Characterization of the Salmonella typhimurium proteome by semi-automated two dimensional HPLC-mass spectrometry: detection of proteins implicated in multiple antibiotic resistance.
The proteome of Salmonella enterica serovar Typhimurium was characterized by 2-dimensional HPLC mass spectrometry to provide a platform for subsequent proteomic investigations of low level multiple antibiotic resistance (MAR). Bacteria (2.15 +/- 0.23 x 10(10) cfu; mean +/- s.d.) were harvested from liquid culture and proteins differentially fractionated, on the basis of solubility, into preparations representative of the cytosol, cell envelope and outer membrane proteins (OMPs). These preparations were digested by treatment with trypsin and peptides separated into fractions (n = 20) by strong cation exchange chromatography (SCX). Tryptic peptides in each SCX fraction were further separated by reversed-phase chromatography and detected by mass spectrometry. Peptides were assigned to proteins and consensus rank listings compiled using SEQUEST. A total of 816 +/- 11 individual proteins were identified which included 371 +/- 33, 565 +/- 15 and 262 +/- 5 from the cytosolic, cell envelope and OMP preparations, respectively. A significant correlation was observed (r2 = 0.62 +/- 0.10; P < 0.0001) between consensus rank position for duplicate cell preparations and an average of 74 +/- 5% of proteins were common to both replicates. A total of 34 outer membrane proteins were detected, 20 of these from the OMP preparation. A range of proteins (n = 20) previously associated with the mar locus in E. coli were also found including the key MAR effectors AcrA, TolC and OmpF.


Mechanical methods for induction of labour.
Mechanical methods were the first methods developed to ripen the cervix and induce labour. During recent decades they have been substituted by pharmacological methods. Potential advantages of mechanical methods, compared with pharmacological methods may include reduction in side effects that could improve neonatal outcomes. This is an update of a review first published in 2001, last updated in 2012. To determine the effectiveness and safety of mechanical methods for third trimester (> 24 weeks' gestation) induction of labour in comparison with prostaglandin E2 (PGE2) (vaginal and intracervical), low-dose misoprostol (oral and vaginal), amniotomy or oxytocin. For this update, we searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP), and reference lists of retrieved studies (9 January 2018). We updated the search in March 2019 and added the search results to the awaiting classification section of the review. Clinical trials comparing mechanical methods used for third trimester cervical ripening or labour induction with pharmacological methods.Mechanical methods include: (1) the introduction of a catheter through the cervix into the extra-amniotic space with balloon insufflation; (2) introduction of laminaria tents, or their synthetic equivalent (Dilapan), into the cervical canal; (3) use of a catheter to inject fluid into the extra-amniotic space (EASI).This review includes the following comparisons: (1) specific mechanical methods (balloon catheter, laminaria tents or EASI) compared with prostaglandins (different types, different routes) or with oxytocin; (2) single balloon compared to a double balloon; (3) addition of prostaglandins or oxytocin to mechanical methods compared with prostaglandins or oxytocin alone. Two review authors independently assessed trials for inclusion and assessed risk of bias. Two review authors independently extracted data and assessed the quality of the evidence using the GRADE approach. This review update includes a total of 113 trials (22,373 women) contributing data to 21 comparisons. Risk of bias of trials varied. Overall, the evidence was graded from very-low to moderate quality. All evidence was downgraded for lack of blinding and, for many comparisons, the effect estimates were too imprecise to make a valid judgement.Balloon versus vaginal PGE2: there may be little or no difference in vaginal deliveries not achieved within 24 hours (average risk ratio (RR) 1.01, 95% confidence interval (CI) 0.82 to 1.26; 7 studies; 1685 women; I² = 79%; low-quality evidence) and there probably is little or no difference in caesarean sections (RR 1.00, 95% CI 0.92 to 1.09; 28 studies; 6619 women; moderate-quality evidence) between induction of labour with a balloon catheter and vaginal PGE2. A balloon catheter probably reduces the risk of uterine hyperstimulation with fetal heart rate (FHR) changes (RR 0.35, 95% CI 0.18 to 0.67; 6 studies; 1966 women; moderate-quality evidence), serious neonatal morbidity or perinatal death (RR 0.48, 95% CI 0.25 to 0.93; 8 studies; 2757 women; moderate-quality evidence) and may slightly reduce the risk of aneonatal intensive care unit (NICU) admission (RR 0.82, 95% CI 0.65 to 1.04; 3647 women; 12 studies; low-quality evidence). It is uncertain whether there is a difference in serious maternal morbidity or death (RR 0.20, 95% CI 0.01 to 4.12; 4 studies; 1481 women) or five-minute Apgar score < 7 (RR 0.74, 95% CI 0.49 to 1.14; 4271 women; 14 studies) because the quality of the evidence was found to be very low and low, respectively.Balloon versus low-dose vaginal misoprostol: it is uncertain whether there is a difference in vaginal deliveries not achieved within 24 hours between induction of labour with a balloon catheter and vaginal misoprostol (RR 1.09, 95% CI 0.85 to 1.39; 340 women; 2 studies; low-quality evidence). A balloon catheter probably reduces the risk of uterine hyperstimulation with FHR changes (RR 0.39, 95% CI 0.18 to 0.85; 1322 women; 8 studies; moderate-quality evidence) but may increase the risk of a caesarean section (average RR 1.28, 95% CI 1.02 to 1.60; 1756 women; 12 studies; I² = 45%; low-quality evidence). It is uncertain whether there is a difference in serious neonatal morbidity or perinatal death (RR 0.58, 95% CI 0.12 to 2.66; 381 women; 3 studies), serious maternal morbidity or death (no events; 4 studies, 464 women), both very low-quality evidence, and five-minute Apgar score < 7 (RR 1.00, 95% CI 0.50 to 1.97; 941 women; 7 studies) and NICU admissions (RR 1.00, 95% CI 0.61 to 1.63; 1302 women; 9 studies) both low-quality evidence.Balloon versus low-dose oral misoprostol: a balloon catheter probably increases the risk of a vaginal delivery not achieved within 24 hours (RR 1.28, 95% CI 1.13 to 1.46; 782 women, 2 studies, and probably slightly increases the risk of a caesarean section (RR 1.17, 95% CI 1.04 to 1.32; 3178 women; 7 studies; both moderate-quality evidence) when compared to oral misoprostol. It is uncertain whether there is a difference in uterine hyperstimulation with FHR changes (RR 0.81, 95% CI 0.48 to 1.38; 2033 women; 2 studies), serious neonatal morbidity or perinatal death (RR 1.11, 95% CI 0.60 to 2.06; 2627 women; 3 studies), both low-quality evidence, serious maternal morbidity or death (RR 0.50, 95% CI 0.05 to 5.52; 2627 women; 3 studies), very low-quality evidence, five-minute Apgar scores < 7 (RR 0.71, 95% CI 0.38 to 1.32; 2693 women; 4 studies) and NICU admissions (RR 0.82, 95% CI 0.58 to 1.17; 2873 women; 5 studies) both low-quality evidence. Low- to moderate-quality evidence shows mechanical induction with a balloon is probably as effective as induction of labour with vaginal PGE2. However, a balloon seems to have a more favourable safety profile. More research on this comparison does not seem warranted.Moderate-quality evidence shows a balloon catheter may be slightly less effective as oral misoprostol, but it remains unclear if there is a difference in safety outcomes for the neonate. When compared to low-dose vaginal misoprostol, low-quality evidence shows a balloon may be less effective, but probably has a better safety profile.Future research could be focused more on safety aspects for the neonate and maternal satisfaction.


Institutional validation of breast cancer treatment guidelines.
Several groups have developed clinical guidelines for the management of breast cancer, yet little data exist regarding their validation. Therefore, we examined the effect of published National Comprehensive Cancer Network (NCCN) guidelines for invasive breast cancer on survival, quality of life (QOL), and hospital cost. From 260 consecutive breast cancer patients, 129 patients were identified for analysis: 93 patients (72%) were treated according to the guidelines (NCCN+), while the treatment of 36 patients (28%), with a similar stage distribution, deviated from the guidelines (NCCN-). Patients were excluded from analysis with a diagnosis of carcinoma in situ, inflammatory cancer, stage IV disease, and comorbid conditions that affected treatment. The 5-year survival was 87.6% for the NCCN+ patients versus 83.3% for NCCN- patients (P = 0.319 by Kaplan-Meier). Twelve QOL parameters were evaluated using a Likert-type scale (1 = severe and 5 = none). NCCN+ patients had a cumulative QOL score of 4.18 +/- 0.08 versus 4.24 +/- 0.14 for NCCN- patients (P = 0.745). Treatment-related costs were $20,300 +/- 1800 for NCCN+ patients versus $59,700 +/- 25,200 for NCCN- patients (P = 0.016 by t test). Although deviation from NCCN breast cancer guidelines had no effect on perceived quality of life or survival, there was a significant decrease in cost in the NCCN+ group. These findings suggest that adherence to NCCN guidelines can significantly reduce the cost of breast cancer care without adversely affecting either survival or quality of life.


Micro- to nanostructure and geochemistry of extant crinoidal echinoderm skeletons.
This paper reports the results of micro- to nanostructural and geochemical analyses of calcitic skeletons from extant deep-sea stalked crinoids. Fine-scale (SEM, FESEM, AFM) observations show that the crinoid skeleton is composed of carbonate nanograins, about 20-100 nm in diameter, which are partly separated by what appears to be a few nm thick organic layers. Sub-micrometre-scale geochemical mapping of crinoid ossicles using a NanoSIMS ion microprobe, combined with synchrotron high-spatial-resolution X-ray micro-fluorescence (μ-XRF) maps and X-ray absorption near-edge structure spectroscopy (XANES) show that high Mg concentration in the central region of the stereom bars correlates with the distribution of S-sulphate, which is often associated with sulphated polysaccharides in biocarbonates. These data are consistent with biomineralization models suggesting a close association between organic components (including sulphated polysaccharides) and Mg ions. Additionally, geochemical analyses (NanoSIMS, energy dispersive spectroscopy) reveal that significant variations in Mg occur at many levels: within a single stereom trabecula, within a single ossicle and within a skeleton of a single animal. Together, these data suggest that physiological factors play an important role in controlling Mg content in crinoid skeletons and that great care should be taken when using their skeletons to reconstruct, for example, palaeotemperatures and Mg/Ca palaeo-variations of the ocean.


Patterns of text reuse in a scientific corpus.
We consider the incidence of text "reuse" by researchers via a systematic pairwise comparison of the text content of all articles deposited to arXiv.org from 1991 to 2012. We measure the global frequencies of three classes of text reuse and measure how chronic text reuse is distributed among authors in the dataset. We infer a baseline for accepted practice, perhaps surprisingly permissive compared with other societal contexts, and a clearly delineated set of aberrant authors. We find a negative correlation between the amount of reused text in an article and its influence, as measured by subsequent citations. Finally, we consider the distribution of countries of origin of articles containing large amounts of reused text.


DNA sequencing with direct blotting electrophoresis.
A method for transferring the DNA molecules of sequencing reaction mixtures onto an immobilizing matrix during electrophoresis has been developed. A blotting membrane moves with constant speed across the end of a very short, denaturing gel and collects the molecules according to size. A constant distance between bands for molecules differing in length by one nucleotide is obtained over a large range (approximately 600 nucleotides with a 5% gel), simplifying the determination of DNA sequences considerably. Reliable sequences of 500 nucleotides can be read and sequence features up to greater than 1000 nucleotides are revealed in a single experiment. The sequencing of a potential Z-DNA-forming fragment from Escherichia coli DNA is given as an example and possible further developments are discussed.


Suppression of invasion and metastasis in aggressive salivary cancer cells through targeted inhibition of ID1 gene expression.
Salivary gland cancer (SGC) represents the most common malignancy in the head and neck region, and often metastasizes to the lungs. The helix-loop-helix ID1 protein has been shown to control metastatic progression in many types of cancers. Using two different approaches to target the expression of ID1 (genetic knockdown and progesterone receptor introduction combined with progesterone treatment), we previously determined that the aggressiveness of salivary gland tumor ACCM cells in culture was suppressed. Here, using the same approaches to target ID1 expression, we investigated the ability of ACCM cells to generate lung metastatic foci in nude mice. Moreover, since both approaches would be challenging for applications in humans, we added a third approach, i.e., treatment of mice with a non-toxic cannabinoid compound known to down-regulate ID1 gene expression. All approaches aimed at targeting the pro-metastatic ID1 gene led to a significant reduction in the formation of lung metastatic foci. Therefore, targeting a key transcriptional regulator using different means results in the same reduction of the metastatic spread of SGC cells in animal models, suggesting a novel approach for the treatment of patients with aggressive SGC.


Electromyographic analysis of transversus abdominis and lumbar multifidus using wire electrodes during lumbar stabilization exercises.
Experimental laboratory study. To measure trunk muscle activity using wire electrodes during lumbar stabilization exercises and to examine if more effective exercises to activate the deep trunk muscles (local muscles) exist. Lumbar stabilization exercises are performed to improve motor control of trunk muscles. However, the magnitude of activation of local muscles during lumbar stabilization exercises is not clear. Nine healthy men with no history of lumbar spine disorders participated in the study. Fine-wire electrodes were inserted into the transversus abdominis (TrA) and lumbar multifidus, bilaterally. In addition, surface electrodes were attached to the rectus abdominis, external obliques, and erector spinae, bilaterally. Electromyographic signal amplitude was measured during the following exercises: elbow-toe, hand-knee, back bridge, side bridge, and curl-up. Two-way analyses of variance were used to compare muscle activity level among exercises and between sides for each muscle. The exercise showing the greatest activity level for the TrA was elbow-toe exercise with contralateral arm and leg lift. In addition, for the TrA, a significant side-to-side difference in activation level was demonstrated for 7 of the 11 exercises that were performed. The activity level of the multifidus was greatest during the back bridge exercises. The curl-up exercise generated the highest activity level for the rectus abdominis and the back bridge, with single-leg lift exercises generating the highest erector spinae activity. The exercises investigated in this study resulted in a wide range of effort level for all 5 muscles monitored. Many of the exercises also resulted in an asymmetrical (right versus left side) activation level for a muscle, including the TrA.


Effectiveness of scapula-focused approaches in patients with rotator cuff related shoulder pain: A systematic review and meta-analysis.
Rotator cuff related shoulder pain (RCSP) is common with a range of conservative treatments currently offered. Evidence supporting superiority of one approach over another is lacking. Scapula focused approaches (SFA) are frequently prescribed and warrant investigation. To evaluate the effectiveness of SFA in RCSP. Systematic review of randomised controlled trials. An electronic search including MEDLINE, PEDro, ENFISPO to January 2016 was supplemented by hand searching. Randomised controlled trials were included; appraised using the PEDro scale and synthesised via meta-analysis or narratively, where appropriate. Four studies (n = 190) reported on pain and three studies (n = 122) reported on disability. Regarding pain, there was statistical but not clinically significant benefit of SFA versus generalised approaches (mean difference (VAS) 0.714; 95% CI 0.402-1.026) in the short term (<6 weeks); regarding disability, there was significant benefit of SFA versus generalised approaches (mean difference 14.0; 95% CI 11.2-16.8) in the short term (<6 weeks). One study (n = 22) reported disability at 3 months, which was not statistically significant. Evidence is conflicting from four studies relating to the effect of SFA on scapula position/movement. SFA for RCSP confers benefit over generalised approaches up to six weeks but this benefit is not apparent by 3 months. Early changes in pain are not clinically significant. With regards to scapula position/movement, the evidence is conflicting. These preliminary conclusions should be treated with significant caution due to limitations of the evidence base.


Adriamycin cardiotoxicity: early detection by systolic time interval and possible prevention by coenzyme Q10.
Recent work suggests that adriamycin (ADM) cardiotoxicity results from the depletion of coenzyme 10 (CoQ10) activity in myocardial mitochondria. CoQ10 is indispensable in the bioenergetics of coupled respiration of oxidative phosphorylation. It exists naturally in mitochondria, especially in the myocardium. Bertazzoli et al have reported a decrease in ADM-induced cardiotoxicity by CoQ10 both in vivo and in the in vitro isolated rabbit heart. The systolic time interval (ATI) (pre-ejection period/left ventricular ejection time ratio) has been shown to increase (indicating cardiac dysfunction) with increasing doses of ADM. We have noted a gradual increase in the STI in eight of ten patients receiving 200-500 mg/m2 of ADM. Two of these eight patients had congestive heart failure (CHF) at doses of 200 and 350 mg/m2. The continued daily oral administration of 50 mg of CoQ10 beginning with the first dose of ADM resulted in a decreased incidence of cardiac dysfunction, and a gradual increase in STI occurred in only two of eight patients receiving 200-400 mg/m2 of ADM. CHF was observed inone patient at a dose of 350 mg/m2. It is suggested that CoQ10 was nontoxic and did not affect the antitumor activity or modify the ADM-induced bone marrow toxicity. A prospective randomized study comparing ADM with and without CoQ10 is in progress.


Development of a model describing the inhibitory effect of selected preservatives on the growth of Listeria monocytogenes in a meat model system.
The objective of this study was to evaluate the impact of seven independent factors consisting of sodium nitrite, pH, sodium chloride, sodium acetate, sodium lactate syrup, calcium propionate and a blend of nisin and hop alpha acids on the growth rate of Listeria monocytogenes in ham as a model of ready-to-eat (RTE) meat products. A central composite consisted of seven factors mentioned above was designed and the response surface methodology was applied for creating a mathematic model to predict the growth rate of L. monocytogenes in RTE meat products. Six parameters showed a significant (P ≤ 0.1) influence on the growth rate of L. monocytogenes. Only the blend of nisin and hop alpha acids did not show any significant effect (P > 0.1) in the concentrations used in this study. Increasing concentration of sodium chloride, sodium nitrite, sodium acetate, potassium lactate and calcium propionate in meat reduced bacterial growth rate while increasing pH in meat increased the growth rate of L. monocytogenes. The current mathematical equation will be an important tool in order to reduce the required number of challenge studies performed in order to ensure a safe food product.


Medical thoracoscopic lung biopsy in interstitial lung disease: a prospective study of biopsy quality.
The aim of this study was to analyse the quality and diagnostic value of lung biopsies for the diagnosis of interstitial lung disease (ILD), taken with diathermy coagulation cup forceps during medical thoracoscopy. Patients with ILD, not specified after thorough clinical assessment, high-resolution CT (HRCT), bronchoalveolar lavage and transbronchial biopsy, were studied. Medical thoracoscopy was performed in an endoscopy suite under neuroleptic anaesthesia with spontaneous ventilation. Biopsy specimens were analysed prospectively by one lung pathologist blinded to the clinical findings. Over 2 yrs, 118 samples were analysed from 24 consecutive patients. A good quality biopsy was obtained in 23 patients, and 78% of the samples were of good quality. Biopsy findings plus clinical and HRCT data revealed a relevant diagnosis in 18 patients and some diagnostic clues in four patients, for whom further examinations were needed. No major complications occurred. Chest tube drainage averaged 5.3+/-4.7 days, and was related to the total lung capacity (p=0.008), which mirrors the severity of ILD. Separate sampling of biopsies from different lobes proved to be useful in one third of the cases. In conclusion, lung biopsy sampling can be performed safely by interventional pulmonary endoscopists and has a good diagnostic yield in interstitial lung disease of unknown origin.


International Study of Definitions of English-Language Terms for Suicidal Behaviours: protocol of an opinion survey.
The objective of present paper is to outline the methodology of the International Study of Definitions of English-Language Terms for Suicidal Behaviours (ISDELTSB). The aim of the study is to survey existing English language terms and definitions used around the world for suicidal behaviour. The ISDELTSB is a worldwide survey based on one 'designated expert' per each WHO-registered country. 'Experts' were contacted through the International Association for Suicide Prevention (IASP), the World Psychiatric Association and the World Organization of Family Doctors. Each individual was sent an invitation to participate and a link to an online questionnaire. A comparison sample was created by inviting all IASP members to respond to the questionnaire. The questionnaire was designed to assess respondents' preferences about a particular set of terms and definitions by using the four major criteria of the definition of suicide identified in the literature (outcome, intent, knowledge and agency). The questionnaire used a multiple-choice question format. Participants were asked to choose one term in the list for each of the proposed definitions. Statements and definitions in the questionnaire were elaborated using the four main features of the definition of suicide, starting by the definitions and terms for which there is already a certain degree of consensus and then progressing to definitions and terms less agreed on. The study protocol obtained approval of Griffith University's Ethics Committee (ethics reference number 2017/601) and in accordance with the Australian National Statement on Ethical Conduct in Human Research. Respondents are asked if they accept to be personally acknowledged in any output originating from this study, and if so to provide their full name, title and affiliations. If respondents do not accept, they are informed that the conduct of this research respects Griffith University's Privacy Plan and that identified personal information is confidential and that anonymity will at all times be safeguarded. As detailed in the questionnaire cover letter, by answering the online or paper version of the questionnaire, respondents express their consent to participate. Dissemination of results will be done through a peer-reviewed journal article publication. This study aims to map the international use of definitions and terms for suicidal behaviour and ideation and favour the future use of an internationally shared set of terms and definitions. This will hopefully avoid undue duplication of efforts and reliably permit meta-analysis of data produced in different countries.


A flexible endotracheal tube introducer improves first-attempt success of intubation in cats by novice anesthetists.
To test whether the use of a flexible endotracheal tube introducer (ETI) facilitates intubation of cats by veterinary students with little or no experience. 125 healthy cats. Cats were sedated with dexmedetomidine and morphine IM, and anesthesia was induced with propofol. They were randomly assigned to be intubated by supervised veterinary students using an ETI within a tracheal tube or an endotracheal tube alone (3.0, 3.5, or 4.0 internal diameter sizes). Success rate at first attempt, number of attempts to intubate (up to 3), and time to intubate were recorded. Multivariate logistic regression was used to test associations between several factors such as use of an ETI, cat's weight, endotracheal tube size, administration of ketamine for sedation, and first-attempt success. Significance was considered when P < 0.05. Success rate for the first attempt was higher with an ETI (79% [51/64) than without it (46% [28/61]), and attempts to intubate were fewer when an ETI was used (both P < 0.001). Time to intubate did not differ between groups (ETI, 30 seconds [4 to 143 seconds]; endotracheal tube, 28 seconds [5 to 180 seconds]). Use of an ETI was positively associated with improved first-attempt success, and the 3.0-mm internal diameter of the tube was negatively associated (both P ≤ 0.001). The use of a flexible ETI improved the success of first-attempt intubation of cats by veterinary students. This technique may help minimize the number of attempts during intubation and incidence of complications that could arise from multiple attempts.


Reproducibility of joint swelling assessments in long-lasting rheumatoid arthritis: influence on Disease Activity Score-28 values (SEA-Repro study part I).
To evaluate the reproducibility of clinical synovitis assessments in rheumatoid arthritis and the effect of variability on the Disease Activity Score-28 (DAS28). Seven healthcare professionals from different cities examined the same patients with active non-early rheumatoid arthritis (RA; duration > 4 yrs), for whom a treatment change was being considered. There was no training session and the examination was to be performed as quickly as possible. The healthcare professionals assessed the 28 joints of the DAS28 in 7 patients (196 joints), then reexamined the same 28 joints in 4 of these 7 patients (112 joints), who had been rendered unrecognizable. Then 7 sonographers examined each of the 7 patients twice, using B-mode and power Doppler ultrasound (PD). The reference standards were presence of synovitis according to at least 50% of clinical examiners and 50% of sonographers. Agreement was assessed by Cohen's kappa statistic. Intraobserver reliability ranged from 0.31 (least experienced research technician) to 0.77 (most experienced physician). Interobserver reliability ranged from 0.18 to 0.62. The largest difference between the lowest and the highest swollen joint counts in the same patient was 15, and the greatest variation in the DAS28 score was 0.92. Agreement between clinical and sonographic reference standards was 0.46, 0.37, and 0.36 for B-mode, PD, and both, respectively. Clinical inter- and intraobserver reliability is highly dependent on the examiner. Consequences on the DAS28 score can be substantial. Agreement with sonography is poor when both B-mode and PD are used but seems better, although low, when B-mode is used alone.


Insulin control of glycogen metabolism in knockout mice lacking the muscle-specific protein phosphatase PP1G/RGL.
The regulatory-targeting subunit (RGL), also called GM) of the muscle-specific glycogen-associated protein phosphatase PP1G targets the enzyme to glycogen where it modulates the activity of glycogen-metabolizing enzymes. PP1G/RGL has been postulated to play a central role in epinephrine and insulin control of glycogen metabolism via phosphorylation of RGL. To investigate the function of the phosphatase, RGL knockout mice were generated. Animals lacking RGL show no obvious defects. The RGL protein is absent from the skeletal and cardiac muscle of null mutants and present at approximately 50% of the wild-type level in heterozygotes. Both the level and activity of C1 protein are also decreased by approximately 50% in the RGL-deficient mice. In skeletal muscle, the glycogen synthase (GS) activity ratio in the absence and presence of glucose-6-phosphate is reduced from 0.3 in the wild type to 0.1 in the null mutant RGL mice, whereas the phosphorylase activity ratio in the absence and presence of AMP is increased from 0.4 to 0.7. Glycogen accumulation is decreased by approximately 90%. Despite impaired glycogen accumulation in muscle, the animals remain normoglycemic. Glucose tolerance and insulin responsiveness are identical in wild-type and knockout mice, as are basal and insulin-stimulated glucose uptakes in skeletal muscle. Most importantly, insulin activated GS in both wild-type and RGL null mutant mice and stimulated a GS-specific protein phosphatase in both groups. These results demonstrate that RGL is genetically linked to glycogen metabolism, since its loss decreases PP1 and basal GS activities and glycogen accumulation. However, PP1G/RGL is not required for insulin activation of GS in skeletal muscle, and rather another GS-specific phosphatase appears to be involved.


Independent association of low serum 25-hydroxyvitamin d and 1,25-dihydroxyvitamin d levels with all-cause and cardiovascular mortality.
In cross-sectional studies, low serum levels of 25-hydroxyvitamin D are associated with higher prevalence of cardiovascular risk factors and disease. This study aimed to determine whether endogenous 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels are related to all-cause and cardiovascular mortality. Prospective cohort study of 3258 consecutive male and female patients (mean [SD] age, 62 [10] years) scheduled for coronary angiography at a single tertiary center. We formed quartiles according to 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels within each month of blood drawings. The main outcome measures were all-cause and cardiovascular deaths. During a median follow-up period of 7.7 years, 737 patients (22.6%) died, including 463 deaths from cardiovascular causes. Multivariate-adjusted hazard ratios (HRs) for patients in the lower two 25-hydroxyvitamin D quartiles (median, 7.6 and 13.3 ng/mL [to convert 25-hydroxyvitamin D levels to nanomoles per liter, multiply by 2.496]) were higher for all-cause mortality (HR, 2.08; 95% confidence interval [CI], 1.60-2.70; and HR, 1.53; 95% CI, 1.17-2.01; respectively) and for cardiovascular mortality (HR, 2.22; 95% CI, 1.57-3.13; and HR, 1.82; 95% CI, 1.29-2.58; respectively) compared with patients in the highest 25-hydroxyvitamin D quartile (median, 28.4 ng/mL). Similar results were obtained for patients in the lowest 1,25-dihydroxyvitamin D quartile. These effects were independent of coronary artery disease, physical activity level, Charlson Comorbidity Index, variables of mineral metabolism, and New York Heart Association functional class. Low 25-hydroxyvitamin D levels were significantly correlated with variables of inflammation (C-reactive protein and interleukin 6 levels), oxidative burden (serum phospholipid and glutathione levels), and cell adhesion (vascular cell adhesion molecule 1 and intercellular adhesion molecule 1 levels). Low 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels are independently associated with all-cause and cardiovascular mortality. A causal relationship has yet to be proved by intervention trials using vitamin D.


Current and future needs for developmental toxicity testing.
A review is presented of the use of developmental toxicity testing in the United States and international regulatory assessment of human health risks associated with exposures to pharmaceuticals (human and veterinary), chemicals (agricultural, industrial, and environmental), food additives, cosmetics, and consumer products. Developmental toxicology data are used for prioritization and screening of pharmaceuticals and chemicals, for evaluating and labeling of pharmaceuticals, and for characterizing hazards and risk of exposures to industrial and environmental chemicals. The in vivo study designs utilized in hazard characterization and dose-response assessment for developmental outcomes have not changed substantially over the past 30 years and have served the process well. Now there are opportunities to incorporate new technologies and approaches to testing into the existing assessment paradigm, or to apply innovative approaches to various aspects of risk assessment. Developmental toxicology testing can be enhanced by the refinement or replacement of traditional in vivo protocols, including through the use of in vitro assays, studies conducted in alternative nonmammalian species, the application of new technologies, and the use of in silico models. Potential benefits to the current regulatory process include the ability to screen large numbers of chemicals quickly, with the commitment of fewer resources than traditional toxicology studies, and to refine the risk assessment process through an enhanced understanding of the mechanisms of developmental toxicity and their relevance to potential human risk. As the testing paradigm evolves, the ability to use developmental toxicology data to meet diverse critical regulatory needs must be retained.


Specificity Re-evaluation of Oligonucleotide Probes for the Detection of Marine Picoplankton by Tyramide Signal Amplification-Fluorescent In Situ Hybridization.
Oligonucleotide probes are increasingly being used to characterize natural microbial assemblages by Tyramide Signal Amplification-Fluorescent in situ Hybridization (TSA-FISH, or CAtalysed Reporter Deposition CARD-FISH). In view of the fast-growing rRNA databases, we re-evaluated the in silico specificity of eleven bacterial and eukaryotic probes and competitor frequently used for the quantification of marine picoplankton. We performed tests on cell cultures to decrease the risk for non-specific hybridization, before they are used on environmental samples. The probes were confronted to recent databases and hybridization conditions were tested against target strains matching perfectly with the probes, and against the closest non-target strains presenting one to four mismatches. We increased the hybridization stringency from 55 to 65% formamide for the Eub338+EubII+EubIII probe mix to be specific to the Eubacteria domain. In addition, we found that recent changes in the Gammaproteobacteria classification decreased the specificity of Gam42a probe, and that the Roseo536R and Ros537 probes were not specific to, and missed part of the Roseobacter clade. Changes in stringency conditions were important for bacterial probes; these induced, respectively, a significant increase, in Eubacteria and Roseobacter and no significant changes in Gammaproteobacteria concentrations from the investigated natural environment. We confirmed the eukaryotic probes original conditions, and propose the Euk1209+NChlo01+Chlo02 probe mix to target the largest picoeukaryotic diversity. Experiences acquired through these investigations leads us to propose the use of seven steps protocol for complete FISH probe specificity check-up to improve data quality in environmental studies.


Density estimation and adaptive bandwidths: a primer for public health practitioners.
Geographic information systems have advanced the ability to both visualize and analyze point data. While point-based maps can be aggregated to differing areal units and examined at varying resolutions, two problems arise 1) the modifiable areal unit problem and 2) any corresponding data must be available both at the scale of analysis and in the same geographic units. Kernel density estimation (KDE) produces a smooth, continuous surface where each location in the study area is assigned a density value irrespective of arbitrary administrative boundaries. We review KDE, and introduce the technique of utilizing an adaptive bandwidth to address the underlying heterogeneous population distributions common in public health research. The density of occurrences should not be interpreted without knowledge of the underlying population distribution. When the effect of the background population is successfully accounted for, differences in point patterns in similar population areas are more discernible; it is generally these variations that are of most interest. A static bandwidth KDE does not distinguish the spatial extents of interesting areas, nor does it expose patterns above and beyond those due to geographic variations in the density of the underlying population. An adaptive bandwidth method uses background population data to calculate a kernel of varying size for each individual case. This limits the influence of a single case to a small spatial extent where the population density is high as the bandwidth is small. If the primary concern is distance, a static bandwidth is preferable because it may be better to define the "neighborhood" or exposure risk based on distance. If the primary concern is differences in exposure across the population, a bandwidth adapting to the population is preferred. Kernel density estimation is a useful way to consider exposure at any point within a spatial frame, irrespective of administrative boundaries. Utilization of an adaptive bandwidth may be particularly useful in comparing two similarly populated areas when studying health disparities or other issues comparing populations in public health.


Risk and protective factors associated with gang-involved youth in Trinidad and Tobago.
To examine the prevalence of gang involvement, the risk and protective factors associated with gang involvement, and the association between gang involvement and exposure to multiple risk and protective factors among school-aged youth in Trinidad and Tobago. A survey instrument was administered to 2 206 students enrolled in 22 high-risk, urban public schools, from March-June 2006. It measured 30 risk factors and 13 protective factors within four domains: community, school, family, and peer-individual, plus levels of alcohol/drug use and delinquency. About 7.7% of youth reported being a gang associate; 6.8%, a former gang member; and 6.2%, a current gang member. Gang involvement was associated with perceived availability of handguns, residential mobility, having parents who favor antisocial behavior, early initiation of antisocial behavior, intention to use drugs, having antisocial peers, and having peers who use drugs. Those with social skills, belief in moral order, and interactions with prosocial peers were significantly less likely to self-report gang membership. Additionally, the probability of gang involvement increased as the number of risk factors increased. Gang membership among public school youth is about as prevalent in Trinidad and Tobago as it is in the United States, Canada, and Western Europe, but further research is needed. Although risk factors associated with gang involvement were present in all four domains, peer-individual risk factors were disproportionately likely to be associated with gang status. The most effective gang prevention strategies might be those that focus on multiple risk factors, with an emphasis on peer-individual factors and promoting a "belief in moral order."


Migraineurs without aura show microstructural abnormalities in the cerebellum and frontal lobe.
The involvement of the cerebellum in migraine pathophysiology is not well understood. We used a biparametric approach at high-field MRI (3 T) to assess the structural integrity of the cerebellum in 15 migraineurs with aura (MWA), 23 migraineurs without aura (MWoA), and 20 healthy controls (HC). High-resolution T1 relaxation maps were acquired together with magnetization transfer images in order to probe microstructural and myelin integrity. Clusterwise analysis was performed on T1 and magnetization transfer ratio (MTR) maps of the cerebellum of MWA, MWoA, and HC using an ANOVA and a non-parametric clusterwise permutation F test, with age and gender as covariates and correction for familywise error rate. In addition, mean MTR and T1 in frontal regions known to be highly connected to the cerebellum were computed. Clusterwise comparison among groups showed a cluster of lower MTR in the right Crus I of MWoA patients vs. HC and MWA subjects (p = 0.04). Univariate and bivariate analysis on T1 and MTR contrasts showed that MWoA patients had longer T1 and lower MTR in the right and left pars orbitalis compared to MWA (p < 0.01 and 0.05, respectively), but no differences were found with HC. Lower MTR and longer T1 point at a loss of macromolecules and/or micro-edema in Crus I and pars orbitalis in MWoA patients vs. HC and vs. MWA. The pathophysiological implications of these findings are discussed in light of recent literature.


Behavior change techniques used by the English Stop Smoking Services and their associations with short-term quit outcomes.
To help identify effective components of behavioral support for smoking cessation, this study identified the behavior change techniques (BCTs) specified in the treatment manuals of 43 English Stop Smoking Services (SSSs) and assessed association between inclusion of specific BCTs and SSS success rates. SSSs (n = 144) were contacted to request their treatment manuals. BCTs included in the manuals were identified using a previously established taxonomy. Associations between inclusion of specific BCTs and short-term (4-week) quit outcomes were assessed. Ninety-eight services responded, of which 43 had suitable treatment manuals. Out of 43 possible BCTs, SSS manuals included a mean of 22 (range 9-37). The number of sessions used for delivery of the smoking cessation intervention differed markedly (range 1-13) across services. Nine of the BCTs were significantly associated with both self-reported and carbon monoxide (CO)-verified 4-week quit rates (e.g., strengthen ex-smoker identity, provide rewards contingent on abstinence, advise on medication, measure CO) and a further 5 were associated with CO-verified 4-week quit rates but not self-reported quit rates (e.g., advise on/facilitate use of social support, provide reassurance). SSSs that scheduled in more sessions had higher quit rates. English SSSs vary widely in how far their treatment manuals include specific behavior change techniques and how many do not have manuals. It is possible to identify BCTs that are reliably associated with better quit outcomes. Behavioral support for smoking cessation could be improved by a more systematic approach to identifying and applying BCTs that are associated with better quit outcomes.


[Stomolophus meleagris fecundity (Rhizostomeae: Stomolophidae) in the Gulf of California].
The cannonball jellyfish Stomolophus meleagris is regarded as a fishery resource with high commercial value, but with scarce biological information. With the aim to generate preliminary information on reproductive aspects, the present study analyzes its fecundity, based on the estimated number of vitellogenic oocytes in the gonad; in addition, we evaluated its relationship with the jellyfish body length, diameter and wet weight; and we established the relationship of the gonadosomatic index (IGS) with the jellyfish diameter and length. For this, a total of 30 specimens were collected, measured and weighed in a monthly basis, in Las Guásimas lagoon from January to May 2006. In order to estimate the gonad volume, 60 mature females were analyzed and their gonads were extracted and stained with hematoxylin-eosin. Gonad images from histological preparations were analyzed and the number of vitellogenic and previtellogenic oocytes obtained. We used catch data from The Guásimas for population recruitment analysis, that was estimated with FISAT II. Among results, we found that fecundity increased with jellyfish length, diameter and total wet weight. The lower fecundity rates occured on February and the highest during May (11 873 071 and 37 528 197 millions of vitellogenic oocytes per gonad, respectively). The IGS increased with length and diameter of the specimens, at its maximum value of 3.7% was observed in May. A continuous production of previtellogenic oocytes were observed during the full collection period. The maximum recruitment was observed in July and November (37.50% and 28.01% respectively). The high fecundity observed in S meleagris, suggests a high population reproductive potential that may support the possibility of an important fishery consolidation on this jellyfish.


Distribution of pfmdr1 and pfcrt chloroquine drug resistance alleles in north-western Nigeria.
In Nigeria, decline in the sensitivity of Plasmodium falciparum to Artemisinin Combination Therapy (ACT) has prompted the unofficial use of chloroquine (CQ) for self-medication. This study was designed to determine the prevalence and distribution of CQ resistant/susceptible alleles of CQ resistance transporter (Pfcrt) and P. falciparum multidrug resistance gene 1 (Pfmdr1) in view of the possible re-introduction of CQ for malaria treatment. Four hundred and sixty six (466) P. falciparum positive samples were randomly collected from five states of northwest Nigeria. The samples were amplified using RT- PCR at codon 76 for Pfcrt and codon 86 for Pfmdr1. Data was analysed using chi-square, odds ratios and paired t-tests. Drug susceptible alleles (N86) were most prevalent in the study population (47.9%; 223/466), followed by the drug resistance alleles 86Y (28.3%; 132/466), followed by the drug susceptible alleles K76 (17.4%; 81/466), the resistant alleles 76T (12.4%; 58/466) and finally the mixed infection mutation K76T (3.6%; 17/466). Differences between the distributions of the Pfmdr1 and Pfcrt alleles were significant (P<0.05). There were significant differences (P<0.05) between N86 and 86Y alleles, but no significant differences between K76 and 76T alleles, including the prevalence of the various alleles across the different age groups. The results of this study suggest the possibility of (re)introducing CQ for malaria treatment in north-western Nigeria and provide insight in the genetic background of P. falciparum in the study area.


Reducing premature infants' length of stay and improving parents' mental health outcomes with the Creating Opportunities for Parent Empowerment (COPE) neonatal intensive care unit program: a randomized, controlled trial.
Although low birth weight premature infants and parents are at high risk for adverse health outcomes, there is a paucity of studies that test early NICU interventions with parents to prevent the development of negative parent-infant interaction trajectories and to reduce hospital length of stay. Our objective was to evaluate the efficacy of an educational-behavioral intervention program (ie, Creating Opportunities for Parent Empowerment) that was designed to enhance parent-infant interactions and parent mental health outcomes for the ultimate purpose of improving child developmental and behavior outcomes. A randomized, controlled trial was conducted with 260 families with preterm infants from 2001 to 2004 in 2 NICUs in the northeast United States. Parents completed self-administered instruments during hospitalization, within 7 days after infant discharge, and at 2 months' corrected age. Blinded observers rated parent-infant interactions in the NICU. All participants received 4 intervention sessions of audiotaped and written materials. Parents in the Creating Opportunities for Parent Empowerment program received information and behavioral activities about the appearance and behavioral characteristics of preterm infants and how best to parent them. The comparison intervention contained information regarding hospital services and policies. Parental stress, depression, anxiety, and beliefs; parent-infant interaction during the NICU stay; NICU length of stay; and total hospitalization were measured. Mothers in the Creating Opportunities for Parent Empowerment program reported significantly less stress in the NICU and less depression and anxiety at 2 months' corrected infant age than did comparison mothers. Blinded observers rated mothers and fathers in the Creating Opportunities for Parent Empowerment program as more positive in interactions with their infants. Mothers and fathers also reported stronger beliefs about their parental role and what behaviors and characteristics to expect of their infants during hospitalization. Infants in the Creating Opportunities for Parent Empowerment program had a 3.8-day shorter NICU length of stay (mean: 31.86 vs 35.63 days) and 3.9-day shorter total hospital length of stay (mean: 35.29 vs 39.19 days) than did comparison infants. A reproducible educational-behavioral intervention program for parents that commences early in the NICU can improve parent mental health outcomes, enhance parent-infant interaction, and reduce hospital length of stay.


Rab1b regulates vesicular transport between the endoplasmic reticulum and successive Golgi compartments.
We report an essential role for the ras-related small GTP-binding protein rab1b in vesicular transport in mammalian cells. mAbs detect rab1b in both the ER and Golgi compartments. Using an assay which reconstitutes transport between the ER and the cis-Golgi compartment, we find that rab1b is required during an initial step in export of protein from the ER. In addition, it is also required for transport of protein between successive cis- and medial-Golgi compartments. We suggest that rab1b may provide a common link between upstream and downstream components of the vesicular fission and fusion machinery functioning in early compartments of the secretory pathway.


Spontaneous pneumomediastinum following pneumonia in a 23-year-old male patient.
Spontaneous pneumomediastinum (SPM) is defined as the presence of interstitial air in the mediastinum without any apparent precipitating factor. We present a case of 23 year old male patient, who has been referred to our outpatient clinic with the complaints of sudden chest pain, dyspnea followed by pneumonia and was diagnosed as SPM. The patient was treated with ampicillin sulbactam (4 gr/day) and methylprednisolon (20 mg/day) for 4 days. and oral intake was stopped during treatment. Post treatment, it was observed that the crepitations were disappeared thoroughly and vesicular sounds were heard by oscultation. The control values of arterial blood gas was as following: pH:7,39 pO2:95 mmHg, pCO2:37 mmHg, SaO2: %97. In the 5th day his oral intake was started and he was discharged.


Gamma interferon and lymphotoxin, released by activated T cells, synergize to inhibit granulocyte/monocyte colony formation.
We have shown that lymphocytes stimulated by PHA produce colony-forming unit of granulocyte/monocyte (CFU-GM)-stimulating and -inhibiting activities, IFN-gamma, and lymphotoxin (LT). IFN-gamma is necessary for inhibition of CFU-GM by PHA-conditioned medium (CM), as shown by experiments in which removal of IFN-gamma from PHA-CM abrogated inhibition. However, experiments in which rIFN-gamma was added to IFN-gamma-depleted PHA-CM revealed the presence, in PHA-CM, of other factors that act in synergy with IFN-gamma to inhibit CFU-GM. Fractionation of PHA-CM on a Sephadex G-100 column was used to separate IFN-gamma and LT. Colony-inhibiting activity was eluted in fractions that contained both IFN-gamma and LT activities, identifying LT as a factor present in PHA-CM that synergizes with IFN-gamma to inhibit CFU-GM. Treatment of PHA-CM with mAb against either IFN-gamma or LT completely abrogated the colony-inhibiting activity, demonstrating a requirement for both lymphokines in PHA-CM-induced inhibition of CFU-GM. Experiments using rIFN-gamma and preparations of purified LT confirmed that neither lymphokine alone, when added to bone marrow cells at the concentrations present in PHA-CM, strongly inhibited day 7 or day 14 CFU-GM, but that the two lymphokines, added together, behaved synergistically to inhibit CFU-GM by up to 70%. The inhibition observed using purified preparations of lymphokines shows that synergy between IFN-gamma and LT is sufficient to explain PHA-CM-induced inhibition of CFU-GM. Our findings suggest that activated T cells regulate hematopoiesis through the release of inhibitory as well as stimulatory factors, and that the simultaneous production of IFN-gamma and LT may represent a mechanism of suppression of hematopoiesis in the cases of bone marrow failure associated with the presence of activated T cells.


Characterization and immunomodulatory function comparison of various bursal-derived peptides isolated from the humoral central immune organ.
The bursa of Fabricius (BF) is the acknowledged central immune organ, which is important to the B cell differentiation and antibody production. However, due to difficult purification, the immunomodulatory peptides from BF were little reported. In this study, the extract samples of BF were taken to a chromatographic analysis by RP-HPLC. Five novel low molecular weight peptides were isolated from BF, with amino acid sequences of YEYAY, RMYEE, GPPAT, AGCCNG, and RRL, and named as Bursal pentapeptide (BPP)-III, -IV, -V, and Bursal hexapeptide (BHP), and Bursal tripeptide (BTP), respectively. BSP-I, BSP-II, BPP-I and BPP-II are recently reported to be the bursal-derived bioactive peptides. In this paper, we analyzed the chemical formula and characteristics of these nine bursal-derived peptides. The immunization comparative experiment verified the different immunomodulatory activity of these nine bursal peptides on antibody and cytokine productions. Furthermore, the results showed that at reachable concentrations, BPP-II and BPP-I induced antibody productions, lymphocyte viabilities and cytokine responses in different dose-dependent manner in the immunized mice model, respectively. These results provided important orientations for the comprehensively understanding and study of the humoral central immune system of human, and provided a novel insight on the treatment of serious disease and immune improvement of human.


Anionic activators for differential sensing with cell-penetrating peptides.
The design, synthesis, and evaluation of small peptides with one to three negative charges and one to three hydrazides as key components of membrane-based synthetic sensing systems are reported. Their spontaneous reaction with hydrophobic aldehydes or ketones gives rapid access to small collections of amphiphilic anions. These anionic amphiphiles can activate polycations as anion transporters in lipid-bilayer membranes. Odorants are used as representative hydrophobic aldehydes and ketones, and cell-penetrating peptides (CPPs) as polycationic transporters in fluorogenic vesicles. Different activities obtained with different counterion activators are used to generate multidimensional patterns that can be recognized by principal component and hierarchical cluster analysis to extract unique "fingerprints" for individual analytes (including enantiomers, cis-trans isomers or perfumes as illustrative analyte mixtures). Comparison of the peptide activators reveals that carboxylates perform better than phosphonates. Gemini-like activators containing two carboxylates and two hydrophobic hydrazone tails are best, whereas excessive charges and tails give weaker activities. This result differs from cationic activators of polyanionic transporters such as DNA, which worked best with octopus amphiphiles with one cationic head and four hydrophobic tentacles.


Re-evaluation of PD-1 expression by T cells as a marker for immune exhaustion during SIV infection.
PD-1 expression is generally associated with exhaustion of T cells during chronic viral infections based on the finding that PD-1 expressing cells respond poorly to antigen activation and blockade of PD-1/PD-ligand interaction restores such antigen specific responses in vitro. We tested this hypothesis by examining PD-1 expression on virus-specific CD8 T cells and total T cells in vivo to determine whether PD-1 expression constitutes a reliable marker of immune exhaustion during SIV infection. The expression of PD-1 and Ki67 was monitored longitudinally on T cell subsets in peripheral blood, bone marrow, lymph node and rectal biopsy specimens from rhesus macaques prior to and post infection with pathogenic SIVmac239. During the course of infection, a progressive negative correlation was noted between PD-1 density and Ki67 expression in p11CM(+) CD8(+) T cells, as seen in other studies. However, for total and memory CD4 and CD8 T cells, a positive correlation was observed between PD-1 and Ki67 expression. Thus, while the levels of non-proliferating PD-1(+) p11CM(+) CD8 T cells were markedly elevated with progressing infection, such an increase was not seen on total T cells. In addition, total memory PD1(+) T cells exhibited higher levels of CCR5 than PD-1(-) T cells. Interestingly, few PD-1(+) CD8(+) T cells expressed CCR7 compared to PD-1(+) CD4 T cells and PD-1(-) T cells. In conclusion, overall PD1(+) T cells likely represent a particular differentiation stage or trafficking ability rather than exhaustion and in the context of chronic SIV infection, the level of PD-1 expression by T cells does not by itself serve as a reliable marker for immune exhaustion.


Modification of oil palm mesocarp fiber characteristics using superheated steam treatment.
In this study, oil palm mesocarp fiber (OPMF) was treated with superheated steam (SHS) in order to modify its characteristics for biocomposite applications. Treatment was conducted at temperatures 190-230 °C for 1, 2 and 3 h. SHS-treated OPMF was evaluated for its chemical composition, thermal stability, morphology and crystallinity. OPMF treated at 230 °C exhibited lower hemicellulose content (9%) compared to the untreated OPMF (33%). Improved thermal stability of OPMF was found after the SHS treatment. Moreover, SEM and ICP analyses of SHS-treated OPMF showed that silica bodies were removed from OPMF after the SHS treatment. XRD results exhibited that OPMF crystallinity increased after SHS treatment, indicating tougher fiber properties. Hemicellulose removal makes the fiber surface more hydrophobic, whereby silica removal increases the surface roughness of the fiber. Overall, the results obtained herewith suggested that SHS is an effective treatment method for surface modification and subsequently improving the characteristics of the natural fiber. Most importantly, the use of novel, eco-friendly SHS may contribute to the green and sustainable treatment for surface modification of natural fiber.


Balance impairment in individuals with COPD: a systematic review with meta-analysis.
People with chronic obstructive pulmonary disease (COPD) are four times more likely to fall than healthy peers, leading to increased morbidity and mortality. Poor balance is a major risk factor for falls. This review aims to quantify the extent of balance impairment in COPD, and establish contributing clinical factors, which at present are sparse. Five electronic databases were searched, in July 2017 and updated searches were performed in March 2019, for studies comparing balance in COPD with healthy controls. Meta-analyses were conducted on sample mean differences (MD) and reported correlations between balance and clinical factors. Meta-regression was used to quantify the association between mean difference in percentage predicted forced expiratory volume in 1 s (FEV1) and mean balance impairment. Narrative summaries were provided where data were insufficient for meta-analysis. Twenty-three studies were included (n=2751). Meta-analysis indicated COPD patients performed worse than healthy controls on timed up and go (MD=2.77 s, 95% CI 1.46 s to 4.089 s, p=<0.005), single leg stance (MD=-11.75 s, 95% CI -15.12 s to -8.38 s, p=<0.005) and berg balance scale (MD=-6.66, 95% CI -8.95 to -4.37, p=<0.005). The pooled correlation coefficient between balance and reduced quadriceps strength was weak-moderate (r=0.37, 95% CI 0.23 to 0.45, p=<0.005). The relationship between differences in percentage predicted FEV1 and balance were negligible (r2 =<0.04). Compared with healthy controls, people with COPD have a clinically meaningful balance reduction, which may be related to reduced muscle strength, physical activity and exercise capacity. Our findings support a need to expand the focus of pulmonary rehabilitation to include balance assessment and training, and further exploration of balance impairment in COPD. PROSPERO registration number CRD4201769041.


Pain Catastrophizing in College Athletes.
Pain is the most common patient-reported symptom but the perception of pain is complex, differs between individuals and is not directly proportional to the extent of injury. The relationship between aberrant pain coping strategies such as pain catastrophizing and the presence of pain in competitive athletes should be further established to employ the most optimal treatment. The hypotheses were that numeric pain rating and pain catastrophizing (Pain Catastrophizing Scale, PCS) scores would have a moderate to strong relationship in college athletes, and athletes with either a current injury or previous injury, or playing with pain, would have significantly higher pain catastrophizing scores compared with noninjured/nonpainful athletes. Cross-sectional study. III. College athletes completed a demographic form, injury questionnaire, numeric pain rating, and the PCS. All athletes were medically cleared for sports participation at the time of survey completion. A total PCS score was calculated in addition to a rumination, magnification, and helplessness score. Spearman rank was utilized to measure the strength of relationship between the PCS score and pain rating. A total of 291 athletes from 15 different sports completed the questionnaires (males: 156, females: 135; age: 19 [2] y). Negligible correlations existed between the PCS score and pain (r = .27). Athletes who were currently injured or previously injured had significantly higher PCS scores compared with uninjured athletes (P < .01). Approximately one-third of college athletes reported playing injured and/or with pain, but the relationship between pain rating and PCS score was negligible. The individualistic nature of pain perception and coping strategies would suggest that clinicians may want to consider screening for pain catastrophizing either prior to athletic participation or for athletes not following an expected recovery after injury in an effort to enhance individualized patient care.


Antiepileptic drug resistant rats differ from drug responsive rats in GABA A receptor subunit expression in a model of temporal lobe epilepsy.
Epidemiological data indicate that 20-40% of the patients with epilepsy are refractory to treatment with antiepileptic drugs (AEDs). The mechanisms underlying pharmacoresistance in epilepsy are unclear, but several plausible hypotheses have emerged, including loss of AED target sensitivity in the epileptic brain, decreased AED concentrations at brain targets because of localized overexpression of drug efflux transporters in epileptogenic brain tissue, and network alterations in response to brain damage associated with epilepsy. Rat models of epilepsy in which part of the animals are resistant to treatment with AEDs offer a means to investigate the mechanisms underlying AED resistance. In the present study, AED-responsive and AED-resistant rats were selected from a model in which spontaneous recurrent seizures develop after a status epilepticus induced by electrical stimulation of the basolateral amygdala. For selection into responders and nonresponders, epileptic rats were treated over two weeks by phenobarbital. Subsequent histological examination showed neurodegeneration of the CA1, CA3 and dentate hilus in only one of eight responders but five of six nonresponders (P=0.0256). Based on previous studies in AED-resistant rats of this model, we hypothesized that changes in the structure and function of inhibitory GABA(A) receptors may contribute to drug resistance. We therefore analyzed the distribution and expression of several GABA(A) receptor subunits (alpha1, alpha2, alpha 3, alpha 4, alpha 5, beta2/3, and gamma 2) immunohistochemically with specific antibodies in the hippocampal formation of responders, nonresponders and nonepileptic controls. In nonresponders, decreased subunit staining was observed in CA1, CA2, CA3, and dentate gyrus, whereas much less widespread alterations were determined in responders. Furthermore, upregulation of the alpha 4-subunit was observed in the CA1 of nonresponders. Our data suggest that alterations in GABA(A) receptor subtypes may be involved in resistance to AEDs.


Relationship Between Body Mass Index and Outcomes Among Hospitalized Patients With Community-Acquired Pneumonia.
The effect of body mass index (BMI) on community-acquired pneumonia (CAP) severity is unclear. We investigated the relationship between BMI and CAP outcomes (hospital length of stay [LOS], intensive care unit [ICU] admission, and invasive mechanical ventilation) in hospitalized CAP patients from the Centers for Disease Control and Prevention Etiology of Pneumonia in the Community (EPIC) study, adjusting for age, demographics, underlying conditions, and smoking status (adults only). Compared with normal-weight children, odds of ICU admission were higher in children who were overweight (adjusted odds ratio [aOR], 1.7; 95% confidence interval [CI], 1.1-2.8) or obese (aOR, 2.1; 95% CI, 1.4-3.2), and odds of mechanical ventilation were higher in children with obesity (aOR, 2.7; 95% CI, 1.3-5.6). When stratified by asthma (presence/absence), these findings remained significant only in children with asthma. Compared with normal-weight adults, odds of LOS >3 days were higher in adults who were underweight (aOR, 1.6; 95% CI, 1.1-2.4), and odds of mechanical ventilation were lowest in adults who were overweight (aOR, 0.5; 95% CI, .3-.9). Children who were overweight or obese, particularly those with asthma, had higher odds of ICU admission or mechanical ventilation. In contrast, adults who were underweight had longer LOS. These results underscore the complex relationship between BMI and CAP outcomes.


Ecological risk assessment of endocrine disruptors.
The European Centre for Ecotoxicology and Toxicology of Chemicals proposes a tiered approach for the ecological risk assessment of endocrine disruptors, integrating exposure and hazard (effects) characterization. Exposure assessment for endocrine disruptors should direct specific tests for wildlife species, placing hazard data into a risk assessment context. Supplementing the suite of mammalian screens now under Organization for Economic Cooperation and Development (OECD) validation, high priority should be given to developing a fish screening assay for detecting endocrine activity in oviparous species. Taking into account both exposure characterization and alerts from endocrine screening, higher tier tests are also a priority for defining adverse effects. We propose that in vivo mammalian and fish assays provide a comprehensive screening battery for diverse hormonal functions (including androgen, estrogen, and thyroid hormone), whereas Amphibia should be considered at higher tiers if there are exposure concerns. Higher tier endocrine-disruptor testing should include fish development and fish reproduction tests, whereas a full life-cycle test could be subsequently used to refine aquatic risk assessments when necessary. For avian risk assessment, the new OECD Japanese quail reproduction test guideline provides a valuable basis for developing a test to detecting endocrine-mediated reproductive effects; this species could be used, where necessary, for an avian life-cycle test. For aquatic and terrestrial invertebrates, data from existing developmental and reproductive tests remain of high value for ecological risk assessment. High priority should be given to research into comparative endocrine physiology of invertebrates to support data extrapolation to this diverse fauna.


Newer antiepileptic drugs as monotherapy: data on vigabatrin.
Studies examining the use of vigabatrin as monotherapy for the treatment of epilepsy are relatively scarce, and of the few that have been reported, only two were of sufficient size to provide definitive data. In both trials, vigabatrin was compared with carbamazepine for efficacy and safety. In one of these studies, carbamasepine was found to be more effective than vigabatrin in reducing seizure frequency, and the two were found to be comparably efficacious in the other study. What differed significantly, however, was vigabatrin's favorable safety profile. Vigabatrin appears to be a reasonable choice for single-drug therapy in the treatment of certain types of seizures. In other patients, it remains useful as an adjunct to other antiepileptic drugs.


Thrombus Imaging Using 3D Printed Middle Cerebral Artery Model and Preclinical Imaging Techniques: Application to Thrombus Targeting and Thrombolytic Studies.
Diseases with the highest burden for society such as stroke, myocardial infarction, pulmonary embolism, and others are due to blood clots. Preclinical and clinical techniques to study blood clots are important tools for translational research of new diagnostic and therapeutic modalities that target blood clots. In this study, we employed a three-dimensional (3D) printed middle cerebral artery model to image clots under flow conditions using preclinical imaging techniques including fluorescent whole-body imaging, magnetic resonance imaging (MRI), and computed X-ray microtomography (microCT). Both liposome-based, fibrin-targeted, and non-targeted contrast agents were proven to provide a sufficient signal for clot imaging within the model under flow conditions. The application of the model for clot targeting studies and thrombolytic studies using preclinical imaging techniques is shown here. For the first time, a novel method of thrombus labeling utilizing barium sulphate (Micropaque®) is presented here as an example of successfully employed contrast agents for in vitro experiments evaluating the time-course of thrombolysis and thus the efficacy of a thrombolytic drug, recombinant tissue plasminogen activator (rtPA). Finally, the proof-of-concept of in vivo clot imaging in a middle cerebral artery occlusion (MCAO) rat model using barium sulphate-labelled clots is presented, confirming the great potential of such an approach to make experiments comparable between in vitro and in vivo models, finally leading to a reduction in animals needed.


Defining Priorities for Action and Research on the Commercial Determinants of Health: A Conceptual Review.
In recent years, the concept of commercial determinants of health (CDoH) has attracted scholarly, public policy, and activist interest. To date, however, this new attention has failed to yield a clear and consistent definition, well-defined metrics for quantifying its impact, or coherent directions for research and intervention. By tracing the origins of this concept over 2 centuries of interactions between market forces and public health action and research, we propose an expanded framework and definition of CDoH. This conceptualization enables public health professionals and researchers to more fully realize the potential of the CDoH concept to yield insights that can be used to improve global and national health and reduce the stark health inequities within and between nations. It also widens the utility of CDoH from its main current use to study noncommunicable diseases to other health conditions such as infectious diseases, mental health conditions, injuries, and exposure to environmental threats. We suggest specific actions that public health professionals can take to transform the burgeoning interest in CDoH into meaningful improvements in health. (Am J Public Health. 2021;111(12):2202-2211. https://doi.org/10.2105/AJPH.2021.306491).


Bioavailability of iron, zinc, and provitamin A carotenoids in biofortified staple crops.
International research efforts, including those funded by HarvestPlus, a Challenge Program of the Consultative Group on International Agricultural Research (CGIAR), are focusing on conventional plant breeding to biofortify staple crops such as maize, rice, cassava, beans, wheat, sweet potatoes, and pearl millet to increase the concentrations of micronutrients that are commonly deficient in specific population groups of developing countries. The bioavailability of micronutrients in unfortified staple crops in developing regions is typically low, which raises questions about the efficacy of these crops to improve population micronutrient status. This review of recent studies of biofortified crops aims to assess the micronutrient bioavailability of biofortified staple crops in order to derive lessons that may help direct plant breeding and to infer the potential efficacy of food-based nutrition interventions. Although reducing the amounts of antinutrients and the conduction of food processing generally increases the bioavailability of micronutrients, antinutrients still possess important benefits, and food processing results in micronutrient loss. In general, biofortified foods with relatively higher micronutrient density have higher total absorption rates than nonbiofortified varieties. Thus, evidence supports the focus on efforts to breed plants with increased micronutrient concentrations in order to decrease the influence of inhibitors and to offset losses from processing.


Experimental spinal cord injury: spatiotemporal characterization of elemental concentrations and water contents in axons and neuroglia.
To examine the role of axonal ion deregulation in acute spinal cord injury (SCI), white matter strips from guinea pig spinal cord were incubated in vitro and were subjected to graded focal compression injury. At several postinjury times, spinal segments were removed from incubation and rapidly frozen. X-ray microanalysis was used to measure percent water and dry weight elemental concentrations (mmol/kg) of Na, P, Cl, K, Ca, and Mg in selected morphological compartments of myelinated axons and neuroglia from spinal cord cryosections. As an index of axon function, compound action potentials (CAP) were measured before compression and at several times thereafter. Axons and mitochondria in epicenter of severely compressed spinal segments exhibited early (5 min) increases in mean Na and decreases in K and Mg concentrations. These elemental changes were correlated to a significant reduction in CAP amplitude. At later postcompression times (15 and 60 min), elemental changes progressed and were accompanied by alterations in compartmental water content and increases in mean Ca. Swollen axons were evident at all postinjury times and were characterized by marked element and water deregulation. Neuroglia and myelin in severely injured epicenter also exhibited significant disruptions. In shoulder areas (adjacent to epicenter) of severely injured spinal strips, axons and mitochondria exhibited modest increases in mean Na in conjunction with decreases in K, Mg, and water content. Following moderate compression injury to spinal strips, epicenter axons exhibited early (10 min postinjury) element and water deregulation that eventually recovered to near control values (60 min postinjury). Na(+) channel blockade by tetrodotoxin (TTX, 1 microM) perfusion initiated 5 min after severe crush diminished both K loss and the accumulation of Na, Cl, and Ca in epicenter axons and neuroglia, whereas in shoulder regions TTX perfusion completely prevented subcellular elemental deregulation. TTX perfusion also reduced Na entry in swollen axons but did not affect K loss or Ca gain. Thus graded compression injury of spinal cord produced subcellular elemental deregulation in axons and neuroglia that correlated with the onset of impaired electrophysiological function and neuropathological alterations. This suggests that the mechanism of acute SCI-induced structural and functional deficits are mediated by disruption of subcellular ion distribution. The ability of TTX to reduce elemental deregulation in compression-injured axons and neuroglia implicates a significant pathophysiological role for Na(+) influx in SCI and suggests Na(+) channel blockade as a pharmacotherapeutic strategy.


Induction of innate immune response genes by Sin Nombre hantavirus does not require viral replication.
Maladaptive immune responses are considered to be important factors in the pathogenesis of the two diseases caused by hantaviruses, hemorrhagic fever with renal syndrome and hantavirus cardiopulmonary syndrome (HCPS). While the intensity of adaptive antiviral T-cell responses seems to correlate with the severity of HCPS, there is increasing evidence that innate antiviral responses by endothelial cells, the native targets for hantavirus infection in vivo, are induced within hours of exposure to infectious hantaviruses. To investigate early events in the innate response to Sin Nombre virus (SNV), the principal etiologic agent of HCPS in North America, we treated human endothelial cells with live virus, or virus subjected to inactivation by UV irradiation at minimal doses required to inhibit replication, and assayed host expression of interferon-stimulated genes (ISG) by microarray and reverse transcription-PCR. We show herein that a variety of ISG are induced between 4 and 24 h after exposure to both live and killed virus. The levels of such induction at early time points (before 24 h) were generally higher in cells treated with SNV particles that had been killed by exposure to UV irradiation. Additionally, SNV exposed to increasing doses of UV irradiation induced ISG better than live virus despite increased disruption of viral RNA integrity. However, SNV replication was required for continued ISG overexpression by 3 days posttreatment. These results suggest that hantavirus particles may themselves be capable of early induction of ISG and that ongoing production of viral particles during infection could contribute to the pathogenic process.


Effect of Estimated Daily Global Solar Radiation Data on the Results of Crop Growth Models.
The results of previous studies have suggested that estimated daily globalradiation (RG) values contain an error that could compromise the precision of subsequentcrop model applications. The following study presents a detailed site and spatial analysis ofthe RG error propagation in CERES and WOFOST crop growth models in Central Europeanclimate conditions. The research was conducted i) at the eight individual sites in Austria andthe Czech Republic where measured daily RG values were available as a reference, withseven methods for RG estimation being tested, and ii) for the agricultural areas of the CzechRepublic using daily data from 52 weather stations, with five RG estimation methods. In thelatter case the RG values estimated from the hours of sunshine using the ångström-Prescottformula were used as the standard method because of the lack of measured RG data. At thesite level we found that even the use of methods based on hours of sunshine, which showedthe lowest bias in RG estimates, led to a significant distortion of the key crop model outputs.When the ångström-Prescott method was used to estimate RG, for example, deviationsgreater than ±10 per cent in winter wheat and spring barley yields were noted in 5 to 6 percent of cases. The precision of the yield estimates and other crop model outputs was lowerwhen RG estimates based on the diurnal temperature range and cloud cover were used (mean bias error 2.0 to 4.1 per cent). The methods for estimating RG from the diurnal temperature range produced a wheat yield bias of more than 25 per cent in 12 to 16 per cent of the seasons. Such uncertainty in the crop model outputs makes the reliability of any seasonal yield forecasts or climate change impact assessments questionable if they are based on this type of data. The spatial assessment of the RG data uncertainty propagation over the winter wheat yields also revealed significant differences within the study area. We found that RG estimates based on diurnal temperature range or its combination with daily total precipitation produced a bias of to 30 per cent in the mean winter wheat grain yields in some regions compared with simulations in which RG values had been estimated using the ångström-Prescott formula. In contrast to the results at the individual sites, the methods based on the diurnal temperature range in combination with daily precipitation totals showed significantly poorer performance than the methods based on the diurnal temperature range only. This was due to the marked increase in the bias in RG estimates with altitude, longitude or latitude of given region. These findings in our view should act as an incentive for further research to develop more precise and generally applicable methods for estimating daily RG based more on the underlying physical principles and/or the remote sensing approach.


Immunoregulation by tumor necrosis factor superfamily member LIGHT.
LIGHT (homologous to lymphotoxins, inducible expression, competes with herpesvirus glycoprotein D for herpesvirus entry mediator, a receptor expressed on T lymphocytes) is a member of the tumor necrosis factor superfamily that contributes to the regulation of immune responses. LIGHT can influence T-cell activation both directly and indirectly by engagement of various receptors that are expressed on T cells and on other types of cells. LIGHT, LIGHT receptors, and their related binding partners constitute a complicated molecular network in the regulation of various processes. The molecular cross-talk among LIGHT and its related molecules presents challenges and opportunities for us to study and to understand the full extent of the LIGHT function. Previous research from genetic and functional studies has demonstrated that dysregulation of LIGHT expression can result in the disturbance of T-cell homeostasis and activation, changing the ability of self-tolerance and of the control of infection. Meanwhile, blockade of LIGHT activity can ameliorate the severity of various T-cell-mediated diseases. These observations indicate the importance of LIGHT and its involvement in many physiological and pathological conditions. Understanding LIGHT interactions offers promising new therapeutic strategies that target LIGHT-engaged pathways to fight against cancer and various infectious diseases.


The CryoEM Method MicroED as a Powerful Tool for Small Molecule Structure Determination.
In the many scientific endeavors that are driven by organic chemistry, unambiguous identification of small molecules is of paramount importance. Over the past 50 years, NMR and other powerful spectroscopic techniques have been developed to address this challenge. While almost all of these techniques rely on inference of connectivity, the unambiguous determination of a small molecule's structure requires X-ray and/or neutron diffraction studies. In practice, however, X-ray crystallography is rarely applied in routine organic chemistry due to intrinsic limitations of both the analytes and the technique. Here we report the use of the electron cryo-microscopy (cryoEM) method microcrystal electron diffraction (MicroED) to provide routine and unambiguous structural determination of small organic molecules. From simple powders, with minimal sample preparation, we could collect high-quality MicroED data from nanocrystals (∼100 nm, ∼10-15 g) resulting in atomic resolution (<1 Å) crystal structures in minutes.


The CD16+ monocyte subset is more permissive to infection and preferentially harbors HIV-1 in vivo.
HIV-1 persists in peripheral blood monocytes in individuals receiving highly active antiretroviral therapy (HAART) with viral suppression, despite these cells being poorly susceptible to infection in vitro. Because very few monocytes harbor HIV-1 in vivo, we considered whether a subset of monocytes might be more permissive to infection. We show that a minor CD16+ monocyte subset preferentially harbors HIV-1 in infected individuals on HAART when compared with the majority of monocytes (CD14highCD16-). We confirmed this by in vitro experiments showing that CD16+ monocytes were more susceptible to CCR5-using strains of HIV-1, a finding that is associated with higher CCR5 expression on these cells. CD16+ monocytes were also more permissive to infection with a vesicular stomatitis virus G protein-pseudotyped reporter strain of HIV-1 than the majority of monocytes, suggesting that they are better able to support HIV-1 replication after entry. Consistent with this observation, high molecular mass complexes of apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like 3G (APOBEC3G) were observed in CD16+ monocytes that were similar to those observed in highly permissive T cells. In contrast, CD14highCD16- monocytes contained low molecular mass active APOBEC3G, suggesting this is a mechanism of resistance to HIV-1 infection in these cells. Collectively, these data show that CD16+ monocytes are preferentially susceptible to HIV-1 entry, more permissive for replication, and constitute a continuing source of viral persistence during HAART.


Translational formulation of nanoparticle therapeutics from laboratory discovery to clinical scale.
"Nanomedicine" is the application of purposely designed nano-scale materials for improved therapeutic and diagnostic outcomes, which cannot be otherwise achieved using conventional delivery approaches. While "translation" in drug development commonly encompasses the steps from discovery to human clinical trials, a different set of translational steps is required in nanomedicine. Although significant development effort has been focused on nanomedicine, the translation from laboratory formulations up to large scale production has been one of the major challenges to the success of such nano-therapeutics. In particular, scale-up significantly alters momentum and mass transfer rates, which leads to different regimes for the formation of nanomedicines. Therefore, unlike the conventional definition of translational medicine, a key component of "bench-to-bedside" translational research in nanomedicine is the scale-up of the synthesis and processing of the nano-formulation to achieve precise control of the nanoscale properties. This consistency requires reproducibility of size, polydispersity and drug efficacy. Here we demonstrate that Flash NanoPrecipitation (FNP) offers a scalable and continuous technique to scale up the production rate of nanoparticles from a laboratory scale to a pilot scale. FNP is a continuous, stabilizer-directed rapid precipitation process. Lumefantrine, an anti-malaria drug, was chosen as a representative drug that was processed into 200 nm nanoparticles with enhanced bioavailability and dissolution kinetics. Three scales of mixers, including a small-scale confined impinging jet mixer, a mid-scale multi-inlet vortex mixer (MIVM) and a large-scale multi-inlet vortex mixer, were utilized in the formulation. The production rate of nanoparticles was varied from a few milligrams in a laboratory batch mode to around 1 kg/day in a continuous large-scale mode, with the size and polydispersity similar at all scales. Nanoparticles of 200 nm were made at all three scales of mixers by operating at equivalent Reynolds numbers (dynamic similarity) in each mixer. Powder X-ray diffraction and differential scanning calorimetry demonstrated that the drugs were encapsulated in an amorphous form across all production rates. Next, scalable and continuous spray drying was applied to obtain dried powders for long-term storage stability. For dissolution kinetics, spray dried samples produced by the large-scale MIVM showed 100% release in less than 2 h in both fasted and fed state intestinal fluids, similar to small-batch low-temperature lyophilization. These results validate the successful translation of a nanoparticle formulation from the discovery scale to the clinical scale. Coupling nanoparticle production using FNP processing with spray drying offers a continuous nanofabrication platform to scale up nanoparticle synthesis and processing into solid dosage forms.


Dispersive transport and symmetry of the dispersion tensor in porous media.
The macroscopic laws controlling the advection and diffusion of solute at the scale of the porous continuum are derived in a general manner that does not place limitations on the geometry and time evolution of the pore space. Special focus is given to the definition and symmetry of the dispersion tensor that is controlling how a solute plume spreads out. We show that the dispersion tensor is not symmetric and that the asymmetry derives from the advective derivative in the pore-scale advection-diffusion equation. When flow is spatially variable across a voxel, such as in the presence of a permeability gradient, the amount of asymmetry can be large. As first shown by Auriault [J.-L. Auriault et al. Transp. Porous Med. 85, 771 (2010)TPMEEI0169-391310.1007/s11242-010-9591-y] in the limit of low Péclet number, we show that at any Péclet number, the dispersion tensor D_{ij} satisfies the flow-reversal symmetry D_{ij}(+q)=D_{ji}(-q) where q is the mean flow in the voxel under analysis; however, Reynold's number must be sufficiently small that the flow is reversible when the force driving the flow changes sign. We also demonstrate these symmetries using lattice-Boltzmann simulations and discuss some subtle aspects of how to measure the dispersion tensor numerically. In particular, the numerical experiments demonstrate that the off-diagonal components of the dispersion tensor are antisymmetric which is consistent with the analytical dependence on the average flow gradients that we propose for these off-diagonal components.


Prognostic value of lymphatic and blood vessel invasion in neuroendocrine tumors of the lung.
Few data on the influence of vessel invasion on the progression of neuroendocrine lung tumors are available. Because of the lack of specific markers, previous studies could not reliably discriminate lymphatic and blood vessels. By immunostaining for podoplanin, specific for lymphatic endothelium, and CD34 antigen, we assessed lymphatic and blood vessel invasion in 120 tissue specimens of patients with neuroendocrine lung tumors. Lymphovascular invasion was correlated with clinicopathologic parameters, and its prognostic relevance was evaluated. Lymphatic vessels were identified exclusively at the tumor invasion front, whereas blood capillaries were also seen within tumors. Lymphatic vessel as well as lymphatic and blood vessel invasion was prevalent in patients with high-grade neuroendocrine tumors and advanced tumor stages, closely associated with lymph node metastases (P < 0.0001). In univariate analysis, these two invasion types correlated with decreased disease-free survival (both P < 0.0001), whereas blood vessel invasion alone did not. In multivariate analysis, only tumor grade and lymph node status remained statistically significant factors for prognosis (P = 0.016 and P < 0.0001). Our results suggest that evaluation of lymphatic vessel invasion is important in neuroendocrine lung tumors serving as a prognostic parameter for disease-free survival.


Serotonin functioning and adolescents' alcohol use: A genetically informed study examining mechanisms of risk.
The current study used data from two longitudinal samples to test whether self-regulation, depressive symptoms, and aggression/antisociality were mediators in the relation between a polygenic score indexing serotonin (5-HT) functioning and alcohol use in adolescence. The results from an independent genome-wide association study of 5-hydroxyindoleacetic acid in the cerebrospinal fluid were used to create 5-HT polygenic risk scores. Adolescents and/or parents reported on adolescents' self-regulation (Time 1), depressive symptoms (Time 2), aggression/antisociality (Time 2), and alcohol use (Time 3). The results showed that 5-HT polygenic risk did not predict self-regulation. However, adolescents with higher levels of 5-HT polygenic risk showed greater depression and aggression/antisociality. Adolescents' aggression/antisociality mediated the relation between 5-HT polygenic risk and later alcohol use. Deficits in self-regulation also predicted depression and aggression/antisociality, and indirectly predicted alcohol use through aggression/antisociality. Pathways to alcohol use were especially salient for males from families with low parental education in one of the two samples. The results provide insights into the longitudinal mechanisms underlying the relation between 5-HT functioning and alcohol use (i.e., earlier aggression/antisociality). There was no evidence that genetically based variation in 5-HT functioning predisposed individuals to deficits in self-regulation. Genetically based variation in 5-HT functioning and self-regulation might be separate, transdiagnostic risk factors for several types of psychopathology.


Burning mouth syndrome: an evaluation of in vivo microcirculation.
Burning mouth syndrome (BMS) is an atypical orofacial algesic syndrome. The aim of the authors' research was to investigate the morphological characteristics of peripheral blood circulation in patients with BMS in comparison with those of the peripheral blood circulation in healthy people. The authors examined 28 subjects, of whom 14 (10 women and four men) had BMS and 14 (nine women and five men) were healthy control subjects. They performed videocapillaroscopic examination with a capillaroscope with a fiber-optic probe at a magnification of x200, which allowed them to examine the morphological characteristics within the capillaroscopic area accurately. The capillaroscopic examination provided important diagnostic results regarding alterations of the local microcirculation in subjects with BMS when compared with healthy subjects. The results also showed a statistically significant increase in the diameter of the capillary ansae, afferent ansae and efferent ansae in subjects with BMS compared with subjects in the control group (P = .05). The results revealed a vascular involvement in BMS. This information could improve the understanding of etiopathogenetic factors and aid in the development of therapeutic strategies for treating this disorder.


Surface area of particle administered versus mass in determining the pulmonary toxicity of ultrafine and fine carbon black: comparison to ultrafine titanium dioxide.
Nanoparticles are characterized by having a high surface area per mass. Particulate surface area has been reported to play an important role in determining the biological activity of nanoparticles. However, recent reports have questioned this relationship. This study was conducted to determine whether mass of particles or surface area of particles is the more appropriate dose metric for pulmonary toxicity studies. In this study, rats were exposed by intratracheal instillation to various doses of ultrafine and fine carbon black. At 1, 7, or 42 days post-exposure, inflammatory and cytotoxic potential of each particle type was compared on both a mass dosage (mg/rat) as well as an equal surface area dosage (cm2 of particles per cm2 of alveolar epithelium). In an additional study, the pulmonary responses to instillation of ultrafine carbon black were compared to equivalent particle surface area doses of ultrafine titanium dioxide. Ultrafine carbon black particles caused a dose dependent but transient inflammatory and cytotoxic response. On a mass basis, these responses were significantly (65 fold) greater than those for fine sized carbon black. However, when doses were equalized based on surface area of particles given, the ultrafine carbon black particles were only slightly (non-significantly) more inflammogenic and cytotoxic compared to the fine sized carbon black. At one day post-exposure, inflammatory potencies of the ultrafine carbon black and ultrafine titanium dioxide particles were similar. However, while the pulmonary reaction to ultrafine carbon black resolved with time, the inflammatory effects of ultrafine titanium dioxide were more persistent over a 42 day post-exposure period. These results indicate that for low toxicity low solubility materials, surface area of particles administered rather than mass burden of particles may be a more appropriate dose metric for pulmonary toxicity studies. In addition, ultrafine titanium dioxide appears to be more bioactive than ultrafine carbon black on an equivalent surface area of particles delivered basis.