Beneficial Effect of Sodium Nitrite on EEG Ischaemic Markers in Patients with Subarachnoid Haemorrhage.
Subarachnoid haemorrhage (SAH) is associated with long-term disability, serious reduction in quality of life and significant mortality. Early brain injury (EBI) refers to the pathological changes in cerebral metabolism and blood flow that happen in the first few days after ictus and may lead on to delayed cerebral ischaemia (DCI). A disruption of the nitric oxide (NO) pathway is hypothesised as a key mechanism underlying EBI. A decrease in the alpha-delta power ratio (ADR) of the electroencephalogram has been related to cerebral ischaemia. In an experimental medicine study, we tested the hypothesis that intravenous sodium nitrite, an NO donor, would lead to increases in ADR. We studied 33 patients with acute aneurysmal SAH in the EBI phase. Participants were randomised to either sodium nitrite or saline infusion for 1 h. EEG measurements were taken before the start of and during the infusion. Twenty-eight patients did not develop DCI and five patients developed DCI. In the patients who did not develop DCI, we found an increase in ADR during sodium nitrite versus saline infusion. In the five patients who developed DCI, we did not observe a consistent pattern of ADR changes. We suggest that ADR power changes in response to nitrite infusion reflect a NO-mediated reduction in cerebral ischaemia and increase in perfusion, adding further evidence to the role of the NO pathway in EBI after SAH. Our findings provide the basis for future clinical trials employing NO donors after SAH.


Traumatic pericarditis in cattle: clinical, radiographic and ultrasonographic findings.
Pericarditis is an inflammation of the pericardium with accumulation of serous or fibrinous inflammatory products. In cattle, it is almost always attributable to a reticular foreign body that has penetrated the reticular wall, diaphragm and pericardial sac. The lead signs of pericarditis are tachycardia, muffled heart sounds, asynchronous abnormal heart sounds, distension of the jugular veins and submandibular, brisket and ventral abdominal oedema. The glutaraldehyde test is an important diagnostic tool because it is positive in >90% of affected cattle. Other common laboratory findings are leukocytosis and hyperfibrinogenaemia (indicating inflammation), and elevation of liver enzyme activity (reflecting hepatic congestion). Radiographs of the thorax and reticulum often show a foreign body cranial to the reticulum. In the majority of cases, massive fibrinopurulent adhesions obscure the cardiophrenic angle, cardiac silhouette and ventral diaphragm. Ultrasonography is the method of choice for diagnosis and characterisation of pericardial effusion. Echogenic deposits and strands of fibrin are seen on the epicardium, and the ventricles are compressed by the effusion. Severe pleural effusion is usually evident. In cattle with distension of the jugular veins and tachycardia, the differential diagnosis includes right-sided cardiac insufficiency attributable to other causes. Distension of the jugular veins without signs of right-sided cardiac insufficiency may occur with obstruction or compression of the cranial vena cava. The prognosis is poor, and pericardiocentesis or pericardiotomy are inadequate methods of treatment. Thus, prompt and humane euthanasia is indicated for cattle with traumatic reticuloperitonitis. Because a definitive diagnosis of traumatic reticuloperitonitis is not always possible based on clinical signs alone, radiography and ultrasonography of the thorax and reticulum are indicated in doubtful cases.


A measure of person-centered practices in assisted living: the PC-PAL.
Develop self-administered questionnaires of person-centeredness for completion by residents and staff in assisted living (AL), in response to concerns that AL is not person-centered; also, demonstrated person-centeredness is necessary for Medicaid support as a home- and community-based services provider. Community-based participatory research partnership among a research team, a consortium of 11 stakeholder organizations, and others. Methods included literature review, item generation and reduction, cognitive testing, field testing, exploratory factor analysis, and convergent and discriminant validity testing. Cognitive testing conducted in 2 AL residences and field testing conducted in 19 diverse, stratified AL residences in 6 states. Eight residents and staff participated in cognitive testing, and 228 residents and 123 staff participated in field testing. Feasibility and psychometric testing of draft questionnaires that included 75 items (resident version) and 102 items (staff version), with parallel items on both versions as appropriate. The final resident questionnaire included 49 items and 4 factors: well-being and belonging, individualized care and services, social connectedness, and atmosphere. The staff questionnaire included 62 items and 5 factors: workforce practices, social connectedness, individualized care and services, atmosphere, and caregiver-resident relationships. Staff scored person-centeredness higher than did residents, reflecting their different perspectives. The Person-Centered Practices in Assisted Living (PC-PAL) questionnaires measure person-centeredness from the perspectives of residents and staff, meaning that they reflect the concepts and items considered to be important to these key stakeholders. Use of these instruments to describe, assess, quantify, ensure, and ultimately improve person-centeredness in AL is feasible and appropriate for all AL settings, and supported by numerous national organizations.


Alcohol consumption and breast cancer recurrence and survival among women with early-stage breast cancer: the life after cancer epidemiology study.
To examine the association of alcohol consumption after breast cancer diagnosis with recurrence and mortality among early-stage breast cancer survivors. Patients included 1,897 LACE study participants diagnosed with early-stage breast cancer between 1997 and 2000 and recruited on average 2 years postdiagnosis, primarily from the Kaiser Permanente Northern California Cancer Registry. Alcohol consumption (ie, wine, beer, and liquor) was assessed at cohort entry using a food frequency questionnaire. Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% CI with adjustment for known prognostic factors. Two hundred ninety-three breast cancer recurrences and 273 overall deaths were ascertained after an average follow-up of 7.4 years. Nine hundred fifty-eight women (51%) were considered drinkers (> 0.5 g/d of alcohol), and the majority drank wine (89%). Drinking ≥ 6 g/d of alcohol compared with no drinking was associated with an increased risk of breast cancer recurrence (HR, 1.35; 95% CI, 1.00 to 1.83) and death due to breast cancer (HR, 1.51; 95% CI, 1.00 to 2.29). The increased risk of recurrence appeared to be greater among postmenopausal (HR, 1.51; 95% CI, 1.05 to 2.19) and overweight and obese women (HR, 1.60; 95% CI, 1.08 to 2.38). Alcohol intake was not associated with all-cause death and possibly associated with decreased risk of non-breast cancer death. Consuming three to four alcoholic drinks or more per week after a breast cancer diagnosis may increase risk of breast cancer recurrence, particularly among postmenopausal and overweight/obese women, yet the cardioprotective effects of alcohol on non-breast cancer death were suggested.


Multiple transcription factors directly regulate Hox gene lin-39 expression in ventral hypodermal cells of the C. elegans embryo and larva, including the hypodermal fate regulators LIN-26 and ELT-6.
Hox genes encode master regulators of regional fate specification during early metazoan development. Much is known about the initiation and regulation of Hox gene expression in Drosophila and vertebrates, but less is known in the non-arthropod invertebrate model system, C. elegans. The C. elegans Hox gene lin-39 is required for correct fate specification in the midbody region, including the Vulval Precursor Cells (VPCs). To better understand lin-39 regulation and function, we aimed to identify transcription factors necessary for lin-39 expression in the VPCs, and in particular sought factors that initiate lin-39 expression in the embryo. We used the yeast one-hybrid (Y1H) method to screen for factors that bound to 13 fragments from the lin-39 region: twelve fragments contained sequences conserved between C. elegans and two other nematode species, while one fragment was known to drive reporter gene expression in the early embryo in cells that generate the VPCs. Sixteen transcription factors that bind to eight lin-39 genomic fragments were identified in yeast, and we characterized several factors by verifying their physical interactions in vitro, and showing that reduction of their function leads to alterations in lin-39 levels and lin-39::GFP reporter expression in vivo. Three factors, the orphan nuclear hormone receptor NHR-43, the hypodermal fate regulator LIN-26, and the GATA factor ELT-6 positively regulate lin-39 expression in the embryonic precursors to the VPCs. In particular, ELT-6 interacts with an enhancer that drives GFP expression in the early embryo, and the ELT-6 site we identified is necessary for proper embryonic expression. These three factors, along with the factors ZTF-17, BED-3 and TBX-9, also positively regulate lin-39 expression in the larval VPCs. These results significantly expand the number of factors known to directly bind and regulate lin-39 expression, identify the first factors required for lin-39 expression in the embryo, and hint at a positive feedback mechanism involving GATA factors that maintains lin-39 expression in the vulval lineage. This work indicates that, as in other organisms, the regulation of Hox gene expression in C. elegans is complicated, redundant and robust.


Does Pain Have a Role When It Comes to Tourniquet Training?
One of the greatest conundrums with tourniquet (TQ) education is the use of an appropriate surrogate of hemorrhage in the training setting to determine whether a TQ has been successfully used. At our facility, we currently use loss of audible Doppler signal or loss of palpable pulse to represent adequate occlusion of vasculature and thus successful TQ application. We set out to determine whether pain can be used to indicate successful TQ application in the training setting. Three tourniquet systems (a pneumatic tourniquet, Combat Application Tourniquet® [C-A-T], and Stretch Wrap and Tuck Tourniquet™ [SWAT-T]) were used to occlude the arterial vasculature of the left upper arm (LUA), right upper arm (RUA), left forearm (LFA), right forearm (RFA), right thigh (RTH), and right calf (RCA) of 41 volunteers. A 4MHz, handheld Doppler ultrasound was used to confirm loss of Doppler signal (LOS) at the radial or posterior tibial artery to denote successful TQ application. Once successful placement of the TQ was noted, subjects rated their pain from 0 to 10 on the visual analog scale. In addition, the circumference of each limb, the pressure with the pneumatic TQ, number of twists with the C-A-T, and length of TQ used for the SWAT-T to obtain LOS was recorded. All 41 subjects had measurements at all anatomic sites with the pneumatic TQ, except one participant who was unable to complete the LUA. In total, pain was rated as 1 or less by 61% of subjects for LUA, 50% for LFA, 57.5% for RUA, 52.5% RFA, 15% for RTH, and 25% for RCA. Pain was rated 3 or 4 by 45% of subjects for RTH. For the C-A-T, data were collected from 40 participants. In total, pain was rated as 1 or less by 57.5% for the LUA, 70% for the LFA, 62.5% for the RUA, 75% for the RFA, 15% for the RTH, and 40% for the RCA. Pain was rated 3 or 4 by 42.5%. The SWAT-T group consisted of 37 participants for all anatomic locations. In total, pain was rated as 1 or less by 27% for LUA, 40.5% for the LFA, 27.0% for the RUA, 43.2 for the RFA, 18.9% for the RTH, and 16.2% for the RCA. Pain was rated 5 by 21.6% for RTH application, and 3 or 4 by 35%. The unexpected low pain values recorded when loss of signal was reached make the use of pain too sensitive as an indicator to confirm adequate occlusion of vasculature and, thus, successful TQ application.


Large-scale genomic sequence data resolve the deepest divergences in the legume phylogeny and support a near-simultaneous evolutionary origin of all six subfamilies.
Phylogenomics is increasingly used to infer deep-branching relationships while revealing the complexity of evolutionary processes such as incomplete lineage sorting, hybridization/introgression and polyploidization. We investigate the deep-branching relationships among subfamilies of the Leguminosae (or Fabaceae), the third largest angiosperm family. Despite their ecological and economic importance, a robust phylogenetic framework for legumes based on genome-scale sequence data is lacking. We generated alignments of 72 chloroplast genes and 7621 homologous nuclear-encoded proteins, for 157 and 76 taxa, respectively. We analysed these with maximum likelihood, Bayesian inference, and a multispecies coalescent summary method, and evaluated support for alternative topologies across gene trees. We resolve the deepest divergences in the legume phylogeny despite lack of phylogenetic signal across all chloroplast genes and the majority of nuclear genes. Strongly supported conflict in the remainder of nuclear genes is suggestive of incomplete lineage sorting. All six subfamilies originated nearly simultaneously, suggesting that the prevailing view of some subfamilies as 'basal' or 'early-diverging' with respect to others should be abandoned, which has important implications for understanding the evolution of legume diversity and traits. Our study highlights the limits of phylogenetic resolution in relation to rapid successive speciation.


Self-care research: How to grow the evidence base?
The number of studies in the area of self-care is growing and international researchers are increasingly developing self-care interventions to improve outcomes of individual patients and communities. However, growth of the evidence is still slow due to challenges with designing and testing self-care interventions. In this article we address major methodological challenges with regard to the definition of self-care, use of theory, and research design, intended to provide guidance to researchers in this field. During the inaugural conference of the International Center for Self-Care Research held in Rome, Italy in June 2019 we identified important issues in existing self-care research. Discussion and literature review lead to eight recommendation for future self-care research. In preparation, begin with a theoretically sound definition of self-care. In planning the intervention, build on and extend previous studies. Use theory to develop self-care interventions and consider translational models to guide development, evaluation and implementation of complex self-care interventions. Employ a study design that fits the current phase and objectives of the research and measure self-care and related factors carefully. In reporting, describe the sample and setting sufficiently so that others can draw conclusions about generalizability and applicability to their practice and patient population. In interpretation, describe how the intervention is assumed to work (causal assumptions) and its key components. Our review of existing self-care research clearly illustrates that the recommendations we provide are needed if we are to substantially grow the evidence base supporting self-care. Embracing a core set of principles will allow us to build on each other's work. Tweetable abstract: A core set of methodological principles is needed to substantially grow the evidence base supporting self-care.


Dietary patterns and breast cancer risk: a study in 2 cohorts.
Evidence for a role of dietary risk factors in the cause of breast cancer has been inconsistent. The evaluation of overall dietary patterns instead of foods in isolation may better reflect the nature of true dietary exposure in a population. We used 2 cohort studies to identify and confirm associations between dietary patterns and breast cancer risk. Dietary patterns were derived by using a principal components factor analysis in 1097 breast cancer cases and an age-stratified subcohort of 3320 women sampled from 39,532 female participants in the Canadian Study of Diet, Lifestyle and Health (CSDLH). We conducted a confirmatory factor analysis in 49,410 subjects in the National Breast Screening Study (NBSS) in whom 3659 cases of incident breast cancer developed. Cox regression models were used to estimate HRs for the association between derived dietary factors and risk of breast cancer in both cohorts. The following 3 dietary factors were identified from the CSDLH: healthy, ethnic, and meat and potatoes. In the CSDLH, the healthy dietary pattern was associated with reduced risk of breast cancer (HR for high compared with low quintiles: 0.73; 95% CI: 0.58, 0.91; P-trend = 0.001), and the meat and potatoes dietary pattern was associated with increased risk in postmenopausal women only (HR for high compared with low quintiles: 1.26; 95% CI: 0.92, 1.73; P-trend = 0.043). In the NBSS, the association between the meat and potatoes pattern and postmenopausal breast cancer risk was confirmed (HR: 1.31; 95% CI: 0.98, 1.76; P-trend = 0.043), but there was no association between the healthy pattern and risk of breast cancer. Adherence to a plant-based diet that limits red meat intake may be associated with reduced risk of breast cancer, particularly in postmenopausal women.


Computational and genetic reduction of a cell cycle to its simplest, primordial components.
What are the minimal requirements to sustain an asymmetric cell cycle? Here we use mathematical modelling and forward genetics to reduce an asymmetric cell cycle to its simplest, primordial components. In the Alphaproteobacterium Caulobacter crescentus, cell cycle progression is believed to be controlled by a cyclical genetic circuit comprising four essential master regulators. Unexpectedly, our in silico modelling predicted that one of these regulators, GcrA, is in fact dispensable. We confirmed this experimentally, finding that ΔgcrA cells are viable, but slow-growing and elongated, with the latter mostly due to an insufficiency of a key cell division protein. Furthermore, suppressor analysis showed that another cell cycle regulator, the methyltransferase CcrM, is similarly dispensable with simultaneous gcrA/ccrM disruption ameliorating the cytokinetic and growth defect of ΔgcrA cells. Within the Alphaproteobacteria, gcrA and ccrM are consistently present or absent together, rather than either gene being present alone, suggesting that gcrA/ccrM constitutes an independent, dispensable genetic module. Together our approaches unveil the essential elements of a primordial asymmetric cell cycle that should help illuminate more complex cell cycles.


The spineless-aristapedia and tango bHLH-PAS proteins interact to control antennal and tarsal development in Drosophila.
The Drosophila spineless (ss) gene encodes a basic-helix-loop-helix-PAS transcription factor that is required for proper specification of distal antennal identity, establishment of the tarsal regions of the legs, and normal bristle growth. ss is the closest known homolog of the mammalian aryl hydrocarbon receptor (Ahr), also known as the dioxin receptor. Dioxin and other aryl hydrocarbons bind to the PAS domain of Ahr, causing Ahr to translocate to the nucleus, where it dimerizes with another bHLH-PAS protein, the aryl hydrocarbon receptor nuclear translocator (Arnt). Ahr:Arnt heterodimers then activate transcription of target genes that encode enzymes involved in metabolizing aryl hydrocarbons. In this report, we present evidence that Ss functions as a heterodimer with the Drosophila ortholog of Arnt, Tango (Tgo). We show that the ss and tgo genes have a close functional relationship: loss-of-function alleles of tgo were recovered as dominant enhancers of a ss mutation, and tgo-mutant somatic clones show antennal, leg, and bristle defects almost identical to those caused by ss(-) mutations. The results of yeast two-hybrid assays indicate that the Ss and Tgo proteins interact directly, presumably by forming heterodimers. Coexpression of Ss and Tgo in Drosophila SL2 cells causes transcriptional activation of reporters containing mammalian Ahr:Arnt response elements, indicating that Ss:Tgo heterodimers are very similar to Ahr:Arnt heterodimers in DNA-binding specificity and transcriptional activation ability. During embryogenesis, Tgo is localized to the nucleus at sites of ss expression. This localization is lost in a ss null mutant, suggesting that Tgo requires heterodimerization for translocation to the nucleus. Ectopic expression of ss causes coincident ectopic nuclear localization of Tgo, independent of cell type or developmental stage. This suggests that the interaction of Ss and Tgo does not require additional signals, unlike the ligand-dependent interaction of Ahr and Arnt. Despite the very different biological roles of Ahr and Arnt in insects and mammals, the molecular mechanisms by which these proteins function appear to be largely conserved.


Dirofilaria immitis and Angiostrongylus vasorum: The current situation of two major canine heartworms in Portugal.
Cardiopulmonary nematodes are life-threatening pet parasites increasingly reported throughout Europe, with overlapping endemic areas. Dirofilaria immitis is a mosquito-borne whilst Angiostrongylus vasorum is a snail-borne pathogen. Both adult nematodes reside in the pulmonary arteries and right cardiac ventricle of domestic and wild canids, causing a wide spectrum of clinical presentations ranging from cough, dyspnoea and exercise intolerance to severe vascular and pulmonary disease with hearth failure that may lead to death. Information about the prevalence and distribution of cardiopulmonary parasites is essential for the control of animal diseases and, in the case of D. immitis, for the control of potentially associated illnesses in humans. However, in Portugal, heartworm studies are limited to few surveys and case reports, possibly underestimating the relevance of these nematodes. The present work reviews the data on cardiopulmonary dirofilariosis and angiostrongylosis in dogs in Portugal, providing a comprehensive update of the epidemiological situation during the past 20 years.


A multitrophic perspective on biodiversity-ecosystem functioning research.
Concern about the functional consequences of unprecedented loss in biodiversity has prompted biodiversity-ecosystem functioning (BEF) research to become one of the most active fields of ecological research in the past 25 years. Hundreds of experiments have manipulated biodiversity as an independent variable and found compelling support that the functioning of ecosystems increases with the diversity of their ecological communities. This research has also identified some of the mechanisms underlying BEF relationships, some context-dependencies of the strength of relationships, as well as implications for various ecosystem services that mankind depends upon. In this paper, we argue that a multitrophic perspective of biotic interactions in random and non-random biodiversity change scenarios is key to advance future BEF research and to address some of its most important remaining challenges. We discuss that the study and the quantification of multitrophic interactions in space and time facilitates scaling up from small-scale biodiversity manipulations and ecosystem function assessments to management-relevant spatial scales across ecosystem boundaries. We specifically consider multitrophic conceptual frameworks to understand and predict the context-dependency of BEF relationships. Moreover, we highlight the importance of the eco-evolutionary underpinnings of multitrophic BEF relationships. We outline that FAIR data (meeting the standards of findability, accessibility, interoperability, and reusability) and reproducible processing will be key to advance this field of research by making it more integrative. Finally, we show how these BEF insights may be implemented for ecosystem management, society, and policy. Given that human well-being critically depends on the multiple services provided by diverse, multitrophic communities, integrating the approaches of evolutionary ecology, community ecology, and ecosystem ecology in future BEF research will be key to refine conservation targets and develop sustainable management strategies.


Shining dead bone-cause for cautious interpretation of [18F]NaF PET scans.
Background and purpose - [18F]Fluoride ([18F]NaF) PET scan is frequently used for estimation of bone healing rate and extent in cases of bone allografting and fracture healing. Some authors claim that [18F]NaF uptake is a measure of osteoblastic activity, calcium metabolism, or bone turnover. Based on the known affinity of fluoride to hydroxyapatite, we challenged this view. Methods - 10 male rats received crushed, frozen allogeneic cortical bone fragments in a pouch in the abdominal wall on the right side, and hydroxyapatite granules on left side. [18F]NaF was injected intravenously after 7 days. 60 minutes later, the rats were killed and [18F]NaF uptake was visualized in a PET/CT scanner. Specimens were retrieved for micro CT and histology. Results - MicroCT and histology showed no signs of new bone at the implant sites. Still, the implants showed a very high [18F]NaF uptake, on a par with the most actively growing and remodeling sites around the knee joint. Interpretation - [18F]NaF binds with high affinity to dead bone and calcium phosphate materials. Hence, an [18F]NaF PET/CT scan does not allow for sound conclusions about new bone ingrowth into bone allograft, healing activity in long bone shaft fractures with necrotic fragments, or remodeling around calcium phosphate coated prostheses.


DOSim: an R package for similarity between diseases based on Disease Ontology.
The construction of the Disease Ontology (DO) has helped promote the investigation of diseases and disease risk factors. DO enables researchers to analyse disease similarity by adopting semantic similarity measures, and has expanded our understanding of the relationships between different diseases and to classify them. Simultaneously, similarities between genes can also be analysed by their associations with similar diseases. As a result, disease heterogeneity is better understood and insights into the molecular pathogenesis of similar diseases have been gained. However, bioinformatics tools that provide easy and straight forward ways to use DO to study disease and gene similarity simultaneously are required. We have developed an R-based software package (DOSim) to compute the similarity between diseases and to measure the similarity between human genes in terms of diseases. DOSim incorporates a DO-based enrichment analysis function that can be used to explore the disease feature of an independent gene set. A multilayered enrichment analysis (GO and KEGG annotation) annotation function that helps users explore the biological meaning implied in a newly detected gene module is also part of the DOSim package. We used the disease similarity application to demonstrate the relationship between 128 different DO cancer terms. The hierarchical clustering of these 128 different cancers showed modular characteristics. In another case study, we used the gene similarity application on 361 obesity-related genes. The results revealed the complex pathogenesis of obesity. In addition, the gene module detection and gene module multilayered annotation functions in DOSim when applied on these 361 obesity-related genes helped extend our understanding of the complex pathogenesis of obesity risk phenotypes and the heterogeneity of obesity-related diseases. DOSim can be used to detect disease-driven gene modules, and to annotate the modules for functions and pathways. The DOSim package can also be used to visualise DO structure. DOSim can reflect the modular characteristic of disease related genes and promote our understanding of the complex pathogenesis of diseases. DOSim is available on the Comprehensive R Archive Network (CRAN) or http://bioinfo.hrbmu.edu.cn/dosim.


Comparative wood anatomy of epacrids (Styphelioideae, Ericaceae s.L.).
The wood anatomy of 16 of the 37 genera within the epacrids (Styphelioideae, Ericaceae s.l.) is investigated by light and scanning electron microscopy. Several features in the secondary xylem occur consistently at the tribal level: arrangement of vessel-ray pits, distribution of axial parenchyma, ray width, and the presence and location of crystals. The primitive nature of Prionoteae and Archerieae is supported by the presence of scalariform perforation plates with many bars and scalariform to opposite vessel pitting. The wood structure of Oligarrheneae is similar to that of Styphelieae, but the very narrow vessel elements, exclusively uniseriate rays and the lack of prismatic crystals in Oligarrheneae distinguish these two tribes. The secondary xylem of Monotoca tamariscina indicates that it does not fit in Styphelieae; a position within Oligarrheneae is possible. Like most Cosmelieae, all Richeeae are characterized by exclusively scalariform perforation plates with many bars, a very high vessel density and paratracheal parenchyma, although they clearly differ in ray width (exclusively uniseriate rays in Cosmelieae vs. uniseriate and wide multiseriate rays in Richeeae). Several wood anatomical features confirm the inclusion of epacrids in Ericaceae s.l. Furthermore, there are significant ecological implications. The small vessel diameter and high vessel frequency in many epacrids are indicative of a high conductive safety to avoid embolism caused by freeze-thaw cycles, while the replacement of scalariform by simple vessel perforation plates and an increase in vessel diameter would suggest an increased conductive efficiency, which is especially found in mesic temperate or tropical Styphelieae.


Economic evaluation of drug abuse treatment programs: methodology and findings.
Research has shown that drug abuse treatment can help many individuals. Yet funding is often lacking for treatment because these programs compete for scarce resources with other important and effective social programs. This study shows how drug abuse treatment programs can be made more attractive to decision makers and funding agencies by first highlighting why economic evaluation is a critical component of drug abuse treatment research. Next, an evaluation methodology is presented that can be followed by program staff and researchers. The evaluation methodology includes aspects of cost-and-outcome analysis, cost-effectiveness analysis, and benefit-cost analysis. Methods and findings are then discussed from most of the major economic evaluation studies of drug and alcoholism treatment. Lastly, guidelines for conducting future economic evaluations are presented along with suggestions for how the results can be used for policy purposes and program planning.


Maternal supplementation with very-long-chain n-3 fatty acids during pregnancy and lactation augments children's IQ at 4 years of age.
Docosahexaenoic acid (DHA; 22:6 n-3) and arachidonic acid (AA; 20:4 n-6) are important for development of the central nervous system in mammals. There is a growth spurt in the human brain during the last trimester of pregnancy and the first postnatal months, with a large increase in the cerebral content of AA and DHA. The fetus and the newborn infant depend on maternal supply of DHA and AA. Our hypothesis was that maternal intake of DHA during pregnancy and lactation is marginal and that high intake of this fatty acid would benefit the child. We examined the effect of supplementing pregnant and lactating women with very-long-chain n-3 polyunsaturated fatty acids (PUFAs; cod liver oil) on mental development of the children, compared with maternal supplementation with long-chain n-6 PUFAs (corn oil). The study was randomized and double-blinded. Pregnant women were recruited in week 18 of pregnancy to take 10 mL of cod liver oil or corn oil until 3 months after delivery. The cod liver oil contained 1183 mg/10 mL DHA, 803 mg/10 mL eicosapentaenoic acid (20:5 n-3), and a total of 2494 mg/10 mL summation operator n-3 PUFAs. The corn oil contained 4747 mg/10 mL linoleic acid (18:2 n-6) and 92 mg/10 mL alpha-linolenic acid (18:3 n-3). The amount of fat-soluble vitamins was identical in the 2 oils (117 micro g/mL vitamin A, 1 micro g/mL vitamin D, and 1.4 mg/mL dl-alpha-tocopherol). A total of 590 pregnant women were recruited to the study, and 341 mothers took part in the study until giving birth. All infants of these women were scheduled for assessment of cognitive function at 6 and 9 months of age, and 262 complied with the request. As part of the protocol, 135 subjects from this population were invited for intelligence testing with the Kaufman Assessment Battery for Children (K-ABC) at 4 years of age. Of the 135 invited children, 90 came for assessment. Six children did not complete the examination. The K-ABC is a measure of intelligence and achievement designed for children aged 2.5 years through 12.5 years. This multisubtest battery comprises 4 scales: Sequential Processing, Simultaneous Processing, Achievement (not used in the present study), and Nonverbal Abilities. The Sequential Processing and Simultaneous Processing scales are hypothesized to reflect the child's style of problem solving and information processing. Scores from these 2 scales are combined to form a Mental Processing Composite, which serves as the measure of intelligence in the K-ABC. We received dietary information from 76 infants (41 in the cod liver oil group and 35 in the corn oil group), documenting that all of them were breastfed at 3 months of age. Children who were born to mothers who had taken cod liver oil (n = 48) during pregnancy and lactation scored higher on the Mental Processing Composite of the K-ABC at 4 years of age as compared with children whose mothers had taken corn oil (n = 36; 106.4 [7.4] vs 102.3 [11.3]). The Mental Processing Composite score correlated significantly with head circumference at birth (r = 0.23), but no relation was found with birth weight or gestational length. The children's mental processing scores at 4 years of age correlated significantly with maternal intake of DHA and eicosapentaenoic acid during pregnancy. In a multiple regression model, maternal intake of DHA during pregnancy was the only variable of statistical significance for the children's mental processing scores at 4 years of age. Maternal intake of very-long-chain n-3 PUFAs during pregnancy and lactation may be favorable for later mental development of children.


Evaluating the Patient Family Advisor Experience in Patient-Oriented Research.
As part of the Saskatchewan Centre for Patient-Oriented Research (SCPOR)'s commitment to improving the experience of patient and family advisors (PFAs) who engage with local patient-oriented research teams, one of the supports offered is an evaluation that assesses the experiences and effectiveness of PFAs as research team members. In a recent evaluation project, SCPOR used an academically validated questionnaire and a survey co-designed by local PFAs. The results showed that PFAs wanted more frequent updates throughout the research project and greater role clarity. They also reported that the best part of their engagement was feeling like a valued team member.


Europe's terrestrial biosphere absorbs 7 to 12% of European anthropogenic CO2 emissions.
Most inverse atmospheric models report considerable uptake of carbon dioxide in Europe's terrestrial biosphere. In contrast, carbon stocks in terrestrial ecosystems increase at a much smaller rate, with carbon gains in forests and grassland soils almost being offset by carbon losses from cropland and peat soils. Accounting for non-carbon dioxide carbon transfers that are not detected by the atmospheric models and for carbon dioxide fluxes bypassing the ecosystem carbon stocks considerably reduces the gap between the small carbon-stock changes and the larger carbon dioxide uptake estimated by atmospheric models. The remaining difference could be because of missing components in the stock-change approach, as well as the large uncertainty in both methods. With the use of the corrected atmosphere- and land-based estimates as a dual constraint, we estimate a net carbon sink between 135 and 205 teragrams per year in Europe's terrestrial biosphere, the equivalent of 7 to 12% of the 1995 anthropogenic carbon emissions.


Maternal Transfer of Persistent Organic Pollutants to Sea Turtle Eggs: A Meta-Analysis Addressing Knowledge and Data Gaps Toward an Improved Synthesis of Research Outputs.
Maternal transfer of persistent organic pollutants (POPs) confronts developing embryos with a pollution legacy and poses conservation concerns due to its potential impacts unto subsequent generations. We conducted a systematic review focusing on: 1) processes of POP maternal transfer, 2) challenges and opportunities to synthesizing current knowledge on POP concentrations in eggs, and 3) a meta-analysis of patterns in current egg pollution data. Results suggest selective maternal transfer of individual compounds. These relate to biological factors such as the foraging and remigration behavior, and to the selective mobilization of POPs during vitellogenesis, such as increased diffusion limitation for lipophilic POPs and slower release and higher reabsorption of apolar POPs. A key gap relates to knowledge of further selective toxicokinetics during embryonic development, as research to date has mainly focused on initial uptake into eggs. Challenges in the synthesis of current data on egg contamination profiles relate to methodological differences, varying analytical approaches, restricted data access, and reporting transparency among studies. To increase opportunities in the use of current data, we propose best practice guidelines, and synthesize a database on POP concentrations within sea turtle eggs. The meta-analysis revealed a geographical and taxonomic bias on the West Atlantic Ocean, including the Gulf of Mexico and Caribbean Sea, with most studies conducted on green turtles. Concentrations of POPs show temporal patterns related to trends in usage, production, release, and persistence in the environment, often with regional patterns. The trophic level has the potential to influence POP patterns with higher concentrations in loggerheads compared to other species, but this is confounded by temporal and geographic trends. We argue for more mechanistically process-focused and methodologically comparable research. Environ Toxicol Chem 2019;39:9-29. © 2019 SETAC.


Diagnosis of acute cerebral infarction: comparison of CT and MR imaging.
The appearance of acute cerebral infarction was evaluated on MR images and CT scans obtained in 31 patients within 24 hr of the ictus; follow-up examinations were performed 7-10 days later in 20 of these patients and were correlated with the initial studies. Acute infarcts were visible more frequently on MR images than on CT scans (82% vs 58%). Proton density- and T2-weighted scans usually demonstrated regions of hyperintensity corresponding to acute infarcts, but proton density-weighted scans often showed better definition of the lesion in terms of regional anatomy. Follow-up MR images and CT scans identified approximately 88% of subacute strokes, 54% of which were better defined and/or larger than on the initial examination. In 20% of lesions, "hemorrhagic" characteristics were seen on at least one examination. CT and MR imaging were comparable in delineating acute hemorrhage, but MR detected more cases with evidence of hemorrhage on follow-up examinations. MR appears to be more sensitive than CT in the imaging of acute stroke.


Comparative genomics approach to detecting split-coding regions in a low-coverage genome: lessons from the chimaera Callorhinchus milii (Holocephali, Chondrichthyes).
Recent development of deep sequencing technologies has facilitated de novo genome sequencing projects, now conducted even by individual laboratories. However, this will yield more and more genome sequences that are not well assembled, and will hinder thorough annotation when no closely related reference genome is available. One of the challenging issues is the identification of protein-coding sequences split into multiple unassembled genomic segments, which can confound orthology assignment and various laboratory experiments requiring the identification of individual genes. In this study, using the genome of a cartilaginous fish, Callorhinchus milii, as test case, we performed gene prediction using a model specifically trained for this genome. We implemented an algorithm, designated ESPRIT, to identify possible linkages between multiple protein-coding portions derived from a single genomic locus split into multiple unassembled genomic segments. We developed a validation framework based on an artificially fragmented human genome, improvements between early and recent mouse genome assemblies, comparison with experimentally validated sequences from GenBank, and phylogenetic analyses. Our strategy provided insights into practical solutions for efficient annotation of only partially sequenced (low-coverage) genomes. To our knowledge, our study is the first formulation of a method to link unassembled genomic segments based on proteomes of relatively distantly related species as references.


Perinatal exposure to oestradiol and bisphenol A alters the prostate epigenome and increases susceptibility to carcinogenesis.
An important and controversial health concern is whether low-dose exposures to hormonally active environmental oestrogens such as bisphenol A can promote human diseases including prostate cancer. Our studies in rats have shown that pharmacological doses of oestradiol administered during the critical window of prostate development result in marked prostate pathology in adulthood that progress to neoplastic lesions with ageing. Our recent studies have also demonstrated that transient developmental exposure of rats to low, environmentally relevant doses of bisphenol A or oestradiol increases prostate gland susceptibility to adult-onset precancerous lesions and hormonal carcinogenesis. These findings indicate that a wide range of oestrogenic exposures during development can predispose to prostatic neoplasia that suggests a potential developmental basis for this adult disease. To identify a molecular basis for oestrogen imprinting, we screened for DNA methylation changes over time in the exposed prostate glands. We found permanent alterations in DNA methylation patterns of multiple cell signalling genes suggesting an epigenetic mechanism of action. For phosphodiesterase type 4 variant 4 (PDE4D4), an enzyme responsible for intracellular cyclic adenosine monophosphate breakdown, a specific methylation cluster was identified in the 5'-flanking CpG island that was gradually hypermethylated with ageing in normal prostates resulting in loss of gene expression. However, in prostates exposed to neonatal oestradiol or bisphenol A, this region became hypomethylated with ageing resulting in persistent and elevated PDE4D4 expression. In total, these findings indicate that low-dose exposures to ubiquitous environmental oestrogens impact the prostate epigenome during development and in so doing, promote prostate disease with ageing.


Waist circumference and central fatness of Egyptian primary-school children.
This cross-sectional study of 1283 healthy children (681 boys, 602 girls) aged 6-11 years tested the degree of correlation between waist circumference measurements and adiposity. The children were classified as normal, overweight or obese according to their body mass index (BMI). For both sexes a highly positive correlation was found between waist circumference and BMI, percentage of body fat, subscapular and suprailiac skinfold thicknesses, and the sum of skinfold measures. Central overweight and obesity were indicators for central fatness for both overweight boys and girls and for obese girls except in age group 6.5 +/- 1 years. Waist circumference was a good indicator of central fatness (overweight and obesity) in children aged 8.5 +/- years and 10.5 +/- 1 years.


Distinct behavioral responses evoked by selective optogenetic stimulation of the major TRPV1+ and MrgD+ subsets of C-fibers.
Primary C-fiber nociceptors are broadly divided into peptidergic and nonpeptidergic afferents. TRPV1 is a thermosensitive cation channel mainly localized in peptidergic nociceptors, whereas MrgD is a sensory G protein-coupled receptor expressed in most nonpeptidergic nociceptive afferents. TRPV1 and MrgD fibers have been reported to be primarily involved in thermal and mechanical nociception, respectively. Yet, their functional assessment in somatosensory transmission relied on ablation strategies that do not account for compensatory mechanisms. To achieve selective activation of these 2 major subsets of C-fibers in vivo in adult mice, we used optogenetics to specifically deliver the excitatory opsin channelrhodopsin-2 (ChR2) to TRPV1 or MrgD primary sensory neurons, as confirmed by histology and electrophysiology. This approach allowed, for the first time, the characterization of behavioral responses triggered by direct noninvasive activation of peptidergic TRPV1 or nonpeptidergic MrgD fibers in freely moving mice. Transdermal blue light stimulation of the hind paws of transgenic mice expressing ChR2 in TRPV1 neurons generated nocifensive behaviors consisting mainly of paw withdrawal and paw licking, whereas paw lifting occurrence was limited. Conversely, optical activation of cutaneous MrgD afferents produced mostly withdrawal and lifting. Of interest, in a conditioned place avoidance assay, blue light induced aversion in TRPV1-ChR2 mice, but not in MrgD-ChR2 mice. In short, we present novel somatosensory transgenic models in which control of specific subsets of peripheral unmyelinated nociceptors with distinct functions can be achieved with high spatiotemporal precision. These new tools will be instrumental in further clarifying the contribution of genetically identified C-fiber subtypes to chronic pain.


Direct medical costs attributable to venous thromboembolism among persons hospitalized for major operation: a population-based longitudinal study.
We estimated medical costs attributable to venous thromboembolism (VTE) among patients currently or recently hospitalized for major operation. Using Rochester Epidemiology Project resources, we identified all Olmsted County, MN, residents with objectively diagnosed incident VTE within 92 days of hospitalization for major operation during an 18-year period, 1988-2005 (n = 355). One Olmsted County resident hospitalized for major operation without VTE was matched to each case on event date (±1 year), type of operation, duration of previous medical history, and active cancer status. Subjects were followed in Rochester Epidemiology Project provider-linked billing data for standardized, inflation-adjusted direct medical costs from 1 year before index (case's VTE event date and control's matched date) to earliest of death, emigration, or December 31, 2011. We used generalized linear modeling to predict costs for cases and controls and used bootstrapping methods to assess uncertainty and significance of mean adjusted cost differences. Adjusted mean predicted costs were more than 1.5-fold greater for cases ($55,956) than for controls ($32,718) (P ≤ .001) from index to up to 5 years postindex. Cost differences between cases and controls were greatest within the first 3 months after index (mean difference = $12,381). Costs were greater for cases than controls (mean difference = $10,797) from 3 months to up to 5 years postindex and together accounted for about half of the overall cost difference. VTE during or after recent hospitalization for major operation contributes a substantial economic burden; VTE-attributable costs are greatest in the initial 3 months but persist for up to 5 years.


Compact and highly-efficient polarization independent vertical resonant couplers for active-passive monolithic integration.
Compact low-loss polarization independent vertical coupling between a 1.55 microm InGaAsP bulk active waveguide and a passive waveguide based on bimodal interference is presented. Simulation results show low coupling loss (<0.1 dB) over coupler lengths more than 5 times shorter than using the adiabatic design. The concept avoids submicron photolithographic features and shows acceptable fabrication tolerances.


Thrombospondin-1 supports blood pressure by limiting eNOS activation and endothelial-dependent vasorelaxation.
Thrombospondin-1 (TSP1), via its necessary receptor CD47, inhibits nitric oxide (NO)-stimulated soluble guanylate cyclase activation in vascular smooth muscle cells, and TSP1-null mice have increased shear-dependent blood flow compared with wild-type mice. Yet, the endothelial basement membrane should in theory function as a barrier to diffusion of soluble TSP1 into the arterial smooth muscle cell layer. These findings suggested that endothelial-dependent differences in blood flow in TSP1-null mice may be the result of direct modulation of endothelial NO synthase (eNOS) activation by circulating TSP1. Here we tested the hypothesis that TSP1 inhibits eNOS activation and endothelial-dependent arterial relaxation. Acetylcholine (ACh)-stimulated activation of eNOS and agonist-driven calcium transients in endothelial cells were inhibited by TSP1. TSP1 also inhibited eNOS phosphorylation at serine(1177). TSP1 treatment of the endothelium of wild-type and TSP1-null but not CD47-null arteries inhibited ACh-stimulated relaxation. TSP1-null vessels demonstrated greater endothelial-dependent vasorelaxation compared with the wild type. Conversely, TSP1-null arteries demonstrated less vasoconstriction to phenylephrine compared with the wild type, which was corrected upon inhibition of eNOS. In TSP1-null mice, intravenous TSP1 blocked ACh-stimulated decreases in blood pressure, and both intravenous TSP1 and a CD47 agonist antibody acutely elevated blood pressure in mice. TSP1, via CD47, inhibits eNOS activation and endothelial-dependent arterial relaxation and limits ACh-driven decreases in blood pressure. Conversely, intravenous TSP1 and a CD47 antibody increase blood pressure. These findings suggest that circulating TSP1, by limiting endogenous NO production, functions as a pressor agent supporting blood pressure.


Similar changes in cognitions following cognitive-behavioral therapy or escitalopram for major depressive disorder: Implications for mechanisms of change.
Psychosocial treatments and medications both have been shown to be effective in treating major depressive disorder. We hypothesized that cognitive-behavioral therapy (CBT) would outperform medication on measures of cognitive change. We randomized depressed individuals to 12 weeks of CBT (n = 15) or escitalopram (n = 11). In an intent-to-treat analysis (n = 26), we conducted a repeated measures analysis of variance to examine changes in depressive symptoms (ie, 17-item Hamilton Depression Rating Scale, Beck Depression Inventory), anhedonia (ie, Snaith-Hamilton Pleasure Scale), cognitive measures (ie, Dysfunctional Attitudes Scale, Automatic Thoughts Questionnaire, Perceived Stress Scale), and quality of life (ie, Quality of Life Enjoyment and Satisfaction Questionnaire) at 4 time points: baseline, week 4, week 8, and week 12. Treatment for both groups started at baseline, and patients received either 12 weeks of individual CBT or 12 weeks of escitalopram with flexible dosing (10 to 20 mg). Collapsing the escitalopram and CBT groups, there were statistically significant pre-post changes on all outcome measures. However, there were no statistically significant differences between treatment groups on any of the outcome measures, including cognitive measures across time points. Our results suggest that both CBT and escitalopram have similar effects across a variety of domains and that, in contrast to our a priori hypothesis, CBT and escitalopram were associated with comparable changes on cognitive measures.


Co-expression networks uncover regulation of splicing and transcription markers of disease.
Gene co-expression networks based on gene expression data are usually used to capture biologically significant patterns, enabling the discovery of biomarkers and interpretation of regulatory relationships. However, the coordination of numerous splicing changes within and across genes can exert a substantial impact on the function of these genes. This is particularly impactful in studies of the properties of the nervous system, which can be masked in the networks that only assess the correlation between gene expression levels. A bioinformatics approach was developed to uncover the role of alternative splicing and associated transcriptional networks using RNA-seq profiles. Data from 40 samples, including control and two treatments associated with sensitivity to stimuli across two central nervous system regions that can present differential splicing, were explored. The gene expression and relative isoform levels were integrated into a transcriptome-wide matrix, and then Graphical Lasso was applied to capture the interactions between genes and isoforms. Next, functional enrichment analysis enabled the discovery of pathways dysregulated at the isoform or gene levels and the interpretation of these interactions within a central nervous region. In addition, a Bayesian biclustering strategy was used to reconstruct treatment-specific networks from gene expression profile, allowing the identification of hub molecules and visualization of highly connected modules of isoforms and genes in specific conditions. Our bioinformatics approach can offer comparable insights into the discovery of biomarkers and therapeutic targets for a wide range of diseases and conditions.


Complicated pneumonia in children.
Complicated community-acquired pneumonia in a previously well child is a severe illness characterised by combinations of local complications (eg, parapneumonic effusion, empyema, necrotising pneumonia, and lung abscess) and systemic complications (eg, bacteraemia, metastatic infection, multiorgan failure, acute respiratory distress syndrome, disseminated intravascular coagulation, and, rarely, death). Complicated community-acquired pneumonia should be suspected in any child with pneumonia not responding to appropriate antibiotic treatment within 48-72 h. Common causative organisms are Streptococcus pneumoniae and Staphylococcus aureus. Patients have initial imaging with chest radiography and ultrasound, which can also be used to assess the lung parenchyma, to identify pleural fluid; CT scanning is not usually indicated. Complicated pneumonia is treated with a prolonged course of intravenous antibiotics, and then oral antibiotics. The initial choice of antibiotic is guided by local microbiological knowledge and by subsequent positive cultures and molecular testing, including on pleural fluid if a drainage procedure is done. Information from pleural space imaging and drainage should guide the decision on whether to administer intrapleural fibrinolytics. Most patients are treated by drainage and more extensive surgery is rarely needed; in any event, in low-income and middle-income countries, resources for extensive surgeries are scarce. The clinical course of complicated community-acquired pneumonia can be prolonged, especially when patients have necrotising pneumonia, but complete recovery is the usual outcome.


Transcriptional silencing of N-Myc downstream-regulated gene 1 (NDRG1) in metastatic colon cancer cell line SW620.
N-Myc downstream-regulated gene 1 (NDRG1) plays vital roles in tumor metastasis suppression and is frequently silenced in metastatic colon cancers. NDRG1 is silenced in a highly metastatic colon cancer cell line SW620. The objective of this study was to investigate the potential mechanisms involved in silencing of the NDRG1 gene. SW480 and SW620 are two colon cancer cell lines established from the same patient with different metastatic potentials, making them an ideal model for investigation of metastatic mechanisms. Knockdown of NDRG1 in SW480 to a level that is similar to that in SW620 also modulated cell cycle and proliferation in SW480 towards the status of the highly metastatic SW620. Epigenetic mechanisms of the transcriptional control of NDRG1 were investigated. The silencing of NDRG1 in SW620 was not due to promoter hyper-methylation as bisulfite sequencing of the NDRG1 promoter showed minimal DNA methylation in both cell lines. On the other hand, chromatin immunoprecipitation showed a significantly higher level of RNA polymerase II (Pol II) association with the NDRG1 promoter in SW480 compared to SW620, in agreement with its gene expression level. The low Pol II binding at the NDRG1 promoter in SW620 was associated with gene-wide decrease in histone H4 acetylation and increase in histone H3 serine 10 phosphorylation. Meanwhile, the NDRG1 coding region showed much higher histone H3 lysine 4 methylation in SW480. In conclusion we observed unique histone modifications in two colon cancer cell lines with different metastatic potentials, indicating possible mechanisms for the down-regulation of NDRG1 in metastatic SW620.


Dysphagia in spinocerebellar ataxias type 1, 2, 3 and 6.
Dysphagia is a common symptom and may be a cause of death in patients with spinocerebellar ataxias (SCAs). However, little is known about at which disease stage dysphagia becomes clinically relevant. Therefore, our study aims to investigate the prevalence of dysphagia in different disease stages of SCA 1, 2, 3 and 6. We studied 237 genetically confirmed patients with SCA 1, 2, 3, 6 from the Clinical Research Consortium for SCAs and investigated the prevalence of self-reported dysphagia and the association between dysphagia and other clinical characteristics. We further stratified ataxia severity and studied the prevalence of dysphagia at each disease stage. Dysphagia was present in 59.9% of SCA patients. Patients with dysphagia had a longer disease duration and more severe ataxia than patients without dysphagia (patients with dysphagia vs. without dysphagia, disease duration (years): 14.51 ± 8.91 vs. 11.22 ± 7.82, p = .001, scale for the assessment and rating of ataxia [SARA]: 17.90 ± 7.74 vs. 13.04 ± 7.51, p = .000). Dysphagia was most common in SCA1, followed by SCA3, SCA 6, and SCA 2. Dysphagia in SCA1 and 3 was associated robustly with ataxia severity, whereas this association was less obvious in SCA2 and 6, demonstrating genotype-specific clinical variation. Dysphagia is a common clinical symptom in SCAs, especially in the severe disease stage. Understanding dysphagia in SCA patients can improve the care of these patients and advance knowledge on the roles of the cerebellum and brainstem control in swallowing.


Evaluating satisfaction of patients with hereditary angioedema with their past and present treatments: Implications for future therapies.
Ever-expanding armamentarium of treatments for hereditary angioedema (HAE) are associated with various adverse effects, issues with vascular access, or lack of self-administration. To understand patients' impressions and confidence in their past and present treatments, and identifying adverse events while also directly asking patients to reveal their hope for the future of HAE management and treatments. After institutional review board approval, all subjects with laboratory-confirmed HAE were mailed a survey that they completed and returned to the researchers, and data were collected and entered into a secure online web application for surveys. Medication confidence data were summarized and expressed as means, medians, standard deviations, and quartiles by using a 5-point Likert scale. Analyses were performed by using statistical software. Of 150 surveys, 38 (25.3%) were completed. Among 36 subjects, 27 (75.0%) were female subjects, and the mean age was 50.1 years. Cinryze and Berinert (both C1-esterase inhibitors) had the highest median scores (5.0) for patient confidence, followed by ecallantide (4.5), icatibant (4.0), and androgens (2.0). For Cinryze, 64.3% selected it as the most effective and 57.1% tolerated it best. For Berinert, 50% of the subjects found it to be most effective and 59.1% tolerated it best. Some subjects listed androgens as most effective (33.3%) or best tolerated (16.7%), and many reported that this class caused the most adverse effects (44.4%). Among those who answered, 50% preferred a noninvasive method of administration, such as oral (24%), subcutaneous (18%), or not intravenous (8%) routes. Determining patient predilections and the reasoning behind them can be valuable for determining specific therapies to achieve each individual's personal goals.


Targeting of two signal transduction pathways to different regions of the bacterial cell.
Components of bacterial chemosensory pathways which sense via transmembrane receptors have been shown to localize to the cell poles. Many species, however, have operons encoding multiple putative chemosensory pathways, some including putative cytoplasmic receptors. In-genome fusions to single or multiple genes encoding components of two chemosensory pathways in Rhodobacter sphaeroides, cheOp2 and cheOp3, revealed that while sensory transducing proteins associated with transmembrane receptors and encoded on cheOp2 were targeted to the cell poles, the proteins associated with putative cytoplasmic receptors and encoded on cheOp3 were all targeted to a cytoplasmic cluster. No proteins were localized to both sites. These data show that bacteria target components of related pathways to different sites in the cell, presumably preventing direct cross-talk between the different pathways, but allowing a balanced response between extracellular and cytoplasmic signals. It also indicates that there is intracellular organization in bacterial cells, with specific proteins targeted and localized to cytoplasmic regions.


Carbon storage, timber production, and biodiversity: comparing ecosystem services with multi-criteria decision analysis.
Increasingly, land managers seek ways to manage forests for multiple ecosystem services and functions, yet considerable challenges exist in comparing disparate services and balancing trade-offs among them. We applied multi-criteria decision analysis (MCDA) and forest simulation models to simultaneously consider three objectives: (1) storing carbon, (2) producing timber and wood products, and (3) sustaining biodiversity. We used the Forest Vegetation Simulator (FVS) applied to 42 northern hardwood sites to simulate forest development over 100 years and to estimate carbon storage and timber production. We estimated biodiversity implications with occupancy models for 51 terrestrial bird species that were linked to FVS outputs. We simulated four alternative management prescriptions that spanned a range of harvesting intensities and forest structure retention. We found that silvicultural approaches emphasizing less frequent harvesting and greater structural retention could be expected to achieve the greatest net carbon storage but also produce less timber. More intensive prescriptions would enhance biodiversity because positive responses of early successional species exceeded negative responses of late successional species within the heavily forested study area. The combinations of weights assigned to objectives had a large influence on which prescriptions were scored as optimal. Overall, we found that a diversity of silvicultural approaches is likely to be preferable to any single approach, emphasizing the need for landscape-scale management to provide a full range of ecosystem goods and services. Our analytical framework that combined MCDA with forest simulation modeling was a powerful tool in understanding trade-offs among management objectives and how they can be simultaneously accommodated.


Modified African Ngoma Healing Ceremony for Stress Reduction: A Pilot Study.
Indigenous people's ceremonies using rhythm and dance have been used for countless generations throughout the world for healing, conflict resolution, social bonding, and spiritual experience. A previous study reported that a ceremony based on the Central African ngoma tradition was favorably received by a group of Americans. The present trial compared the effects of the modified ngoma ceremony (Ngoma) with those of mindfulness-based stress reduction (MBSR) in a randomized pilot study. Twenty-one women were randomized to either Ngoma or MBSR. Both groups had sessions on a weekly basis for 8 weeks and completed questionnaires at baseline, week 8, and 1 month after the intervention. Participants completed questionnaires, which included self-report of depressive and anxiety symptoms, health status (e.g., quality of life and functioning), social bonding, and perception of the credibility of the two interventions. Both groups showed improvements in depression, anxiety, emotional well being, and social functioning as measured by respective scales. Social bonding also increased in both groups during the study and may be a mechanism for both interventions. Participants found both interventions credible. In this pilot study, Ngoma showed significant and durable beneficial effects comparable to MBSR. The effects of Ngoma and other indigenous rhythm-dance ceremonies on distress and health status in western culture should be investigated in larger clinical studies.


Nymphaea nouchali Burm. f. hydroalcoholic seed extract increases glucose consumption in 3T3-L1 adipocytes through activation of peroxisome proliferator-activated receptor gamma and insulin sensitization.
Nymphaea nouchali Burm. f. (Family - Nymphaeaceae) is a well-known medicinal plant used in the Indian ayurvedic system of medicine for treating diabetes. The seeds especially have been prescribed for diabetes. The hydroalcoholic extract of N. nouchali seeds has been demonstrated to possess anti-hyperglycemic effects in diabetic rats, but the functional mechanism remains unknown. The nuclear receptor, peroxisome proliferator-activated receptor gamma (PPARγ) is noted to play an important role in glucose and lipid homeostasis. This study was hence focused in evaluating the effect of the extract on PPARγ activation, adipocyte differentiation, and glucose consumption in 3T3-L1 cells. Cell viability was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT), followed by adipogenesis assay using Oil Red O technique. Glucose consumption of preadipocytes and adipocytes in the presence of the extract was also determined. Real-time polymerase chain reaction was performed to identify the expression of genes involved in glucose consumption in the adipocytes. MTT assay confirmed the extract to be nontoxic, and Oil Red O staining confirmed enhanced adipocyte differentiation of 3T3-L1 cells in a dose-dependent manner. The extract also increased the expression of PPARγ target gene, which in turn enhanced the expression of GLUT-4. The data, therefore, suggests that N. nouchali seed extract promotes adipocyte differentiation and glucose consumption by inducing PPARγ activation, which in turn increases mRNA GLUT-4 expression and subsequently enhances insulin-responsiveness in insulin target tissues.


Pathways and intermediates of amyloid fibril formation.
The lack of understanding of amyloid fibril formation at the molecular level is a major obstacle in devising strategies to interfere with the pathologies linked to peptide or protein aggregation. In particular, little is known on the role of intermediates and fibril elongation pathways as well as their dependence on the intrinsic tendency of a polypeptide chain to self-assembly by beta-sheet formation (beta-aggregation propensity). Here, coarse-grained simulations of an amphipathic polypeptide show that a decrease in the beta-aggregation propensity results in a larger heterogeneity of elongation pathways, despite the essentially identical structure of the final fibril. Protofibrillar intermediates that are thinner, shorter and less structured than the final fibril accumulate along some of these pathways. Moreover, the templated formation of an additional protofilament on the lateral surface of a protofibril is sometimes observed as a collective transition. Conversely, for a polypeptide model with a high beta-aggregation propensity, elongation proceeds without protofibrillar intermediates. Therefore, changes in intrinsic beta-aggregation propensity modulate the relative accessibility of parallel routes of aggregation.


Mutational signatures in tumours induced by high and low energy radiation in Trp53 deficient mice.
Ionising radiation (IR) is a recognised carcinogen responsible for cancer development in patients previously treated using radiotherapy, and in individuals exposed as a result of accidents at nuclear energy plants. However, the mutational signatures induced by distinct types and doses of radiation are unknown. Here, we analyse the genetic architecture of mammary tumours, lymphomas and sarcomas induced by high (56Fe-ions) or low (gamma) energy radiation in mice carrying Trp53 loss of function alleles. In mammary tumours, high-energy radiation is associated with induction of focal structural variants, leading to genomic instability and Met amplification. Gamma-radiation is linked to large-scale structural variants and a point mutation signature associated with oxidative stress. The genomic architecture of carcinomas, sarcomas and lymphomas arising in the same animals are significantly different. Our study illustrates the complex interactions between radiation quality, germline Trp53 deficiency and tissue/cell of origin in shaping the genomic landscape of IR-induced tumours.


Transformational Teaching: Theoretical Underpinnings, Basic Principles, and Core Methods.
Approaches to classroom instruction have evolved considerably over the past 50 years. This progress has been spurred by the development of several learning principles and methods of instruction, including active learning, student-centered learning, collaborative learning, experiential learning, and problem-based learning. In the present paper, we suggest that these seemingly different strategies share important underlying characteristics and can be viewed as complimentary components of a broader approach to classroom instruction called transformational teaching. Transformational teaching involves creating dynamic relationships between teachers, students, and a shared body of knowledge to promote student learning and personal growth. From this perspective, instructors are intellectual coaches who create teams of students who collaborate with each other and with their teacher to master bodies of information. Teachers assume the traditional role of facilitating students' acquisition of key course concepts, but do so while enhancing students' personal development and attitudes toward learning. They accomplish these goals by establishing a shared vision for a course, providing modeling and mastery experiences, challenging and encouraging students, personalizing attention and feedback, creating experiential lessons that transcend the boundaries of the classroom, and promoting ample opportunities for preflection and reflection. We propose that these methods are synergistically related and, when used together, maximize students' potential for intellectual and personal growth.


Wine drinking is associated with increased heart rate variability in women with coronary heart disease.
To test the hypothesis that alcohol consumption is positively related to heart rate variability (HRV) in women with coronary heart disease (CHD) and therefore that cardiac autonomic activity is potentially implicated in the mediation of the favourable effects of moderate drinking. Cross sectional study of female patients who survived hospitalisation for acute myocardial infarction or underwent a revascularisation procedure, percutaneous transluminal coronary angioplasty, or coronary artery bypass grafting. Ambulatory 24 hour ECG was recorded during normal activities. The mean of the standard deviations of all normal to normal intervals for all five minute segments of the entire recording (SDNNI) and the following frequency domain parameters were assessed: total power, high frequency power, low frequency power, and very low frequency power. A standardised questionnaire evaluated self reported consumption of individual alcoholic beverage types: beer, wine, and spirits. Other clinical characteristics, such as age, body mass index, smoking habits, history of diabetes mellitus, menopausal status, educational status, and treatment, were also assessed. Wine intake was associated with increased HRV in both time and frequency domains independently of other clinical covariates (for example, ln SDNNI was 3.89 among wine drinkers v 3.59 among wine non-drinkers in the multivariate model; p = 0.014). In contrast, consumption of beer and spirits and the total amount of alcohol consumed did not relate significantly to any of the HRV parameters. Intake of wine, but not of spirits or beer, is positively and independently associated with HRV in women with CHD. These results may contribute to the understanding of the complex relation between alcohol consumption and CHD.


Glucose reduction prevents replicative senescence and increases mitochondrial respiration in human mesenchymal stem cells.
The unique self-renewal and multilineage differentiation potential of mesenchymal stem cells (MSCs) make them a promising candidate for cell therapy applications. However, during in vitro expansion of MSCs, replicative senescence may occur and will compromise the quality of the expanded cells. Because calorie restriction has been shown to effectively extend the life span of various organisms, the purpose of this study is to investigate the effect of glucose reduction on MSCs and the coordinated changes in energy utilization. It was found that the frequency of cycling cells was significantly increased, while senescence markers such as β-galactosidase activities and p16(INK4a) expression level were markedly reduced in MSCs under low-glucose culture condition. Quantitative real-time PCR analysis demonstrated the preserved trilineage differentiation potentials of MSCs after low-glucose treatment. Interestingly, the ability of osteogenic lineage commitment was improved, while the ability of adipogenic lineage commitment was delayed in MSCs after glucose reduction. In addition, we observed decreased lactate production, increased electron transport chain complexes expression, and increased oxygen consumption in MSCs after glucose reduction treatment. Increased antioxidant defensive responses were evidenced by increased antioxidant enzymes expression and decreased superoxide production after glucose reduction. Taken together, our findings suggest that MSCs utilize energy more efficiently under restricted glucose treatment and exhibit greater self-renewal and antisenescence abilities, while their differentiation potentials remain unaffected.


25-Hydroxyvitamin D3 Deficiency Independently Predicts Cognitive Impairment in Patients with Systemic Lupus Erythematosus.
Cognitive dysfunction has been reported in 20-80% of SLE patients. Converging evidence has indicated the importance of vitamin D as a neuroimmunomodulator for cognitive function. In this study, we evaluated the relationship between vitamin D and cognitive dysfunction. Consecutive age- and gender-matched SLE patients and healthy controls (HCs) were administered Automated Neuropsychological Assessment Metrics in this cross-sectional study. The primary outcome was the total throughput score (TTS). Anxiety and depression were measured using the Hospital Anxiety and Depression Scale (HADS). Levels of 25-hydroxyvitamin D [25(OH)D3 and total 25(OH)D] were measured using Liquid Chromatography-Tandem Mass Spectrometry. In total, 61 SLE patients and 61 HCs were studied. SLE patients scored significantly lower than HCs in the TTS (p = 0.004). There were no statistically significant differences in 25(OH)D3 levels, total 25(OH)D levels and total 25(OH)D deficiency between SLE patients and HCs. However, more SLE patients had 25(OH)D3 deficiency compared to HCs [12 (19.7%) versus 2 (3.3%), p = 0.003]. Deficiency of 25(OH)D3 (β = -63.667, SE = 27.456, p = 0.025), but not other vitamin D variables, independently predicted worse TTS after adjusting for age, education, gender, ethnicity, HADS-Total, duration of SLE, SELENA-SLEDAI, SLICC/ACR Damage Index and cumulative steroid dose in SLE patients. Age (β = -4.261, SE = 0.866, p < 0.001) was the only predictor of TTS after adjusting for education, gender, ethnicity, HADS-Total, vitamin D levels or status in HCs. Deficiency of 25(OH)D3, a potentially modifiable risk factor, independently predicted cognitive impairment in SLE patients.


Temper tantrums in young children: 2. Tantrum duration and temporal organization.
This article completes the analysis of parental narratives of tantrums had by 335 children aged 18 to 60 months. Modal tantrum durations were 0.5 to 1 minute; 75% of the tantrums lasted 5 minutes or less. If the child stamped or dropped to the floor in the first 30 seconds, the tantrum was likely to be shorter and the likelihood of parental intervention less. A novel analysis of behavior probabilities that permitted grouping of tantrums of different durations converged with our previous statistically independent results to yield a model of tantrums as the expression of two independent but partially overlapping emotional and behavioral processes: Anger and Distress. Anger rises quickly, has its peak at or near the beginning of the tantrum, and declines thereafter. Crying and comfort-seeking, components of Distress, slowly increase in probability across the tantrum. This model indicates that tantrums can provide a window on the intense emotional processes of childhood.


Circulating Immune Complexes and Heat Shock Protein 70 in the Sera of Patients with Sudden Sensorineural Hearing Loss.
The aim of this paper is to analyze and assess the usefulness of heat shock protein 70 (Hsp70) and circulating immune complexes (CIC) in patients with sudden sensorineural hearing loss (SSHL) in a tertiary care hospital in a research university (2014-2017). Patients were interviewed about the history of diseases; underwent an ear, nose, and throat (ENT) examination; a hearing test; and were analyzed for the presence of CIC and Hsp70 protein. A simple dot blot method was designed for the purpose of identification of Hsp70 bound to CIC and free Hsp70. In 59.4% of patients with idiopathic SSHL, elevated levels of immune complexes were observed. Compared with healthy subjects, a significant difference was noted (p=0.00016). Positive reactions to the presence of free Hsp70 protein were noted in the sera of 48.4% of patients. In the control group, free Hsp70 was observed in 8% of patients (p=0.0000034). Hsp70 bound to CIC was detected in the sera of 62.5% of patients; and in healthy cases, in 12% (p<0.0001). In the sera of persons with SSHL, there are elevated levels of CIC and Hsp70. After the application of the innovative method for determining the occurrence of Hsp70 bound to CIC, it was stated that its presence is greater than that of free Hsp70, commonly detected by means of the Western-blot method. The dot blot method applied in the present study increases the Hsp70 identification and by the same token increases the probability of detection of autoimmunological background of SSHL.


Gastric Fluid Volume Change After Oral Rehydration Solution Intake in Morbidly Obese and Normal Controls: A Magnetic Resonance Imaging-Based Analysis.
Although preoperative fluid intake 2 hours before anesthesia is generally considered safe, there are concerns about delayed gastric emptying in obese subjects. In this study, the gastric fluid volume (GFV) change in morbidly obese subjects was investigated after ingesting an oral rehydration solution (ORS) and then compared with that in nonobese subjects. GFV change over time after the ingestion of 500 mL of ORS containing 2.5% carbohydrate (OS-1) was measured in 10 morbidly obese subjects (body mass index [BMI], >35) scheduled for bariatric surgery and 10 nonobese (BMI, 19-24) using magnetic resonance imaging. After 9 hours of fasting, magnetic resonance imaging scans were performed at preingestion, 0 min (just after ingestion), and every 30 minutes up to 120 minutes. GFV values were compared between morbidly obese and control groups and also between preingestion and postingestion time points. The morbidly obese group had a significantly higher body weight and BMI than the control group (mean body weight and BMI in morbidly obese, 129.6 kg and 46.3 kg/m, respectively; control, 59.5 kg and 21.6 kg/m, respectively). GFV was significantly higher in the morbidly obese subjects compared with the control group at preingestion (73 ± 30.8 mL vs 31 ± 19.9 mL, P = .001) and at 0 minutes after ingestion (561 ± 30.8 mL vs 486 ± 42.8 mL; P < .001). GFV declined rapidly in both groups and reached fasting baseline levels by 120 minutes (morbidly obese, 50 ± 29.5 mL; control, 30 ± 11.6 mL). A significant correlation was observed between preingestion residual GFV and body weight (r = .66; P = .001). Morbidly obese subjects have a higher residual gastric volume after 9 hours of fasting compared with subjects with a normal BMI. However, no differences were observed in gastric emptying after ORS ingestion in the 2 populations, and GFVs reached baseline within 2 hours after ORS ingestion. Further studies are required to confirm whether the preoperative fasting and fluid management that are recommended for nonobese patients could also be applied to morbidly obese patients.


Does the goose really lay golden eggs? A methodological review of Workmen's Compensation studies.
To assess the value of workmen's compensation (WC) studies to determine the effectiveness of chiropractic. Therefore, the results of the available WC studies are summarized and the methodological quality of WC studies is discussed. All studies were eligible without time restriction. Studies were identified by a Medline search from 1966 to 1990 (key words: chiropractic, and manipulation-orthopedic in combination with comparative studies, follow-up studies, evaluation studies) by manual examination of the most important chiropractic reference systems (CRAC and Index to Chiropractic Literature), by tracking the reference lists of identified (reviews of) WC studies and by correspondence with researchers. Studies were regarded as WC studies if by means of databases of WC boards, a comparison was made between claimants treated by chiropractors and those treated by other health care professionals. At least one of the following outcomes should be reported: compensated days, compensation paid or treatment costs. Relevant data (authors, year, state, study population, number of patients, days compensated, compensation paid, number of treatments, consultation costs, additional treatment costs and total cost per case) were extracted by one nonblinded observer. The methodological value was reviewed narratively. The retrospective character of WC studies and the use of large WC databases harbor severe methodological problems like incomparability of study groups, absence of information on prognostic indicators, insufficient outcome measures and missing data. The results of older WC studies (before 1980) and the more recent WC studies, which were of better methodological quality, are presented separately. The older studies are in favor of chiropractic. Two of the six more recent WC studies challenge chiropractic effectiveness. WC studies in general report positive results for chiropractic. Recent results are more ambiguous. Because of the methodological drawbacks identified, WC studies are insufficient to enable a valid study made of chiropractic effectiveness. Therefore, chiropractic (cost-) effectiveness is not yet convincingly proven. More effort should be directed at establishing randomized clinical trials including the question of (cost-) effectiveness.


Neuromuscular alterations exist with knee osteoarthritis presence and severity despite walking velocity similarities.
Neuromuscular strategies during walking in individuals with knee osteoarthritis are being explored for diagnostic information; however, isolating differences to disease progression is difficult given walking velocity decreases with osteoarthritis severity. This study investigated lower extremity electromyograms during walking in asymptomatic individuals and individuals with different severities of knee osteoarthritis who walked with similar self-selected velocities. Muscle activity in lateral and medial gastrocnemius, vastus lateralis and medialis, rectus femoris and the lateral and medial hamstrings was monitored during self-selected walking in 230 subjects with asymptomatic knees, moderate and severe knee osteoarthritis. Sixteen asymptomatic individuals, 16 individuals with moderate and 15 individuals with severe knee osteoarthritis were identified based on similarities in average walking velocity. Principal component analysis was employed to derive amplitude and temporal characteristics of the electromyographic (EMG) waveforms. Analysis of variance models tested for group and muscle differences in principal pattern scores (α=0.05). Bonferroni post hoc testing was utilized on all significant findings. Despite similar walking velocities, individuals with moderate knee OA had elevated and prolonged quadriceps and elevated lateral hamstring activity compared to asymptomatic individuals (P<0.05). A diminished phase shift between medial and lateral gastrocnemius muscle activation, greater and prolonged lateral compared to medial hamstring activation were found in the severe group compared to asymptomatic and moderate knee OA groups (P<0.05). Lower extremity neuromuscular function during walking is altered with the presence and severity of knee osteoarthritis and not simply a direct function of walking velocity.


Novel three-dimensional analysis tool for vascular trees indicates complete micro-networks, not single capillaries, as the angiogenic endpoint in mice overexpressing human VEGF(165) in the brain.
To adequately supply tissues with oxygen and nutrients, the formation of functional vascular networks requires generation of normal, healthy vessels and their arrangement into an effective network architecture. While our knowledge about the development of single vessels significantly increased during the last years, mechanisms responsible for network formation are still poorly understood. This is probably due to the lack of suitable methods for quantification of structural properties of microvascular networks. Previously we showed that cerebral blood flow is not increased in mice exhibiting a 2- to 3-fold higher density of normal and perfused capillaries as a result of transgenic overexpression of the human vascular endothelial growth factor (VEGF(165)). Here we used vascular corrosion casting and hierarchical micro-computed tomography combined with a new network analysis tool to characterize the vascular architecture in gray and white matter of these mice. Our results indicate that VEGF overexpression leads to formation of additional micro-networks connected to higher order vessels rather than insertion of individual capillaries into the existing vessel structure. This implies that the smallest "angiogenic quantum", i.e. the final, stable result of angiogenesis and subsequent remodeling, is not a single microvessel, but a complete micro-network. In conclusion, high-resolution 3D imaging combined with network analysis can substantially improve our understanding of vascular architecture, beneficial for the development of therapeutic angiogenesis as a clinical tool for applications such as wound healing or treatment of ischemic diseases.


Strategies used by hospitals to improve speed of tissue-type plasminogen activator treatment in acute ischemic stroke.
The benefits of intravenous tissue-type plasminogen activator in acute ischemic stroke are time dependent, and several strategies have been reported to be associated with more rapid door-to-needle (DTN) times. However, the extent to which hospitals are using these strategies and their association with DTN times have not been well studied. We surveyed 304 Get With The Guidelines-Stroke hospitals joining Stroke regarding their baseline use of strategies to reduce DTN times in the January 2008 to December 2009 time frame before the initiation of Stroke and determined the association between hospital strategies and DTN times. Among 5460 patients receiving tissue-type plasminogen activator within 3 hours of symptom onset in surveyed hospitals, the median DTN time was 72 minutes (interquartile range, 55-94). Reported use of the different strategies varied considerably. Of 11 hospital strategies analyzed individually by multivariable analysis, 3 strategies were independently associated with shorter DTN times. These included rapid triage/stroke team notification (209/304 [69%] hospitals, 8.1-minute reduction in DTN time), single-call activation system (190/304 [63%] hospitals, 4.3 minutes), and tissue-type plasminogen activator stored in the emergency department (189/304 [62%] hospitals, 3.5 minutes). When analyzed incrementally, hospitals that used a greater number of strategies had shorter DTN times with 1.3 minutes (adjusted mean difference) saved for each strategy implemented (14 minutes if all strategies were used). Although the majority of participating hospitals reported using some strategy to reduce delays in tissue-type plasminogen activator administration for acute ischemic stroke, the strategies applied vary considerably and those most strongly associated with shorter DTN times were applied relatively less frequently.


Genetically engineered SCN5A mutant pig hearts exhibit conduction defects and arrhythmias.
SCN5A encodes the α subunit of the major cardiac sodium channel Na(V)1.5. Mutations in SCN5A are associated with conduction disease and ventricular fibrillation (VF); however, the mechanisms that link loss of sodium channel function to arrhythmic instability remain unresolved. Here, we generated a large-animal model of a human cardiac sodium channelopathy in pigs, which have cardiac structure and function similar to humans, to better define the arrhythmic substrate. We introduced a nonsense mutation originally identified in a child with Brugada syndrome into the orthologous position (E558X) in the pig SCN5A gene. SCN5A(E558X/+) pigs exhibited conduction abnormalities in the absence of cardiac structural defects. Sudden cardiac death was not observed in young pigs; however, Langendorff-perfused SCN5A(E558X/+) hearts had an increased propensity for pacing-induced or spontaneous VF initiated by short-coupled ventricular premature beats. Optical mapping during VF showed that activity often began as an organized focal source or broad wavefront on the right ventricular (RV) free wall. Together, the results from this study demonstrate that the SCN5A(E558X/+) pig model accurately phenocopies many aspects of human cardiac sodium channelopathy, including conduction slowing and increased susceptibility to ventricular arrhythmias.


Evaluation of Econem™, a formulated Pasteuria sp. Bionematicide, for management of Belonolaimus longicaudatus on golf course turf.
In 2010, a turfgrass bionematicide containing in vitro produced Pasteuria sp. for management of Belonolaimus longicaudatus was launched under the tradename Econem(™). Greenhouse pot studies and field trials on golf course fairways and tee boxes evaluated Econem at varied rates and application frequencies. Trials on putting greens compared efficacy of three applications of Econem at 98 kg/ha to untreated controls and 1,3-dichloropropene at 53 kg a.i/ha. Further putting green trials evaluated the ability of three applications of Econem at 98 kg/ha to prevent resurgence of population densities of B. longicaudatus following treatment with 1,3-dichloropropene at 53 kg a.i./ha. None of the Econem treatments in pot studies were effective at reducing B. longicaudatus numbers (P ≤ 0.05). Econem was associated with reduction in population densities of B. longicaudatus (P ≤ 0.1) on only a single sampling date in one of the eight field trials and did not improve turf health in any of the trials (P > 0.1). These results did not indicate that Econem is an effective treatment for management of B. longicaudatus on golf course turf.


Lichen Planus Pigmentosus: A Clinico-etiological Study.
Lichen planus pigmentosus (LPP) is a distinct clinical entity commonly encountered in the Indian population. To study the clinicoetiological profile of LPP at a tertiary care hospital. A total of 100 patients with clinically and histopathologically confirmed diagnosis of LPP were included. Demographic details including the age of onset, duration of disease, symptoms, and family history were obtained. History regarding any precipitating factors, cosmetics, drug intake, and associated cutaneous or systemic diseases was taken. Clinical examination of the skin, oral cavity, hair, and nails was carried out. Of the total 100 patients, 56 (56%) were females and 44 (44%) males with age ranging from 18 to 54 years (mean age - 31.23 years). The duration of disease ranged from 2 to 60 months with a mean of 19.31 months. Cosmetic disfigurement (68%) was the commonest complaint, followed by itching (41%) while, 30% of the patients were asymptomatic. History of topical mustard oil and hair dye application was present in 62% and 48% of the cases each. Other topicals included perfumes (24%), aftershave lotion (36%), and cosmetics (20%). Face (54%) and neck (48%) were the commonest sites affected, followed by upper back (36%), upper limbs, and chest (each 32%). A total of 11 patients showed only flexural involvement. The commonest pattern of pigmentation was diffuse (56%) followed by reticular in 16%. The color of the pigmentation varied from slate grey to brownish-black in varying proportions. A positive association was found between hypothyroidism with diffuse LPP where the P value was <0.001. LPP is a distinct clinical entity caused by diverse etiological factors and shows varied clinical patterns. All the patients should be advised to stop using mustard oil/henna/hair dye/after shave lotions and cosmetics. Hypothyroidism can be considered to be a disease associated with LPP and all the patients should be investigated for the same.


Normal urate transport into erythrocytes in familial renal hypouricemia and in the Dalmatian dog.
It has been hypothesized that humans with familial renal hypouricemia may have a generalized defect of urate transport across cell membranes due to the genetic deletion of a specific carrier, a defect similar to that reported in the Dalmatian dog. In this study the transport of urate labelled with carbon 14 by the erythrocytes of four patients with familial renal hypouricemia was identical to that of five healthy controls. The addition of hypoxanthine to the incubation medium inhibited the transport to a similar extent in the two groups of patients, demonstrating the presence of a carrier specific for urate. This carrier was also found to be present in the erythrocytes of Dalmatian and mongrel dogs. Thus, the renal anomaly causing the hypouricemia in both species is not related to a generalized deletion of a urate-transporting protein on cell membranes.


Use of ribotyping for characterization of Salmonella serotypes.
Forty-five isolates of Salmonella serotype reading, 20 isolates of Salmonella serotype senftenberg, and 56 isolates of Salmonella serotype typhimurium from domestic and wild animals were characterized genotypically to differentiate within serotypes for epidemiologic studies. The genotypic method of characterization used was ribotyping, a method for highlighting highly conserved rRNA genes and associated sequences. Isolates were obtained from diverse geographic sources (farms located in Fresno, Sonoma, Stanislaus, and Yolo counties) as well as different hosts (avian, equine, bovine, murine, and environmental) during a period of 8 months. Within a given serotype, ribotying was able to establish subclassifications (ribotypes) that grouped isolates by a common source regardless of host or geographic origin. There were four distinct ribosomal banding patterns observed for Salmonella serotype reading, six were observed for Salmonella serotype senftenberg, and two were observed for Salmonella serotype typhimurium.


The postfusion structure of baculovirus gp64 supports a unified view of viral fusion machines.
Viral fusion proteins mediate the merger of host and viral membranes during cell entry for all enveloped viruses. Baculovirus glycoprotein gp64 (gp64) is unusual in promoting entry into both insect and mammalian cells and is distinct from established class I and class II fusion proteins. We report the crystal structure of its postfusion form, which explains a number of gp64's biological properties including its cellular promiscuity, identifies the fusion peptides and shows it to be the third representative of a new class (III) of fusion proteins with unexpected structural homology with vesicular stomatitis virus G and herpes simplex virus type 1 gB proteins. We show that domains of class III proteins have counterparts in both class I and II proteins, suggesting that all these viral fusion machines are structurally more related than previously thought.


From frog integument to human skin: dermatological perspectives from frog skin biology.
For over a century, frogs have been studied across various scientific fields, including physiology, embryology, neuroscience, (neuro)endocrinology, ecology, genetics, behavioural science, evolution, drug development, and conservation biology. In some cases, frog skin has proven very successful as a research model, for example aiding in the study of ion transport through tight epithelia, where it has served as a model for the vertebrate distal renal tubule and mammalian epithelia. However, it has rarely been considered in comparative studies involving human skin. Yet, despite certain notable adaptations that have enabled frogs to survive in both aquatic and terrestrial environments, frog skin has many features in common with human skin. Here we present a comprehensive overview of frog (and toad) skin ontogeny, anatomy, cytology, neuroendocrinology and immunology, with special attention to its unique adaptations as well as to its similarities with the mammalian integument, including human skin. We hope to provide a valuable reference point and a source of inspiration for both amphibian investigators and mammalian researchers studying the structural and functional properties of the largest organ of the vertebrate body.