Anti-PEG immunity: emergence, characteristics, and unaddressed questions.
The modification of protein and nanoparticle therapeutics with polyethylene glycol (PEG), a flexible, uncharged, and highly hydrophilic polymer, is a widely adopted approach to reduce RES clearance, extend circulation time, and improve drug efficacy. Nevertheless, an emerging body of literature, generated by numerous research groups, demonstrates that the immune system can produce antibodies that specifically bind PEG, which can lead to the 'accelerated blood clearance' of PEGylated therapeutics. In animals, anti-PEG immunity is typically robust but short-lived and consists of a predominantly anti-PEG IgM response. Rodent studies suggest that the induction of anti-PEG antibodies (α-PEG Abs) primarily occurs through a type 2 T-cell independent mechanism. Although anti-PEG immunity is less well-studied in humans, the presence of α-PEG Abs has been correlated with reduced efficacy of PEGylated therapeutics in clinical trials. The prevalence of anti-PEG IgG and reports of memory immune responses, as well as the existence of α-PEG Abs in healthy untreated individuals, suggests that the mechanism(s) and features of human anti-PEG immune responses may differ from those of animal models. Many questions, including the incidence rate of pre-existing α-PEG Abs and immunological mechanism(s) of α-PEG Ab formation in humans, must be answered in order to fully address the potential complications of anti-PEG immunity.


Pharmacotherapy of hypertension in patients with pre-dialysis chronic kidney disease.
Hypertension is the most common co-morbidity in patients with chronic kidney disease (CKD), with prevalence gradually increasing across CKD Stages to the extent that about 90% of end-stage renal disease (ESRD) patients are hypertensives. Several factors contribute to blood pressure (BP) elevation and guide the therapeutic interventions that should be employed in these patients. This review summarizes the existing data for the management of hypertension, regarding optimal BP targets and the use of major antihypertensive classes in patients with CKD. Management of hypertension in CKD requires both lowering BP levels and reducing proteinuria to minimize the risk of both CKD progression and cardiovascular disease. In this respect, aggressive control of office BP to levels <130/80 mmHg has long been proposed for patients with proteinuric nephropathies. Following evidence from recent studies that confirmed significant reductions in renal and cardiovascular outcomes with strict BP control, most, but not all, of international guidelines, suggest such BP goals for all hypertensive patients, including those with CKD. Use of renin-angiotensin system (RAS) blockers is the treatment of choice for patients with proteinuric nephropathies, while, in most patients with CKD, combination treatment with two, three, or more antihypertensive agents is often required to control BP.


Coagulation and rheological behaviors of soy milk colloidal dispersions.
Coagulation and rheological behaviors of soy milk are reviewed from the viewpoint of colloidal dispersion system. From the results of relative viscosity in the range of small oil body volume fractions, oil bodies containing oleosin behave as rigid spheres. The Krieger-Dougherty equation was found to describe relative viscosities well under high oil body volume fraction. These results indicate that oil bodies in soy milk behave as though suspended matter. Cross-linking between colloid particles occurs when the coagulant is added, and bulky clusters are formed. The viscosity rises due to the hydrodynamic effects of these bulky clusters. A new viscosity equation that combines the Krieger-Dougherty equation and the effective volume fraction could describe the viscos behavior well for wide range of solid contents. Tofu is made by adding a coagulant to soy milk. For lipid concentrations of less than 2%, rupture stress increases depending on the lipid concentration, whereas at concentrations of more than 3%, rupture stress tends to decline. Kinugoshi tofu samples have a maximum value for rupture stress depending on lipid concentration. Digestion of oleosin in high-fat soy milk using papain treatment results in the centrifugal separation of soy milk cream easily. This result indicates that oleosin let oil bodies in soy milk stable. Therefore, it is important to control the state of soy milk colloidal dispersions.


Magnet Ingestions in Children Presenting to Emergency Departments in the United States 2009-2019: A Problem in Flux.
Small rare-earth magnet (SREM) ingestions are a dangerous, potentially fatal health hazard in children. The U.S. Consumer Safety Commission removed these products from the market in 2012 until a federal court decision vacated this action in 2016. The present study aims to investigate whether the reintroduction of SREMs is associated with an increase in the national frequency of magnet ingestions in children. Data from the National Electronic Injury Surveillance System (NEISS) were used to evaluate suspected magnet ingestion (SMI) trends within patients (0-17 years) from 2009 to 2019. SMI cases were stratified (total, small/round, and multiple magnet ingestions) and trend analyses were performed for 2 periods: 2013-2016 (off-market) and 2017-2019 (on-market). National SMI estimates calculated using the NEISS-supplied weights and variance variables. An estimated 23,756 children (59% males, 42% < 5 years old) presented with a SMI from 2009 to 2019 with an average annual case increase of 6.1% (P = 0.01). There was a significant increase in both small/round SMI encounters and multiple magnet ingestion encounters from 2009 to 2019 (P < 0.001 and P < 0.01, respectively). From 2017 to 2019, there was a greater proportion of small/round type SMIs to total SMIs estimated n = 541 (confidence interval [CI], 261-822) and a greater proportion of multiple magnet ingestions to total SMIs estimated n = 797 (CI, 442-1152) (both, P < 0.01). After 2017, there was a 5-fold increase in the escalation of care for multiple magnet ingestions (estimated n = 1094; CI 505-1686). The significant increase in magnet ingestions by children from 2017 to 2019 indicates that regulatory actions are urgently needed to protect children and reverse these trends.


Selection and application of aptamers for p-hydroxybenzyl hydrogen sulfite after Gastrodia elata Bl. fumigated with sulfur.
Gastrodia elata Bl. is a widely used traditional Chinese medicine known for its medicinal properties. However, during the drying process, G. elata is often fumigated with sulfur to prevent corrosion and improve its appearance. Sulfur-fumigation can result in a reduction in the effective components of the herb and can also be hazardous to human health due to the remaining sulfur dioxide. Sulfur-fumigation of G. elata poses a significant challenge to both end-users and researchers. The detection of p-hydroxybenzyl hydrogen sulfite (p-HS) is a useful tool in determining whether G. elata has been fumigated with sulfur. Unfortunately, the current method for detecting p-HS is costly and requires sophisticated instruments. Therefore, there is a need to develop a more cost-effective and user-friendly method for the detection of p-HS. This study utilized the Capture-SELEX technique to screen high-affinity aptamers for p-HS, which were subsequently characterized by isothermal titration calorimetry (ITC). An aptamer sequence (seq 6) with a high affinity of Kd = 26.5 μM was obtained following 8 rounds of selection against p-HS. With the aptamer serving as the recognition element and gold nanoparticles as the colorimetric indicator, a simple and efficient colorimetric sensor was developed for the specific detection of p-HS. This detection method exhibited a limit of detection of 1 μg/ml, while the p-HS recoveries demonstrated a range of between 88.5 % and 105 % for samples of G. elata obtained in the market. In summary, the aptamer exhibited a high affinity for p-HS, and the sensor developed through the use of a colloidal gold detector based on nucleic acid aptamer can be utilized for rapid detection of sulfur-fumigated G. elata. With these findings, this research paper provides valuable scientific insights and highlights significant potential for future studies in this area.


Plate-Like Bi4Ti3O12 Particles and their Topochemical Conversion to SrTiO3 Under Hydrothermal Conditions.
Plate-like Bi4Ti3O12 particles were synthesized using a one-step, molten-salt method from Bi2O3 and TiO2 nanopowders at 800 °C. The reaction parameters that affect the crystal structure and morphology were identified and systematically investigated. The differences between various Bi4Ti3O12 plate-like particles were examined in terms of the ferroelectric-to-paraelectric phase transition and the photocatalytic activity for the degradation of Rhodamine B under UV-Alight irradiation. The results encouraged us to conduct further testing of the as-prepared Bi4Ti3O12 plate-like particles as templates for the preparation of plate-like SrTiO3 perovskite particles using a topochemical conversion under hydrothermal conditions. The characteristics of the Bi4Ti3O12 plates and the reaction parameters for which the SrTiO3 preserved the shape of the initial Bi4Ti3O12 template particles were determined.


Living as a chameleon: girls, anger, and mental health.
One's practice as a school nurse affords numerous privileges. One that stands out in my mind is the privilege of bearing witness to the lives of countless girls as they navigated their own aspirations and the expectations of the culture. The stories they iterated to me in my school nurse office form the basis for this discussion regarding the relationship between anger and mental health. I've come to realize that as a school nurse, I was an anger-story listener. In so being, I was given the opportunity and responsibility to influence positive mental health for numerous girls and young women. This feminist qualitative research project explored girls' lived experiences of anger. The findings suggest that experiences of disrespect, dismissal, denied agency, and a denial of the right to verbalize anger eventually led to self-silencing and an eventual disconnect from this important emotion. The girls described strategies associated with the societal response to their anger that are likened here to the ultra-adaptive strategies that chameleons show to survive.


Whole-Genome DNA Methylation Profiling of CD14+ Monocytes Reveals Disease Status and Activity Differences in Crohn's Disease Patients.
Crohn's disease (CD) is a multifactorial incurable chronic disorder. Current medical treatment seeks to induce and maintain a state of remission. During episodes of inflammation, monocytes infiltrate the inflamed mucosa whereupon they differentiate into macrophages with a pro-inflammatory phenotype. Here, we sought to characterize the circulating monocytes by profiling their DNA methylome and relate it to the level of CD activity. We gathered an all-female age-matched cohort of 16 CD patients and 7 non-CD volunteers. CD patients were further subdivided into 8 CD patients with active disease (CD-active) and 8 CD patients in remission (CD-remissive) as determined by the physician global assessment. We identified 15 and 12 differentially methylated genes (DMGs) when comparing CD with non-CD and CD-active with CD-remissive, respectively. Differential methylation was predominantly found in the promoter regions of inflammatory genes. Comparing our observations with gene expression data on classical (CD14++CD16-), non-classical (CD14+CD16++) and intermediate (CD14++CD16+) monocytes indicated that while 7 DMGs were differentially expressed across the 3 subsets, the remaining DMGs could not immediately be associated with differences in known populations. We conclude that CD activity is associated with differences in DNA methylation at the promoter region of inflammation-associated genes.


Imprinting of molecular recognition sites through electropolymerization of functionalized Au nanoparticles: development of an electrochemical TNT sensor based on pi-donor-acceptor interactions.
Electrochemical sensors for the analysis of TNT with enhanced sensitivities are described. The enhanced sensitivities are achieved by tailoring pi-donor-acceptor interactions between TNT and pi-donor-modified electrodes or pi-donor-cross-linked Au nanoparticles linked to the electrode. In one configuration a p-aminothiophenolate monolayer-modified electrode leads to the analysis of TNT with a sensitivity corresponding to 17 ppb (74 nM). In the second configuration, the cross-linking of Au NPs by oligothioaniline bridges to the electrode yields a functionalized electrode that detects TNT with a sensitivity that corresponds to 460 ppt (2 nM). Most impressively, the imprinting of molecular TNT recognition sites into the pi-donor oligoaniline-cross-linked Au nanoparticles yields a functionalized electrode with a sensitivity that corresponds to 46 ppt (200 pM). The electrode reveals high selectivity, reusability, and stability.


Herbicide (Roundup) pneumonitis.
A case of acute intoxication presented as toxic pneumonitis after exposure to Roundup (glyphosate) (Solaris Group, Monsanto; San Ramon, CA) herbicide in an agriculture worker. The correct etiologic factor causing this specific clinical picture was identified only 2 weeks later, after a thorough occupational history was taken and meticulous delineation of the working conditions and exposures of the involved worker were made. As a rule, occupational related diseases are not readily elucidated by nonoccupational physicians. However, most acute intoxication events are first encountered by such physicians. In these situations, rapid and comprehensive evaluation is necessary in order to clearly identify the causative agent(s) and to initiate the appropriate treatment. Consulting occupational physicians at this early stage may facilitate early and accurate diagnosis.


Biopsychosocial functioning and pain self-efficacy in chronic low back pain patients.
The aim of this study was to examine the relationship between biopsychosocial functioning and pain severity and to evaluate whether pain self-efficacy (PSE) mediates this relationship. This study used archival data from a multidisciplinary pain management program. Participants were 99 individuals (69% female) with chronic low back pain who completed measures of biological, psychological, and social functioning, pain severity, and PSE at admission. They ranged in age from 18 to 72 yr (mean = 42.6, standard deviation = 12.1). Structural equation modeling and bootstrapping techniques were used to test the significance of the mediated model. As we predicted, lower biological functioning (beta = -0.011; 95% confidence interval [CI] = -0.019 to -0.004, p = 0.002) and social functioning (beta = -0.009; 95% CI = -0.016 to -0.003, p = 0.007) were found to significantly predict higher pain severity, and lower social functioning was found to significantly predict lower PSE (beta = 0.196; 95% CI = -0.130 to 0.273, p = 0.002). PSE did not mediate the relationship between biopsychosocial functioning and pain severity, and psychological functioning did not significantly predict pain severity or PSE. These findings suggest that social functioning is an important factor in predicting outcomes and has a number of treatment implications.


Genome-wide association study for feed efficiency and growth traits in U.S. beef cattle.
Single nucleotide polymorphism (SNP) arrays for domestic cattle have catalyzed the identification of genetic markers associated with complex traits for inclusion in modern breeding and selection programs. Using actual and imputed Illumina 778K genotypes for 3887 U.S. beef cattle from 3 populations (Angus, Hereford, SimAngus), we performed genome-wide association analyses for feed efficiency and growth traits including average daily gain (ADG), dry matter intake (DMI), mid-test metabolic weight (MMWT), and residual feed intake (RFI), with marker-based heritability estimates produced for all traits and populations. Moderate and/or large-effect QTL were detected for all traits in all populations, as jointly defined by the estimated proportion of variance explained (PVE) by marker effects (PVE ≥ 1.0%) and a nominal P-value threshold (P ≤ 5e-05). Lead SNPs with PVE ≥ 2.0% were considered putative evidence of large-effect QTL (n = 52), whereas those with PVE ≥ 1.0% but < 2.0% were considered putative evidence for moderate-effect QTL (n = 35). Identical or proximal lead SNPs associated with ADG, DMI, MMWT, and RFI collectively supported the potential for either pleiotropic QTL, or independent but proximal causal mutations for multiple traits within and between the analyzed populations. Marker-based heritability estimates for all investigated traits ranged from 0.18 to 0.60 using 778K genotypes, or from 0.17 to 0.57 using 50K genotypes (reduced from Illumina 778K HD to Illumina Bovine SNP50). An investigation to determine if QTL detected by 778K analysis could also be detected using 50K genotypes produced variable results, suggesting that 50K analyses were generally insufficient for QTL detection in these populations, and that relevant breeding or selection programs should be based on higher density analyses (imputed or directly ascertained). Fourteen moderate to large-effect QTL regions which ranged from being physically proximal (lead SNPs ≤ 3Mb) to fully overlapping for RFI, DMI, ADG, and MMWT were detected within and between populations, and included evidence for pleiotropy, proximal but independent causal mutations, and multi-breed QTL. Bovine positional candidate genes for these traits were functionally conserved across vertebrate species.


[Computer tomographic evaluation of mediastinal lymph nodes in bronchial cancer].
Of all the mediastinal lymph nodes, the retrocaval and pre-tracheal groups can be most frequently demonstrated by computer tomography. With the aim of providing better quantitative assessment, the maximal diameter of these lymph nodes was measured in five patient groups: I Control group (132 cases), II patients with inflammatory lung disease (17 patients), III patients operated for bronchial carcinoma, but without lymph node involvement (62 patients), IV patients operated for bronchial carcinoma with lymph node involvement (eight patients), V patients who have not had surgery, but who had enlarged lymph nodes (16 patients).


[Outbreaks of acute viral gastroenteritis in geriatric homes: threshold detection system for prevalence (SiDUP)].
We describe the interventions carried out in a local epidemiology unit related to the epidemiology of gastroenteritis due to norovirus in geriatric homes in Castellón (Spain) during several years. These range from various outbreaks in the same geriatric home to the study of sporadic cases which determine the endemic situation. This study focuses on the analysis of this endemic situation of digestive symptoms in silent epidemic periods and proposes a simple method to detect the initiation of GEA of progressive transmission (person-person) which we call System of Detection by Prevalence Threshold (SiDUP). The epidemiological spectrum of gastroenteritis due to norovirus in geriatric homes is discussed.


Effects of second-generation histamine H1 receptor antagonists on the sleep-wakefulness cycle in rats.
The present study was performed to examine the sedative effects of second-generation histamine H(1) receptor antagonist using power spectrum analysis in the rat. Similar to ketotifen, olopatadine caused a decrease in sleep latency at a dose of 50 mg/kg, while epinastine and cetirizine showed no significant effect even at a dose of 50 mg/kg. On the other hand, no significant difference was observed in the total times of wakefulness, non-rapid eye movement sleep and rapid eye movement sleep by any drugs used in the experiments. The number of sleep phases and interval between sleep phases were also unchanged by these drugs. Ketotifen and olopatadine inhibited [(3)H]mepyramine binding to rat brain homogenates in parallel with a decrease in sleep latency. No significant effect was observed with epinastine and cetirizine on [(3)H]mepyramine binding. These findings suggest that the differences in the central nervous system (CNS) depressant effect observed in second generation H(1) receptor antagonists may be due to their liability to penetrate into the CNS.


Observation of live ticks (Haemaphysalis flava) by scanning electron microscopy under high vacuum pressure.
Scanning electron microscopes (SEM), which image sample surfaces by scanning with an electron beam, are widely used for steric observations of resting samples in basic and applied biology. Various conventional methods exist for SEM sample preparation. However, conventional SEM is not a good tool to observe living organisms because of the associated exposure to high vacuum pressure and electron beam radiation. Here we attempted SEM observations of live ticks. During 1.5×10(-3) Pa vacuum pressure and electron beam irradiation with accelerated voltages (2-5 kV), many ticks remained alive and moved their legs. After 30-min observation, we removed the ticks from the SEM stage; they could walk actively under atmospheric pressure. When we tested 20 ticks (8 female adults and 12 nymphs), they survived for two days after SEM observation. These results indicate the resistance of ticks against SEM observation. Our second survival test showed that the electron beam, not vacuum conditions, results in tick death. Moreover, we describe the reaction of their legs to electron beam exposure. These findings open the new possibility of SEM observation of living organisms and showed the resistance of living ticks to vacuum condition in SEM. These data also indicate, for the first time, the usefulness of tick as a model system for biology under extreme condition.


Empathy and psychoanalytic technique.
I have attempted to review the major psychoanalytic contributions to our understanding of empathy within the psychoanalytic situation. In doing so, I have discussed the relation between empathy and identification, reviewed aspects of the metapsychology of analytic comprehension, and have described the role of the analyst's evenly hovering attention in empathic responsiveness, as noted by several analytic investigators of empathy. The interrelations between empathy and countertransference have been described, and neutrality issues as they relate to empathy have been noted. Certain themes around the development of empathy have been grouped together and critically examined. The work of Kohut with regard to empathy has been discussed in relation to earlier psychoanalytic contributions of which it is an outgrowth and expansion. The changes in meaning and emphasis of empathic processes in Kohut's works have been described and critically reviewed. Empathy in its popular usage refers to the capacity of one person to communicatively partake, in a limited way, in the experience of another. In its differentiation from sympathy and pity, its noncritical or value-neutral character is emphasized. This description of empathy indicates its relevance to psychoanalytic technique, which shares many similar characteristics. Empathy is a general or superordinate term for many more specific aspects of the sensitive interpersonal interactions in the intimacy of relationships like the psychoanalytic one. Attempts to assign a particular psychoanalytic technical meaning to empathy or build clinical and developmental theory around empathy are limited by the multiple referents and generality of the concept. Empathy as a term has its place as descriptive of the analyst's emotional relatedness to the patient. It does not refer to any specific psychoanalytic technical intervention or theoretical construct; rather, it describes in a general way the sensitive, tactful, and experience-near way in which the analyst approaches the inner life of his patients.


Association of a green tea extract with serum immunoglobulin G status and neonatal vitality in newborn dairy calves.
Poor vigor at birth has been associated with reduced IgG absorption from colostrum and a reduced vitality in neonatal dairy calves. Some natural compounds, such as green tea extract, may improve vitality in compromised calves. The objective of this randomized controlled trial was to evaluate the potential of supplementing a green tea extract (15 mL) to calves to improve vigor and activity behavior for the first 72 h postnatal. Also, this study aimed to investigate the influence of green tea extract supplementation on calf serum IgG concentration and the apparent efficiency of absorption (AEA) of colostral IgG. Holstein calves (n = 24) weighing 42.49 ± 1.07 kg postnatal received a complete random assignment at 3 h of one 15-mL dose of green tea extract (Calf Perk, TechMix) or distilled water orally before tube feeding colostrum replacer (Premolac Plus IgG, Zinpro) at 4 h postnatal. Two observers assessed for calving time and dystocia by live video stream to retrieve all calves within 2 h postnatal. One veterinarian performed a baseline vigor assessment based on heart rate and response to stimuli on all calves at 2.5 h, before colostrum feeding at 3.75 h, as well as at 24, 48, and 72 h postnatal. Calf blood samples were taken to assess total IgG by radial immunodiffusion assay at 2.5, 6, 12, 24, 48, and 72 h. Calf vitality was also observed continuously by video for all calves to determine whether treatment was associated with attempts to stand, lying time, and exploration of their pen environment for the first 24 h. We used an ordinal logistic model to evaluate the odds of green tea extract improving a calf's vigor category from 2.5 h postnatal to 72 h of age. Vigor score was categorized as abnormal (≤4), average (5), or alert (≥6), with hour as a fixed effect. We also ran mixed linear models to evaluate the effect of extract on total IgG and AEA, with time and dystocia as fixed effects. Five dystocia calves were enrolled (2 control, 3 extract), but assistance was minor (e.g., manual assistance and all were assisted within 1 h). Baseline vigor scores and baseline total IgG were not different between groups. Vigor score category was not associated with green tea extract supplementation (odds ratio 1.17; 95% CI: 0.43-3.15) but increased with time compared with controls. We observed no association of treatment with total IgG or AEA in the calves, suggesting green tea extract does not compromise IgG absorption. Calf vitality, lying behavior, and exploratory behavior were not associated with green tea extract treatment. Our findings suggest that green tea extract supplementation does not affect AEA and serum IgG concentration in calves. Future research should evaluate whether green tea extract improves vitality in calves experiencing severe dystocia.


Exploring the use of social network methods in designing healthcare quality improvement teams.
Teams are an integral component of quality improvement efforts in healthcare organizations. Quality improvement teams may involve persons either from the same or different disciplines. In either case, the selection of team members may be critical to the team's success. However, there is little research to guide selection of team members for quality improvement teams. In this paper, we use tools from social network analysis (SNA) to derive principles for the design of effective clinical quality improvement teams and explore the implementation of these principles using social network data collected from the inpatient general medicine services at a large academic medical center in Chicago, USA. While the concept of multidisciplinary teams focuses on the importance of the professional background of team members, SNA emphasizes the importance of the individual and collective connections of team members, both to persons outside the team and to each other. SNA also focuses on the location of individuals and groups between other actors in the flow of information and other resources within larger organizational networks. We hypothesize that external connections may be most important when the collection or dissemination of information or influence are the greatest concerns, while the relationship of team members to each other may matter most when internal coordination, knowledge sharing, and within-group communication are most important. Our data suggest that the social networks of the attending physicians can be characterized sociometrically and that new sociometric measures such as "net degree" may be useful in identifying teams with the greatest potential for external influence.


Purinergic dysregulation causes hypertensive glaucoma-like optic neuropathy.
Glaucoma is an optic neuropathy characterized by progressive degeneration of retinal ganglion cells (RGCs) and visual loss. Although one of the highest risk factors for glaucoma is elevated intraocular pressure (IOP) and reduction in IOP is the only proven treatment, the mechanism of IOP regulation is poorly understood. We report that the P2Y6 receptor is critical for lowering IOP and that ablation of the P2Y6 gene in mice (P2Y6KO) results in hypertensive glaucoma-like optic neuropathy. Topically applied uridine diphosphate, an endogenous selective agonist for the P2Y6 receptor, decreases IOP. The P2Y6 receptor was expressed in nonpigmented epithelial cells of the ciliary body and controlled aqueous humor dynamics. P2Y6KO mice exhibited sustained elevation of IOP, age-dependent damage to the optic nerve, thinning of ganglion cell plus inner plexiform layers, and a reduction of RGC numbers. These changes in P2Y6KO mice were attenuated by an IOP lowering agent. Consistent with RGC damage, visual functions were impaired in middle-aged P2Y6KO mice. We also found that expression and function of P2Y6 receptors in WT mice were significantly reduced by aging, another important risk factor for glaucoma. In summary, our data show that dysfunctional purinergic signaling causes IOP dysregulation, resulting in glaucomatous optic neuropathy.


Reconciling seasonal hydraulic risk and plant water use through probabilistic soil-plant dynamics.
Current models used for predicting vegetation responses to climate change are often guided by the dichotomous needs to resolve either (i) internal plant water status as a proxy for physiological vulnerability or (ii) external water and carbon fluxes and atmospheric feedbacks. Yet, accurate representation of fluxes does not always equate to accurate predictions of vulnerability. We resolve this discrepancy using a hydrodynamic framework that simultaneously tracks plant water status and water uptake. We couple a minimalist plant hydraulics model with a soil moisture model and, for the first time, translate rainfall variability at multiple timescales - with explicit descriptions at daily, seasonal, and interannual timescales - into a physiologically meaningful metric for the risk of hydraulic failure. The model, parameterized with measured traits from chaparral species native to Southern California, shows that apparently similar transpiration patterns throughout the dry season can emerge from disparate plant water potential trajectories, and vice versa. The parsimonious set of parameters that captures the role of many traits across the soil-plant-atmosphere continuum is then used to establish differences in species sensitivities to shifts in seasonal rainfall statistics, showing that co-occurring species may diverge in their risk of hydraulic failure despite minimal changes to their seasonal water use. The results suggest potential shifts in species composition in this region due to species-specific changes in hydraulic risk. Our process-based approach offers a quantitative framework for understanding species sensitivity across multiple timescales of rainfall variability and provides a promising avenue toward incorporating interactions of temporal variability and physiological mechanisms into drought response models.


Determination of the best level of dietary energy with two diet formulation methods based on total and digestible amino acid on broiler diet.
In order to evaluate the effects of different levels of energy and methods of formulation of Amino Acid (AA) requirements of diets, this experiment was conducted using 392 broiler chicks. The experiment was carried out using a complete randomize block design with 7 levels of energy 3175, 3075, 2975, 2875, 2775, 2675 and 2575 kcal kg(-1) for grower diet and 3225, 3125, 3025, 2925, 2825, 2725 and 2625 kcal kg(-1) for finisher diet and two methods of formulation of diets AA requirements (total and digestible) as a factorial arrangement. Results showed that by increasing level of energy feed intake, body weight and FCR were promoted in grower diet (p<0.05). Effect of decreasing level of energy up to 2725 and 2825 kcal kg(-1) was not significant on body weight and FCR in finisher diet, respectively. Formulating of diet based on total or digestible AA affected feed intake and FCR in finisher diet (p<0.05). Interaction effect of independent factors affected on body weight in grower diet (p<0.05). Decreasing level of energy increased gastrointestinal tract percentage weight (p<0.05). Formulation of diet based on digestible AA decreased gastrointestinal tract percentage weight (p<0.05). Abdominal fat decreased significantly as ME content of diets decreased. Results showed that it's possible to reduce the level of energy up to 3175 kcal kg(-1) in grower and 2725 kcal kg(-1) in finisher diet for giving the best and economical performance response. Formulation of diet based on digestible AA in finisher diet resulted in promotion of performance.


RNA helicase DDX5 regulates microRNA expression and contributes to cytoskeletal reorganization in basal breast cancer cells.
RNA helicase DDX5 (also p68) is involved in all aspects of RNA metabolism and serves as a transcriptional coregulator, but its functional role in breast cancer remains elusive. Here, we report an integrative biology study of DDX5 in breast cancer, encompassing quantitative proteomics, global MicroRNA profiling, and detailed biochemical characterization of cell lines and human tissues. We showed that protein expression of DDX5 increased progressively from the luminal to basal breast cancer cell lines, and correlated positively with that of CD44 in the basal subtypes. Through immunohistochemistry analyses of tissue microarrays containing over 200 invasive human ductal carcinomas, we observed that DDX5 was up-regulated in the majority of malignant tissues, and its expression correlated strongly with those of Ki67 and EGFR in the triple-negative tumors. We demonstrated that DDX5 regulated a subset of MicroRNAs including miR-21 and miR-182 in basal breast cancer cells. Knockdown of DDX5 resulted in reorganization of actin cytoskeleton and reduction of cellular proliferation. The effects were accompanied by up-regulation of tumor suppressor PDCD4 (a known miR-21 target); as well as up-regulation of cofilin and profilin, two key proteins involved in actin polymerization and cytoskeleton maintenance, as a consequence of miR-182 down-regulation. Treatment with miR-182 inhibitors resulted in morphologic phenotypes resembling those induced by DDX5 knockdown. Using bioinformatics tools for pathway and network analyses, we confirmed that the network for regulation of actin cytoskeleton was predominantly enriched for the predicted downstream targets of miR-182. Our results reveal a new functional role of DDX5 in breast cancer via the DDX5→miR-182→actin cytoskeleton pathway, and suggest the potential clinical utility of DDX5 and its downstream MicroRNAs in the theranostics of breast cancer.


Endothelin immunoreactivity in cerebrospinal fluid of patients with subarachnoid haemorrhage.
A radioimmunoassay method for endothelin was developed. Antisera raised against endothelin 1 showed significant crossreaction with endothelin 2 and 3 (45 and 13%, respectively). Considerable endothelin immunoreactivity was shown to be present in the cerebrospinal fluid of patients with a subarachnoid hemorrhage, ranging from 0.3 pmol/l cerebrospinal fluid to 4.5 pmol/l cerebrospinal fluid, though no endothelin immunoreactivity was observed in the cerebrospinal fluid of controls and patients with cerebral infarction, subdural haematoma or brain tumours. Endothelin immunoreactivity was also observed in two out of five cerebrospinal fluid samples from patients with cerebral bleeding. Reverse phase high performance liquid chromatography showed that the main immunoreactive component in cerebrospinal fluid appeared to elute at the same position. There was, however, an immunoreactive component which eluted at the same position as endothelin 3. These results may support the idea that endothelin immunoreactivity in the cerebrospinal fluid originate mainly from endothelial and neural tissues and that endothelin may contribute to the generation of the vasospasm often observed in subarachnoid hemorrhage, a conclusion based on the exceptionally high endothelin immunoreactivity in cerebrospinal fluid observed in patients with subarachnoid haemorrhage.


New therapy in cardioprotection.
An increasing number of patients are presenting for major surgery with cardiovascular comorbidities. Evidence of myocardial injury was found in 8% of all noncardiac surgery patients older than 45 years and was associated with adverse outcome. For this reason, there has been a lot of interest in finding and evaluating effective cardioprotective interventions. Current evidence suggests that statins, volatile anesthetic agents, and propofol are cardioprotective. Beta blockers reduce myocardial injury, but the resultant hypotension may contribute to the increased all-cause mortality and stroke risk seen. Likewise, alpha 2 agonists can be a cause of cardiac injury if hypotension is not promptly managed. Continuation of aspirin perioperatively can increase the risk of major bleeding with or without the benefit of reduced myocardial risk. Contrary to the initial Evaluation of Nitrous Oxide in the Gas Mixture for Anaesthesia study, nitrous oxide does not seem to increase the risk of myocardial injury. It is recommended that patients already on statins or beta blockers should have them continued perioperatively. If beta blockers are initiated, the dose should be titrated to heart rate and blood pressure. The decision regarding continuation of aspirin should be on a case-to-case basis based on patient and surgical risk factors.


Cherubism allele heterozygosity amplifies microbe-induced inflammatory responses in murine macrophages.
Cherubism is a rare autoinflammatory bone disorder that is associated with point mutations in the SH3-domain binding protein 2 (SH3BP2) gene, which encodes the adapter protein 3BP2. Individuals with cherubism present with symmetrical fibro-osseous lesions of the jaw, which are attributed to exacerbated osteoclast activation and defective osteoblast differentiation. Although it is a dominant trait in humans, cherubism appears to be recessively transmitted in mice, suggesting the existence of additional factors in the pathogenesis of cherubism. Here, we report that macrophages from 3BP2-deficient mice exhibited dramatically reduced inflammatory responses to microbial challenge and reduced phagocytosis. 3BP2 was necessary for LPS-induced activation of signaling pathways involved in macrophage function, including SRC, VAV1, p38MAPK, IKKα/β, RAC, and actin polymerization pathways. Conversely, we demonstrated that the presence of a single Sh3bp2 cherubic allele and pathogen-associated molecular pattern (PAMP) stimulation had a strong cooperative effect on macrophage activation and inflammatory responses in mice. Together, the results from our study in murine genetic models support the notion that infection may represent a driver event in the etiology of cherubism in humans and suggest limiting inflammation in affected individuals may reduce manifestation of cherubic lesions.


The neuroethology of friendship.
Friendship pervades the human social landscape. These bonds are so important that disrupting them leads to health problems, and difficulties forming or maintaining friendships attend neuropsychiatric disorders like autism and depression. Other animals also have friends, suggesting that friendship is not solely a human invention but is instead an evolved trait. A neuroethological approach applies behavioral, neurobiological, and molecular techniques to explain friendship with reference to its underlying mechanisms, development, evolutionary origins, and biological function. Recent studies implicate a shared suite of neural circuits and neuromodulatory pathways in the formation, maintenance, and manipulation of friendships across humans and other animals. Health consequences and reproductive advantages in mammals additionally suggest that friendship has adaptive benefits. We argue that understanding the neuroethology of friendship in humans and other animals brings us closer to knowing fully what it means to be human.


Origin of the autoreactive anti-type II collagen response. I. Frequency of specific and multispecific B cells in primed murine lymph nodes.
DBA/1 mice develop systemic polyarthritis and high titres of collagen autoantibodies after immunization with type II collagen. In this study we have analysed the frequency and specificity of antibody-producing B cells in draining lymph nodes 11 days after a primary immunization with rat type II collagen. A remarkably high frequency of type II collagen-reactive hybridomas (30%, n = 71), the majority cross-reacting with autologous type II collagen, were generated. Most of the collagen-reactive hybridomas produced IgG antibodies specific for type II collagen. Many other hybridomas produced multispecific antibodies (9%): these were preferentially of the IgM class. Some of the monoclonal multispecific hybridomas produced antibodies that cross-reacted with specific epitopes on the collagen molecule. One type II collagen-reactive hybridoma also displayed rheumatoid factor activity. Different mechanisms for the generation of the high frequency of collagen reactive antibodies are discussed.


[The advances of HIV in the Netherlands: indications but still no definite answers].
Investigations in the province of Limburg demonstrate an increasing HIV prevalence and a high prevalence of injecting and sexual risk behaviour as well as a substantial risk of HIV transmission to the general population. It is recommended that HIV surveillance be directed towards 'bridge populations' such as prostitutes, their customers and immigrants from HIV endemic countries, instead of just drug users. In view of the apparent increase in sexual risk behaviour and sexually transmitted diseases in homosexual men (possibly due to a reduced fear of the disease because of the availability of anti-HIV medication) surveillance should be intensified in that area as well. Only then will it be possible to ascertain whether or not the incidence of HIV in the Netherlands is increasing.


Methadone maintenance dose/weight ratio, long QTc, and EKG screening.
Electrocardiogram (EKG) monitoring during methadone maintenance treatment (MMT) has been recommended to prevent potentially fatal prolonged computed QT intervals (QTc). However, risk indicators for obtaining EKGs do not exist. This study assessed 23 variables that might help identify prolonged QTc during MMT. EKGs concurrent with methadone serum levels were obtained from 69 veterans during a 5-year study, encompassing 302.8 person-years. Two cardiologists hand-measured QT intervals, selecting each patient's longest QTc. QTc categories included: normal duration <440 ms; borderline duration of 440-469 ms; and abnormal duration ≥470 ms. QTc's were compared with seven methadone parameters and 16 bio-psycho-social variables using two QTc cut-offs (440 and 470 ms). Among the 69 patients, 19 had normal QTc's, 28 had borderline QTc's, and 22 had abnormal QTc's. Methadone dose/weight was moderately correlated with QTc, and independently associated with longer QTc at both 440 and 470 cut-offs. Dose/weight ≥.49 is useful for screening EKGs for QTc's ≥440 cut-off. Dose/weight ≥.65 produces high-yield abnormal QTc's ≥470 cut-off. Methadone dose/weight provides moderately reliable thresholds for making routine screening decisions and urgent clinical decisions to obtain an EKG for prolonged QTc. (Am J Addict 2016;25:499-507).


Assessment of self-conscious emotions: a Swedish psychometric and structure evaluation of the Test of Self-Conscious Affect (TOSCA).
The Test of Self-Conscious Affect (TOSCA) is a well-established scenario-based questionnaire assessing self-conscious emotions, such as shame and guilt, which have been shown to be differentially associated with a variety of functional, motivational, behavioral and health outcomes. The aim of this study was to evaluate the psychometric properties and internal structure of a Swedish version of TOSCA in a sample of 361 healthy adults. The psychometric properties and internal consistency of the Swedish version were at level with the original US TOSCA version for shame, guilt and detachment. The internal structure of the Swedish version was acceptable for shame, guilt and detachment but contained shortcomings in assessment of externalization.


Value and level of circulating endothelial progenitor cells, angiogenesis factors and mononuclear cell apoptosis in patients with chronic kidney disease.
Chronic renal failure on dialysis can reduce the number of circulating endothelial progenitor cells (EPCs), but this biomarker has not been fully investigated in patients with chronic kidney disease (CKD). A link between CKD and increased mononuclear cell apoptosis (MCA) in circulation has been reported but the effect of vascular endothelial growth factor (VEGF) and stromal cell-derived factor (SDF)-1α, two angiogenesis factors, on circulating EPC levels in CKD has not been clarified. This study examined the relationships between the numbers of circulating EPCs and the severity of CKD, degree of MCA and serum levels of VEGF and SDF-1α in CKD patients. The numbers of circulating EPCs (CD31/CD34+, CD62E/CD34+, KDR/CD34+, CXCR4/CD34+) were measured in 166 patients with varying degrees of CKD under regular treatment at an outpatient department and in 30 volunteer control subjects. CKD patients had significantly lower numbers of EPCs (p < 0.007), higher MCA in circulation and higher serum levels of VEGF and SDF-1 compared with the control subjects (all p < 0.001). Compared with patients with early CKD (stages I-III), patients with late CKD [stage IV-V or end-stage renal disease (ESRD)] had significantly lower numbers of EPCs (CXCR4/CD34+), higher MCA, and elevated serum levels of VEGF and SDF-1α (all p < 0.01). Serum VEGF level but not MCA or SDF-1α was strongly correlated with increased numbers of circulating EPCs. Multivariate analysis showed that ESRD along with lower serum albumin was independently predictive of lower numbers of circulating EPCs (p < 0.04). Circulating EPCs were markedly reduced in CKD patients. ESRD was strongly and independently predictive of decreased numbers of circulating EPCs.


[Hydrological indications in the therapy of pharyngitis].
Pharyngitis is an inflammatory disease of the mucosal and submucosal structures of the throat. Infection may or may not be a component of the disease. Pharyngitis is one of the common illness for which patients visit primary care physicians. Most of them are diagnosed by clinical evaluation and usually respond to treatment with antibiotics, but exceptions occur when pharyngitis is caused by non bacterial inflammatory processes like virus, mycoses, reflux of gastric juices, tobacco or alcohol abuse. In these cases, as alternative and preventive, could be indicated the thermal therapy. For many centuries thermal waters have been used in the treatment of chronic inflammations of the upper respiratory airway, such as pharyngitis, with good results. Different thermal waters are currently used, in particular sulfur or sulfur- salty- bromine-, iodine- or sulfur-sulfate-bicarbonate-carbonate alkaline or sulfur-arsenical-ferruginous, normally utilized by inhalation or irrigation or aerosol-therapy. The principal pharmacological activity of these waters is connected to the concentrations of H2S, halogens (Iodine e Bromine), sulfates, arsenic and the level of radioactivity, concerning their antimicrobial power and the mucolytic effect of sulphur.


Transconjunctival dacryocystorhinostomy: An aesthetic approach.
To report the anatomical and cosmetic outcome of transconjunctival dacryocystorhinostomy (TDCR) in an Asian Indian population. TDCR was initially performed in cadaver eyes followed by patients with primary acquired nasolacrimal duct obstruction (NLDO). This was a prospective noncomparative case series of all consecutive TDCRs performed between April 2013 and June 2015. Outcome measures were anatomical patency, epiphora, presence of diplopia, aesthetic outcome, and health status. A total of 17 (18 eyes) patients with a mean age 43.9 ± 11.8 years (range, 32-75) were included in the study. Eight were males, and one patient underwent TDCR in both eyes. TDCR was successfully performed in 15/18 (82%) eyes under local anesthesia. Procedure converted to transcutaneous external DCR in two and dacryocystectomy in one patient each. Mean duration of surgery was 52.6 (range, 29-110) min. Anatomical patency and relief from epiphora was achieved in all (15/15) eyes after TDCR at a median follow-up of 15.5 months. At final follow-up, objective assessment of the cosmetic outcome graded the surgical scar at the lateral canthus as invisible in all except one and conjunctival fornix as visible only after eyelid eversion in all patients. Disturbance of the medial fat pad was not seen in any patient. A questionnaire-based health status evaluation showed marked improvement in anxiety/depression before and after TDCR with an overall well-being score of 88 on a scale of 0-100 (worst-best) after TDCR. TDCR offers a promising aesthetic approach in patients with primary acquired NLDO and gives excellent functional and cosmetic outcome.


Metabolic Power Method: Underestimation of Energy Expenditure in Field-Sport Movements Using a Global Positioning System Tracking System.
The purpose of this study was to assess the validity of a global positioning system (GPS) tracking system to estimate energy expenditure (EE) during exercise and field-sport locomotor movements. Twenty-seven participants each completed a 90-min exercise session on an outdoor synthetic futsal pitch. During the exercise session, they wore a 5-Hz GPS unit interpolated to 15 Hz and a portable gas analyzer that acted as the criterion measure of EE. The exercise session was composed of alternating 5-minute exercise bouts of randomized walking, jogging, running, or a field-sport circuit (×3) followed by 10 min of recovery. One-way analysis of variance showed significant (P < .01) and very large underestimations between GPS metabolic power- derived EE and oxygen-consumption (VO2) -derived EE for all field-sport circuits (% difference ≈ -44%). No differences in EE were observed for the jog (7.8%) and run (4.8%), whereas very large overestimations were found for the walk (43.0%). The GPS metabolic power EE over the entire 90-min session was significantly lower (P < .01) than the VO2 EE, resulting in a moderate underestimation overall (-19%). The results of this study suggest that a GPS tracking system using the metabolic power model of EE does not accurately estimate EE in field-sport movements or over an exercise session consisting of mixed locomotor activities interspersed with recovery periods; however, is it able to provide a reasonably accurate estimation of EE during continuous jogging and running.


Low heavy metal bioavailability in soil at contaminated Korean shooting sites.
The bioavailability of metals at eight military shooting ranges in the Kyungkido and Kangwondo districts in Korea was examined through measurements of the metal content of the tissues of plants growing at the sites. Analysis of the metals in soil samples showed that only a small fraction of the total metal in the soil was soluble (soluble Cd, 0.01-0.43 mg/kg; soluble Cu, 1.63-10.05 mg/kg; soluble Pb, 0.01-414.46 mg/kg; and soluble Zn, 0.01-0.32 mg/kg). Correlation analyses of the levels of Cd, Pb, Cu, and Zn in soil samples and in 14 plant species collected near the sites showed that plant concentrations of Cd and Pb (shoot and root) were significantly correlated to the levels of Cd and Pb in the soil, whereas the concentrations of Cu and Zn in shoot and root tissue showed no correlation with the concentrations of metal in soil. Moreover, no direct relationship was found between the soil microbial respiration activity and soil metal concentration. These results indicate that there are only small amounts of bioavailable metal in the soil at the military shooting ranges studied.


Association of MiR-126 with soluble mesothelin-related peptides, a marker for malignant mesothelioma.
Improved detection methods for diagnosis of malignant pleural mesothelioma (MPM) are essential for early and reliable detection as well as treatment. Since recent data point to abnormal levels of microRNAs (miRNAs) in tumors, we hypothesized that a profile of deregulated miRNAs may be a marker of MPM and that the levels of specific miRNAs may be used for monitoring its progress. miRNAs isolated from fresh-frozen biopsies of MPM patients were tested for the expression of 88 types of miRNA involved in cancerogenesis. Most of the tested miRNAs were downregulated in the malignant tissues compared with the normal tissues. Of eight significantly downregulated, three miRNAs were assayed in cancerous tissue and adjacent non-cancerous tissue sample pairs collected from 27 formalin-fixed, paraffin-embedded MPM tissues by quantitative RT-PCR. Among the miRNAs tested, only miR-126 significantly remained downregulated in the malignant tissues. Furthermore, the performance of the selected miR-126 as biomarker was evaluated in serum samples of asbestos-exposed subjects and MPM patients and compared with controls. MiR-126 was not affected by asbestos exposure, whereas it was found strongly associated with VEGF serum levels. Levels of miR-126 in serum, and its levels in patients' serum in association with a specific marker of MPM, SMRPs, correlate with subjects at high risk to develop MPM. We propose miR-126, in association with SMRPs, as a marker for early detection of MPM. The identification of tumor biomarkers used alone or, in particular, in combination could greatly facilitate the surveillance procedure for cohorts of subjects exposed to asbestos.


[Evidence-based medicine tratment of chronic viral hepatitis B and C].
Worldwide, viral hepatitis is the most common cause of jaundice, chronic liver disease, cirrhosis and hepatocellular carcinoma. Although mayor advances have been made in the field of treatment and prevention, there is not a totally satisfactory treatment for each of both diseases. They account for a high percentage of the etiology of viral hepatitis and have a tendency towards chronicity and developing cirrhosis, resulting in a tremendous waste of medical resources. On the other hand, their treatments are long-term ones and the drugs, which are employed, are expensive. Thus, it is necessary to make an evidence-based medicine approach in this particular kind of illness to obtain the best benefit/cost ratio. In this current review, we analyzed the different drugs and therapeutic schedules, which are used in the chronic viral hepatitis B and C, and as well as their obtained response.


Maternal health care amid political unrest: the effect of armed conflict on antenatal care utilization in Nepal.
Armed conflicts, which primarily occur in low- and middle-income countries, have profound consequences for the health of affected populations, among them a decrease in the utilization of maternal health care services. The quantitative relationship between armed conflict and maternal health care utilization has received limited attention in the public health literature. We evaluate this relationship for a particular type of health care service, antenatal care, in Nepal. Using count regression techniques, household survey data and sub-national conflict data, we find a negative correlation between the number of antenatal care visits and incidents of conflict-related violence within a respondent's village development committee. Specifically, we find that under high-intensity conflict conditions women receive between 0.3 and 1.5 fewer antenatal care check-ups. These findings imply that maternal health care utilization is partially determined by characteristics of the social environment (e.g. political instability) and suggest health care providers need to revise maternal health strategies in conflict-affected areas. Strategies may include decentralization of services, maintaining neutrality among factions, strengthening community-based health services and developing mobile clinics.


Diffuse neutrino background from past core collapse supernovae.
Core collapse supernovae are among the most powerful explosions in the Universe, which emit thermal neutrinos that carry away most of the gravitational binding energy released. These neutrinos produce a diffuse supernova neutrino background (DSNB), which is one of the largest energy budgets among all radiation backgrounds. Detecting the DSNB is an important goal of modern high-energy astrophysics and particle physics, which provides valuable insights into core collapse modeling, neutrino physics, and cosmic supernova rate history. In this review, the key ingredients of DSNB calculation and what can be learned from future detections, including black hole formation and non-standard neutrino interactions are discussed. Moreover, an overview of the latest updates in neutrino experiments, which could lead to the detection of the DSNB in the next decade, is provided. With the promise of this breakthrough discovery on the horizon, the study of DSNB has great potential to further our understanding of the Universe.


Compensatory sleep responses to wakefulness induced by the dopamine autoreceptor antagonist (-)DS121.
The effect of the dopamine autoreceptor antagonist (-)DS121 on wakefulness, locomotor activity, body temperature and subsequent compensatory sleep responses was examined in the rat. Animals entrained to a light-dark cycle were treated at 5 h after lights-on (CT-5) with 0.5, 1, 5 or 10 mg/kg i.p. (-)DS121 or methylcellulose vehicle. An additional group received 5 mg/kg i.p. (-)DS121 or vehicle 6 h after lights-off (CT-18). At CT-5, (-)DS121 dose-dependently increased wakefulness, locomotor activity and body temperature, and decreased both non-rapid eye movement sleep (NREM) and rapid eye movement sleep (REM) during the first 4 h post-treatment relative to vehicle controls. REM interference lasted up to 3 h longer than NREM. Low doses of (-)DS121 (0.5 and 1 mg/kg) produced relatively little waking that was not followed by significant compensatory sleep responses. In contrast, higher doses (5 and 10 mg/kg) produced compensatory hypersomnolence (robust increases in NREM immediately after the primary waking effect) that was proportional to the duration of drug-induced wakefulness. NREM recovery 24 h post-treatment was the same for the 5 mg/kg (65.4 +/- 9.9 min) and 10 mg/kg (64.8 +/- 9.3 min) doses, but was not proportional to prior wake duration. NREM displaced by drug-induced wakefulness was recovered completely by 24 h post-treatment at the 5 mg/kg dose, but only 63.5% recovered at 10 mg/kg. In contrast, equivalent wakefulness produced by sleep deprivation yielded 100% NREM recovery. At CT-18, (-)DS121 (5 mg/kg) increased wakefulness without disproportionately increasing locomotor activity, and was compensated fully by 24 h post-treatment. These data show that (-)DS121 dose-dependently increases wakefulness, which is followed by hypersomnolence that is proportional to drug-induced wake-promoting efficacy.


Cdc34p ubiquitin-conjugating enzyme is a component of the tombusvirus replicase complex and ubiquitinates p33 replication protein.
To identify host proteins interacting with Tomato bushy stunt virus (TBSV) replication proteins in a genome-wide scale, we have used a yeast (Saccharomyces cerevisiae) proteome microarray carrying 4,088 purified proteins. This approach led to the identification of 58 yeast proteins that interacted with p33 replication protein. The identified host proteins included protein chaperones, ubiquitin-associated proteins, translation factors, RNA-modifying enzymes, and other proteins with yet-unknown functions. We confirmed that 19 of the identified host proteins bound to p33 in vitro or in a split-ubiquitin-based two-hybrid assay. Further analysis of Cdc34p E2 ubiquitin-conjugating enzyme, which is one of the host proteins interacting with p33, revealed that Cdc34p is a novel component of the purified viral replicase. Downregulation of Cdc34p expression in yeast, which supports replication of a TBSV replicon RNA (repRNA), reduced repRNA accumulation and the activity of the tombusvirus replicase by up to fivefold. Overexpression of wild-type Cdc34p, but not that of an E2-defective mutant of Cdc34p, increased repRNA accumulation, suggesting a significant role for the ubiquitin-conjugating enzyme function of Cdc34p in TBSV replication. Also, Cdc34p was able to ubiquitinate p33 in vitro. In addition, we have shown that p33 becomes ubiquitinated in vivo. We propose that ubiquitination of p33 likely alters its function or affects the recruitment of host factors during TBSV replication.


Economic analysis: randomized placebo-controlled clinical trial of erlotinib in advanced non-small cell lung cancer.
The NCIC Clinical Trials Group conducted the BR.21 trial, a randomized placebo-controlled trial of erlotinib (an epidermal growth factor receptor tyrosine kinase inhibitor) in patients with previously treated advanced non-small cell lung cancer. This trial accrued patients between August 14, 2001, and January 31, 2003, and found that overall survival and quality of life were improved in the erlotinib arm than in the placebo arm. However, funding restrictions limit access to erlotinib in many countries. We undertook an economic analysis of erlotinib treatment in this trial and explored different molecular and clinical predictors of outcome to determine the cost-effectiveness of treating various populations with erlotinib. Resource utilization was determined from individual patient data in the BR.21 trial database. The trial recruited 731 patients (488 in the erlotinib arm and 243 in the placebo arm). Costs arising from erlotinib treatment, diagnostic tests, outpatient visits, acute hospitalization, adverse events, lung cancer-related concomitant medications, transfusions, and radiation therapy were captured. The incremental cost-effectiveness ratio was calculated as the ratio of incremental cost (in 2007 Canadian dollars) to incremental effectiveness (life-years gained). In exploratory analyses, we evaluated the benefits of treatment in selected subgroups to determine the impact on the incremental cost-effectiveness ratio. The incremental cost-effectiveness ratio for erlotinib treatment in the BR.21 trial population was $94,638 per life-year gained (95% confidence interval = $52,359 to $429,148). The major drivers of cost-effectiveness included the magnitude of survival benefit and erlotinib cost. Subgroup analyses revealed that erlotinib may be more cost-effective in never-smokers or patients with high EGFR gene copy number. With an incremental cost-effectiveness ratio of $94 638 per life-year gained, erlotinib treatment for patients with previously treated advanced non-small cell lung cancer is marginally cost-effective. The use of molecular predictors of benefit for targeted agents may help identify more or less cost-effective subgroups for treatment.


Validation of Available Extended-Spectrum-Beta-Lactamase Clinical Scoring Models in Predicting Drug Resistance in Patients with Enteric Gram-Negative Bacteremia Treated at South Texas Veterans Health Care System.
Extended-spectrum-beta-lactamase (ESBL)-producing Enterobacteriaceae are increasingly common; however, predicting which patients are likely to be infected with an ESBL pathogen is challenging, leading to increased use of carbapenems. To date, five prediction models have been developed to distinguish between patients infected with ESBL pathogens. The aim of this study was to validate and compare each of these models to better inform antimicrobial stewardship. This was a retrospective cohort study of patients with Gram-negative bacteremia treated at the South Texas Veterans Health Care System over 3 months from 2018 to 2019. We evaluated isolate, clinical syndrome, and score variables for the five published prediction models/scores: Italian "Tumbarello," Duke, University of South Carolina (USC), Hopkins clinical decision tree, and modified Hopkins. Each model was assessed using the area under the receiver operating characteristic curve (AUROC) and Pearson correlation. One hundred forty-five patients were included for analysis, of which 20 (13.8%) were infected with an ESBL Escherichiacoli or Klebsiella spp. The most common sources of infection were genitourinary (55.8%) and gastrointestinal/intraabdominal (24.1%), and the most common pathogen was E. coli (75.2%). The prediction model with the strongest discriminatory ability (AUROC) was Tumbarello (0.7556). The correlation between prediction model score and percent ESBL was strongest with the modified Hopkins model (R2 = 0.74). In this veteran population, the modified Hopkins and Duke prediction models were most accurate in discriminating between Gram-negative bacteremia patients when considering both AUROC and correlation. However, given the moderate discriminatory ability, many patients with ESBL Enterobacteriaceae (at least 25%) may still be missed empirically.


Genome-wide screens reveal shared and strain-specific genes that facilitate enteric colonization by Klebsiella pneumoniae.
Gastrointestinal (GI) colonization by Klebsiella pneumoniae is a risk factor for subsequent infection as well as transmission to other patients. Additionally, colonization is achieved by many strain types that exhibit high diversity in genetic content. Thus, we aimed to study strain-specific requirements for K. pneumoniae GI colonization by applying transposon insertion sequencing to three classical clinical strains: a carbapenem-resistant strain, an extended-spectrum beta-lactamase-producing strain, and a non-epidemic antibiotic-susceptible strain. The transposon insertion libraries were screened in a murine model of GI colonization. At 3 days post-inoculation, 27 genes were required by all three strains for colonization. Isogenic deletion mutants for three genes/operons (acrA, carAB, and tatABCD) confirmed colonization defects in each of the three strains. Additionally, deletion of acrA reduced bile tolerance in vitro, while complementation restored both bile tolerance in vitro and colonization ability in vivo. Transposon insertion sequencing suggested that some genes were more important for the colonization of one strain than the others. For example, deletion of the sucrose porin-encoding gene scrY resulted in a colonization defect in the carbapenemase-producing strain but not in the extended-spectrum beta-lactamase producer or the antibiotic-susceptible strain. These findings demonstrate that classical K. pneumoniae strains use both shared and strain-specific strategies to colonize the mouse GI tract. IMPORTANCE Klebsiella pneumoniae is a common cause of difficult-to-treat infections due to its propensity to express resistance to many antibiotics. For example, carbapenem-resistant K. pneumoniae has been named an urgent threat by the United States Centers for Disease Control and Prevention. Gastrointestinal colonization in patients with K. pneumoniae has been linked to subsequent infection, making it a key process to control in the prevention of multidrug-resistant infections. However, the bacterial factors which contribute to K. pneumoniae colonization are not well understood. Additionally, individual strains exhibit large amounts of genetic diversity, begging the question of whether some colonization factors are strain dependent. This study identifies the enteric colonization factors of three classical strains using transposon mutant screens to define a core colonization program for K. pneumoniae as well as detecting strain-to-strain differences in colonization strategies.


Computation of Single-Cell Metabolite Distributions Using Mixture Models.
Metabolic heterogeneity is widely recognized as the next challenge in our understanding of non-genetic variation. A growing body of evidence suggests that metabolic heterogeneity may result from the inherent stochasticity of intracellular events. However, metabolism has been traditionally viewed as a purely deterministic process, on the basis that highly abundant metabolites tend to filter out stochastic phenomena. Here we bridge this gap with a general method for prediction of metabolite distributions across single cells. By exploiting the separation of time scales between enzyme expression and enzyme kinetics, our method produces estimates for metabolite distributions without the lengthy stochastic simulations that would be typically required for large metabolic models. The metabolite distributions take the form of Gaussian mixture models that are directly computable from single-cell expression data and standard deterministic models for metabolic pathways. The proposed mixture models provide a systematic method to predict the impact of biochemical parameters on metabolite distributions. Our method lays the groundwork for identifying the molecular processes that shape metabolic heterogeneity and its functional implications in disease.


A Case Report of Large Tailgut Cyst Located from the Perirenal to the Perivesical Spaces.
Tailgut cysts are known to originate from the remnants of the embryonic hindgut. They occur exclusively in the retrorectal and presacral spaces. There have been limited reports of tailgut cysts occurring in the left perirenal space. The present case features a huge tailgut cyst extending from the right perirenal to the perivesical space. We believe that this case report will help to further elucidate the characteristics of perirenal and perivesical tailgut cysts.


The effect of a selective 5-HT2 antagonist, ketanserin, on the pulmonary responses to Escherichia coli endotoxin.
5-Hydroxytryptamine (5-HT, 5-160 microgram kg-1) injected intravenously in pentobarbitone-anaesthetized, open-chest cats caused dose-dependent increases in pulmonary arterial and intratracheal pressures. There was also a marked systemic hypotension and bradycardia. The pulmonary effects were completely prevented by ketanserin (0.2 mg kg-1), a selective 5-HT2 blocking drug. Ketanserin (0.2 mg kg-1) itself lowered arterial pressure (by 30-40 mmHg) but this systemic hypotension was relatively transient. Endotoxin (E. coli) administration resulted in pulmonary hypertension, increases in intratracheal pressure and airways resistance and reductions in lung compliance and in arterial PO2. Only the airways resistance response was modified by ketanserin (0.2 mg kg-1), suggesting a relatively unimportant role for 5-HT in mediating the acute, pulmonary effects of endotoxin in this species. The reductions in arterial (mixed venous) pH and in PO2 that resulted from endotoxin administration were not affected by pretreatment with ketanserin.


Osteocutaneous radial forearm free flaps: prophylactic fixation of donor site using locking plate augmented with mineral cement.
Prophylactic plating of donor site in osteocutaneous radial forearm free flaps have demonstrated improvement in fracture rates. Previous series used conventional plating systems which rely on plate-bone friction forces to generate stability and can result in iatrogenic fractures if not accurately contoured. Locking plates have superior stability and do not require contouring. This retrospective series reports our experience using locking plate fixation augmented with calcium phosphate mineral cement. Twenty patients' records were reviewed; 13 were alive and reviewed clinically. Mean radiological follow-up was 28.2 months. Two deceased patients had donor site fractures diagnosed on the first postoperative radiograph. These fractures were related to technical fixation errors and failure to apply correct locking fixation principles. None of the other patients with proper locking fixation had fractures or metalwork related complications. We believe that locking fixation augmented with mineral cement can provide more biological stability and enhance restoration of bone structural strength.


Positive Impacts of Aphanizomenon Flos Aquae Extract on Obesity-Related Dysmetabolism in Mice with Diet-Induced Obesity.
The present study evaluated the ability of KlamExtra®, an Aphanizomenon flos aquae (AFA) extract, to counteract metabolic dysfunctions due to a high fat diet (HFD) or to accelerate their reversion induced by switching an HFD to a normocaloric diet in mice with diet-induced obesity. A group of HFD mice was fed with an HFD supplemented with AFA (HFD-AFA) and another one was fed with regular chow (standard diet-STD) alone or supplemented with AFA (STD-AFA). AFA was able to significantly reduce body weight, hypertriglyceridemia, liver fat accumulation and adipocyte size in HFD mice. AFA also reduced hyperglycaemia, insulinaemia, HOMA-IR and ameliorated the glucose tolerance and the insulin response of obese mice. Furthermore, in obese mice AFA normalised the gene and the protein expression of factors involved in lipid metabolism (FAS, PPAR-γ, SREBP-1c and FAT-P mRNA), inflammation (TNF-α and IL-6 mRNA, NFkB and IL-10 proteins) and oxidative stress (ROS levels and SOD activity). Interestingly, AFA accelerated the STD-induced reversion of glucose dysmetabolism, hepatic and VAT inflammation and oxidative stress. In conclusion, AFA supplementation prevents HFD-induced dysmetabolism and accelerates the STD-dependent recovery of glucose dysmetabolism by positively modulating oxidative stress, inflammation and the expression of the genes linked to lipid metabolism.


Protective effects of apigenin on LPS-induced endometritis via activating Nrf2 signaling pathway.
Endometritis is a puzzling disease that often associates with severe pelvic pain. In this study, we aimed to detect whether apigenin had protective effect against LPS-induced endometritis, if so, the underlying mechanism was further investigated. Apigenin was administrated 1 h before LPS treatment. The levels of inflammatory cytokines were measured by ELISA. The expression of NF-κB and Nrf2 were detected by Western blot analysis. The results showed that LPS treatment induced severe histological alteration of uterus and this change was attenuated by the treatment of apigenin. Apigenin significantly attenuated LPS-induced MPO activity, MDA content, and inflammatory cytokines TNF-α and IL-1β production. LPS-induced NF-κB activation was suppressed by apigenin. Furthermore, apigenin elevated the expression of Nrf2 and HO-1 in uterine tissues. In conclusion, the present study demonstrated that apigenin protected against LPS-induced endometritis through activation of Nrf2 signaling pathway and inhibition of NF-κB signaling pathway.


The effectiveness of interventions to increase physical activity. A systematic review.
The Guide to Community Preventive Service's methods for systematic reviews were used to evaluate the effectiveness of various approaches to increasing physical activity: informational, behavioral and social, and environmental and policy approaches. Changes in physical activity behavior and aerobic capacity were used to assess effectiveness. Two informational interventions ("point-of-decision" prompts to encourage stair use and community-wide campaigns) were effective, as were three behavioral and social interventions (school-based physical education, social support in community settings, and individually-adapted health behavior change) and one environmental and policy intervention (creation of or enhanced access to places for physical activity combined with informational outreach activities). Additional information about applicability, other effects, and barriers to implementation are provided for these interventions. Evidence is insufficient to assess a number of interventions: classroom-based health education focused on information provision, and family-based social support (because of inconsistent findings); mass media campaigns and college-based health education and physical education (because of an insufficient number of studies); and classroom-based health education focused on reducing television viewing and video game playing (because of insufficient evidence of an increase in physical activity). These recommendations should serve the needs of researchers, planners, and other public health decision makers.


Lung ultrasound in ruling out COVID-19 pneumonia in the ED: a multicentre prospective sensitivity study.
Early diagnosis of COVID-19 has a crucial role in confining the spread among the population. Lung ultrasound (LUS) was included in the diagnostic pathway for its high sensitivity, low costs, non-invasiveness and safety. We aimed to test the sensitivity of LUS to rule out COVID-19 pneumonia (COVIDp) in a population of patients with suggestive symptoms. Multicentre prospective observational study in three EDs in Northeastern Italy during the first COVID-19 outbreak. A convenience sample of 235 patients admitted to the ED for symptoms suggestive COVIDp (fever, cough or shortness of breath) from 17 March 2020 to 26 April 2020 was enrolled. All patients underwent a sequential assessment involving: clinical examination, LUS, CXR and arterial blood gas. The index test under investigation was a standardised protocol of LUS compared with a pragmatic composite reference standard constituted by: clinical gestalt, real-time PCR test, radiological and blood gas results. Of the 235 enrolled patients, 90 were diagnosed with COVIDp according to the reference standard. Among the patients with suspected COVIDp, the prevalence of SARS-CoV-2 was 38.3%. The sensitivity of LUS for diagnosing COVIDp was 85.6% (95% CI 76.6% to 92.1%); the specificity was 91.7% (95% CI 86.0% to 95.7%). The positive predictive value and the negative predictive value were 86.5% (95%CI 78.8% to 91.7%) and 91.1% (95% CI 86.1% to 94.4%) respectively. The diagnostic accuracy of LUS for COVIDp was 89.4% (95% CI 84.7% to 93.0%). The positive likelihood ratio was 10.3 (95% CI 6.0 to 17.9), and the negative likelihood ratio was 0.16 (95% CI 0.1 to 0.3). In a population with high SARS-CoV-2 prevalence, LUS has a high sensitivity (and negative predictive value) enough to rule out COVIDp in patients with suggestive symptoms. The role of LUS in diagnosing patients with COVIDp is perhaps even more promising. Nevertheless, further research with adequately powered studies is needed. NCT04370275.


Reversal of Multidrug Resistance by the Chinese Medicine Yiqi Jianpi Huaji Decoction and the Mechanism of Action in Human Gastric Cancer SGC7901/VCR Cells.
Yiqi Jianpi Huaji Decoction (YJHD), a traditional Chinese medicinal formula composed of twelve ingredients, has recently been reported to have a good clinical curative effect. The purpose of the present study was to evaluate the effects of YJHD on SGC7901/VCR gastric cancer cells and to elucidate the possible mechanism of action. First, the effects of a low dose of YJHD in combination with chemotherapeutic agents on SGC7901/VCR cells were assessed using the CCK-8 assay and flow cytometry, and the effects of YJHD on genes and proteins involved in drug resistance (MDR1, MRP, TUBB3, STMN1, and TS) were evaluated. Furthermore, transfection of SGC7901/VCR cells with siRNAs targeting these genes inhibited their expression, and the efficacy of vincristine against the cells was dramatically improved in vitro when these genes were silenced. These results demonstrate that low-dose YJHD inhibited cell proliferation, induced apoptosis, reversed MDR, and increased sensitivity to chemotherapeutic agents in vitro by downregulating P-gp, MRP, TUBB3, and STMN1 expression. MDR can be reversed by siRNAs targeting genes involved in MDR, and this strategy for cancer treatment should be evaluated in future studies.


CC chemokine ligand 1 promotes recruitment of eosinophils but not Th2 cells during the development of allergic airways disease.
One of the characteristic features of allergic asthma is recruitment of large numbers of inflammatory cells including eosinophils and Th2 lymphocytes to the lung. This influx of inflammatory cells is thought to be a controlled and coordinated process mediated by chemokines and their receptors. It is thought that distinct, differential expression of chemokine receptors allows selective migration of T cell subtypes in response to the chemokines that bind these receptors. Th2 cells preferentially express CCR8 and migrate selectively to its ligand, CC chemokine ligand (CCL)1. We studied the role of the CCR8 ligand, CCL1, in the specific recruitment of Th2 cells and eosinophils to the lung in a murine model of allergic airway disease. We have demonstrated for the first time that CCL1 is up-regulated in the lung following allergen challenge. Moreover, a neutralizing Ab to CCL1 reduced eosinophil migration to the lung, but had no effect on recruitment of Th2 cells following allergen challenge. In addition, there was no change in airway hyperresponsiveness or levels of Th2 cytokines. In a Th2 cell transfer system of pulmonary inflammation, anti-CCL1 also failed to affect recruitment of Th2 cells to the lung following allergen challenge. Significantly, intratracheal instillation of rCCL1 increased recruitment of eosinophils but not Th2 cells to the lung in allergen-sensitized and -challenged mice. In summary, our results indicate that CCL1 is important for the pulmonary recruitment of eosinophils, rather than allergen-specific Th2 cells, following allergen challenge.


High incidence of mild hyponatraemia in females using ecstasy at a rave party.
Globally, millions of subjects regularly use ecstasy, a drug popular due to its empathogenic and entactogenic effects. Dilutional hyponatraemia, mainly caused by direct stimulation of antidiuretic hormone (ADH) secretion by ecstasy, is among the many side effects of the drug (active substance 3, 4-methylenedioxymethamphetamine, MDMA). Severe, symptomatic hyponatraemia related to the use of MDMA has been reported in more than 30 cases. The mortality of this complication is high and mainly females are involved. Dramatic cases that reach the literature probably represent the tip of the iceberg. We decided to study the incidence of hyponatraemia in subjects using MDMA at an indoor rave party. The study was performed at the indoor event 'Awakenings', held in Amsterdam in the fall of 2010. The plasma sodium concentration was measured at the party using a point of care method in 63 subjects using MDMA and 44 controls. The use of MDMA was confirmed by a urine test. The plasma sodium concentration in subjects using MDMA was significantly lower than in those not using the drug (138 ± 2 mmol/L versus 140 ± 2 mmol/L, respectively, P < 0.001). The overall incidence of hyponatraemia, defined as a plasma sodium concentration <136 mmol/L, was 14.3% in MDMA users (9/63 subjects). Most cases of hyponatraemia occurred in females, in whom the incidence was 26.7% (8 of 30 females), with lowest values of 133 mmol/L. The number of ecstasy pills ingested by the females developing hyponatraemia was not different from that ingested by those who did not develop this complication. Fluid intake in ecstasy users exceeded that of non-users, suggesting a dipsogenic effect of the drug. Only 3% of males, but no less than ∼25% of females attending a rave party and using MDMA developed mild hyponatraemia during the event. Especially females are therefore probably also at risk of developing severe symptomatic hyponatraemia. Not using MDMA is obviously the best option to prevent MDMA-induced hyponatraemia. However, accepting the fact that millions use the drug every weekend, strategies should also be developed to prevent hyponatraemia in subjects choosing to take MDMA. This would include matching the electrolyte content of the fluids and food ingested to that of the fluids that are lost during the use of MDMA, mainly by perspiration. Users of MDMA and emergency health care workers should become more aware of the relatively high incidence of MDMA-induced hyponatraemia and of potential strategies to prevent this complication.


Diffuse Gastric Cancer During Pregnancy: Report of a Rare Association.
Gastric cancer during pregnancy is a rare event and difficult to diagnose, as the symptoms can be confused with those of an ordinary pregnancy. We report a case of a 25-year-old patient with a 29-week gestation, with asthenia complaint, vomiting and weight loss. During the investigation of wasting syndrome endoscopy was performed with infiltrative ulcerative lesions in pre-pyloric region with biopsy revealing carcinoma with signet ring, undifferentiated type. It was held on a strict control of fetal vitality, and pregnancy was interrupted via the abdominal delivery at 34 weeks. Soon after the cesarean section was performed, exploratory laparotomy was performed to perform inventory of the abdominal cavity, being observed the presence of carcinomatous implants in the peritoneum. In the face of irresectability clinical conduct was adopted and the patient was sent to chemotherapy, ensuring nutrition via a jejunostomy. The article reviews the gastric carcinoma association with pregnancy, discussing the initiation of treatment and continuity of pregnancy.


miR-149 as a Potential Molecular Target for Cancer.
MicroRNAs (miRNAs) are frequently dysregulated in cancers and serve as attractive targets for prognostication and therapeutic applications. Besides cancer, the biological functions of miR-149 have been studied in various diseases. This review aims to summarize the reports available in the literature, regarding miR-149 as a molecular target for cancer therapeutics. An extensive literature search was conducted using the Pubmed database to sieve out articles related to the roles of miR-149 in carcinogenesis and cancer progression, and potential miRNA-based therapies. A total of 89 publications were selected for inclusion in this review. Depending on the cancer type, miR-149 can behave either as a tumor suppressor or as an 'onco-miR' that promotes tumorigenesis and cancer spread, suggesting that this miRNA has diverse functions. Potential miRNA-based therapies include the use of miRNA mimics, miRNA inhibitors, demethylating agents and circular RNAs. Although targeting miRNA is an attractive anti-cancer strategy, not all cancers can be treated by the same miRNA-based strategy. A comprehensive understanding of miRNA regulatory mechanism is also necessary to improve the design of miRNA-based therapeutics and there is a need for safe and efficient delivery methods when using this approach for anti-cancer treatment.


MMP-Responsive Nanoparticle-Loaded, Injectable, Adhesive, Self-Healing Hydrogel Wound Dressing Based on Dynamic Covalent Bonds.
Developing a multifunctional hydrogel wound dressing with good injectability, self-healing, tissue adhesion, biocompatibility, and fast skin wound healing efficiency remains challenging. In this work, an injectable adhesive dopamine-functionalized oxidized hyaluronic acid/carboxymethyl chitosan/collagen (AHADA/CCS/Col) hydrogel was constructed. The Schiff dynamic bond between AHADA and CCS, the N-Ag-N bond between CCS and Ag ions, and the S-Ag-S dynamic bond between sulfhydryl-modified collagen (ColSH) and Ag ions allowed the hydrogel to be both injectable and self-healing. Moreover, the aldehyde groups and catechol groups presented in the hydrogel could generate force with several groups on the tissue interface; therefore, the hydrogel also had good tissue adhesion. In vitro experiments proved that this hydrogel exhibited good biocompatibility and could promote cell proliferation. Additionally, curcumin (Cur)-loaded gelatin nanoparticles (Cur@Gel NPs) were prepared, which could respond to matrix metalloproteinases (MMPs) and controllably release Cur to hasten wound healing efficiency. Animal experiment results showed that this AHADA/CCS/Col hydrogel loaded with Cur@Gel NPs promoted wound repairing better, indicating its potential as a wound dressing.


Electron microscope and experimental investigations of the neurofilamentous network in Deiters' neurons. Relationship with the cell surface and nuclear pores.
The assembly of filamentous elements and their relations to the plasma membrane and to the nuclear pores have been studied in Deiters' neurons of rabbit brain. Electron microscopy of thin sections and of ectoplasm spread preparations have been integrated with physicochemical experiments and differential interference microscopy of freshly isolated cells. A neurofilamentous network extends as a continuous, three-dimensional, semilattice structure throughout the ectoplasm, the "plasma roads," and the perinuclear zone of the perikaryon. This space network consists of approximately 90-A wide neurofilaments arranged in fascicles which are interconnected by an exchange of neurofilaments. The neurofilaments consist of intercoiled approximately 20-A wide unit-filaments and are associated through cross-associating filaments with other neurofilaments of the fascicle and with microfilaments. The approximately 20-50-A wide microfilaments display intimate associations with the plasma membrane and with the nuclear pores. Electron microscopy of thin sections from glycerinated and heavy meromyosin-treated Deiters' neurons shows that actin-like filaments are present in the pre- and postsynaptic regions of synapses terminating on these neurons. It is proposed that the neurofilamentous space network serves a transducing function by linking plasma membrane activities with the genetic machinery of the neuron.


Fabrication and characterization of polyaniline-znO hybrid nanocomposite thin films.
Polyaniline (PANI)-ZnO nanocomposite thin film has been successfully fabricated on glass substrates by using vacuum deposition technique. The as-grown PANI-ZnO nanocomposite thin films have been characterized using X-ray diffraction, Scanning Electron Microscopy, Atomic Force Microscopy, UV-visible spectrophotometer and Fourier Transform Infrared (FTIR) spectroscopy, respectively. X-ray diffraction of as-grown film shows the reflection of ZnO nanoparticles along with a broad peak of PANI. The surface morphology of nanocomposite films has been investigated using scanning electron microscopy and atomic force microscopy. The hypsochromic shift of the UV absorption band corresponding to pi-pi* transition in polymeric chain of PANI and a band at 504 cm(-1) due to ZnO nanoparticles has been observed in the FTIR spectra. The hydrogen bonding between the imine group of PANI and ZnO nanoparticle has been confirmed from the presence of the absorbance band at 1151 cm(-1) in the FTIR spectra of the nanocomposite thin films.


A genome map of Salmonella enterica serovar Agona: numerous insertions and deletions reflecting the evolutionary history of a human pathogen.
Salmonella enterica serovar Agona is an important zoonotic pathogen, causing serious human illness worldwide, but knowledge about its genetics and evolution, especially regarding the genomic events that might have contributed to the formation of S. Agona as an important pathogen, is lacking. As a first step toward understanding this pathogen and characterizing its genomic differences with other salmonellae, we constructed a physical map of S. Agona in strain SARB1 using I-CeuI, XbaI, AvrII and Tn10 insertions with pulsed-field gel electrophoresis techniques. On the 4815-kb genomic map, we located 82 genes, revealed one inversion of about 1000 kb and resolved seven deletions and seven insertions ranging from 10 to 67 kb relative to the genome of Salmonella typhimurium LT2. These genomic features clearly distinguish S. Agona from other previously analyzed salmonellae and provide clues to the molecular basis for its genomic divergence. Additionally, these kinds of physical maps, combined with emerging high-speed sequencing technologies, such as the Solexa or SOLiD techniques, which require a pre-existing high-resolution physical map such as the S. Agona map reported here, will play important roles in genomic comparative studies of bacteria involving large numbers of strains.


Therapeutic role and ligands of medium- to long-chain Fatty Acid receptors.
Medium- and long-chain free fatty acids (FFAs) are energy source for whole body and biological metabolites and components. In these decades, some research groups have reported that the biological functions of medium- to long-chain FFAs are exerted through G-protein coupled receptor designated free fatty acid receptor (FFAR). As the medium- to long-chain FFAs-activated FFARs, FFA1 and FFA4 are reported to be expressed widely in whole body and regulate various physiological processes. FFA1 expressed in pancreatic β-cells has been shown to be involved in insulin secretion. FFA4 expressed in intestine, adipocytes, and macrophages has been shown to be involved in incretin secretion, differentiation, and anti-inflammatory effect, respectively. These physiological functions have been focused on the treatment of metabolic disorders. In addition, these receptors have been also reported to be expressed in several other tissues such as intestine for FFA1, and tongue and stomach for FFA4. The recent functional studies indicated that they also contributed to energy homeostasis. Further, the number of synthetic compounds of FFA1 and FFA4 strongly promoted the physiological characterization of the receptors and their own therapeutic utility. In this article, we will discuss the recent progress regarding the therapeutic potential of these receptors and its ligands.


Adventitial recruitment of Lyve-1- macrophages drives aortic aneurysm in an angiotensin-2-based murine model.
Aortic macrophage accumulation is characteristic of the pathogenesis of abdominal aortic aneurysm (AAA) but the mechanisms of macrophage accumulation and their phenotype are poorly understood. Lymphatic vessel endothelial receptor-1 (Lyve-1+) resident aortic macrophages independently self-renew and are functionally distinct from monocyte-derived macrophages recruited during inflammation. We hypothesized that Lyve-1+ and Lyve-1- macrophages differentially contribute to aortic aneurysm. Approach and results: Angiotensin-2 and β-aminopropionitrile (AT2/BAPN) were administered to induce AAA in C57BL/6J mice. Using immunohistochemistry (IHC), we demonstrated primarily adventitial accumulation of aortic macrophages, and in association with areas of elastin fragmentation and aortic dissection. Compared with controls, AAA was associated with a relative percent depletion of Lyve-1+ resident aortic macrophages and accumulation of Lyve-1- macrophages. Using CD45.1/CD45.2 parabiosis, we demonstrated aortic macrophage recruitment in AAA. Depletion of aortic macrophages in CCR2-/- mice was associated with reduced aortic dilatation indicating the functional role of recruitment from the bone marrow. Depletion of aortic macrophages using anti-macrophage colony-stimulating factor 1 receptor (MCSF1R)-neutralizing antibody (Ab) reduced the incidence of AAA. Conditional depletion of Lyve-1+ aortic macrophages was achieved by generating Lyve-1wt/cre Csf1rfl/fl mice. Selective depletion of Lyve-1+ aortic macrophages had no protective effects following AT2/BAPN administration and resulted in increased aortic dilatation in the suprarenal aorta. Aortic macrophage accumulation in AAA derives from adventitial recruitment of Lyve-1- macrophages, with relative percent depletion of Lyve-1+ macrophages. Selective targeting of macrophage subtypes represents a potential novel therapeutic avenue for the medical treatment of AAA.


Formal and informal care costs of hospitalized older people at risk of poor functioning: A prospective cohort study.
Hospitalized older people are at risk of poor functioning after hospital discharge. We aimed to relate formal and informal care costs to level of risk for low functioning of hospitalized older people up to one year after admission. We studied 460 patients 65 years or older who were admitted to a 450-bed hospital in the Netherlands between June 2010 and October 2010. Participants were classified into five risk groups at hospital admission using the Identification Seniors At Risk-Hospitalized Patients (ISAR-HP). Patients were interviewed at hospital admission and at three and twelve months after admission using validated questionnaires to measure health care utilization. Informal caregivers were interviewed by mailed paper questionnaires at the same time as patients. We estimated costs per unit from hospital information systems and nationally representative research. Mean healthcare costs were €30k euro per person per year, with one third for initial hospital stay (€9,8k), one third for formal healthcare costs between hospital discharge and twelve month follow up (€10,3k), and one third for informal healthcare costs between hospital discharge and twelve month follow up (€9,5k). Informal and formal healthcare costs were almost double for people with the highest risk score compared to people not at risk (p<0.001). Older patients with high risk scores at hospital admission have substantially higher formal and informal care costs in the year after initial hospital admission than people with low risk scores. This implies that substantial investments may be made in preventive interventions for at-risk hospitalized older people.