Suppression of wound healing in tumor bearing animals as a model for tumor-host interaction: mechanism of suppression.
Tumor wound healing was explored as a possible model for tumor-host interactions. Wound healing within tumors progressed normally through the hemorrhagic and inflammatory stages but failed at the mesenchymal ingrowth phase. Due to this failure of mesenchymal ingrowth, no significant collagen deposition could be detected within tumor wounds. Fluid collected from tumor wounds markedly altered fibroblast cytoskeletal structures and profoundly inhibited fibroblast proliferation and collagen synthesis. This suppression did not appear to be the direct consequence of tumor products, since tumor conditioned media enhanced fibroblast proliferation and had no effects on collagen synthesis and fibroblast cytoskeleton. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of lysed fibroblasts demonstrated that two polypeptides (Mr 280,000 and 240,000) were induced in or adherent to fibroblasts exposed to fluid from the tumor wound but not in fibroblasts exposed to fluid obtained from wounds in normal tissue or tumor conditioned media. These findings suggest that tumor wound healing is a model for mesenchymal inhibition within tumors but that the inhibitors are not tumor derived products.


QUANTITATIVE REAL-TIME POLYMERASE CHAIN REACTION FOR COCHLODINIUM FULVESCENS (DINOPHYCEAE), A HARMFUL DINOFLAGELLATE FROM CALIFORNIA COASTAL WATERS(1).
Harmful blooms formed by species of the dinoflagellate Cochlodinium have caused massive fish kills and substantial economic losses in the Pacific Ocean. Recently, prominent blooms of Cochlodinium have occurred in central and southern California (2004-2008), and Cochlodinium cells are now routinely observed in microscopical analysis of algal assemblages from Californian coastal waters. The first documented economic loss due to a Cochlodinium bloom in California occurred in Monterey Bay and resulted in the mortality of commercially farmed abalone. Increasing occurrences of Cochlodinium blooms, the fact that these cells preserve poorly using standard techniques, and the difficulty of identifying preserved specimens using morphological criteria make Cochlodinium species prime candidates for the development of a quantitative real-time polymerase chain reaction (qPCR) approach. The 18S rDNA gene sequenced from Cochlodinium cells obtained from California coastal waters, as well as GenBank sequences of Cochlodinium, were used to design and test a Molecular Beacon(®) approach. The qPCR method developed in this study is species specific, sensitive for the detection of C. fulvescens that has given rise to the recent blooms in the eastern Pacific Ocean, and spans a dynamic abundance range of seven orders of magnitude. Initial application of the method to archived field samples collected during blooms in Monterey Bay revealed no statistically significant correlations between gene copy number and environmental parameters. However, the onset of Cochlodinium blooms in central California was consistent with previously reported findings of correlations to decreased surface temperature and increased inputs of nitrogenous nutrients.


Genetic heterogeneity of skin microvasculature.
Angiogenesis, the formation of new blood vessels from existing vasculature, is a complex process that is essential for normal embryonic development. Current models for experimental evaluation of angiogenesis often use tissue from large vessels like the aorta and umbilical vein, which are phenotypically distinct from microvasculature. We demonstrate that the utilization of skin to measure microvascular angiogenesis in embryonic and adult tissues is an efficient way to quantify microvasculature angiogenesis. We validate this approach and demonstrate its added value by showing significant differences in angiogenesis in monogenic and polygenic mouse models. We discovered that the pattern of angiogenic response among inbred mouse strains in this ex vivo assay differs from the strain distributions of previous in vivo angiogenesis assays. The difference between the ex vivo and in vivo assays may be related to systemic factors present in whole animals. Expression analysis of cultured skin biopsies from strains of mice with opposing angiogenic response was performed to identify pathways that contribute to differential angiogenic response. Increased expression of negative regulators of angiogenesis in C57Bl/6J mice was associated with lower growth rates.


The effects of nicotine on cone and rod b-wave responses in larval zebrafish.
Acetylcholine is present in and released from starburst amacrine cells in the inner plexiform layer (IPL), but its role in retinal function except, perhaps, in early development, is unclear. Nicotinic acetylcholine receptors are thought to be present on ganglion, amacrine, and bipolar cell processes in the IPL, and it is known that acetylcholine increases the spontaneous and light-evoked responses of retinal ganglion cells. The effects of acetylcholine on bipolar cells are not known, and here we report the effects of nicotine on the b-wave of the electroretinogram in larval zebrafish. The b-wave originates mainly from ON-bipolar cells, and the larval zebrafish retina is cone-dominated. Only small rod responses can be elicited with dim lights in wild-type larval zebrafish retinas, but rod responses can be recorded over a range of intensities in a mutant ( n o optokinetic response f ) fi sh that has no cone function. We fi nd that nicotine strongly enhances cone-driven b-wave response amplitudes but depresses rod driven b-wave response amplitudes without, however, affecting rod- or cone-driven b-wave light sensitivity.


Effects of single-dose zileuton on bronchial hyperresponsiveness in asthmatic patients treated with inhaled corticosteroids.
The aim of the study was to determine whether zileuton, an inhibitor of 5-lipoxygenase, attenuated bronchial hyperresponsiveness (BHR) in asthmatic subjects who had marked BHR during maintenance treatment with inhaled corticosteroids (ICS). In a randomized, double-blind, placebo-controlled, cross-over study, a challenge test with histamine (provocative concentration of histamine producing a 20% fall in forced expiratory volume in one second (FEV1) (PC20,Hist)) and with ultrasonically nebulized distilled water (UNDW) (provocative dose of UNDW producing a 20% fall in FEV1 (PD20,UNDW)) was performed in seven patients with asthma after intake of either 400 mg zileuton or placebo. All patients (mean age 33 yrs, mean FEV1 111% of predicted) had marked BHR, as indicated by a mean PD20,UNDW of 4.74 mL under treatment for at least 6 months with up to 800 microg ICS (mean 536 microg daily). On four different occasions, separated by at least 5 days, two UNDW and two histamine challenge tests were performed in random order 3 h after a morning dose of either zileuton or placebo. Neither zileuton nor placebo changed baseline airway calibre prior to provocation. Zileuton increased PC20,Hist from 0.99 to 5.64 mg x mL(-1) (2.1 doubling doses; p<0.03 compared to placebo), and increased PD20,UNDW from 3.10 to 9.31 mL (1.3 doubling doses; p<0.05 compared to placebo). In conclusion, a single dose of 400 mg zileuton attenuates bronchial hyperresponsiveness to histamine and ultrasonically nebulized distilled water in asthmatic patients with marked bronchial hyperresponsiveness during treatment with inhaled corticosteroids.


Non-alcoholic fatty liver diseases: current challenges and future directions.
Non-alcoholic fatty liver diseases (NAFLD) is rapidly becoming the most common cause of chronic liver disease in Western Countries, and a similar trend is expected in Eastern Countries within the next years. This review focusses on the definition of NAFLD and NASH, possible screening mechanisms and the question who should be screened. Still there is a need for non-invasive diagnostic tools and biomarkers for NASH that can quickly and easily diagnose the severity of NAFLD, monitor liver changes, and identify high risk patients. In addition, treatment strategies are discussed as well as the clientele, who should be treated. There are currently no drugs approved for NAFLD. Successful clinical studies with e.g., obeticholic acid and new substances (e.g., cenicriviroc with anti-inflammatory activity) have already been published. If weight-reducing diets and a change in lifestyle fail in the case of severe obesity, bariatric surgery (e.g., gastric bypass or stomach reduction) should be considered. In the case of manifest type 2 diabetes, metformin can be used as an oral antidiabetic of first choice, and GLP-1 agonists have shown beneficial effects on NAFLD. However, up to now the prevention of overweight and lack of exercise targets the most important risk factors. This review aims to identify therapy relevant risk factors, management strategies, and open questions concerning NAFLD patients.


A service-academic partnership in primary care research: one practice's experience.
Further development of a strong research base for general practice is important if the profession is to respond appropriately to its central role in service provision. It can be difficult for general practitioners (GPs) who have not pursued an academic career path to make a significant contribution to research. The development of a service-academic partnership is described, together with an honest account of the difficulties encountered.


Aclarubicin enhances tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis through death receptor 5 upregulation.
Anthracycline drugs are potent anti-tumor agents. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a death ligand with promising anti-cancer effects. However, some tumor types develop resistance to TRAIL. We examined the effect of aclarubicin (ACR), an anthracycline, in combination with TRAIL. The combination of TRAIL and ACR synergistically induced apoptosis in human acute lymphoblastic leukemia Jurkat cells and human lung cancer A549 cells. In contrast, another anthracycline, doxorubicin (DOX), only slightly sensitized Jurkat cells and A549 cells to TRAIL-induced apoptosis, with weaker enhancement of death receptor 5 (DR5) expression than ACR. The RNase protection assay, real time RT-PCR and western blot demonstrated that ACR upregulated the expression of a TRAIL receptor, DR5. Caspase inhibitors and dominant negative DR5 efficiently reduced the apoptotic response to the treatment with ACR and TRAIL, indicating that the combined effect depends on caspase activities and the interaction between TRAIL and its receptor. ACR but not DOX increased the activity of the DR5 gene promoter in Jurkat cells carrying a mutation in the p53 gene, suggesting that ACR upregulates DR5 expression through p53-independent transcription. These results suggest the combination of TRAIL and ACR to be a promising treatment for malignant tumors.


Silicon electro-optic modulators using p-i-n diodes embedded 10-micron-diameter microdisk resonators.
We demonstrate a silicon electro-optic modulator using a 10-micron-diameter microdisk resonator with a laterally integrated p-i-n diode surrounding essentially the entire microdisk. Our experiments reveal a modulation bandwidth of 510 MHz using a Q ~ 16,900 resonance mode under a square-wave drive voltage of ~0.9 V forward bias and ~-6 V reverse bias.


Community factors shaping early age at first sex among adolescents in Burkina Faso, Ghana, Malawi, and Uganda.
Using data from the National Survey of Adolescents (2004), we examine the community-level factors associated with early age at first sex among adolescents 14-19 years old in four African countries. Regression models are fitted separately by sex for each country for an outcome measuring early age at first sex, with a focus on community-level factors as potential influences of age on sexual debut. The community-level factors associated with adolescents' sexual debut vary widely by both country and gender. Community influences that emerge as risk or protective factors of early sexual debut include community levels of adolescent marriage, wealth, religious group affiliation, sex education, parental monitoring, reproductive health knowledge, media exposure, membership in adolescent social group, and use of alcohol. Results indicate the importance of context-specific understanding of adolescents' sexual behaviour and suggest how elements of place should be harnessed in the development of effective HIV and sexual health interventions.


Predicting the relative efficacy of shock waveforms for transthoracic defibrillation in dogs.
Previous work has shown that a passive membrane model using a parallel resistor-capacitor circuit is capable of predicting optimal waveforms for transvenous defibrillation. This study tested the ability of that model to predict optimal waveforms for transthoracic defibrillation. This study was divided into 3 parts, each of which determined transthoracic defibrillation thresholds (DFTs) in 6 dogs for several different waveform shapes and durations. For each part, strength-duration relationships were determined from both experimental and model data and then compared with test model predictions. Part 1 DFTs were determined at various durations for 3 different monophasic waveforms-the ascending ramp, descending ramp, and square waveform. Part 2 DFTs were determined for 3 biphasic waveforms. Phase 1 was a 30-ms ascending ramp, and phase 2 was an ascending ramp, a descending ramp, or a square waveform. Part 3 DFTs were determined for 3 biphasic waveforms with very short second-phase durations. Phase 1 was a 30-ms ascending ramp, and phase 2 was a descending ramp. For part 1, the model was able to predict the relative defibrillation efficacy of the 3 monophasic waveforms ( P < .05). For parts 2 and 3, the model was able to predict the biphasic waveforms with the lowest DFTs. These predictions were based on the criterion that the model response at the end of the second phase should return to or slightly pass the model response value at the beginning of the first phase. The resistor-capacitor model successfully predicted the relative defibrillation efficacy of several different waveforms delivered transthoracically.


Ligand Design for Specific MHC Class I Molecules on the Cell Surface.
We have validated that ligand peptides designed from antigen peptides could be used for targeting specific major histocompatibility complex class I (MHC-I) molecules on the cell surface. To design the ligand peptides, we used reported antigen peptides for each MHC-I molecule with high binding affinity. From the crystal structure of the peptide/MHC-I complexes, we determined a modifiable residue in the antigen peptides and replaced this residue with a lysine with an ε-amine group modified with functional molecules. The designed ligand peptides successfully bound to cells expressing the corresponding MHC-I molecules via exchange of peptides bound to MHC-I. We demonstrated that the peptide ligands could be used to transport a protein or a liposome to cells expressing the corresponding MHC-I. This strategy may be useful for targeted delivery to cells overexpressing MHC-I, which have been observed in autoimmune diseases.


Examining Mental Workload in a Spatial Navigation Transfer Game via Functional near Infrared Spectroscopy.
The goal of this study was to examine the effects of task-related variables, such as the difficulty level, problem scenario, and experiment week, on performance and mental workload of 27 healthy adult subjects during problem solving within the spatial navigation transfer (SNT) game. The study reports task performance measures such as total time spent on a task (TT) and reaction time (RT); neurophysiological measures involving the use of functional near-infrared spectroscopy (fNIRS); and a subjective rating scale for self-assessment of mental workload (NASA TLX) to test the related hypotheses. Several within-subject repeated-measures factorial ANOVA models were developed to test the main hypothesis. The results revealed a number of interaction effects for the dependent measures of TT, RT, fNIRS, and NASA TLX. The results showed (1) a decrease in TT and RT across the three levels of difficulty from Week 1 to Week 2; (2) an increase in TT and RT for high and medium cognitive load tasks as compared to low cognitive load tasks in both Week 1 and Week 2; (3) an overall increase in oxygenation from Week 1 to Week 2. These findings confirmed that both the behavioral performance and mental workload were sensitive to task manipulations.


Mutations in the COL3A1 gene result in the Ehlers-Danlos syndrome type IV and alterations in the size and distribution of the major collagen fibrils of the dermis.
Ehlers-Danlos syndrome type IV (EDS type IV) results from heterozygosity for mutations in the COL3A1 gene that encodes the chains of type III procollagen. By using light, transmission, and scanning electron microscopy, we examined skin biopsies from 22 individuals with EDS type IV in whom the COL3A1 mutations had been identified. The most striking changes in EDS type IV were correlated with point mutations that substituted a residue for a glycine near the carboxyl-terminal end of the triple-helical domain of pro alpha1(III). In three cases with the mutation G1012R, G1018V, or G1021E, cells in the dermis had extremely dilated rough endoplasmic reticulum (RER), the dermis was thin, and there was a reduced proportion of collagen although the proportion of elastic fibers appeared increased. In these tissues, collagen fibrils were small (65-80 nm) compared to normal (95-110 nm). Fibrils 80-90 nm in diameter and moderately dilated RER were found with mutations G769R, G373R, and G061E and with exon-skipping mutations of exons 34 and 45. With mutations G034R and G016C and exon-skipping mutations that deleted the sequences of exons 7, 8, 14, 18, 24, and 27, fibrils were more variable in size (85-120 nm). The composite collagen fibrils characteristic of EDS types I and II were not found in EDS type IV. These findings indicate that mutations in the COL3A1 gene have effects on secretion, fibrillogenesis, and skin architecture that reflect the position and nature of the mutation.


Prehospital Predictors of Traumatic Spinal Cord Injury in Victoria, Australia.
To identify the predictors of traumatic spinal cord injury (TSCI) and describe the differences between confirmed and potential TSCI cases in the prehospital setting. A retrospective cohort study including all adult patients over a six-year period (2007-12) with potential TSCI who were attended and transported by Ambulance Victoria (AV). We extracted potential TSCI cases from the AV data warehouse and linked with the Victorian State Trauma Registry to compare with final hospital diagnosis. We included a total of 106,059 patients with potential TSCI in the study, with 257 having a spinal cord injury confirmed at hospital (0.2%). The median [First and third Quartiles] age of confirmed TSCI cases was 49 [32-69] years, with males comprising 84.1%. Confirmed TSCI were mainly due to falls (44.8%) and traffic incidents (40.5%). AV spinal care guidelines had a sensitivity of 100% to detect confirmed TSCI. There were several factors associated with a diagnosis of TSCI. These were meeting AV Potential Major Trauma criteria, male gender, presence of neurological deficit, presence of an altered state of consciousness, high falls (> 3 meters), diving, or motorcycle or bicycle collisions. This study identified several predictors of TSCI including meeting AV Potential Major Trauma criteria, male gender, presence of neurological deficit, presence of an altered state of consciousness, high falls (> 3 meters), diving, or motorcycle or bicycle collisions. Most of these predictors are included in NEXUS and/or CCR criteria, however, Potential Major Trauma criteria have not previously been linked to the presence of TSCI. Therefore, Emergency Medical Systems are encouraged to integrate similar Potential Major Trauma criteria into their guidelines and protocols to further improve the provider's accuracy in identifying TSCI and to be more selective in their spinal immobilization, thereby reducing unwarranted adverse effects of this practice.


Effect of Free or Immobilized Lactiplantibacillus plantarum T571 on Feta-Type Cheese Microbiome.
Cheese microbiome plays a key role in determining the organoleptic and physico-chemical properties and may be also used as an authenticity tool for distinguishing probiotic cultures. Due to significant reduction of cell viability often witnessed during food production processes and storage, immobilization is proposed to ascertain high probiotic cell loads required to confer the potential health benefits. Hence, the aim of the present study was to investigate the effect of free or immobilized Lactiplantibacillus plantarum T571 on whey protein on feta cheese microbiome. Next-Generation Sequencing technology was used to investigate cheese microbiome. Cheese samples containing free or immobilized Lactiplantibacillus plantarum T571 (a wild type strain isolated from Feta cheese brine) on whey protein, along with products containing commercial starter culture, were analyzed. The results showed a great diversity of bacteria and fungi genera among the samples. An increased presence of Lactobacillus OTUs in cheese with immobilized cells on whey protein was witnessed, highlighting the survival of the strain in the final product. The immobilized culture had also a significant impact on other genera, such as Lactococcus, Leuconostoc and Debaryomyces, which are associated with improved technological characteristics and health benefits. Enrichment of feta cheese with immobilized potential probiotics to secure cell viability consists of an industrial challenge and leads to distinct microbiome composition that may be used as a valuable food authenticity tool.


Clinical features of sustained ventricular tachycardia among various underlying heart diseases.
Clinical findings of 52 patients with sustained ventricular tachycardia (VT) were analyzed to assess the importance of the underlying etiology. Among patients with organic heart diseases, no differences were found in the VT rate, the incidence of syncope, and the number of patients who required DC shock, regardless of the difference of the underlying organic heart diseases. Patients without organic heart disease had usually more benign clinical presentations. The electrophysiologic findings of VT such as inducibility, a mode of induction and incidence of pleomorphism were similar in patients who had organic heart disease of various causes. Neither the incidence of pleomorphism nor occurrence of acceleration of VT rate was found in patients with idiopathic VT, and the incidence of VT induction was low in patients with idiopathic VT of RV origin. Patients with organic heart diseases often died suddenly, and patients when their VT rate was 200/min or higher, developed syncope, even who had normal LV function.


Surgical Reduction and Fixation of Tibial Spine Fractures in Children: Multiple Fixation Strategies.
A tibial spine fracture is an osseous avulsion of the anterior cruciate ligament (ACL) from its attachment on the intercondylar tibial eminence. Most commonly affecting the immature skeletal systems of children between 8 and 14 years old, tibial spine fractures are frequently regarded as the pediatric equivalent to adult midsubstance ACL injuries. While all nondisplaced and selected partially displaced fractures can be treated nonoperatively, surgical fixation is most frequently used for completely displaced tibial spine fractures. The goals of surgery include osseous union, restoration of knee stability, return to function, treatment of associated injuries, and restoration of the range of motion. Current evidence has demonstrated equivalent outcomes for open and arthroscopic reduction strategies, as well as for screw-based and suture-based fixation techniques. The surgeon should be prepared to offer a multitude of fixation techniques based on intraoperative findings that will provide stable anatomic reduction, including, for instance, the use of suture-based fixation in comminuted fragments. This video article demonstrates an arthroscopic procedure to repair a tibial spine fracture, including 3 methods of fixation, in the following major steps: (1) preoperative planning, (2) patient positioning and surgical exposure, (3) evacuation of the hemarthrosis, (4) diagnostic arthroscopy, (5) preparation of the fracture fragment, (6) reduction of the fracture fragment, (7) fixation option 1: screw fixation, (8) fixation option 2: suture anchor, (9) fixation option 3: suture, and (10) dynamic assessment of stability and closure. Excellent functional outcomes using this procedure have been documented and, with appropriate postoperative care that includes range-of-motion exercises beginning as early as 1 to 2 weeks postoperatively, patients are expected to recover function and to resume a normal activity level. Complications, including nonunion, malunion, and arthrofibrosis, can be reduced when patients with completely displaced tibial spine fractures are treated with surgical management.


Phylogenetic and Functional Substrate Specificity for Endolithic Microbial Communities in Hyper-Arid Environments.
Under extreme water deficit, endolithic (inside rock) microbial ecosystems are considered environmental refuges for life in cold and hot deserts, yet their diversity and functional adaptations remain vastly unexplored. The metagenomic analyses of the communities from two rock substrates, calcite and ignimbrite, revealed that they were dominated by Cyanobacteria, Actinobacteria, and Chloroflexi. The relative distribution of major phyla was significantly different between the two substrates and biodiversity estimates, from 16S rRNA gene sequences and from the metagenomic data, all pointed to a higher taxonomic diversity in the calcite community. While both endolithic communities showed adaptations to extreme aridity and to the rock habitat, their functional capabilities revealed significant differences. ABC transporters and pathways for osmoregulation were more diverse in the calcite chasmoendolithic community. In contrast, the ignimbrite cryptoendolithic community was enriched in pathways for secondary metabolites, such as non-ribosomal peptides (NRP) and polyketides (PK). Assemblies of the metagenome data produced population genomes for the major phyla found in both communities and revealed a greater diversity of Cyanobacteria population genomes for the calcite substrate. Draft genomes of the dominant Cyanobacteria in each community were constructed with more than 93% estimated completeness. The two annotated proteomes shared 64% amino acid identity and a significantly higher number of genes involved in iron update, and NRPS gene clusters, were found in the draft genomes from the ignimbrite. Both the community-wide and genome-specific differences may be related to higher water availability and the colonization of large fissures and cracks in the calcite in contrast to a harsh competition for colonization space and nutrient resources in the narrow pores of the ignimbrite. Together, these results indicated that the habitable architecture of both lithic substrates- chasmoendolithic versus cryptoendolithic - might be an essential element in determining the colonization and the diversity of the microbial communities in endolithic substrates at the dry limit for life.


Endotoxin-induced renal failure. I. A role for altered renal microcirculation.
The pathogenesis of sepsis-induced renal failure is multifactorial and only partially understood. In these studies we evaluated intrarenal microcirculatory changes during endotoxemia and the potential role of nitric oxide (NO) and endothelin in these changes. In anesthetized rats endotoxin infusion [lipopolysaccharide (LPS), Escherichia coli serotype 0127:B8; 10 mg/kg/h] resulted in hypotension and a transient enhancement of renal blood flow, with cortical vasodilation and a loss of outer medullary vasodilatory response to hypotension. The initial cortical vasodilation was abolished by the NO synthase inhibitor NG-nitro-L-arginine methyl ester, but not by indomethacin. Direct NO measurements disclosed a gradual rise in cortical NO, despite the waning vasodilatory effect, suggesting antagonizing vasoconstrictive stimuli. In rats pretreated by LPS (1 mg/kg i.p. 1 day earlier) the renal blood flow was reduced to 55% of that of controls. Moreover, the vasodilatory response to LPS infusion was converted into profound cortical and medullary vasoconstriction. In these preconditioned rats the endothelin receptor antagonist bosentan evoked a vasodilatory response and attenuated the vasoconstrictive reaction to LPS infusion. The infusion of another LPS (E. coli serotype 0111:B4) exerted predominant and protracted renal vasodilation without hypotension. In conclusion, different LPS exert diverse systemic and renal hemodynamic responses. The 0127:B8 serotype attenuates renal medullary vasodilation during hypotension, exerts transient cortical vasodilation, and following repeated exposure induces profound renal vasoconstriction. NO and endothelin participate in LPS-induced vascular responses that may predispose to hypoxic tubular damage.


'COVID-19 is just another way to die…': a qualitative longitudinal study of frontline COVID-19 response governance across Syria.
Governance of COVID-19 responses has been challenging for all countries. Syria has been particularly challenged due to protracted multiparty conflict and debilitated health systems fragmented across different areas of control. To improve response governance, better understanding of frontline response policy implementation across the country is needed. This study thus explored perspectives of COVID-19 response governance among frontline healthcare providers over time and across major areas of control. We used a qualitative longitudinal study design, conducting five rounds of remote semistructured interviews in Arabic (ie, approximately eight interviews each in March 2020, July 2020, September 2020, December 2020 and September 2021) with 14 purposively sampled public and private healthcare providers in the three main areas of control (ie, opposition-controlled area, Autonomous Administration-controlled area and al-Assad government-controlled area (GCA)). We conducted integrative thematic analysis in Arabic within and across geography and time. Almost all participants across all areas and rounds expressed distrust of local health authorities and dissatisfaction with COVID-19 response governance. This was most apparent in initial rounds and in GCA. Response planning was identified as insufficient, non-participatory and non-transparent. Limited infrastructure and resources were the main challenges across time, though anticipated rapid virus spread and health systems' collapse did not occur and participant optimism increased over time. Public adherence to prevention measures varied-initially weak due to general scepticism, increasing after first cases were confirmed and then fluctuating with case numbers and challenges of insecurity and misinformation. Perceptions of COVID-19 vaccination varied, with low uptake and hesitancy attributed to misinformation, disinformation and disinterest. Suggested improvements to COVID-19 response governance focused on strengthening health systems' capacity and coordination. This is a unique longitudinal study of COVID-19 responses. Addressing transparency and misinformation should be a first step to improving public engagement and trust and thus response governance for health emergencies in Syria.


Inhibiting pollen reduced nicotinamide adenine dinucleotide phosphate oxidase-induced signal by intrapulmonary administration of antioxidants blocks allergic airway inflammation.
Ragweed extract (RWE) contains NADPH oxidases that induce oxidative stress in the airways independent of adaptive immunity (signal 1) and augment antigen (signal 2)-induced allergic airway inflammation. To test whether inhibiting signal 1 by administering antioxidants inhibits allergic airway inflammation in mice. The ability of ascorbic acid (AA), N-acetyl cystenine (NAC), and tocopherol to scavenge pollen NADPH oxidase-generated reactive oxygen species (ROS) was measured. These antioxidants were administered locally to inhibit signal 1 in the airways of RWE-sensitized mice. Recruitment of inflammatory cells, mucin production, calcium-activated chloride channel 3, IL-4, and IL-13 mRNA expression was quantified in the lungs. Antioxidants inhibited ROS generation by pollen NADPH oxidases and intracellular ROS generation in cultured epithelial cells. AA in combination with NAC or Tocopherol decreased RWE-induced ROS levels in cultured bronchial epithelial cells. Coadministration of antioxidants with RWE challenge inhibited 4-hydroxynonenal adduct formation, upregulation of Clca3 and IL-4 in lungs, mucin production, recruitment of eosinophils, and total inflammatory cells into the airways. Administration of antioxidants with a second RWE challenge also inhibited airway inflammation. However, administration of AA+NAC 4 or 24 hours after RWE challenge failed to inhibit allergic inflammation. Signal 1 plays a proinflammatory role during repeated exposure to pollen extract. We propose that inhibiting signal 1 by increasing antioxidant potential in the airways may be a novel therapeutic strategy to attenuate pollen-induced allergic airway inflammation. Administration of antioxidants in the airways may constitute a novel therapeutic strategy to prevent pollen induced allergic airway inflammation.


Androgen and estrogen metabolism in the reproductive tract and accessory sex glands of the domestic boar (Sus scrofa).
Steroid metabolism in target tissues has relevance in assessing biological response. We have investigated the metabolism of testosterone and estrogens in the reproductive tract and accessory sex glands in the boar. Seminal vesicles were taken from four 6-mo-old animals; and seminal vesicles, prostate, vas deferens, and regions of the epididymis were taken from two mature boars (10 and 24 mo old). Tissues were incubated in 5 ml medium (TC-199) at 34 degrees C under 5% CO(2) and 95% air for 2 h with (3)H-labeled testosterone, estrone, and estradiol-17beta. Aliquots of spent media were taken to measure radioactivity before separation of unconjugated and conjugated steroids on Waters C(18) Sep-Pak cartridges. Sulfoconjugated steroids and glucuronidates were recovered in series from C(18) cartridges after solvolysis and enzyme hydrolysis, respectively. Profiles of metabolites for free and hydrolyzed fractions were obtained from gradient HPLC with acetonitrile:water on a reversed-phase C(18) column. No clear evidence of conjugation was seen for testosterone metabolites. 5alpha-Dihydrotestosterone was the principal metabolite, but the amounts formed depended on the source, with little from the epididymal tissues and seminal vesicles, but greater quantities from the vas deferens (>25%) and prostate (>30%). The most noteworthy feature of estrogen metabolism was the extent of conjugation by all tissues. Almost all radioactivity in the conjugate fractions for the epididymis and vas was present as sulfates. Glucuronidates were seen for the prostate and were the dominant form of conjugation (about 60%) for the seminal vesicles. A striking parallel existed for the profiles of estrogen metabolites from all tissues for unconjugated and hydrolyzed fractions. Only in quantitative terms were some distinctions noted. These overall findings underscore a need to consider local metabolism of steroid hormones in target tissues of the male reproductive system.


Nocturia reported in nightly sleep diaries: common occurrence with significant implications?
Nocturia (nocturnal awakenings associated with urination) is so common a nocturnal behavior that its association with poor sleep is often overlooked. This study examined nocturia and its potential role in poor sleep by examining reported nightly awakenings and associated bathroom trips. Sleep diaries were kept by 119 adults with poor sleep for intervals up to 14 days. Diaries collected data on nightly number of awakenings and nightly number of bathroom trips. The proportion of nocturnal awakenings accompanied by voiding for each night was calculated and averaged within each individual. Demographics and various health conditions were examined in relation to this measure. Nocturia was defined when at least two-thirds of all awakenings were associated with nocturnal voiding. Absence of nocturia was defined when less than one-third of awakenings were associated with voiding. Remaining cases were defined as having possible nocturia. Estimates of nocturia derived from prestudy screening were related to nocturia as defined by sleep diaries. Neither gender nor sleep apnea was associated with nocturia. Unadjusted analyses indicated that individuals with nocturia were more likely to have arthritis and attribute their nighttime awakenings to urge to void than individuals without nocturia. Nocturia is an exceedingly common phenomenon and may be associated with multiple morbidities. RESULTS are discussed in terms of causality and whether the perceived urge to void precedes or follows nocturnal awakening. Correlates of nocturia have important implications, because they can inform interventions that target brain (e.g., cognitive-behavioral treatments for insomnia, sedative/hypnotic medications) versus bladder (e.g., bladder control exercises, medications affecting urine production or urgency).


Trends in the incidence and treatment of necrotizing soft tissue infections: an analysis of the National Hospital Discharge Survey.
Necrotizing soft tissue infections are a rare but potentially fatal condition of the soft tissues caused by virulent, toxin-producing bacteria. In the United States, there is an estimated annual incidence of 0.04 cases per 1000 annually, but previous estimates of the Centers for Disease Control and Prevention had the incidence at 500 to 1500 cases yearly. Early reports of mortality were variable with rates ranging from 46 to 76% but outcomes have been improving over time. The National Hospital Discharge Survey was analyzed to study current trends in the demographics, incidence, use, and mortality of patients diagnosed with necrotizing soft tissue infections. The authors analyzed the 1999, 2002, and 2007 National Hospital Discharge Survey by using a sampling weighting method. A total of 13,648 cases of necrotizing soft tissue infections were identified in 2007. This represents an increase from 12,153 cases in 2002 and 6612 cases in 1999. In the 9 years from 1999 to 2007 the gross incidence of necrotizing soft tissue infections more than doubled. Hospital stay was essentially unchanged within study years, at 16 days. Mean age increased from approximately 50 years in 1999 to 54 years in 2007. Further, mortality went from 10.45% in 1999 to 9.75% in the 2007 survey. The population-adjusted incidence rate increased 91% in the studied years. Rising use of immunosupression, exponential growth in the incidence of obesity, and type 2 diabetes could be a major contributing factor. The mortality rate is far below the rate in reports published from as early as 20 years ago, and at 9.75% compares with modern case series, but is a more accurate measure of mortality in this condition.


Domestication Impacts the Wheat-Associated Microbiota and the Rhizosphere Colonization by Seed- and Soil-Originated Microbiomes, Across Different Fields.
The seed-transmitted microorganisms and the microbiome of the soil in which the plant grows are major drivers of the rhizosphere microbiome, a crucial component of the plant holobiont. The seed-borne microbiome can be even coevolved with the host plant as a result of adaptation and vertical transmission over generations. The reduced genome diversity and crossing events during domestication might have influenced plant traits that are important for root colonization by seed-borne microbes and also rhizosphere recruitment of microbes from the bulk soil. However, the impact of the breeding on seed-transmitted microbiome composition and the plant ability of microbiome selection from the soil remain unknown. Here, we analyzed both endorhiza and rhizosphere microbiome of two couples of genetically related wild and cultivated wheat species (Aegilops tauschii/Triticum aestivum and T. dicoccoides/T. durum) grown in three locations, using 16S rRNA gene and ITS2 metabarcoding, to assess the relative contribution of seed-borne and soil-derived microbes to the assemblage of the rhizosphere microbiome. We found that more bacterial and fungal ASVs are transmitted from seed to the endosphere of all species compared with the rhizosphere, and these transmitted ASVs were species-specific regardless of location. Only in one location, more microbial seed transmission occurred also in the rhizosphere of A. tauschii compared with other species. Concerning soil-derived microbiome, the most distinct microbial genera occurred in the rhizosphere of A. tauschii compared with other species in all locations. The rhizosphere of genetically connected wheat species was enriched with similar taxa, differently between locations. Our results demonstrate that host plant criteria for soil bank's and seed-originated microbiome recruitment depend on both plants' genotype and availability of microorganisms in a particular environment. This study also provides indications of coevolution between the host plant and its associated microbiome resulting from the vertical transmission of seed-originated taxa.


Localized sequence heterogeneity in the long terminal repeats of in vivo isolates of equine infectious anemia virus.
The role of in vivo long terminal repeat (LTR) sequence variation of the lentivirus equine infectious anemia virus (EIAV) has not been explored. In this study, we investigated the heterogeneity found in the LTR sequences from seven EIAV-seropositive horses: three horses with clinical disease and four horses without any detectable signs of disease. LTR sequences were targeted in this study because the LTR U3 enhancer region of tissue culture-derived isolates has been identified as one of the few hypervariable regions of the EIAV genome. Furthermore, LTR variation may regulate EIAV expression in vivo. Both intra- and interanimal sequence variations were investigated. The intra-animal variation was low in seropositive, healthy horses (on average 0.44%). Intra-animal variation was consistently higher in clinically ill horses (0.99%), suggesting that greater numbers of quasispecies of EIAV are present when active virus replication is ongoing. Interanimal comparisons of consensus sequences generated from each horse demonstrated that the enhancer region is a hotspot of sequence variation in vivo. Thirty-seven of the 83 nucleotides that compose the U3 enhancer region were variable between the different in vivo-derived LTRs. The remainder of the LTR that was analyzed was more conserved, 8 of 195 nucleotide positions being variable. Results of electrophoretic mobility shift assays demonstrated that some nucleotide substitutions that occurred in the enhancer region eliminated or altered transcription factor binding motifs that are known to be important for EIAV LTR expression. These data suggested that the selective pressures exerted on the EIAV LTR enhancer sequences are different from those exerted on the remainder of the LTR. Our findings are consistent with the possibility that enhancer sequence hypervariability can alter expression of the virus in tissue macrophages and therefore contribute to clinical disease in infected horses.


Worldwide socioeconomic status and stroke mortality: an ecological study.
The effect of socioeconomic status (SES) on stroke mortality at population level has been controversial. This study explores the association of SES in childhood and adulthood with stroke mortality, as well as variations in this association among countries/regions. Sex-specific stroke mortality at country level with death registry covering ≥ 70% population was obtained from the World Health Organization. Human Development Index (HDI) developed by the United Nations was chosen as the SES indicator. The associations between the latest available stroke mortality with HDI in 1999 (adulthood SES) and with HDI in 1960 (childhood SES) for the group aged 45-54 years among countries were examined with regression analysis. Age-standardized stroke mortality and HDI during 1974-2001 were used to estimate the association by time point. The population data were available mostly for low-middle to high income countries. HDI in 1960 and 1999 were both inversely associated with stroke mortality in the group aged 45-54 years in 39 countries/regions. HDI in 1960 accounted for 37% of variance of stroke mortality among countries/regions; HDI in 1999 for 35% in men and 53% in women (P < 0.001). There was a quadratic relationship between age-standardized stroke mortality and HDI for the countries from 1974 to 2001: the association was positive when HDI < 0.77 but it became negative when HDI > 0.80. SES is a strong predictor of stroke mortality at country level. Stroke mortality increased with improvement of SES in less developed countries/region, while it decreased with advancing SES in more developed areas.


MORPHIN: a web tool for human disease research by projecting model organism biology onto a human integrated gene network.
Despite recent advances in human genetics, model organisms are indispensable for human disease research. Most human disease pathways are evolutionally conserved among other species, where they may phenocopy the human condition or be associated with seemingly unrelated phenotypes. Much of the known gene-to-phenotype association information is distributed across diverse databases, growing rapidly due to new experimental techniques. Accessible bioinformatics tools will therefore facilitate translation of discoveries from model organisms into human disease biology. Here, we present a web-based discovery tool for human disease studies, MORPHIN (model organisms projected on a human integrated gene network), which prioritizes the most relevant human diseases for a given set of model organism genes, potentially highlighting new model systems for human diseases and providing context to model organism studies. Conceptually, MORPHIN investigates human diseases by an orthology-based projection of a set of model organism genes onto a genome-scale human gene network. MORPHIN then prioritizes human diseases by relevance to the projected model organism genes using two distinct methods: a conventional overlap-based gene set enrichment analysis and a network-based measure of closeness between the query and disease gene sets capable of detecting associations undetectable by the conventional overlap-based methods. MORPHIN is freely accessible at http://www.inetbio.org/morphin.


Systematic regional variations in Purkinje cell spiking patterns.
In contrast to the uniform anatomy of the cerebellar cortex, molecular and physiological studies indicate that significant differences exist between cortical regions, suggesting that the spiking activity of Purkinje cells (PCs) in different regions could also show distinct characteristics. To investigate this possibility we obtained extracellular recordings from PCs in different zebrin bands in crus IIa and vermis lobules VIII and IX in anesthetized rats in order to compare PC firing characteristics between zebrin positive (Z+) and negative (Z-) bands. In addition, we analyzed recordings from PCs in the A2 and C1 zones of several lobules in the posterior lobe, which largely contain Z+ and Z- PCs, respectively. In both datasets significant differences in simple spike (SS) activity were observed between cortical regions. Specifically, Z- and C1 PCs had higher SS firing rates than Z+ and A2 PCs, respectively. The irregularity of SS firing (as assessed by measures of interspike interval distribution) was greater in Z+ bands in both absolute and relative terms. The results regarding systematic variations in complex spike (CS) activity were less consistent, suggesting that while real differences can exist, they may be sensitive to other factors than the cortical location of the PC. However, differences in the interactions between SSs and CSs, including the post-CS pause in SSs and post-pause modulation of SSs, were also consistently observed between bands. Similar, though less strong trends were observed in the zonal recordings. These systematic variations in spontaneous firing characteristics of PCs between zebrin bands in vivo, raises the possibility that fundamental differences in information encoding exist between cerebellar cortical regions.


Development and validation of a measurement-based source model for kilovoltage cone-beam CT Monte Carlo dosimetry simulations.
The purpose of this study is to adapt an equivalent source model originally developed for conventional CT Monte Carlo dose quantification to the radiation oncology context and validate its application for evaluating concomitant dose incurred by a kilovoltage (kV) cone-beam CT (CBCT) system integrated into a linear accelerator. In order to properly characterize beams from the integrated kV CBCT system, the authors have adapted a previously developed equivalent source model consisting of an equivalent spectrum module that takes into account intrinsic filtration and an equivalent filter module characterizing the added bowtie filtration. An equivalent spectrum was generated for an 80, 100, and 125 kVp beam with beam energy characterized by half-value layer measurements. An equivalent filter description was generated from bowtie profile measurements for both the full- and half-bowtie. Equivalent source models for each combination of equivalent spectrum and filter were incorporated into the Monte Carlo software package MCNPX. Monte Carlo simulations were then validated against in-phantom measurements for both the radiographic and CBCT mode of operation of the kV CBCT system. Radiographic and CBCT imaging dose was measured for a variety of protocols at various locations within a body (32 cm in diameter) and head (16 cm in diameter) CTDI phantom. The in-phantom radiographic and CBCT dose was simulated at all measurement locations and converted to absolute dose using normalization factors calculated from air scan measurements and corresponding simulations. The simulated results were compared with the physical measurements and their discrepancies were assessed quantitatively. Strong agreement was observed between in-phantom simulations and measurements. For the radiographic protocols, simulations uniformly underestimated measurements by 0.54%-5.14% (mean difference = -3.07%, SD = 1.60%). For the CBCT protocols, simulations uniformly underestimated measurements by 1.35%-5.31% (mean difference = -3.42%, SD = 1.09%). This work demonstrates the feasibility of using a measurement-based kV CBCT source model to facilitate dose calculations with Monte Carlo methods for both the radiographic and CBCT mode of operation. While this initial work validates simulations against measurements for simple geometries, future work will involve utilizing the source model to investigate kV CBCT dosimetry with more complex anthropomorphic phantoms and patient specific models.


Reporting a single case of cystic echinococcosis in retroperitoneal mass of uncertain origin.
Echinococcal disease (hydatid disease (HD) is an endemic parasitosis caused by Echinococcus granulosus in the larval stage, and it is typically due to the production of unilocular cystic lesions, usually involving the liver for the majority of patients and the lungs in 25%, but also any other organs can be potentially involved in developing echinococcal disease. We report a case of extrahepatic, retroperitoneal echinococcal disease, caused by Echinococcus granulosus. The patient underwent a surgical removal of the abdominal mass, revealed by abdominal ultrasound and computerized tomography scanning, and in the founded clinical and radiological suspicion of echinococcal disease, multiple bioptical samples were sent for microbiological analysis and albendazole therapy was started; Echinococcus granulosus protoscolices were found on the bioptical sample, and the diagnosis was successfully confirmed. According to the current parasitology literature on echinococcal disease, extrahepatic localization, although rare, can be found, and it should be considered in the differential diagnosis of an abdominal mass when epidemiological risk factors and anamnestic data are present, regardless of the usual site of the disease.


Serum ferritin is a marker of morbidity and mortality in hemodialysis patients.
We tested the hypothesis that a high concentration of serum ferritin, a frequently used marker of iron stores in dialysis patients and an acute-phase reactant, may be a marker of morbidity and mortality in these patients. To evaluate the impact of ferritin on morbidity and mortality, we reviewed the 6-month hospitalization rates in our dialysis patients retrospectively and subsequently reviewed the mortality among these patients over a 12-month period of time prospectively. One hundred one adult hemodialysis patients (59 men and 42 women; age, 54 +/- 15 years) who had been on hemodialysis for 38 +/- 27 months were studied. All but 5 patients were on intravenous iron with similar iron administration pattern. In the retrospective cohort, ferritin's correlation coefficients for hospitalization days and frequency (both r = +0.39, P: < 0.001) were higher compared with the albumin correlations for hospitalization days (r = -0.31, P: = 0.001) and frequency (r = -0.28, P: = 0.005) and correlation coefficients remained similarly significant after case-mix adjustment. In the prospective study, the "predeath" value of serum ferritin for 17 deceased patients (891 +/- 476 ng/mL) was higher than both their "initial" value (619 +/- 345 ng/mL, P: = 0.007) and the mean ferritin value of 84 surviving and withdrawing patients (639 +/- 358 ng/mL, P: = 0.001). Although Cox proportional hazard analysis showed a significant odds ratio of death only for serum albumin and not for ferritin, logistic regression analysis using the predeath values confirmed the significant impact of both decreased serum albumin and increased serum ferritin as markers of dialysis mortality. After case-mix adjustment, the relative risks of death for a 500 ng/dL increase in serum ferritin was 2.71 (95% confidence interval, 1.06 to 7.02) and for a 0.5 g/dL decrease in serum albumin was 4.48 (95% confidence interval, 1.77 to 11.33). Hence, serum ferritin is a strong predictor of hospitalization in dialysis patients. Although serum albumin is found to be a strong long-term marker of mortality in hemodialysis patients, an increase in serum ferritin appears to be a more reliable short-term marker of death over a 12-month period. Therefore, in the setting of uniform iron administration, a high serum ferritin may be a morbidity risk factor and a recent increase in serum ferritin may carry an increase in the risk of death in these patients.


Computer-assisted design of orbital implants.
The purpose of this study is to report on the use of a computer-assisted design (CAD) system for predictable preoperative planning of orbital implant surgery (determination of the optimal number and position of orbital implants). Preoperative computed tomographic data were processed by interactive software for predictable surgical planning of orbital implant placement. Reformatted images from axial scans were used to analyze the structure of orbital bone and to plan the number of implants to place and the sites in which to place them. Surgeries to correct orbital defects in 6 patients were successfully designed with this method. Seventeen implants were placed in 6 patients with the CAD system with no intraoperative injuries. Satisfactory anatomic and esthetic results were achieved. The new CAD system optimized preoperative surgical planning for orbital implant placement. The software may be applied in other craniofacial areas for implant placement in the future.


Engraftment of human chronic lymphocytic leukemia cells in SCID mice: in vivo and in vitro studies.
Chronic lymphocytic leukemia (CLL) is a heterogeneous disease of the elderly which can present in one of three stages; benign, intermediate or advanced. The molecular events governing the progression of CLL are poorly understood. In order to develop model systems for predicting the aggressiveness of leukemic clones in CLL, in vivo transplantation of SCID mice with CLL cells, and the in vitro growth of CLL cells on mouse and human stromal layers, were investigated. Bone marrow or peripheral blood cells from 40 patients at different stages of CLL were transplanted into 172 immune-deficient SCID mice. Thirty-five percent of SCID mice injected with CLL cells were positive for the presence of human DNA by Southern blot or PCR analysis. The most frequently involved sites were the spleen, lung, kidney and bone marrow, at levels corresponding from 0.1 to 10 percent human DNA. Thrice-weekly intraperitoneal injections of IL-2, alone or in combination with IL-7, did not increase the level of human cell engraftment. SCID mice developed endogenous thymic lymphomas at an incidence of 10-33 percent, a rate that was not increased by CLL cell transplantation. In vitro, CLL cells were able to proliferate for 9 weeks on human stromal layers supplemented with CM (conditioned media from a culture of the human bladder carcinoma cell line 5637), but failed to thrive on the murine stromal cell line MTE cultured either in CM or autologous serum. FACS analysis revealed that 81 percent of proliferating cells on human stromal layers carried the CD5 cell surface marker, identifying them as CLL cells. Previously EBV-negative CLL cells became EBV-positive after 9 to 12 weeks in culture. The results of this study provide a firm foundation for the development of in vivo and in vitro model systems for the study of human CLL.


Predicting fluid responsiveness in children: a systematic review.
Administration of fluid to improve cardiac output is the mainstay of hemodynamic resuscitation. Not all patients respond to fluid therapy, and excessive fluid administration is harmful. Predicting fluid responsiveness can be challenging, particularly in children. Numerous hemodynamic variables have been proposed as predictors of fluid responsiveness. Dynamic variables based on the heart-lung interaction appear to be excellent predictors of fluid responsiveness in adults, but there is no consensus on their usefulness in children. We systematically reviewed the current evidence for predictors of fluid responsiveness in children. A systematic search was performed using PubMed (1947-2013) and EMBASE (1974-2013). Search terms included fluid, volume, response, respond, challenge, bolus, load, predict, and guide. Results were limited to studies involving pediatric subjects (infant, child, and adolescent). Extraction of data was performed independently by 2 authors using predefined data fields, including study quality indicators. Any variable with an area under the receiver operating characteristic curve that was significantly above 0.5 was considered predictive. Twelve studies involving 501 fluid boluses in 438 pediatric patients (age range 1 day to 17.8 years) were included. Twenty-four variables were investigated. The only variable shown in multiple studies to be predictive was respiratory variation in aortic blood flow peak velocity (5 studies). Stroke volume index, stroke distance variation, and change in cardiac index (and stroke volume) induced by passive leg raising were found to be predictive in single studies only. Static variables based on heart rate, systolic arterial blood pressure, preload (central venous pressure, pulmonary artery occlusion pressure), thermodilution (global end diastolic volume index), ultrasound dilution (active circulation volume, central blood volume, total end diastolic volume, total ejection fraction), echocardiography (left ventricular end diastolic area), and Doppler (stroke volume index, corrected flow time) did not predict fluid responsiveness in children. Dynamic variables based on arterial blood pressure (systolic pressure variation, pulse pressure variation and stroke volume variation, difference between maximal or minimal systolic arterial blood pressure and systolic pressure at end-expiratory pause) and plethysmography (pulse oximeter plethysmograph amplitude variation) were also not predictive. There were contradicting results for plethymograph variation index and inferior vena cava diameter variation. Respiratory variation in aortic blood flow peak velocity was the only variable shown to predict fluid responsiveness in children. Static variables did not predict fluid responsiveness in children, which was consistent with evidence in adults. Dynamic variables based on arterial blood pressure did not predict fluid responsiveness in children, but the evidence for dynamic variables based on plethysmography was inconclusive.


Interfering Role of ERα on Adiponectin Action in Breast Cancer.
Obesity is characterized by an excess of adipose tissue, due to adipocyte hypertrophy and hyperplasia. Adipose tissue is an endocrine organ producing many bioactive molecules, called adipokines. During obesity, dysfunctional adipocytes alter adipokine secretion, contributing to pathophysiology of obesity-associated diseases, including metabolic syndrome, type 2-diabetes, cardiovascular diseases and many types of malignancies. Circulating adiponectin levels are inversely correlated with BMI, thus adiponectin concentrations are lower in obese than normal-weight subjects. Many clinical investigations highlight that low adiponectin levels represent a serious risk factor in breast carcinogenesis, and are associated with the development of more aggressive phenotype. A large-scale meta-analysis suggests that BMI was positively associated with breast cancer mortality in women with ERα-positive disease, regardless menopausal status. This suggests the importance of estrogen signaling contribution in breast tumorigenesis of obese patients. It has been largely demonstrated that adiponectin exerts a protective role in ERα-negative cells, promoting anti-proliferative and pro-apoptotic effects, while controversial data have been reported in ERα-positive cells. Indeed, emerging data provide evidences that adiponectin in obese patients behave as growth factor in ERα-positive breast cancer cells. This addresses how ERα signaling interference may enhance the potential inhibitory threshold of adiponectin in ERα-positive cells. Thus, we may reasonably speculate that the relatively low adiponectin concentrations could be still not adequate to elicit, in ERα-positive breast cancer cells, the same inhibitory effects observed in ERα-negative cells. In the present review we will focus on the molecular mechanisms through which adiponectin affects breast cancer cell behavior in relationship to ERα expression.


Evidence to support a food-based dietary guideline on sugar consumption in South Africa.
Since 1997, South Africa has been developing and implementing food-based dietary guidelines for people aged >6 years. The complexity of the population, which contains different ethnic groups, as well as the rapid urbanization that is taking place, means that food-based dietary guidelines need to consider both overnutrition and undernutrition. The initial guidelines did not include guidance on sugar, and the Department of Health was not prepared to approve them until appropriate guidance on sugar was included. This paper summarizes the evidence available for such a guideline and the nature of that evidence. Other low- and middle-income countries, particularly those in Africa, may face a similar dilemma and might learn from our experience.


Atomic and electronic structure at Au/CdSe interfaces.
By means of plane-wave pseudopotential periodic-supercell density functional theory calculations with a gradient-corrected exchange-correlation functional, we investigated the formation and the electronic structure of thin Au overlayers on CdSe(0001) and CdSe(0001) surfaces. We explored several possible Au/CdSe interfaces, including nonstoichiometric cases in which the very interface layer is mixed, namely, contains atoms of both the metal and the semiconductor. The relative formation energies of the computed model structures indicate that the formation of a very thin Au layer on CdSe surfaces can be epitaxial in the very early deposition stages but only in rather Au-rich conditions. The analysis of the band structures, densities of states, and wave functions for the low-energy interfaces reveals that hybridization occurs between the metal and the semiconductor electron states. This hybridization is confined at the very interface and is not expected to have significant consequences on the plasmonic and excitonic excitations that are appealing for nanotechnology applications of metal-semiconductor nanoparticles.


Self-reported mammography use following BRCA1/2 genetic testing may be overestimated.
Adherence to mammographic screening recommendations following BRCA1/2 testing is generally assessed through self-reports. However, the validity of self-reported mammography by women who had undergone BRCA1/2 genetic testing is still unknown. This study aimed to assess the validity of self-reported mammography use in the past 12 months among women who had undergone BRCA1/2 testing. Using a self-administered questionnaire, 307 women who never had cancer were asked 1 year following BRCA1/2 test result disclosure whether they undergone a mammography in the past 12 months. For each participant, this information was compared to that provided by the Quebec Health Insurance Board administrative data set for mammography claims during the same period, here considered as the gold standard. Sensitivity (Sn), specificity (Sp), predictive values, and Cohen's kappa (κ) were calculated. The robustness of these estimates was assessed using sensitivity analysis in which we varied the administrative data time lapses up to 18 months. Overall, the agreement between self-reports and administrative data was 88% (κ = 0.74). Among the 180 participants who had a mammography according to the administrative data, 172 adequately reported this information (Sn = 96%). Sp was moderate (76%), meaning that 24% of those who did not have a mammography reported one. Extending the time lapses to 18 months increased the Sp substantially (Sp = 90%). Self-report overestimates the use of mammography, mainly because women tend to minimize the elapsed time since their last mammography. Self-reports should be used cautiously to assess adherence to mammographic screening following BRCA1/2 testing.


Strength of spatial correlation between structural brain network connectivity and brain-wide patterns of proto-oncogene and neural network construction gene expression is associated with diffuse glioma survival.
Like other forms of neuropathology, gliomas appear to spread along neural pathways. Accordingly, our group and others have previously shown that brain network connectivity is highly predictive of glioma survival. In this study, we aimed to examine the molecular mechanisms of this relationship via imaging transcriptomics. We retrospectively obtained presurgical, T1-weighted MRI datasets from 669 adult patients, newly diagnosed with diffuse glioma. We measured brain connectivity using gray matter networks and coregistered these data with a transcriptomic brain atlas to determine the spatial co-localization between brain connectivity and expression patterns for 14 proto-oncogenes and 3 neural network construction genes. We found that all 17 genes were significantly co-localized with brain connectivity (p < 0.03, corrected). The strength of co-localization was highly predictive of overall survival in a cross-validated Cox Proportional Hazards model (mean area under the curve, AUC = 0.68 +/- 0.01) and significantly (p < 0.001) more so for a random forest survival model (mean AUC = 0.97 +/- 0.06). Bayesian network analysis demonstrated direct and indirect causal relationships among gene-brain co-localizations and survival. Gene ontology analysis showed that metabolic processes were overexpressed when spatial co-localization between brain connectivity and gene transcription was highest (p < 0.001). Drug-gene interaction analysis identified 84 potential candidate therapies based on our findings. Our findings provide novel insights regarding how gene-brain connectivity interactions may affect glioma survival.


Unexpected Inflammatory Effects of Intravaginal Gels (Universal Placebo Gel and Nonoxynol-9) on the Upper Female Reproductive Tract: A Randomized Crossover Study.
Intravaginal anti-HIV microbicides could provide women with a self-controlled means for HIV prevention, but results from clinical trials have been largely disappointing. We postulated that unrecognized effects of intravaginal gels on the upper female reproductive tract might contribute to the lower-than-expected efficacy of HIV microbicides. Our objective was to study the effects of intravaginal gels on the immune microenvironment of the cervix and uterus. In this randomized crossover study, 27 healthy female volunteers used a nightly application of intravaginal nonoxynol-9 (N9) gel as a "failed" microbicide or the universal placebo gel (UPG) as a "safe" gel (intervention cycles), or nothing (control cycle) from the end of menses to the mid-luteal phase. At a specific time-point following ovulation, all participants underwent sample collection for measurements of T-cell phenotypes, gene expression, and cytokine/chemokine protein concentrations from 3 anatomic sites above the vagina: the cervical transformation zone, the endocervix and the endometrium. We used hierarchical statistical models to estimate mean (95% CI) intervention effects, for N9 and UPG relative to control. Exposure to N9 gel and UPG generated a common "harm signal" that included transcriptional up-regulation of inflammatory genes chemokine (C-C motif) ligand 20 (macrophage inflammatory factor-3alpha) and interleukin 8 in the cervix, decreased protein concentrations of secretory leukocyte protease inhibitor, and transcriptional up-regulation of inflammatory mediators glycodelin-A and osteopontin in the endometrium. These results need to be replicated with a larger sample, but underscore the need to consider the effects of microbicide agents and gel excipients on the upper female reproductive tract in studies of vaginal microbicides.


Epidemiological characteristics and clinical features of 32 critical and 67 noncritical cases of COVID-19 in Chengdu.
In December 2019, Wuhan, China, experienced an outbreak of coronavirus (COVID-19). The number of cases has increased rapidly, but information on the clinical characteristics remains limited. This paper describes the epidemiological and clinical characteristics of COVID-19. Early detection and identification of critically ill patients is necessary to facilitate scientific classification and treatment. This study included a retrospective, single-center case series of 99 consecutively hospitalized patients with confirmed COVID-19 at Chengdu Public Health Clinical Medical Center in Chengdu, China, from January 16 to February 20, 2020. The final date of follow-up was February 23, 2020. We collected and analyzed epidemiological, demographic, clinical, laboratory, radiological, and treatment data. We compared outcomes of critically ill patients and noncritically ill patients. Of the 99 hospitalized patients with COVID-19, the median age was 49 years (minimum, 3 months; maximum, 87 years) and 51 (52 %) were men; 42 (42 %) had traveled to or lived in Wuhan and 48 (49 %) had come into close contact with patients with new coronavirus pneumonia; 41 (41 %) patients had underlying disease. Common symptoms included fever (85 [86 %]), dry cough (84 [85 %]), and fatigue (72 [73 %]). We analyzed the clinical characteristics of patients. We expressed the measurement data as mean ± standard deviation. We collected data for age (49.39 ± 18.45 years), number of hospital days (12.32 ± 6.70 days), and laboratory indicators. We compared critically ill and noncritically ill patients: p-values for age, C-reactive protein, high-sensitivity troponin T, prothrombin time, fibrin degradation products, D-Dimer, and CD4+ count were p < 0.001; and p-values for hospital days, white blood cell, neutrophil, lymphocyte, creatine kinase isoenzyme, myoglobin, N-terminal brain natriuretic peptide, and CD8+ count were p < 0.05. We collected data from a single-center case series of 32 hospitalized patients who were critically ill with confirmed COVID-19 in Chengdu, China, and compared data with 67 noncritically ill patients. Elderly patients had chronic underlying diseases, notably cardiovascular disease. Higher C-reactive protein levels, higher levels of myocardial damage, and higher brain natriuretic peptide levels; lower white blood cells, neutrophils, and lymphocytes; and lower CD4 and CD8 counts could be used for early detection and identification of critically ill patients, and dynamic Data observation was more important than at a single moment.


Genomic Variation: Lessons Learned from Whole-Genome CNV Analysis.
One of the most fundamental goals of the study of human genetics was to determine the relationship between genomic variation and human disease. The effects of large-scale structural variation, such as aneuploidy and other cytogenetically visible imbalances, as well as sequence-level variation, have been studied for several decades. However, compared to these, the impact of submicroscopic copy number variants (CNV) has only recently been appreciated. Despite this, lessons learned from the study of CNVs have already proven significant and broadly applicable. From expanding the concept of normal human variation to providing concrete examples of the utility of genomics in clinical care and challenging notions of the genetic architecture of complex disease, CNVs have provided valuable insights into the genomics of human health and development.


Stochastic and spatial dynamics of nematode parasites in farmed ruminants.
Host-parasite systems provide powerful opportunities for the study of spatial and stochastic effects in ecology; this has been particularly so for directly transmitted microparasites. Here, we construct a fully stochastic model of the population dynamics of a macroparasite system: trichostrongylid gastrointestinal nematode parasites of farmed ruminants. The model subsumes two implicit spatial effects: the host population size (the spatial extent of the interaction between hosts) and spatial heterogeneity ('clumping') in the infection process. This enables us to investigate the roles of several different processes in generating aggregated parasite distributions. The necessity for female worms to find a mate in order to reproduce leads to an Allee effect, which interacts nonlinearly with the stochastic population dynamics and leads to the counter-intuitive result that, when rare, epidemics can be more likely and more severe in small host populations. Clumping in the infection process reduces the strength of this Allee effect, but can hamper the spread of an epidemic by making infection events too rare. Heterogeneity in the hosts' response to infection has to be included in the model to generate aggregation at the level observed empirically.


Chemotherapy for colorectal cancer with 5-fluorouracil, cyclophosphamide, and CCNU: comparison of oral and continuous iv administration of 5-fluorouracil.
Forty-six adult patients with colorectal cancer were treated with cyclophosphamide and CCNU administered orally and 5-fluorouracil (5-FU) administered either orally or by continuous iv infusion (FCC-CIF), depending on the availability of hospital beds. The overall response rate in 37 patients with measurable disease was 25%. The response was greater in patients who had had no prior treatment (seven of 20 versus two of 17) and in patients treated with FCC-CIF (six of 19 versus three of 18). Among patients receiving FCC-CIF, response was also greater in those who had received no prior therapy (five of nine versus one of ten). The overall median survival was 7.5 months, regardless of the route of administration of 5-FU. Further investigations are indicated to study the efficacy of 5-FU administered by continuous iv infusion in combination with other agents in patients who have had no prior treatment.


Nutritional aspects of hydrogenated and regular soybean oil added to diets of broiler chickens.
The objective of the present study was to evaluate the effect of degree of saturation of fat incorporated into broiler diets on performance and body fatty acid (FA) profile. The various degrees of saturation were achieved by using regular soybean oil (SO) and hydrogenated soybean oil (HSO), mixed at different proportions. The work was carried out on commercial broilers (Experiment 1) and on lines of chickens divergently selected for high (HF) or low (LF) abdominal fat (Experiment 2). Daily BW gain and gain:feed ratio increased and the amount of feed intake decreased as the dietary fat saturation decreased. Digestibility of total fat and of each of the FA was lowest in the HSO group and reached maximal values when 23% or more of the added oil was SO. The AMEn values of the diets were almost parallel to fat digestibility. The performance of the HF and LF chickens was affected by the degree of saturation similarly to that observed for the commercial stock. The degree of dietary fat saturation had very little effect on saturated FA (C16:0 and C18:0) in body lipids, reduced the level of monoenoic FA (C16:1 and C18:1), and raised that of polyunsaturated FA (PUFA) (C18:2, C18:3, and C20:4). Monoenoic FA were higher, whereas PUFA were lower in the HF than in the LF line. The improved AMEn in diets containing unsaturated fat is probably due to higher fat digestibility, direct deposition of PUFA in body lipids, and lower lipogenesis, associated with lower heat production.


Biomarkers in Aortic Valve Stenosis and their Clinical Significance in Transcatheter Aortic Valve Implantation.
Aortic valve stenosis is one of the most common valvular heart disorders and the prevalence will rise as the population ages. Once symptomatic patients with aortic valve stenosis tend to fare worse with high mortality rates. Aortic valve replacement is indicated in these patients and besides the standard surgical replacement, a less invasive approach, transcatheter aortic valve implantation, has gained momentum and has showed promising and solid results in patients with high surgical risk. An important aspect of evaluating patients with aortic valve stenosis is the ability to choose the best possible candidate for the procedure. In addition, predicting the short and long-term clinical outcomes after the valve replacement could offer the treating physicians a better insight and provide information for optimal therapy. Biomarkers are biological parameters that can be objectively measured and evaluated as indicators of normal biological processes and are easily monitored. The aim of this review is to critically assess some of the most widely used biomarkers at present (natriuretic peptides, troponins, C-reactive protein) and provide an insight in novel biomarkers that are currently being investigated (galectin-3, growth differentiation factor-15, microRNAs) for possible diagnostic and prognostic use in aortic valve stenosis and transcatheter aortic valve implantation respectively.


Silk Fibroin Dissolution in Tetrabutylammonium Hydroxide Aqueous Solution.
Bombyx mori L. silk fibroin (SF) is widely used in different areas due to its ability to form durable and resilient materials with notable mechanical properties. However, in some of these applications the dissolution of SF is required, and this is not often straightforward due to its inability to be dissolved in the majority of common solvents. This work reports a novel approach to dissolve SF using 40 wt % aqueous tetrabutylammonium hydroxide, TBAOH(aq), at mild temperature. A thorough rheological study combined with small-angle X-ray scattering is presented to correlate the SF state in solution with changes in the rheological parameters. The scattering data suggest that the SF conformation in TBAOH(aq) is close to a random coil, possibly having some compact domains linked with flexible random chains. The radius of gyration (Rg) and the molecular weight (Mw) were estimated to be ca. 17.5 nm and 450 kDa, respectively, which are in good agreement with previous works. Nevertheless, a lower Mw value was deduced from rheometry (i.e., 321 kDa) demonstrating a low degree of depolymerization during dissolution in comparison to other harsh processes. The transition from a dilute to a semidilute regime coincides with the estimated critical concentration and is marked by the presence of a shear-thinning behavior in the flow curves, violation of the empirical Cox-Merz rule, and an upward increase in the activation energy. This work paves the way toward the development of advanced high-tech SF-based materials.


Acute effects of smoking of cigarettes with different tar content on plasma oxidant/antioxidant status.
In this study, acute effects of two different types of cigarette smoking on plasma oxidant/antioxidant status were investigated. For this purpose, malondialdehyde (MDA) levels and antioxidant potential (AOP) values were measured in the plasma samples before and after cigarette smoking at fasting. After the first blood sample was obtained, second and third samples were withdrawn at 1.5 h and 3 h. In the first group, subjects smoked five cigarettes with full flavor (FF), and in the second group, five cigarettes with full-flavor low tar (FFLT). Quality classification is made mainly on the basis of tar content of the products. The cigarette with 23 mg tar is defined as FF and that with 12 mg tar as FFLT. MDA level was found to be significantly increased in the 1.5-h plasma samples of both groups, but the increase was greater in the FF group. AOP values, however, were found to be lower in the 3-h plasma samples of both groups, but the decrease was greater in the FF group compared with the FFLT group. It appears that acute smoking causes oxidant stress in blood plasma once exposed to smoke, and then this effect (MDA) begins to decrease. On the other hand, AOP is lowered due to oxidant stress created by smoke. With regard to the types of cigarettes, the FF product seems to be more oxidant than the FFLT product. Our results suggest that antioxidant supplementation might be beneficial for the smokers to cope with the oxidant load derived from cigarette smoke. It is also clearly seen from these results that cigarette manufacturers should reduce tar/nicotine ratio in their products in order to lessen the toxic effects of smoking without causing increased need to smoke.


The "cut-in patch-out" technique for Pancoast tumor resections results in postoperative pain reduction: a case control study.
Since 2001 we have utilized a novel surgical approach for Pancoast tumors in which lobectomy and mediastinal lymph node dissection are performed directly though the chest wall defect. The defect is then patched at the completion of the procedure ("cut-in patch-out") thereby avoiding a separate thoracotomy with rib spreading. We undertook a study to compare outcomes of this novel "cut-in patch-out" technique with traditional thoracotomy for patients with Pancoast tumors. We retrospectively identified 41 patients undergoing surgical resection of Pancoast tumors requiring en-bloc removal of at least 3 ribs at our institution from 1999 to 2012. Surgery was accomplished by either a "cut-in patch-out" technique (n = 25) or traditional posterolateral thoracotomy and separate chest wall resection (n = 16). Multiple variables including patient demographics, neoadjuvant therapy, extent of resection, and pathology were analyzed with respect to outcomes from morbidity, narcotic use, and oncologic perspectives. Baseline demographics, neoadjuvant therapy, and perioperative factors including extent of surgery, complete resections (R0), nodal status and lymph node number, morbidity, and mortality were similar between the two groups. The mean duration of out-patient narcotic use was significantly lower in the "cut-in patch-out" group compared to the thoracotomy group (80.6 days ± 62.4 vs. 158.2 days ± 119.2, p < 0.01). Using multivariate regression analysis, the traditional thoracotomy technique (OR 7.72; p = 0.01) was independently associated with prolonged oral narcotic requirements (>100 days). Additionally, five year survival for the "cut-in patch-out" group was 48% versus the traditional group at 12.5% (p = 0.04). Compared with a traditional thoracotomy and separate chest wall resection approach for P-NSCLC, a "cut-in patch-out" technique offers an alternative approach that appears to have at least oncologic equivalence while decreasing pain. We have more recently adapted this technique to select patients with pulmonary neoplasms involving chest wall invasion and believe further investigation is warranted.


Comparative pathogenicity of Escherichia coli O157 and intimin-negative non-O157 Shiga toxin-producing E coli strains in neonatal pigs.
We compared the pathogenicity of intimin-negative non-O157:H7 Shiga toxin (Stx)-producing Escherichia coli (STEC) O91:H21 and O104:H21 strains with the pathogenicity of intimin-positive O157:H7 and O157:H(-) strains in neonatal pigs. We also examined the role of Stx2d-activatable genes and the large hemolysin-encoding plasmid of O91:H21 strain B2F1 in the pathogenesis of STEC disease in pigs. We found that all E. coli strains that made wild-type levels of Stx caused systemic illness and histological lesions in the brain and intestinal crypts, whereas none of the control Stx-negative E. coli strains evoked comparable central nervous system signs or intestinal lesions. By contrast, the absence of intimin, hemolysin, or motility had little impact on the overall pathogenesis of systemic disease during STEC infection. The most striking differences between pigs inoculated with non-O157 STEC strains and pigs inoculated with O157 STEC strains were the absence of attaching and effacing intestinal lesions in pigs inoculated with non-O157:H7 strains and the apparent association between the level of Stx2d-activatable toxin produced by an STEC strain and the severity of lesions.


Recyclable, Repairable, and Reshapable (3R) Thermoset Materials with Shape Memory Properties from Bio-Based Epoxidized Vegetable Oils.
The preparation of thermosets based on epoxidized vegetable oils (EVOs) involved a peculiar attention in recent years; however, most of them cannot be recycled once cross-linked. In the present work, epoxy thermosetting resins like-vitrimers with dynamic disulfide covalent bonds were prepared by copolymerizing twelve EVOs with 2,2'-dithiodibenzoic acid, as hardener. Here, we show for the first time the reprocessability, repairability, and recyclability properties of EVOs thermosets. The 3R abilities were evaluated in correlation with the EVO epoxy contents, which influence the final thermo-mechanical properties of the recycled material. The virgin versus recycled materials' comparison was studied by FT-IR, DSC, TGA, and DMA, also comparing their swelling ability and high gel content. The study investigates, in addition, the excellent shape memory properties of the reprocessed EVOs/disulfide materials.


An ensemble deep learning approach to evaluate haptic delay from a single trial EEG data.
Haptic technologies are becoming increasingly valuable in Human-Computer interaction systems as they provide means of physical interaction with a remote or virtual environment. One of the persistent challenges in tele-haptic systems, communicating haptic information over a computer network, is the synchrony of the delivered haptic information with the rest of the sensory modalities. Delayed haptic feedback can have serious implications on the user performance and overall experience. Limited research efforts have been devoted to studying the implication of haptic delay on the human neural response and relating it to the overall haptic experience. Deep learning could offer autonomous brain activity interpretation in response to a haptic experience such as haptic delay. In this work, we propose an ensemble of 2D CNN and transformer models that is capable of detecting the presence and redseverity of haptic delay from a single-trial Electroencephalography data. Two EEG-based experiments involving visuo-haptic interaction tasks are proposed. The first experiment aims to collect data for detecting the presence of haptic delay during discrete force feedback using a bouncing ball on a racket simulation, while the second aims to collect data for detecting the severity level (none, mild, moderate, severe) of the haptic delay during continuous force feedback via grasping/releasing of an object in a bucket. The ensemble model showed a promising performance with an accuracy of 0.9142 ± 0.0157 for detecting haptic delay during discrete force feedback and 0.6625 ± 0.0067 for classifying the severity of haptic delay during continuous force feedback (4 levels). These results were obtained based on training the model with raw EEG data as well as their wavelet transform using several wavelet kernels. This study is a step forward towards developing cognitive evaluation of the user experience while interaction with haptic interfaces.


De novo designed peptides for biological applications.
In recent years our ability to design and assemble peptide-based materials and objects de novo (i.e. from first principles) has improved considerably. This brings us to a point where the resulting assemblies are quite sophisticated and amenable to engineering in new functions. Whilst such systems could be used in a variety of ways, biological applications are of particular interest because of the demand for biocompatible, readily produced systems with potential as drug-delivery agents, components of biosensors and scaffolds for 3D cell and tissue culture. This tutorial review describes the building blocks (or tectons) that are being used in peptide assembly, highlights a range of materials and objects that have been produced, notably hydrogels and virus-like particles, and introduces a number of potential applications for the designs.


Heterogeneous susceptibility for uraemic media calcification and concomitant inflammation within the arterial tree.
End-stage renal disease (ESRD) is strongly associated with arterial calcification of the tunica media, decreased vascular compliance and sudden cardiac death. Here, we analysed the distribution pattern of uraemic media calcification and concomitant inflammation in mice and men. Uraemia was induced in DBA/2 mice with high-phosphate diet. Subsequently, we analysed arterial medial calcification using histology, mass spectrometry, and wire myography. Gene expression was quantified using a whole transcriptome array and quantitative PCR. In a cohort of 36 consecutive patients with CKD stage 4-5, we measured the calcium score of the coronary arteries, the ascending thoracic aorta and the infrarenal abdominal aorta using computed tomography scans. Uraemic DBA/2 mice showed only minor calcifications in thoracic aortas, whereas there was overt media calcification in abdominal aortas. The transcriptional profile and immunohistochemistry revealed induction of Vcam1 expression by vascular smooth muscle cells in uraemic abdominal aortas. Macrophages infiltrated the tunica media of the abdominal aorta. Anti-inflammatory treatment did not improve uraemic media calcification in our animal model. Arterial calcifications in ESRD patients showed a similar distribution pattern in computed tomography scans, with higher calcium scores of the abdominal aorta when compared with the thoracic aorta. Taken together, there was a similar heterogeneous pattern of calcification in both mice and humans, where the abdominal aorta was more prone to media calcification when compared with the thoracic aorta. In uraemia, smooth muscle cells of the abdominal aorta showed a phenotypic switch to an inflammatory and osteoblastic phenotype.


Visual art dialogues with elderly persons: effects on perceived life situation.
The investigation was aimed towards constructing a visual art programme for communication with elderly. Pictures of works of art were used in a controlled intervention study. Dialogues were performed with elderly persons (age 82.6 years) at a senior's apartment building. The Wheel Questionnaire parameters structure, motivation, and emotional investment were analysed using ANOVA (mixed model). Significant improvement was found in the visual art group (n = 20) compared with a matched control group (n = 20) over the studied period of time. Communication directions were different in the intervention group compared with the control group. In the intervention group there was an inexhaustible source of topics to be discussed that originated from pictures of works of art. In the control group the dialogues dealt with daily events in the elderly persons' lives. During the final phase of the intervention period it was difficult to find topics of conversation in the control group compared with the intervention group. The visual art programme is an example of how the language of works of art could be used for nursing management. The findings show a new way to care for elderly persons that builds upon elderly persons' knowledge and personal experience.


Incorporating prior information into differential network analysis using non-paranormal graphical models.
Understanding how gene regulatory networks change under different cellular states is important for revealing insights into network dynamics. Gaussian graphical models, which assume that the data follow a joint normal distribution, have been used recently to infer differential networks. However, the distributions of the omics data are non-normal in general. Furthermore, although much biological knowledge (or prior information) has been accumulated, most existing methods ignore the valuable prior information. Therefore, new statistical methods are needed to relax the normality assumption and make full use of prior information. We propose a new differential network analysis method to address the above challenges. Instead of using Gaussian graphical models, we employ a non-paranormal graphical model that can relax the normality assumption. We develop a principled model to take into account the following prior information: (i) a differential edge less likely exists between two genes that do not participate together in the same pathway; (ii) changes in the networks are driven by certain regulator genes that are perturbed across different cellular states and (iii) the differential networks estimated from multi-view gene expression data likely share common structures. Simulation studies demonstrate that our method outperforms other graphical model-based algorithms. We apply our method to identify the differential networks between platinum-sensitive and platinum-resistant ovarian tumors, and the differential networks between the proneural and mesenchymal subtypes of glioblastoma. Hub nodes in the estimated differential networks rediscover known cancer-related regulator genes and contain interesting predictions. The source code is at https://github.com/Zhangxf-ccnu/pDNA. email@example.com. Supplementary data are available at Bioinformatics online.


Dual efficacy of delta opioid receptor-selective ligands for ethanol drinking and anxiety.
Alcoholism and anxiety disorders have a huge impact on society and afflict 17.6 million and 40 million people in the United States, respectively. A strong comorbidity exists between alcoholism and anxiety disorders. Indeed, alcohol withdrawal-induced anxiety is a primary contributing factor for relapse, and anxiolytics are a common adjuvant therapy prescribed for treatment-seeking alcoholics. It is thought that the use of alcohol to self-medicate and relieve anxiety contributes to the development of addiction. Treatment for anxiety disorders and alcoholism exist but are not universally effective. The delta opioid receptor (DOR) plays a role in both alcohol consumption and anxiety, making it a very interesting clinical target. Two pharmacologically distinct DORs have been described: DOR1 and DOR2. We find here that the relative specificity of DOR agonists for DOR1 or DOR2 can greatly affect the effects they exert on ethanol consumption and anxiety. The DOR1 agonist 2-methyl-4aα-(3-hydroxyphenyl)-1,2,3,4,4a,5,12,12aα-octahydro-quinolino[2,3,30g]isoquinoline (TAN-67), although not effective in decreasing anxiety-like behavior in naive mice, has anxiolytic-like properties in ethanol-withdrawn mice. In contrast, a less subtype-selective agonist, (+)-4-[(αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide (SNC80), while also reducing anxiety-like behavior, increases ethanol consumption. In addition, we found that the conical anxiolytic diazepam [DZ; 7-chloro-1-methyl-5-phenyl-3H-1,4-benzodiazepin-2(1H)-one] is a less effective anxiolytic in ethanol-withdrawn mice than in naive mice. Together, our findings suggest that selective DOR agonists can decrease anxiety-like behavior and are more effective than diazepam at reducing ethanol consumption. We believe the dual efficacy of DOR1 agonists makes these receptors an interesting therapeutic target for treatment-seeking alcoholics.