of CHD, these findings indicate that situation characteristics mediate the relationship between Ho scores and cardiovascular reactivity, and that there may be a differential biological link between anger/irritation and cardiovascular responses in men with high and low Ho scores.


Antiretroviral regimen complexity, self-reported adherence, and HIV patients' understanding of their regimens: survey of women in the her study.
Research regarding treatment adherence in chronic diseases, such as hypertension, suggests that increasing complexity in the medication regimen is associated with decreasing patient adherence. However, less is known about the relationship between regimen complexity and adherence in the treatment of HIV/AIDS. To examine the relationship between antiretroviral (ART) regimen complexity and patient understanding of correct regimen dosing to adherence (missing doses in the past 1 and 3 days). Cross-sectional survey of a cohort of women living with HIV/AIDS and enrolled in the HER (HIV Epidemiologic Research) Study. Seventy-five percent of patients correctly understood the dosing frequency of their ART medications, 80% understood the food-dosing restrictions, whereas only 63% understood both. The percentage of patients with a correct understanding of dosing decreased with increasing regimen complexity (increased dosing frequency and food-dosing restrictions). Patients were more likely to have missed doses in the previous 3 days if they were taking ART medications three or more times per day or had to take one or more antiretrovirals on an empty stomach. A multivariate logistic regression model demonstrated that patients with less complex regimens (twice daily or less in frequency, no food-dosing restrictions) who correctly understood the dosing and food restrictions of their ART regimen were less likely to have skipped doses in the past three days (odds ratio [OR], 0.4; 95% confidence interval [CI], 0.2-0.7) than those with more complex regimens. Younger age and higher CD4 count were also associated with a reduced likelihood of skipping doses. No association was found between adherence and race/ethnicity, current or past injection drug use, or education. Self-reported adherence is better among patients with less complex ART regimens. This is in part because patients' understanding of regimen dosing decreases as regimen complexity increases. Therefore, simplifying antiretroviral regimens may have an important role in improving patients' adherence.


[A molecular method of diagnosis of congenital adrenal hyperplasia].
Congenital adrenal hyperplasia (CAH) is caused mainly by deficiency of the 21-hydroxylase enzyme. The disease may appear in the classical salt-losing, simple virilizing forms or as a mild, nonclassical form. 21-hydroxylase is encoded by the CYP21B gene on the short arm of chromosome 6, in the midst of the human leukocyte antigen (HLA) complex, between HLA Class I and Class II regions. We describe a method for identifying mutations in the CYP21B gene. It is based on amplification of the gene using the polymerase chain reaction and identification of mutations with sequence-specific oligo-probes. The mutations identified were: V281 and P30L responsible for nonclassical CAH, and 12 splice, Q318X, I172N, cluster E6, and a deletion including 8bP in the third exon (8bP del) responsible for the classical form of CAH. We also analyzed 2 families affected with the classical form of CAH which demonstrate possible complications in genotyping. Typing for HLA haplotypes can be helpful in certain cases, as demonstrated in 1 of the families presented. In this case it was necessary to distinguish between 2 possible genotypes: 1 with the mutations in tandem on 1 chromosome and the other with the mutated genes on both chromosomes. HLA haplotyping enabled the assignment of the mutations to the relevant chromosomes and thus allowed correct genetic counseling. The other family demonstrated the importance of CYP21B genotyping in individuals with the nonclassical form of CAH. This form may consist of 1 mild and 1 severe mutation, representing a serious potential for transmitting the classical form of CAH.


Mortality in chemical workers potentially exposed to 2,4-dichlorophenoxyacetic acid (2,4-D) 1945-94: an update.
To update and add to a previously identified cohort of employees potentially exposed to the herbicide 2,4-dichlorophenoxyacetic acid (2,4-D). The putative association between 2,4-D and non-Hodgkin's lymphoma has been debated for more than a decade. Cohort members were male employees of The Dow Chemical Company who manufactured or formulated 2,4-D any time from 1945 to the end of 1994. Their mortality experience was compared with national rates and with more than 40 000 other company employees who worked at the same location. 330 Deaths were observed among 1517 people compared with 365 expected (standardised mortality ratio (SMR)=0.90, 95% confidence interval (95% CI) 0.81 to 1.01). There were no significantly increased SMRs for any of the causes of death analyzed. When compared with the United States rates, the SMR for non-Hodgkin's lymphoma (NHL) was 1.00 (95% CI 0.21 to 2.92). The internal comparison with other Dow employees showed a non-significant relative risk of 2.63, (95% CI 0.85 to 8.33). Death was attributed to amyotrophic lateral sclerosis (ALS) for three cohort members. Compared with the other company employees, the relative risk was 3.45 (95% CI 1.10 to 11.11). The cases were employed in the manufacture or formulation of 2,4-D at different periods (1947-9, 1950-1, and 1968-86), and for varying durations of time (1.3, 1.8, and 12.5 years). There was no evidence of a causal association between exposure to 2,4-D and mortality due to all causes and total malignant neoplasms. No significant risk due to NHL was found. Although not an initial hypothesis, an increased relative risk of ALS was noted. This finding is unsupported by other animal and human studies.


Entropy-based consensus clustering for patient stratification.
Patient stratification or disease subtyping is crucial for precision medicine and personalized treatment of complex diseases. The increasing availability of high-throughput molecular data provides a great opportunity for patient stratification. Many clustering methods have been employed to tackle this problem in a purely data-driven manner. Yet, existing methods leveraging high-throughput molecular data often suffers from various limitations, e.g. noise, data heterogeneity, high dimensionality or poor interpretability. Here we introduced an Entropy-based Consensus Clustering (ECC) method that overcomes those limitations all together. Our ECC method employs an entropy-based utility function to fuse many basic partitions to a consensus one that agrees with the basic ones as much as possible. Maximizing the utility function in ECC has a much more meaningful interpretation than any other consensus clustering methods. Moreover, we exactly map the complex utility maximization problem to the classic K -means clustering problem, which can then be efficiently solved with linear time and space complexity. Our ECC method can also naturally integrate multiple molecular data types measured from the same set of subjects, and easily handle missing values without any imputation. We applied ECC to 110 synthetic and 48 real datasets, including 35 cancer gene expression benchmark datasets and 13 cancer types with four molecular data types from The Cancer Genome Atlas. We found that ECC shows superior performance against existing clustering methods. Our results clearly demonstrate the power of ECC in clinically relevant patient stratification. The Matlab package is available at http://scholar.harvard.edu/yyl/ecc . email@example.com or email@example.com. Supplementary data are available at Bioinformatics online.


A biophysical model of synaptic plasticity and metaplasticity can account for the dynamics of the backward shift of hippocampal place fields.
Hippocampal place cells in the rat undergo experience-dependent changes when the rat runs stereotyped routes. One such change, the backward shift of the place field center of mass, has been linked by previous modeling efforts to spike-timing-dependent plasticity (STDP). However, these models did not account for the termination of the place field shift and they were based on an abstract implementation of STDP that ignores many of the features found in cortical plasticity. Here, instead of the abstract STDP model, we use a calcium-dependent plasticity (CaDP) learning rule that can account for many of the observed properties of cortical plasticity. We use the CaDP learning rule in combination with a model of metaplasticity to simulate place field dynamics. Without any major changes to the parameters of the original model, the present simulations account both for the initial rapid place field shift and for the subsequent slowing down of this shift. These results suggest that the CaDP model captures the essence of a general cortical mechanism of synaptic plasticity, which may underlie numerous forms of synaptic plasticity observed both in vivo and in vitro.


Safety evaluation of the food enzyme containing chymosin and pepsin from the abomasum of suckling lambs and goats.
The food enzyme containing chymosin (EC 126.96.36.199) and pepsin (EC 22.214.171.124) is derived from the abomasum of suckling lambs and goats by Caporal Enzymes, S.L. The food enzyme is intended to be used in milk processing for cheese production. As no concerns arise from the animal source of the food enzyme, from its manufacture, and based on the history of safe use and consumption, the Panel considered that toxicological data were not required and no exposure assessment was necessary. On the basis of literature data, the Panel considered that, under the intended conditions of use, the risk of allergic sensitisation and elicitation reactions by dietary exposure could not be excluded, but the likelihood for this to occur was considered to be low. Based on the data provided, the Panel concluded that this food enzyme does not give rise to safety concerns under the intended conditions of use.


An interdigitated electrode with dense carbon nanotube forests on conductive supports for electrochemical biosensors.
A highly sensitive interdigitated electrode (IDE) with vertically aligned dense carbon nanotube forests directly grown on conductive supports was demonstrated by combining UV lithography and a low temperature chemical vapor deposition process (470 °C). The cyclic voltammetry (CV) measurements of K4[Fe(CN)6] showed that the redox current of the IDE with CNT forests (CNTF-IDE) reached the steady state much more quickly compared to that of conventional gold IDE (Au-IDE). The performance of the CNTF-IDE largely depended on the geometry of the electrodes (e.g. width and gap). With the optimum three-dimensional electrode structure, the anodic current was amplified by a factor of ∼18 and ∼67 in the CV and the chronoamperometry measurements, respectively. The collection efficiency, defined as the ratio of the cathodic current to the anodic current at steady state, was improved up to 97.3%. The selective detection of dopamine (DA) under the coexistence of l-ascorbic acid with high concentration (100 μM) was achieved with a linear range of 100 nM-100 μM, a sensitivity of 14.3 mA mol-1 L, and a limit of detection (LOD, S/N = 3) of 42 nM. Compared to the conventional carbon electrodes, the CNTF-IDE showed superior anti-fouling property, which is of significant importance for practical applications, with a negligible shift of the half-wave potential (ΔE1/2 < 1.4 mV) for repeated CV measurements of DA at high concentration (100 μM).


Difference in the recruitment of hip and knee muscles between back squat and plyometric squat jump.
Athletes who aim to improve both muscular endurance and power often perform exercises that involve similar joint actions under different lifting conditions, such as changes in the load or speed, which are implemented at different times during a periodized exercise program or simultaneously. The prescribed exercises are considered to recruit the same muscles even if the lifting conditions differ to each other. The present study aimed to clarify this by examining whether the recruitment of individual hip and knee muscles during the squat exercise differs between lifting conditions adopted for muscular endurance and power training regimens. Moderately trained men performed back squats (BS), with a load of approximately 60% of one repetition maximum, as a muscular endurance training exercise, and they performed plyometric squat jumping (PSJ) for power training. During each exercise, the lower limb joint torques and the recruitment of five hip and knee muscles were determined with inverse-dynamics and T2-weighted magnetic resonance imaging, respectively. While the maximal and mean knee joint torques were greater during PSJ than during BS (p<0.01), the T2 values for the quadriceps femoris muscle did not differ between the exercises. In contrast, the T2 values of the gluteus maximus and hip adductor muscles were higher during PSJ (p<0.05) than during BS, although there was no significant difference in the mean hip extension torque between the two exercises. The current results indicate that the individual use of the agonist muscles differs between BS and PSJ, and it does not always correspond with the joint kinetics during the exercises. Therefore, in addition to the exercise type, the lifting condition should also be taken into consideration as a determinant of the major muscles trained during a resistance exercise.


Interventions for heartburn in pregnancy.
Heartburn is a common symptom in pregnancy affecting up to 80% of women in the third trimester. The reasons for the increase in symptoms in pregnancy are not well understood, but the effects of pregnancy hormones on the lower oesophageal sphincter and gastric clearance are thought to play a part. A range of interventions have been used to relieve symptoms including advice on diet and lifestyle, antacids, antihistamines, and proton pump inhibitors. The safety and effectiveness of these interventions to relieve heartburn in pregnancy have not been established. To assess the effect of interventions to relieve heartburn in pregnancy. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (April 2008). We included randomised controlled trials evaluating interventions to relieve heartburn. We assessed eligibility for inclusion and extracted data independently. Three studies were eligible for inclusion, together they included a total of 286 women. All three were placebo controlled trials, each examining a different medication to relieve heartburn (intramuscular prostigmine, an antacid preparation and an antacid plus ranitidine). All three produced positive findings in favour of the intervention groups. It was not possible to pool findings from studies to produce an overall treatment effect. There was little information to draw conclusions on the overall effectiveness of interventions to relieve heartburn in pregnancy.


BET inhibition as a single or combined therapeutic approach in primary paediatric B-precursor acute lymphoblastic leukaemia.
Paediatric B-precursor ALL is a highly curable disease, however, treatment resistance in some patients and the long-term toxic effects of current therapies pose the need for more targeted therapeutic approaches. We addressed the cytotoxic effect of JQ1, a highly selective inhibitor against the transcriptional regulators, bromodomain and extra-terminal (BET) family of proteins, in paediatric ALL. We showed a potent in vitro cytotoxic response of a panel of primary ALL to JQ1, independent of their prognostic features but dependent on high MYC expression and coupled with transcriptional downregulation of multiple pro-survival pathways. In agreement with earlier studies, JQ1 induced cell cycle arrest. Here we show that BET inhibition also reduced c-Myc protein stability and suppressed progression of DNA replication forks in ALL cells. Consistent with c-Myc depletion and downregulation of pro-survival pathways JQ1 sensitised primary ALL samples to the classic ALL therapeutic agent dexamethasone. Finally, we demonstrated that JQ1 reduces ALL growth in ALL xenograft models, both as a single agent and in combination with dexamethasone. We conclude that targeting BET proteins should be considered as a new therapeutic strategy for the treatment of paediatric ALL and particularly those cases that exhibit suboptimal responses to standard treatment.


Hemochromatosis gene (HFE) mutations in South East Asia: a potential for iron overload.
Hereditary hemochromatosis (HH) is an autosomal recessive disease caused by mutations in the HFE gene that mainly affects populations of European descent. Recently a novel mutation (IVS5+1 G-->A) has been described in a Vietnamese patient with HH that was not detected in a European control population. We have developed a novel method to screen for this mutation based on restriction enzyme digestion of a PCR product using a modified forward primer. We have screened 314 Vietnamese people from several ethnic groups and 154 people from Thailand for this mutation and have detected two heterozygotes in the Vietnamese subjects (allele frequency 0.003). Analysis of these heterozygotes indicates that the mutation is on the same haplotype as that found in the original proband. Screening for the widely distributed HFE mutation, H63D, gave an allele frequency of 0.049 in the Vietnamese subjects and 0.032 in the subjects from Thailand. This is the first report of H63D allele frequencies in these populations. We suggest that the presence of the IVS5+1 G-->A and H63D mutations should be considered when investigating iron overload in Vietnamese patients and those of mixed origin as co-inheritance of both mutations is likely to be a risk factor for iron overload.


Using Smart Socks to Detect Step-count at Slow Walking Speeds in Healthy Adults.
We examined the accuracy of Smart Socks - a device that measures foot pressure during gait for detecting step-count across various walking speeds. Thirty-six participants (17 men; 19 women) wore Smart Socks (Sock), a pedometer (Pedometer), and a smartphone with a commercially available Phone Application (Phone) pedometer to measure step-count during 3-min of treadmill or over-ground walking at 1.3, 2.2, 3.0, 3.8, and 4.7 km/h. Steps were compared to a gold-standard tally-counter (Count), collected by independent assessors. All devices (Sock, Pedometer, and Phone) underestimated step-count when compared to Count at 1.3 km/h (p<0.05); however, Sock (27±18%) demonstrated a lower percent error compared to Phone (40±28%) and Pedometer (98±5%) (both p<0.01). At 2.2 km/h, Sock was not different compared to Count (Sock: 213±39; Count: 229±24 steps, p=0.25); however, both Phone (271±55 steps) and Pedometer (169±166 steps) were different compared to Count (p<0.05). At 3.0 km/h, both Sock (258±30 steps) and Pedometer (254±45 steps) were similar to Count (267±22 steps) (p>0.05); however, Phone (291±28 steps) overestimated step-count (p<0.01). All devices (Sock, Pedometer, and Phone) were similar to Count at 3.8, and 4.7 km/h (p>0.05). These findings demonstrate that Smart Socks are more accurate than pedometers used in the present study for detecting step-count during treadmill or over-ground ambulation at slower walking speeds.


Phytocystatins and their Potential Application in the Development of Drought Tolerance Plants in Soybeans (Glycine max L.).
Plant cystatins, also called phytocystatins constitute a family of specific cysteine protease inhibitors found in several monocots and dicots. In soybean, phytocystatins regulate several endogenous processes contributing immensely to this crop's tolerance to abiotic stress factors. Soybeans offer numerous nutritional, pharmaceutical and industrial benefits; however, their growth and yields is hampered by drought, which causes more than 10% yield losses recorded every harvest period worldwide. This review analyses the role of papain-like cysteine proteases and their inhibitors in soybean plant growth and development under drought stress. It also describes their localisation, regulation, target organs and tissues, and the overall impact of cystatins on generating drought tolerance soybean plants. These proteins have many functions that remain poorly characterized, particularly under abiotic stress. Although much information is available on the utilisation of proteases for industrial applications, very few reports have focused on the impact of proteases on plant stress responses. The exploitation of cystatins in plant engineering, as competitive proteases inhibitors is one of the means that will guarantee the continued utilisation of soybeans as an important oilseed crop.


Cholesterol affects C₆₀ translocation across lipid bilayers.
Cholesterol plays an important role in regulating the structural properties of phospholipid membranes and further influences the permeability of molecules and nanoparticles. However, nanoparticles' translocation across phospholipid membranes in the presence of cholesterol on the molecular scale is rarely studied. Here, we performed coarse-grained molecular dynamics simulations to probe the translocation of C60, one of the most popular nanoparticles, across dipalmitoylphosphatidylcholine bilayers with different concentrations of cholesterol molecules (0-50 mol%). The results reveal that the presence of cholesterol molecules induces lower area per lipid, larger bilayer thickness, and more ordered orientation of lipid tails. The higher the concentration of cholesterol molecules, the more significant is the condensing effect of lipid bilayer as just mentioned. Besides, dynamic processes, free energy profiles and permeability coefficients further indicate that the permeability of C60 decreases with increasing cholesterol concentration, which can be explained by the condensation effect and reduced free volume. Our researches provide an explicit description of the impact of cholesterol on C60 translocation across lipid bilayers.


Theory of intermodal four-wave mixing with random linear mode coupling in few-mode fibers.
We study intermodal four-wave mixing (FWM) in few-mode fibers in the presence of birefringence fluctuations and random linear mode coupling. Two different intermodal FWM processes are investigated by including all nonlinear contributions to the phase-matching condition and FWM bandwidth. We find that one of the FWM processes has a much larger bandwidth than the other. We include random linear mode coupling among fiber modes using three different models based on an analysis of the impact of random coupling on differences of propagation constants between modes. We find that random coupling always reduces the FWM efficiency relative to its vale in the absence of linear coupling. The reduction factor is relatively small (about 3 dB) when only a few modes are linearly coupled but can become very large (> 40 dB) when all modes couple strongly. In the limit of a coupling length much shorter than the nonlinear length, intermodal FWM efficiency becomes vanishingly small. These results should prove useful in the context of space-division multiplexing with few-mode and multimode fibers.


A cost-benefit analysis of lipid standardization in the United States.
By improving lipid standardization, the Centers for Disease Control and Prevention's (CDC's) Lipid Standardization Program and Cholesterol Reference Method Laboratory Network have contributed to the marked reduction in heart disease deaths since 1980. The objective of this study was to estimate the benefits (ie, the value of reductions in heart disease deaths) and costs attributable to these lipid standardization programs. We developed a logic model that shows how the inputs and activities of the lipid standardization programs produce short- and medium-term outcomes that in turn lead to improvements in rates of cardiovascular disease and death. To calculate improvements in long-term outcomes, we applied previous estimates of the change in heart disease deaths between 1980 and 2000 that was attributable to statin treatment and to the reduction in total cholesterol during the period. Experts estimated the share of cholesterol reduction that could be attributed to lipid standardization. We applied alternative assumptions about the value of a life-year saved to estimate the value of life-years saved attributable to the programs. Assuming that 5% of the cholesterol-related benefits were attributable to the programs and a $113,000 value per life-year, the annual benefit attributable to the programs was $7.6 billion. With more conservative assumptions (0.5% of cholesterol-related benefits attributable to the programs and a $50,000 value per life-year), the benefit attributable to the programs was $338 million. In 2007, the CDC lipid standardization programs cost $1.7 million. Our estimates suggest that the benefits of CDC's lipid standardization programs greatly exceed their costs.


Lactobacillus reuteri to Treat Infant Colic: A Meta-analysis.
Lactobacillus reuteri DSM17938 has shown promise in managing colic, but conflicting study results have prevented a consensus on whether it is truly effective. Through an individual participant data meta-analysis, we sought to definitively determine if L reuteri DSM17938 effectively reduces crying and/or fussing time in infants with colic and whether effects vary by feeding type. We searched online databases (PubMed, Medline, Embase, the Cumulative Index to Nursing and Allied Health Literature, the Database of Abstracts of Reviews of Effects, and Cochrane), e-abstracts, and clinical trial registries. These were double-blind randomized controlled trials (published by June 2017) of L reuteri DSM17398 versus a placebo, delivered orally to infants with colic, with outcomes of infant crying and/or fussing duration and treatment success at 21 days. We collected individual participant raw data from included studies modeled simultaneously in multilevel generalized linear mixed-effects regression models. Four double-blind trials involving 345 infants with colic (174 probiotic and 171 placebo) were included. The probiotic group averaged less crying and/or fussing time than the placebo group at all time points (day 21 adjusted mean difference in change from baseline [minutes] -25.4 [95% confidence interval (CI): -47.3 to -3.5]). The probiotic group was almost twice as likely as the placebo group to experience treatment success at all time points (day 21 adjusted incidence ratio 1.7 [95% CI: 1.4 to 2.2]). Intervention effects were dramatic in breastfed infants (number needed to treat for day 21 success 2.6 [95% CI: 2.0 to 3.6]) but were insignificant in formula-fed infants. There were insufficient data to make conclusions for formula-fed infants with colic. L reuteri DSM17938 is effective and can be recommended for breastfed infants with colic. Its role in formula-fed infants with colic needs further research.


The roles of Chk 1 and Chk 2 in hypoxia and reoxygenation.
Both Chk 1 and Chk 2 are critically important checkpoint kinases. Chk 1 is an essential gene that is required for normal cell division and Chk 2 has been found to be mutated in an ever-growing list of human malignancies. Our recent studies indicate that both Chk 1 and Chk 2 have roles to play in the physiological stress of hypoxia/reoxygenation. Loss or inhibition of either kinase sensitizes cells to hypoxia/reoxygenation indicating that either or both could represent significant therapeutic targets.


Metabolic Engineering of Synechocystis sp. PCC 6803 for Production of the Plant Diterpenoid Manoyl Oxide.
Forskolin is a high value diterpenoid with a broad range of pharmaceutical applications, naturally found in root bark of the plant Coleus forskohlii. Because of its complex molecular structure, chemical synthesis of forskolin is not commercially attractive. Hence, the labor and resource intensive extraction and purification from C. forskohlii plants remains the current source of the compound. We have engineered the unicellular cyanobacterium Synechocystis sp. PCC 6803 to produce the forskolin precursor 13R-manoyl oxide (13R-MO), paving the way for light driven biotechnological production of this high value compound. In the course of this work, a new series of integrative vectors for use in Synechocystis was developed and used to create stable lines expressing chromosomally integrated CfTPS2 and CfTPS3, the enzymes responsible for the formation of 13R-MO in C. forskohlii. The engineered strains yielded production titers of up to 0.24 mg g(-1) DCW 13R-MO. To increase the yield, 13R-MO producing strains were further engineered by introduction of selected enzymes from C. forskohlii, improving the titer to 0.45 mg g(-1) DCW. This work forms a basis for further development of production of complex plant diterpenoids in cyanobacteria.


Evaluation of treatment adherence and illness perception in cardiology patients.
The aim of this study was to investigate the effects of the cardiology patients' illness perception on their medication adherence will guide in the development of training and consultancy strategies. The study was conducted with 110 patients who were followed up in the cardiology clinics of a university hospital. The study included patients over the age of 18 years, who agreed to participate in the study and were diagnosed with a cardiovascular disease at least six months before. The data were collected using a patient information form questioning the subjects such as the patients' age, gender, marital status and economic condition, the Illness Perception Questionnaire and the Morisky Medication Adherence Scale. The results showed that 72.7% (n=80) of the group had forgotten to take their medicine, 38.2% (n=42) had a trouble remembering to take their medicine, 29.1% (n=32) stopped taking their medicine when they felt good and 32.7% (n=36) stopped taking their medicine because they sometimes felt bad after taking their medicine. It was determined that there was no statistically significant correlation between Morisky Medication Adherence Scale scores and Illness Perception Questionnaire subscale scores (P >0.05). It was determined that there was a statistically significant difference between the educational backgrounds, in terms of the personal control subscale mean scores (P=0.003; P<0.01). Patients try to explain their disease in the light of their personal experiences, knowledge, values, beliefs, and needs. Illness perception which is among the most important factors providing treatment adherence is an important factor affecting many areas from the person's psychological adaptation to the course of disease. Illness perception and treatment adherence are affected by educational level.


The role of chromatin accessibility in directing the widespread, overlapping patterns of Drosophila transcription factor binding.
In Drosophila embryos, many biochemically and functionally unrelated transcription factors bind quantitatively to highly overlapping sets of genomic regions, with much of the lowest levels of binding being incidental, non-functional interactions on DNA. The primary biochemical mechanisms that drive these genome-wide occupancy patterns have yet to be established. Here we use data resulting from the DNaseI digestion of isolated embryo nuclei to provide a biophysical measure of the degree to which proteins can access different regions of the genome. We show that the in vivo binding patterns of 21 developmental regulators are quantitatively correlated with DNA accessibility in chromatin. Furthermore, we find that levels of factor occupancy in vivo correlate much more with the degree of chromatin accessibility than with occupancy predicted from in vitro affinity measurements using purified protein and naked DNA. Within accessible regions, however, the intrinsic affinity of the factor for DNA does play a role in determining net occupancy, with even weak affinity recognition sites contributing. Finally, we show that programmed changes in chromatin accessibility between different developmental stages correlate with quantitative alterations in factor binding. Based on these and other results, we propose a general mechanism to explain the widespread, overlapping DNA binding by animal transcription factors. In this view, transcription factors are expressed at sufficiently high concentrations in cells such that they can occupy their recognition sequences in highly accessible chromatin without the aid of physical cooperative interactions with other proteins, leading to highly overlapping, graded binding of unrelated factors.


Leishmania development in sand flies: parasite-vector interactions overview.
Leishmaniases are vector-borne parasitic diseases with 0.9 - 1.4 million new human cases each year worldwide. In the vectorial part of the life-cycle, Leishmania development is confined to the digestive tract. During the first few days after blood feeding, natural barriers to Leishmania development include secreted proteolytic enzymes, the peritrophic matrix surrounding the ingested blood meal and sand fly immune reactions. As the blood digestion proceeds, parasites need to bind to the midgut epithelium to avoid being excreted with the blood remnant. This binding is strictly stage-dependent as it is a property of nectomonad and leptomonad forms only. While the attachment in specific vectors (P. papatasi, P. duboscqi and P. sergenti) involves lipophosphoglycan (LPG), this Leishmania molecule is not required for parasite attachment in other sand fly species experimentally permissive for various Leishmania. During late-stage infections, large numbers of parasites accumulate in the anterior midgut and produce filamentous proteophosphoglycan creating a gel-like plug physically obstructing the gut. The parasites attached to the stomodeal valve cause damage to the chitin lining and epithelial cells of the valve, interfering with its function and facilitating reflux of parasites from the midgut. Transformation to metacyclic stages highly infective for the vertebrate host is the other prerequisite for effective transmission. Here, we review the current state of knowledge of molecular interactions occurring in all these distinct phases of parasite colonization of the sand fly gut, highlighting recent discoveries in the field.


A systematic review of the impact of including both waist and hip circumference in risk models for cardiovascular diseases, diabetes and mortality.
Both a larger waist and narrow hips are associated with heightened risk of diabetes, cardiovascular diseases and premature mortality. We review the risk of these outcomes for levels of waist and hip circumferences when terms for both anthropometric measures were included in regression models. MEDLINE and EMBASE were searched (last updated July 2012) for studies reporting the association with the outcomes mentioned earlier for both waist and hip circumferences (unadjusted and with both terms included in the model). Ten studies reported the association between hip circumference and death and/or disease outcomes both unadjusted and adjusted for waist circumference. Five studies reported the risk associated with waist circumference both unadjusted and adjusted for hip circumference. With the exception of one study of venous thromboembolism, the full strength of the association between either waist circumference or hip circumference with morbidity and/or mortality was only apparent when terms for both anthropometric measures were included in regression models. Without accounting for the protective effect of hip circumference, the effect of obesity on risk of death and disease may be seriously underestimated. Considered together (but not as a ratio measure), waist and hip circumference may improve risk prediction models for cardiovascular disease and other outcomes.


Optical metrology for two large highly aspheric telescope mirrors.
We describe a relatively simple, but highly effective, approach to the system design and alignment of an all-refractive Offner null corrector and phase-measuring Shack cube interferometer. In addition we outline procedures for fabricating and testing the optical components. Allowable errors for all parameters are determined by a tolerance analysis that separates axisymmetric and residual figure errors. An open construction optics frame provides a high degree of metering flexibility by incorporating simple kinematic mounts that provide adjustment of each lens while also allowing the lens to be removed and replaced with <2microm absolute repeatability. Nonaxisymmetric alignment errors are removed by rotating the optics on a high-precision bearing. Axial spacings are measured with contact transducers attached to both ends of an Invar metering rod. Two completed systems have guided the stressed-lap polishing of 1.8-m f/ 1.0 and 3.5-m f/ 1.5 aspheric mirrors.


Glyphosate induces toxicity and modulates calcium and NO signaling in zebrafish embryos.
Glyphosate, an herbicide used worldwide, has emerged as a pollutant. However, its toxic effects are debated by regulatory authorities. Therefore, it is essential to keep the use of such chemicals under continuous observation, and their effects must be re-evaluated. We used zebrafish embryos to evaluate the toxic effects of glyphosate and its mechanisms. We found that glyphosate induced significant toxicity in a time and concentration-dependent manner. We observed an LD50 of 66.04 ± 4.6 μg/mL after 48 h of exposure. Glyphosate significantly reduced the heartbeat in a time and concentration-dependent manner indicating cardiotoxicity. Selective downregulation of Cacana1C (L-type calcium channel) and ryr2a (Ryanodine receptor) genes along with selective upregulation of hspb11 (heat shock protein) gene was observed upon exposure to glyphosate indicating alterations in the calcium signaling. A reduction in the nitric oxide (NO) generation was also observed in the zebrafish embryos upon exposure to glyphosate. Our results indicate that glyphosate induces significant toxicity including cardiotoxicity in zebrafish embryos in a time and concentration-dependent manner. Further, cardiotoxicity may be due to changes in calcium and NO signaling.


Management of blunt major pancreatic injury.
Major duct injury is the principal determinant of outcome for patients with pancreatic trauma, and there are a number of therapeutic choices available specific to the location of the insult. We report a series of blunt major pancreatic injury cases, with a review of the different procedures used and a discussion of the results. A total of 48 cases of blunt major pancreatic injury treated during a 10-year period at one trauma center were reviewed retrospectively. Diagnosis and assessment of injury severity were based on imaging studies and proved by surgical findings. Charts were reviewed to establish the mechanism of injury, surgical indications and imaging studies, management strategy, and outcome. Of the 32 grade III patients, 19 underwent distal pancreatectomy with splenectomy, 8 had pancreatectomy with preservation of the spleen, and 2 received a pancreatic duct stent, with the remaining 3 individuals undergoing nonsurgical treatment, pancreaticojejunostomy, and drainage alone, respectively. The grade III complication rate was 60.6%. Of the 14 grade IV patients, 4 underwent drainage alone because of the severity of the associated injuries, 4 underwent pancreaticojejunostomy, 3 had distal pancreatectomy with splenectomy, and 1 underwent distal pancreatectomy. The two remaining patients received a pancreatic duct stent. The grade IV complication rate was 53.8%. The Whipple procedure was performed for two grade V patients; one died subsequently. For all 48 patients, intraabdominal abscess was the most common morbidity (n = 11) followed, in order of prevalence, by major duct stricture (n = 4), pancreatitis (n = 2), pseudocyst (n = 2), pancreatic fistula (n = 1), and biliary fistula (n = 1). All stented cases developed complications, with one dying and three experiencing major duct stricture. The complication rate for our cases of blunt major pancreatic injury was high (62.2%), especially when treatment was delayed more than 24 hours; the same result was also noted for cases transferred from other institutions. Distal pancreatectomy with spleen preservation had a lower complication rate (22.2%) compared with other procedures and is suggested for grade III and grade IV injuries. Magnetic resonance pancreatography was unreliable early after injury but was effective in the chronic stage. Although pancreatic duct stenting can be used to treat posttraumatic pancreatic fistula and pseudocyst, the major duct stricture in the chronic stage of recovery and the risk of sepsis in the acute stage must be overcome.


Shear-affected depletion interaction.
We investigate the influence of flow fields on the strength of the depletion interaction caused by disc-shaped depletants. At low mass concentration of discs, it is possible to continuously decrease the depth of the depletion potential by increasing the applied shear rate until the depletion force is not perceivable experimentally. Above a threshold in the platelet mass concentration, the depletion potential can no longer be affected by flow in the accessible range of shear rates. While the observed decrease of depletion strength at low depletant concentration may be ascribed to flow alignment of the discs, it is not clear why the influence of flow is vanishing at high concentrations. In order to observe these effects, a modification of the established total internal reflexion microscopy (TIRM) technique is be implemented. We show the suitability of these modifications to measure particle-wall interaction potentials under non-equilibrium conditions for systems where particles are exposed to a shear.


Lung function and self-rated symptoms in healthy volunteers after exposure to hydrotreated vegetable oil (HVO) exhaust with and without particles.
Diesel engine exhaust causes adverse health effects. Meanwhile, the impact of renewable diesel exhaust, such as hydrotreated vegetable oil (HVO), on human health is less known. Nineteen healthy volunteers were exposed to HVO exhaust for 3 h in a chamber with a double-blind, randomized setup. Exposure scenarios comprised of HVO exhaust from two modern non-road vehicles with 1) no aftertreatment system ('HVOPM+NOx' PM1: 93 µg m-3, EC: 54 µg m-3, NO: 3.4 ppm, NO2: 0.6 ppm), 2) an aftertreatment system containing a diesel oxidation catalyst and a diesel particulate filter ('HVONOx' PM1: ~ 1 µg m-3, NO: 2.0 ppm, NO2: 0.7 ppm) and 3) filtered air (FA) as control. The exposure concentrations were in line with current EU occupational exposure limits (OELs) of NO, NO2, formaldehyde, polycyclic aromatic hydrocarbons (PAHs), and the future OEL (2023) of elemental carbon (EC). The effect on nasal patency, pulmonary function, and self-rated symptoms were assessed. Calculated predicted lung deposition of HVO exhaust particles was compared to data from an earlier diesel exhaust study. The average total respiratory tract deposition of PM1 during HVOPM+NOx was 27 µg h-1. The estimated deposition fraction of HVO PM1 was 40-50% higher compared to diesel exhaust PM1 from an older vehicle (earlier study), due to smaller particle sizes of the HVOPM+NOx exhaust. Compared to FA, exposure to HVOPM+NOx and HVONOx caused higher incidence of self-reported symptoms (78%, 63%, respectively, vs. 28% for FA, p < 0.03). Especially, exposure to HVOPM+NOx showed 40-50% higher eye and throat irritation symptoms. Compared to FA, a decrement in nasal patency was found for the HVONOx exposures (- 18.1, 95% CI: - 27.3 to - 8.8 L min-1, p < 0.001), and for the HVOPM+NOx (- 7.4 (- 15.6 to 0.8) L min-1, p = 0.08). Overall, no clinically significant change was indicated in the pulmonary function tests (spirometry, peak expiratory flow, forced oscillation technique). Short-term exposure to HVO exhaust concentrations corresponding to EU OELs for one workday did not cause adverse pulmonary function changes in healthy subjects. However, an increase in self-rated mild irritation symptoms, and mild decrease in nasal patency after both HVO exposures, may indicate irritative effects from exposure to HVO exhaust from modern non-road vehicles, with and without aftertreatment systems.


Association of human papillomavirus type 31 variants with risk of cervical intraepithelial neoplasia grades 2-3.
Although the lineages of human papillomavirus type 31 (HPV31) variants are recognized, their clinical relevance is unknown. The purpose of our study was to examine risk of cervical intraepithelial neoplasia Grades 2-3 (CIN2/3) by HPV31 variants. Study subjects were women who participated in the atypical squamous cells of undetermined significance and low-grade squamous intraepithelial lesion Triage Study and who had HPV31 infections detected at one or more visits. They were followed semi-annually over 2 years for detection of HPV DNA and cervical lesion. HPV31 isolates were characterized by DNA sequencing and assigned into 1 of 3 variant lineages. CIN2/3 was histologically confirmed in 127 (27.0%) of the 470 HPV31-positive women, 83 diagnosed at the first HPV31-positive visit and 44 thereafter. The odds ratio for the association of 2-year cumulative risk of CIN2/3 was 1.7 (95% CI: 1.0-2.9) for infections with A variants and 2.2 (95% CI: 1.2-3.9) for infections with B variants as compared to those with C variants. Among women without CIN2/3 at the first HPV31-positive visit, the risk of subsequent CIN2/3 was 2.2-fold greater for those with A variants (95% CI: 1.0-4.8) and 2.0-fold greater for those with B variants (95% CI: 0.9-4.9) as compared to those with C variants. Similar associations were observed when CIN3 was used as the endpoint. The findings from our study help to tag HPV31 variants that differ in risk of CIN2/3 and to explain in part why some HPV31 infections regress spontaneously and others lead to disease progression.


The effect of varying LED intensity on pulse oximeter accuracy.
Most pulse oximeters automatically alter the intensity of their light-emitting diodes (LEDs) according to the absorption of the finger, toe or earlobe to which they are attached. This paper investigates the effect of changing LED intensity on pulse oximeter accuracy. Our results show that the peak wavelength of a red LED typically increases by 8 nm as its intensity is increased ten-fold. To determine whether this shift introduces a significant error, a simple theoretical model based on the Beer-Lambert law is used. The model predicts that a 10:1 change in LED intensity results in a 2.5% error at 50% arterial oxygen saturation (SpO2). At high saturations (SpO2 greater than or equal to 85%) the model predicts little loss of accuracy and thus any effect due to changes in LED intensity will be apparent only at low saturations.


Capillary supply and fiber morphometry in rat myocardium after intermittent exposure to hypobaric hypoxia.
Three groups of male rats were submitted to an intermittent hypobaric hypoxia (IHH) program for 22 days (4 h/day, 5 days/week) in a hypobaric chamber at a simulated altitude of 5000 m. Hearts were removed at the end of the program (H group) and 20 and 40 days later (P20 and P40 groups). A control group (C) was maintained at sea-level pressure. Transverse sections from myocardium were cut and histochemically stained in order to measure fiber morphometry and capillaries. We observed a progressive increase from C to H to P20 animals in capillary (4124 to 4733 to 4816 capillaries/mm(2)) and fiber densities (2844 to 3125 to 3284 fibers/mm(2)) associated with significant reductions in fiber area (273, 235, and 227 microm(2)), perimeter (69, 64, and 62 microm), and diffusion distances (18.2, 16.9, and 16.6 microm). The most significant differences between C and hypoxic groups were found when morphometrical and vascular fiber parameters were combined. The myocardium of the latter had more capillaries per fiber area and per fiber perimeter. These findings indicate that the IHH program elicits an adaptive response of rat myocardium to a more efficient O2 delivery to mitochondria of cardiac muscle cells. Capillarization and fiber morphometric changes showed marked differences over time. In all cases, P20 had higher capillarization parameters and fiber morphometry reductions than H, thus indicating that a delay of about 20 days exists after the hypoxic stimulus ceases to reach complete angiogenesis and fiber morphometry changes. However, P40 animals showed a recovery to basal values of the parameters related to fiber morphometry (area, perimeter, and diffusion distances), but maintained high capillarity values (capillary density, NCF, CCA, CCP).


Helicobacter pylori downregulates expression of human β-defensin 1 in the gastric mucosa in a type IV secretion-dependent fashion.
Helicobacter pylori establishes a chronic lifelong infection in the human gastric mucosa, which may lead to peptic ulcer disease or gastric adenocarcinoma. The human beta-defensins (hβDs) are antimicrobial peptides, hβD1 being constitutively expressed in the human stomach. We hypothesized that H. pylori may persist, in part, by downregulating gastric hβD1 expression. We measured hβD1 and hβD2 expression in vivo in relation to the presence, density and severity of H. pylori infection, investigated differential effects of H. pylori virulence factors, and studied underlying signalling mechanisms in vitro. Significantly lower hβD1 and higher hβD2 mRNA and protein concentrations were present in gastric biopsies from infected patients. Those patients with higher-level bacterial colonization and inflammation had significantly lower hβD1 expression, but there were no differences in hβD2. H. pylori infection of human gastric epithelial cell lines also downregulated hβD1. Using wild-type strains and isogenic mutants, we showed that a functional cag pathogenicity island-encoded type IV secretion system induced this downregulation. Treatment with chemical inhibitors or siRNA revealed that H. pylori usurped NF-κB signalling to modulate hβD1 expression. These data indicate that H. pylori downregulates hβD1 expression via NF-κB signalling, and suggest that this may promote bacterial survival and persistence in the gastric niche.


Cost effectiveness of using ursodeoxycholic acid to treat primary biliary cholangitis.
Primary biliary cholangitis is a chronic inflammatory, autoimmune cholestatic liver disease, which untreated will usually progress to end-stage biliary cirrhosis. The aims of treatment and management of primary biliary cholangitis are the amelioration of associated symptoms, particularly pruritis and fatigue, and the prevention of end-stage liver disease. The presentation, natural history and clinical course are variable. Recent published European and UK clinical guidelines have emphasized the need for risk stratification and an individualized approach to patient management in primary biliary cholangitis. The bile acid, ursodeoxycholic acid, is established as the first-line treatment of primary biliary cholangitis. Assessment of clinical response to treatment is based on specified improvements in serum liver tests including near normalization of the serum alkaline phosphatase level at 1 year. At least two thirds of patients with primary biliary cholangitis should respond to ursodeoxycholic acid after 1 year's treatment. The correct dosage of ursodeoxycholic acid is determined by body weight viz 13-15 mg/kg/day. A significant number of patients with primary biliary cholangitis in the UK are being underdosed. Over a third of ursodeoxycholic acid partial responders become responders within 2 years after increasing the ursodeoxycholic acid doses to recommended levels. While transplant rates for primary biliary cholangitis have halved over the last 20 years, it is clear that optimizing the dose of ursodeoxycholic acid in partial responders would further decrease morbidity, mortality and the need for liver transplantation.


Donkey dental anatomy. Part 2: Histological and scanning electron microscopic examinations.
Ten normal cheek teeth (CT) were extracted at post mortem from donkeys that died or were euthanased for humane reasons. Decalcified histology was performed on three sections (sub-occlusal, mid-tooth and pre-apical) of each tooth, and undecalcified histology undertaken on sub-occlusal sections of the same teeth. The normal histological anatomy of primary, regular and irregular secondary dentine was found to be similar to that of the horse, with no tertiary dentine present. Undecalcified histology demonstrated the normal enamel histology, including the presence of enamel spindles. Scanning electron microscopy was performed on mid-tooth sections of five maxillary CT, five mandibular CT and two incisors. The ultrastructural anatomy of primary and secondary dentine, and equine enamel types-1, -2 and -3 (as described in horses) were identified in donkey teeth. Histological and ultrastructural donkey dental anatomy was found to be very similar to equine dental anatomy with only a few quantitative differences observed.


Effects of action relations on the configural coding between objects.
Configural coding is known to take place between the parts of individual objects but has never been shown between separate objects. We provide novel evidence here for configural coding between separate objects through a study of the effects of action relations between objects on extinction. Patients showing visual extinction were presented with pairs of objects that were or were not co-located for action. We first confirmed the reduced extinction effect for objects co-located for action. Consistent with prior results showing that inversion disrupts configural coding, we found that inversion disrupted the benefit for action-related object pairs. This occurred both for objects with a standard canonical orientation (e.g., teapot and teacup) and those without, but where grasping and using the objects was made more difficult by inversion (e.g., spanner and nut). The data suggest that part of the affordance effect may reflect a visuo-motor response to the configural relations between stimuli. Experiment 2 showed that distorting the relative sizes of the objects also reduced the advantage for action-related pairs. We conclude that action-related pairs are processed as configurations.


Illegal substance use among Italian high school students: trends over 11 years (1999-2009).
To monitor changes in habits in drug use among Italian high school students. Cross-sectional European School Survey Project on Alcohol and Other Drugs (ESPAD) carried out in Italy annually for 11 years (1999-2009) with representative samples of youth attending high school. The sample size considered ranges from 15,752 to 41,365 students and response rate ranged from 85.5% to 98.6%. Data were analyzed to obtain measures of life-time prevalence (LT), use in the last year (LY), use in the last 30 days (LM), frequent use. Comparisons utilized difference in proportion tests. Tests for linear trends in proportion were performed using the Royston p trend test. When the time-averaged value was considered, cannabis (30% LT) was the most, and heroin the least (2%) frequently used, with cocaine (5%), hallucinogens (2%) and stimulants (2%) in between. A clear gender gap is evident for all drugs, more obvious for hallucinogens (average M/F LY prevalence ratio 2, range 1.7-2.4, p<0.05), less for cannabis (average M/F LY prevalence ratio 1.3, range 1.2-1.5, p<0.05). Data shows a change in trend between 2005 and 2008; in 2006 the trend for cannabis use and availability dropped and the price rose, while from 2005 cocaine and stimulant use prevalence showed a substantial increase and the price went down. After 2008 use of all substances seems to have decreased. Drug use is widespread among students in Italy, with cannabis being the most and heroin the least prevalent. Girls are less vulnerable than boys to illegal drug use. In recent years, a decrease in heroin use is overbalanced by a marked rise in hallucinogen and stimulant use.


Cost-effectiveness of drug monitoring of anti-TNF therapy in inflammatory bowel disease and rheumatoid arthritis: a systematic review.
Therapeutic drug monitoring (TDM) of anti-TNF is increasingly used to manage inflammatory bowel diseases (IBD) and rheumatoid arthritis (RA). The cost-effectiveness of this strategy is debated. All studies comparing the cost-effectiveness of a TDM-based strategy and an empirical dose management of anti-TNF in IBD or RA were screened. Studies were identified through the MEDLINE electronic database (up to July 2016), and annual international meeting abstracts were also manually reviewed. Seven studies were included: two randomized controlled trials (RCTs) enrolling 332 patients [247 Crohn's disease (CD) and 85 ulcerative colitis (UC)] and five modeling approaches. Four studies included only CD patients, one included both CD and UC patients, and two included only RA patients. Three studies compared the cost-effectiveness of the two strategies in patients with secondary infliximab (IFX) failure (dose-escalation strategy), one in patients in remission on optimized IFX (de-escalation strategy), one in patients starting adalimumab, and two in patients with clinical response to maintenance anti-TNF therapy. The two RCTs demonstrated that a TDM strategy led to major cost savings, ranging from 28 to 34 %. The three modeling approaches with regard to CD patients demonstrated cost savings ranging from $5396 over a 1-year period to €13,130 per patient at 5 years of follow-up. A TDM strategy also led to major cost savings in the two modeling approaches in RA patients. Available evidence indicates that a TDM strategy leads to major cost savings related to anti-TNF therapy in both IBD and RA patients, with no negative impact on efficacy.


Hepatitis B seroprevalence in Latin America.
The seroprevalence of hepatitis B was investigated in over 12,000 subjects in six countries of Latin America: Argentina, Brazil, Chile, the Dominican Republic, Mexico, and Venezuela. Each study population was stratified according to age, gender, and socioeconomic status. Antibodies against hepatitis B core antigen (anti-HBc) were measured in order to determine hepatitis B infection. The highest overall seroprevalence was found in the Dominican Republic (21.4%), followed by Brazil (7.9%), Venezuela (3.2%), Argentina (2.1%), Mexico (1.4%), and Chile (0.6%). In all the countries an increase in seroprevalence was found among persons 16 years old and older, suggesting sexual transmission as the major route of infection. In addition, comparatively high seroprevalence levels were seen at an early age in the Dominican Republic and Brazil, implicating a vertical route of transmission.