NMR analysis on microfluidic devices by remote detection.
We present a novel approach to perform high-sensitivity NMR imaging and spectroscopic analysis on microfluidic devices. The application of NMR, the most information-rich spectroscopic technique, to microfluidic devices remains a challenge because the inherently low sensitivity of NMR is aggravated by small fluid volumes leading to low NMR signal and geometric constraints resulting in poor efficiency for inductive detection. We address the latter by physically separating signal detection from encoding of information with remote detection. Thereby, we use a commercial imaging probe with sufficiently large diameter to encompass the entire device, enabling encoding of NMR information at any location on the chip. Because large-diameter coils are too insensitive for detection, we store the encoded information as longitudinal magnetization and flow it into the outlet capillary. There, we detect the signal with optimal sensitivity, using a solenoidal microcoil, and reconstruct the information encoded in the fluid. We present a generally applicable design for a detection-only microcoil probe that can be inserted into the bore of a commercial imaging probe. Using hyperpolarized 129Xe gas, we show that this probe enables sensitive reconstruction of NMR spectroscopic information encoded by the large imaging probe while keeping the flexibility of a large coil.


Explaining accesses to electronic medical records using diagnosis information.
Ensuring the security and appropriate use of patient health information contained within electronic medical records systems is challenging. Observing these difficulties, we present an addition to the explanation-based auditing system (EBAS) that attempts to determine the clinical or operational reason why accesses occur to medical records based on patient diagnosis information. Accesses that can be explained with a reason are filtered so that the compliance officer has fewer suspicious accesses to review manually. Our hypothesis is that specific hospital employees are responsible for treating a given diagnosis. For example, Dr Carl accessed Alice's medical record because Hem/Onc employees are responsible for chemotherapy patients. We present metrics to determine which employees are responsible for a diagnosis and quantify their confidence. The auditing system attempts to use this responsibility information to determine the reason why an access occurred. We evaluate the auditing system's classification quality using data from the University of Michigan Health System. The EBAS correctly determines which departments are responsible for a given diagnosis. Adding this responsibility information to the EBAS increases the number of first accesses explained by a factor of two over previous work and explains over 94% of all accesses with high precision. The EBAS serves as a complementary security tool for personal health information. It filters a majority of accesses such that it is more feasible for a compliance officer to review the remaining suspicious accesses manually.


Injury of the collateral ligaments of the distal interphalangeal joint diagnosed by magnetic resonance.
We describe the clinical, imaging, and necropsy findings of two horses with severe injury of the collateral ligaments of the distal interphalangeal (DIP) joint diagnosed using magnetic resonance (MR) imaging. In MR images it was possible to examine the collateral ligaments of the DIP joint from the origin at the middle phalanx to the insertion on the distal phalanx. Both horses in this report had abnormal high signal intensity within the collateral ligaments of the DIP joint, and one horse had abnormal high signal intensity within the bone of the distal phalanx on short tau inversion recovery (STIR) and T2-weighted imaging sequences. High signal intensity on STIR and T2-weighted images represents abnormal fluid accumulation indicative of inflammation, within ligament, tendon, or bone on these imaging sequences. Abnormalities were confirmed on necropsy in both horses. Injury of the collateral ligaments of the DIP joint should be considered as a source of pain in horses with lameness localized to the foot.


Gene doctoring: a method for recombineering in laboratory and pathogenic Escherichia coli strains.
Homologous recombination mediated by the lambda-Red genes is a common method for making chromosomal modifications in Escherichia coli. Several protocols have been developed that differ in the mechanisms by which DNA, carrying regions homologous to the chromosome, are delivered into the cell. A common technique is to electroporate linear DNA fragments into cells. Alternatively, DNA fragments are generated in vivo by digestion of a donor plasmid with a nuclease that does not cleave the host genome. In both cases the lambda-Red gene products recombine homologous regions carried on the linear DNA fragments with the chromosome. We have successfully used both techniques to generate chromosomal mutations in E. coli K-12 strains. However, we have had limited success with these lambda-Red based recombination techniques in pathogenic E. coli strains, which has led us to develop an enhanced protocol for recombineering in such strains. Our goal was to develop a high-throughput recombineering system, primarily for the coupling of genes to epitope tags, which could also be used for deletion of genes in both pathogenic and K-12 E. coli strains. To that end we have designed a series of donor plasmids for use with the lambda-Red recombination system, which when cleaved in vivo by the I-SceI meganuclease generate a discrete linear DNA fragment, allowing for C-terminal tagging of chromosomal genes with a 6xHis, 3xFLAG, 4xProteinA or GFP tag or for the deletion of chromosomal regions. We have enhanced existing protocols and technologies by inclusion of a cassette conferring kanamycin resistance and, crucially, by including the sacB gene on the donor plasmid, so that all but true recombinants are counter-selected on kanamycin and sucrose containing media, thus eliminating the need for extensive screening. This method has the added advantage of limiting the exposure of cells to the potential damaging effects of the lambda-Red system, which can lead to unwanted secondary alterations to the chromosome. We have developed a counter-selective recombineering technique for epitope tagging or for deleting genes in E. coli. We have demonstrated the versatility of the technique by modifying the chromosome of the enterohaemorrhagic O157:H7 (EHEC), uropathogenic CFT073 (UPEC), enteroaggregative O42 (EAEC) and enterotoxigenic H10407 (ETEC) E. coli strains as well as in K-12 laboratory strains.


Traumatic brain injury education for adult patients and families: a scoping review.
Traumatic brain injury (TBI) is increasingly viewed as a chronic condition, bringing long-term needs for patient and caregiver knowledge pertaining to symptom and problem management over time. In light of these needs, we performed a scoping review of the literature on brain injury education provided to adult patients and/ or family members affected by TBI. Objectives were to describe the types of educational interventions that have been developed; to review the effects of these interventions; and to determine gaps that might be filled by future research efforts. Of 88 articles meeting search criteria and subjected to data extraction, 34 concerned education about mild TBI and 54, moderate to severe TBI. Most mild TBI articles focused on education in the Emergency Room, while most moderate/ severe TBI education was directed toward family members/ caregivers and was frequently combined with other treatment components, making the effects of education difficult to discern. Only 1 article incorporated elements of self-management training (SMT), a model proved effective in other chronic health conditions. We recommend further exploration of SMT principles in long-term TBI care, as well as more precise definition of treatment components in all patient and family interventions, so that the specific effects of education and other treatment elements may be more readily evaluated.


Assessment of upper tropospheric and stratospheric water vapor and ozone in reanalyses as part of S-RIP.
Reanalysis data sets are widely used to understand atmospheric processes and past variability, and are often used to stand in as "observations" for comparisons with climate model output. Because of the central role of water vapor (WV) and ozone (O3) in climate change, it is important to understand how accurately and consistently these species are represented in existing global reanalyses. In this paper, we present the results of WV and O3 intercomparisons that have been performed as part of the SPARC (Stratosphere-troposphere Processes and their Role in Climate) Reanalysis Intercomparison Project (S-RIP). The comparisons cover a range of timescales and evaluate both inter-reanalysis and observation-reanalysis differences. We also provide a systematic documentation of the treatment of WV and O3 in current reanalyses to aid future research and guide the interpretation of differences amongst reanalysis fields. The assimilation of total column ozone (TCO) observations in newer reanalyses results in realistic representations of TCO in reanalyses except when data coverage is lacking, such as during polar night. The vertical distribution of ozone is also relatively well represented in the stratosphere in reanalyses, particularly given the relatively weak constraints on ozone vertical structure provided by most assimilated observations and the simplistic representations of ozone photochemical processes in most of the reanalysis forecast models. However, significant biases in the vertical distribution of ozone are found in the upper troposphere and lower stratosphere in all reanalyses. In contrast to O3, reanalysis estimates of stratospheric WV are not directly constrained by assimilated data. Observations of atmospheric humidity are typically used only in the troposphere, below a specified vertical level at or near the tropopause. The fidelity of reanalysis stratospheric WV products is therefore mainly dependent on the reanalyses' representation of the physical drivers that influence stratospheric WV, such as temperatures in the tropical tropopause layer, methane oxidation, and the stratospheric overturning circulation. The lack of assimilated observations and known deficiencies in the representation of stratospheric transport in reanalyses result in much poorer agreement amongst observational and reanalysis estimates of stratospheric WV. Hence, stratospheric WV products from the current generation of reanalyses should generally not be used in scientific studies.


Coping with problems that impact on the health of a socially vulnerable community from the residents' perspective.
This research aims to identify the strategies adopted by dwellers of a socially vulnerable community, characterized by social and economic inequality, to address the problems that interfere in the health conditions. A participant investigation anchored in hermeneutics was conducted through participatory diagnosis, with 31 residents of the Dendê community, who were called vital informants. Data were collected from semi-structured interviews, street walking and focus groups. WebQDA software was adopted to support data analysis, based on content analysis in the thematic modality, which resulted in the following categories: "individual or small group actions", "partnerships between residents and social organizations" and "partnerships with public and private sectors". We considered that the condition of vulnerability motivated by a diversity of social determinants generates negative impacts on health, requiring planning and implementation of policies and actions geared to people's well-being. This reflects the relevance of the participatory diagnosis, which can be supported by people and Information and Communication Technologies to increase community participation in health promotion actions.


Cognitive and Situational Precipitants of Loneliness Among Patients With Cancer: A Qualitative Analysis.
To identify situations and thoughts that may precipitate or protect against loneliness experienced by patients with cancer. Qualitative. The hematology/oncology clinic at the Indiana University Melvin and Bren Simon Cancer Center, an outpatient oncology center in Indianapolis. Purposive sample of 15 patients undergoing treatment for multiple myeloma or non-Hodgkin lymphoma. Individual, semistructured qualitative interviews were conducted. Theoretical thematic analysis was used to analyze interview data. Factors that appeared to precipitate loneliness included several situations (e.g., physical isolation, social constraints such as criticism) and thoughts (e.g., unmet expectations for visits or questions about health, belief that others do not understand their cancer experience). Several situations (e.g., social support, normal routine) and thoughts (e.g., beliefs that time alone is desirable and that others' discomfort with cancer-related discussions is normative) appeared to protect against loneliness. Certain social situations were loneliness-inducing for some patients and not for others, suggesting that patients' thoughts about their situations, rather than the situations themselves, have the greatest impact on their loneliness. The current study fills gaps in loneliness theory by identifying cancer-related situations and thoughts that patients associate with their loneliness. Consistent with theory, patients reported feeling lonely when they had negative thoughts about their social situations. Findings inform nursing assessment and intervention strategies to incorporate into care plans. For instance, when conducting assessments, nurses should be more attentive to patients' satisfaction with their social environment than actual characteristics of the environment. Normalizing patients' experiences and encouraging positive thoughts about others' behavior may reduce patients' loneliness.


Old people in pain: a comparative study.
To investigate the prevalence of pain in older people (75+), compare those in pain to those without regarding demographics, social network, functional limitations, fatigue, sleeping problems, depressed mood and quality of life (QOL), and identify variables associated with pain, a cross-sectional, prospective survey was conducted in an age-stratified sample of 4,093 people aged 75-105 years old. Those reporting pain (n=1,654) were compared with those who did not (n=2,439). Pain was more common with higher age, as were all complaints among those in pain and among those without, except sleeping problems. Lower QOL was found with higher age, as well as with pain. Pain was found to be associated with functional limitations, fatigue, sleeping problems, depressed mood, and QOL. These data highlight the importance of identifying old people in pain. Those who are older and those affected by pain are at greater risk of also being troubled by other problems, such as functional limitations and lowered QOL.


Predictors of the impact of nonpharmacologic interventions for agitation in nursing home residents with advanced dementia.
Research is needed to determine specific factors that contribute to the success of nonpharmacologic interventions. In this study, we examined the influence of personal characteristics (demographic, medical, and functional variables) and possible barriers (eg, staff or family barriers) on the efficacy of nonpharmacological interventions in reducing agitation. Agitation was systematically observed at baseline and intervention stages using the Agitation Behavior Mapping Instrument (ABMI) in a sample of 89 residents from 6 Maryland nursing homes (mean age = 85.9 years). Each participant received interventions based on an individualized algorithm (TREA-Treatment Routes for Exploring Agitation), which identifies unmet needs and matches interventions to needs and to the participant's sensory, cognitive, and functional abilities, as well as to self-identity and preferences. The study was conducted between June 2006 and December 2011. Analyses revealed that decreased levels of agitation during intervention correlated significantly with higher levels of cognitive function (r = 0.36, P < .001), with fewer difficulties in the performance of activities of daily living (r = 0.29, P < .01), speech (r = 0.47, P < .001), communication (r = 0.23, P < .05), and responsiveness (r = 0.28, P < .01). In addition, less reduction of agitation during intervention was significantly related to the presence of staff barriers (eg, refusals, interruptions) (r = -0.38, P < .001) and the occurrence of pain (r = -0.21, P ≤ .05). The findings elucidate the characteristics of those who are most likely to respond to TREA intervention, and point to the need of systemic changes to reduce staff-related barriers and to improve methodologies for increasing the impact of intervention on those at the lowest levels of functioning.


Pulmonary function in adolescent idiopathic scoliosis relative to the surgical procedure.
The long-term pulmonary function of patients with adolescent idiopathic scoliosis undergoing surgical correction is uncertain. To our knowledge, no report has demonstrated the changes in pulmonary function five years or more following spinal arthrodesis with use of modern segmental spinal instrumentation techniques for the treatment of all types of adolescent idiopathic scoliosis in a similar adolescent population. One hundred and eighteen patients with adolescent idiopathic scoliosis undergoing surgical treatment at a single institution were evaluated with pulmonary function tests to assess the absolute and percent-predicted value of forced vital capacity and forced expiratory volume in one second at the preoperative examination and at regular intervals postoperatively. The patients were divided into four groups depending upon the surgical procedure: Group 1 comprised forty-nine patients who had posterior spinal arthrodesis with iliac crest bone graft; Group 2, forty-one patients who had posterior spinal arthrodesis with thoracoplasty; Group 3, sixteen patients who had open anterior spinal arthrodesis with a rib resection thoracotomy; and Group 4, twelve patients who had combined anterior and posterior spinal arthrodesis with a rib resection thoracotomy and iliac crest bone graft, respectively. A comparison of absolute pulmonary function values from the preoperative and final follow-up evaluations demonstrated a significant (p < 0.0001) increase in both the forced vital capacity and the forced expiratory volume in one second for Group 1, whereas no change was seen in those values for Groups 2, 3, and 4. A comparison of the changes in the percent-predicted pulmonary function values demonstrated significant (p < 0.05) decreases in forced vital capacity and forced expiratory volume in one second for Groups 2, 3, and 4, except for the latter value for Group 4, whereas Group 1 had no change. Patients who have had any type of chest cage disruption during the surgical treatment of adolescent idiopathic scoliosis demonstrate no change in the absolute value and a significant decline in the percent-predicted value of pulmonary functions at five years following surgery. Chest cage preservation is recommended to maximize both absolute and percent-predicted pulmonary function values after surgical treatment of adolescent idiopathic scoliosis.


The evolution of the scrotum and testicular descent in mammals: a phylogenetic view.
The adaptive significance of the scrotum and the evolution of the descent of the testicles and epididymis have been a focus of interest among biologists for a long time. In this paper we use three anatomical character states of the scrotum and descensus: (1) testicles descended and scrotal; (2) testicles descended but ascrotal; (3) testicles not descended (testicondy). These states are then mapped on an up to date phylogeny of the Mammalia. Three main points arise out of this mapping procedure: (1) the presence of a scrotum is either primitive in extant Mammalia or primitive within eutherian mammals except Insectivora; (2) evolution has generally proceeded from a scrotal condition to progressively more ascrotal; (3) loss of testicular descensus is less common in mammalian evolution than is loss of the scrotum. In the light of these findings we discuss some current hypotheses regarding the origin and evolution of the scrotum. We find that these are all incomplete in so far as it is not the presence of the scrotum in various mammal groups that requires explaining. Instead, it is the reverse process, why the scrotum has been lost in so many groups, that should be explained. We suggest that the scrotum may have evolved before the origin of mammals, in concert with the evolution of endothermy in the mammalian lineage, and that the scrotum has been lost in many groups because descensus in many respects is a costly process that will be lost in mammal lineages as soon as an alternative solution to the problem of the temperature sensitivity of spermatogenesis is available.


Comparative study of different Portuguese samples of propolis: pollinic, sensorial, physicochemical, microbiological characterization and antibacterial activity.
The aim of this work was to study four propolis samples from Trás-os-Montes region of Portugal. The propolis samples' color was different, which pollen analysis showed to be due to different botanical sources: Populus sp., Pinus sp., Quercus sp. and Castanea sativa. The data from physicochemical analysis (moisture, soluble and insoluble solids content, pH, conductivity, ash content, wax, total phenolics and flavonoids content) was treated using multivariate statistical tools as cluster heat map, principal components analysis and linear discriminant analysis with the purpose of classifying the sample accordingly to the botanical/geographical origin. The discriminant analysis was applied with stepwise to select the variables that most contribute to sample identification accordingly to pollinic profile. The cross-validation technique was applied, using the leave-one-out procedure, which showed good prediction capabilities of the samples. Microbiologically, the commercial quality was satisfactory, since the samples didn't contain deterioration or pathogenic microorganisms. All the samples studied presented antimicrobial activity against Methicillin-resistant Staphylococcus aureus, in a dose dependent way. The antimicrobial activity was strictly related to the physicochemical composition. This work will allow connecting a particular chemical propolis type to a specific type of biological activity, what is essential for the use in therapeutic applications.


Stac3 is required for myotube formation and myogenic differentiation in vertebrate skeletal muscle.
Stac3 was identified as a nutritionally regulated gene from an Atlantic salmon subtractive hybridization library with highest expression in skeletal muscle. Salmon Stac3 mRNA was highly correlated with myogenin and myoD1a expression during differentiation of a salmon primary myogenic culture and was regulated by amino acid availability. In zebrafish embryos, stac3 was initially expressed in myotomal adaxial cells and in fast muscle fibers post-segmentation. Morpholino knockdown resulted in defects in myofibrillar protein assembly, particularly in slow muscle fibers, and decreased levels of the hedgehog receptor patched. The function of Stac3 was further characterized in vitro using the mammalian C2C12 myogenic cell line. Stac3 mRNA expression increased during the differentiation of the C2C12 myogenic cell line. Knockdown of Stac3 by RNAi inhibited myotube formation, and microarray analysis revealed that transcripts involved in cell cycle, focal adhesion, cytoskeleton, and the pro-myogenic factors Igfbp-5 and Igf2 were down-regulated. RNAi-treated cells had suppressed Akt signaling and exogenous insulin-like growth factor (Igf) 2 was unable to rescue the phenotype, however, Igf/Akt signaling was not blocked. Overexpression of Stac3, which results in increased levels of Igfbp-5 mRNA, did not lead to increased differentiation. In synchronized cells, Stac3 mRNA was most abundant during the G(1) phase of the cell cycle. RNAi-treated cells were smaller, had higher proliferation rates and a decreased proportion of cells in G(1) phase when compared with controls, suggesting a role in the G(1) phase checkpoint. These results identify Stac3 as a new gene required for myogenic differentiation and myofibrillar protein assembly in vertebrates.


Do specific or nonspecific interactions with proteins underlie inhalational anesthetic action?
To determine whether specific or nonspecific interactions between inhaled anesthetics and proteins are more likely to underlie anesthetic actions, analysis of hydrogen/tritium exchange was used to measure effects on the stability of two model proteins that had been previously shown to bind anesthetics specifically (bovine serum albumin) or only nonspecifically (myoglobin). The data indicated that stabilization of albumin correlated with the potencies of a wide range of anesthetic compounds significantly better than did destabilization of myoglobin. In addition, sensitivity to nonanesthetics, isoflurane stereoselectivity, and temperature and pressure effects all influenced the stabilization of bovine serum albumin, but not the destabilization of myoglobin, in a manner strongly supporting the premise that specific binding interactions with protein targets underlie anesthetic action. These observations significantly increase the likelihood that such interactions can be found and optimized.


High levels of gene flow and genetic diversity in Irish populations of Salix caprea L. inferred from chloroplast and nuclear SSR markers.
Salix caprea is a cold-tolerant pioneer species that is ecologically important in Europe and western and central Asia. However, little data is available on its population genetic structure and molecular ecology. We describe the levels of geographic population genetic structure in natural Irish populations of S. caprea and determine the extent of gene flow and sexual reproduction using both chloroplast and nuclear simple sequence repeats (SSRs). A total of 183 individuals from 21 semi-natural woodlands were collected and genotyped. Gene diversity across populations was high for the chloroplast SSRs (H T = 0.21-0.58) and 79 different haplotypes were discovered, among them 48% were unique to a single individual. Genetic differentiation of populations was found to be between moderate and high (mean G ST = 0.38). For the nuclear SSRs, G ST was low at 0.07 and observed heterozygosity across populations was high (H O = 0.32-0.51); only 9.8% of the genotypes discovered were present in two or more individuals. For both types of markers, AMOVA showed that most of the variation was within populations. Minor geographic pattern was confirmed by a Bayesian clustering analysis. Gene flow via pollen was found to be approximately 7 times more important than via seeds. The data are consistent with outbreeding and indicate that there are no significant barriers for gene flow within Ireland over large geographic distances. Both pollen-mediated and seed-mediated gene flow were found to be high, with some of the populations being more than 200 km apart from each other. These findings could simply be due to human intervention through seed trade or accidental transportation of both seeds and pollen. These results are of value to breeders wishing to exploit natural genetic variation and foresters having to choose planting material.


Distribution of nerve endings in human distal interphalangeal joint and surrounding structures.
To examine the distribution of encapsulated nerve endings called mechanoreceptors in the human distal interphalangeal (DIP) joint and surrounding structures. We processed 12 right index finger DIP joints and surrounding structures from fresh cadavers for immunohistochemistry of the anti-protein gene product 9.5 (PGP9.5) and silver staining to detect encapsulated nerve endings. Serial transverse sections were cut throughout the whole specimen and divided into 3 regions along the longitudinal axis: distal, middle, and proximal. Each of the transverse sections was partitioned into dorsal capsule (DC), radial capsule (RC), ulnar capsule (UC), volar plate (VP), and radial and ulnar assemblage nuclei (RAN and UAN); the RAN and UAN are located on both the radial and ulnar side of the VP. The C3 pulley contained the proximal region of the RAN and UAN, whereas the A5 pulley contained the middle and distal. The accessory collateral ligament contained all the regions of the RAN and UAN. We analyzed and compared the density of encapsulated nerve endings among the 18 different regions. According to the modified Freeman and Wyke classification, we identified type I (eg, Ruffini-like endings) and type II (eg, Pacini-like endings) nerve endings. The density of type II nerve endings in the proximal region of the RAN and UAN was considerably higher than that in the proximal region of the VP, RC, UC and DC, and that in the proximal region of the VP, RC, UC, and DC, respectively. Our examination of the distribution of type I and type II nerve endings provides new information on the sensory systems of the DIP joints and surrounding structures.


Carboplatin hypersensitivity.
Carboplatin has established an important role in many different cancers. As its use increased, the documented cases of hypersensitivity also picked up. Although the mechanism of these reactions remains unknown, the immediate type of hypersensitivity reaction mediated by IgE may be involved. It takes a while for the reaction to develop, but cases are reported even after 1st cycle. The incidence of hypersensitivity is highest at about 8th cycle of therapy with decline after that. These reactions themselves ranged from facial flushing or itching to seizures, dyspnea, and anaphylaxis. Many physicians currently do not use skin testing prior to 8th cycle of carboplatin therapy and retreat their patients with carboplatin after the first hypersensitivity reaction. Therefore, it is suggested that skin test should be conducted prior to the 8th cycle, preferably before the 6th cycle, as hypersensitivity tends to increase on the 6th cycle-treatment. Methods published so far involve: desensitization, skin testing, switching therapy to another platinum analogue, and premedication. Despite all the process, the most effective drug toxicity prevention method remains skin testing prior to 8th cycle. It can accurately predict patients who will develop hypersensitivity reactions. Other methods so far have not shown consistent results.


Dopaminergic stimulation increases selfish behavior in the absence of punishment threat.
People often face decisions that pit self-interested behavior aimed at maximizing personal reward against normative behavior such as acting cooperatively, which benefits others. The threat of social sanctions for defying the fairness norm prevents people from behaving overly selfish. Thus, normative behavior is influenced by both seeking rewards and avoiding punishment. However, the neurochemical processes mediating the impact of these influences remain unknown. Several lines of evidence link the dopaminergic system to reward and punishment processing, respectively, but this evidence stems from studies in non-social contexts. The present study investigates dopaminergic drug effects on individuals' reward seeking and punishment avoidance in social interaction. Two-hundred one healthy male participants were randomly assigned to receive 300 mg of L-3,4-dihydroxyphenylalanine (L-DOPA) or a placebo before playing an economic bargaining game. This game involved two conditions, one in which unfair behavior could be punished and one in which unfair behavior could not be punished. In the absence of punishment threats, L-DOPA administration led to more selfish behavior, likely mediated through an increase in reward seeking. In contrast, L-DOPA administration had no significant effect on behavior when faced with punishment threats. The results of this study broaden the role of the dopaminergic system in reward seeking to human social interactions. We could show that even a single dose of a dopaminergic drug may bring selfish behavior to the fore, which in turn may shed new light on potential causal relationships between the dopaminergic system and norm abiding behaviors in certain clinical subpopulations.


Blocking fatty acid-fueled mROS production within macrophages alleviates acute gouty inflammation.
Gout is the most common inflammatory arthritis affecting men. Acute gouty inflammation is triggered by monosodium urate (MSU) crystal deposition in and around joints that activates macrophages into a proinflammatory state, resulting in neutrophil recruitment. A complete understanding of how MSU crystals activate macrophages in vivo has been difficult because of limitations of live imaging this process in traditional animal models. By live imaging the macrophage and neutrophil response to MSU crystals within an intact host (larval zebrafish), we reveal that macrophage activation requires mitochondrial ROS (mROS) generated through fatty acid oxidation. This mitochondrial source of ROS contributes to NF-κB-driven production of IL-1β and TNF-α, which promote neutrophil recruitment. We demonstrate the therapeutic utility of this discovery by showing that this mechanism is conserved in human macrophages and, via pharmacologic blockade, that it contributes to neutrophil recruitment in a mouse model of acute gouty inflammation. To our knowledge, this study is the first to uncover an immunometabolic mechanism of macrophage activation that operates during acute gouty inflammation. Targeting this pathway holds promise in the management of gout and, potentially, other macrophage-driven diseases.


Evolution and metabolic significance of the urea cycle in photosynthetic diatoms.
Diatoms dominate the biomass of phytoplankton in nutrient-rich conditions and form the basis of some of the world's most productive marine food webs. The diatom nuclear genome contains genes with bacterial and plastid origins as well as genes of the secondary endosymbiotic host (the exosymbiont), yet little is known about the relative contribution of each gene group to diatom metabolism. Here we show that the exosymbiont-derived ornithine-urea cycle, which is similar to that of metazoans but is absent in green algae and plants, facilitates rapid recovery from prolonged nitrogen limitation. RNA-interference-mediated knockdown of a mitochondrial carbamoyl phosphate synthase impairs the response of nitrogen-limited diatoms to nitrogen addition. Metabolomic analyses indicate that intermediates in the ornithine-urea cycle are particularly depleted and that both the tricarboxylic acid cycle and the glutamine synthetase/glutamate synthase cycles are linked directly with the ornithine-urea cycle. Several other depleted metabolites are generated from ornithine-urea cycle intermediates by the products of genes laterally acquired from bacteria. This metabolic coupling of bacterial- and exosymbiont-derived proteins seems to be fundamental to diatom physiology because the compounds affected include the major diatom osmolyte proline and the precursors for long-chain polyamines required for silica precipitation during cell wall formation. So far, the ornithine-urea cycle is only known for its essential role in the removal of fixed nitrogen in metazoans. In diatoms, this cycle serves as a distribution and repackaging hub for inorganic carbon and nitrogen and contributes significantly to the metabolic response of diatoms to episodic nitrogen availability. The diatom ornithine-urea cycle therefore represents a key pathway for anaplerotic carbon fixation into nitrogenous compounds that are essential for diatom growth and for the contribution of diatoms to marine productivity.


Measuring patient preferences for colorectal cancer screening using a choice-format survey.
Colorectal cancer (CRC) screening uptake remains poor. Until we understand patient motivation and preferences for undertaking screening, it is unlikely the uptake will be optimal. Our objective is to examine patient preferences for CRC screening modalities and uptake rates using utility-based methods. The preference survey was mailed to a random sample of Canadian subjects aged 40 to 60 years from a primary care network. A fractional factorial experimental design maximized D-efficiency and included four blocks with 12 choice tasks in a conditional two-step design, two-alternative discrete choice format with five screening attributes (process, pain, preparation, sensitivity, and specificity). Bivariate probit regression analysis was used to estimate patient preferences for attributes, choice probabilities for alternative modalities and expected rates of uptake. Five hundred forty-seven of 1047 surveys were returned. Almost 30% of respondents preferred no screening. The most preferred test attribute levels were noninvasive process (e.g., CT), no preparation, no pain, 100% specificity, and 90% sensitivity. Accuracy-related attributes were more important than test process-related attributes. Virtual colonoscopy was the most preferred, followed by colonoscopy, barium enema, sigmoidoscopy, and fecal DNA testing, based on simulated choice probability estimates. Fecal occult blood testing (FOBT) was least preferred. Adjusted screening uptake rate estimates showed the greatest impact (42% increase) would be achieved if all CRC screening modalities were available rather than FOBT alone. Our findings emphasize the important role of patient preferences for no screening and in selecting alternative CRC screening modalities. CRC screening implementation in Canada should consider patient preferences to optimize uptake.


Fabrication and characterization of fluorescent rare-earth-doped glass-particle-based tips for near-field optical imaging applications.
Fluorescent rare-earth-doped glass particles glued to the end of an atomic force microscope tip have been used to perform scanning near-field optical measurements on nanostructured samples. The fixation procedure of the fluorescent fragment at the end of the tip is described in detail. The procedure consists of depositing a thin adhesive layer on the tip. Then a tip approach is performed on a fragment that remains stuck near the tip extremity. To displace the particle and position it at the very end of the tip, a nanomanipulation is achieved by use of a second tip mounted on piezoelectric scanners. Afterward, the particle size is reduced by focused ion beam milling. These particles exhibit a strong green luminescence where excited in the near infrared by an upconversion mechanism. Images obtained near a metallic edge show a lateral resolution in the 180-200-nm range. Images we obtained by measuring the light scattered by 250-nm holes show a resolution well below 100 nm. This phenomenon can be explained by a local excitation of the particle and by the nonlinear nature of the excitation.


Negative Effects of "Predatory" Journals on Global Health Research.
Predatory journals (PJ) exploit the open-access model promising high acceptance rate and fast track publishing without proper peer review. At minimum, PJ are eroding the credibility of the scientific literature in the health sciences as they actually boost the propagation of errors. In this article, we identify issues with PJ and provide several responses, from international and interdisciplinary perspectives in health sciences. Authors, particularly researchers with limited previous experience with international publications, need to be careful when considering potential journals for submission, due to the current existence of large numbers of PJ. Universities around the world, particularly in developing countries, might develop strategies to discourage their researchers from submitting manuscripts to PJ or serving as members of their editorial committees.


Genetic variation associated with preterm birth: a HuGE review.
Preterm birth (PTB) is a major public health concern because of its high prevalence, associated mortality and morbidity, and expense from both short-term hospitalization and long-term disability. In 2002, 11.9% of U.S. births occurred before 37 weeks gestation. Epidemiologic studies have identified many demographic, behavioral, and medical characteristics associated with PTB risk. In addition, recent evidence indicates a role for genetic susceptibility. We reviewed 18 studies published before June 1, 2004, that examined associations between polymorphisms in the maternal or fetal genome and PTB risk. Studies of a polymorphism in tumor necrosis factor-alpha, a proinflammatory cytokine, showed the most consistent increase in the risk of PTB. Environmental factors such as infection, stress, and obesity, which activate inflammatory pathways, have been associated with PTB, suggesting that environmental and genetic risk factors might operate and interact through related pathways. This review highlights maternal and fetal genetic susceptibilities to PTB, the potential relationships with environmental risk factors, and the need for additional well-designed studies of this critical public health problem.


Acquisition and extinction of second-order context conditioned fear: Role of the amygdala.
Second-order fear conditioning has been demonstrated in protocols using discrete and simple stimuli, and much is now known about its behavioral and neural characteristics. In contrast, the mechanisms of second-order conditioning to more complex stimuli, such as contexts, are unknown. To address this gap in our knowledge, we conducted a series of experiments to investigate the neural and behavioral characteristics of second-order context fear conditioning in rats. We found that rats acquire fear to a context in which a first-order conditioned stimulus is presented (Experiment 1); neuronal activity in the basolateral amygdala (BLA) is required for the acquisition (Experiment 2) and extinction (Experiment 3) of second-order context fear; second-order context fear can be reduced by extinction of its first-order conditioned stimulus associate (Experiment 4); and that second-order fear reduced in this way is restored when fear of the first-order conditioned stimulus spontaneously recovers or is reconditioned (Experiment 5). Thus, second-order context fear requires neuronal activity in the BLA, and once established, tracks the level of fear to its first-order conditioned stimulus-associate. These results are discussed with respect to the substrates of second-order fear conditioning in other protocols, and the role of the amygdala in different forms of conditioning.


Risk factors for anemia in children under 6 years of age in Ethiopia: analysis of the data from the cross-sectional Malaria IndicatorSurvey, 2007.
Malaria is a leading cause of morbidity in Ethiopia. However, its transmission varies in both space and time, and large areas of the country are hypoendemic and epidemic-prone. The Ethiopia National Malaria Indicator Survey 2007 is a cross-sectional, nationally-representative household survey. The objective of the analyses presented here were to use the survey's data to identify factors associated with anemia presence in children under 6 years of age (U6); specifically, investigate the association between malaria and anemia; and discuss using anemia as a malaria proxy biomarker in the Ethiopian hypo-endemic transmission setting. The survey sampled 4185 households in 347 enumeration areas ≤2500 m above sea level. Primary outcome was increasing anemia severity in sampled children: no anemia (Hb: ≥11g/dl); mild anemia (Hb: ≥8g/dl and <11g/dl); and moderate-severe anemia (Hb: <8g/dl). Secondary outcomes were positive malaria rapid diagnostic test (RDT) or blood slide microscopy. The analysis included 6054 (92.0%) children U6 in 3962 households. The proportion of children with no anemia, mild anemia, and moderate-severe anemia was 63.6%, 31.3%, and 5.1%, respectively. The overall prevalence of anemia (Hb <11g/dl) was 36.4% (95% CI 34.4-38.4). Factors independently associated with reduced relative odds of anemia categories were age (OR=0.7, 95% CI 0.7-0.7) and female sex (OR=0.9, 95% CI 0.8-1.0); malaria RDT positivity was associated with increased relative odds of a more severe anemia category (OR=5.8, 95% CI 3.7-9.2). We conclude that at altitudes ≤2500 m malaria appears to be a significant risk factor for anemia; potentially anemia could be used as a useful proxy biomarker for malaria and its control in Ethiopia.


Influence of nutrients involved in one-carbon metabolism on DNA methylation in adults-a systematic review and meta-analysis.
Aberrant DNA methylation is linked to various diseases. The supply of methyl groups for methylation reactions is mediated by S-adenosylmethionine, which depends on the availability of folate and related B vitamins. To investigate the influence of key nutrients involved in 1-carbon metabolism on DNA methylation in adults. Systematic literature searches were conducted in the Cochrane Library, Medline, Embase, Cumulative Index to Nursing and Allied Health Literature Plus, Scopus, and Web of Science databases. Studies that met the inclusion criteria and were published in English were included. The first author, study design, sample size, population characteristics, type and duration of intervention, tissue type or cells analyzed, molecular techniques, and DNA methylation outcomes. A meta-analysis of randomized, controlled trials (RCTs) was conducted to investigate the effect of 1-carbon metabolism nutrients on global DNA methylation. Functional analysis and visualization were performed using BioVenn software. From a total of 2620 papers screened by title, 53 studies met the inclusion criteria. Qualitative analysis indicated significant associations between 1-carbon metabolism nutrients and DNA methylation. In meta-analysis of RCTs stratified by method of laboratory analysis, supplementation with folic acid alone or in combination with vitamin B12 significantly increased global DNA methylation in studies using liquid chromatography-mass spectrometry, which had markedly lower heterogeneity (n = 3; Z = 3.31; P = 0.0009; I2 = 0%) in comparison to other methods. Functional analysis highlighted a subset of 12 differentially methylated regions that were significantly related to folate and vitamin B12 biomarkers. This study supports significant associations between 1-carbon metabolism nutrients and DNA methylation. However, standardization of DNA methylation techniques is recommended to reduce heterogeneity and facilitate comparison across studies. PROSPERO registration number: CRD42018091898.


On the diverse and opposing effects of nutrition on pathogen virulence.
Climate change and anthropogenic activity are currently driving large changes in nutritional availability across ecosystems, with consequences for infectious disease. An increase in host nutrition could lead to more resources for hosts to expend on the immune system or for pathogens to exploit. In this paper, we report a meta-analysis of studies on host-pathogen systems across the tree of life, to examine the impact of host nutritional quality and quantity on pathogen virulence. We did not find broad support across studies for a one-way effect of nutrient availability on pathogen virulence. We thus discuss a hypothesis that there is a balance between the effect of host nutrition on the immune system and on pathogen resources, with the pivot point of the balance differing for vertebrate and invertebrate hosts. Our results suggest that variation in nutrition, caused by natural or anthropogenic factors, can have diverse effects on infectious disease outcomes across species.


Induced Pluripotent Stem Cell-Based Systems for Personalising Epilepsy Treatment: Research Ethics Challenges and New Insights for the Ethics of Personalised Medicine.
ABSTRACTThis paper examines potential ethical and legal issues arising during the research, development and clinical use of a proposed strategy in personalized medicine (PM): using human induced pluripotent stem cell (iPSC)-derived tissue cultures as predictive models of individual patients to inform treatment decisions. We focus on epilepsy treatment as a likely early application of this strategy, for which early-stage stage research is underway. In relation to the research process, we examine issues associated with biological samples; data; health; vulnerable populations; neural organoids; and what level of accuracy justifies using the iPSC-derived neural tissue system. In relation to clinical use, we examine potential uses in pre-natal screening, and effects on clinical decision-making. Although our focus is providing recommendations for researchers developing work in this area, we identify the novel issue of deciding on an acceptable accuracy level for the system. We also emphasize an issue thus far neglected in the ethics of PM: PM tends to represent treatment decisions as though they should be directed solely by biomedical information, but this in itself could be detrimental to best personalizing treatment decisions in the clinic.


Vector diffraction analysis by discrete-dipole approximation.
The discrete-dipole approximation is applied to vector diffraction analysis in a system with large-numerical-aperture (NA) optics and subwavelength targets. Distributions of light diffracted by subwavelength dielectric targets are calculated in a solid angle that corresponds to a NA of 0.9, and their dependence on incident polarization, target shape, and target size is studied. Electric field distributions inside the target are also shown. Basic features of the vector diffraction are clearly demonstrated. This technique facilitates understanding of the vectorial effects in systems that are expected to be applied in the future to optical data storage.


Naringenin and hesperetin, two flavonoids derived from Citrus aurantium up-regulate transcription of adiponectin.
The dried, immature fruit of Citrus aurantium L., 'Zhiqiao' in Chinese, has been used to treat cardiovascular diseases in traditional Chinese medicine for centuries. Naringenin and hesperetin and their glycosides present in considerable amounts (about 10 approximately 15%) in the herb. The aim of this study is to test whether naringenin and hesperetin influence adiponectin expression, which plays an important role in glucose and lipid metabolism with antiatherogenic and anti-inflammatory properties. Treatment with naringenin and hesperetin enhanced adiponectin transcription in differentiated 3T3-L1 cells. Both naringenin and hesperetin induced peroxisome proliferator-activated receptor (PPAR)gamma-controlled luciferase expression in a dose-dependent manner (20-160 microM), whereas only naringenin possessed significant activity to activate PPARalpha. These results suggested the two flavonoids might exert antiatherogenic effects partly through activating PPAR and up-regulating adiponectin expression in adipocytes. Our findings give new insight for the molecular explanations for the therapeutic effects of Zhiqiao.


Highly selective acylation of polyamines and aminoglycosides by 5-acyl-5-phenyl-1,5-dihydro-4H-pyrazol-4-ones.
5-Acyl-5-phenyl-1,5-dihydro-4H-pyrazol-4-ones, accessible from arylpropargyl phenyldiazoacetates, are highly selective acyl transfer reagents for di- and polyamines, as well as aminoalcohols and aminothiols. As reagents with a carbon-based leaving group, they have been applied for benzoyl transfer with a broad selection of substrates containing aliphatic amino in combination with other competing nucleophilic functional groups. The substrate scope and levels of selectivity for direct benzoyl transfer exceed those of known benzoylating reagents. With exceptional selectivity for acylation between primary amines bound to primary and secondary carbons, these new reagents have been used in direct site-selective monobenzoylation of aminoglycoside antibiotics.


Revisiting the "Golden Hour": An Evaluation of Out-of-Hospital Time in Shock and Traumatic Brain Injury.
We evaluate patients with shock and traumatic brain injury who were previously enrolled in an out-of-hospital clinical trial to test the association between out-of-hospital time and outcome. This was a secondary analysis of patients with shock and traumatic brain injury who were aged 15 years or older and enrolled in a Resuscitation Outcomes Consortium out-of-hospital clinical trial by 81 emergency medical services agencies transporting to 46 Level I and II trauma centers in 11 sites (May 2006 through May 2009). Inclusion criteria were systolic blood pressure less than or equal to 70 mm Hg or systolic blood pressure 71 to 90 mm Hg with pulse rate greater than or equal to 108 beats/min (shock cohort) and Glasgow Coma Scale score less than or equal to 8 (traumatic brain injury cohort); patients meeting both criteria were placed in the shock cohort. Primary outcomes were 28-day mortality (shock cohort) and 6-month Glasgow Outcome Scale-Extended score less than or equal to 4 (traumatic brain injury cohort). There were 778 patients in the shock cohort (26% 28-day mortality) and 1,239 patients in the traumatic brain injury cohort (53% 6-month Glasgow Outcome Scale-Extended score ≤4). Out-of-hospital time greater than 60 minutes was not associated with worse outcomes after accounting for important confounders in the shock cohort (adjusted odds ratio [aOR] 1.42; 95% confidence interval [CI] 0.77 to 2.62) or traumatic brain injury cohort (aOR 0.77; 95% CI 0.51 to 1.15). However, shock patients requiring early critical hospital resources and arriving after 60 minutes had higher 28-day mortality (aOR 2.37; 95% CI 1.05 to 5.37); this finding was not observed among a similar traumatic brain injury subgroup. Among out-of-hospital trauma patients meeting physiologic criteria for shock and traumatic brain injury, there was no association between time and outcome. However, the subgroup of shock patients requiring early critical resources and arriving after 60 minutes had higher mortality.


Liver-Specific, but Not Retina-Specific, Hepcidin Knockout Causes Retinal Iron Accumulation and Degeneration.
The liver secretes hepcidin (Hepc) into the bloodstream to reduce blood iron levels. Hepc accomplishes this by triggering degradation of the only known cellular iron exporter ferroportin in the gut, macrophages, and liver. We previously demonstrated that systemic Hepc knockout (HepcKO) mice, which have high serum iron, develop retinal iron overload and degeneration. However, it was unclear whether this is caused by high blood iron levels or, alternatively, retinal iron influx that would normally be regulated by retina-produced Hepc. To address this question, retinas of liver-specific and retina-specific HepcKO mice were studied. Liver-specific HepcKO mice had elevated blood and retinal pigment epithelium (RPE) iron levels and increased free (labile) iron levels in the retina, despite an intact blood-retinal barrier. This led to RPE hypertrophy associated with lipofuscin-laden lysosome accumulation. Photoreceptors also degenerated focally. In contrast, there was no change in retinal or RPE iron levels or degeneration in the retina-specific HepcKO mice. These data indicate that high blood iron levels can lead to retinal iron accumulation and degeneration. High blood iron levels can occur in patients with hereditary hemochromatosis or result from use of iron supplements or multiple blood transfusions. Our results suggest that high blood iron levels may cause or exacerbate retinal disease.


Early biases and developmental changes in self-generated object views.
Object recognition depends on the seen views of objects. These views depend in part on the perceivers' own actions as they select and show object views to themselves. The self-selection of object views from manual exploration of objects during infancy and childhood may be particularly informative about the human object recognition system and its development. Here, we report for the first time on the structure of object views generated by 12 to 36 month old children (N = 54) and for comparison adults (N = 17) during manual and visual exploration of objects. Object views were recorded via a tiny video camera placed low on the participant's forehead. The findings indicate two viewing biases that grow rapidly in the first three years: a bias for planar views and for views of objects in an upright position. These biases also strongly characterize adult viewing. We discuss the implications of these findings for a developmentally complete theory of object recognition.


Environmental Exposures and the Risk of Central Venous Catheter Complications and Readmissions in Home Infusion Therapy Patients.
BACKGROUND Patients are frequently discharged with central venous catheters (CVCs) for home infusion therapy. OBJECTIVE To study a prospective cohort of patients receiving home infusion therapy to identify environmental and other risk factors for complications. DESIGN Prospective cohort study between March and December 2015. SETTING Home infusion therapy after discharge from academic medical centers. PARTICIPANTS Of 368 eligible patients discharged from 2 academic hospitals to home with peripherally inserted central catheters and tunneled CVCs, 222 consented. Patients remained in the study until 30 days after CVC removal. METHODS Patients underwent chart abstraction and monthly telephone surveys while the CVC was in place, focusing on complications and environmental exposures. Multivariable analyses estimated adjusted odds ratios and adjusted incident rate ratios between clinical, demographic, and environmental risk factors and 30-day readmissions or CVC complications. RESULTS Of 222 patients, total parenteral nutrition was associated with increased 30-day readmissions (adjusted odds ratio, 4.80 [95% CI, 1.51-15.21) and CVC complications (adjusted odds ratio, 2.41 [95% CI, 1.09-5.33]). Exposure to soil through gardening or yard work was associated with a decreased likelihood of readmissions (adjusted odds ratio, 0.09 [95% CI, 0.01-0.74]). Other environmental exposures were not associated with CVC complications. CONCLUSIONS complications and readmissions were common and associated with the use of total parenteral nutrition. Common environmental exposures (well water, cooking with raw meat, or pets) did not increase the rate of CVC complications, whereas soil exposures were associated with decreased readmissions. Interventions to decrease home CVC complications should focus on total parenteral nutrition patients. Infect Control Hosp Epidemiol 2016;1-8.


Growth hormone stimulates interferon regulatory factor-1 gene expression in the liver.
Interferon regulatory factor-1 (IRF-1) is a transcription factor first identified as part of the nuclear response to interferons. IRF-1 has been shown to be activated by many cytokines, including PRL, and has been thought to play a role in PRL-regulated gene expression in several experimental systems, including the Nb2 T lymphoma cell line, where it was first characterized as a PRL-responsive gene. We now find that IRF-1 gene expression is rapidly activated in vivo by both PRL and GH treatment. A single i.p. injection of rat PRL to hypophysectomized female rats caused a transient increase in nascent hepatic nuclear IRF-1 RNA within 15 min of hormone treatment. The rise in IRF-1 transcripts was accompanied by induction of nuclear protein binding to a DNA element from the proximal IRF-1 promoter, as assessed by gel mobility shift assays; this element was shown previously to mediate PRL-activated gene transcription. GH treatment stimulated a greater and more sustained increase in nascent IRF-1 RNA than PRL, leading to accumulation of IRF-1 transcripts for up to 16 h after a single hormone injection. GH also caused a pronounced induction of hepatic nuclear protein binding to the IRF-1 promoter element. Supershift experiments with specific antibodies showed that signal transducer and activator of transcription 1 (STAT1) and to a lesser extent STAT3 were components of the GH-activated protein-DNA complexes. By contrast, these two STATs were not induced in the liver by PRL. Protein binding to the IRF-1 DNA element and IRF-1 gene activation by GH were not blunted by pretreatment with the protein synthesis inhibitor, cycloheximide, indicating that these hormonal effects are primary consequences of GH-activated signal transduction pathways. Our results identify another component of the rapid nuclear response to GH, and support the idea that multiple primary and secondary signaling pathways contribute to the acute actions of GH on gene expression.


Novel epididymis-specific mRNAs downregulated by HE6/Gpr64 receptor gene disruption.
Targeted disruption of the epididymis-specific HE6/Gpr64 receptor gene in mice led to male infertility. In order to characterize the phenotype at a molecular level, we compared the gene expression patterns of wild type (wt) versus knockout (KO) caput epididymides. The caput region of KO males, although morphologically normal, nevertheless showed an aberrant expression pattern. Combining micro array analysis, differential library screening, Northern blot analysis and quantitative RT-PCR, we found that the knockout of the HE6/Gpr64 receptor was mainly associated with the downregulation of genes specific to the initial segment. The list of KO downregulated transcripts comprised Enpp2/autotaxin, the lipocalins 8 and 9, the beta-defensin Defb42, cystatins 8 and 12, as well as the membrane proteins Adam (A Disintegrin And Metalloprotease) 28, claudin-10, EAAC1, and the novel Me9. Clusterin/ApoJ and osteopontin/Spp1 mRNAs, on the other hand, were upregulated in the KO tissues. The Me9 transcript was studied in further detail, and we report here a cluster of related epididymis-specific genes. Me9 is specifically expressed in the initial segment and is representative of a novel and highly conserved mammalian gene family. The family consists of single-exon genes only; intron-containing paralogs have not yet been ascertained. The cloned cDNA sequences predicted hydrophobic polytopic membrane proteins containing the DUF716 motif. Protein expression was shown in the rodent caput epididymidis but remained uncertain in primates.


Magnesium deficiency and endothelial dysfunction: is oxidative stress involved?
Low magnesium (Mg) has been associated with oxidative stress, an important player in aging, atherosclerosis and other vascular diseases. In vivo, low Mg and immune system activation seem to cooperate to promote endothelial dysfunction. We therefore evaluated whether exposure of human endothelial cells to low Mg in vitro determines oxidative stress features. We therefore measured intracellular reactive oxygen species (ROS) by dichlorofluorescein (DCF) fluorescence after Mg deprivation with or without treatment with H2O2 While we did not observe any alteration of DCF-detectable intracellular ROS under basal conditions, we show that, early after exposure to low Mg (2 h), endothelial cells are more sensitive to the oxidant action of H2O2 than the controls cultured in physiologic concentrations of Mg. This increase of ROS in Mg deprived cells is transient and followed by a stable reduction of DCF-fluorescence below the levels measured in the controls. We also evaluated oxidative DNA damage and observed higher 8-hydroxy-deoxyguanine levels early (2 h) after Mg deprivation in respect to the controls, both in basal conditions and after treatment with H2O2 Mg deficiency in vivo associates with the onset of an inflammatory response leading to increased circulating levels of cytokines, which trigger an oxidative response in endothelial cells. We here show that exposure to IL-1 and IL-6 significantly increased the levels of DCF-detectable ROS in cells cultured in physiologic concentrations of Mg, but not in Mg-deprived cells. We conclude that low Mg transiently leads to pro-oxidant effects. We suggest that different molecules, including pro-inflammatory cytokines, might be involved in promoting endothelial dysfunction.


Reconstituting multivesicular body biogenesis with purified components.
Activated cell surface receptors are rapidly removed from the plasma membrane through clathrin mediated endocytosis and transported to the endosome where they are either recycled or sorted to the lysosomal pathway to be degraded. Receptors, destined for degradation in the lysosome, are packaged into intraluminal vesicles (ILVs) of endosomes by a reaction that is topologically unrelated to other budding reactions in cells. First, receptors are clustered at the endosomal membrane and receptor-rich membrane patches then bud towards the lumen of the endosome. The nascent membrane buds are finally cleaved from the limiting membrane to release cargo-bearing vesicles into the endosomal interior. The molecular machinery that drives multivesicular body biogenesis, the endosomal sorting complex required for transport (ESCRT) machinery, has been identified through genetic screens. It consists of the cytoplasmic, hetero-multimeric complexes ESCRT-0, -I, -II, and -III, and of the Vps4/VtaI complex. Although the ESCRT machinery has been characterized extensively using cell-biological and biochemical approaches, the molecular mechanism of multivesicular body biogenesis remained unclear. In this chapter, I will present in vitro reconstitution systems that we used to study ESCRT-driven membrane remodeling reactions with purified components on artificial membranes. This includes generation of large and giant unilamellar liposomes, as well as in vitro reconstitution reactions of fluorescently labeled proteins on such membranes. I will discuss both, the potential of in vitro systems to analyze membrane-remodeling events and also their limitations.


Recurrent lower-limb varicose veins: effect of direct contrast-enhanced three-dimensional MR venographic findings on diagnostic thinking and therapeutic decisions.
To assess the effect of direct three-dimensional (3D) magnetic resonance (MR) venographic findings on diagnostic thinking and therapeutic decisions in patients with complex recurrent varicose vein anatomy who were being evaluated for surgical treatment. The study was approved by the Institutional Review Board; informed consent was obtained from patients. MR venography was performed before surgery in 22 legs of 14 patients (seven women: mean age, 53 years; seven men: mean age, 59 years) thought to have recurrent varicose veins. Two radiologists assessed image quality and evaluated sites and sources of varicose veins on MR venograms. One vascular surgeon completed a questionnaire before and after MR venography and noted diagnosis and therapeutic decisions. Diagnoses at MR venography were compared with surgical results in 19 legs that underwent surgery. Differences between diagnosed and treated varicose veins per leg before and after MR venography were analyzed with logistic regression for survey data. kappa Values were calculated to illustrate interobserver agreement for grading image quality of venous segments and for diagnosing recurrent varicose veins. Mean graded image quality of the deep venous system and the recurrent varicose veins was good or excellent in 89% of segments. There was good agreement between readers regarding grading of image quality of venous segments (kappa = 0.80). After MR venography, diagnosis of the sites and sources of recurrent varicose veins changed in 17 of 22 legs of nine of 14 patients. In one of 14 patients, the preoperative diagnosis of recurrent varicose veins was withdrawn. A change in treatment plan occurred in 17 of 22 legs after MR venography. The number of diagnosed and treated sources of reflux increased significantly after MR venography. MR venographic diagnoses were confirmed at surgery in all 19 legs. MR venographic results have a substantial effect on diagnostic thinking and therapeutic decisions when recurrent lower-limb varicose veins are suspected.


Medium-Dependent Antibacterial Properties and Bacterial Filtration Ability of Reduced Graphene Oxide.
Toxicity of reduced graphene oxide (rGO) has been a topic of multiple studies and was shown to depend on a variety of characteristics of rGO and biological objects of interest. In this paper, we demonstrate that when studying the same dispersions of rGO and fluorescent Escherichia coli (E. coli) bacteria, the outcome of nanotoxicity experiments also depends on the type of culture medium. We show that rGO inhibits the growth of bacteria in a nutrition medium but shows little effect on the behavior of E. coli in a physiological saline solution. The observed effects of rGO on E. coli in different media could be at least partially rationalized through the adsorption of bacteria and nutrients on the dispersed rGO sheets, which is likely mediated via hydrogen bonding. We also found that the interaction between rGO and E. coli is medium-dependent, and in physiological saline solutions they form stable flocculate structures that were not observed in nutrition media. Furthermore, the aggregation of rGO and E. coli in saline media was observed regardless of whether the bacteria were alive or dead. Filtration of the aggregate suspensions led to nearly complete removal of bacteria from filtered liquids, which highlights the potential of rGO for the filtration and separation of biological contaminants, regardless of whether they include live or dead microorganisms.


Anticlusterin treatment of breast cancer cells increases the sensitivities of chemotherapy and tamoxifen and counteracts the inhibitory action of dexamethasone on chemotherapy-induced cytotoxicity.
Overexpression of the apoptosis-related protein clusterin is associated with breast cancer development and tumor progression. We describe the use of clusterin-specific antisense oligonucleotides and antibodies to sensitize breast carcinoma cells to anticancer drugs routinely used in breast cancer therapy. MCF-7 and MDA-MB-231 cells were treated with the oligonucleotide or antibody, chemotherapeutic agents (doxorubicin or paclitaxel), tamoxifen, or with combinations of these. Treatments that include antisense clusterin oligonucleotide or antibody to clusterin have been shown to reduce the number of viable cells more effectively than treatment with the drugs alone. We also demonstrate that dexamethasone pretreatment of breast cancer cell lines inhibits chemotherapy-induced cytotoxicity and is associated with the transcriptional induction of clusterin. However, anticlusterin treatment increases chemotherapy-induced cytotoxicity, even in the presence of glucocorticoids, suggesting a possible role for these proteins in glucocorticoid-mediated survival. These data suggest that combined treatment with antibodies to clusterin or antisense clusterin oligodeoxynucleotides and paclitaxel, doxorubicin, or tamoxifen could be a novel and attractive strategy to inhibit the progression of breast carcinoma by regulation of the clusterin function. Moreover, glucocorticoid activation in breast cancer cells regulates survival signaling by the direct transactivation of genes like clusterin which encode proteins that decrease susceptibility to apoptosis. Given the widespread clinical administration of dexamethasone before chemotherapy, understanding glucocorticoid-induced survival mechanisms is essential for achieving optimal therapeutic responses.


Fully automated longitudinal segmentation of new or enlarged multiple sclerosis lesions using 3D convolutional neural networks.
The quantification of new or enlarged lesions from follow-up MRI scans is an important surrogate of clinical disease activity in patients with multiple sclerosis (MS). Not only is manual segmentation time consuming, but inter-rater variability is high. Currently, only a few fully automated methods are available. We address this gap in the field by employing a 3D convolutional neural network (CNN) with encoder-decoder architecture for fully automatic longitudinal lesion segmentation. Input data consist of two fluid attenuated inversion recovery (FLAIR) images (baseline and follow-up) per patient. Each image is entered into the encoder and the feature maps are concatenated and then fed into the decoder. The output is a 3D mask indicating new or enlarged lesions (compared to the baseline scan). The proposed method was trained on 1809 single point and 1444 longitudinal patient data sets and then validated on 185 independent longitudinal data sets from two different scanners. From the two validation data sets, manual segmentations were available from three experienced raters, respectively. The performance of the proposed method was compared to the open source Lesion Segmentation Toolbox (LST), which is a current state-of-art longitudinal lesion segmentation method. The mean lesion-wise inter-rater sensitivity was 62%, while the mean inter-rater number of false positive (FP) findings was 0.41 lesions per case. The two validated algorithms showed a mean sensitivity of 60% (CNN), 46% (LST) and a mean FP of 0.48 (CNN), 1.86 (LST) per case. Sensitivity and number of FP were not significantly different (p < 0.05) between the CNN and manual raters. New or enlarged lesions counted by the CNN algorithm appeared to be comparable with manual expert ratings. The proposed algorithm seems to outperform currently available approaches, particularly LST. The high inter-rater variability in case of manual segmentation indicates the complexity of identifying new or enlarged lesions. An automated CNN-based approach can quickly provide an independent and deterministic assessment of new or enlarged lesions from baseline to follow-up scans with acceptable reliability.


Transdermal delivery of nalbuphine and its prodrugs by electroporation.
The aim of this study was to assess the effects of electroporation on transdermal permeation of nalbuphine (NA) and its prodrugs. The permeation characteristics were investigated under various electrical factors and skin barriers to elucidate the mechanisms involved in transdermal delivery of NA and its prodrugs by skin electroporation. The in vitro permeation studies were performed using side-by-side diffusion cells. The various electrical factors investigated were pulse voltage, pulse duration and pulse number; the different skin barriers studied were intact hairless mouse skin, stratum corneum (SC)-stripped skin, delipid skin as well as furry Wistar rat skin. The prodrugs were fully converted to parent drug after skin permeation. Application of electroporation significantly enhanced transdermal permeation of NA and its prodrugs. The enhancement ratios were highest for NA and the four prodrugs showed the similar permeability after electroporation. The permeation amounts of NA and its prodrugs may be increased by application of higher pulse voltage, pulse duration as well as pulse number. Various kinetics and mechanisms were observed for the permeation of the hydrophilic NA and lipophilic nalbuphine enanthate through different skin barriers by applying electroporation. This study demonstrated that electroporation may enhance and control transdermal permeation of NA and its prodrugs. The results also indicated that the physicochemical properties of prodrug had significant effects on kinetics as well as mechanisms of transdermal permeation by electroporation.


Hemophagocytic Lymphohistiocytosis in Adults with Intraocular Involvement: Clinicopathologic Features of 3 Cases.
Hemophagocytic lymphohistiocytosis (HLH) is an infrequent inflammatory multisystemic syndrome. Only rare cases with ophthalmic involvement describing their pathologic features have been previously reported. We report 3 cases of adult-onset HLH with bilateral ocular involvement and describe their clinicopathologic features. Three adult males - 2 with a history of viral infection - developed persistent fever, fatigue, bone marrow abnormalities, and irreversible multiorgan failure. Visual impairment was also documented in 2 cases. Complete autopsies were performed. Ophthalmic pathology demonstrated a bilateral histiocytic infiltrate with scant lymphocytes affecting the uvea. Focal extension to the retina, optic nerve, and trabecular meshwork were also identified, as well as hemophagocytosis in 1 case. Macrophages showed strong immunoreactivity for CD163 antibody and lacked BRAF p.V600E mutant protein. HLH is an unusual disorder associated with several systemic conditions. Histologic features in the eye are poorly documented, with prior reports restricted to children. Our 3 adult cases are reported using updated criteria and, despite the difference in age, show changes similar to those observed in the pediatric population.


Automatic electronic-controlled mode locking self-start in fibre lasers with non-linear polarisation evolution.
The present work demonstrates a fibre-laser system with automatic electronic-controlled triggering of dissipative soliton generation mode. Passive mode locking based on the effect of non-linear polarisation evolution has been achieved through a polarisation controller containing a single low-voltage liquid crystal plate whose optimal wave delay was determined from analysis of inter-mode beat spectrum of the output radiation.


Evoked mechanical responses of isolated cochlear outer hair cells.
Intracellular current administration evokes rapid, graded, and bidirectional mechanical responses of isolated outer hair cells from the mammalian inner ear. The cells become shorter in response to depolarizing and longer in response to hyperpolarizing currents in the synaptic end of the cell. The cells respond with either an increase or decrease in length to transcellular alternating current stimulation. The direction of the movement with transcellular stimuli appears to be frequency dependent. Iontophoretic application of acetylcholine to the synaptic end of the cell decreases its length. The microarchitecture of the organ of Corti permits length changes of outer hair cells in a manner that could significantly influence the mechanics of the cochlear partition and thereby contribute to the exquisite sensitivity of mammalian hearing.


Salpingoscopy: light microscopic and electron microscopic correlations.
In order to examine the ability of salpingoscopy to diagnose intratubal pathology, 32 fallopian tubes were evaluated salpingoscopically and histologically. Both flexible and rigid salpingoscopes were used, and observations were documented by intratubal photography. Salpingoscopic criteria were established and each criterion assigned a numerical value. Each tube was evaluated for patency, mucosal fold architecture, erythema, adhesions, and dilatation. Based on these criteria, tubes were graded as normal or as abnormal with mild, moderate, or severe changes. Histologically, each tube was evaluated for patency, epithelial changes, vascularity, dilatation, adhesions, and active inflammation. Six tubes with significant histologic findings and two histologically normal fallopian tubes were also examined by transmission electron microscopy. In five discordant cases, histology revealed epithelial and stromal changes not detected by salpingoscopy. Fallopian tubes with severe disease were diagnosed by both methods. Transmission electron microscopy of histologically abnormal tubes showed flattening of the epithelium with markedly reduced ciliary distribution, degenerating secretory epithelial cells with large intracellular vacuoles, and swollen nuclei containing sparse chromatin. Our results indicate that salpingoscopic observations are consistent with histologic findings when endotubal disease is severe. However, moderate pathologic changes as documented by light microscopy and transmission electron microscopy were frequently not diagnosed salpingoscopically, even with magnification.


Nanomechanical Study of Enzyme: Coenzyme Complexes: Bipartite Sites in Plastidic Ferredoxin-NADP+ Reductase for the Interaction with NADP.
Plastidic ferredoxin-NADP+ reductase (FNR) transfers two electrons from two ferredoxin or flavodoxin molecules to NADP+, generating NADPH. The forces holding the Anabaena FNR:NADP+ complex were analyzed by dynamic force spectroscopy, using WT FNR and three C-terminal Y303 variants, Y303S, Y303F, and Y303W. FNR was covalently immobilized on mica and NADP+ attached to AFM tips. Force-distance curves were collected for different loading rates and specific unbinding forces were analyzed under the Bell-Evans model to obtain the mechanostability parameters associated with the dissociation processes. The WT FNR:NADP+ complex presented a higher mechanical stability than that reported for the complexes with protein partners, corroborating the stronger affinity of FNR for NADP+. The Y303 mutation induced changes in the FNR:NADP+ interaction mechanical stability. NADP+ dissociated from WT and Y303W in a single event related to the release of the adenine moiety of the coenzyme. However, two events described the Y303S:NADP+ dissociation that was also a more durable complex due to the strong binding of the nicotinamide moiety of NADP+ to the catalytic site. Finally, Y303F shows intermediate behavior. Therefore, Y303, reported as crucial for achieving catalytically competent active site geometry, also regulates the concerted dissociation of the bipartite nucleotide moieties of the coenzyme.


Developmental Mechanisms of Aortic Valve Malformation and Disease.
Normal aortic valves are composed of valve endothelial cells (VECs) and valve interstitial cells (VICs). VICs are the major cell population and have distinct embryonic origins in the endocardium and cardiac neural crest cells. Cell signaling between the VECs and VICs plays critical roles in aortic valve morphogenesis. Disruption of major cell signaling pathways results in aortic valve malformations, including bicuspid aortic valve (BAV). BAV is a common congenital heart valve disease that may lead to calcific aortic valve disease (CAVD), but there is currently no effective medical treatment for this beyond surgical replacement. Mouse and human studies have identified causative gene mutations for BAV and CAVD via disrupted VEC to VIC signaling. Future studies on the developmental signaling mechanisms underlying aortic valve malformations and the pathogenesis of CAVD using genetically modified mouse models and patient-induced pluripotent stem cells may identify new effective therapeutic targets for the disease.


Breast cancer risk associated with CHEK2 mutations.
Most efforts to identify individuals who have a hereditary predisposition for developing breast cancer had focused on the BRCA1 and BRCA2 genes. Less common susceptibility genes also are associated with increased risk for developing breast cancer, but until recently have often gone undetected. With the advent of next generation sequencing (NGS), many families with suspected hereditary risk are undergoing testing for multiple genes associated with increased cancer risk (Mahon, 2013a). One gene that is commonly included on NGS hereditary breast cancer panels is CHEK2. Increasingly, oncology nurses will encounter patients and families affected with mutations on this gene and need to understand the implications it has for screening and treatment.


The interaction of light and gravity on the transmission of Echinostoma caproni (Digenea: Echinostomatidae) cercariae to the second intermediate host, Biomphalaria glabrata (Gastropoda: Pulmonata).
The current experiments were designed to assess the interaction of light and gravity on the transmission of Echinostoma caproni cercariae to the second intermediate host, Biomphalaria glabrata. Transmission chambers were constructed of clear polyvinyl chloride pipe covered with a black sleeve to exclude light. Snails were constrained within the chamber to prevent movement, while permitting the cercariae to swim freely. A trial consisted of 2 infected B. glabrata shedding E. caproni cercariae placed at the center of the chamber with 5 uninfected B. glabrata placed 10 cm above and below the shedding snails as sentinels. Three experiments, consisting of 12 trials each, were conducted under the following lighting conditions, i.e., above and below the transmission chamber, and in complete darkness. In all 3 experiments, the proportion of metacercariae was significantly higher in snails at the top of the chamber. The results suggest that a negative geotaxis is the primary factor in the initial dispersal of E. caproni cercariae. Coupling negative geotaxis and positive phototaxis (light from above) resulted in a significantly higher proportion of metacercariae in sentinel snails at the top of the transmission chamber when corrected for cercarial density. There was no significant difference in the proportion of metacercariae in snails at the top or bottom of the transmission chamber with light at the bottom of the chamber or in complete darkness. Cercariae of E. caproni only respond to light in context, i.e., from above, and ignore the light stimulus when it comes from an unexpected location (bottom of the water column). Significantly greater numbers of cercariae were released from shedding snails when light was present, suggesting that emergence of cercariae from B. glabrata is dependent on light regardless of the position of the light source.


Insights into the regulation of intrinsically disordered proteins in the human proteome by analyzing sequence and gene expression data.
Disordered proteins need to be expressed to carry out specified functions; however, their accumulation in the cell can potentially cause major problems through protein misfolding and aggregation. Gene expression levels, mRNA decay rates, microRNA (miRNA) targeting and ubiquitination have critical roles in the degradation and disposal of human proteins and transcripts. Here, we describe a study examining these features to gain insights into the regulation of disordered proteins. In comparison with ordered proteins, disordered proteins have a greater proportion of predicted ubiquitination sites. The transcripts encoding disordered proteins also have higher proportions of predicted miRNA target sites and higher mRNA decay rates, both of which are indicative of the observed lower gene expression levels. The results suggest that the disordered proteins and their transcripts are present in the cell at low levels and/or for a short time before being targeted for disposal. Surprisingly, we find that for a significant proportion of highly disordered proteins, all four of these trends are reversed. Predicted estimates for miRNA targets, ubiquitination and mRNA decay rate are low in the highly disordered proteins that are constitutively and/or highly expressed. Mechanisms are in place to protect the cell from these potentially dangerous proteins. The evidence suggests that the enrichment of signals for miRNA targeting and ubiquitination may help prevent the accumulation of disordered proteins in the cell. Our data also provide evidence for a mechanism by which a significant proportion of highly disordered proteins (with high expression levels) can escape rapid degradation to allow them to successfully carry out their function.


Mitochondrial RNA Expression and Single Nucleotide Variants in Association with Clinical Parameters in Primary Breast Cancers.
The human mitochondrial DNA (mtDNA) encodes 37 genes, including thirteen proteins essential for the respiratory chain, and RNAs functioning in the mitochondrial translation apparatus. The total number of mtDNA molecules per cell (mtDNA content) is variable between tissue types and also between tumors and their normal counterparts. For breast cancer, tumors tend to be depleted in their mtDNA content compared to adjacent normal mammary tissue. Various studies have shown that primary breast tumors harbor somatic mtDNA variants. A decrease in mtDNA content or the presence of somatic variants could indicate a reduced mitochondrial function within breast cancer. In this explorative study we aimed to further understand genomic changes and expression of the mitochondrial genome within breast cancer, by analyzing RNA sequencing data of primary breast tumor specimens of 344 cases. We demonstrate that somatic variants detected at the mtRNA level are representative for somatic variants in the mtDNA. Also, the number of somatic variants within the mitochondrial transcriptome is not associated with mutational processes impacting the nuclear genome, but is positively associated with age at diagnosis. Finally, we observe that mitochondrial expression is related to ER status. We conclude that there is a large heterogeneity in somatic mutations of the mitochondrial genome within primary breast tumors, and differences in mitochondrial expression among breast cancer subtypes. The exact impact on metabolic differences and clinical relevance deserves further study.


Prediagnostic circulating markers of inflammation and risk of oesophageal adenocarcinoma: a study within the National Cancer Institute Cohort Consortium.
Cross-sectional data indicate that systemic inflammation is important in oesophageal adenocarcinoma. We conducted a prospective study to assess whether prediagnostic circulating markers of inflammation were associated with oesophageal adenocarcinoma and to what extent they mediated associations of obesity and cigarette smoking with cancer risk. This nested case-control study included 296 oesophageal adenocarcinoma cases and 296 incidence density matched controls from seven prospective cohort studies. We quantitated 69 circulating inflammation markers using Luminex-based multiplex assays. Conditional logistic regression models estimated associations between inflammation markers and oesophageal adenocarcinoma, as well as direct and indirect effects of obesity and smoking on risk of malignancy. Soluble tumour necrosis factor receptor 2 (sTNFR2) (ORsquartile 4 vs 1=2.67, 95% CI 1.52 to 4.68) was significantly associated with oesophageal adenocarcinoma. Additional markers close to the adjusted significance threshold included C reactive protein, serum amyloid A, lipocalin-2, resistin, interleukin (IL) 3, IL17A, soluble IL-6 receptor and soluble vascular endothelial growth factor receptor 3. Adjustment for body mass index, waist circumference or smoking status slightly attenuated biomarker-cancer associations. Mediation analysis indicated that sTNFR2 may account for 33% (p=0.005) of the effect of waist circumference on oesophageal adenocarcinoma risk. Resistin, plasminogen activator inhibitor 1, C reactive protein and serum amyloid A were also identified as potential mediators of obesity-oesophageal adenocarcinoma associations. For smoking status, only plasminogen activator inhibitor 1 was a nominally statistically significant (p<0.05) mediator of cancer risk. This prospective study provides evidence of a link between systemic inflammation and oesophageal adenocarcinoma risk. In addition, this study provides the first evidence that indirect effects of excess adiposity and cigarette smoking, via systemic inflammation, increase the risk of oesophageal adenocarcinoma.


Evolution of worldwide stock markets, correlation structure, and correlation-based graphs.
We investigate the daily correlation present among market indices of stock exchanges located all over the world in the time period January 1996 to July 2009. We discover that the correlation among market indices presents both a fast and a slow dynamics. The slow dynamics reflects the development and consolidation of globalization. The fast dynamics is associated with critical events that originate in a specific country or region of the world and rapidly affect the global system. We provide evidence that the short term time scale of correlation among market indices is less than 3 trading months (about 60 trading days). The average values of the nondiagonal elements of the correlation matrix, correlation-based graphs, and the spectral properties of the largest eigenvalues and eigenvectors of the correlation matrix are carrying information about the fast and slow dynamics of the correlation of market indices. We introduce a measure of mutual information based on link co-occurrence in networks in order to detect the fast dynamics of successive changes of correlation-based graphs in a quantitative way.


Prevention of postpartum hemorrhage: options for home births in rural Ethiopia.
This paper sought to determine the safety and feasibility of home-based prophylaxis of postpartum hemorrhage (PPH) with misoprostol, including assessment of the need for referrals and additional interventions. In rural Tigray, Ethiopia, traditional birth attendants (TBAs) in intervention areas were trained to administer 600mcg of oral misoprostol. In non-intervention areas women were referred to the nearest health facility. Of the 966 vaginal deliveries attended by TBAs, only 8.9% of those who took misoprostol prophylactically (n = 485) needed additional intervention due to excessive bleeding compared to 18.9% of those who did not take misoprostol (n = 481).The experience of symptoms among those who used misoprostol can be considered of minor relevance and self-contained. This study found that prophylactic use of misoprostol in home births is a safe and feasible intervention. Community health care workers trained in its use can correctly and effectively administer misoprostol and be a champion in reducing PPH morbidity and mortality.


Frailty is associated with long-term outcome in patients with sepsis who are over 80 years old: results from an observational study in 241 European ICUs.
Sepsis is one of the most frequent reasons for acute intensive care unit (ICU) admission of very old patients and mortality rates are high. However, the impact of pre-existing physical and cognitive function on long-term outcome of ICU patients ≥ 80 years old (very old intensive care patients (VIPs)) with sepsis is unclear. To investigate both the short- and long-term mortality of VIPs admitted with sepsis and assess the relation of mortality with pre-existing physical and cognitive function. Prospective cohort study. 241 ICUs from 22 European countries in a six-month period between May 2018 and May 2019. Acutely admitted ICU patients aged ≥80 years with sequential organ failure assessment (SOFA) score ≥ 2. Sepsis was defined according to the sepsis 3.0 criteria. Patients with sepsis as an admission diagnosis were compared with other acutely admitted patients. In addition to patients' characteristics, disease severity, information about comorbidity and polypharmacy and pre-existing physical and cognitive function were collected. Out of 3,596 acutely admitted VIPs with SOFA score ≥ 2, a group of 532 patients with sepsis were compared to other admissions. Predictors for 6-month mortality were age (per 5 years): Hazard ratio (HR, 1.16 (95% confidence interval (CI), 1.09-1.25, P < 0.0001), SOFA (per one-point): HR, 1.16 (95% CI, 1.14-1.17, P < 0.0001) and frailty (CFS > 4): HR, 1.34 (95% CI, 1.18-1.51, P < 0.0001). There is substantial long-term mortality in VIPs admitted with sepsis. Frailty, age and disease severity were identified as predictors of long-term mortality in VIPs admitted with sepsis.


Combined vacuum impregnation and electron-beam irradiation treatment to extend the storage life of sliced white button mushrooms (Agaricus bisporus).
This study assessed the application of an antibrowning solution using vacuum impregnation (VI) and then electron-beam irradiation as a means to extend the shelf life of sliced white button mushrooms (Agaricus bisporus). A preliminary study helped to determine the best antibrowning solution and VI process parameters. Mushroom slices were impregnated with 2 g/100 g ascorbic acid + 1 g/100 g calcium lactate; 2 g/100 g citric acid + 1 g/100 g calcium lactate; 1 g/100 g chitosan + 1 g/100 g calcium lactate; and 1 g/100 g calcium lactate at different vacuum pressures and times and atmospheric restoration times. Selection of the antibrowning solution and VI parameters was based on texture and color of the mushroom slices. Next, the slices were irradiated at 1 kGy using a 1.35-MeV e-beam accelerator. Physicochemical, sensory, and microbial quality of mushrooms was monitored for 15 d at 4 °C. The best impregnation process in this study was 2 g/100 g ascorbic acid and 1 g/100 g calcium lactate at 50 mm Hg for 5 min and an atmospheric restoration time of 5 min. The control (untreated) samples suffered structural losses throughout storage. Only the vacuum impregnated-irradiated samples had acceptable color by the end of storage. Sensory panelists consistently preferred the samples produced with VI and irradiation because exposure to ionizing radiation inhibited growth of spoilage microorganisms.


Pitfalls in the interpretation of spectral analysis of the heart rate variability during exercise in humans.
The recent use of spectral analysis of the R-R interval variability to assess the autonomic drive during exercise has produced inconsistent results. The purpose of this study was to assess whether the spectral components of the R-R interval variability reflect different mechanisms at rest and during exercise. Autoregressive spectral analysis of the electrocardiographic and breathing signals was performed in 11 healthy young men at rest and during incremental cycle ergometry. The amplitude of respiratory sinus arrhythmia, i.e. the absolute power of the high frequency spectral component, fell at the onset of exercise, consistent with a reduction in cardiac vagal activity. Conversely, the normalized power of the high frequency component, (i.e. the percentage of R-R interval variance due to the respiratory sinus arrhythmia) increased with increasing work rates. The low frequency spectral component of the R-R interval variability, which when expressed in normalized units is believed to reflect cardiac sympathetic activity, was no longer detectable in severe exercise when the adrenergic drive is known to be elevated. In conclusion, autoregressive spectral analysis of the R-R interval variability does not adequately reflect the autonomic changes that occur during incremental exercise. In particular, the evidence indicates that as the cardiac vagal tone falls with increasing levels of exercise, a greater percentage of the residual power of the high frequency component may be due to non-neural mechanisms.