Consensus on global health competencies for Korean medical students using a modified Delphi method.
This study aimed to reach a consensus among experts on the global health competencies for medical students in Korea. A global health competency model was developed to identify domains and competencies for medical education, and a three-round modified Delphi method was used to reach consensus among 21 experts on the essential global health competencies. The degree of convergence, degree of consensus, and content validity ratio of the model were used to reach a consensus. A list of 52 competencies in 12 domains were identified according to a literature review. In the first-round Delphi survey, the global health competencies were refined to 30 competencies in eight domains. In the second round, the competencies were reduced to 24. In the final round, consensus was reached among the expert panel members, and the competencies were finalized. The global health competency domains for medical students include global burden of disease (three items), globalization of health and healthcare (five items), determinants of health (two items), healthcare in low-resource settings (two items), global health governance (three items), health as a human right (four items), cultural diversity and health (three items), and participation in global health activities (two items). The group of experts in global health achieved a consensus that 24 global health competencies in eight domains were essential for undergraduate medical education in Korea. The domains and competencies identified herein can be used to develop an undergraduate medical education curriculum in global health.


Montessori education: a review of the evidence base.
The Montessori educational method has existed for over 100 years, but evaluations of its effectiveness are scarce. This review paper has three aims, namely to (1) identify some key elements of the method, (2) review existing evaluations of Montessori education, and (3) review studies that do not explicitly evaluate Montessori education but which evaluate the key elements identified in (1). The goal of the paper is therefore to provide a review of the evidence base for Montessori education, with the dual aspirations of stimulating future research and helping teachers to better understand whether and why Montessori education might be effective.


Normalization of Non-Drinking? Health, School Situation and Social Relations among Swedish Ninth Graders That Drink and Do Not Drink Alcohol.
Alcohol consumption is a major contributor to the disease burden among adolescents. The adolescent alcohol abstainer is still often depicted as problematic in the research literature and in prominent theoretical frameworks. However, over the past two decades, there has been a marked trend of declining youth drinking in Sweden. The declining trend has led to a shift in the majority behaviour of youth, from drinking to non-drinking. It is plausible that this trend has also shifted the position of non-drinkers. This paper examines the position of non-drinkers in a nationally representative sample of Swedish adolescents. A survey was carried out in 2017 in 500 randomly selected schools. A total of 5549 respondents (15-16-year-olds) agreed to participate and answered the questionnaire. A minority (42.8%) had consumed alcohol during their lifetime. The results show that non-drinkers had better health and school performance when compared to drinkers. The results also showed that there were no differences in the social position between non-drinkers and drinkers. These findings are new and indicate a changed position of non-drinkers among Swedish adolescents. With non-drinking being the majority behaviour among Swedish adolescents this seems to have shifted the position of non-drinkers. There is a need for research on the long-term importance of not drinking during adolescence.


Parainfluenza virus type 2 haemagglutinin-neuraminidase glycoprotein characterized with monoclonal antibodies.
Thirteen monoclonal antibodies (MAbs) were prepared against human parainfluenza virus type 2 (PIV2). These MAbs reacted with the haemagglutinin-neuraminidase glycoprotein with an Mr of 84K. The MAbs defined one antigenic site which could be divided into five epitopes. A correlation between haemagglutination inhibition (HI) and neutralization activity could be seen although one MAb, which recognized a distinct epitope, showed neutralization and no HI activity to PIV2. The reactivity of the MAbs was tested against Sendai virus, parainfluenza virus type 3, simian virus 5 (SV5), mumps virus, Newcastle disease virus, measles virus and canine distemper virus. Only one MAb showed any cross-reaction with a low HI titre to SV5.


Efficacy and safety of daptomycin for the treatment of infectious disease: a meta-analysis based on randomized controlled trials.
A systematic review and meta-analysis based on randomized controlled trials (RCTs) of the efficacy and safety of daptomycin versus comparators. Electronic databases (PubMed, Embase, Cochrane Central Register of Controlled Trials and clinical registered trials) were searched to identify RCTs that assessed the efficacy and safety of daptomycin versus therapy with comparators. Two reviewers independently applied selection criteria, performed a quality assessment and extracted the data. The I(2) statistic was calculated for heterogeneity, and a random-effects or fixed-effects model was used for estimates of risk ratio (RR). The primary outcome assessed was clinical treatment success among the intention-to-treat (ITT) population. Thirteen trials fulfilled the inclusion criteria. Daptomycin was as efficacious as comparator regimens among the ITT population (RR = 0.98, 95% CI 0.93-1.03) but had a lower efficacy among the clinically evaluable (CE) population (RR = 0.96, 95% CI 0.93-1.00). Subgroup analyses according to the quality of the trial, the type of antibiotic and the type of infection did not alter the outcomes. No significant difference was identified for all-cause mortality between the daptomycin and comparator groups (RR = 1.17, 95% CI 0.76-1.79) but daptomycin therapy did reduce the duration of treatment. Daptomycin caused a significantly lower incidence of renal impairment, nausea and headache but caused a reversible increase in creatine phosphokinase (CPK). Subgroup analysis indicated that daptomycin was significantly associated with a higher incidence of CPK elevation and fewer renal impairments among the population with a mean age ≤60 years and a dose of daptomycin ≥6 mg/kg/24 h. Daptomycin showed efficacy similar to the comparator regimens among the ITT population but lower efficacy among the CE population. Fewer adverse effects in total, but more CPK elevation effects, were observed in patients treated with daptomycin.


Evaluation of tapelifting as a collection method for touch DNA.
The use of tapelifting for collection of touch DNA from fabrics is routine in many jurisdictions. However, there is a paucity of data relating to the effectiveness of different types of tapes for tapelifting, the amount of tapelifting required to generate a useful profile, and whether or not tapelifting is more effective than swabbing from various substrates. This research investigates these questions by comparing two tapes of different adhesive strength currently used in forensic casework (Scotch Magic tape and Scenesafe FAST minitapes), for sampling from touch deposits on four different fabrics-cotton flannelette, cotton drill woven fabric, polyester/cotton plain woven fabric and polyester strapping. Touch DNA was deposited on four replicates of each substrate. Separate areas of each substrate replicate were sampled, either by taping with one of the two tapes or by wet/dry swabbing with cotton swabs. Tape was applied over the defined sampling area once or repeatedly for various numbers of applications. DNA was extracted, quantified and profiled from all tape and swab samples as well as the corresponding sampled substrates. Significantly more DNA was extracted, and a higher proportion of alleles detected, from Scenesafe FAST tape than from Scotch Magic tape. The amount of DNA and number of donor alleles detected generally increased as the tape was reapplied to the surface, although a threshold of collection was seen for both types of tape. For two out of four substrates, taping with Scenesafe FAST collected more DNA than swabbing and, for three substrates, generated a greater median number of donor alleles. There was no significant difference in numbers of alleles between swabbing and taping from flannelette. Based on these findings, it is recommended that a tape with stronger adhesion (such as Scenesafe FAST tapelifters) is generally preferable; that more than one application of tape is suggested (however, increasing the amount of times the area is sampled can diminish collection efficiency); and that there is an advantage using tapelifting rather than swabbing for fabrics unless, such as with flannelette, there are many loose fibres easily removed during the sampling process.


Free volume, gas permeation, and proton conductivity in MIL-101-SO3H/Nafion composite membranes.
A series of MIL-101-SO3H/Nafion composite membranes was synthesized. They show an improved proton conductivity, due to the abundance of SO3H groups, which fosters proton conduction by binding the water molecules and enabling a larger number of conducting sites. Gas (including water vapor, hydrogen, and oxygen) permeability, crystallinity, and free volumes of the MIL-101-SO3H/Nafion composite membranes were investigated, as well as their correlation. By increasing the MIL-101-SO3H content, the gas permeability of the membranes significantly decreases, since the crystalline region is larger and the water-bearing MIL-101-SO3H particles are efficient barriers for the gas molecules. The gas permeation in the composite membranes is a very complex process and the results indicate no simple linear relation between the gas permeability and the free volume size (VFV), or between the gas permeability and the crystallinity. Moreover, it is very interesting to observe that the influence of VFV on the gas permeability is closely related to the size of the particular gas molecules: the larger the size of the gas molecules, the larger the free volume needed to achieve their rapid diffusion in the membrane. The results suggest the presence of a threshold value for VFV, which depends on the size of the gas molecules: when VFV is lower than this value, the gas molecules cannot easily jump through neighboring free volumes to a neighboring site, and, as a result, the permeability drops quickly.


In science communication, why does the idea of a public deficit always return? The eternal recurrence of the public deficit.
After several years of loud and clear rejection, the idea of a public cognitive deficit insistently reappears in the agenda of Science Communication and Public Understanding of Science studies. This essay addresses two different kinds of reason - practical and epistemic - converging at that point. In the first part, it will be argued that the hypothesis of the lack of knowledge among laypeople and its controversial relationships with their interests and attitudes towards science prevails because it is an intuitive and optimistic way to frame the gap between science and society and, therefore, to cope with its causes and consequences. In the second part, a deeper level of reasons will be examined, in order to show that the persistence of the idea has its roots in the objective epistemic asymmetry between scientists and the public, the scope of which is not always properly judged. To recognize this asymmetry as a previous condition for their interactions may help to surpass the byzantine debate: deficit yes or no and open up original questions for the field, summarized in the closing remarks.


Antitumor effect of SIRT1 inhibition in human HCC tumor models in vitro and in vivo.
Sirtuins (SIRT1-7) are a highly conserved family of NAD(+)-dependent enzymes that control the activity of histone and nonhistone regulatory proteins. SIRT1 is purposed to promote longevity and to suppress the initiation of some cancers. Nevertheless, SIRT1 is reported to function as a tumor suppressor as well as an oncogenic protein. Our data show that compared with normal liver or surrounding tumor tissue, SIRT1 is strongly overexpressed in human hepatocellular carcinoma (HCC). In addition, human HCC cell lines (Hep3B, HepG2, HuH7, HLE, HLF, HepKK1, skHep1) were screened for the expression of the sirtuin family members and only SIRT1 was consistently overexpressed compared with normal hepatocytes. To determine its effect on HCC growth, SIRT1 activity was inhibited either with lentiviruses expressing short hairpin RNAs or with the small molecule inhibitor, cambinol. Knockdown or inhibition of SIRT1 activity had a cytostatic effect, characterized by an altered morphology, impaired proliferation, an increased expression of differentiation markers, and cellular senescence. In an orthotopic xenograft model, knockdown of SIRT1 resulted in 50% fewer animals developing tumors and cambinol treatment resulted in an overall lower tumor burden. Taken together, our data show that inhibition of SIRT1 in HCC cells impairs their proliferation in vitro and tumor formation in vivo. These data suggest that SIRT1 expression positively influences the growth of HCC and support further studies aimed to block its activity alone or in combination as a novel treatment strategy.


Spontaneous regression of migrated ventriculoperitoneal shunt catheter from scrotum to peritoneum: a case-based review.
The incidence of scrotal migration of a ventriculoperitoneal shunt (VPS) catheter is rare and may lead to life-threatening visceral complications. Management requires prompt removal of the migrated portion of the shunt and closure of the scrotal sac. We report an interesting case of a young child who presented with asymptomatic unilateral swelling of his scrotum secondary to a migrated VPS catheter. A repeat X-ray prior to his surgery to remove the migrated catheter showed that the entire length of the distal VPS catheter was back in the peritoneal cavity. In view of this unusual phenomenon, the case is discussed in corroboration with published literature. A systematic search of publications in the English language is performed in PubMed and Google Scholar. Our findings show that there are 49 reported cases (including our patient) of scrotal migration of shunt catheters in patients less than 18 years old. There is only 1 other case of spontaneous resolution of shunt catheter from the scrotum. Favoured management of choice is repositioning the distal shunt catheter back into the peritoneal cavity and herniotomy in the same setting, if possible. Overall, the literature suggests this is a shunt-related complication that has a good prognosis if intervention is timely. Scrotal migration of a VPS catheter is a rare but potentially life-threatening complication in children. Our case report highlights the role of updated preoperative imaging and the need for consistent long-term shunt surveillance in children.


Biobank Recruitment: Motivations for Nonparticipation.
Molecular data, essential for genomics research, can be captured more efficiently in large-scale, population-based biobanks of genetic material rather than by individual studies. Biobanks also offer improved quality and reliability of genetic samples and access through automated sample retrieval. However, it is challenging to adequately inform participants of the broad nature of the research and participation risks and benefits. In addition, recent studies suggest concerns about data sharing and return of research results, or future research topics (eg, stereotypical or potentially stigmatizing traits). We evaluated the interest in participating in a biobank and reasons for nonparticipation.


The relationship of white blood cell and platelet counts to cigarette smoking in adult Nigerians.
This study was undertaken to examine the relationship between cigarette-smoking and total white blood cell count (wbcc) and platelet count (pc) in adult Nigerians. We also studied the relationship of the white blood cell and platelet counts to the duration of the smoking habit and number of cigarette smoked per day. Three hundred and fifty-two healthy male adults, aged 18-52 years, were studied. They were randomly allocated to two groups--176 smokers and 176 non-smokers. The smoking habit was assessed from a minimum period of 1 year and a minimum number of 5 cigarettes per day. Results revealed that platelet count was higher for the regular Nigerian smoker than for non-smoker. The difference between mean platelet counts for smokers and non-smokers was statistically significant (t = 2.64 p = 0.0046). Man WBC count in smokers was slightly higher than for non-smokers. However, unlike in the case of platelet counts, the mean difference in WBC count between smokers and non-smokers is not statistically significant (t = 0.07, p value = 0.9442). Similar studies based on white population has showed statistically significant increases in wbcc and pc in smokers.


The rationale for microcirculatory guided fluid therapy.
The ultimate purpose of fluid administration in states of hypovolemia is to correct cardiac output to improve microcirculatory perfusion and tissue oxygenation. Observation of the microcirculation using handheld microscopes gives insight into the nature of convective and diffusive defect in hypovolemia. The purpose of this article is to introduce a new platform for hemodynamic-targeted fluid therapy based on the correction of tissue and microcirculatory perfusion assumed to be at risk during hypovolemia. Targeting systemic hemodynamic targets and/or clinical surrogates of hypovolemia gives inadequate guarantee for the correction of tissue perfusion by fluid therapy especially in conditions of distributive shock as occur in inflammation and sepsis. Findings are presented, which support the idea that only clinical signs of hypovolemia associated with low microcirculatory flow can be expected to benefit from fluid therapy and that fluid overload causes a defect in the diffusion of oxygen transport. We hypothesized that the optimal amount of fluid needed for correction of hypovolemia is defined by a physiologically based functional microcirculatory hemodynamic platform where convection and diffusion need to be optimized. Future clinical trials using handheld microscopes able to automatically evaluate the microcirculation at the bedside will show whether such a platform will indeed optimize fluid therapy.


Cerebrospinal fluid D-serine concentrations in major depressive disorder negatively correlate with depression severity.
D-serine is an endogenous co-agonist of N-methyl-D-aspartate receptor (NMDAR) and plays an important role in glutamate neurotransmission. Several studies suggested the possible involvement of D-serine related in the pathophysiology of psychiatric disorders including major depression disorders (MDD). We tried to examine whether cerebrospinal fluid (CSF) or plasma D-serine concentrations are altered in MDD and whether D-serine concentrations correlated with disease severity. 26 MDD patients and 27 healthy controls matched for age, sex and ethnicity were enrolled. We measured amino acids in these samples using by high-performance liquid chromatography with fluorometric detection. D-serine and L-serine, precursor of D-serine, levels in CSF or plasma were not significantly different in patients of MDD compared to controls. Furthermore, a significant correlation between D-serine levels in CSF and Hamilton Depression Rating Scale (HAMD)-17 score was observed (r = -0.65, p = 0.006). Furthermore, we found a positive correlation between CSF D-serine and HVA concentrations in MDD patients (r = 0.54, p = 0.007). CSF D-serine concentrations were correlated with those of plasma in MDD (r = 0.61, p = 0.01) but not in controls. In CSF, we also confirmed a significant correlation between D-serine and L-serine levels in MDD (r = 0.72, p < 0.0001) and controls (r = 0.70, p < 0.0001). The study has some limitations; sample size was relatively small and most patients were medicated. We revealed that CSF D-serine concentrations were correlated with depression severity and HVA concentrations and further investigation were required to reveal the effect of medication and disease heterogeneity.


Repeat induction of labour for post-term pregnancy.
A previous post-term pregnancy is thought to influence the gestation of a subsequent pregnancy. Adverse maternal and perinatal outcomes are associated with post-term pregnancy and routine induction of labour by 42+0 weeks is advised to reduce these complications. To determine the recurrence rate of a post-term pregnancy and the need for repeat induction of labour. This observational cohort study featured women with a first and second singleton pregnancy, based on data recorded in the Aberdeen Maternity and Neonatal Databank (1986-2012). Term and post-term pregnancies were defined as ≥37+0 - 40+6 and ≥41+0 weeks, respectively. The exposure was a post-term pregnancy and the control a term pregnancy. Logistic regression was used to assess post-term recurrence and repeat induction of labour. The study population consisted of 25,669 women with 33% of the women delivering post-term in their first pregnancy. In these women, the rate of a subsequent post-term pregnancy was 35.7% compared to 18.6% for women with an initial term pregnancy (adjusted odds ratio (aOR) 2.27, 95% confidence interval (CI) 2.11-2.44). Compared to women who had spontaneous term deliveries in both pregnancies, women who were induced post-term in the second pregnancy had increased odds of having been induced post-term in their first pregnancy. The adjusted odds ratio was found to be 6.08 (95% CI 5.30-6.98). Women with a first post-term pregnancy are less likely to labour spontaneously and more likely to have a second post-term pregnancy with a higher risk of repeat induction of labour, than women who have previously delivered at term. These findings could be useful in the counselling of women with a previous post-term pregnancy. Given that these women are less likely to labour spontaneously, the offer of an elective induction could also be considered to potentially improve maternal and perinatal outcomes.


Predictors of having paid work in older workers with and without chronic disease: a 3-year prospective cohort study.
As the prevalence of chronic disease amongst older workers is high and increasing, it is important to know if the large subgroup of older workers with chronic disease has specific needs when it comes to prolonging participation in paid work. To investigate differences and similarities in predictors of having paid work in workers aged 55+ with and without chronic disease. Workers aged 55-62 years were selected from the 2002-2003 cohort of the Longitudinal Aging Study Amsterdam (n = 333). Potential predictors were: health, personality, work characteristics, and demographics. Per potential predictor, a logistic regression coefficient for 'having paid work in 2005-2006' was calculated for workers with and without chronic disease. A pooled estimate was computed and differences between the pooled estimate and the coefficients were tested. Results Follow-up data were available for 95 %, of whom 67 % still had paid work. Predictors of having paid work were similar for workers with and without chronic diseases, except for physical workload (χ(2) = 5.37; DF = 1) and psychosocial resources at work (χ(2) = 5.94; DF = 1). Having more psychosocial resources (OR = 3.57; 95 %CI 1.33-10.0) was predictive for having paid work in workers with chronic disease and not in workers without chronic disease. Lower age, more weekly working hours, no functional limitations, fewer depressive symptoms, lower neuroticism scores, and more sense of mastery were significantly associated with having paid work in all workers. Differences between predictors of having paid work between workers with and without chronic disease should be taken into account when aiming to prevent exit from the workforce. In particular the vulnerable subgroup of older workers with chronic disease and low psychosocial resources at work is more likely to quit working.


Active versus expectant management in the third stage of labour.
Expectant management of the third stage of labour involves allowing the placenta to deliver spontaneously or aiding by gravity or nipple stimulation. Active management involves administration of a prophylactic oxytocic after delivery, early cord clamping and cutting, and controlled cord traction of the umbilical cord. The objective of this review was to assess the effects of active versus expectant management on blood loss, post partum haemorrhage and other maternal and perinatal complications of the third stage of labour. We searched the Cochrane Pregnancy and Childbirth Group trials register. Randomised trials comparing active and expectant management of the third stage of labour in women with singleton pregnancies whose babies were presenting head first and who were expecting a vaginal delivery. Trial quality was assessed and data were extracted independently by the reviewers. Four studies were included. Three of the trials were of good quality. Compared to expectant management, active management (in the setting of a maternity hospital) was associated with the following reduced risks: maternal blood loss (weighted mean difference -79.33 millilitres, 95% confidence interval -94.29 to -64. 37); post partum haemorrhage of more than 500 millilitres (odds ratio 0.34, 95% confidence interval 0.28 to 0.41); prolonged third stage of labour (weighted mean difference -3.40 minutes, 95% confidence interval -4.66 to -2.13). Active management was associated with an increased risk of maternal nausea (odds ratio 1. 95, 95% confidence interval 1.58 to 2.42), vomiting and raised blood pressure (probably due to the use of ergometrine). No advantages or disadvantages were apparent for the baby. Routine 'active management' is superior to 'expectant management' in terms of blood loss, post partum haemorrhage and other serious complications of the third stage of labour. Active managment is, however, associated with an increased risk of unpleasant side effects (eg nausea and vomiting), and hypertension, where ergometrine is used. Active management should be the routine management of choice for women expecting a single baby by vaginal delivery in a maternity hospital. The implications are less clear for other settings including domiciliary practice (in developing and industrialised countries).


Pteridine derivatives as modulators of oxidative stress.
Pteridine derivatives which have a widespread occurrence in nature have been investigated upon their interactions with free radicals and free radical mediated reactions utilizing a number of different experimental systems. Searching for biological functions, which are still unknown for the majority of pteridine compounds, the effect of pteridines in systems like luminol-induced chemiluminescence, enzyme activity, DNA photodamage, EPR experiments or radical induced injury--just to name a few--have been investigated. The general view during the initial phase of investigations on this special field was, that reduced pterins, i. e., tetra- as well as dihydropterins, generally act as radical scavengers, while aromatic pterins, if not inactive, exert radical promoting activity. Meanwhile the data available provide a more complex view: pteridines of all oxidation states have been shown to act anti- or prooxidatively, depending on the special conditions of the experiment. The reason is that reduced pterins, besides of being scavengers of free radicals, also are strongly reducing agents and therefore, in the presence of transition metal ions promote Fenton chemistry. Aromatic pterins have been described as inhibitors or substrates of enzymes involved--in vitro and in vivo--in free radical generation. Together with the unknown local concentrations of, e.g., neopterin and dihydroneopterin occurring in vivo, these reasons make it impossible to unequivocally predict a physiological net effect of pterins of different oxidation states concerning free radical mediated reactions in real biological systems.


Anion binding to mutants of the Schiff base counterion in heliorhodopsin 48C12.
Heliorhodopsin (HeR), a recently discovered new rhodopsin family, contains a single counterion, E107, which is specific to HeR 48C12. In this paper, we examined possible anion binding into the wild-type (WT) and E107 mutants of HeR 48C12. We prepared E107A, E107Q, and E107D, and chloride binding was tested by measuring absorption spectra using UV-visible spectroscopy under various anionic conditions. The experimental results clearly showed no anion binding to WT and E107D, where E107 and D107 acted as the Schiff base counterion, respectively. On the other hand, anion binding was observed to the Schiff base region in E107A and E107Q. In the case of E107A, λmax was 553, 559, 565, and 549 nm for Cl-, Br-, I-, and NO3-, respectively. Similar halide-size dependence on the absorption spectra of the chromophore in solution strongly suggests that the anion acted as the direct hydrogen-bonding acceptor of the protonated Schiff base in E107A. In the case of E107Q, λmax was 577, 578, 579, and 581 nm for Cl-, Br-, I-, and NO3-, respectively. Based on the small halide dependence, we interpreted the C[double bond, length as m-dash]O group of the Q107 side chain as the hydrogen-bonding acceptor. Moreover, the anion stabilized the protonated state without a direct hydrogen bond with the Schiff base. Structures around the Schiff base region are discussed for the WT and E107 mutants of HeR 48C12.


Insights into human colonic physiology obtained from the study of flatus composition.
To better understand the physiology of colonic gas production, each flatus passage of 16 subjects over a 4-h period was analyzed by gas chromatography for N2, O2, H2, CO2, CH4, and for odoriferous sulfur-containing gases. Appreciable intraindividual and enormous interindividual variability was observed, indicating that each gas passage reflected the interaction of highly variable liberation and/or removal mechanisms. The predominant flatus gas was CO2, H2, and N2 in seven, six, and three subjects, respectively. Gases produced intraluminally (H2, CO2, and CH4) comprised approximately 74% of flatus, and rapid CO2 and H2 productions were responsible for high passage rates. A positive correlation between flatus H2 and CO2 suggested that CO2, like H2, mainly was a bacterial product. Whereas methanogens and H2S-producing bacteria usually are mutually exclusive in feces, CH4 and H2S did not negatively correlate, indicating coexistence of both organisms in the colon. We conclude that analysis of flatus composition provides a novel means of assessing colonic physiology, particularly ongoing bacterial metabolism throughout the unperturbed colon.


Biological properties of ribonucleic acid from virulent and attenuated poliovirus.
Concentrates of type I poliovirus were extracted with phenol by Gierer and Schramm's method. The infectivity of these extracts in tissue culture and mice appeared to be associated with viral RNA. Studies on neurovirulence based on the "t" marker and intraspinal pathogenicity in mice demonstrated that the viral progeny of RNA isolated from virulent viruses had the "t(+)" character and were highly neurotropic for mice. Conversely, RNA extracted from attenuated virus gave rise to a progeny of "t" type which were avirulent for mice. The results suggest that the infective RNA from type, I poliovirus carries the genetic information which determines the degree of neurovirulence.


Where Does Life Begin? Discerning the Impact of Dobbs on Assisted Reproductive Technologies.
This article explores the impact of Dobbs on access to assisted reproductive technologies. Clinical aspects of IVF, including embryo discard and cryopreservation, preimplantation genetic testing, and selective reduction of multiple pregnancy are potentially jeopardized by a new legal landscape that protects embryos over the interest of infertility patients.


P-glycoprotein- and organic anion-transporting polypeptide-mediated transport of periplocin may lead to drug-herb/drug-drug interactions.
Periplocin, an active and toxic component of the traditional Chinese herbal medicine Periploca sepium Bge, is a cardiac glycoside compound that has been implicated in various clinical accidents. This study investigated the role of transporters in the intestinal absorption and biliary excretion of periplocin, as well as the possible metabolic mechanism of periplocin in liver S9. In a bidirectional transport assay using Madin-Darby canine kidney (MDCK) and MDCK multidrug-resistance protein (MRP)-1 cell monolayers, both in situ intestinal and liver-perfusion models were used to evaluate the role of efflux and uptake transporters on the absorption and biliary excretion of periplocin. In addition, in vitro metabolism of periplocin was investigated by incubating with human/rat liver S9 homogenate fractions to evaluate its metabolic mechanisms in liver metabolic enzymes. The results showed that P-glycoprotein (P-gp) was involved in the intestinal absorption of periplocin, whereas MRP2 and breast cancer-resistance protein were not. The efflux function of P-gp may be partly responsible for the low permeability and bioavailability of periplocin. Moreover, both inhibitors of P-gp and organic anion-transporting polypeptides (OATPs) increased periplocin biliary excretion. No obvious indications of metabolism were observed in the in vitro incubation system, which suggests that periplocin did not interact with the hepatic drug metabolic enzymes. The results of this study showed that the efflux and uptake transporters P-gp and OATPs were involved in the absorption and biliary excretion of periplocin, which may partially account for its low permeability and bioavailability. As a toxic compound, potential drug-herb/herb-herb interactions based on OATPs and P-gp should be taken into account when using P. sepium Bge in the clinic.


Proliferative responses of central and peripheral rat lymphocytes elicited by cord factor (trehalose 6,6'-dimycolate).
Cord factor--a mixture of 6,6'-diesters of alpha, alpha-D-trehalose with natural mycolic acids--which is purified from mycobacteria and other microorganisms, is known to have adjuvant activity as well as to enhance nonspecific resistance to infections and tumor development. In this work, trehalose 6,6'-dimycolate (TDM) was found to induce proliferative responses in rat thymus and lymph node cells. With the thymus cells, TDM responses were greater after removal of the adherent cell subpopulation. Consistent with this observation was the finding that addition of phagocytic cells purified from peritoneal or lymph node cell suspensions to nonadherent thymocytes abrogated the response of thymocytes to TDM. With the lymph node cells, the presence or removal of adherent cells had no major consequence on the TDM-induced proliferative response, since similar increases in deoxyribonucleic acid synthesis were observed with unfractionated and nonadherent cells. The difference between the sensitivities of thymus cells and lymph node cells to regulation by adherent cells indicated the existence of more than one type of TDM responder cell in rats. TDM also displayed marked stimulatory activity on thymus and lymph node cells from germ-free rats, ruling out the possibility that TDM might have triggered a specific, secondary, in vitro immune response. Expansion of a selected cell population(s) triggered by TDM may be involved in the manifestation of adjuvant activity and possibly other immunological properties of cord factor.


Patterns and risk factors of opioid-suspected EMS overdose in Houston metropolitan area, 2015-2019: A Bayesian spatiotemporal analysis.
Opioid-related overdose deaths are the top accidental cause of death in the United States, and development of regional strategies to address this epidemic should begin with a better understanding of where and when overdoses are occurring. In this study, we relied on emergency medical services data to investigate the geographical and temporal patterns in opioid-suspected overdose incidents in one of the largest and most ethnically diverse metropolitan areas (Houston Texas). Using a cross sectional design and Bayesian spatiotemporal models, we identified zip code areas with excessive opioid-suspected incidents, and assessed how the incidence risks were associated with zip code level socioeconomic characteristics. Our analysis suggested that opioid-suspected overdose incidents were particularly high in multiple zip codes, primarily south and central within the city. Zip codes with high percentage of renters had higher overdose relative risk (RR = 1.03; 95% CI: [1.01, 1.04]), while crowded housing and larger proportion of white citizens had lower relative risks (RR = 0.9; 95% CI: [0.84, 0.96], RR = 0.97, 95% CI: [0.95, 0.99], respectively). Our analysis illustrated the utility of Bayesian spatiotemporal models in assisting the development of targeted community strategies for local prevention and harm reduction efforts.


Role of human-tissue transglutaminase IgG and anti-gliadin IgG antibodies in the diagnosis of coeliac disease in patients with selective immunoglobulin A deficiency.
Selective IgA deficiency is associated with coeliac disease, and studies have shown an increased prevalence of coeliac disease in these patients ranging from 0.71 to 30.7%, depending on the test used for screening. To determine the sensitivity of IgG anti-gliadin-antibodies and of IgG human-tissue-transglutaminase for diagnosing coeliac disease and assessing its prevalence in subjects with IgA deficiency. We tested serum samples from 126 IgA-deficient children (66 female, median age: 10.8 years). All samples were analysed to measure IgG anti-gliadin-antibodies and IgG anti-human-tissue-transglutaminase. Patients testing positive to either test underwent intestinal biopsy. Subjects testing positive for IgG anti-human-tissue-transglutaminase underwent genetic testing for the human leucocyte antigen heterodimer. Twenty-seven of 126 subjects tested positive for IgG anti-gliadin-antibodies (five of whom tested positive also for IgG anti-human-tissue-transglutaminase) and 18 (including the aforementioned five) for IgG anti-human-tissue-transglutaminase. Intestinal biopsy was performed in 37 of the 40 patients who tested positive (three subjects refused). Eleven had positive intestinal biopsies all of whom tested positive for IgG anti-human-tissue-transglutaminase, but only five of these tested positive also for IgG anti-gliadin-antibodies. All 22 patients testing positive for anti-gliadin-antibody alone had normal intestinal mucosa. All the patients who tested positive for IgG anti-human-tissue-transglutaminase and underwent genetic screening (15/18) had the coeliac-related human leucocyte antigen. Overall, coeliac disease was diagnosed in 11 of the 126 subjects with IgA deficiency (8.7%). The prevalence of coeliac disease in subjects with total IgA deficiency was 8.7%. Assay of IgG anti-human-tissue-transglutaminase can be recommended for screening coeliac disease in IgA-deficient subjects.


Land-use change increases climatic vulnerability of migratory birds: Insights from integrated population modelling.
Knowledge of land-use patterns that could affect animal population resiliency or vulnerability to environmental threats such as climate change is essential, yet the interactive effects of land use and climate on demography across space and time can be difficult to study. This is particularly true for migratory species, which rely on different landscapes throughout the year. Unlike most North American migratory waterfowl, populations of northern pintails (Anas acuta; hereafter pintails) have not recovered since the 1980s despite extended periods of abundant flooded wetlands (i.e. ponds). The mechanisms and drivers involved in this discrepancy remain poorly understood. While pintails are similar to other ducks in their dependence on ponds throughout their annual cycle, their extensive use of croplands for nesting differentiates them and makes them particularly vulnerable to changes in agricultural land use on prairie breeding grounds. Our intent was to quantify how changes in land use and ponds on breeding grounds have influenced pintail population dynamics by developing an integrated population model to analyse over five decades (1961-2014) of band-recovery, breeding population survey, land-use and pond count data. We focused especially on the interactive effects of pond counts and land use on pintail productivity, while accounting for density-dependent processes. Pintail populations responded more strongly to annual variation in productivity than survival. Productivity was positively correlated with pond count and negatively correlated with agricultural intensification. Further, a positive interaction between pond count and agricultural intensification was insufficient to overcome the strong negative effect of agricultural intensification on pintail productivity across nearly all pond counts. The interaction also indicated that pintail populations were more negatively impacted by the decrease in ponds associated with climate change under higher agricultural intensification. Our results indicate that pintail populations have become more vulnerable to climate change under intensified land use, which suggests that future conservation strategies must adapt to these altered relationships. The interactive effects of land use and climate on demography should be considered more frequently in animal ecology, and integrated population models provide an adaptable framework to understand vital rates and their drivers simultaneously.


Clinical manifestations of Korean female gouty patients.
In an endeavor to analyse the clinical characteristics of female gout, we reviewed 36 women with gout. Twenty-seven (75%) developed the first symptomatic episode of gout after the onset of the menopause. The mean age at onset of gout was 54.3 years (range 15-87 years). Twenty-two patients (61%) had hypertension, 17 (47%) had renal insufficiency, 13 (36%) used diuretics and 10 (28%) were taking cyclosporine for a renal allograft. Tophaceous gout occurred in 10 patients (27%) and polyarticular involvement was seen in 16 (44%) at initial presentation. Five of nine premenopausal patients were taking cyclosporine and four had renal insufficiency. A comparison with a control group of 72 randomly selected male patients with gout showed that the female patients were frequently receiving diuretics at the time of the attack and had significantly lower mean uric acid excretion, whereas significantly more male patients showed heavy alcohol consumption and precipitating events for an acute attack compared with the female patients. There were no significant differences between the sexes for onset age, hypertension, renal insufficiency, distribution of joint involvement, tophi and mean serum uric acid concentration. The female patients in this study had a lower mean age at onset of gout than in previous studies, which was attributed to the inclusion of renal transplantation patients. Transplantation gout patients receiving cyclosporine lower the mean age at onset of female gout and this is an emerging problem in female gout.


Oncogenic functions of the transcription factor Nrf2.
Nuclear factor E2-related factor 2 (Nrf2) is a transcription factor that controls the expression of a large pool of antioxidant and cytoprotective genes regulating the cellular response to oxidative and electrophilic stress. Nrf2 is negatively regulated by Kelch-like ECH-associated protein 1 (Keap1) and, upon stimulation by an oxidative or electrophilic insult, is rapidly activated by protein stabilization. Owing to its cytoprotective functions, Nrf2 has been traditionally studied in the field of chemoprevention; however, there is accumulated evidence that Keap1/Nrf2 mutations or unbalanced regulation that leads to overexpression or hyperactivation of Nrf2 may participate in tumorigenesis and be involved in chemoresistance of a wide number of solid cancers and leukemias. In addition to protecting cells from reactive oxygen species, Nrf2 seems to play a direct role in cell growth control and is related to apoptosis-regulating pathways. Moreover, Nrf2 activity is connected with oncogenic kinase pathways, structural proteins, hormonal regulation, other transcription factors, and epigenetic enzymes involved in the pathogenesis of various types of tumors. The aim of this review is to compile and summarize existing knowledge of the oncogenic functions of Nrf2 to provide a solid basis for its potential use as a molecular marker and pharmacological target in cancer.


Investigating the cases of novel coronavirus disease (COVID-19) in China using dynamic statistical techniques.
The initial investigation by local hospital attributed the outbreak of the novel coronavirus disease (COVID-19) to pneumonia with unknown cause that appeared like the 2003 severe acute respiratory syndrome (SARS). The World Health Organization declared COVID-19 as public health emergency after it spread outside China to several countries. Thus, an assessment of the novel coronavirus disease (COVID-19) with novel estimation approaches is essential to the global debate. This study is the first to develop both time series and panel data models to construct conceptual tools that examine the nexus between death from COVID-19 and confirmed cases. We collected daily data on four health indicators namely deaths, confirmed cases, suspected cases, and recovered cases across 31 Provinces/States in China. Due to the complexities of the COVID-19, we investigated the unobserved factors including environmental exposures accounting for the spread of the disease through human-to-human transmission. We used estimation methods capable of controlling for cross-sectional dependence, endogeneity, and unobserved heterogeneity. We predicted the impulse-response between confirmed cases of COVID-19 and COVID-19-attributable deaths. Our study revealed that the effect of confirmed cases on the novel coronavirus attributable deaths is heterogeneous across Provinces/States in China. We found a linear relationship between COVID-19 attributable deaths and confirmed cases whereas a nonlinear relationship was confirmed for the nexus between recovery cases and confirmed cases. The empirical evidence revealed that an increase in confirmed cases by 1% increases coronavirus attributable deaths by ~0.10%-~1.71% (95% CI). Our empirical results confirmed the presence of unobserved heterogeneity and common factors that facilitates the novel coronavirus attributable deaths caused by increased levels of confirmed cases. Yet, the role of such a medium that facilitates the transmission of COVID-19 remains unclear. We highlight safety precaution and preventive measures to circumvent the human-to-human transmission.


Diabetes-prone and diabetes-resistant BB rats share a common major diabetes susceptibility locus, iddm4: additional evidence for a "universal autoimmunity locus" on rat chromosome 4.
Diabetes-prone (DP) BB rats develop autoimmune type 1 diabetes spontaneously. At least five loci are linked to disease expression: the major histocompatibility complex (iddm2), two susceptibility loci (iddm4, iddm5), and, possibly, a resistance locus (iddm3). Spontaneous disease also requires homozygosity for lyp/iddm1, which causes lymphopenia. It has not been determined whether lyp/iddm1 is required for predisposition to diabetes autoimmunity in addition to being required for its spontaneous expression. We analyzed backcross rats segregating for diabetes but not lymphopenia using Wistar-Furth (WF) and diabetes-resistant (DR) BB animals. The latter are nonlymphopenic (lyp+/+) and develop diabetes only in response to immunological perturbants. Treatment of (DR-BB x WF)F1 x WF animals (all lyp+/+) using a standard induction protocol caused type 1 diabetes in 58% of progeny. Expression of type 1 diabetes was strongly linked to iddm4. The results suggest that lyp/iddm1 does not determine the predisposition to autoimmunity in BB rats and that iddm4 is a major diabetogenic locus in both DP- and DR-BB animals. The iddm4 gene maps to a region containing several major autoimmunity loci, including aia2, aia3, and cia3. We propose that BB rat diabetes requires 1) class II RT1u (iddm2) for susceptibility, 2) additional loci for disease initiation and progression in response to perturbants, and 3) lyp for spontaneous disease.


Neurophysiological indexes of speech processing deficits in children with specific language impairment.
We used neurophysiological and behavioral measures to examine whether children with specific language impairment (SLI) have deficits in automatic processing of brief, phonetically similar vowels, and whether attention plays a role in such deficits. The neurophysiological measure mismatch negativity (MMN) was used as an index of discrimination in two tasks; one in which children ignored the auditory stimuli and watched a silent video and a second in which they attended to the auditory modality. Children with SLI showed good behavioral discrimination, but significantly poorer behavioral identification of the brief vowels than the children with typical language development (TLD). For the TLD children, two neurophysiological measures (MMN and a later negativity, LN) indexed discrimination of the vowels in both tasks. In contrast, only the LN was elicited in either task for the SLI group. We did not see a direct correspondence between the absence of MMN and poor behavioral performance in the children with SLI. This pattern of findings indicates that children with SLI have speech perception deficiencies, although the underlying cause may vary.


The referential communication skills of children with imaginary companions.
The present study investigated the referential communication skills of children with imaginary companions (ICs). Twenty-two children with ICs aged between 4 and 6 years were compared to 22 children without ICs (NICs). The children were matched for age, gender, birth order, number of siblings, and parental education. All children completed the Test of Referential Communication (Camaioni, Ercolani & Lloyd, 1995). The results showed that the children with ICs performed better than the children without ICs on the speaker component of the task. In particular, the IC children were better able to identify a specific referent to their interlocutor than were the NIC children. Furthermore, the IC children described less redundant features of the target picture than did the NIC children. The children did not differ in the listening comprehension component of the task. Overall, the results suggest that the IC children had a better understanding of their interlocutor's information requirements in conversation. The role of pretend play in the development of communicative competence is discussed in light of these results.


Induction of Regulatory T Cells as a Novel Mechanism Underlying the Therapeutic Action of Kakkonto, a Traditional Japanese Herbal Medicine, in a Murine Food Allergy Model.
The number of patients with food allergy (FA) has dramatically increased. Although satisfactory drug therapies for FA are not available, we have found that kakkonto, a traditional Japanese herbal medicine, suppressed the occurrence of allergic symptoms in an FA mouse model. Thus, we investigated whether kakkonto could regulate the activation and differentiation of T cells in the colon. BALB/c mice were systemically sensitized and then orally challenged with ovalbumin. FA mice were orally treated with kakkonto. Lamina propria (LP) cells from their colons were isolated and analyzed. Kakkonto significantly reduced the proportion of CD69+ cells and the elevated helper T cell type 2-specific transcription factor GATA-3 mRNA expression in the LP CD4+ T cells, showing that kakkonto has a suppressive effect on the activation and Th2 differentiation of LP effector CD4+ T cells of the FA mouse colon. Furthermore, kakkonto significantly increased the proportion of Foxp3+CD4+ regulatory T cells in the LP CD4+ T cells of the FA mouse colon. Similarly, the number of Foxp3-positive cells was dramatically increased in the colonic mucosa of kakkonto-administered FA mice. However, the pharmacological effect and Foxp3+CD4+ regulatory T cell-inducing ability of kakkonto were not attenuated by the administration of an anti-CD25 monoclonal antibody in the FA model. The induction of Foxp3+CD4+CD25- regulatory T cells in the colon as a novel mechanism underlying the therapeutic action of kakkonto could be utilized for the development of a novel anti-FA drug.


Failure of interferon-gamma and tumor necrosis factor in mediating anemia of chronic disease in a mouse model of protracted septic peritonitis.
Interferon-gamma (IFN-gamma) is considered one of the main inflammatory cytokines contributing to the generation of anemia of chronic disease (ACD). In this study, we used a previously described murine model for ACD based on sublethal cecal ligation and puncture (CLP) with ensuing protracted peritonitis. Within 2 weeks after CLP, a moderate normochromic anemia with low serum iron concentration and preserved iron stores develops, which is consistent with ACD. In order to determine whether IFN-gamma contributes to the development of ACD in vivo, we neutralized IFN-gamma after CLP shortly before and during the phase of most severe bone marrow depression in order to prevent anemia. Additionally, we studied IFN-gamma receptor-deficient mice that underwent CLP. Two weeks after CLP, we determined the red blood cell count, hemoglobin concentration, hematocrit, serum iron concentration, and iron stores in spleens of wild-type mice, IFN-gamma receptor-deficient mice, and mice after neutralization of IFN-gamma. Neutralization of IFN-gamma after CLP could not prevent mice from becoming anemic. Accordingly, IFN-gamma receptor-deficient mice developed anemia to the same extent as wild-type mice. Serum iron concentration was lowered both in IFN-gamma receptor-deficient and wild-type mice. Iron stores in untreated IFN-gamma receptor-deficient mice were elevated compared to untreated wild-type mice. After CLP both IFN-gamma receptor-deficient and wild-type mice had equally overloaded iron stores. Additional neutralization of TNF in IFN-gamma receptor-deficient mice also did not attenuate CLP-induced anemia. Our results clearly demonstrate that neither IFN-gamma alone nor in combination with TNF is a mediator of ACD in our model with transient anemia induced by protracted septic peritonitis.


In vitro activities of amphotericin B in combination with four antifungal agents and rifampin against Aspergillus spp.
Strains of Aspergillus fumigatus, Aspergillus flavus, and Aspergillus niger were tested for in vitro susceptibility with a microtiter plate system in buffered yeast-nitrogen base and in buffered minimal essential medium. Isolates were tested against amphotericin B, flucytosine, rifampin, ketoconazole, ICI 153,066, and Bay n 7133 and against combinations of amphotericin B with each of the other five drugs. Combinations of amphotericin B and rifampin were the most active against all three species of Aspergillus. Flucytosine combined with amphotericin B produced little or no reduction of the MICs at which 90% of the strains were inhibited compared with amphotericin B alone. With one exception, the addition of ketoconazole, ICI 153,066, or Bay n 7133 to amphotericin B did not consistently alter the MICs. The addition of ICI 153,066 markedly increased the MICs of amphotericin B against the A. flavus isolates in both media. When the azoles were tested alone, Bay n 7133 was the most active against A. fumigatus, but was two- to fivefold less active against A. flavus. Ketoconazole was the most active azole against A. flavus.


Characterisation of Gas-Chromatographic Poly(Siloxane) Stationary Phases by Theoretical Molecular Descriptors and Prediction of McReynolds Constants.
Retention in gas-liquid chromatography is mainly governed by the extent of intermolecular interactions between the solute and the stationary phase. While molecular descriptors of computational origin are commonly used to encode the effect of the solute structure in quantitative structure-retention relationship (QSRR) approaches, characterisation of stationary phases is historically based on empirical scales, the McReynolds system of phase constants being one of the most popular. In this work, poly(siloxane) stationary phases, which occupy a dominant position in modern gas-liquid chromatography, were characterised by theoretical molecular descriptors. With this aim, the first five McReynolds constants of 29 columns were modelled by multilinear regression (MLR) coupled with genetic algorithm (GA) variable selection applied to the molecular descriptors provided by software Dragon. The generalisation ability of the established GA-MLR models, evaluated by both external prediction and repeated calibration/evaluation splitting, was better than that reported in analogous studies regarding nonpolymeric (molecular) stationary phases. Principal component analysis on the significant molecular descriptors allowed to classify the poly(siloxanes) according to their chemical composition and partitioning properties. Development of QSRR-based models combining molecular descriptors of both solutes and stationary phases, which will be applied to transfer retention data among different columns, is in progress.


Quality of reporting of the literature on gastrointestinal reflux after repair of esophageal atresia-tracheoesophageal fistula.
There is variation in the management of postoperative gastroesophageal reflux (GER) in esophageal atresia-tracheoesophageal fistula (EA-TEF). Well-reported literature is important for clinical decision-making. We assessed the quality of reporting (QOR) of postoperative GER management in EA-TEF. A comprehensive search of MEDLINE, EMBASE, CINHAL, CENTRAL databases and gray literature was conducted. Included articles reported a primary diagnosis of EA-TEF, a secondary diagnosis of postoperative GER, and primary treatment of GER with antireflux medications. The QOR was assessed using the STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) checklist. Retrieval of 2910 articles resulted in 48 relevant articles (N=2592 patients) with an overall quality percentage score of 48%-95% (median=65%). The best reported items were "participants" and "outcome data" (93.8% each), "generalisability" (91.7%) and "background/rationale" (89.6%). Less than 20% of studies provided detailed "main results"; less than 5% of studies reported adequately on "bias" or "funding." Sample size calculation and study limitations were included in 17 (35.4%) and 16 (33.3%) studies respectively. Follow-up time was inconsistently reported. Although the overall QOR is moderate using STROBE, important areas are underreported. Inadequate methodological reporting may lead to inappropriate clinical decisions. Awareness of STROBE, emphasizing proper reporting is needed.


Axon Guidance Molecules Promote Perineural Invasion and Metastasis of Orthotopic Pancreatic Tumors in Mice.
Little is known about mechanisms of perineural invasion (PNI) by pancreatic ductal adenocarcinomas (PDAs) or other tumors. Annexin A2 (ANXA2) regulates secretion of SEMA3D, an axon guidance molecule, which binds and activates the receptor PLXND1 to promote PDA invasion and metastasis. We investigated whether axon guidance molecules promote PNI and metastasis by PDA cells in mice. We performed studies in a dorsal root ganglion (DRG) invasion system, wild-type C57BL/6 mice (controls), mice with peripheral sensory neuron-specific disruption of PlxnD1 (PLAC mice), LSL-KRASG12D/+;LSL-TP53R172H/+;PDX-1-CRE+/+ (KPC) mice, and KPC mice crossed with ANXA2-knockout mice (KPCA mice). PDA cells were isolated from KPC mice and DRG cells were isolated from control mice. Levels of SEMA3D or ANXA2 were knocked down in PDA cells with small hairpin and interfering RNAs and cells were analyzed by immunoblots in migration assays, with DRGs and with or without antibodies against PLXND1. PDA cells were injected into the pancreas of control and PLAC mice, growth of tumors was assessed, and tumor samples were analyzed by histology. DRG cells were incubated with SEMA3D and analyzed by live imaging. We measured levels of SEMA3D and PLXND1 in PDA specimens from patients with PNI and calculated distances between tumor cells and nerves. DRG cells increase the migration of PDC cells in invasion assays; knockdown of SEMA3D in PDA cells or antibody blockade of PLXND1 on DRG cells reduced this invasive activity. In mice, orthotopic tumors grown from PDA cells with knockdown of SEMA3D, and in PLAC mice, orthotopic tumors grown from PDA cells, had reduced innervation and formed fewer metastases than orthotopic tumors grown from PDA cells in control mice. Increased levels of SEMA3D and PLXND1 in human PDA specimens associated with PNI. DRG cells increase the migratory and invasive activities of pancreatic cancer cells, via secretion of SEMA3D by pancreatic cells and activation of PLXND1 on DRGs. Knockdown of SEMA3D and loss of neural PLXND1 reduces innervation of orthotopic PDAs and metastasis in mice. Increased levels of SEMA3D and PLXND1 in human PDA specimens associated with PNI. Strategies to disrupt the axon guidance pathway mediated by SEMA3D and PLXND1 might be developed to slow progression of PDA.


Mechanisms responsible for F-actin stabilization after lysis of polymorphonuclear leukocytes.
While actin polymerization and depolymerization are both essential for cell movement, few studies have focused on actin depolymerization. In vivo, depolymerization can occur exceedingly rapidly and in a spatially defined manner: the F-actin in the lamellipodia depolymerizes in 30 s after chemoattractant removal (Cassimeris, L., H. McNeill, and S. H. Zigmond. 1990. J. Cell Biol. 110:1067-1075). To begin to understand the regulation of F-actin depolymerization, we have examined F-actin depolymerization in lysates of polymorphonuclear leukocytes (PMNs). Surprisingly, much of the cell F-actin, measured with a TRITC-phalloidin-binding assay, was stable after lysis in a physiological salt buffer (0.15 M KCl): approximately 50% of the F-actin did not depolymerize even after 18 h. This stable F-actin included lamellar F-actin which could still be visualized one hour after lysis by staining with TRITC-phalloidin and by EM. We investigated the basis for this stability. In lysates with cell concentrations greater than 10(7) cells/ml, sufficient globular actin (G-actin) was present to result in a net increase in F-actin. However, the F-actin stability was not solely because of the presence of free G-actin since addition of DNase I to the lysate did not increase the F-actin loss. Nor did it appear to be because of barbed end capping factors since cell lysates provided sites for barbed end polymerization of exogenous added actin. The stable F-actin existed in a macromolecular complex that pelleted at low gravitational forces. Increasing the salt concentration of the lysis buffer decreased the amount of F-actin that pelleted at low gravitational forces and increased the amount of F-actin that depolymerized. Various actin-binding and cross-linking proteins such as tropomyosin, alpha-actinin, and actin-binding protein pelleted with the stable F-actin. In addition, we found that alpha-actinin, a filament cross-linking protein, inhibited the rate of pyrenyl F-actin depolymerization. These results suggested that actin cross-linking proteins may contribute to the stability of cellular actin after lysis. The activity of crosslinkers may be regulated in vivo to allow rapid turnover of lamellipodia F-actin.


[The influence of a standardized soybean extract (Glycine max) on the expression level of CYP3A enzymes and pregnane X receptor in in vivo model].
Soybean phytoestrogens, such as genistein and daidzein, have become a popular alternative for women undergoing the treatment of menopause symptoms. These isoflavones are also commonly used in traditional medicine in the prevention and treatment of osteoporosis, cardiovascular diseases and cancer Despite the widespread use of soybean preparations as functional foods and dietary supplements, data regarding the safety as well as interactions between herbal medicines and synthetic drugs, especially with antineoplastic agents, remain scarce. Therefore, the aim of the present study was to determine the influence of soybean extract on the expression levels of CYP3A and PXR genes using real-time PCR (RT-PCR). Male Wistar rats were given a standardized soybean extract (100 mg/kg p.o.) for 3 and 10 days. Total RNA isolated from the liver tissue was transcribed into cDNA. The level of CYP3A 1/2 and PXR mRNAs expression was analyzed by real-time quantitative PCR using SYBR Green I dye. Our findings showed that soybean extract containing 37% isoflavones resulted in a significant decrease of CYP3A1 expression level by almost 35% (p<0.05), both after 3 and 10 days, when compared with the control group. No statistically significant differences were noted for CYP3A2 enzyme and the PXR nuclear factor. These results suggest that soybean extract can decrease the CYP3A1 (homolog to human CYP3A4) expression and may participate in clinically significant interactions with drugs metabolized by CYP3A4 enzyme. Moreover it is postulated that gene expression of CYP3A1 and CYP3A2 (homolog to human CYP3A5) can be regulated indirectly by the PXR transcription factor.


Regeneration of adult rat corticospinal axons induced by transplanted olfactory ensheathing cells.
Precisely localized focal stereotaxic electrolytic lesions were made in the corticospinal tract at the level of the first to second cervical segments in the adult rat. This consistently destroyed all central nervous tissue elements (axons, astrocytes, oligodendrocytes, microglia, and microvessels) in a highly circumscribed area. In a group of these rats immediately after lesioning, a suspension of cultured adult olfactory ensheathing cells was transplanted into the lesion site. Within the first week after transplantation, the cut corticospinal axons (identified by anterograde transport of biotin dextran) extended caudally along the axis of the corticospinal tract as single, fine, minimally branched sprouts that ended in a simple tip, often preceded by a small varicosity. By 3 weeks, the regenerating axons, ensheathed by P0-positive peripheral myelin had accumulated into parallel bundles, which now extended across the full length of the lesioned area and reentered the caudal part of the host corticospinal tract. The transplants contained two main types of cells: (1) p75-expressing S cells, which later formed typical peripheral one-to-one myelin sheaths around individual ensheathed axons, and (2) fibronectin-expressing A cells, which aggregated into tubular sheaths enclosing bundles of myelinated axons. The point of reentry of the axons into the central nervous territory of the caudal host corticospinal tract was marked by the resumption of oligodendrocytic myelination. Thus the effect of the transplant was to form a "patch" of peripheral-type tissue across which the cut central axons regenerated and then continued to grow along their original central pathway.


ITEMAS ontology for healthcare technology innovation.
The Platform for Innovation in Medical and Health Technologies (ITEMAS) is a network of 66 healthcare centres focused on fostering innovation in medical and health technologies as an essential tool for increasing the sustainability of the Spanish healthcare system. The present research is focused on defining a formal representation that details the most relevant concepts associated with the creation and adoption of innovative medical technology in the Spanish healthcare system. The methodology applied is based on the methontology process, including peer-review identification and selection of concepts from the ITEMAS innovation indicators and innovation management system standards. This stage was followed by an iterative validation process. Concepts were then conceptualised, formalised and implemented in an ontology. The ontology defined describes how relationships between employees, organisations, projects and ideas can be applied to generate results that are transferrable to the market, general public and scientific forums. Overall, we identified 136 concepts, 138 object properties and 30 properties in a five-level hierarchy. The ontology was tested and validated as an appropriate framework for calculating the ITEMAS innovation indicators. The consensus concepts were expressed in the form of an ontology to be used as a single communication format between the members of the ITEMAS network. Healthcare centres can compare their innovation results and obtain a better understanding of their innovation context based on the reasoning techniques of artificial intelligence. As a result, they can benefit from advanced analytical capabilities to define the most appropriate innovation policies for each centre based on the common experience of the large number of healthcare centres involved. The results can be used to create a map of agents and knowledge to show capabilities, projects and services provided by each of the participating centres. The ontology could also be applied as an instrument to match needs with existing projects and capabilities from the community of organisations working in healthcare technology innovation.


Mysteries of TGF-β Paradox in Benign and Malignant Cells.
TGF-β regulates a wide range of biological functions including embryonic development, wound healing, organogenesis, immune modulation, and cancer progression. Interestingly, TGF-β is known to inhibit cell growth in benign cells but promote progression in cancer cells; this phenomenon is known as TGF-β paradox. To date, the mechanism of this paradox still remains a scientific mystery. In this review, we present our experience, along with the literature, in an attempt to answer this mystery. First, we observed that, on TGF-β engagement, there is a differential activation of Erk between benign and cancer cells. Since activated Erk is a major mediator in tumor progression and metastasis, a differentially activated Erk represents the answer to this mystery. Second, we identified a key player, PP2A-B56α, which is differentially recruited by the activated type I TGF-β receptor (TBRI) in benign and tumor cells, resulting in differential Erk activation. Finally, TGF-β stimulation leads to suppressed TBRs in tumor cells but not in benign cells. This differentially suppressed TBRs triggers differential recruitment of PP2A-B56α and, thus, differential activation of Erk. The above three events explain the mysteries of TGF-β paradox. Understanding the mechanism of TGF-β paradox will help us to predict indolent from aggressive cancers and develop novel anti-cancer strategies.


Segregation of male-sterility alleles across a species boundary.
Hybrid zones may serve as bridges permitting gene flow between species, including alleles influencing the evolution of breeding systems. Using greenhouse crosses, we assessed the likelihood that a hybrid zone could serve as a conduit for transfer of nuclear male-sterility alleles between a gynodioecious species and a hermaphroditic species with very rare females in some populations. Segregation patterns in progeny of crosses between rare females of hermaphroditic Schiedea menziesii and hermaphroditic plants of gynodioecious Schiedea salicaria heterozygous at the male-sterility locus, and between female S. salicaria and hermaphroditic plants from the hybrid zone, were used to determine whether male-sterility was controlled at the same locus in the parental species and the hybrid zone. Segregations of females and hermaphrodites in approximately equal ratios from many of the crosses indicate that the same nuclear male-sterility allele occurs in the parent species and the hybrid zone. These rare male-sterility alleles in S. menziesii may result from gene flow from S. salicaria through the hybrid zone, presumably facilitated by wind pollination in S. salicaria. Alternatively, rare male-sterility alleles might result from a reversal from gynodioecy to hermaphroditism in S. menziesii, or possibly de novo evolution of male sterility. Phylogenetic analysis indicates that some species of Schiedea have probably evolved separate sexes independently, but not in the lineage containing S. salicaria and S. menziesii. High levels of selfing and expression of strong inbreeding depression in S. menziesii, which together should favour females in populations, argue against a reversal from gynodioecy to hermaphroditism in S. menziesii.


Late complications and quality of life after atrial correction of transposition of the great arteries in 12 to 18 year follow-up.
Most adolescents and young adults born with transposition of the great arteries and survivors of Mustard operation are alive today and are leading ordinary lives. How far is the quality of their life influenced by residual findings? We have analysed the oldest group of 177 children operated on with the Mustard procedure during 1979-1984 from our total experience of 609 corrections of transposition of the great arteries until 1996. In the long-term follow-up 12 to 18 years after Mustard operation the clinical investigation, 24 hours ECG Holter monitoring, 2D and colour flow Doppler echocardiography, radionuclide angiocardiography and exercise testing were performed. Basic sinus rhythm had 61% of 137 survivors, sinus node dysfunction had 51%. All but 4 patients needed no antiarrhythmic therapy. There were 10 sudden deaths. Severe tricuspid valve regurgitation developed in 15.9% of children, and decreased to 6% after intensive medical treatment. The right ventricular systolic dysfunction was found on radionuclide ventriculography in 8% of children after surgery. The left ventricular ejection fraction was subnormal in 10% and left ventricular diastolic function expressed by rapid filling fraction was subnormal in 80% of patients and may cause inability to increase cardiac output at exercise The obstruction of caval veins was found in 9%. There were neurological complications in 13.3% (10% already preoperatively) but severe brain damage was found in 4.4% only. Exercise tolerance with the maximum oxygen consumption over 30 ml/kg/min in 96% of investigated children suggests the good ability and full efficiency for recreation sports. Most survivors (84%) are reported to lead ordinary lives and function in NYHA class I.


Tumor-targeted Salmonella. Highly selective delivery vectors.
Genetically engineered Salmonella offer an intriguing new approach to selectively target solid tumors, including melanoma, lung, colon, breast, kidney and liver. These bacteria target tumors after systemic administration and selectively replicate within them. Specificity for tumors is often more than 1,000 times greater than for any other tissue. Auxotrophic mutations make these bacteria highly safe and form the basis for maintaining tumor specificity. An altered lipid greatly reduces the potential for septic shock yet also retains the antitumor properties of these bacteria. These bacteria have innate antitumor activity towards both primary and metastatic tumors and the ability to deliver proteins capable of activating chemotherapeutic agents directly within tumors. The delay in tumor growth results in mice that survive up to twice as long. These bacteria are susceptible to a wide range of antibiotics, allowing external control of the vector after administration. The combination of these features within a single vector seems specially surprising considering their unlikely source.


Expanded consumer niche widths may signal an early response to spatial protection.
Marine management interventions are increasingly being implemented with the explicit goal of rebuilding ocean ecosystems, but early responses may begin with alterations in ecological interactions preceding detectable changes in population-level characteristics. To establish a baseline from which to monitor the effects of spatial protection on reef fish trophic ecology and track future ecosystem-level changes, we quantified temperate reef fish densities, size, biomass, diets and isotopic signatures at nine sites nested within two fished and one five-year old marine protected area (MPA) on the northwest coast of Canada. We calculated rockfish (Sebastes spp.) community and species-specific niche breadth for fished and protected areas based on δ13C and δ15N values. We found that rockfish community niche width was greater inside the MPA relative to adjacent fished reefs due to an expanded nitrogen range, possibly reflecting early changes in trophic interactions following five years of spatial protection. Our data also demonstrated that the MPA had a positive effect on the δ15N signature of rockfish (i.e., trophic position), but the effect of rockfish length on its own was not well-supported. In addition, we found a positive interaction between rockfish length and δ15N signature, such that δ15N signatures of rockfish caught within the MPA increased more rapidly with body size than those caught in fished areas. Differences in rockfish size structure and biomass among fished and unfished areas were not clearly evident. Species of rockfish and lingcod varied in trophic and size responses, indicating that life-history traits play an important role in predicting MPA effects. These results may suggest early changes in trophic behavior of slow-growing rockfish due to predation risk by faster growing higher trophic level predators such as lingcod inside MPAs established on temperate reefs. Consequently, spatial protection may restore both the trophic and behavioral roles of previously fished consumers earlier and in measurable ways sooner than observable changes in abundance and size.


Accumulation of Pollutants in Proglacial Lake Sediments: Impacts of Glacial Meltwater and Anthropogenic Activities.
With global warming, the melting of glaciers can result in the release of pollutants into the environment. For remote Alpine lakes, both atmosphere-deposited anthropogenic pollutants and glacier-released pollutants can eventually sink in the sediment. To date, there has, to the best of our knowledge, been no attempt at quantifying the contributions of these processes to the accumulation of pollutants in glacial lake sediment. To fill this gap, a semi-enclosed proglacial lake located in the southern Tibetan Plateau was chosen and a 28 cm sediment core, which can be dated back to 1836, was used to explore the temporal trends of trace elements, Hg, and black carbon (BC) during the past two centuries. Geochemical indicators (Rb/Sr, Ti-Zr-Hf, and sedimentary rate) in sediment showed an overall continuous warming of the lake, while the temporal trends of fluxes of toxic elements and BC were broadly associated with their emission patterns. By using a positive matrix factorization model, the contribution of the anthropogenic source rose from <10% in the 1850s to >40% after the 1980s. However, the signal of glacial meltwater release was also distinct, and the greatest contribution of ice-snow meltwater reached up to 61% in the 1950s. Regarding the most recent two decades, 90% of pollutant deposition in the Tibetan sediment can be attributed to the combined forces of primary emissions and glacial release.


Sleeve gastrectomy relieves steatohepatitis in high-fat-diet-induced obese rats.
Sleeve gastrectomy is thought to decrease the appetite and body weight of morbid obesity patients in the clinic. The purpose is to investigate the effect of sleeve gastrectomy on preventing steatohepatitis in morbid obesity rats. Thirty rats were randomized into normal chow group (NC), high-fat-diet group (HD), and sleeve group (SG). Rats in the SG group received sleeve gastrectomy operation. After operation, rats in SG and HD group received a high-fat diet, while rats in the NC group received normal chow. Body weight was measured every 10 days. Thirty days later, animals were sacrificed and blood samples were collected to check total cholesterol, HDL, and triglyceride. Fresh liver sections were made and stained with Nile red and observed under a fluorescence microscope. Rats in the SG group received a moderate body weight decrease (191 +/- 16.2 g) in the first 10 days, while this did not happen in the other two groups (213 +/- 13.7 g and 243 +/- 11.9 g). At the sacrifice date, weight of rats in the SG group was still much lower than those in the HD group. Plasma triglycerol (102.3 +/- 18.6 mg/dL) and cholesterol (84.3 +/- 6.1 mg/dL) of rats in the SG group were much lower than those in the HD group (198.5 +/- 18.5 mg/dL, 133.9 +/- 22.0 mg/dL). Under the fluorescence microscope, adipose infiltration was very obvious in the liver of the HD animals, while adipose infiltration was not serious in the SG group. High-fat diet can result in obvious body weight increase and hepatic adipose infiltration compared with normal chow. Sleeve gastrectomy can decrease body weight even in high-fat-diet models. Body weight control caused by sleeve gastrectomy can relieve high-fat-diet-induced steatohepatitis in rats.


Ultrasound imaging of a scar on the knee: Sonopalpation for fascia and subcutaneous tissues.
Persistent scar pain associated with healed surgical incisions after a trauma is a common and potentially debilitating type of fascial pain. At present, there is no universally effective treatment for persistent surgical or post-trauma scar pain. Herein we describe the successful objective diagnosis of debilitating scar pain by Ultrasound (US) imaging. The sonopalpation of the fasciae and subcutaneous tissues seems to be relevant to diagnose the real cause of the pain and why not to monitor the treatment.


Modulation of NADH Levels by Arabidopsis Nudix Hydrolases, AtNUDX6 and 7, and the Respective Proteins Themselves Play Distinct Roles in the Regulation of Various Cellular Responses Involved in Biotic/Abiotic Stresses.
Arabidopsis Nudix hydrolases, AtNUDX6 and 7, exhibit pyrophosphohydrolase activities toward NADH and contribute to the modulation of various defense responses, such as the poly(ADP-ribosyl)ation (PAR) reaction and salicylic acid (SA)-induced Nonexpresser of Pathogenesis-Related genes 1 (NPR1)-dependent defense pathway, against biotic and abiotic stresses. However, the mechanisms by which these enzymes regulate such cellular responses remain unclear. To clarify the functional role(s) of AtNUDX6 and 7 and NADH metabolism, we examined the effects of the transient expression of the active and inactive forms of AtNUDX6 and 7 under the control of an estrogen (ES)-inducible system on various stress responses. The transient expression of active AtNUDX6 and 7 proteins suppressed NADH levels and induced PAR activity, whereas that of their inactive forms did not, indicating the involvement of NADH metabolism in the regulation of the PAR reaction. A transcriptome analysis using KO-nudx6, KO-nudx7 and double KO-nudx6/7 plants, in which intracellular NADH levels increased, identified genes (NADH-responsive genes, NRGs) whose expression levels positively and negatively correlated with NADH levels. Many NRGs did not overlap with the genes whose expression was reported to be responsive to various types of oxidants and reductants, suggesting a novel role for intracellular NADH levels as a redox signaling cue. The active and inactive AtNUDX6 proteins induced the expression of thioredoxin-h5, the activator of NPR1 and SA-induced NPR1-dependent defense genes, while the active and inactive AtNUDX7 proteins suppressed the accumulation of SA and subsequent gene expression, indicating that AtNUDX6 and 7 proteins themselves play distinct roles in stress responses.


Do regular check ups and preventive drug use reduce asthma severity in school children?
To investigate whether regular check ups and preventive drug use reduce asthma symptoms in school children. Cross sectional retrospective questionnaire responses obtained from 2193 children aged 6-7 years in 34 primary schools, and 3650 children aged 13-14 years in nine secondary schools, selected at random by cluster sampling. Asthma severity in the past 12 months as measured by the number of attacks of wheezing, visits to a doctor, visits to a hospital emergency department, and hospital admissions, all for wheezing or asthma. Multivariate ordinal logistic regression. Regular general practitioner check ups were associated with reduced asthma severity. Regular use of prophylactic and bronchodilator medications was associated with reduced symptoms. Asthma action plans and peak flow meter usage were associated with reduced hospital admissions. If these associations are causal, then regular GP check ups are effective in reducing the health consequences of asthma in children.


Efficient Monte Carlo modelling of individual tumour cell propagation for hypoxic head and neck cancer.
A Monte Carlo tumour model has been developed to simulate tumour cell propagation for head and neck squamous cell carcinoma. The model aims to eventually provide a radiobiological tool for radiation oncology clinicians to plan patient treatment schedules based on properties of the individual tumour. The inclusion of an oxygen distribution amongst the tumour cells enables the model to incorporate hypoxia and other associated parameters, which affect tumour growth. The object oriented program FORTRAN 95 has been used to create the model algorithm, with Monte Carlo methods being employed to randomly assign many of the cell parameters from probability distributions. Hypoxia has been implemented through random assignment of partial oxygen pressure values to individual cells during tumour growth, based on in vivo Eppendorf probe experimental data. The accumulation of up to 10 million virtual tumour cells in 15 min of computer running time has been achieved. The stem cell percentage and the degree of hypoxia are the parameters which most influence the final tumour growth rate. For a tumour with a doubling time of 40 days, the final stem cell percentage is approximately 1% of the total cell population. The effect of hypoxia on the tumour growth rate is significant. Using a hypoxia induced cell quiescence limit which affects 50% of cells with and oxygen levels less than 1 mm Hg, the tumour doubling time increases to over 200 days and the time of tumour growth for a clinically detectable tumour (10(9) cells) increases from 3 to 8 years. A biologically plausible Monte Carlo model of hypoxic head and neck squamous cell carcinoma tumour growth has been developed for real time assessment of the effects of multiple biological parameters which impact upon the response of the individual patient to fractionated radiotherapy.


Bullying victimisation, self harm and associated factors in Irish adolescent boys.
School bullying victimisation is associated with poor mental health and self harm. However, little is known about the lifestyle factors and negative life events associated with victimisation, or the factors associated with self harm among boys who experience bullying. The objectives of the study were to examine the prevalence of bullying in Irish adolescent boys, the association between bullying and a broad range of risk factors among boys, and factors associated with self harm among bullied boys and their non-bullied peers. Analyses were based on the data of the Irish centre of the Child and Adolescent Self Harm in Europe (CASE) study (boys n = 1870). Information was obtained on demographic factors, school bullying, deliberate self harm and psychological and lifestyle factors including negative life events. In total 363 boys (19.4%) reported having been a victim of school bullying at some point in their lives. The odds ratio of lifetime self harm was four times higher for boys who had been bullied than those without this experience. The factors that remained in the multivariate logistic regression model for lifetime history of bullying victimisation among boys were serious physical abuse and self esteem. Factors associated with self harm among bullied boys included psychological factors, problems with schoolwork, worries about sexual orientation and physical abuse, while family support was protective against self harm. Our findings highlight the mental health problems associated with victimisation, underlining the importance of anti-bullying policies in schools. Factors associated with self harm among boys who have been bullied should be taken into account in the identification of boys at risk of self harm.


Comparison of the structure and composition of bacterial communities from temperate and tropical freshwater ecosystems.
We used a partial 16S rRNA sequencing approach to compare the structure and composition of the bacterial communities in three large, deep subalpine lakes in France with those of communities in six shallow tropical reservoirs in Burkina Faso. Despite the very different characteristics of these ecosystems, we found that their bacterial communities share the same composition in regard to the relative proportions of the different phyla, suggesting that freshwater environmental conditions lead to convergence in this composition. In the same way, we found no significant difference in the richness and diversity of the bacterial communities in France and Burkina Faso. We defined core and satellite operational taxonomic units (OTUs) (sequences sharing at least 98% identity) on the basis of their abundance and their geographical distribution. The core OTUs were found either ubiquitously or only in temperate or tropical and subtropical areas, and they contained more than 70% of all the sequences retrieved in this study. In contrast, satellite OTUs were characterized by having a more restricted geographical distribution and by lower abundance. Finally, the bacterial community composition of these freshwater ecosystems in France and Burkina Faso was markedly different, showing that the history of these ecosystems and regional environmental parameters have a greater impact on the relative abundances of the different OTUs in each bacterial community than the local environmental conditions.


Therapy of spinal wound infections using vacuum-assisted wound closure: risk factors leading to resistance to treatment.
This study retrospectively reviewed spine surgical procedures complicated by wound infection and managed by a protocol including the use of vacuum-assisted wound closure (VAC). To define factors influencing the number of debridements needed before the final wound closure by applying VAC for patients with postoperative spinal wound infections. VAC has been suggested as a safe and probably effective method for the treatment of spinal wound infections. The risk factors for infection resistance and need for debridement revisions after VAC placement are unknown. Seventy-three consecutive patients with 79 wound infections after undergoing spine surgery were studied (6 of them had recurrence of infection). All patients were taken to the operating room for irrigation and debridement under general anesthesia followed by placement of the VAC with subsequent delayed closure of the wound. Linear regression and t test were used to identify if the following variables were risk factors for the resistance of infection to VAC treatment: timing of clinical appearance of infection, depth of infection (deep or superficial), presence of instrumentation, positive culture for methicillin-resistant Staphylococcus aureus (MRSA) or more than 1 microorganism, age of the patient, and presence of other comorbidities. There were 34 males and 39 females with an average age of 58.4 years (21 to 82). Once the VAC was initiated, there was an average of 1.4 procedures until and including closure of the wound. The wound was closed an average of 7 days (range 5 to 14) after the placement of the initial VAC on the wound. The average follow-up was 14 months (range 12 to 28). All of the patients but 2 achieved a clean, closed wound without removal of instrumentation at a minimum follow-up of 1 year. Sixty patients had implants (instrumentation or allograft) within the site of wound infection. Thirteen patients had a decompression with exposed dura. Sixty-four infections (81%) presented with a draining wound within the first 6 weeks postoperatively. Sixty-nine infections (87.3%) were deep below the fascia. There was no statistical significance (P>0.05) of all tested risk factors for the resistance of infection to treatment with the VAC system. The parameter more related to repeat VAC procedures was the culture of MRSA or multiple bacteria. VAC therapy may be an effective adjunct in closing spinal wounds even after the repeat procedures. The MRSA or multibacterial infections seem to be most likely to need repeat debridements and VAC treatment before final wound closure.


Nrf2 is not required for epithelial prohibitin-dependent attenuation of experimental colitis.
Inflammatory bowel disease is associated with increased reactive oxygen species (ROS) and decreased antioxidant response in the intestinal mucosa. Expression of the mitochondrial protein prohibitin (PHB) is also decreased during intestinal inflammation. Our previous study showed that genetic restoration of colonic epithelial PHB expression [villin-PHB transgenic (PHB Tg) mice] attenuated dextran sodium sulfate (DSS)-induced colitis/oxidative stress and sustained expression of colonic nuclear factor erythroid 2-related factor 2 (Nrf2), a cytoprotective transcription factor. This study investigated the role of Nrf2 in mediating PHB-induced protection against colitis and expression of the antioxidant response element (ARE)-regulated antioxidant genes heme oxygenase-1 (HO-1) and NAD(P)H quinone oxidoreductase-1 (NQO-1). PHB-transfected Caco-2-BBE human intestinal epithelial cells maintained increased ARE activation and decreased intracellular ROS levels compared with control vector-transfected cells during Nrf2 knockdown by small interfering RNA. Treatment with the ERK inhibitor PD-98059 decreased PHB-induced ARE activation, suggesting that ERK constitutes a significant portion of PHB-mediated ARE activation in Caco-2-BBE cells. PHB Tg, Nrf2(-/-), and PHB Tg/Nrf2(-/-) mice were treated with DSS or 2,4,6-trinitrobenzene sulfonic acid (TNBS), and inflammation and expression of HO-1 and NQO-1 were assessed. PHB Tg/Nrf2(-/-) mice mimicked PHB Tg mice, with attenuated DSS- or TNBS-induced colitis and induction of colonic HO-1 and NQO-1 expression, despite deletion of Nrf2. PHB Tg/Nrf2(-/-) mice exhibited increased activation of ERK during colitis. Our results suggest that maintaining expression of intestinal epithelial cell PHB, which is decreased during colitis, reduces the severity of inflammation and increases colonic levels of the antioxidants HO-1 and NQO-1 via a mechanism independent of Nrf2.


Size and performance of anoxic limestone drains to neutralize acidic mine drainage.
Acidic mine drainage (AMD) can be neutralized effectively in underground, anoxic limestone drains (ALDs). Owing to reaction between the AMD and limestone (CaCO3), the pH and concentrations of alkalinity and calcium increase asymptotically with detention time in the ALD, while concentrations of sulfate, ferrous iron, and manganese typically are unaffected. This paper introduces a method to predict the alkalinity produced within an ALD and to estimate the mass of limestone required for its construction on the basis of data from short-term, closed-container (cubitainer) tests. The cubitainer tests, which used an initial mass of 4 kg crushed limestone completely inundated with 2.8 L AMD, were conducted for 11 to 16 d and provided estimates for the initial and maximum alkalinities and corresponding rates of alkalinity production and limestone dissolution. Long-term (5-11 yr) data for alkalinity and CaCO3 flux at the Howe Bridge, Morrison, and Buck Mountain ALDs in Pennsylvania, USA, indicate that rates of alkalinity production and limestone dissolution under field conditions were comparable with those in cubitainers filled with limestone and AMD from each site. The alkalinity of effluent and intermediate samples along the flow path through the ALDs and long-term trends in the residual mass of limestone and the effluent alkalinity were estimated as a function of the computed detention time within the ALD and second-order dissolution rate models for cubitainer tests. Thus, cubitainer tests can be a useful tool for designing ALDs and predicting their performance.


Update and clinical utility of alcaftadine ophthalmic solution 0.25% in the treatment of allergic conjunctivitis.
Allergic disorders of the ocular surface are primarily characterized as IgE- and/or T-lymphocyte-mediated disorders that affect the cornea, conjunctiva, and eyelid. Approximately 40% of individuals in the developed countries have allergic conjunctivitis, and as such, it is the most common form of ocular allergy. Seasonal allergic conjunctivitis is the most prevalent type of allergic conjunctivitis that impacts the quality of life of patients. This article reviews the pharmacology, pharmacodynamics, pharmacokinetics, clinical trials, clinical efficacy, and safety of alcaftadine. Histamine and the pathological mechanism of ocular allergy will be briefly reviewed with the intent of providing a background for the detailed discussion on the clinical utility of alcaftadine in allergic conjunctivitis. The Medline PubMed, Elsevier Science Direct, and Google Scholar databases were used to search for evidence-based literature on histamine and immunopathological mechanism of allergic conjunctivitis, as well as on pharmacology, pharmacodynamics, pharmacokinetics, clinical trials, and clinical efficacy of alcaftadine. The treatment and management goals of allergic conjunctivitis are to prevent or minimize the inflammatory cascade associated with allergic response in the early stages of the pathological mechanism. It is of note that activation of histamine receptors on immune and nonimmune cells are associated with allergen-induced inflammation of the conjunctiva and its associated ocular allergic manifestations, including itching, edema, hyperemia, and tearing. Alcaftadine is an efficacious multiple action antiallergic therapeutic agent with inverse agonist activity on H1, H2, and H4 receptors, as well as anti-inflammatory and mast cell stabilizing effects that could provide therapeutic benefits to patients with allergic conjunctivitis.