Asterid Phylogenomics/Phylotranscriptomics Uncover Morphological Evolutionary Histories and Support Phylogenetic Placement for Numerous Whole-Genome Duplications.
Asterids are one of the most successful angiosperm lineages, exhibiting extensive morphological diversity and including a number of important crops. Despite their biological prominence and value to humans, the deep asterid phylogeny has not been fully resolved, and the evolutionary landscape underlying their radiation remains unknown. To resolve the asterid phylogeny, we sequenced 213 transcriptomes/genomes and combined them with other data sets, representing all accepted orders and nearly all families of asterids. We show fully supported monophyly of asterids, Berberidopsidales as sister to asterids, monophyly of all orders except Icacinales, Aquifoliales, and Bruniales, and monophyly of all families except Icacinaceae and Ehretiaceae. Novel taxon placements benefited from the expanded sampling with living collections from botanical gardens, resolving hitherto uncertain relationships. The remaining ambiguous placements here are likely due to limited sampling and could be addressed in the future with relevant additional taxa. Using our well-resolved phylogeny as reference, divergence time estimates support an Aptian (Early Cretaceous) origin of asterids and the origin of all orders before the Cretaceous-Paleogene boundary. Ancestral state reconstruction at the family level suggests that the asterid ancestor was a woody terrestrial plant with simple leaves, bisexual, and actinomorphic flowers with free petals and free anthers, a superior ovary with a style, and drupaceous fruits. Whole-genome duplication (WGD) analyses provide strong evidence for 33 WGDs in asterids and one in Berberidopsidales, including four suprafamilial and seven familial/subfamilial WGDs. Our results advance the understanding of asterid phylogeny and provide numerous novel evolutionary insights into their diversification and morphological evolution.


Amygdalar GABAergic-rich neural grafts attenuate anxiety-like behavior in rats.
Transplantation experiments have shown that neurologic deficits may be reversed by engrafting fresh tissue or engineered cells within dysfunctional neural circuitry. In experimental and clinical settings, this approach has provided insights into the pathology and treatment of neurologic diseases, primarily movement disorders. The present experiments were designed to investigate whether a similar strategy is feasible as a method to investigate, and perhaps repair, circuitry integral to emotional disorders. We focused on the amygdala, a macrostructure known to be involved in the expression of anxiety- and fear-related behaviors. GABAergic cell-rich suspensions were prepared from E17 rat lateral ganglionic eminence and engrafted bilaterally into the lateral and basolateral amygdaloid nuclei of young adult rats. After 6 weeks, increased numbers of GABAergic neurons were identified in the vicinity of the graft sites, and electron microscopy provided evidence for functional integration of transplanted cells. Rats with these grafts spent more time in the open arms of the elevated-plus maze, consistent with an anxioloytic-like phenotype. These rats were also less sensitive to the unconditioned anxiogenic effects of light on the acoustic startle response, although fear-potentiated startle was not affected, suggesting that the grafts produced an attenuation of unlearned fear but did not affect acquisition of conditioned fear. Our results raise the possibility that distinct components of emotion can be modulated by strategic neural engraftment.


Tilt aftereffects and tilt illusions induced by fast translational motion: evidence for motion streaks.
Fast-moving visual features are thought to leave neural 'streaks' that can be detected by orientation-selective cells. Here, we tested whether 'motion streaks' can induce classic tilt aftereffects (TAEs) and tilt illusions (TIs). For TAEs, participants adapted to random arrays of small Gaussian blobs drifting at 9.5 deg/s. Following adaptation to directions of 15, 30, 45, 60, 75, and 90 degrees (clockwise from vertical) subjective vertical was measured for a briefly presented test grating. For TIs, the same motions were presented in an annular surround and subjective vertical was measured for a simultaneously presented central grating. All motions were 50% coherent, with half the blobs following random-walk paths and half following a fixed direction. Strong and weak streaks were compared by varying streak length (the number of fixed-walk frames), rather than by manipulating speed, so that speed and coherence were matched in all conditions. Strong motion streaks produced robust TAEs and TIs, similar in magnitude and orientation tuning to those induced by tilted lines. These effects were weak or absent in weak streak conditions, and when motion was too slow to form streaks. Together, these results indicate that motion streaks produced by temporal integration of fast translating features do effectively adapt orientation-selective cells and may therefore be exploited to improve perception of motion direction as described in the 'motion streaks' model.


Wasting is associated with stunting in early childhood.
The longitudinal relationship between stunting and wasting in children is poorly characterized. Instances of wasting or poor weight gain may precede linear growth retardation. We analyzed longitudinal anthropometric data for 1599 children from 8 cohort studies to determine the effect of wasting [weight-for-length Z-score (WLZ) < -2] and variability in WLZ in the first 17 mo on length-for-age Z-score (LAZ) at 18-24 mo of age. In addition, we considered the effects of change in WLZ during the previous 6-mo period on length at 18 and 24 mo. Wasting at 6-11 or 12-17 mo was associated with decreased LAZ; however, children who experienced wasting only at 0-5 mo did not suffer any long-term growth deficits compared with children with no wasting during any period. Children with greater WLZ variability (≥0.5 SD) in the first 17 mo of life were shorter [LAZ = -0.51 SD (95% CI: -0.67, -0.36 SD)] at 18-24 mo of age than children with WLZ variability <0.5. Change in WLZ in the previous 6-mo period was directly associated with greater attained length at 18 mo [0.33 cm (95% CI: 0.11, 0.54 cm)] and 24 mo [0.72 cm (95% CI: 0.52, 0.92 cm)]. Children with wasting, highly variable WLZ, or negative changes in WLZ are at a higher risk for linear growth retardation, although instances of wasting may not be the primary cause of stunting in developing countries.


Icatibant. Attacks of hereditary angioedema: continue to use C1 esterase inhibitor.
Hereditary angioedema is a severe genetic disorder due to C1 esterase inhibitor deficiency, which leads to an excess of bradykinin. It is characterised by attacks of subcutaneous or mucosal oedema, which can carry a risk of asphyxiation if the larynx is involved. The first-choice symptomatic treatment for attacks is intravenous C1 esterase inhibitor administration. Tranexamic acid is sometimes used. Icatibant, a decapeptide bradykinin B2 receptor antagonist, is now authorised in the European Union for use in this situation. We found no trials comparing icatibant versus C1 esterase inhibitor. The two principal clinical trials were both comparative trials, one versus tranexamic acid (74 patients), and the other versus placebo (56 patients). No mortality data were reported in either trial. Icatibant seemed to be more effective than tranexamic acid in relieving symptoms and also yielded a higher response rate. However, these positive results were not confirmed in the placebo-controlled trial. Both trials suffer from several biases, ruling out firm conclusions on the efficacy of icatibant, the trials were underpowered, some criteria were difficult to measure, the blinding was incomplete, and tranexamic acid was given at a lower dose than that recommended. The main adverse effects of icatibant are reactions at the injection site, which occur in almost all patients. A potential risk of cardiac disorders (especially angina) needs to be investigated. Subcutaneous administration of icatibant requires a large volume of solution (3 ml). In practice, in the absence of head-to-head comparisons, it remains to be shown whether or not icatibant has a better risk-benefit balance than C1 esterase inhibitor. Due to inconsistencies between the results and numerous biases in the two main clinical trials, the evidence supporting the efficacy of icatibant is weak. C1 esterase inhibitor remains the first-choice treatment for patients with acute attacks of hereditary angioedema.


Set membership experimental design for biological systems.
Experimental design approaches for biological systems are needed to help conserve the limited resources that are allocated for performing experiments. The assumptions used when assigning probability density functions to characterize uncertainty in biological systems are unwarranted when only a small number of measurements can be obtained. In these situations, the uncertainty in biological systems is more appropriately characterized in a bounded-error context. Additionally, effort must be made to improve the connection between modelers and experimentalists by relating design metrics to biologically relevant information. Bounded-error experimental design approaches that can assess the impact of additional measurements on model uncertainty are needed to identify the most appropriate balance between the collection of data and the availability of resources. In this work we develop a bounded-error experimental design framework for nonlinear continuous-time systems when few data measurements are available. This approach leverages many of the recent advances in bounded-error parameter and state estimation methods that use interval analysis to generate parameter sets and state bounds consistent with uncertain data measurements. We devise a novel approach using set-based uncertainty propagation to estimate measurement ranges at candidate time points. We then use these estimated measurements at the candidate time points to evaluate which candidate measurements furthest reduce model uncertainty. A method for quickly combining multiple candidate time points is presented and allows for determining the effect of adding multiple measurements. Biologically relevant metrics are developed and used to predict when new data measurements should be acquired, which system components should be measured and how many additional measurements should be obtained. The practicability of our approach is illustrated with a case study. This study shows that our approach is able to 1) identify candidate measurement time points that maximize information corresponding to biologically relevant metrics and 2) determine the number at which additional measurements begin to provide insignificant information. This framework can be used to balance the availability of resources with the addition of one or more measurement time points to improve the predictability of resulting models.


Paths to leisure physical activity among adults with intellectual disabilities: self-efficacy and social support.
This study tested a path model that included perceptions of social support and self-efficacy for leisure physical activity and leisure physical activity participation among adults with intellectual disabilities. A cross-sectional design was used. Data was collected via oral interview. Community-based group, supported-living settings in one Midwestern state. A total of 152 adults with mild to moderate intellectual disabilities, which provided a 39% response rate. Self-efficacy and social support (from family, residential staff and peers with disabilities) for leisure physical activity were assessed using self-reported scales. Leisure physical activity participation was measured with a self-reported checklist of the frequency of leisure physical activity participation. Path analysis was conducted for the entire sample and was repeated for younger and older age groups. The hypothesized model fit the data from each group. Social support and self-efficacy predicted physical activity participation, and self-efficacy served as a mediator between social support and physical activity. Significant sources of social support differed between groups; among younger participants, social support from family predicted physical activity, whereas, for the older group, social support from staff and peers predicted physical activity. Self-efficacy and social support for leisure physical activity are related to leisure physical activity participation among adults with intellectual disabilities who are receiving supported-living services. The results provide information to guide health promotion programs for this group.


Roles of dopamine receptor subtypes in mediating modulation of T lymphocyte function.
Dopamine exists in the immune system and has obvious immunomodulating action. However, receptor mechanism underlying the dopamine immunomodulation remains to be clarified. In the present study, we provide the evidence for existence of dopamine receptor subtypes in T lymphocytes and show the roles of the receptors and the receptor-coupled signaling in mediating the dopamine immunomodulation. The purified T lymphocytes from the mesenteric lymph nodes of mice were detected for expressions of all five subtypes of dopamine receptor mRNAs by reverse transcription-polymerase chain reaction. Lymphocyte proliferation and production of interferon-γ (IFN-γ) and interleukin-4 (IL-4) in response to concanavalin A (Con A) were measured by colorimetric methyl-thiazole-tetrazolium assay and cytometric bead array, respectively, after the cells were exposed to dopamine D1-like or D2-like receptor agonists and antagonists. Meanwhile, content of cAMP and phosphorylation of cAMP-response element-binding (CREB) in the lymphocytes were examined by 125I-cAMP radioimmunoassay and Western blot assay, respectively. T lymphocytes expressed all the five subtypes of dopamine receptor mRNAs, i.e., D1, D2, D3, D4 and D5 receptors. SKF38393, an agonist of dopamine D1-like receptors (D1 and D5 receptors) only reduced the IFN-γ production, but did not significantly affect the proliferative response, IL-4 production, cAMP content or CREB activation of the lymphocytes. The SKF38393-induced decrease in IFN-γ level was blocked by the D1-like receptor antagonist SCH23390. Quinpirole, an agonist of dopamine D2-like receptors (D2, D3 and D4 receptors) attenuated the lymphocyte proliferation to Con A, and decreased the IFN-γ but increased the IL-4 production. Meanwhile, the quinpirole diminished the cAMP content and the phosphorylated CREB level in the lymphocytes. All the quinpirole-induced changes were reversed by dopamine D2-like receptor antagonist haloperidol. Five dopamine receptor subtypes of the two families, D1-like and D2-like receptors, exist on T lymphocytes of mice. Of the two families, D2-like receptors are more important in mediating modulation of T cell function than D1-like receptors. D2-like receptors are involved in suppression of T helper 1 (Th1) cell function and enhancement of Th2 cell function through negative link to cAMP-CREB pathway.


Method for evaluating the potential of C labeled plant polyphenols to cross the blood-brain barrier using accelerator mass spectrometry.
Bioactive compounds in botanicals may be beneficial in preventing age-related neurodegenerative diseases, but for many compounds conventional methods may be inadequate to detect if these compounds cross the blood brain barrier or to track the pharmacokinetics in the brain. By combining a number of unique technologies it has been possible to utilize the power of AMS to study the pharmacokinetics of bioactive compounds in the brain at very low concentrations. (14)C-labeled compounds can be biosynthesized by plant cell suspension cultures co-incubated with radioisotopically-labeled sucrose and isolated and separated into a series of bioactive fractions.To study the pharmacokinetics and tissue distribution of (14)C labeled plant polyphenols, rats were implanted with jugular catheters, subcutaneous ultrafiltration probes and brain microdialysis probes. Labeled fractions were dosed orally. Interstitial fluid (ISF) and brain microdialysate samples were taken in tandem with blood samples. It was often possible to determine (14)C in blood and ISF with a β-counter. However, brain microdialysate samples (14)C levels on the order of 10(7) atoms/sample required AMS technology. The Brain Microdialysate(AUC)/Serum(AUC) ranged from .021- to .029, with the higher values for the glycoside fractions. By using AMS in combination with traditional methods, it is possible to study uptake by blood, distribution to ISF and determine the amount of a dose which can reach the brain and follow the pharmacokinetics in the brain.


Phylogenetic Analyses of Meloidogyne Small Subunit rDNA.
Phylogenies were inferred from nearly complete small subunit (SSU) 18S rDNA sequences of 12 species of Meloidogyne and 4 outgroup taxa (Globodera pallida, Nacobbus abberans, Subanguina radicicola, and Zygotylenchus guevarai). Alignments were generated manually from a secondary structure model, and computationally using ClustalX and Treealign. Trees were constructed using distance, parsimony, and likelihood algorithms in PAUP* 4.0b4a. Obtained tree topologies were stable across algorithms and alignments, supporting 3 clades: clade I = [M. incognita (M. javanica, M. arenaria)]; clade II = M. duytsi and M. maritima in an unresolved trichotomy with (M. hapla, M. microtyla); and clade III = (M. exigua (M. graminicola, M. chitwoodi)). Monophyly of [(clade I, clade II) clade III] was given maximal bootstrap support (mbs). M. artiellia was always a sister taxon to this joint clade, while M. ichinohei was consistently placed with mbs as a basal taxon within the genus. Affinities with the outgroup taxa remain unclear, although G. pallida and S. radicicola were never placed as closest relatives of Meloidogyne. Our results show that SSU sequence data are useful in addressing deeper phylogeny within Meloidogyne, and that both M. ichinohei and M. artiellia are credible outgroups for phylogenetic analysis of speciations among the major species.


Sudden death after isobutane sniffing: a report of two forensic cases.
The intentional inhalation of a volatile substance ("sniffing") causing euphoria and hallucinations is an under-recognised form of substance abuse in children and adolescents with a high morbidity and mortality. Sudden death can be caused by cardiac arrhythmia, asphyxia or trauma. Two fatal cases of isobutane sniffing of cigarette lighter refill containing isobutane are reported. Toxicological investigations revealed the presence of isobutane in the heart blood and brain tissue of both cases (case 1: heart blood 0.1 microg/g, brain tissue 2.3 microg/g; case 2: heart blood 4.6 microg/g, brain tissue 17.4 microg/g) and the presence of its metabolite 2-methyl-2-propanol in the heart blood of both cases (0.5 and 1.8 microg/g, respectively). The histological investigations of the inner organs showed similar results in both victims. Autopsy findings, results of the histological and immunohistochemical investigations, toxicological findings and analytical procedures are discussed.


Network analysis of human and simian immunodeficiency virus sequence sets reveals massive recombination resulting in shorter pathways.
The intrinsic recombination rate of human immunodeficiency virus (HIV) exceeds the point mutation rate by a factor of 10. As the majority of infected cells in vivo harbour multiple proviruses, the stage is set for rampant recombination. Therefore, it may be presumed that phylogenic relationships and mutation frequencies will probably be affected by recombination. However, the proportion of homoplasies arising from recombination and mutation is not known. By studying the evolution of the hypervariable regions of the simian immunodeficiency virus envelope gene among four macaques, it is shown that homoplasies arise more from recombination than from point mutation. When recombination is accounted for, the minimum number of substitutions in a sequence set may be reduced by as much as 45 %. In fact, the true number of point mutations in a set of HIV sequences tends to the number of discrete substitutions. Hence, lineages are younger than anticipated previously, although not in proportion to the ratio of the intrinsic recombination/point mutation rate. Recombination also inflates codon polymorphisms.


Video segmentation based on motion coherence of particles in a video sequence.
This work describes an approach for object-oriented video segmentation based on motion coherence. Using a tracking process based on adaptively sampled points (namely, particles), 2-D motion patterns are identified with an ensemble clustering approach. Particles are clustered to obtain a pixel-wise segmentation in space and time domains. The segmentation result is mapped to an image spatio-temporal feature space. Thus, the different constituent parts of the scene that move coherently along the video sequence are mapped to volumes in this spatio-temporal space. These volumes make the redundancy in the temporal sense more explicit, leading to potential gains in video coding applications. The proposed solution is robust and more generic than similar approaches for 2-D video segmentation found in the literature. In order to illustrate the potential advantages of using the proposed motion segmentation approach in video coding applications, the PSNR of the temporal predictions and the entropies of prediction errors obtained in our experiments are presented, and compared with other methods. Our experiments with real and synthetic sequences suggest that our method also could be used in other image processing and computer vision tasks, besides video coding, such as video information retrieval and video understanding.


Attention-deficit hyperactivity disorder: critical appraisal of extended treatment studies.
We undertook a systematic review of the literature on the long-term treatment of attention-deficit hyperactivity disorder (ADHD). We used systematic strategies to identify randomized treatment studies in which treatment was administered for 12 weeks or more. We included 14 studies involving 1379 subjects. Because of the limited number of high-quality studies and the heterogeneity of outcome measures, we did not perform meta-analysis. We rated 5 studies as adequate for methodological quality. Five studies followed children for more than 26 weeks. Pharmacologic interventions were studied more frequently than non-pharmacologic ones. Six studies permitted evaluation of the effects of combined drug and behavioural intervention. Twenty-five different outcomes were measured using 26 different tests. Stimulant medication appears to reduce ADHD (7 studies), dysfunctional social behaviour (6 studies), and internalizing symptoms (2 studies). Available studies provide little evidence for improved academic performance with stimulants (3 studies). Medications other than stimulants have not been studied extensively (3 studies). Only 1 study showed that combination therapy adds to the effects of medication. Rigorous treatment research among representative samples of ADHD individuals is needed.


Efficacy of theory-based interventions to promote physical activity. A meta-analysis of randomised controlled trials.
Implementing theory-based interventions is an effective way to influence physical activity (PA) behaviour in the population. This meta-analysis aimed to (1) determine the global effect of theory-based randomised controlled trials dedicated to the promotion of PA among adults, (2) measure the actual efficacy of interventions against their theoretical objectives and (3) compare the efficacy of single- versus combined-theory interventions. A systematic search through databases and review articles was carried out. Our results show that theory-based interventions (k = 82) significantly impact the PA behaviour of participants (d = 0.31, 95% CI [0.24, 0.37]). While moderation analyses revealed no efficacy difference between theories, interventions based on a single theory (d = 0.35; 95% CI [0.26, 0.43]) reported a higher impact on PA behaviour than those based on a combination of theories (d = 0.21; 95% CI [0.11, 0.32]). In spite of the global positive effect of theory-based interventions on PA behaviour, further research is required to better identify the specificities, overlaps or complementarities of the components of interventions based on relevant theories.


Characterization of blood dendritic and regulatory T cells in asymptomatic adults with sub-microscopic Plasmodium falciparum or Plasmodium vivax infection.
Plasmodium falciparum and Plasmodium vivax infections compromise dendritic cell (DC) function and expand regulatory T (Treg) cells in both clinical disease (malaria) and experimental human sub-microscopic infection. Conversely, in asymptomatic microscopy-positive (patent) P. falciparum or P. vivax infection in endemic areas, blood DC increase or retain HLA-DR expression and Treg cells exhibit reduced activation, suggesting that DC and Treg cells contribute to the control of patent asymptomatic infection. The effect of sub-microscopic (sub-patent) asymptomatic Plasmodium infection on DC and Treg cells in malaria-endemic area residents remains unclear. In a cross-sectional household survey conducted in Papua, Indonesia, 162 asymptomatic adults were prospectively evaluated for DC and Treg cells using field-based flow cytometry. Of these, 161 individuals (99 %) were assessed retrospectively by polymerase chain reaction (PCR), 19 of whom had sub-microscopic infection with P. falciparum and 15 with sub-microscopic P. vivax infection. Flow cytometric data were re-analysed after re-grouping asymptomatic individuals according to PCR results into negative controls, sub-microscopic and microscopic parasitaemia to examine DC and Treg cell phenotype in sub-microscopic infection. Asymptomatic adults with sub-microscopic P. falciparum or P. vivax infection had DC HLA-DR expression and Treg cell activation comparable to PCR-negative controls. Sub-microscopic P. falciparum infection was associated with lower peripheral CD4(+) T cells and lymphocytes, however sub-microscopic Plasmodium infection had no apparent effect on DC sub-set number or Treg cell frequency. In contrast to the impairment of DC maturation/function and the activation of Treg cells seen with sub-microscopic parasitaemia in primary experimental human Plasmodium infection, no phenotypic evidence of dysregulation of DC and Treg cells was observed in asymptomatic sub-microscopic Plasmodium infection in Indonesian adults. This is consistent with DC and Treg cells retaining their functional capacity in sub-microscopic asymptomatic infection with P. falciparum or P. vivax in malaria-endemic areas.


Lipid signalling drives proteolytic rewiring of mitochondria by YME1L.
Reprogramming of mitochondria provides cells with the metabolic flexibility required to adapt to various developmental transitions such as stem cell activation or immune cell reprogramming, and to respond to environmental challenges such as those encountered under hypoxic conditions or during tumorigenesis1-3. Here we show that the i-AAA protease YME1L rewires the proteome of pre-existing mitochondria in response to hypoxia or nutrient starvation. Inhibition of mTORC1 induces a lipid signalling cascade via the phosphatidic acid phosphatase LIPIN1, which decreases phosphatidylethanolamine levels in mitochondrial membranes and promotes proteolysis. YME1L degrades mitochondrial protein translocases, lipid transfer proteins and metabolic enzymes to acutely limit mitochondrial biogenesis and support cell growth. YME1L-mediated mitochondrial reshaping supports the growth of pancreatic ductal adenocarcinoma (PDAC) cells as spheroids or xenografts. Similar changes to the mitochondrial proteome occur in the tumour tissues of patients with PDAC, suggesting that YME1L is relevant to the pathophysiology of these tumours. Our results identify the mTORC1-LIPIN1-YME1L axis as a post-translational regulator of mitochondrial proteostasis at the interface between metabolism and mitochondrial dynamics.


Orthostatic hypotension: From pathophysiology to clinical applications and therapeutic considerations.
Orthostatic hypotension (OH), that is blood pressure fall when standing from the supine to the erect position, is a common cardiovascular disorder, highly prevalent in elderly and frail individuals and in patients with multiple comorbidities. Orthostatic hypotension is considered a manifestation of dysfunction of the autonomic nervous system, caused or facilitated by several neurological or non-neurological diseases and conditions, while its clinical significance is increasingly recognized as a cause of impairment of quality of life and potentially of worse outcomes. Indeed, OH has been extensively studied and numerous prospective cohort studies support its association with adverse events, including coronary artery disease, heart failure, stroke, cognitive dysfunction, and, most importantly, mortality rates. Specific pharmacological and non-pharmacological interventions have been established for the treatment of OH. However, randomized data evaluating the impact of therapeutic interventions on morbidity and mortality outcomes are lacking. Thus, despite that OH seems to have important prognostic implications indicated by several reported associations with adverse events, it remains unclear whether OH treatment could improve prognosis. In the present review, we discuss the clinical applications associated with ΟΗ by outlining the current perspectives on ΟΗ definition, diagnosis, pathophysiology, prognostic role, and treatment.


Critical role of angiopoietins/Tie-2 in hyperglycemic exacerbation of myocardial infarction and impaired angiogenesis.
Angiopoietin-1 (Ang-1) and angiopoietin-2 (Ang-2) are the two ligands of the Tie-2 receptor, a receptor tyrosine kinase that is expressed on the endothelium. A balanced angiopoietin/Tie-2 system is critical for the maintenance of vascular integrity. We investigated the potential role of a disrupted angiopoietin/Tie-2 system on hyperglycemic exacerbation of myocardial infarction and impaired angiogenesis. Using streptozotocin (STZ) mice subjected to myocardial ischemia, we examined the effects of shifting the Ang-2-to-Ang-1 ratio on myocardial infarction size, apoptosis, bone marrow (BM) cell-endothelial progenitor cell (EPC) differentiation, and angiogenesis. In control mice, myocardial ischemia increased expression of both Ang-2 and Tie-2. In STZ mice, Ang-2 expression was elevated, whereas Tie-2 expression was reduced, and neither was significantly altered by ischemia. Myocardial infarct size and apoptosis were increased in STZ compared with control mice. Using in vivo administration of an adenovirus containing Ang-1 or Ang-2, we found that shifting the Ang-2-to-Ang-1 ratio to favor Ang-1 reduced myocardial apoptosis and infarct size in STZ mice, while shifting the Ang-2-to-Ang-1 ratio to favor Ang-2 resulted in a significant increase in myocardial infarct size and apoptosis in control mice. Myocardial ischemia-stimulated BM cell-EPC differentiation was inhibited and myocardial angiogenesis was reduced in STZ mice. Systemic administration of Ad-Ang-1 restored BM cell-EPC differentiation and increased myocardial VEGF expression and angiogenesis in STZ mice. Our data demonstrate that disturbed angiopoietin/Tie-2 signaling contributes to the hyperglycemic exacerbation of myocardial infarction and impaired angiogenesis. Restoration of the Ang-2-to-Ang-1 ratio may be a novel therapeutic strategy for the treatment of diabetic myocardial ischemic diseases.


3D shape recovery of a newborn skull using thin-plate splines.
The objective of this paper is to construct a mesh-model of a newborn skull for finite element analysis to study its deformation when subjected to the forces present during labour. The current state of medical imaging technology has reached a level which allows accurate visualisation and shape recovery of biological organs and body-parts. However, a sufficiently large set of medical images cannot always be obtained, often because of practical or ethical reasons, and the requirement to recover the shape of the biological object of interest has to be met by other means. Such is the case for a newborn skull. A method to recover the three-dimensional (3D) shape from (minimum) two orthogonal atlas images of the object of interest and a homologous object is described. This method is based on matching landmarks and curves on the orthogonal images of the object of interest with corresponding landmarks and curves on the homologous or 'master'-object which is fully defined in 3D space. On the basis of this set of corresponding landmarks, a thin-plate spline function can be derived to warp from the 'master'-object space to the 'slave'-object space. This method is applied to recover the 3D shape of a newborn skull. Images from orthogonal view-planes are obtained from an atlas. The homologous object is an adult skull, obtained from CT-images made available by the Visible Human Project. After shape recovery, a mesh-model of the newborn skull is generated.


Harnessing Telemedicine for the Provision of Health Care: Bibliometric and Scientometric Analysis.
In recent decades, advances in information technology have given new momentum to telemedicine research. These advances in telemedicine range from individual to population levels, allowing the exchange of patient information for diagnosis and management of health problems, primary care prevention, and education of physicians via distance learning. This scientometric investigation aims to examine collaborative research networks, dominant research themes and disciplines, and seminal research studies that have contributed most to the field of telemedicine. This information is vital for scientists, institutions, and policy stakeholders to evaluate research areas where more infrastructural or scholarly contributions are required. For analyses, we used CiteSpace (version 4.0 R5; Drexel University), which is a Java-based software that allows scientometric analysis, especially visualization of collaborative networks and research themes in a specific field. We found that scholarly activity has experienced a significant increase in the last decade. Most important works were conducted by institutions located in high-income countries. A discipline-specific shift from radiology to telestroke, teledermatology, telepsychiatry, and primary care was observed. The most important innovations that yielded a collaborative influence were reported in the following medical disciplines, in descending order: public environmental and occupational health, psychiatry, pediatrics, health policy and services, nursing, rehabilitation, radiology, pharmacology, surgery, respiratory medicine, neurosciences, obstetrics, and geriatrics. Despite a continuous rise in scholarly activity in telemedicine, we noticed several gaps in the literature. For instance, all the primary and secondary research central to telemedicine was conducted in the context of high-income countries, including the evidence synthesis approaches that pertained to implementation aspects of telemedicine. Furthermore, the research landscape and implementation of telemedicine infrastructure are expected to see exponential progress during and after the COVID-19 era.


Diabetes and atherosclerosis: epidemiology, pathophysiology, and management.
Complications of atherosclerosis cause most morbidity and mortality in patients with diabetes mellitus. Despite the frequency and severity of disease, proven medical therapy remains incompletely understood and underused. To review the epidemiology, pathophysiology, and medical and invasive treatment of atherosclerosis in patients with diabetes mellitus. Using the index terms diabetes mellitus, myocardial infarction, peripheral vascular diseases, cerebrovascular accident, endothelium, vascular smooth muscle, platelets, thrombosis, cholesterol, hypertension, hyperglycemia, insulin, angioplasty, and coronary artery bypass, we searched the MEDLINE and EMBASE databases from 1976 to 2001. Additional data sources included bibliographies of identified articles and preliminary data presented at recent cardiology conferences. We selected original investigations and reviews of the epidemiology, pathophysiology, and therapy of atherosclerosis in diabetes. We selected randomized, double-blind, controlled studies, when available, to support therapeutic recommendations. Criteria for data inclusion (168 of 396) included publication in a peer-reviewed journal or presentation at a national cardiovascular society-sponsored meeting. Data quality was determined by publication in peer-reviewed literature. Data extraction was performed by one of the authors. Diabetes mellitus markedly increases the risk of myocardial infarction, stroke, amputation, and death. The metabolic abnormalities caused by diabetes induce vascular dysfunction that predisposes this patient population to atherosclerosis. Blood pressure control, lipid-lowering therapy, angiotensin-converting enzyme inhibition, and antiplatelet drugs significantly reduce the risk of cardiovascular events. Although diabetic patients undergo revascularization procedures because of acute coronary syndromes or critical limb ischemia, the outcomes are less favorable than in nondiabetic cohorts. Since most patients with diabetes die from complications of atherosclerosis, they should receive intensive preventive interventions proven to reduce their cardiovascular risk.


Mouthguards for the Prevention of Orofacial Injuries in Military and Sports Activities: Part 2, Effectiveness of Mouthguard for Protection From Orofacial Injuries.
This is second of a two-part series on the history and effectiveness of mouthguards (MGs) for protection from orofacial injuries. MGs are hypothesized to reduce orofacial injuries by separating the upper and lower dentation, preventing tooth fractures, redistributing and absorbing the force of direct blows to the mouth, and separating teeth from soft tissue which helps prevent lacerations and bruises. The single study on MG use in military training found that when boil-and-bite MGs were required for four training activities, orofacial injury rates were reduced 56% compared with when MGs were required for just one training activity. A recent systematic review on the effectiveness of MGs for prevention of orofacial injuries included 23 studies involving MG users and nonusers and a wide variety of sports. For cohort studies that directly collected injury data, the risk of an orofacial injury was 2.33 times higher among MG nonusers (95% confidence interval, 1.59-3.44). More well-designed studies are needed on the effectiveness of MGs during military training. Despite some methodological limitations, the current data suggest that MGs can substantially reduce the risk of orofacial injuries in sport activities. MGs should be used in activities where there is a significant risk of orofacial injuries.


Confirmation of crayfish plague in Italy: detection of Aphanomyces astaci in white clawed crayfish.
In the summer of 2009, high levels of mortality among white clawed crayfish Austropotamobius pallipes were observed in 3 watercourses of central Italy. PCR and culture methods were used to detect the causative agent of the disease. Two strains of Aphanomyces spp. were isolated and identified by PCR and DNA sequencing as Aphanomyces astaci and A. repetans. This is the first crayfish plague outbreak in Italy to be confirmed by the isolation in culture of a pathogen from Austropotamobius pallipes.


Medium-term results of ultrasound-guided foam sclerotherapy for small saphenous varicose veins.
The results of surgery for small saphenous varicose vein (SSV) varicosities may be suboptimal in terms of recurrence and complications. The role of minimally invasive alternatives remains incompletely defined. The aim was to review the medium-term outcomes of ultrasound-guided foam sclerotherapy (UGFS) for SSV. Eighty-six patients (92 legs) undergoing UGFS for SSV were assessed before, and 1, 6 and 12 months after treatment. Outcome measures were occlusion of, and abolition of reflux in, the SSV (technical success), absence of visible varicose veins (clinical success) and improvement in disease-specific health-related quality of life (HRQL) following treatment (Aberdeen Varicose Vein Symptom Severity Score (AVSS)). The technical and clinical success rates at 12 months were 91 and 93 per cent respectively; only three patients required a second treatment. After treatment of isolated SSV varicosities there was a significant improvement in AVSS, from a median of 19.0 (interquartile range 13.4-26.8) before treatment to 10.2 (4.0-18.3) and 9.7 (3.5-19.1) at 6 and 12 months respectively. The only complication was a popliteal vein thrombosis that required anticoagulation. UGFS was an effective treatment for SSV, with abolition of reflux and visible varicose veins, and improvement in HRQL for at least 12 months.


The influence of the season and market class of broiler chickens on breast meat quality traits.
The influence of the season and market class of broiler chickens on breast meat quality traits was determined on a total of 18 flocks reared and processed under commercial conditions. According to the Italian poultry production system the following classes of birds were considered: light size (1.2 kg of carcass weight; n = 90) and medium size (1.8 kg of carcass weight; n = 90), represented by females slaughtered at 40 and 52 d old, respectively, whereas heavy size were 57-d-old male broilers (2.4 kg of carcass weight; n = 90). After slaughter, 15 carcasses per flock (n = 270) were randomly collected during winter (n = 135) and summer (n = 135) seasons and used at 24 h postmortem to determine breast (pectoralis major) meat color (lightness, redness, and yellowness), pH, drip and cook loss, as well as Allo-Kramer (AK) shear values. Furthermore, pectoralis minor muscles were used to determine lipid, protein, moisture, and ash content. Finally, because the flocks included white- and yellow-skinned broilers, the color of the carcass skin was measured to assess the relationship between skin and raw breast meat color. With regard to the season, breast meat from birds slaughtered during summer exhibited a paler and less red color, lower pH, higher drip and cook losses, lower AK-shear, and a higher content of moisture and a lower content of protein and ash. In respect to medium and heavy birds, light broilers produced breast meat with higher values of redness, lower pH and cook loss, higher AK-shear values, and a higher content of moisture and ash. Finally, a positive correlation (r = +0.92; P < or = 0.001) between skin and breast meat yellowness was found. These results indicate that during summer, broiler breast meat undergoes a depression of its functionality and quality. Moreover, the market class of birds also determined some differences in breast meat quality attributes.


Development and Characterization of Sodium Hyaluronate Microparticle-Based Sustained Release Formulation of Recombinant Human Growth Hormone Prepared by Spray-Drying.
The purpose of this study was to develop and characterize a sodium hyaluronate microparticle-based sustained release formulation of recombinant human growth hormone (SR-rhGH) prepared by spray-drying. Compared to freeze-drying, spray-dried SR-rhGH showed not only prolonged release profiles but also better particle property and injectability. The results of size-exclusion high-performance liquid chromatography showed that no aggregate was detected, and dimer was just about 2% and also did not increase with increase of inlet temperature up to 150 °C. Meanwhile, the results of reversed-phase high-performance liquid chromatography revealed that related proteins increased slightly from 4.6% at 100 °C to 6.3% at 150 °C. Thermal mapping test proved that product temperature did not become high to cause protein degradation during spray-drying because thermal energy was used for the evaporation of surface moisture of droplets. The structural characterization by peptide mapping, sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and circular dichroism revealed that the primary, secondary, and tertiary structures of rhGH in SR-rhGH were highly comparable to those of reference somatropin materials. The biological characterization by rat weight gain and cell proliferation assays provided that bioactivity of SR-rhGH was equivalent to that of native hGH. These data establish that spray-dried SR-rhGH is highly stable by preserving intact rhGH and hyaluronate microparticle-based formulation by spray-drying can be an alternative delivery system for proteins.


Inducible lethal ventricular arrhythmias in swine with pacing-induced heart failure.
Rapid pacing-induced heart failure provides an excellent animal model for the study of heart failure. We studied the development of ventricular tachyarrhythmias using programmed stimulation in a pacing-induced heart failure model. We also studied action potential characteristics and the relationship between action potential and heart rate. Ten pigs were instrumented and were studied before the onset and every week after rapid pacing was instituted. Weekly echocardiograms and programmed stimulation were done in a sedated state. In vitro electrophysiologic studies were done on left ventricular myocardium in 4 heart-failure animals and 4 controls. All animals developed progressive heart failure with left ventricular dilatation and reduced percentage fractional shortening. No arrhythmias were induced at baseline or the first and second weeks. Ventricular fibrillation was induced in one animal on the third week and 4 animals on week 4, while there was no appreciable worsening in echocardiographic indices of ventricular dysfunction between weeks 3 and 4. Ventricular effective refractory period was unchanged during the 4 weeks. In vitro studies showed action potential prolongation in heart failure myocardium. However, action potential duration at pacing rates >100 bpm were similar to controls. No early or delayed afterdepolarizations were observed. This study demonstrated an increased susceptibility to ventricular fibrillation with the development of heart failure which was not related to the degree of ventricular dysfunction. Also, the normalization of action potential duration at higher heart rates suggests that the increased incidence of inducible ventricular fibrillation in this model may not be solely due to prolonged action potential duration.


Identification of proteins to predict the molecular basis for the observed gender susceptibility in a rat model of alcoholic steatohepatitis by 2-D gel proteomics.
Females are reported to be highly susceptible to alcoholic steatohepatitis (ASH) compared to the males. Although a variety of mechanisms have been proposed to explain this higher sensitivity of females, the precise mechanism is not well understood. The objective of this study was to identify changes in global protein expression in liver tissues of male and female rats with pathologically evident ASH by 2-DE (dimensional electrophoresis). ASH was induced in the SD (Sprague-Dawley) rats by feeding ethanol (EtOH) containing Lieber-DeCarli diet for 6 wk followed by a single injection of lipopolysaccharide (LPS, 10 mg/kg, i.p.). Higher liver injury in females in the ASH group as compared to the males was confirmed by HE stained liver sections. As identified by 2-DE, 22 protein-spots were differentially expressed in the females in the ASH group as compared to the males. Following identification of these proteins by MALDI-MS, they were mainly categorized into metabolism and oxidative stress-related proteins. The expression pattern of a few of these oxidative stress-related proteins like Ferritin Heavy chain (Ferritin-H chain), ER stress protein 60 (ER 60) and Heat-shock protein-60 (HSP 60) were verified by Western blotting. To conclude, the current study has identified a set of proteins that highlights potential novel mechanisms associated with higher liver injury noted in the female rat ASH model.


Controlled in situ nanoscale enhancement of gold nanowire arrays with plasmonics.
The controlled in situ growth of ordered gold nanoparticles and nanowire arrays has been studied by optically tracking changes in the local surface plasmon resonance (LSPR) spectrum. A spectrometer and custom-programmed analysis software track changes in the LSPR spectrum. The peak position, peak height (i.e. extinction intensity) and peak width (e.g. radius of curvature) were tracked over time to quantify the dynamic growth of gold as soon as the system was exposed to a commercial gold enhancement solution. This enables the controlled dynamic growth of nano-objects without the necessity of characterizing the growth and aggregation kinetics of the gold enhancement solution. The result was the successful enhancement of their electrically conductive and plasmonic properties, as well as the controlled growth and transformation of line-patterned nanoparticles into conductive particle-based nanowires.


Current updates in perioperative management of intracerebral hemorrhage.
Spontaneous ICH remains a formidable disease that continues to disable and kill the majority of its victims. Treatment of the disease continues to be controversial and without any proved success, such as improvement in the disease mortality or the resulting disability in survivors. Primary prevention is the most effective medical intervention. Nevertheless, as the population continues to age and patients remain undertreated for hypertension, the incidence of ICH likely will increase, resulting in significant socioeconomic impact on society in the coming years. It is imperative that more research be conducted to improve treatment and outcomes of patients who have ICH. Unlike ischemic stokes or other causes of hemorrhagic stroke, such as SAH, where major advancement of treatment has led to improved outcomes, the increased incidence of ICH has not been matched with any considerable improvement in treatment. This burden to improve therapeutic interventions for patients who have ICH should be shared by all neurosurgeons, stroke neurologists, and critical care physicians who care for these patients on a regular basis. It is hoped that early diagnosis and resuscitation, prevention of hematoma growth, selective surgery or minimally invasive clot evacuation, and judicious critical care and rehabilitation will combine to lessen the burden of this disease.


Comparison of foot orthoses made by podiatrists, pedorthists and orthotists regarding plantar pressure reduction in The Netherlands.
There is a need for evidence of clinical effectiveness of foot orthosis therapy. This study evaluated the effect of foot orthoses made by ten podiatrists, ten pedorthists and eleven orthotists on plantar pressure and walking convenience for three patients with metatarsalgia. Aims were to assess differences and variability between and within the disciplines. The relationship between the importance of pressure reduction and the effect on peak pressure was also evaluated. Each therapist examined all three patients and was asked to rate the 'importance of pressure reduction' through a visual analogue scale. The orthoses were evaluated twice in two sessions while the patient walked on a treadmill. Plantar pressures were recorded with an in-sole measuring system. Patients scored walking convenience per orthosis. The effects of the orthoses on peak pressure reduction were calculated for the whole plantar surface of the forefoot and six regions: big toe and metatarsal one to five. Within each discipline there was an extensive variation in construction of the orthoses and achieved peak pressure reductions. Pedorthists and orthotists achieved greater maximal peak pressure reductions calculated over the whole forefoot than podiatrists: 960, 1020 and 750 kPa, respectively (p < .001). This was also true for the effect in the regions with the highest baseline peak pressures and walking convenience rated by patients A and B. There was a weak relationship between the 'importance of pressure reduction' and the achieved pressure reduction for orthotists, but no relationship for podiatrists and pedorthotists. The large variation for various aspects of foot orthoses therapy raises questions about a consistent use of concepts for pressures management within the professional groups.


CDIP-58 can measure the impact of botulinum toxin treatment in cervical dystonia.
We compared the responsiveness of the Cervical Dystonia Impact Profile (CDIP-58), Medical Outcome Study Short Form-Health Survey (SF-36), Functional Disability Questionnaire (FDQ), and Pain and Activities of Daily Living subscales of the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) in participants with cervical dystonia treated with botulinum toxin A. Subscales of CDIP-58 were more sensitive in detecting statistical and clinical change than comparable subscales of the SF-36, FDQ, and TWSTRS.


Cyclostome studies in the context of vertebrate evolution.
The proceedings in this volume follow from the 15(th) Center for Developmental Biology meeting on "Advances in Cyclostome Research" that we organized. The meeting was held at the CDB RIKEN Kobe Institute on 24 and 25 January 2008 with support from the CDB. Jawless vertebrates have been of interest to embryologists and comparative morphologists for more than a century. While the comparative morphology among lampreys, hagfishes, and gnathostomes has long been recognized in contributing to understanding the origin of jaws and other gnathostome traits, the availability of modern molecular methods has rekindled interest in these topics, and evolutionary developmental biology coupled with paleontology has opened new avenues into the study of gnathostome origins. Within the last decade, because of renewed interest in evolutionary developmental biology, the importance of lampreys and hagfishes to our understanding of vertebrate evolution has undergone resurgence in interest, as evidenced by the sea lamprey genome project currently underway at the National Human Genome Research Institute. As new molecular and imaging techniques become available, both paleontological and neontological questions are being readdressed and are providing new insights and speculation into vertebrate evolution. Thus, we determined the timing was optimal to bring together many of the researchers currently contributing to our understanding of the biology of agnathans. The diversity of speakers at the meeting included evolutionary developmental biologists, phylogenetics and genomics investigators, paleontologists, and endocrinology researchers, because as we move into the 21(st) century, integration among these disciplines has encouraged synergistic activities to develop. The goal of this meeting was to highlight in a single setting the most recent advances in this important basal group of vertebrates to facilitate interactions among the cyclostome community. Secondarily, we also hope that this gathering will enhance the visibility of jawless vertebrates as important models in the vertebrate "evo-devo" community. Several topics for further discussion emerged at this symposium, including: genomic data that have spurred renewed interest in gene duplications and their contribution to our understanding of cyclostome phylogeny and vertebrate evolution; the use of paleontology coupled with modern imaging techniques to clarify vertebrate phylogeny; and the evolution of the neuroendocrine and adaptive immune systems. These were among the topics that led to fruitful discussion. Here we summarize key research topics from the symposium that continue to advance as we move forward in the 21(st) century.


Reductions in Drinking Predict Increased Distress: Between- and Within-Person Associations between Alcohol Use and Psychological Distress During and Following Treatment.
As the nature of the association between alcohol use disorder (AUD) and other disorders is not well understood, the ways in which psychological distress changes during the course of treatment for AUD are relatively unknown. Existing literatures posit 2 competing hypotheses such that treatment for AUD concurrently decreases alcohol use and psychological distress or treatment for AUD decreases alcohol use and increases psychological distress. The current study examined the ways in which psychological distress changed as a function of treatment for AUD, including the relationship between psychological distress and drinking behaviors. Secondary data analysis was conducted on an existing clinical trial dataset that investigated the effect of cognitive-behavioral therapy and therapeutic alliance feedback on AUDs. Specifically, data collected at baseline, posttreatment, 3-month, 6-month, 9-month, and 12-month follow-up assessments were examined. Results indicated decreases in heavy drinking days, increases in percentage of days abstinent, and decreases in overall psychological distress. Findings also revealed that changes in psychological distress did not predict changes in drinking at the next time interval; however, decreases in drinking predicted higher psychological distress at the next assessment. Further, average levels of psychological distress were positively associated with rates of drinking. The current study provides some insight into how psychological distress changes during the course of treatment for AUD, including the relationship between changes in drinking and such symptoms. Future research should continue to explore these relationships, including the ways in which treatment efforts can address what may be seen as paradoxical effects.


The role of radiation therapy in the treatment of medullary thyroid cancer.
Medullary thyroid cancer (MTC) is a neuroendocrine tumor derived from parafollicular or C cells of the thyroid gland. Surgical resection is the mainstay of treatment for MTC. External-beam radiation treatment (EBRT) has traditionally played a limited role in the management of MTC. Despite aggressive surgery, patients at high risk for local recurrence may benefit from adjuvant EBRT. With improvements in radiation technique, adequate dose can be effectively delivered to the region at risk while minimizing dose to surrounding critical structures. Although the role of EBRT in the management of these tumors has thus far been poorly defined, EBRT should be considered as a treatment option for patients with locally advanced MTC to optimize locoregional control.


E-assessment and an e-training program among elderly care staff lacking formal competence: results of a mixed-methods intervention study.
Among staff working in elderly care, a considerable proportion lack formal competence for their work. Lack of formal competence, in turn, has been linked to higher staff ratings of stress symptoms, sleep disturbances and workload. 1) To describe the strengths and weaknesses of an e-assessment and subsequent e-training program used among elderly care staff who lack formal competence and 2) to study the effects of an e-training program on staff members' working life (quality of care and psychological and structural empowerment) and well-being (job satisfaction and psychosomatic health). The hypothesis was that staff who had completed the e-assessment and the e-training program would rate greater improvements in working life and well-being than would staff who had only participated in the e-assessments. An intervention study with a mixed-methods approach using quantitative (2010-2011) and qualitative data (2011) was conducted in Swedish elderly care. Participants included a total of 41 staff members. To describe the strengths and weaknesses of the e-assessment and the e-training program, qualitative data were gathered using semi-structured interviews together with a study-specific questionnaire. To study the effects of the intervention, quantitative data were collected using questionnaires on: job satisfaction, psychosomatic health, psychological empowerment, structural empowerment and quality of care in an intervention and a comparison group. Staff who completed the e-assessments and the e-training program primarily experienced strengths associated with this approach. The results were also in line with our hypotheses: Staff who completed the e-assessment and the e-training program rated improvements in their working life and well-being. Use of the e-assessments and e-training program employed in the present study could be one way to support elderly care staff who lack formal education by increasing their competence; increased competence, in turn, could improve their self-confidence, working life, and well-being.


C1q nephropathy among children with nephrotic syndrome: Ten-year experience from a pediatric nephrology unit.
Abu-Shahin N, Al-Khader A, Qattan D, Akl K. C1q nephropathy among children with nephrotic syndrome: Ten-year experience from a pediatric nephrology unit. Turk J Pediatr 2018; 60: 14-21. C1q nephropathy (C1qN) is a rare glomerulopathy mostly seen in children, and presents with nephrotic syndrome (NS). Diagnosis depends on immunoflourescence or immunohistochemical C1q mesangial deposition, excluding other immune-mediated diseases. We retrospectively investigated C1qN incidence, clinicopathological features, and outcome among pediatric NS in our institution.Clinical data, microscopic slides and corresponding tissue blocks of pediatric renal biopsies were retrieved. According to diagnostic criteria for C1qN, 53 pediatric NS renal biopsies were selected for Anti-C1qA IHC stain microscopic examination. Clinicopathological features and follow up data were recorded. C1qN incidence was 9.4% among pediatric NS biopsies. Mesangial proliferation was the most common histopathological pattern. Steroid dependency with frequent relapses was the most frequent outcome, with a second line immunosuppressant added, yet without impact on progression. Small sample size hinders coherent conclusions; nevertheless, it indicates that C1qN is a rare cause of pediatric NS. C1qN may require second line immunosupressants more often than non-C1q NS.


Health perception, pain, and disability as correlates of anxiety and depression symptoms in primary care patients.
Anxiety and depression occur frequently, and recognition of their symptoms can be difficult because of comorbid medical conditions. The purpose of this study was to analyze the relations among symptoms, diagnoses, and severity of illness as indicators of anxiety and depression in primary care. This was an observational, cross-sectional study of adult patients in a large, academic family medicine clinic. Patients completed the Duke Health Profile, which measures health-related quality of life and screens for anxiety and depression. Providers recorded patient diagnoses and assessed severity of illness. Patients with higher levels of anxiety and depression symptoms were more likely to have the diagnoses of headache, osteoarthritis, abdominal pain, and diabetes mellitus. These diagnoses, however, were no longer highly associated with anxiety and depression after controlling for age, sex, payer status, perceived health, pain, and disability. The indicators of high anxiety and depression symptom levels that persisted after controlling for all the other variables were female sex, low perceived health, more pain, and greater disability. In a primary care setting, female sex, self-reported perceived health, pain, and disability were more predictive of anxiety and depression than any of the most prevalent medical illnesses. Primary care providers need to be knowledgeable about these health measures so they can recognize patients at risk for anxiety and depression regardless of their medical diagnoses.


Identification of prognostic markers in bone sarcomas using proton-decoupled phosphorus magnetic resonance spectroscopy.
It has been hypothesized that the (31)Phosphorus ((31)P) nuclear magnetic resonance spectrum from certain tumors may provide prognostic information. The goal of the present study was to identify prognostic metabolic markers by using proton-decoupled phosphorus magnetic resonance spectroscopic imaging ((31)P MRSI). Twenty patients with bone [osteogenic (OS) and Ewing's (ES) and/or primitive neuroectodermal tumor (PNET)] sarcoma, treated with chemotherapy and surgery or with chemotherapy alone, underwent (31)P MRSI studies pre- and post-therapy. The studies were performed on a 1.5 Tesla General Electric (GE) clinical scanner equipped with a stand-alone proton decoupler and a dual (1)H/(31)P surface coil pair. The limited sensitivity of the (31)P nucleus required that a large soft tissue component of the disease be located within 10 cm (maximum distance) of the body surface and the use of a highly sensitive coil placed near the skin surface. Proton decoupling and nuclear Overhauser enhancement were used to improve the spectral resolution and signal:noise ratio. Baseline (31)P spectral features and metabolic changes with treatment were compared with treatment outcome. The patients were categorized depending on survival as event-free survivors or those who died. The pretreatment nucleoside triphosphate:inorganic phosphate (NTP:P(i)) ratio, an index of tumor bioenergetic status, was significant (P = 0.003) in differentiating event-free survivors versus those who died. The pretreatment NTP:P(i) was higher in patients who were destined to undergo a durable event-free survival compared with those who died. The results are promising, although a prospective study is necessary for confirmation. (31)P MRSI appears to be a useful tool for the prediction of survival before therapy in bone sarcomas.


Ultrasound-enhanced drug delivery for cancer.
Ultrasound, which has traditionally been used as a diagnostic tool, is increasingly being used in non-invasive therapy and drug delivery. Of particular interest to this review is the rapidly accumulating evidence that ultrasound may have a key role to play both in improving the targeting and the efficacy of drug delivery for cancer. Currently available ultrasound-triggerable vehicles are first described, with particular reference to the ultrasonic mechanism that can activate release and the suitability of the size range of the vehicle used for drug delivery. Further mechanical and thermal effects of ultrasound that can enhance extravasation and drug distribution following release are then critically reviewed. Acoustic cavitation is found to play a potentially key role both in achieving targeted drug release and enhanced extravasation at modest pressure amplitudes and acoustic energies, whilst simultaneously enabling real-time monitoring of the drug delivery process. The next challenge in ultrasound-enhanced drug delivery will thus be to develop a new generation of drug-carrying nanoparticles which are of the right size range for delivery to tumours, yet still capable of achieving initiation of cavitation activity and drug release at modest acoustic pressures and energies that have no safety implications for the patient.


Regulatory T cell proliferative potential is impaired in human autoimmune disease.
Human CD4(+)CD25(high)CD127(-)FoxP3(+) regulatory T (Treg) cells suppress immune responses in vitro and in vivo. Reduced suppressive function and/or number of peripheral Treg cells has been previously reported in autoimmune disorders. Treg cells represent the most actively replicating compartment within the CD4(+) cells in vivo, but they are hyporesponsive to classical T cell receptor (TCR) stimulation in vitro, a condition that is secondary to their overactive metabolic state. Here we report that proliferation of Treg cells after TCR stimulation is impaired in subjects with relapsing-remitting multiple sclerosis (RRMS) because of altered interleukin-2 (IL-2) secretion and IL-2 receptor (IL-2R)-signal transducer and activator of transcription 5 (STAT5) signaling. This is associated with decreased expression of the forkhead box P3 (FoxP3) 44- and 47-kDa splicing forms, overactivation of S6 ribosomal protein (a downstream target of the mammalian target of rapamycin, mTOR) and altered activity of the cyclin-dependent kinase inhibitor p27 (p27(kip1)) and extracellular signal-related kinases 1 and 2 (ERK1/2). The impaired capacity of Treg cells to proliferate in RRMS correlates with the clinical state of the subject, where increasing disease severity is associated with a decline in Treg cell expansion. These results suggest a previously unrecognized mechanism that may account for the progressive loss of Treg cells in autoimmune disease.


Mortality at For-Profit Versus Not-For-Profit Hemodialysis Centers: A Systematic Review and Meta-analysis.
We conducted a systematic review and meta-analysis to assess differences in risk-adjusted mortality rates between for-profit (FP) and not-for-profit (NFP) hemodialysis facilities. We searched 10 databases for studies published between January 2001 to December 2019 that compared mortality at private hemodialysis facilities. We included observational studies directly comparing adjusted mortality rates between FP and NFP private hemodialysis providers in any language or country. We excluded evaluations of dialysis facilities that changed their profit status, studies with overlapping data, and studies that failed to adjust for patient age and some measure of clinical severity. Pairs of reviewers independently screened all titles and abstracts and the full text of potentially eligible studies, abstracted data, and assessed risk of bias, resolving disagreement by discussion. We included nine observational studies of hemodialysis facilities representing 1,163,144 patient-years. In pooled random-effects meta-analysis, the odds ratio of mortality in FP relative to NFP facilities was 1.07 (95% CI 1.04-1.11). Patients at FP hemodialysis facilities have 7 percent greater odds of death annually than patients with similar risk profiles at NFP facilities. Approximately 3,800 excess deaths might be averted annually if U.S. FP hemodialysis operators matched NFP mortality rates.


Effects of weight loss on asthma control in obese patients with severe asthma.
Studies on the effects of weight loss in patients with asthma are scarce. No studies have been performed in patients with severe asthma. Therefore, the aim of the present study was to assess the impact of weight loss in patients with severe asthma associated with obesity. This was an open, prospective, randomised study of two parallel groups, in patients with severe uncontrolled asthma and moderate obesity. The primary outcome was the level of asthma control 6 months after initiation of the weight reduction programme, quantified using the Asthma Control Questionnaire (ACQ). We evaluated clinical parameters, lung function, markers of airway inflammation and circulating cytokines. 22 patients were randomised to undergo treatment for obesity and 11 to the control group. The weight reduction programme was associated with significant improvements in asthma control (mean ± se ACQ score 3.02 ± 0.19 to 2.25 ± 0.28 in the treatment group versus 2.91 ± 0.25 to 2.90 ± 0.16 in the controls, p=0.001). This improvement was not accompanied by changes in markers of airway inflammation or bronchial reactivity, but by an increase in forced vital capacity. Our results suggest that weight reduction in obese patients with severe asthma improves asthma outcomes by mechanisms not related to airway inflammation.


Toll-like receptor 3 increases antigen-presenting cell responses to a pro-apoptotic stimulus, yet does not contribute to systemic lupus erythematosus genetic susceptibility.
TLR3 mediates skin solar injury by binding nuclear material released from apoptotic keratinocytes, resulting in the production of pro-inflammatory cytokines. Because the TLR3 gene is located in 4q35, a known systemic lupus erythematosus (SLE) susceptibility locus, we wondered whether TLR3 single nucleotide polymorphisms (SNPs) were associated with inflammatory mechanisms relevant to the development of SLE, and disease susceptibility. Functional assays were carried out in TLR3-transfected HEK293 cells and in monocyte-derived dendritic cells (moDCs). TLR3 and IFNβ immunofluorescence studies were performed in skin samples from 7 SLE patients and 3 controls. We performed a SNP association study in a discovery cohort of 153 patients and 105 controls, followed by a confirmation study in an independent cohort of 1,380 patients and 2,104 controls. TLR3 and IFNβ are overexpressed in SLE skin lesions. TLR3 overexpression in HEK293 cells amplifies their sensitivity to a pro-apoptotic stimulus. Taking advantage of a naturally occurring polymorphic TLR3 variant (rs3775291) that weakly versus strongly responds to poly I:C stimulation, we found that TLR3 is associated with amplified apoptotic responses, production of the Ro/SSA autoantigen and increased maturation of myeloid-derived dendritic cells (moDC) after exposure to UV irradiation. However, TLR3 SNPs are not associated with susceptibility to SLE in a large population of patients and controls. TLR3 is overexpressed in SLE skin lesions and amplifies apoptotic and inflammatory responses to UV-irradiation in antigen-presenting cells in vitro. However, TLR3 SNPs do not impact susceptibility to the development of the disease.


Efficacy of baths with mineral-medicinal water in patients with fibromyalgia: a randomized clinical trial.
The layout of this study, designed as a randomized crossover clinical trial, is to evaluate the efficacy of an intervention with mineral-medicinal water from As Burgas (Ourense) in patients suffering from fibromyalgia. This sample was randomly divided into two groups: group A and group B. In phase 1, group A had 14 baths in thermal water for a month and standard pharmacological treatment; group B, standard pharmacological treatment. Washout period is 3 months. In phase 2, group A had standard treatment and group B had 14 baths in thermal water for a month plus standard treatment. The Fibromyalgia Impact Questionnaire (FIQ) was used; this grades the impact of the illness from 1 (minimum) to 10 (maximum), which was measured in both phases. Twenty-five patients were included in each group and the study was concluded with 20 patients in group A and 20 in group B. The intervention group obtained, once the baths finished, a mean score of 60.3 (± 11.8) and the control group of 70.8 (± 13.0) (p < 0.001). Three months later, the intervention group presented a mean score of 64.4 (± 10.6) and the control group of 5.0 (± 11.3) (p < 0.001). We can therefore conclude that the simple baths with mineral-medicinal water from As Burgas can make an improvement on the impact caused by fibromyalgia.


Improving standards in flexible bronchoscopy for lung cancer.
Can the detection rate of flexible bronchoscopy for lung cancer be increased by a series of simple quality improvement measures? Bronchoscopy-associated clinical parameters were prospectively recorded between 2001 and 2007 in patients with suspected lung malignancy. The detection rate of bronchoscopy, diagnostic yield of each biopsy modality and the possible impact of different service-improvement measures were assessed. 746 bronchoscopies were performed in 704 patients. The detection rate of bronchoscopy for malignancy was 83.6%, and increased over time (67.3% detection rate in 2001 (95% CI 52.9-79.7), 89.7% detection rate in 2007 (95% CI 81.3-95.2); p<0.001). Detection rate increased for bronchoscopically visible (75.0% in 2001 to 94.5% in 2007) and non-visible tumours (41.7% in 2001 to 81.2% in 2007; p<0.001 for both analyses). Prior computed tomography availability was associated with a higher diagnostic yield that did not reach statistical significance. Logistic regression analysis identified tumour visibility, year of study, use of transbronchial needle aspiration and pathologist identity as independent predictors of a positive diagnosis. A significant increase in bronchoscopic detection rate for malignancy occurred in association with a number of simple improvement measures.


The Boston-area HASWIC Research Circle: an innovative participatory method for coloring in the picture of a special work environment.
Recent qualitative studies have investigated some of the hazards affecting women in non-traditional trades such as construction. However, one-time interactions among researcher participants, and between researchers and participants, in standard settings such as focus groups and interviews, cannot provide the time, space, and relationships to fully explore tradeswomen's in-depth knowledge of their work environment. This study applied a Scandinavian method called the Research Circle to convene a group of experienced women construction workers repeatedly over a period of two years so they could collaborate with researchers in explaining workplace issues. The results both validated and expanded upon previous findings about health and safety for women in construction, including gender discrimination, lack of access to sanitary facilities, retaliation for reporting hazards and injuries, and inadequate training and equipment. Especially important, findings illustrate some of the complex hierarchical social structures involved in both female and male construction workers responding to hazardous conditions.


Interpretation and content validity of the items of the numeric rating version short-WORC to evaluate outcomes in management of rotator cuff pathology: a cognitive interview approach.
The shortened version of the Western Ontario Rotator Cuff Index (Short-WORC) is a patient reported outcome measure that evaluates quality of life (QoL) of patients with rotator cuff pathology. However, formal content validation of the full or Short-WORC has not been reported. This study aims to understand how 1) people interpret and calibrate responses to items on the Short-WORC and 2) compensatory strategies that might enhance function and thereby affect responses. This study uses cognitive interviewing, a qualitative methodology that focuses on the interpretation of questionnaire items. Patients with rotator cuff disorders (n = 10), clinicians (n = 6) and measurement researchers (n = 10) were interviewed using a talk aloud structured interview that evaluated each of the 7 items of the Short-WORC. All interviews were recorded and transcribed verbatim by one researcher (R.F). Analysis was done through an open coding scheme using a previously established framework. Overall, the items on the Short-WORC were well received by participants. Through the interviews, the 6 themes of: Comprehension, Inadequate response definition, Reference Point, Relevance, Perspective Modifiers and Calibration Across Items emerged. The items of working above the shoulder (90%), compensating with the unaffected arm (88%) and lifting heavy objects (92%) were the most relevant to participants. Participants calibrated their scores on the items of sleeping and styling (19%) the most. Perspective modifiers of gender, influenced the calibrations of items of styling your hair (30%) and dressing or undressing (19%). Compensatory strategies of task-re allocation and using assistive devices/resources were frequently mentioned by participants. Overall, participants had minor comprehension issues, but found the 7- items of the Short-WORC to be relevant to QoL. Therefore, the findings demonstrate that the Short-WORC is not cognitively complex, but varies with patient perspectives. Overall, the Short-WORC provides evidence of demonstrating strong content validity when used for rotator cuff disorder patients.


Design and characterization of microporous hyaluronic acid hydrogels for in vitro gene transfer to mMSCs.
The effective and sustained delivery of DNA locally could increase the applicability of gene therapy in tissue regeneration and therapeutic angiogenesis. One promising approach is to use porous hydrogel scaffolds to encapsulate and deliver nucleotides in the form of nanoparticles to the affected sites. We have designed and characterized microporous (μ-pore) hyaluronic acid hydrogels which allow for effective cell seeding in vitro post-scaffold fabrication and allow for cell spreading and proliferation without requiring high levels of degradation. These factors, coupled with high loading efficiency of DNA polyplexes using a previously developed caged nanoparticle encapsulation (CnE) technique, then allowed for long-term sustained transfection and transgene expression of incorporated mMSCs. In this study, we examined the effect of pore size on gene transfer efficiency and the kinetics of transgene expression. For all investigated pore sizes (30, 60, and 100 μm), encapsulated DNA polyplexes were released steadily, starting by day 4 for up to 10 days. Likewise, transgene expression was sustained over this period, although significant differences between different pore sizes were not observed. Cell viability was also shown to remain high over time, even in the presence of high concentrations of DNA polyplexes. The knowledge acquired through this in vitro model can be utilized to design and better predict scaffold-mediated gene delivery for local gene therapy in an in vivo model where host cells infiltrate the scaffold over time.


Inference in road ecology research: what we know versus what we think we know.
Roads and traffic impacts on wildlife populations are well documented. Three major mechanisms can cause them: reduced connectivity, increased mortality and reduced habitat quality. Researchers commonly recommend mitigation based on the mechanism they deem responsible. We reviewed the 2012-2016 literature to evaluate authors' inferences, to determine whether they explicitly acknowledge all possible mechanisms that are consistent with their results. We found 327 negative responses of wildlife to roads, from 307 studies. While most (84%) of these responses were consistent with multiple mechanisms, 60% of authors invoked a single mechanism. This indicates that many authors are over-confident in their inferences, and that the literature does not allow estimation of the relative importance of the mechanisms. We found preferences in authors' discussion of mechanisms. When all three mechanisms were consistent with the response measured, authors were 2.4 and 2.9 times as likely to infer reduced habitat quality compared to reduced connectivity or increased mortality, respectively. When both reduced connectivity and increased mortality were consistent with the response measured, authors were 5.2 times as likely to infer reduced connectivity compared to increased mortality. Given these results, road ecologists and managers are likely over-recommending mitigation for improving habitat quality and connectivity, and under-recommending measures to reduce road-kill.


Development of flexible fibre biofilm reactor for treatment of food processing wastewater.
Biological treatment methods are usually effective and commonly used in the treatment of organic wastewater. However, there are a number of problems for conventional biological treatment methods in treating wastewater from industries such as food processing. For example, microorganisms in the aeration tank in an activated sludge process cannot survive a continuous series of shock loads and the process could become operationally unstable. The associated problem of sludge bulking often occurs when the organic loading to the treatment process is high. In this paper, a new flexible fibre biofilm reactor was developed for the treatment of wastewater from fruit and vegetable processing plants. Experiments were carried out to evaluate the performance of the treatment process. Acclimatisation characteristics of the treatment process were also evaluated. The removal efficiencies for COD and BOD5 for different influent organic strengths evaluated. Results indicated that over 90% COD removal and 95% BOD5 removal could be achieved. The performance parameters were also compared with a conventional activated sludge process under similar conditions, operated in parallel. It was found that the biofilm reactor exhibited a number of advantages over the conventional reactor. These include (a) high organic loading rate, (b) long sludge retention times and low sludge discharge rate in the settling tank (about 10%), (c) elimination of the sludge recycle stream, and (d) no sludge bulking problem at high organic loading rates. Therefore, the flexible fibre biofilm reactor can provide a more efficient and cost effective treatment for wastewater from food processing industries.


The prevalence of anti-hepatitis C antibody among acute febrile illness cases in Idar Taluk, Gujarat, West India.
The major cause of chronic hepatitis is infections with hepatitis B virus and hepatitis C virus (HCV) globally. However, there exists sparse epidemiological data regarding the prevalence of HCV infection from India. We carried out a cross-sectional study to estimate the prevalence of anti-HCV antibody among acute febrile illness cases aged between 1 and 65 years in Idar Taluk, Sabarkantha district, Gujarat state located in West India. A total of 702 serum samples collected from the study area during the year 2017, were screened for anti-hepatitis C IgG by enzyme-linked immunosorbent assay. The serum samples screened positive were then subjected to molecular testing for confirmation. Among the 702 study participants screened, 16 cases were reported to be anti-HCV IgG positive with an estimated seroprevalence rate of 2.3% (95% confidence interval: 1.4%-3.7%). Out of the 16 cases, two samples were confirmed positive by molecular testing indicating active infection. When analysed phylogenetically, one strain was genotyped as HCV1b genotype, and the other one was clustered along with HCV3a genotype. Both the patients with hepatitis C infection were observed to be having a probable 1-year survival rate of 100% and a 2-year survival rate of 85% when the Child-Turcotte-Pugh classification was applied. The estimated seroprevalence of hepatitis C in Idar Taluk, Sabarkantha district, west India was 2.3%. HCV genotypes 1b and 3a were observed to be circulating in the study area.


Piriformis muscle: clinical anatomy and consideration of the piriformis syndrome.
Patients with lumbosacral and buttock pain provide tacit support for recognizing the piriformis muscle as a contributing factor to the pain (piriformis syndrome). One hundred and twelve cadaveric specimens were observed to elucidate the anatomical variations of the piriformis muscle referred to the diagnostic and treatment of the piriformis syndrome. The distance between the musculotendinous junction and the insertion was measured and the piriformis categorized into three types: Type A (71, 63.39%): long upper and short lower muscle belly; Type B (40, 35.71%): short upper and long lower muscle belly; Type C (1, 0.9%): fusion of both muscle bellies at the same level. The diameter of the piriformis tendon at the level of the musculotendinous junction ranged from 3 to 9 mm (mean: 6.3 mm). The piriformis showed the following possible fusions with adjacent tendons. In type one (60, 53.57%) a rounded tendon of the piriformis reached the upper border of the greater trochanter. In type two (33, 29.46%) it first joined into the gemellus superior tendon and at last both fused with the obturator internus tendon and inserted into the medial surface of the greater trochanter. A fusion of the piriformis, obturator internus and gluteus medius tendon with the same insertion area as above was observed in type three (15, 13.39%) and finally in type four (4, 3.57%) the tendon fused with the gluteus medius to reach the upper surface of the greater trochanter. Based on this survey anatomical causes for the piriformis syndrome are rare and a more precise workup is necessary to rule out more common diagnosis.


[Consumption of alcohol and other drugs by the active population in Spain].
To describe consumption patterns of alcohol and other drugs in the active population in Spain by gender. Based on 15,082 active persons selected from the Domiciliary Survey of Alcohol and Drugs (Encuesta Domiciliaria de Alcohol y Drogas [EDADES]) 2007, we estimated prevalences for high-risk alcohol consumption (>50 g/day in males, >30 g/day in females), daily intake of tranquilizers, cannabis consumption in the last 30 days, and consumption of any other illegal drug in the last 12 months, by employment status, economic sector and occupational categories. Odds ratios (OR) and their confidence intervals (95% CI) were estimated by logistic regression models. The following prevalences were found: high-risk alcohol consumption, 3.4%; daily use of tranquilizers, 2.3%; cannabis consumption in the last 30 days, 7.9%; and consumption of any illegal drug in the last 12 months, 11.9%. Except for tranquilizer use, prevalences were higher in men than in women. Consumption of tranquilizers (OR = 1.68; 95%CI: 1.04-2.73), cannabis and other illegal drugs were all higher in unemployed men than in employed men, while only tranquilizer consumption was higher in unemployed women (OR = 1.70; 95% CI: 1.23-2.34). High-risk alcohol consumption was greater among men engaged in the catering, primary production and construction sectors in comparison to manufacturing industries: OR = 1.63 (95% CI: 1.11-2.38), OR = 1.52 (95% CI: 1.04-2.20), and OR = 1.50 (95% CI: 1.10-2.04), respectively. For women, those in catering showed higher consumptions of cannabis (OR = 2.34; 95% CI: 1.28-4.27) and of other illegal drugs (OR = 2.85; 95% CI: 1.71-4.76); the latter were also higher in commerce, transport and administration sectors than in manufacturing industries. These findings could serve as a useful reference for companies wanting to carry out preventive programs, and also for future studies assessing the impact of preventive measures.


What is the risk of acquiring SARS-CoV-2 from the use of public toilets?
Public toilets and bathrooms may act as a contact hub point where community transmission of SARS-CoV-2 occurs between users. The mechanism of spread would arise through three mechanisms: inhalation of faecal and/or urinary aerosol from an individual shedding SARS-CoV-2; airborne transmission of respiratory aerosols between users face-to-face or during short periods after use; or from fomite transmission via frequent touch sites such as door handles, sink taps, lota or toilet roll dispenser. In this respect toilets could present a risk comparable with other high throughput enclosed spaces such as public transport and food retail outlets. They are often compact, inadequately ventilated, heavily used and subject to maintenance and cleaning issues. Factors such as these would compound the risks generated by toilet users incubating or symptomatic with SARS-CoV-2. Furthermore, toilets are important public infrastructure since they are vital for the maintenance of accessible, sustainable and comfortable urban spaces. Given the lack of studies on transmission through use of public toilets, comprehensive risk assessment relies upon the compilation of evidence gathered from parallel studies, including work performed in hospitals and prior work on related viruses. This narrative review examines the evidence suggestive of transmission risk through use of public toilets and concludes that such a risk cannot be lightly disregarded. A range of mitigating actions are suggested for both users of public toilets and those that are responsible for their design, maintenance and management.


The role of gene polymorphisms in endometriosis.
Endometriosis is a benign gynecologic disorder, affecting up to 10% of women, characterized by the presence of functional endometrial tissue at ectopic positions generally within the peritoneum. It is a heritable condition influenced by multiple genetic and environmental factors, with an overall heritability estimated at approximately 50%. In this study, we investigated whether single nucleotide polymorphisms (SNPs) rs7521902, rs10859871 and rs11031006, mapping to WNT4, VEZT and FSHB genetic loci, respectively, are associated with risk for endometriosis in a Greek population. This study included 166 women with histologically confirmed endometriosis diagnosed through surgery and 150 normal controls. Genotyping of the rs7521902, rs10859871 and rs11031006 SNPs was performed with Taqman primer/probe sets. A significant association was detected with the AC genotype of rs7521902 (WNT4) in patients with stage III and IV disease only. Evidence for association with endometriosis was also found for the AC genotype of the rs10859871 of VEZT. Notably, a significant difference in the distribution of the AG genotype and the minor allele A of FSHB rs11031006 SNP was found between the endometriosis patients and controls. We found a genetic association between rs11031006 (FSHB) SNP and endometriosis. WNT4 and VEZT genes constitute the most consistently associated genes with endometriosis. In the present study, an association of rs7521902 (WNT4) and rs10859871 (VEZT) was confirmed in women with endometriosis at the genotypic but not the allelic level.


HER2-positive breast cancer brain metastases: multiple responses to systemic chemotherapy and trastuzumab--a case report.
Brain metastases from metastatic breast cancer typically occur in 10-15% of patients and are associated with survival of 3-6 months. Recent series have shown that women with HER2-positive metastatic breast cancer receiving the drug trastuzumab develop brain metastases more frequently than this, but also that continuation of trastuzumab after diagnosis of brain metastases in such patients is associated with extended survival. Authors have speculated that this is due to improved systemic control of disease; however, a possibility is that trastuzumab may have a beneficial effect on cerebral metastases themselves. We report the case of a woman with HER2-positive metastatic breast cancer who developed multiple brain metastases while on trastuzumab, in whom the addition of systemic chemotherapy to continued trastuzumab has produced multiple treatment responses associated with prolonged survival. This is the first report of its kind.


Hypoxia-induced regulation of nitric oxide synthase in cardiac endothelial cells and myocytes and the role of the PI3-K/PKB pathway.
The roles of endothelial nitric oxide synthase (eNOS), and its putative association with protein kinase B (PKB), and inducible nitric oxide synthase (iNOS) are not well characterized in hypoxic cardiac cells and there is a lack of studies that measure nitric oxide (NO) directly. To measure NO production in cardiomyocytes and cardiac microvascular endothelial cells (CMECs) under baseline and hypoxic conditions and to evaluate the expression, regulation and activation of eNOS, iNOS and PKB. The effect of PI3-K/PKB inhibition on NO production and eNOS expression/activation was also investigated. Adult rat cardiomyocytes and rat CMECs were made hypoxic by cell pelleting and low PO(2) incubation. Intracellular NO was measured by FACS analysis of DAF-2/DA fluorescence, and eNOS, iNOS and PKB were evaluated by Western blotting or flow cytometry. Upstream PKB inhibition was achieved with wortmannin. (1) NO levels increased in both cell types after exposure to hypoxia. (2) In hypoxic CMECs, eNOS was upregulated and activated, no iNOS expression was observed and PKB was activated. (3) In myocytes, hypoxia did not affect eNOS expression, but increased its activation. Activated PKB also increased during hypoxia. FACS analysis showed increased iNOS in hypoxic myocytes. (4) Wortmannin resulted in decreased hypoxia-induced NO production and reduced activated eNOS levels. Cardiomyocytes and CMECs show increased NO production during hypoxia. eNOS seems to be the main NOS isoform involved as source of the increased NO generation, although there may be a role for iNOS and other non-eNOS sources of NO in the hypoxic myocytes. Hypoxia-induced PKB and eNOS activation occurred simultaneously in both cell types, and the PI3-K/PKB pathway was associated with hypoxia-induced NO production via eNOS activation.


Short Communication: Leaf trait relationships in Australian plant species.
Leaf trait data were compiled for 258 Australian plant species from several habitat types dominated by woody perennials. Specific leaf area (SLA), photosynthetic capacity, dark respiration rate and leaf nitrogen (N) and phosphorus (P) concentrations were positively correlated with one another and negatively correlated with average leaf lifespan. These trait relationships were consistent with previous results from global datasets. Together, these traits form a spectrum of variation running from species with cheap but frequently replaced leaves to those with strategies more attuned to a nutrient-conserving lifestyle. Australian species tended to have SLAs at the lower end of the spectrum, as expected in a dataset dominated by sclerophyllous species from low fertility or low rainfall sites. The existence of broad-scale, 'global' relationships does not imply that the same trait relationships will always be observed in small datasets. In particular, the probability of observing concordant patterns depends on the range of trait variation in a dataset, which, itself, may vary with sample size or species-sampling properties such as the range of growth forms, plant functional 'types', or taxa included in a particular study. The considerable scatter seen in these broad-scale trait relationships may be associated with climate, physiology and phylogeny.


A computational model unifies apparently contradictory findings concerning phantom pain.
Amputation often leads to painful phantom sensations, whose pathogenesis is still unclear. Supported by experimental findings, an explanatory model has been proposed that identifies maladaptive reorganization of the primary somatosensory cortex (S1) as a cause of phantom pain. However, it was recently found that BOLD activity during voluntary movements of the phantom positively correlates with phantom pain rating, giving rise to a model of persistent representation. In the present study, we develop a physiologically realistic, computational model to resolve the conflicting findings. Simulations yielded that both the amount of reorganization and the level of cortical activity during phantom movements were enhanced in a scenario with strong phantom pain as compared to a scenario with weak phantom pain. These results suggest that phantom pain, maladaptive reorganization, and persistent representation may all be caused by the same underlying mechanism, which is driven by an abnormally enhanced spontaneous activity of deafferented nociceptive channels.