ACE inhibitor and angiotensin II type 1 receptor antagonist therapies in elderly patients with diabetes mellitus: are they underutilized?
Diabetes mellitus is highly prevalent in older adults in the industrialized world. These patients are at high risk of complications from diabetes, including diabetic kidney disease. ACE inhibitors and their newer cousins, angiotensin II type 1 receptor antagonists (angiotensin receptor blockers [ARBs]), are powerful medications for the prevention of progression of diabetic renal disease. Unfortunately, among the elderly, these medications have been underutilized. The reasons for this include physician concerns regarding patient age and limited life expectancy and potential complications of ACE inhibitor or ARB use, specifically an increase in creatinine levels and hyperkalaemia. As discussed in this article, there have been several studies that show that the effects of inhibition of the renin-angiotensin system can be beneficial for the treatment of cardiovascular disease and renal disease among elderly patients with diabetes and that the potential risks mentioned above are no greater in this group than in the general population. For these reasons, several professional societies recommend that elderly patients with diabetes and hypertension (systolic blood pressure >or=140 mmHg or diastolic blood pressure >or=90 mmHg) be treated with an ACE inhibitor or ARB (as is recommended for younger diabetics). Use of ACE inhibitors or ARBs is also recommended for those with cardiovascular disease or those who are at risk of cardiovascular disease. Furthermore, in the management of diabetic kidney disease in elderly patients, treatment with ACE inhibitors or ARBs is also recommended to reduce the risk or slow the progression of nephropathy. Renal function and potassium levels should be monitored within the first 12 weeks of initiation of these medications, with each dose increase, and on a yearly basis thereafter. This article summarizes the current guidelines on the use of ACE inhibitors and ARBs in older adults with diabetes, reviews the evidence for their use in the elderly population, and suggests potential reasons for the observed underuse of these powerful drugs in this vulnerable population.


DNA amplification methods for diagnosis and epidemiological investigations of avian mycoplasmosis.
Rapid, sensitive and specific tests that detect nucleic acid from pathogenic mycoplasmas are very attractive for the laboratory detection of infected flocks, and methods for direct detection of the four main pathogenic mycoplasmas have been developed. Moreover, most avian mycoplasma species can be differentiated, according to their unique restriction fragment length polymorphism (RFLP) patterns generated with different restriction enzymes. However, this method is limited to the identification of pure cultures of avian mycoplasmas as other bacteria may be amplified by the set of primers chosen. Another application of PCR-RFLP is the ability to distinguish between very closely related species such as M. gallisepticum and M. imitans. In order to characterise isolates below the species level, PCR-based subtyping methods have been introduced. One of them, arbitrarily primed-PCR, results in strain-specific arrays of DNA fragments that can distinguish even closely related strains of a given species. This method was successfully used to investigate the molecular epidemiology of vaccine strains or of Mycoplasma gallisepticum conjunctivitis in songbirds. Major issues in the development of DNA amplification tests concern the selection of the appropriate target for amplification, specimen collection, DNA preparation and detection of amplification reaction inhibitors. Detection of amplified products is most commonly performed after gel electrophoresis or probe-based methods. Careful consideration to the design and work flow of the facility are necessary to avoid false-positive results.


The global spread of drug-resistant influenza.
Resistance to oseltamivir, the most widely used influenza antiviral drug, spread to fixation in seasonal influenza A(H1N1) between 2006 and 2009. This sudden rise in resistance seemed puzzling given the low overall level of the oseltamivir usage and the lack of a correlation between local rates of resistance and oseltamivir usage. We used a stochastic simulation model and deterministic approximations to examine how such events can occur, and in particular to determine how the rate of fixation of the resistant strain depends both on its fitness in untreated hosts as well as the frequency of antiviral treatment. We found that, for the levels of antiviral usage in the population, the resistant strain will eventually spread to fixation, if it is not attenuated in transmissibility relative to the drug-sensitive strain, but not at the speed observed in seasonal H1N1. The extreme speed with which the resistance spread in seasonal H1N1 suggests that the resistant strain had a transmission advantage in untreated hosts, and this could have arisen from genetic hitchhiking, or from the mutations responsible for resistance and compensation. Importantly, our model also shows that resistant virus will fail to spread if it is even slightly less transmissible than its sensitive counterpart--a finding of relevance given that resistant pandemic influenza (H1N1) 2009 may currently suffer from a small, but nonetheless experimentally perceptible reduction in transmissibility.


Stress and food allergy: mechanistic considerations.
Recent years have seen a marked increase in food allergy prevalence among children, particularly in Western countries, that cannot be explained by genetic factors alone. This has resulted in an increased effort to identify environmental risk factors underlying food allergies and to understand how these factors may be modified through interventions. Food allergy is an immune-mediated adverse reaction to food. Consequently, considerations of candidate risk factors have begun to focus on environmental influences that perturb the healthy development of the emerging immune system during critical periods of development (eg, prenatally and during early childhood), particularly in the gut. Given that psychosocial stress is known to play an important role in other allergic and inflammatory diseases, such as asthma, its potential role in food allergy is a growing area of research. However, research to date has largely focused on animal studies. This review synthesizes relevant animal research and epidemiological data, providing proof of concept for moderating influences of psychological stress on food allergy outcomes in humans. Pathways that may underlie associations between psychosocial stress and the expression of food allergy are discussed.


Poly-γ-glutamic acid derived nanopolyplexes for up-regulation of gamma-glutamyl transpeptidase to augment tumor active targeting and enhance synergistic antitumor therapy by regulating intracellular redox homeostasis.
The active targeting strategy has achieved inspiring progress for drug accumulation in tumor therapy; however, the insufficient expression level of many potential receptors poses challenges for drug delivery. Poly-γ-glutamic acid (γ-pGluA), a naturally occurring anionic biopolymer, showed high affinity with tumor-associated gamma-glutamyl transpeptidase (GGT), which localized on the cell surface and exhibited intracellular redox homeostasis-dependent expression pattern; thus, GGT was utilized for mediating endocytosis of nanoparticles. Herein, GGT-targeting nanopolyplexes (γ-pGluA-CSO@Fe3+, PCFN) consisting of cationic chitosan and GGT-targeting γ-pGluA blended with iron ion were constructed to load reactive oxygen species-induced menadione (MA) and doxorubicin, which were utilized to investigate the mechanism of GGT up-regulation. Briefly, the pretreated PCFN/MA induced an intracellular oxidative stress environment, which facilitated adjusted up-regulated GGT expression and boosted tumor targeting. Subsequently, the destroyed redox homeostasis sensitized tumors for synergistic therapy. The innovative strategy of augmenting active targeting by disturbing intracellular redox homeostasis offers insight for the application of γ-pGluA-derived nanopolyplexes.


Role of Locoregional Treatment in Vulvar Cancer With Pelvic Lymph Node Metastases: Time to Reconsider FIGO Staging?
Vulvar cancer with pelvic nodal involvement is considered metastatic (M1) disease per AJCC staging. The role of definitive therapy and its resulting impact on survival have not been defined. Patients with pelvic lymph node-positive vulvar cancer diagnosed in 2009 through 2015 were evaluated from the National Cancer Database. Patients with known distant metastatic disease were excluded. Logistic regression was used to evaluate use of surgery and radiation therapy (RT). Overall survival (OS) was evaluated with log-rank test and Cox proportional hazards modeling (multivariate analysis [MVA]). A 2-month conditional landmark analysis was performed. A total of 1,304 women met the inclusion criteria. Median follow-up was 38 months for survivors. Chemotherapy, RT, and surgery were used in 54%, 74%, and 62% of patients, respectively. Surgery was associated with prolonged OS (hazard ratio [HR], 0.58; P<.001) but had multiple significant differences in baseline characteristics compared with nonsurgical patients. In patients managed nonsurgically, RT was associated with prolonged OS (HR, 0.66; P=.019) in MVA. In patients undergoing surgery, RT was associated with better OS (3-year OS, 55% vs 48%; P=.033). Factors predicting use of RT were identified. MVA revealed that RT was associated with prolonged OS (HR, 0.75; P=.004). In this cohort of women with vulvar cancer and positive pelvic lymph nodes, use of RT was associated with prolonged survival in those who did not undergo surgery. Surgery followed by adjuvant RT was associated with prolonged survival compared with surgery alone.


Endoplasmic Reticulum Stress and the Hallmarks of Cancer.
Tumor cells are often exposed to intrinsic and external factors that alter protein homeostasis, thus producing endoplasmic reticulum (ER) stress. To cope with this, cells evoke an adaptive mechanism to restore ER proteostasis known as the unfolded protein response (UPR). The three main UPR signaling branches initiated by IRE1α, PERK, and ATF6 are crucial for tumor growth and aggressiveness as well as for microenvironment remodeling or resistance to treatment. We provide a comprehensive overview of the contribution of the UPR to cancer biology and the acquisition of malignant characteristics, thus highlighting novel aspects including inflammation, invasion and metastasis, genome instability, resistance to chemo/radiotherapy, and angiogenesis. The therapeutic potential of targeting ER stress signaling in cancer is also discussed.


Geography and the debate over Medicare reform.
Medicare spending varies more than twofold among regions, and the variations persist even after differences in health are corrected for. Higher levels of Medicare spending are due largely to increased use of "supply-sensitive" services--physician visits, specialist consultations, and hospitalizations, particularly for those with chronic illnesses or in their last six months of life. Also, higher spending does not result in more effective care, elevated rates of elective surgery, or better health outcomes. To improve the quality and efficiency of care, we propose a new approach to Medicare reform based on the principles of shared decision making and the promotion of centers of medical excellence. We suggest that our proposal be tested in a major demonstration project


An anti-inflammatory effect of red microalga polysaccharides in coronary artery endothelial cells.
Polysaccharides (PSs) produced by the red microalga Porphyridium sp. were reported to exhibit anti-inflammatory bioactivities in the human skin. The primary goal of the present research was to assess whether PSs attenuate inflammatory processes by interfering with tumour necrosis factor-alpha (TNF-α)-induced inflammation, in human coronary artery endothelial cells (HCAECs). Functional and inflammatory markers were quantified in TNF-α-stimulated HCAECs, with and without pre-treatment with PSs. The expression/activation of these markers was assessed by Western immunoblotting and a luciferase reporter assay. NO levels were measured using the Griess method and intracellular reactive oxygen stress (ROS) was determined with the fluorescent probe 2',7'-dichlorodihydro-fluorescein diacetate (H2DCFDA). The TNF-α-induced up-regulation of inter-cellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) translocation, as well as IκB degradation were significantly attenuated in cells pre-treated with PSs. In addition, PSs were able to inhibit NF-κB activation as well as TNF-α-induced oxidative stress in HCAECs. Endothelial function was also improved, as measured by increased nitric oxide (NO) formation and decreased endothelin (ET-1) protein expression. This is the first report that demonstrates the anti-inflammatory effect and vaso-relaxing property of red microalgae PSs in a HCAEC-TNF-α induced system. This study lays the foundation for basic research concerning the PS mode of action in biochemical processes involving endothelial dysfunction, and it also holds potential for applied research, possibly promoting the use of PSs as a therapeutic agent or food additive to improve vascular health.


Cosmic X-ray Sources, Galactic and Extragalactic.
Instruments carried aboard an Aerobee rocket in April 1965 provided evidence for x-ray emission from the directions of the radio galaxies Cygnus A and M-87 and from the galactic supernova remnant Cassiopeia A. A survey of the Cygnus region revealed a marked decrease in the flux of x-rays from Cygnus XR-1, which was identified in June 1964 as the second brightest object in the first Naval Research Laboratory list of x-ray sources. The detection sensitivity was improved over previous surveys and several new sources were detected at lower flux levels.


Biochemical biomarkers alterations in Coronavirus Disease 2019 (COVID-19).
Coronavirus Disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a respiratory disease, which can evolve into multi-organ failure (MOF), leading to death. Several biochemical alterations have been described in COVID-19 patients. To date, many biomarkers reflecting the main pathophysiological characteristics of the disease have been identified and associated with the risk of developing severe disease. Lymphopenia represents the hallmark of the disease, and it can be detected since the early stage of infection. Increased levels of several inflammatory biomarkers, including c-reactive protein, have been found in COVID-19 patients and associated with an increased risk of severe disease, which is characterised by the so-called "cytokine storm". Also, the increase of cardiac and liver dysfunction biomarkers has been associated with poor outcome. In this review, we provide an overview of the main biochemical characteristics of COVID-19 and the associated biomarkers alterations.


Stimulation of in vitro muscle cell proliferation by sera from swine injected with porcine growth hormone.
The proliferation-promoting activity of sera obtained from pigs before and after porcine growth hormone injections was tested in a muscle cell culture bioassay. For 3 d, purified porcine growth hormone (pGH) was administered by intramuscular injection to crossbred barrows. Two levels of pGH were administered: 18 micrograms pGH X kg-1 body weight X d-1 (low dose) or 143 micrograms pGH X kg-1 body weight X d-1 (high dose). Multiple blood samples were withdrawn from jugular catheters for 3 d prior to the injection, during the injection period and for 6 d after the last injection. Although serum pGH levels in low-dose pigs were raised from two to three times pre-injection levels, there was no significant change in serum proliferation-promoting activity or somatomedin-C (SmC), insulin or cortisol levels during or after administration of pGH. In contrast, the proliferation-promoting activity of sera obtained during and after the high-dose pGH injections was higher (P less than .005) than the pre-injection levels. Serum pGH levels were increased approximately 30-fold by 4 h after each injection, and increases in SmC levels were observed 10 to 16 h after the pGH injection. During the injection period SmC levels increased from 1.7 to 4 times pre-injection levels. Insulin and cortisol levels did not change significantly during the 3-d treatment period. We believe that this muscle cell culture bioassay system will be a useful addition to traditional radioimmunoassays and whole animal studies in elucidating the mode of action of pGH in pituitary-intact swine.


Opening the amino acid toolbox for peptide-based NTS2-selective ligands as promising lead compounds for pain management.
Chronic pain is one of the most critical health issues worldwide. Despite considerable efforts to find therapeutic alternatives, opioid drugs remain the gold standard for pain management. The administration of μ-opioid receptor (MOR) agonists is associated with detrimental and limiting adverse effects. Overall, these adverse effects strongly overshadow the effectiveness of opioid therapy. In this context, the development of neurotensin (NT) ligands has shown to be a promising approach for the management of chronic and acute pain. NT exerts its opioid-independent analgesic effects through the binding of two G protein-coupled receptors (GPCRs), NTS1 and NTS2. In the last decades, modified NT analogues have been proven to provide potent analgesia in vivo. However, selective NTS1 and nonselective NTS1/NTS2 ligands cause antinociception associated with hypothermia and hypotension, whereas selective NTS2 ligands induce analgesia without altering the body temperature and blood pressure. In light of this, various structure-activity relationship (SAR) studies provided findings addressing the binding affinity of ligands towards NTS2. Herein, we comprehensively review peptide-based NTS2-selective ligands as a robust alternative for future pain management. Particular emphasis is placed on SAR studies governing the desired selectivity and associated in vivo results.


Perception of Dental Public Health Competency among recent graduates.
This study aimed to assess how competent the recent dental graduates perceive themselves to be in Dental Public Health. A 21-item structured, close-ended questionnaire study was carried out at the KLEVK Institute of Dental Sciences, Belgaum, India. Students assessed their competencies using a three-point ordinal scale. One hundred and thirty-three students were asked to rate their proficiency on a 21-item matrix of the dental public health program. The responses were grouped using the Likert-type scale. Frequencies descriptive data were generated, and statistical analysis of examined variables was carried out using the Chi-square test. Mann-Whitney test was conducted to identify the correlation between variables. The overall mean score was 22.61 ± 10.94, highlighting confidence of the graduates in managing the oral health problems at the community level. Females showed higher competencies in functions related "to develop activities to motivate the community development," "to motivate health and oral health through health education," and "to motivate health and oral health through the creation of healthy settings." While males reported greater competency for the function "to adjust the dental practice to situations of restrictions that limits it." Recent dental graduates at the Institute perceived themselves competent in managing oral and dental health problems at the public level. Additional countrywide evidence regarding teaching and learning of public health dentistry is essential to compare the current experiences of dental graduates and ultimately enhance patient care.


Reaching low density lipoprotein cholesterol targets.
Cardiovascular disease is a major health problem and within the leading causes of death worldwide. Low-density lipoprotein cholesterol (LDL-C) is strongly associated with the development and progression of cardiovascular disease and is among the main targets of lipid lowering therapy. Despite the various lipid lowering agents for the management of hyperlipidemia, a significant number of patients do not reach their LDL-C target goals. Data from studies in various world regions identify an often poor achievement of LDL-C goals, especially in high risk patient groups. The causes of this suboptimal management of hyperlipidemia are multifactorial and measures should be taken in order to identify and address these shortcomings in dyslipidemia therapy.


Microbiome analysis of circulating bacterial extracellular vesicles in obsessive-compulsive disorder.
The present study examined the microbiome abundance and composition of drug-naive or drug-free patients with obsessive-compulsive disorder (OCD) compared with healthy controls. In addition, in the OCD group, the microbiome composition was compared between early-onset and late-onset OCD. Serum samples were collected from 89 patients with OCD and 107 age- and sex-matched healthy controls. Bacterial DNA was isolated from bacteria-derived extracellular vesicles in serum and then amplified and quantified using primers specific to the V3-V4 hypervariable region of the 16S ribosomal RNA gene. The 16S ribosomal DNA gene amplicon sequencing was performed. The pooled estimate showed that α-diversity was significantly reduced in patients with OCD compared with that in healthy controls (PShannon = 0.00015). In addition, a statistically significant difference was observed in β-diversity between patients with OCD and healthy controls at the order (P = 0.012), family (P = 0.003), genus (P < 0.001), and species (P = 0.005) levels. In the microbiome composition, Pseudomonas, Caulobacteraceae (f), Streptococcus, Novosphingobium, and Enhydrobacter at the genus level were significantly less prevalent in patients with OCD than in controls. In addition, among patients with OCD, the microbial composition in the early-onset versus late-onset types was significantly different with respect to the genera Corynebacterium and Pelomonas. The present study showed an aberrant microbiome in patients with OCD, suggesting a role of the microbiota-brain interaction in the pathophysiology of OCD. Further longitudinal studies with larger sample sizes adjusting for various confounders are warranted.


Adaptation of pulmonary receptors in the spontaneously breathing anaesthetized rat.
It has been suggested that species with high breathing frequencies have pulmonary stretch receptors which adapt more rapidly than species with low breathing frequencies. This has proved not to be so. Our hypothesis is that this theory is in fact correct if modified so that overall rate of adaptation of afferent vagal activity, i.e. the sum of stretch and rapidly adapting receptors, is considered. A rapidly breathing species, such as the rat, would thus have a greater proportion of rapidly adapting receptors, than a more slowly breathing species. To test this hypothesis, we measured the proportion of rapidly adapting pulmonary mechanoreceptors in spontaneously breathing rats for comparison with existing results from more slowly breathing species. We found there to be one rapidly adapting receptor for every three slowly adapting receptors present. This measurement has not previously been made in spontaneously breathing rats. The ratio of rapidly to slowly adapting pulmonary receptors in the species sequence cat-rabbit-rat is the same as the ratio of their breathing frequencies (3:4:10). We propose that the difference in proportion of slowly to rapidly adapting pulmonary receptors in different species may be related to their eupnoeic breathing frequency.


Deiminated proteins and extracellular vesicles as novel biomarkers in pinnipeds: Grey seal (Halichoerus gryptus) and harbour seal (Phoca vitulina).
Peptidylarginine deiminases (PADs) are phylogenetically conserved calcium-dependent enzymes which post-translationally convert arginine into citrulline in target proteins in an irreversible manner, leading to functional and structural changes in target proteins. Protein deimination can cause the generation of neo-epitopes, affect gene regulation and also allow for protein moonlighting and therefore facilitate multifaceted functions of the same protein. PADs are furthermore a key regulator of cellular release of extracellular vesicle (EVs), which are found in most body fluids and participate in cellular communication via transfer of cargo proteins and genetic material. In this study, post-translationally deiminated proteins and EVs were assessed in sera of two seal species, grey seal and harbour seal. We report a poly-dispersed population of serum-EVs, which were positive for phylogenetically conserved EV-specific markers and characterised by transmission electron microscopy. A number of deiminated proteins critical for immune and metabolic functions were identified in the seal sera and varied somewhat between the two species under study, while some targets were in common. EV profiles of the seal sera further revealed that key microRNAs for inflammation, immunity and hypoxia also vary between the two species. Protein deimination and EVs profiles may be useful biomarkers for assessing health status of sea mammals, which face environmental challenges, including opportunistic infection, pollution and shifting habitat due to global warming.


Dynamic Patterns of N6-Methyladenosine Profiles of Messenger RNA Correlated with the Cardiomyocyte Regenerability during the Early Heart Development in Mice.
N6-Methyladenosine (m6A) plays important roles in regulating mRNA processing. Despite rapid progress in this field, little is known about the role and mechanism of m6A modification in myocardial development and cardiomyocyte regeneration. Existing studies have shown that the heart tissues of newborn mice have the capability of proliferation and regeneration, but its mechanism, particularly its relation to m6A methylation, remains unknown. Methods. To systematically profile the mRNA m6A modification pattern in the heart tissues of mice at different developmental stages, we jointly performed methylated RNA immunoprecipitation sequencing (MeRIP-seq) and RNA sequencing (RNA-seq) of heart tissues of mice, respectively, aged 1 day old, 7 days old, and 28 days old. Results. We identified the linkages and association between differentially expressed mRNA transcripts and hyper or hypomethylated m6A peaks in C57BL/6J mice at different heart developmental stages. Results showed that the amount of m6A peaks and the level of m6A modification were the lowest in the heart of mice at 1 day old. By contrast, heart tissues from 7-day-old mice tended to possess the most m6A peaks and the highest global m6A level. However, the m6A characteristics of myocardial tissue changed little after 7 days old as compared to that of 1 day old. Specifically, we found 1269 downmethylated genes of 1434 methylated genes in 7-day-old mouse heart tissues as compared to those in 1-day-old mice. Hypermethylation of some specific genes may correlate with the heart's strong proliferative and regenerative capability at the first day after birth. In terms of m6A density, the tendency shifted from coding sequences (CDS) to 3'-untranslated regions (3'UTR) and stop codon with the progression of heart development. In addition, some genes demonstrated remarkable changes both in methylation and expression, like kiss1, plekha6, and megf6, which may play important roles in proliferation. Furthermore, signaling pathways highly related to proliferation such as "Wnt signaling pathway," "ECM-receptor interaction," and "cardiac chamber formation" were significantly enriched in 1-day-old methylated genes. Conclusions. Our results reveal a pattern that different m6A modifications are distributed in C57BL/6J heart tissue at different developmental stages, which provides new insights into a novel function of m6A methylation of mRNA in myocardial development and regeneration.


IL-17 suppresses immune effector functions in human papillomavirus-associated epithelial hyperplasia.
Persistent infection with high-risk human papillomaviruses (HPV) causes epithelial hyperplasia that can progress to cancer and is thought to depend on immunosuppressive mechanisms that prevent viral clearance by the host. IL-17 is a cytokine with diverse functions in host defense and in the pathology of autoimmune disorders, chronic inflammatory diseases, and cancer. We analyzed biopsies from patients with HPV-associated cervical intraepithelial neoplasia grade 2/3 and murine skin displaying HPV16 E7 protein-induced epithelial hyperplasia, which closely models hyperplasia in chronic HPV lesions. Expression of IL-17 and IL-23, a major inducer of IL-17, was elevated in both human HPV-infected and murine E7-expressing lesions. Using a skin-grafting model, we demonstrated that IL-17 in HPV16 E7 transgenic skin grafts inhibited effective host immune responses against the graft. IL-17 was produced by CD3(+) T cells, predominantly CD4(+) T cells in human, and CD4(+) and γδ T cells in mouse hyperplastic lesions. IL-23 and IL-1β, but not IL-18, induced IL-17 production in E7 transgenic skin. Together, these findings demonstrate an immunosuppressive role for IL-17 in HPV-associated epithelial hyperplasia and suggest that blocking IL-17 in persistent viral infection may promote antiviral immunity and prevent progression to cancer.


Tailored Vessel-Catheter Diameter Ratio in a Direct Aspiration First-Pass Technique: Is It a Matter of Caliber?
The aspiration technique has gained a prominent role in mechanical thrombectomy. The thrombectomy goal is successful revascularization (modified TICI ≥ 2b) and first-pass effect. The purpose of this study was to evaluate the impact of the vessel-catheter ratio on the modified TICI ≥ 2b and first-pass effect. This was a retrospective, single-center, cohort study. From January 2018 to April 2020, 111/206 (53.9%) were eligible after applying the exclusion criteria. Culprit vessel diameters were measured by 2 neuroradiologists, and the intraclass correlation coefficient was calculated. The receiver operating characteristic curve was used for assessing the vessel-catheter ratio cutoff for modified TICI ≥ 2b and the first-pass effect. Time to groin puncture and fibrinolysis were weighted using logistic regression. All possible intervals (interval size, 0.1; sliding interval, 0.01) of the vessel-catheter ratio were plotted, and the best and worst intervals were compared using the χ2 test. Modified TICI ≥ 2b outcome was achieved in 75/111 (67.5%), and first-pass effect was achieved in 53/75 (70.6%). The MCA diameter was 2.1 mm with an intraclass correlation coefficient of 0.92. The optimal vessel-catheter ratio cutoffs for modified TICI ≥ 2b were ≤1.51 (accuracy = 0.67; 95% CI, 0.58-0.76; P = 0.001), and for first-pass effect, they were significant (≤1.33; P = .31). The modified TICI ≥ 2b odds ratio and relative risk were 9.2 (95% CI, 2.4-36.2; P = 0.002) and 3.2 (95% CI, 1.2-8.7; P = .024). The odds ratio remained significant after logistic regression (7.4; 95% CI, 1.7-32.5; P = .008). First-pass effect odds ratio and relative risk were not significant (2.1 and 1.5; P > .05, respectively). The modified TICI ≥ 2b best and worst vessel-catheter ratio intervals were not significantly different (55.6% versus 85.7%, P = .12). The first-pass effect best vessel-catheter ratio interval was significantly higher compared with the worst one (78.6% versus 40.0%, P = .03). The aspiration catheter should be selected according to culprit vessel diameter. The optimal vessel-catheter ratio cutoffs were ≤1.51 for modified TICI ≥ 2b with an odds ratio of 9.2 and a relative risk of 3.2.


Predicting risk and diminishing the consequences of anastomotic dehiscence following rectal resection.
Anastomotic dehiscence is a serious, life-threatening complication of any rectal anastomosis and may be associated with an increased risk of local cancer recurrence. The leak rate following low anterior resection is in the region of 10% as supported by the recent randomised Dutch rectal cancer trial. Although accurate prediction of risk is impossible, certain factors are known to influence leak rates. There is an inverse relationship between the height of anastomoses from the anal verge and leak rate, with the lower anastomoses carrying the highest risk. Proximal defunctioning mitigates the consequences of leakage but does not abolish risk. There is little difference in rates of dehiscence between stapled and sutured colorectal anastomoses. A short colon pouch may reduce the chance of leakage. The highest risks are in unprotected anastomoses less than 5 cm from the anal verge in men who smoke and/or drink excessively, particularly if they have received pre-operative chemotherapy or chemo-radiotherapy. A high index of suspicion is required in detecting the early nonspecific signs of a leak and urgent surgical intervention is usually required to avert a life-threatening situation. Judicious use of faecal diversion should never be regarded as surgical timidity.


Better late than early: Marital timing and subjective well-being in midlife.
Drawing on data from 405 Canadian adults surveyed as high school seniors (Age 18) and again in midlife (Age 43), the present study examined whether marital timing, a variable rooted in the age norm hypothesis (whether marriage was early, on time, or late in relation to peers), might contribute additional insight into the well-documented association between marital status and subjective well-being (SWB; happiness, symptoms of depression, and self-esteem). The analysis also considered 3 alternative explanations of the marriage-SWB link: the social selection hypothesis, social role theory, and the adaptation perspective. Path analysis results demonstrated marrying on time or late compared with marrying early predicted fewer symptoms of depression in midlife, offering some support for the age norm hypothesis. Little support was found for the social selection hypothesis, but getting married and divorcing were consistently linked with future SWB, in accordance with social role theory. Marrying at an older age predicted higher self-esteem in midlife for men, implying potential adaptation. (PsycINFO Database Record


Complete genome sequence of a raccoon rabies virus isolate.
The entire genome of a mid-Atlantic raccoon strain rabies virus (RRV) isolated in Canada was sequenced; this is the second North American wildlife rabies virus isolate to be fully characterized. The overall organization and length of the genome was similar to that of other lyssaviruses. The nucleotide sequence identity of the raccoon strain ranged between 32.7% and 85.0% when compared to other lyssaviruses, while the deduced amino acid sequence identity ranged between 22.9% and 94.2% with the nucleoprotein and polymerase being the most conserved. Notable features of RRV include the phosphoprotein's four amino acid extension compared to most other rabies viruses, and a nucleotide substitution immediately prior to the normal start codon that results in an additional methionine at the beginning of the L protein. This is the first report of the RRV L gene sequence and its 2128 amino acid product. Rates of non-synonymous and synonymous nucleotide changes within the lyssavirus L gene identified the conserved blocks II, III and IV as being most constrained. Analysis of L gene codon substitution patterns favoured models that supported positive selection, but only one site, corresponding to Leu62 of the RRV L protein, was identified as being under weak positive selection.


Cost of a naturally occurring two-amino acid deletion in cytochrome c oxidase subunit 7A in Drosophila simulans.
This study aimed to determine whether a naturally occurring (DeltaTrp85, DeltaVal86) deletion from a protein subunit of cytochrome c oxidase (complex IV) influenced cytochrome c oxidase activity, mRNA expression levels of electron transport chain genes, and aspects of adult female fitness in the fly Drosophila simulans. We modeled the tertiary structure of D. simulans cox7A containing the deletion by homology to the bovine cox7A structure and predicted that it would decrease the function of complex IV. This prediction led to the hypothesis that flies with the deletion would have lower cytochrome c oxidase activity and higher levels of mRNA expression from cox7A. This result was observed, but unexpectedly, elevated levels of mRNA expression were also observed in genes encoding subunits of complexes I, III, and IV. Together these data suggest that the deletion causes a high bioenergetic cost to the organism. To investigate the predicted cost at a physiological level, we assayed aspects of adult female fitness. Starvation sensitivity but not feeding rate was significantly influenced by the two-amino acid deletion. Further, we observed that carbohydrate and protein levels but not lipid levels were higher in the mutant flies. Together, these data show that quaternary structure modeling and biochemistry can be used to link the genotype with the organismal phenotype.


Functional aggregation of cell-free proteins enables fungal ice nucleation.
Biological ice nucleation plays a key role in the survival of cold-adapted organisms. Several species of bacteria, fungi, and insects produce ice nucleators (INs) that enable ice formation at temperatures above -10 °C. Bacteria and fungi produce particularly potent INs that can promote water crystallization above -5 °C. Bacterial INs consist of extended protein units that aggregate to achieve superior functionality. Despite decades of research, the nature and identity of fungal INs remain elusive. Here, we combine ice nucleation measurements, physicochemical characterization, numerical modeling, and nucleation theory to shed light on the size and nature of the INs from the fungus Fusarium acuminatum. We find ice-binding and ice-shaping activity of Fusarium IN, suggesting a potential connection between ice growth promotion and inhibition. We demonstrate that fungal INs are composed of small 5.3 kDa protein subunits that assemble into ice-nucleating complexes that can contain more than 100 subunits. Fusarium INs retain high ice-nucleation activity even when only the ~12 kDa fraction of size-excluded proteins are initially present, suggesting robust pathways for their functional aggregation in cell-free aqueous environments. We conclude that the use of small proteins to build large assemblies is a common strategy among organisms to create potent biological INs.


Staged versus one-step approach for multivessel percutaneous coronary interventions.
Percutaneous coronary interventions (PCIs) in patients with multivessel coronary artery disease (CAD) may be staged or performed in a single session. No data exist about the relative safety and efficacy of these 2 strategies. Our aim was to compare short-term and long-term outcomes of patients with multivessel CAD who underwent PCI in 1 versus 2 sessions. The study included 264 consecutive patients who underwent treatment in our center during 1997 and 1998. PCI was conducted in a single session in 129 patients and was staged in 135 patients. The mean interval between the sessions in the staged group was 45.6 +/- 22.3 days. The rates of major adverse cardiac events (MACEs) during in-hospital stay did not differ significantly between the staged (combined for both stages) and nonstaged groups (2.2% vs 4.6%; P =.28). A trend for lower event rates at 30-day (2.9% vs 6.9%; P =.13) and 1-year follow-up (26.1 vs 35.9; P =.08) favored the staged arm. Diameter stenosis > or =50% was found in 17% of patients in the staged group in the second session and was successfully retreated in most of them. No MACE occurred between the sessions. Multivariate analysis identified staging of the procedure as a single independent predictor of MACE at 1-year follow-up (P =.05). Our results suggest that a practical staging strategy within 4 to 8 weeks is safe and allows for identification and treatment of potential excessive proliferative response in the previously intervened lesions during the second procedure.


A comparison of INRs determined with a whole blood prothrombin time device and two international reference preparations for thromboplastin.
Oral anticoagulant therapy is usually monitored with the prothrombin time (PT) on citrate plasma samples. In recent years instruments have been developed for measurement of the PT in non-citrated whole blood. In the present study, the manufacturer's calibration of one type of device (CoaguChek) in terms of the international normalized ratio (INR) was evaluated by one laboratory. Three subsequent lots of test strips for the CoaguChek were investigated using blood samples from 56 coumarin-treated patients. Citrated plasma samples from the same patients were analysed with two international reference preparations for thromboplastin (IRP), i.e., rTF/95 (recombinant human) and RBT/90 (rabbit brain). There were statistically significant INR differences between CoaguChek and the international reference preparations (p <0.001), but the mean relative deviation of the INR was not greater than 0.104. Clinically relevant criteria were used to assess the agreement between the CoaguChek and the IRP results. Standard agreement ranged from 82% to 95%. It is concluded that these test strips achieved a clinically acceptable level of accuracy. Further studies of patient management with these strips are justified.


Hilbert-Huang transform for analysis of heart rate variability in cardiac health.
This paper introduces a modified technique based on Hilbert-Huang transform (HHT) to improve the spectrum estimates of heart rate variability (HRV). In order to make the beat-to-beat (RR) interval be a function of time and produce an evenly sampled time series, we first adopt a preprocessing method to interpolate and resample the original RR interval. Then, the HHT, which is based on the empirical mode decomposition (EMD) approach to decompose the HRV signal into several monocomponent signals that become analytic signals by means of Hilbert transform, is proposed to extract the features of preprocessed time series and to characterize the dynamic behaviors of parasympathetic and sympathetic nervous system of heart. At last, the frequency behaviors of the Hilbert spectrum and Hilbert marginal spectrum (HMS) are studied to estimate the spectral traits of HRV signals. In this paper, two kinds of experiment data are used to compare our method with the conventional power spectral density (PSD) estimation. The analysis results of the simulated HRV series show that interpolation and resampling are basic requirements for HRV data processing, and HMS is superior to PSD estimation. On the other hand, in order to further prove the superiority of our approach, real HRV signals are collected from seven young health subjects under the condition that autonomic nervous system (ANS) is blocked by certain acute selective blocking drugs: atropine and metoprolol. The high-frequency power/total power ratio and low-frequency power/high-frequency power ratio indicate that compared with the Fourier spectrum based on principal dynamic mode, our method is more sensitive and effective to identify the low-frequency and high-frequency bands of HRV.


Range Charts for Agreement in Measurement Comparison Studies, With Application to Replicate Mass Spectrometry Experiments.
It is important to investigate the reproducibility of raw mass spectrometry (MS) features of abundance, such as spectral count, peptide number and ion intensity values, when conducting replicate mass spectrometry measurements. Reproducibility can be inferred from these replicate data either formally with analyses of variance techniques or informally with graphical procedures, particularly, Bland-Altman plots on paired runs. In this note, we suggest range plots to provide a suitable generalization of Bland-Altman plots to experiments with more than two replicate runs. We describe range charts and their interpretation, and illustrate their use with data from a recent proteomic study relating to label-free analysis.


Symptom- and Prevention-Based Testing of COVID-19 in Nursing Home Residents: A Retrospective Cohort Study.
Nursing homes (NH) residents with COVID-19 can either be tested because of presence of core symptoms (S-based) or because of transmission prevention (TP-based). The investigated study sample included all NH residents who underwent SARS-CoV-2 RT-PCR testing between March 16, 2020 and May 31, 2020 (n = 380). Clinical symptoms, temperature, and oxygen saturation were extracted from medical records, 7 days before to 14 days after testing. COVID-19 was confirmed in 81 (21%) residents; 36 (44%) S-based and 45 (56%) TP-based: 45. Cycle threshold (CT) values did not differ between the groups. In the 7 days prior to the test falling (32%), somnolence (25%) and fatigue (21%) occurred in both groups. Two days before the test, we observed a stronger decrease in oxygen saturation and an increase in temperature for the S-based group compared to the T-based group that remained up to 10 days after testing. Residents within the S-based group were 2.5 times more likely to increased mortality within 30 days than residents in the TP-based group (HR, 2.56; 95% 1.3-5.2). Although, 73% of the T-based group did eventually develop core symptoms. Thus, attention to falling and daily measures of temperature and oxygen saturation can contribute to earlier detection.


Baseline plasma proteomic analysis to identify biomarkers that predict radiation-induced lung toxicity in patients receiving radiation for non-small cell lung cancer.
To identify new plasma proteomic markers before radiotherapy start to predict later grade ≥2 radiation-induced lung toxicity (RILT2). Fifty-seven patients with non-small cell lung cancer received radiotherapy (RT) were eligible. Forty-eight patients with minimum follow-up of 1 year, nine with RILT2 with tumor stage matched to 39 without RILT2, were enrolled for this analysis. Platelet-poor plasma was obtained within 2 weeks before radiotherapy. The plasma proteomes were compared using a multiplexed quantitative proteomics approach involving ExacTag labeling, reverse-phase high-performance liquid chromatography, and nano liquid chromatography electrospray ionization tandem mass spectrometry. Z scores and Bonferroni-adjusted p values for the two-sample mean comparison were used to identify the differential protein expression between patients with and without RILT2. More than 200 proteins were identified and quantified. After excluding proteins that were not detected in at least 40% of the 48 patient samples, C4b-binding protein alpha chain and vitronectin had significantly higher (p < 0.001 and p = 0.02) expression levels in patients with RILT2 compared with patients without RILT2. These two proteins were validated by Western blot. Ingenuity pathway analysis revealed that they both play important roles in the inflammatory response and are associated with the known pathways of radiation-induced lung damage. This proteomic approach demonstrates new plasma protein biomarkers before treatment for future studies on RILT2 prediction.


Can Panton Valentine Leukocidin Gene And Clindamycin Susceptibility Serve As Predictors of Community Origin of MRSA From Skin and Soft Tissue Infections?
Community associated Methicillin-resistant Staphylococcus aureus (CA-MRSA) strains have begun to replace Hospital Associated MRSA (HA-MRSA) strains in hospital settings all over the world. With the epidemiological distinctions between these strains beginning to become ill-defined, the categorisation of a strain as CA-MRSA or HA-MRSA is dependent on molecular methods to detect the presence of SCCmec (Staphylococcal Cassette Chromosome mec) elements. However other markers like the presence of Panton Valentine Leukocidin toxin (pvl) genes or Clindamycin susceptibility may also be associated with community origin of MRSA. To determine the prevalence of CA-MRSA among MRSA strains isolated from skin and soft tissue infections and to evaluate the usefulness of Panton Valentine Leukocidin and Clindamycin susceptibility as markers of community origin of MRSA. One hundred isolates of MRSA from skin and soft tissue were studied for the presence of SCCmec IV and V genes and Panton valentine leukocidin gene by Polymerase chain reaction. Inducible clindamycin resistance was screened for using the D-test. Fischer's exact test. A p-value <0.05 was considered significant. Eighteen out of 100 MRSA strains were found to be CA-MRSA based on presence of SCCmecV. The proportion of Panton Valentine Leukocidin gene carriage among CA- MRSA as compared to HA-MRSA was found to be statistically significant (p<0.0001). Among the CA-MRSA strains, 94.4% were found to be susceptible to Clindamycin as against only 13.4% of the HA-MRSA strains (p<0.0001). The odds of an MRSA strain being CA-MRSA if it was both Clindamycin susceptible and PVL gene positive was calculated to be 68.25 (p<0.0001). Both Clindamycin susceptibility and pvl gene carriage were found to be independent predictors of community origin of MRSA, but taken together the association was highly significant.


Protective effects of methanolic extract of Juglans regia L. leaf on streptozotocin-induced diabetic peripheral neuropathy in rats.
Oxidative stress has a pivotal role in the pathogenesis and development of diabetic peripheral neuropathy (DPN), the most common and debilitating complications of diabetes mellitus. There is accumulating evidence that Juglans regia L. (GRL) leaf extract, a rich source of phenolic components, has hypoglycemic and antioxidative properties. This study aimed to determine the protective effects of Juglans regia L. leaf extract against streptozotocin-induced diabetic neuropathy in rat. The DPN rat model was generated by intraperitoneal injection of a single 55 mg/kg dose of streptozotocin (STZ). A subset of the STZ-induced diabetic rats intragastically administered with GRL leaf extract (200 mg/kg/day) before or after the onset of neuropathy, whereas other diabetic rats received only isotonic saline as the same volume of GRL leaf extract. To evaluate the effects of GRL leaf extract on the diabetic neuropathy various parameters, including histopathology and immunohistochemistry of apoptotic and inflammatory factors were assessed along with nociceptive and biochemical assessments. Degeneration of the sciatic nerves which was detected in the STZ-diabetic rats attenuated after GRL leaf extract administration. Greater caspase-3, COX-2, and iNOS expression could be detected in the STZ-diabetic rats, which were significantly attenuated after GRL leaf extract administration. Also, attenuation of lipid peroxidation and nociceptive response along with improved antioxidant status in the sciatic nerve of diabetic rats were detected after GRL leaf extract administration. In other word, GRL leaf extract ameliorated the behavioral and structural indices of diabetic neuropathy even after the onset of neuropathy, in addition to blood sugar reduction. Our results suggest that GRL leaf extract exert preventive and curative effects against STZ-induced diabetic neuropathy in rats which might be due to its antioxidant, anti-inflammatory, and antiapoptotic properties. Protection against neuropathy.


Efficacy of a new electronic toothbrush in removing bacterial dental plaque in young adults.
Although a high level of oral cleanliness is essential for long-term maintenance of dental health, many people cannot maintain good oral hygiene consistently. A new electronic toothbrush has been developed that induces a small electric charge onto tooth surfaces. This charge damages electrostatic bonding of plaque proteins to tooth surfaces; thus, plaque removal is enhanced while the toothbrush is used. Young men were issued identical toothbrushes; some were electrically active. Plaque levels were assessed at baseline, and after two and four weeks, concurrently with oral-hygiene instruction and professional prophylaxis. The electrically active toothbrushes demonstrated better plaque removal than the inactive toothbrushes. This better performance was statistically significant linguopalatally, indicating that significantly more plaque was removed where mechanical access was poorest. Thus, the electrical activity of this toothbrush significantly enhances plaque removal where toothbrushing access is limited.


Remote continuous physiological monitoring in the home.
As part of a larger study we established a remote physiological monitoring network to investigate cardiorespiratory function during sleep in 400 infants in their homes. The objective of the study was to link measurements made at three weeks and three months of age with detailed measurements of maternal and fetal nutrition during pregnancy and subsequent outcome (growth, development and cardiorespiratory diseases). Five infants per night were monitored anywhere within a radius of 10 miles (16 km) of the remote hub. Of 800 overnight studies on 64 (of 400) infants, 99 were completed. Options allowed downloading data from monitor memory as well as review (on- and off-line) from the infants' or nurses' homes, the hub and the Oxford telemonitoring centre. The reasons for these measurements being made at home were to ensure physiological accuracy and to reduce cost. The network was effectively run by local community nurses; with the exception of the size and cost of the monitors, it had all the elements of a remote primary-care clinical service.


Aerobic Exercise Decreases Lung Inflammation by IgE Decrement in an OVA Mice Model.
Aerobic exercise (AE) reduces lung function decline and risk of exacerbations in asthmatic patients. However, the inflammatory lung response involved in exercise during the sensitization remains unclear. Therefore, we evaluated the effects of exercise for 2 weeks in an experimental model of sensitization and single ovalbumin-challenge. Mice were divided into 4 groups: mice non-sensitized and not submitted to exercise (Sedentary, n=10); mice non-sensitized and submitted to exercise (Exercise, n=10); mice sensitized and exposed to ovalbumin (OVA, n=10); and mice sensitized, submitted to exercise and exposed to OVA (OVA+Exercise, n=10). 24 h after the OVA/saline exposure, we counted inflammatory cells from bronchoalveolar fluid (BALF), lung levels of total IgE, IL-4, IL-5, IL-10 and IL-1ra, measurements of OVA-specific IgG1 and IgE, and VEGF and NOS-2 expression via western blotting. AE reduced cell counts from BALF in the OVA group (p<0.05), total IgE, IL-4 and IL-5 lung levels and OVA-specific IgE and IgG1 titers (p<0.05). There was an increase of NOS-2 expression, IL-10 and IL-1ra lung levels in the OVA groups (p<0.05). Our results showed that AE attenuated the acute lung inflammation, suggesting immunomodulatory properties on the sensitization process in the early phases of antigen presentation in asthma.


Treatment failure in celiac disease due to coexistent exocrine pancreatic insufficiency.
A 17-year-old white adolescent had a history of chronic diarrhea, delayed puberty, and growth failure. Investigations excluded cystic fibrosis, Shwachman syndrome, and endocrine causes of growth failure. Severe steatorrhea was diagnosed from fecal fat studies, and a jejunal suction biopsy showed total villus atrophy, consistent with a diagnosis of celiac disease. Following introduction of a gluten-free diet, his appetite and growth improved, but he continued to have abdominal discomfort and loose offensive bowel motions. One year later, severe steatorrhea was present. A repeat jejunal biopsy showed partial recovery of villus architecture. Serum immuno-reactive trypsinogen level was low, which was highly suggestive of exocrine pancreatic failure. Results of quantitative pancreatic stimulation test confirmed the presence of primary pancreatic insufficiency. After introduction of oral pancreatic enzyme supplements with meals, his gastrointestinal symptoms resolved and growth velocity accelerated. Previously, primary pancreatic insufficiency has only been described in elderly patients with long-standing untreated celiac disease. This case, however, emphasizes that pancreatic failure can occur with celiac disease at any age. Determination of a serum immunoreactive trypsinogen level should be considered a useful screening tool for pancreatic insufficiency in patients with celiac disease who have not responded to a gluten-free diet.


Testing a culturally appropriate, theory-based intervention to improve colorectal cancer screening among Native Hawaiians.
We tested an intervention based on social learning theory (SLT) to improve colorectal cancer (CRC) screening among Native Hawaiians, a group with low CRC screening rates. Sixteen Hawaiian civic clubs agreed to randomization. Eight control clubs received a culturally targeted presentation, a free Fecal Occult Blood Test (FOBT), and a reminder call. Eight experimental clubs also received culturally targeted education and free testing; but, in line with SLT, education was delivered by a Native Hawaiian physician and Native Hawaiian CRC survivor, and members received an FOBT demo, were challenged to involve a family member in screening, and were telephoned multiple times to address change-related emotions and barriers. One hundred twenty-one members age 50 and older from 16 clubs participated. At the club level, screening rates were modestly increased in four experimental clubs and six control clubs. Surprisingly, 64% of participants reported being up to date with CRC screening at baseline. Only 13 individuals (five in experimental arm and eight in the control arm) were screened for the first time through this intervention, increasing the percent screened from 59% to 67% in the experimental group and from 69% to 85% in the control group. Although individuals in the experimental arm were more likely to rate the intervention as culturally appropriate, both arms realized similar and significant gains in CRC knowledge, attitudes, intent, and self-efficacy. For Native Hawaiian individuals belonging to a network of civic clubs, an intervention based on SLT delivered by a Native Hawaiian physician and CRC survivor was less effective at further increasing compliance than was a culturally targeted educational session delivered by a non-Hawaiian nurse. That CRC screening compliance was high prior to our intervention suggests that we targeted a very health conscious segment of the Native Hawaiian population. Future work should focus on underserved segments of this indigenous group.


TRPC1 and metabotropic glutamate receptor expression in rat auditory midbrain neurons.
Canonical transient receptor potential (TRPC) channels are plasma membrane cation channels included in the TRP superfamily. TRPC1 is expressed widely in the central nervous system and is linked to group I metabotropic glutamate receptors (mGluRs). In the auditory brainstem, TRPC1 expression has never been described, although group I mGluRs are present. In the central nucleus of the inferior colliculus (CIC), activation of group I mGluRs induces an extracellular Ca(2+) influx after store depletion. Therefore, this study examines whether TRPC1 is expressed in this region to establish a correlation with mGluRs. By quantitative reverse transcription-polymerase chain reaction and Western blotting, this study assesses the presence of TRPC1 along with both group I mGluR subtypes mGluR1 and mGluR5 in the rat inferior colliculus (IC). All these molecules present a robust expression in the IC. By confocal double immunofluorescence, this study also demonstrates that TRPC1 colocalizes with parvalbumin, a CIC neuronal marker, in many cells. Conversely, TRPC1 was lacking in glial fibrillary acidic protein-positive glial cells. All the glutamate acid decarboxylase 67 (GAD67)-immunoreactive neurons and many GAD67-negative neurons were positive to TRPC1, which indicates the presence of TRPC1 in γ-aminobutyric acid (GABA)-ergic and non-GABAeregic neurons. With regard to subcellular distribution, TRPC1 was absent in synaptophysin-immunoreactive axonic terminals but colocalized with postsynaptic marker microtubule-associated protein 2 in cell bodies and dendrites. TRPC1 totally overlapped group I mGluRs, which supports the involvement of TRPC1 in the mGluR pathway and, likely, in auditory signal processing at the midbrain level. .


The relation between the amount of sunscreen applied and the sun protection factor in Asian skin.
The measurement of the sun protection factor (SPF) is the usual method in the examination of the effectiveness of sunscreen. The declared SPF is based on the use of a sunscreen layer of 2 mg/cm(2). However, only around a quarter (0.5 mg/cm(2)) of this amount is generally used in real life. Theoretical calculations have suggested that the effectiveness of SPF is related to sunscreen quantity in an exponential way but this was not confirmed in Asian skin. This study was performed to investigate the change in SPF values when less than the recommended amount of sunscreen was applied. A board divided into 10 areas measuring 7 x 4 cm was placed on the back of 15 healthy volunteers. Low- and high-SPF standard reference sunscreens, and two types of sunscreen (SPF 30 and 35) were each applied on 4 areas, 0.5, 1.0, 1.5, and 2.0 mg/cm(2), respectively, and were left to dry for 20 minutes. The irradiation was conducted at a distance of 50 cm using a template (1 x 1 cm) placed directly on the skin with 10 windows allowing ultraviolet (UV) radiation to pass through with a dose increment of 20%. Erythema was evaluated 20 to 24 hours after exposure to UV radiation. Sunscreen showed its expected SPF value when 2.0 mg/cm(2) was applied. The SPF values of the different amounts were significantly different from each other and decreased when less was applied (P < .05). The relation between the amount of sunscreen applied and the SPF provided was most likely to follow exponential growth. Spectral differences between our solar simulator and the UV sources of commercial laboratories are likely to be important. In addition, differences in sunscreen application techniques may have influenced the ultimate SPF values. This study concludes that to get the expected SPF value, it is important to apply the UV protective sunscreen precisely in the amount of 2.0 mg/cm(2) on Asian skin as recommended by the Food and Drug Administration. In addition, it was difficult to predict the SPF values when the usual amount of 0.5 mg/cm(2) was applied.


The global atmospheric circulation on moist isentropes.
The global atmospheric circulation transports energy from the equatorial regions to higher latitudes through a poleward flow of high-energy and -entropy parcels and an equatorward flow of air with lower energy and entropy content. Because of its turbulent nature, this circulation can only be described in some averaged sense. Here, we show that the total mass transport by the circulation is twice as large when averaged on moist isentropes than when averaged on dry isentropes. The additional mass transport on moist isentropes corresponds to a poleward flow of warm moist air near Earth's surface that rises into the upper troposphere within mid-latitudes and accounts for up to half of the air in the upper troposphere in polar regions.


Improvement on the catalytic performance of Mg-Zr mixed oxides for furfural-acetone aldol condensation by supporting on mesoporous carbons.
A new procedure for improving the performance of the most common catalysts used in aqueous-phase aldol condensation (Mg-Zr mixed oxides) reactions is presented. This reaction is of interest for upgrading carbohydrate feedstocks. The procedure involves supporting Mg-Zr oxides on non-microporous carbonaceous materials, such as carbon nanofibers (CNFs) or high-surface-area graphites (HSAGs), using either incipient wetness or coprecipitation procedures. The use of HSAGs together with the coprecipitation method provides the best performance. Results obtained for the cross-condensation of acetone and furfural at 323 K reveal that the catalyst performance is greatly improved compared to the bulk oxides (96.5 % conversion vs. 81.4 % with the bulk oxide; 87.8 % selectivity for C13 and C8 adducts vs. 76.2 % with the bulk oxide). This difference is even more prominent in terms of rates per catalytically active basic site (four and seven times greater for C8 and C13 adducts, respectively). The improved performance is explained in terms of a more appropriate basic site distribution and by greater interaction of the reactants with the carbon surface. In addition, deactivation behavior of the catalyst is improved by tuning the morphology of the carbonaceous support. An important enhancement of the catalytic stability can be obtained selecting a HSAG with an appropriate pore diameter. With HSAG100 the activity decreased by less than 20 % between successive reaction cycles and the selectivity for the condensation products remained almost unaltered. The decrease is greater than 80 % for the bulk oxides tested at these conditions, with important increases in the selectivity for by-product formation.


Phthalate exposure and reproductive hormones and sex-hormone binding globulin before puberty - Phthalate contaminated-foodstuff episode in Taiwan.
In May 2011, a major incident involving phthalates-contaminated foodstuffs occurred in Taiwan. Di-(2-ethylhexyl) phthalate (DEHP) was added to foodstuffs, mainly juice, jelly, tea, sports drink, and dietary supplements. Concerns arose that normal pubertal development, especially reproductive hormone regulation in children, could be disrupted by DEHP exposure. To investigate the association between phthalate exposure and reproductive hormone levels among children following potential exposure to phthalate-tainted foodstuffs. A total of 239 children aged <12 years old were recruited from 3 hospitals in north, central, and south Taiwan after the episode. Structured questionnaires were used to collect the frequency and quantity of exposures to 5 categories of phthalate-contaminated foodstuffs to assess phthalate exposure in children. Urine samples were collected for the measurement of phthalate metabolites. The estimated daily intake of DEHP exposure at the time of the contamination incident occurred was calculated using both questionnaire data and urinary DEHP metabolite concentrations. Multiple regression analyses were applied to assess associations between phthalate exposure and reproductive hormone levels in children. After excluding children with missing data regarding exposure levels and hormone concentrations and girls with menstruation, 222 children were included in the statistical analyses. After adjustment for age and birth weight, girls with above median levels of urinary mono-(2-ethyl-5-hydroxyhexyl) phthalate, mono-(2-ethyl-5-oxohexyl) phthalate, and sum of mono-(2-ethylhexyl) phthalate concentrations had higher odds of above median follicle-stimulating hormone concentrations. Girls with above median estimated average daily DEHP exposures following the contamination episode also had higher odds of sex hormone-binding globulin above median levels. Phthalate exposure was associated with alterations of reproductive hormone levels in girls.


Validity of serum adenosine deaminase in diagnosis of tuberculosis.
Tuberculosis is one of the most important infectious causes of death worldwide. Ziehl-Neelsen staining of sputum has high specificity in tuberculosis endemic countries, but modest sensitivity which varies among laboratories. This study was set up to investigate the diagnostic value of serum Adenosine deaminase in diagnosis of tuberculosis. In a cross sectional and prospective study Serums of 200 patients of positive sputum smear, negative sputum smear, extra-pulmonary tuberculosis and bacterial community acquired pneumonia collected from March 2011 to May 2012 were evaluated. The data were analyzed using SPSS software and P-value of <0.05 was considered significant. A total of 200 subjects were included in the study designed in four groups. In cut-off value of ≥24 U/l for ADA in smear positive patients defined the sensitivity, specificity and positive predictive value 12%, 98% and 86% respectively. In smear negative patients defined the 6%, 98% and 75%, and in extra-pulmonary tuberculosis patients defined the sensitivity 14%, 98% and 88% respectively. This study indicated that measurement of serum ADA level do not have enough sensitivity to assist in the diagnoses of tuberculosis patients from other respiratory diseases and not evaluated perform well enough to replace sputum smear microscopy. Thus, this tests have little role in the diagnosis of pulmonary tuberculosis.


Cytokine regulation of colony-stimulating factor production in cultured human synovial fibroblasts: I. Induction of GM-CSF and G-CSF production by interleukin-1 and tumor necrosis factor.
The cytokines, interleukin-1 (IL-1) and tumor necrosis factor (TNF), induce a dose-dependent production of both granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte CSF (G-CSF) in cultured human synovial cells, as measured by immunoassay. With IL-1, significant levels of both CSFs were first detected within 6 to 12 hours, with a maximum reached 24 to 48 hours after commencement of stimulation. A synergistic effect was detected between IL-1 and TNF in production of both CSFs in these cells. No evidence was obtained for the IL-1-induced effect to be mediated by induction of endogenous TNF nor for the TNF-induced stimulation to involve IL-1. IL-1-stimulated synovial cells were shown to secrete biologically active GM-CSF and G-CSF, which were specifically inhibited by their respective monoclonal antibodies. The transcription inhibitor, actinomycin D, and protein synthesis inhibitor, cycloheximide, inhibited the increase in GM-CSF and G-CSF production induced by IL-1 and TNF. Finally, other cytokines, IL-3, interferon gamma (IFN gamma), IL-2, platelet-derived growth factor (PDGF), epidermal growth factor (EGF) and transforming growth factor alpha (TGF alpha), failed to stimulate either GM-CSF or G-CSF production, whether alone or in the presence of IL-1. These results suggest that cytokine-stimulated synovial fibroblasts may be a major source of intraarticular CSF production in the joints of patients with inflammatory arthritis; as a result, monocyte/macrophages and granulocytes may be activated, leading to perpetuation of the inflammation and destructive events occurring in these lesions.


Peginesatide in patients with anemia undergoing hemodialysis.
Peginesatide, a synthetic peptide-based erythropoiesis-stimulating agent (ESA), is a potential therapy for anemia in patients with advanced chronic kidney disease. We conducted two randomized, controlled, open-label studies (EMERALD 1 and EMERALD 2) involving patients undergoing hemodialysis. Cardiovascular safety was evaluated by analysis of an adjudicated composite safety end point--death from any cause, stroke, myocardial infarction, or serious adverse events of congestive heart failure, unstable angina, or arrhythmia--with the use of pooled data from the two EMERALD studies and two studies involving patients not undergoing dialysis. In the EMERALD studies, 1608 patients received peginesatide once monthly or continued to receive epoetin one to three times a week, with the doses adjusted as necessary to maintain a hemoglobin level between 10.0 and 12.0 g per deciliter for 52 weeks or more. The primary efficacy end point was the mean change from the baseline hemoglobin level to the mean level during the evaluation period; noninferiority was established if the lower limit of the two-sided 95% confidence interval was -1.0 g per deciliter or higher in the comparison of peginesatide with epoetin. The aim of evaluating the composite safety end point in the pooled cohort was to exclude a hazard ratio with peginesatide relative to the comparator ESA of more than 1.3. In an analysis involving 693 patients from EMERALD 1 and 725 from EMERALD 2, peginesatide was noninferior to epoetin in maintaining hemoglobin levels (mean between-group difference, -0.15 g per deciliter; 95% confidence interval [CI], -0.30 to -0.01 in EMERALD 1; and 0.10 g per deciliter; 95% CI, -0.05 to 0.26 in EMERALD 2). The hazard ratio for the composite safety end point was 1.06 (95% CI, 0.89 to 1.26) with peginesatide relative to the comparator ESA in the four pooled studies (2591 patients) and 0.95 (95% CI, 0.77 to 1.17) in the EMERALD studies. The proportions of patients with adverse and serious adverse events were similar in the treatment groups in the EMERALD studies. The cardiovascular safety of peginesatide was similar to that of the comparator ESA in the pooled cohort. Peginesatide, administered monthly, was as effective as epoetin, administered one to three times per week, in maintaining hemoglobin levels in patients undergoing hemodialysis. (Funded by Affymax and Takeda Pharmaceutical; ClinicalTrials.gov numbers, NCT00597753 [EMERALD 1], NCT00597584 [EMERALD 2], NCT00598273 [PEARL 1], and NCT00598442 [PEARL 2].).


Caregiver-proxy reliability of the Igbo-culture adapted Maleka Stroke Community Reintegration Measure: a validation study.
This study was designed to determine the caregiver-proxy reliability of the Igbo-culture adapted urban version of the Maleka Stroke Community Reintegration Measure (I-MSCRIM). This was a validation study involving 74 consenting stroke survivors and their 74 primary informal caregivers consecutively recruited from selected tertiary hospitals in South-East Nigeria (Igboland). The I-MSCRIM was researcher-administered to the participants. Obtained data was analyzed using frequency counts, percentages, range, mean, standard deviation, Spearman rank order correlation, Mann-Whitney U test, Kruskal-Wallis test and Intra-class Correlation Coefficient. Alpha level was set at 0.05. The mean ages of the stroke survivors (55.4% males) and their primary informal caregivers (41.9% males) were 50.14 ± 12.24 and 31.93 ± 10.9 years respectively. There was no significant difference in the community reintegration (CR) scores as rated by stroke survivors and their primary informal caregivers (p > 0.05). The correlations between stroke survivors' and primary informal caregivers' rated CR scores were all adequate and acceptable (ICC = 0.602-0.917). The discrepancy in the total CR scores between the two ratings was significantly influenced by primary informal caregivers' educational attainment (k = 13.15; p < 0.01). The I-MSCRIM has acceptable caregiver-proxy reliability among Igbo stroke survivors in South-East Nigeria. This suggests that primary informal caregivers of stroke survivors can reliably estimate the CR of their care recipients when I-MSCRIM is administered to them. This will be useful when a stroke survivor cannot respond to I-MSCRIM.


Alymphoplasia (aly)-type nuclear factor kappaB-inducing kinase (NIK) causes defects in secondary lymphoid tissue chemokine receptor signaling and homing of peritoneal cells to the gut-associated lymphatic tissue system.
Alymphoplasia (aly) mice, which carry a point mutation in the nuclear factor kappaB-inducing kinase (NIK) gene, are characterized by the systemic absence of lymph nodes and Peyer's patches, disorganized splenic and thymic architectures, and immunodeficiency. Another unique feature of aly/aly mice is that their peritoneal cavity contains more B1 cells than normal and aly/+ mice. Transfer experiments of peritoneal lymphocytes from aly/aly mice into recombination activating gene (RAG)-2(-/-) mice revealed that B and T cells fail to migrate to other lymphoid tissues, particularly to the gut-associated lymphatic tissue system. In vivo homing defects of aly/aly peritoneal cells correlated with reduction of their in vitro chemotactic responses to secondary lymphoid tissue chemokine (SLC) and B lymphocyte chemoattractant (BLC). The migration defect of aly/aly lymphocytes was not due to a lack of expression of chemokines and their receptors, but rather to impaired signal transduction downstream of the receptors for SLC, indicating that NIK is involved in the chemokine signaling pathway known to couple only with G proteins. The results showed that the reduced serum levels of immunoglobulins (Igs) and the absence of class switch to IgA in aly/aly mice are due, at least in part, to a migration defect of lymphocytes to the proper microenvironment where B cells proliferate and differentiate into Ig-producing cells.


Recruitment of lymphocytes to the lung through vaccination enhances the immunity of mice exposed to irradiated schistosomes.
The effector mechanism, which operates against challenge parasites in the lungs of C57BL/6 mice vaccinated once with irradiated cercariae of Schistosoma mansoni, is mediated by CD4+ T helper lymphocytes. However, adoptive transfer of immunity from vaccinated donors to naive recipients by using sensitized T cells has not proved successful. One explanation may be that the recruitment of sensitized T lymphocytes to the lungs by vaccinating parasites to arm that organ is not reproduced by transfer protocols. We have used the technique of parabiosis, as a means of adoptive transfer, to demonstrate the relevance of pulmonary T cells to protection. Sensitized and naive partners were joined surgically for a 28-day period, coincident with priming of the immune system. A vascular union rapidly developed, and sensitized T cells were detected in the spleens of the naive partners. When parabionts were challenged percutaneously 10 days after separation, the level of immunity transferred to the naive partners was approximately two-thirds that of their vaccinated counterparts. The naive partners, unlike the vaccinated animals, did not recruit lymphocytes to the lungs during the priming period. In contrast, after percutaneous challenge, schistosome-specific lymphocytes were recruited to the lungs of both separated parabionts. The importance of lymphocytes recruited to the lungs during the primary response was revealed by an intravenous challenge with lung schistosomula; this eliminates the opportunity for secondary immune responses prior to parasite arrival in the lungs. In this situation, the vaccinated partners showed 47% immunity while the naive partners were not protected. We conclude that the presence of specific T cells in the lungs at the time of challenge confers a significant advantage, permitting a more effective recall response than in animals lacking such resident cells.


Lectin histochemistry of human fetal notochord, ecchordosis physaliphora, and chordomas.
Lectin histochemical studies of human fetal notochord, ecchordosis physaliphora, and eight chordomas were performed. Ecchordosis physaliphora and eight chordomas were stained with Ricinus communis type I, Canavalia ensiformis, Triticum vulgaris, and Limax flavus. Ricinus communis type I, T vulgaris, and L flavus reacted with both tumor cells and the extracellular mucinous matrix, while C ensiformis mainly reacted with the cytoplasm of tumor cells. Thus, tumor cells were most recognizable with the C ensiformis stain. After neuraminidase treatment, ecchordosis physaliphora and chordomas invariably showed positivities for Arachis hypogaea. The lectin-binding patterns of chordomas closely reflected those of the human fetal notochord. Chordomas were completely sialylated regardless of either the clinical course or histopathological findings. Among the eight lectins, C ensiformis heavily labeled chordoma cells but not extracellular space. This was probably because asparagine-linked N-glycosylation was active in the chordomas, while the high-mannose-type oligosaccharides were apt to remain in the cytoplasm.


Emergence of highly degenerate excited states in the frustrated magnet MgCr2O4.
High degeneracy in ground states leads to the generation of exotic zero-energy modes, a representative example of which is the formation of molecular spin-liquid-like fluctuations in a frustrated magnet. Here we present single-crystal inelastic neutron scattering results for the frustrated magnet MgCr(2)O(4), which show that a common set of finite-energy molecular spin excitation modes is sustained in both the liquid-like phase above magnetic ordering temperature T(N) and an ordered phase with an extremely complex magnetic structure below T(N). Based on this finding, we propose the concept of high degeneracy in excited states, which promotes local resonant elementary excitations. This concept is expected to have ramifications on our understanding of excitations in many complex systems, including not only spin but also atomic liquids, complex order systems, and amorphous systems.


Activation of an early feedback survival loop involving phospho-ErbB3 is a general response of melanoma cells to RAF/MEK inhibition and is abrogated by anti-ErbB3 antibodies.
Treatment of advanced melanoma has been improved with the advent of the BRAF inhibitors. However, a limitation to such treatment is the occurrence of resistance. Several mechanisms have been identified to be responsible for the development of resistance, either MEK-dependent or MEK-independent. In order to overcome resistance due to reactivation of MEK signaling, MEK inhibitors are being clinically developed with promising results. However, also in this case resistance inevitably occurs. It has been recently reported that ErbB3, a member of the EGFR receptor family, may be involved in the establishment of drug resistance. Three melanoma cell lines were tested: LOX IMVI (BRAF V600E), MST-L (BRAF V600R) and WM266 (BRAF V600D). Phosphorylation of Receptor Tyrosine Kinases (RTKs) was assessed by an RTK array. Western blot analysis was performed on total protein extracts using anti-ErbB3, anti-AKT and anti-ERK 1/2 antibodies. The expression of neuregulin after vemurafenib treatment was assessed by Real Time PCR and Western blotting. The growth inhibitory effects of vemurafenib, GSK1120212b and/or anti-ErbB3 mAbs were evaluated by in vitro colony formation assays. In the present study we demonstrate that ErbB3 is the main RTK undergoing rapidly hyperphosphorylation upon either treatment with a BRAF inhibitor or with a MEK inhibitor in a panel of melanoma cell lines harboring a variety of V600BRAF mutations and that this results in a strong activation of phospho-AKT. Importantly, ErbB3 activation is fully abrogated by the simultaneous use of anti-ErbB3 monoclonal antibodies, which are also shown to potently synergize with BRAF inhibitors in the inactivation of both AKT and ERK pathways and in the inhibition of melanoma cell growth. We show that upregulation of phospho-ErbB3 is due to an autocrine loop involving increased transcription and production of neuregulin by melanoma cells. On the basis of these results, we propose that initial co-treatment with BRAF and/or MEK inhibitors and anti-ErbB3 antibodies should be pursued as a strategy to reduce the ErbB3-dependent feedback survival mechanism and enhance duration of clinical response.


Likelihood-based parameter estimation and comparison of dynamical cognitive models.
Dynamical models of cognition play an increasingly important role in driving theoretical and experimental research in psychology. Therefore, parameter estimation, model analysis and comparison of dynamical models are of essential importance. In this article, we propose a maximum likelihood approach for model analysis in a fully dynamical framework that includes time-ordered experimental data. Our methods can be applied to dynamical models for the prediction of discrete behavior (e.g., movement onsets); in particular, we use a dynamical model of saccade generation in scene viewing as a case study for our approach. For this model, the likelihood function can be computed directly by numerical simulation, which enables more efficient parameter estimation including Bayesian inference to obtain reliable estimates and corresponding credible intervals. Using hierarchical models inference is even possible for individual observers. Furthermore, our likelihood approach can be used to compare different models. In our example, the dynamical framework is shown to outperform nondynamical statistical models. Additionally, the likelihood based evaluation differentiates model variants, which produced indistinguishable predictions on hitherto used statistics. Our results indicate that the likelihood approach is a promising framework for dynamical cognitive models. (PsycINFO Database Record


Alternative Splicing of the Aryl Hydrocarbon Receptor Nuclear Translocator (ARNT) Is Regulated by RBFOX2 in Lymphoid Malignancies.
Aberrant alternative splicing (AS) of pre-mRNAs promotes the development and proliferation of cancerous cells. Accordingly, we had previously observed higher levels of the aryl hydrocarbon receptor nuclear translocator (ARNT) spliced variant isoform 1 in human lymphoid malignancies compared to that in normal lymphoid cells, which is a consequence of increased inclusion of alternative exon 5. ARNT is a transcription factor that has been implicated in the survival of various cancers. Notably, we found that ARNT isoform 1 promoted the growth and survival of lymphoid malignancies, but the regulatory mechanism controlling ARNT AS is unclear. Here, we report cis- and trans-regulatory elements which are important for the inclusion of ARNT exon 5. Specifically, we identified recognition motifs for the RNA-binding protein RBFOX2, which are required for RBFOX2-mediated exon 5 inclusion. RBFOX2 upregulation was observed in lymphoid malignancies, correlating with the observed increase in ARNT exon 5 inclusion. Moreover, suppression of RBFOX2 significantly reduced ARNT isoform 1 levels and cell growth. These observations reveal RBFOX2 as a critical regulator of ARNT AS in lymphoid malignancies and suggest that blocking the ARNT-specific RBFOX2 motifs to decrease ARNT isoform 1 levels is a viable option for targeting the growth of lymphoid malignancies.


The effect of hypothyroidism, hyperthyroidism, and their treatment on parameters of oxidative stress and antioxidant status.
Free radical-mediated oxidative stress has been implicated in the etiopathogenesis of several autoimmune disorders. Also, there is growing evidence supporting the role of reactive oxygen species in the pathogenesis of thyroid disorders. The aim of this study was to investigate the influence of hypothyroidism, hyperthyroidism, and their treatments on the metabolic state of oxidative stress, and antioxidant status markers. A total of 20 newly diagnosed patients with overt hypothyroidism due to Hashimoto's thyroiditis, 20 patients with overt hyperthyroidism due to Graves' disease, and 20 healthy subjects as the control group were enrolled in the study. Fasting blood samples (12 h), taken at the initiation, after the 30th and 60th day of therapy were analyzed for malondialdehyde, nitrite, vitamin E, vitamin A, beta-carotene, ascorbate, and myeloperoxidase and superoxide dismutase activity. No patient presented additional risk factors for increased reactive oxygen species levels. Malondialdehyde, nitrite, vitamin E, and myeloperoxidase activity increased in patients with hypothyroidism. After 2 months, the levels of nitrite and vitamin E were reduced to control levels by treatment. The patients with hyperthyroidism had increased levels of malondialdehyde and myeloperoxidase activity in comparison with the controls. Treatment with propylthiouracil attenuated these increments after 1 month. Our results reveal an increased generation of reactive oxygen species and impairment of the antioxidant system in patients with hyperthyroidism, and particularly in patients with hypothyroidism. These findings indicate that thyroid hormones have a strong impact on oxidative stress and the antioxidant system.


The UL84 protein of human cytomegalovirus acts as a transdominant inhibitor of immediate-early-mediated transactivation that is able to prevent viral replication.
The 86-kilodalton immediate-early (IE) 2 protein (IE2-p86) of human cytomegalovirus (HCMV) is a multifunctional regulator of HCMV gene expression which appears to be essential for triggering the lytic replicative cycle. IE2-p86 functions as a promiscuous transactivator of both viral and cellular gene expression and can repress transcription from its own promoter. In this study we demonstrate that a viral early protein, termed pUL84, which is able to interact with IE2-p86 both in vivo and in vitro, modulates IE2-p86 in a specific manner. First, pUL84 acts as a transdominant inhibitor of IE2-p86-mediated transactivation of both homologous and heterologous promoters. Second, negative autoregulation by IE2-p86 is augmented in the presence of pUL84. Using two in vivo assays, we obtained evidence that expression of pUL84 during the IE phase of the viral replicative cycle leads to an inhibition of viral early gene expression which prevents replication of HCMV and results in a persistent infection of UL84-positive cell lines. Transdominant inhibition of a viral IE function by a protein expressed during the later phases of replication appears to be a novel principle used by herpesviruses which could account for the slow replication of HCMV and may be useful in the development of new antiviral strategies.


Characteristics and Mechanism of Liver Injury in 2019 Coronavirus Disease.
An outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (2019 coronavirus disease, COVID-19) since December 2019, from Wuhan, China, has been posing a significant threat to global human health. The clinical features and outcomes of Chinese patients with COVID-19 have been widely reported. Increasing evidence has witnessed the frequent incident liver injury in COVID-19 patients, and it is often manifested as transient elevation of serum aminotransferases; however, the patients seldom have liver failure and obvious intrahepatic cholestasis, unless pre-existing advanced liver disease was present. The underlying mechanisms of liver injury in cases of COVID-19 might include psychological stress, systemic inflammation response, drug toxicity, and progression of pre-existing liver diseases. However, there is insufficient evidence for SARS-CoV-2 infected hepatocytes or virus-related liver injury in COVID-19 at present. The clinical, pathological and laboratory characteristics as well as underlying pathophysiology and etiology of liver injury in COVID-19 remain largely unclear. In this review, we highlight these important issues based on the recent developments in the field, for optimizing the management and treatment of liver injury in Chinese patients with COVID-19.


Evidence that the 37 kDa protein of Soil-borne wheat mosaic virus is a virus movement protein.
Experiments were conducted to determine if the 37 kDa protein (37K) of Soil-borne wheat mosaic virus (SBWMV) is a virus movement protein. First, evidence was obtained that indicated that 37K has the ability to move from cell to cell, similar to other virus movement proteins (MPs). Plasmids containing the GFP gene fused to the SBWMV 37K, the coat protein (CP) or the CP readthrough domain (RT) ORFs were delivered by biolistic bombardment to wheat and tobacco leaves. In wheat leaves, cell-to-cell movement of GFP-37K was observed, while GFP, GFP-CP and GFP-RT accumulated primarily in single cells. All fusion proteins accumulated in single cells in tobacco leaves. Thus, cell-to-cell movement is a specific property of 37K that occurs in SBWMV host plants. Subcellular accumulation of 37K was studied using SBWMV-infected and 37K-expressing transgenic wheat. In infected and transgenic wheat leaves, 37K accumulated in the cell wall, similar to other virus MPs, and in aggregates in the cytoplasm. Phylogenetic studies were conducted to compare the furovirus 37K proteins with members of the 30K superfamily of virus MPs. Amino acid sequences of the furovirus 37K proteins were aligned with the MPs from 43 representative viruses. The furovirus 37K proteins were found to reside in a clade that also contained the dianthovirus MPs. Combined, these data suggest that SBWMV 37K is probably a virus MP.


Association of in vitro fertilization with global and IGF2/H19 methylation variation in newborn twins.
In vitro fertilization (IVF) and its subset intracytoplasmic sperm injection (ICSI), are widely used medical treatments for conception. There has been controversy over whether IVF is associated with adverse short- and long-term health outcomes of offspring. As with other prenatal factors, epigenetic change is thought to be a molecular mediator of any in utero programming effects. Most studies focused on DNA methylation at gene-specific and genomic level, with only a few on associations between DNA methylation and IVF. Using buccal epithelium from 208 twin pairs from the Peri/Postnatal Epigenetic Twin Study (PETS), we investigated associations between IVF and DNA methylation on a global level, using the proxies of Alu and LINE-1 interspersed repeats in addition to two locus-specific regulatory regions within IGF2/H19, controlling for 13 potentially confounding factors. Using multiple correction testing, we found strong evidence that IVF-conceived twins have lower DNA methylation in Alu, and weak evidence of lower methylation in one of the two IGF2/H19 regulatory regions and LINE-1, compared with naturally conceived twins. Weak evidence of a relationship between ICSI and DNA methylation within IGF2/H19 regulatory region was found, suggesting that one or more of the processes associated with IVF/ICSI may contribute to these methylation differences. Lower within- and between-pair DNA methylation variation was also found in IVF-conceived twins for LINE-1, Alu and one IGF2/H19 regulatory region. Although larger sample sizes are needed, our results provide additional insight to the possible influence of IVF and ICSI on DNA methylation. To our knowledge, this is the largest study to date investigating the association of IVF and DNA methylation.


Uptake of [(15)N] Ammonium and [(15)N]Nitrate in a 140-Year-Old Spruce Stand (Picea abies) in the Fichtelgebirge (NE Bavaria).
Abstract In April 1994 a (15)N tracer pulse study was started in a 140-year-old spruce stand (Picea abies [L.] Karst.) located at the Fichtelgebirge (NE Bavaria). Highly enriched (98%) [(15)N]ammonium and [(15)N]nitrate were applied simulating wet deposition. For two growing seasons the pathways and dynamics of the tracer were followed in all compartments of spruce (needles and twigs of all age classes, stem wood and bark, roots) and understorey vegetation and in soils of the organic (L/Of and Oh) and mineral horizons (A(0-5) and A(5-10)). By variations of the application time on different plots within the growing season (spring, summer and autumn) a seasonal effect of labelling on uptake and distribution patterns was tested. First results of this tracer study indicate that young and old spruce stands do not differ basically in pattern of uptake and distribution of mineral nitrogen. There are indications that spruce uses preferentially ammonium versus nitrate and that the ratio of ammonium/nitrate which is being consumed depends on the ammonium/nitrate ratio in the soil solution. The uptake rates decrease within the growing season.


Ondansetron versus promethazine to treat acute undifferentiated nausea in the emergency department: a randomized, double-blind, noninferiority trial.
The authors sought to compare ondansetron and promethazine among emergency department (ED) patients with undifferentiated nausea. The hypothesis was that ondansetron was not inferior to promethazine and that rates of adverse effects were similar. This was a randomized double-blind noninferiority clinical trial conducted in an urban academic ED. A convenience sample of nonpregnant adults with at least 40 mm of self-reported nausea measured on a 100-mm visual analog scale (VAS) were enrolled. Patients who had already received more than 1 L of intravenous fluid or an antiemetic agent were excluded. Subjects were block-randomized in groups of 10 to either 4 mg of ondansetron or 25 mg of promethazine delivered intravenously. The primary outcome was change in nausea over 30 minutes. The authors used a 15-mm margin of noninferiority. Secondary endpoints included changes in anxiety, sedation, and other adverse effects. Analyses included t-tests, tests for proportions, and 95% confidence intervals (CIs). A total of 120 subjects completed the study, 60 in each arm. Baseline nausea, anxiety, and sedation scores were similar. Ondansetron and promethazine reduced nausea similarly (ondansetron -34 mm, promethazine -36 mm; difference -2 mm; 95% CI = -13 to 8 mm). The reduction in anxiety was similar (ondansetron -13 mm, promethazine -14 mm; difference -1 mm; 95% CI = -10 to 10 mm). Promethazine was associated with significantly more sedation than ondansetron (ondansetron 5 mm, promethazine 19 mm; difference 14 mm; 95% CI = 5 to 24 mm). There were no cases of akathisia in the ondansetron group and 2 cases in the promethazine group. Promethazine and ondansetron have similar efficacy in reducing nausea among ED patients. Change in anxiety was similar, but promethazine was associated with greater sedation.