A prospective study of the synergistic effects of arsenic exposure and smoking, sun exposure, fertilizer use, and pesticide use on risk of premalignant skin lesions in Bangladeshi men.
Skin lesions are classic clinical signs of toxicity due to long-term exposure to arsenic, and they are considered precursors to arsenic-related skin cancer. The authors prospectively evaluated synergisms between effects of arsenic exposure and those of tobacco use, sun exposure, and pesticide and fertilizer use on incident skin lesions using risk factor data from 5,042 men from the Health Effects of Arsenic Longitudinal Study in Araihazar, Bangladesh, which recruited participants from October 2000 to May 2002. Discrete time hazard models were used to estimate measures of synergistic interactions on the additive scale. The authors observed significant synergistic effects between various measures of arsenic exposure and smoking and fertilizer use. The relative excess risks for the interactions between smoking status and arsenic exposure were 0.12 (95% confidence interval: 0.06, 0.19) for water arsenic and 0.11 (95% confidence interval: 0.05, 0.15) for urinary arsenic measures, respectively. Significant synergistic effects were also observed between fertilizer use and water arsenic (relative excess risk for the interaction = 0.06, 95% confidence interval: 0.01, 0.12). This is the first prospective study based on individual-level data that supports a role for smoking and certain occupational risk factors in modification of the effect of long-term arsenic exposure on skin lesions. Understanding differential arsenic susceptibility allows researchers to develop interventions to prevent the health consequences of this massive problem in the Bangladeshi population and beyond.


Child with idiopathic pulmonary hemosiderosis: a case report from Pakistan with multiple ethical and moral issues.
This report discusses the case of a young Pakistani child diagnosed with idiopathic pulmonary hemosiderosis (IPH). The key features of IPH were iron deficiency anemia and pulmonary symptoms due to recurrent pulmonary hemorrhages. The child showed complications of the disease process because of late diagnosis. Because various ethical and moral issues were associated with the diagnosis and management of IPH, this case provides insights about the care burden of health care professionals and a child's parents in a Pakistani pediatric setting. During the course of the child's treatment at one of the private tertiary care settings of Karachi, Pakistan, the key challenges were as follows: declaring the diagnosis to the parents, dealing with the request of the child's parents for withdrawal of ventilatory support and withholding treatment, deciding the code status of the child, and ensuring the quality of the child's life after discharge from the hospital. It was learned from this case report that shared decision making and open communication with the child's family enabled the pediatric health care professionals to determine what was in the best interest of the child, resulting in provision of effective palliative care to the child. Moreover, it was realized that early detection of the disease and availability of hospice care can facilitate palliative care of children diagnosed with IPH.


Long-term agricultural management does not alter the evolution of a soybean-rhizobium mutualism.
Leguminous crops, like soybeans, often rely on biologically fixed nitrogen via their symbiosis with rhizobia rather than synthetic nitrogen inputs. However, agricultural management practices may influence the effectiveness of biological nitrogen fixation (BNF). While the ecological effects of agricultural management on rhizobia have received some attention, the evolutionary effects have been neglected in comparison. Resource mutualism theory predicts that evolutionary effects are likely, however. Both fertilization and tillage are predicted to cause the evolution of rhizobia that provide fewer growth benefits to plant hosts and fix less nitrogen. This study capitalized on a Long-Term Ecological Research experiment that manipulated agricultural management practices in a corn-soybean-wheat row crop system for 24 yr to investigate whether four different management practices (conventional, no-till, low chemical input, and certified organic) cause rhizobia populations to evolve to become more or less cooperative. We found little evidence that 24 yr of varying management practices affect the net growth benefits rhizobia provide to soybeans, although soybean plants inoculated with soils collected from conventional treatments tended to have lower BNF rates than plants inoculated with soils from the no-till, low input, and organic management treatments. These findings suggest that rhizobia will continue to provide adequate growth benefits to leguminous crops in the future, even in intensively managed systems.


Toward a manifesto for the 'public understanding of big data'.
In this article, we sketch a 'manifesto' for the 'public understanding of big data'. On the one hand, this entails such public understanding of science and public engagement with science and technology-tinged questions as follows: How, when and where are people exposed to, or do they engage with, big data? Who are regarded as big data's trustworthy sources, or credible commentators and critics? What are the mechanisms by which big data systems are opened to public scrutiny? On the other hand, big data generate many challenges for public understanding of science and public engagement with science and technology: How do we address publics that are simultaneously the informant, the informed and the information of big data? What counts as understanding of, or engagement with, big data, when big data themselves are multiplying, fluid and recursive? As part of our manifesto, we propose a range of empirical, conceptual and methodological exhortations. We also provide Appendix 1 that outlines three novel methods for addressing some of the issues raised in the article.


The effects of growth factors on the survival and differentiation of cultured dentate gyrus neurons.
Dentate granule cells (DGCs) are the principal cell population of the hippocampal dentate gyrus, and granule cells provide the main excitation to the hippocampus proper via their mossy fibers axons. Although it is well established that granule cells express various growth factors and growth factor receptors, the functional effects of growth factors on the normal development and response to injury of granule cells are relatively unknown. To address this question, primary cultures enriched in DGCs were prepared by microdissecting hippocampal slices from neonatal rats and growing dissociated cells in defined media with added nerve growth factor, brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), neurotrophin-4/5 (NT4/5), ciliary neurotrophic factor, basic fibroblast growth factor (bFGF), or vehicle. The effects on cell survival and morphology were quantified by studying neuron-specific enolase-immunostained cells at various time points, plating densities, host ages, and growth factor concentrations. BDNF or bFGF significantly increased both neuronal survival and differentiation by 30-80% compared with control cultures. Maximal effects were observed at relatively longer time points (5-12 d), with younger cells (postnatal day 3-5) and at lowest plating densities. Addition of a trkB-IgG fusion protein that blocks the activity of BDNF or NT4/5 inhibited the effects of BDNF and attenuated the differentiation of cells cultured at high plating densities. Furthermore, treatment of cultures with the kinase inhibitor K252b specifically blocked the effects of BDNF, suggesting involvement of trkB (the high-affinity BDNF receptor) in BDNF-induced differentiation. These results show that growth properties of cultured neonatal DGCs are influenced by exogenously applied BDNF or bFGF in a time-, age-, and density-dependent manner. The effect of plating density suggests an endogenous expression of growth factors in these culture conditions, and this is mediated in part by endogenous BDNF acting via a tyrosine kinase receptor. Combined with previous work showing that various growth factors and their receptors are expressed by DGCs, these findings provide strong support for the hypothesis that BDNF and bFGF influence both the growth and development of DGCs in vivo.


Are survey-based estimates of the burden of drug resistant TB too low? Insight from a simulation study.
The emergence of tuberculosis resistant to multiple first- and second-line antibiotics poses challenges to a global control strategy that relies on standard drug treatment regimens. Highly drug-resistant strains of Mycobacterium tuberculosis have been implicated in outbreaks and have been found throughout the world; a comprehensive understanding the magnitude of this threat requires an accurate assessment of the worldwide burden of resistance. Unfortunately, in many settings where resistance is emerging, laboratory capacity is limited and estimates of the burden of resistance are obtained by performing drug sensitivity testing on a sample of incident cases rather than through the use of routine surveillance. Using an individual-based dynamic tuberculosis model to simulate surveillance strategies for drug resistance, we found that current surveys may underestimate the total burden of resistant tuberculosis because cases of acquired resistance are undercounted and resistance among prevalent cases is not assessed. We explored how this bias is affected by the maturity of the epidemic and by the introduction of interventions that target the emergence and spread of resistant tuberculosis. Estimates of drug resistant tuberculosis based on samples of incident cases should be viewed as a lower bound of the total burden of resistance.


Hybrid life cycle assessment of agro-industrial wastewater valorisation.
Wastewater from food processing facilities can have high nutrient valorisation potential. Valorising sugar-rich agro-industrial wastewater may have significant impacts on sustainability of wastewater treatment plant (WWTP). The objective of this study is to evaluate the environmental, economic and social impacts of a novel wastewater valorisation technology. This technology is designed to produce single cell protein (SCP) from wastewater of a fruit juice processing facility. To evaluate the comprehensive sustainability impacts on WWTP and overall background economy, a hybrid life cycle assessment model was developed by combining the multi-regional input-output database (Exiobase) with process-based life cycle inventories of conventional and AgroCycle WWTP. The results indicated the upstream impacts of wastewater could have significant influence on sustainability of WWTP with nutrient valorisation. Therefore the 'zero burden assumption' should not be adopted for upstream wastewater. For the sustainability performance, valorising nutrients from WWTP with AgroCycle technology can improve the environmental performance of WWTP. However, the positive social-economic impacts were directly associated with WWTP system, not the whole background economy. The production of SCP could reduce the Gross Value Added (GVA) and employment in the 'oil seeds sector'. In order to improve the social-economic impacts and promote a circular bioeconomy model in the fruit juice sector, further development is required to improve valorisation productivity and create a better value chain for valorised products.


Vitamin A and retinoid derivatives for lung cancer: a systematic review and meta analysis.
Despite reported antiproliferative activity of vitamin A and its common use for cancer, there is no comprehensive synthesis of its safety and efficacy in lung cancers. To address this issue we conducted a systematic review of the safety and efficacy of vitamin A for the treatment and prevention of lung cancers. Two independent reviewers searched six electronic databases from inception to July 2009 for clinical, observational, and preclinical evidence pertaining to the safety and efficacy of vitamin A and related retinoids for lung cancers. 248 studies were included for full review and analysis. Five RCTs assessed treatment of lung cancers, three assessed primary prevention, and three looked at secondary prevention of lung cancers. Five surrogate studies, 26 phase I/II, 32 observational, and 67 preclinical studies were also included. 107 studies were included for interactions between vitamin A and chemo- or radiation-therapy. Although some studies demonstrated benefits, there was insufficient evidence overall to support the use of vitamin A or related retinoids for the treatment or prevention of lung cancers. Retinyl palmitate combined with beta carotene increased risk of lung cancer in smokers in the large CARET trial. Pooling of three studies pertaining to treatment and three studies on secondary prevention revealed no significant effects on response rate, second primary tumor, recurrence, 5-year survival, and mortality. There was a small improvement in event free survival associated with vitamin A compared to controls, RR 1.24 (95% CI 1.13-1.35). The synthetic rexinoid bexarotene increased survival significantly among a subset of patients in two RCTs (p<0.014, <0.087). There is a lack of evidence to support the use of naturally occurring retinoids for the treatment and prevention of lung cancers. The rexinoid bexarotene may hold promise for use among a subset of patients, and deserves further study.


Lung and respiratory muscle function in limb girdle muscular dystrophy.
Pulmonary involvement is frequently observed in patients with limb girdle muscular dystrophy and occurs early in the disease. The aim of this study was to establish the prevalence of pulmonary dysfunction; the type of dysfunction; and any correlation between patient age, disease duration, or limb weakness and lung or respiratory muscle dysfunction. Twenty patients with strictly delineated limb girdle muscular dystrophy and 20 healthy controls were evaluated. Full inspiration chest radiographs were obtained. Standard lung and respiratory muscle function tests were performed and the data were statistically analysed. The mean age of the patients was 40.6 years, the mean disease duration was 18.9 years, and the mean average muscle score (a numerical expression of limb weakness) was 5.73 out of 10. Chest radiography showed unilateral paresis of the diaphragm in three patients. Increased residual volumes, with either increased or decreased total lung capacity, correlated inversely with disease duration. Respiratory muscle weakness was common but mild. Expiratory muscle function was more impaired than inspiratory muscle function and correlated positively with expiratory reserve volume. Respiratory muscle strength is commonly impaired in limb girdle muscle dystrophy. A dissociation of the limb and mild respiratory muscle involvement is observed; wheelchair restriction does not predict worsening of pulmonary function, and patient age, disease duration, or degree of limb weakness do not predict pulmonary morbidity. The diaphragm is not disproportionately affected by the dystrophic process compared with limb muscles.


WAY-100635, a potent and selective 5-hydroxytryptamine1A antagonist, increases serotonergic neuronal activity in behaving cats: comparison with (S)-WAY-100135.
We reported previously that pharmacological blockade of somatodendritic 5-hydroxytryptamine (5-HT)1A autoreceptors with spiperone, a nonselective 5-HT1A antagonist, increases the spontaneous firing rate of central serotonergic neurons in awake cats. The present study examined the effects of systemic administration of two reportedly selective 5-HT1A receptor antagonists, (S)-WAY-100135 {N-tert-butyl-3-[4-(2-methoxyphenyl) piperazin-1-yl]-2-phenylpropanamide} and its more potent analog WAY-100635 {N-[2-[4-(2-methoxyphenyl)-1-piperazinyl] ethyl]-N-(2-pyridinyl)cyclohexanecarboxamide}, on the single-unit activity of serotonergic neurons in the dorsal raphe nucleus of freely moving cats. In addition, we assessed the antagonist action of these compounds at the 5-HT1A autoreceptor by examining their ability to block the inhibition of serotonergic neuronal activity produced by systemic administration of 8-hydroxy-2-(di-n-propylamino)tetralin, a highly selective 5-HT1A agonist. Administration of (S)-WAY-100135 (0.025-1.0 mg/kg i.v.) moderately depressed neuronal activity at all doses tested. In contrast, administration of WAY-100635 (0.025-0.5 mg/kg i.v.) significantly increased neuronal activity. The stimulatory action of WAY-100635, like that of spiperone, was evident during wakefulness (when serotonergic neurons typically display a relatively high level of activity) but not during sleep (when serotonergic neurons display little or no spontaneous activity). Pretreatment with (S)-WAY-100135 (0.5 mg/kg i.v.) weakly attenuated the inhibitory action of 8-hydroxy-2-(di-n-propylamino)tetralin. In contrast, WAY-100635 at doses as low as 0.1 mg/kg i.v. completely blocked the action of 8-hydroxy-2-(di-n-propylamino)tetralin. The antagonist action of WAY-100635 at 5-HT1A autoreceptors closely paralleled its ability to increase neuronal activity. Overall, WAY-100635 appears to act as a selective 5-HT1A antagonist, whereas (S)-WAY-100135 does not. The results obtained with WAY-100635 confirm our previous findings obtained with spiperone and further support the hypothesis that 5-HT1A autoreceptor-mediated feedback inhibition operates under physiological conditions.


Pharmacodynamics of Glyburide, Metformin, and Glyburide/Metformin Combination Therapy in the Treatment of Gestational Diabetes Mellitus.
In gestational diabetes mellitus (GDM), women are unable to compensate for the increased insulin resistance during pregnancy. Data are limited regarding the pharmacodynamic effects of metformin and glyburide during pregnancy. This study characterized insulin sensitivity (SI), β-cell responsivity, and disposition index (DI) in women with GDM utilizing a mixed-meal tolerance test (MMTT) before and during treatment with glyburide monotherapy (GLY, n = 38), metformin monotherapy (MET, n = 34), or GLY and MET combination therapy (COMBO; n = 36). GLY significantly decreased dynamic β-cell responsivity (31%). MET and COMBO significantly increased SI (121% and 83%, respectively). Whereas GLY, MET, and COMBO improved DI, metformin (MET and COMBO) demonstrated a larger increase in DI (P = 0.05) and a larger decrease in MMTT peak glucose concentrations (P = 0.03) than subjects taking only GLY. Maximizing SI with MET followed by increasing β-cell responsivity with GLY or supplementing with insulin might be a more optimal strategy for GDM management than monotherapy.


Quantitative Imaging of Cholinergic Interneurons Reveals a Distinctive Spatial Organization and a Functional Gradient across the Mouse Striatum.
Information processing in the striatum requires the postsynaptic integration of glutamatergic and dopaminergic signals, which are then relayed to the output nuclei of the basal ganglia to influence behavior. Although cellularly homogeneous in appearance, the striatum contains several rare interneuron populations which tightly modulate striatal function. Of these, cholinergic interneurons (CINs) have been recently shown to play a critical role in the control of reward-related learning; however how the striatal cholinergic network is functionally organized at the mesoscopic level and the way this organization influences striatal function remains poorly understood. Here, we systematically mapped and digitally reconstructed the entire ensemble of CINs in the mouse striatum and quantitatively assessed differences in densities, spatial arrangement and neuropil content across striatal functional territories. This approach demonstrated that the rostral portion of the striatum contained a higher concentration of CINs than the caudal striatum and that the cholinergic content in the core of the ventral striatum was significantly lower than in the rest of the regions. Additionally, statistical comparison of spatial point patterns in the striatal cholinergic ensemble revealed that only a minor portion of CINs (17%) aggregated into cluster and that they were predominantly organized in a random fashion. Furthermore, we used a fluorescence reporter to estimate the activity of over two thousand CINs in naïve mice and found that there was a decreasing gradient of CIN overall function along the dorsomedial-to-ventrolateral axis, which appeared to be independent of their propensity to aggregate within the striatum. Altogether this work suggests that the regulation of striatal function by acetylcholine across the striatum is highly heterogeneous, and that signals originating in external afferent systems may be principally determining the function of CINs in the striatum.


Plant science. Genomic-scale exchange of mRNA between a parasitic plant and its hosts.
Movement of RNAs between cells of a single plant is well documented, but cross-species RNA transfer is largely unexplored. Cuscuta pentagona (dodder) is a parasitic plant that forms symplastic connections with its hosts and takes up host messenger RNAs (mRNAs). We sequenced transcriptomes of Cuscuta growing on Arabidopsis and tomato hosts to characterize mRNA transfer between species and found that mRNAs move in high numbers and in a bidirectional manner. The mobile transcripts represented thousands of different genes, and nearly half the expressed transcriptome of Arabidopsis was identified in Cuscuta. These findings demonstrate that parasitic plants can exchange large proportions of their transcriptomes with hosts, providing potential mechanisms for RNA-based interactions between species and horizontal gene transfer.


Predicting road test performance in drivers with dementia.
To develop a cognitive and functional screening battery for the on-road performance of older drivers with dementia. Prospective observational study. On-road driving evaluation clinic at an academic rehabilitation center. Ninety-nine older people with dementia (63% male, mean age 74.2 ± 9), referred by community physicians to an occupational therapy driving clinic. The outcome variable was pass or fail on the modified Washington University Road Test. Predictor measures were tests of visual, motor, and cognitive functioning, selected for their empirical or conceptual relationship to the complex task of driving safely. Sixty-five (65%) participants failed the on-road driving test. The best predictive model, with an overall accuracy of up to 85% when participants were blinded, included the Eight-item Informant Interview to Differentiate Aging and Dementia, Clock Drawing Test score, and time to complete the Snellgrove Maze Test or Trail Making Test Part A. Visual and motor functioning were not associated with road test failure. A screening battery that could be performed in less than 10 minutes predicted with good accuracy failure rate for the on-road driving test in this sample of older drivers with dementia. A probability of failure calculator is provided from a logistic regression model that may be useful for clinicians in their decision to refer impaired older adults for further testing. More studies are needed in larger community-based samples, along with discussions with patients, families, and clinicians, with regard to acceptable levels of test uncertainty.


Decreased sperm DNA fragmentation after surgical varicocelectomy is associated with increased pregnancy rate.
We prospectively evaluated changes in sperm chromatin structure in infertile patients before and after surgical repair of varicocele, and the impact on the pregnancy rate. Included in the study were 49 men with at least a 1-year history of infertility, a palpable varicocele and oligospermia. World Health Organization semen analysis and sperm DNA damage expressed as the DNA fragmentation index using the sperm chromatin structure assay were assessed preoperatively and postoperatively. Pregnancy (spontaneous and after assisted reproductive technique) was recorded 2 years after surgery. Mean sperm count, sperm concentration and sperm progressive motility improved significantly after varicocelectomy from 18.3 × 10(6) to 44.4 × 10(6), 4.8 × 10(6)/ml to 14.3 × 10(6)/ml and 16.7% to 26.6%, respectively (p <0.001). The DNA fragmentation index decreased significantly after surgery from 35.2% to 30.2% (p = 0.019). When the definition of greater than 50% improvement in sperm concentration after varicocelectomy was applied, 31 of 49 patients (63%) responded to varicocelectomy. After varicocelectomy 37% of the couples conceived spontaneously and 24% achieved pregnancy with assisted reproductive technique. The mean postoperative DNA fragmentation index was significantly higher in couples who did not conceive spontaneously or with assisted reproductive technique (p = 0.033). After varicocelectomy sperm parameters significantly improved and sperm DNA fragmentation was significantly decreased. Low DNA fragmentation index values are associated with a higher pregnancy rate (spontaneous and with assisted reproductive technique). We suggest that varicocelectomy should be considered in infertile men with palpable varicocele, abnormal semen analysis and no major female factors.


Consumption, silicosis, and the social construction of industrial disease.
In the wake of the bacterial revolution after Robert Koch identified the tuberculosis bacillus, medical and public health professionals classified the various forms of consumption and phthisis as a single disease--tuberculosis. In large measure, historians have adopted that perspective. While there is undoubtedly a great deal of truth in this conceptualization, we argue that it obscures almost as much as it illuminates. By collapsing the nineteenth-century terms phthisis and consumption into tuberculosis, we maintain that historians have not understood the effect of non-bacterial consumption on working-class populations who suffered from the symptoms of coughing, wasting away, and losing weight. In this essay, we explore how, in the nineteenth century, what we now recognize as silicosis was referred to as miners' "con," stonecutters' phthisis, and other industry-specific forms of phthisis and consumption. We examine how the later and narrower view of the bacterial origins of tuberculosis limited the medical professions' ability to diagnose and understand diseases caused by industrial dust. This paper explores the contention that developed at the turn of the century over occupational lung disease and tuberculosis and the circumstances that led to the unmasking of silicosis as a disease category.


Inpatient medication reconciliation at admission and discharge: A retrospective cohort study of age and other risk factors for medication discrepancies.
Medication discrepancies are unintended differences between medication regimens (ie, between a patient's home regimen and medications prescribed on admission to the hospital). The goal of this study was to describe the incidence, drug classes, and probable importance of hospital admission medication discrepancies and discharge regimen differences, and to determine whether factors such as age and specific hospital services were associated with greater frequency of medication discrepancies and differences. This was a retrospective cohort study of a random sample of adult patients admitted to the general medicine, cardiology, or general surgery services of a tertiary care academic teaching hospital between July 1, 2006, and August 31, 2006. A chart review was performed to collect the following information: patient demographic characteristics, comorbid conditions, number of preadmission medications, discrepant medications identified by the hospital's reconciliation process, reasons for the discrepancies, and discharge medications that differed from the home regimen. Potentially high-risk discrepancies and differences were identified by determining if the medications were included on either the Institute for Safe Medication Practices high-alert list or the North Carolina Narrow Therapeutic Index list. Univariate and multivariate logistic regression analyses were used to identify factors associated with medication discrepancies and differences. Of the 205 patients (mean age, 59.9 years; 116 men, 89 women; 60% white) included in the study, 27 did not have any medications recorded on admission. Of the 178 patients who did have medications listed, 41 had >or=1 discrepancy identified by the reconciliation process on admission (23%; 95% CI, 17-29); 19% (95% CI, 11-31) of these medications were considered to be potentially high risk. In the multivariate logistic regression model, age (odds ratio [OR] per 5-year increase = 1.16; 95% CI, 1.01-1.33; P = 0.035), presence of high-risk medications on admission (OR = 76.68; 95% CI, 9.13-643.76; P < 0.001), and general surgery service (OR = 3.31; 95% CI, 1.40-7.87; P < 0.007) were associated with a higher proportion of patients with discrepancies on admission. At discharge, 196 patients (96% [95% CI, 93<98]) had >or=1 medication change from their home regimen, with 1102 total differences for 205 patients. Less than half (44% [95% CI, 37-51]) of these patients were explicitly alerted at discharge to new medications or dose changes; 12% (95% CI, 7-18) were given written instructions to stop taking discontinued home medications. Cardiovascular drugs were the most frequent class involved at both admission (31%) and discharge (27%) in medication discrepancies or differences. Medication discrepancies on admission and medication differences at discharge were prevalent for adult patients admitted to the general medicine, cardiology, and general surgery services in this academic teaching hospital. Medication reconciliation processes have a high potential to identify clinically important discrepancies for all patients.


CLU genetic variants and cognitive decline among elderly and oldest old.
The CLU gene is one of the prime genetic candidates associated with Alzheimers disease. In the present study CLU genotypes and haplotypes were associated with baseline cognition and the rate of cognitive decline in two cohorts, the Danish 1905 birth cohort (93 years of age in 1998) and the Longitudinal Study of Aging Danish twins (LSADT) (73-83 year old twins in 1997). Both Mini Mental State Examination (MMSE) and a cognitive composite score was attained up to six times for up to 10 years and analysed using random effects models and vital status. The rs11136000 T allele was associated with better baseline cognitive performance both in the LSADT (effect on intercept: 0.41 95% CI [-0.04; 0.87]) and the 1905 birth cohort (effect on intercept: 0.28 95% CI [0.01; 0.55]), although it did not reach significance in the LSADT cohort. However, the rs11136000 T allele was significantly associated with a steeper decline (effect on slope: -0.06 95% CI [-0.11; -0.01]) in the LSADT cohort, but not in the 1905 birth cohort. Haplotype analyses revealed that carriers of the common rs11136000, rs1532278 and rs9331888 TTC haplotype (36%) in the CLU gene performed cognitively better than non-carriers in the 1905 birth cohort (effect on intercept: 0.50 95% CI [0.12; 0.91]) and carriers of a rare TCC haplotype (1%) performed worse on the cognitive composite score (effect on intercept: -1.51 95% CI [-2.92; -0.06]). The association between the TTC haplotype and better cognitive composite score was higher among those surviving past the age of 98 (p = 0.014), and among these the TTC haplotype was borderline associated with a steep decline (effect on slope: -0.13 95% CI [-0.27; 0.00]). In summery CLU genetic variants associate with cognition in two cohorts, but the genetic effect of CLU seems to regress toward the mean when aging.


Optimal cut-off points on the health anxiety inventory, illness attitude scales and whiteley index to identify severe health anxiety.
Health anxiety can be viewed as a dimensional phenomenon where severe health anxiety in form of DSM-IV hypochondriasis represents a cut-off where the health anxiety becomes clinically significant. Three of the most reliable and used self-report measures of health anxiety are the Health Anxiety Inventory (HAI), the Illness Attitude Scales (IAS) and the Whiteley Index (WI). Identifying the optimal cut-offs for classification of presence of a diagnosis of severe health anxiety on these measures has several advantages in clinical and research settings. The aim of this study was therefore to investigate the HAI, IAS and WI as proximal diagnostic instruments for severe health anxiety defined as DSM-IV hypochondriasis. We investigated sensitivity, specificity and predictive value on the HAI, IAS and WI using a total of 347 adult participants of whom 158 had a diagnosis of severe health anxiety, 97 had obsessive-compulsive disorder and 92 were healthy non-clinical controls. Diagnostic assessments were conducted using the Anxiety Disorder Interview Schedule. Optimal cut-offs for identifying a diagnosis of severe health anxiety was 67 on the HAI, 47 on the IAS, and 5 on the WI. Sensitivity and specificity were high, ranging from 92.6 to 99.4%. Positive and negative predictive values ranged from 91.6 to 99.4% using unadjusted prevalence rates. The HAI, IAS and WI have very good properties as diagnostic indicators of severe health anxiety and can be used as cost-efficient proximal estimates of the diagnosis.


Improved detection and biopsy of solid liver lesions using pulse-inversion ultrasound scanning and contrast agent infusion.
The purpose of this study was to assess the ability of pulse-inversion ultrasound (US) scanning (PIUS), combined with an IV contrast agent, to detect malignant liver lesions and its impact on patient management (resectability). Additionally, to determine the feasibility of US-guided biopsy of new PIUS-findings at the same session. A total of 30 patients with known or clinically suspected cancer underwent conventional B-mode scanning and PIUS with IV-administered contrast agent. The number of liver metastases in the right and the left liver lobe, respectively, was recorded. All patients with additional findings by PIUS underwent US-guided biopsy. PIUS provided additional information in 18 patients (60%); of these, 13 (43%) had additional metastases. Of 19 patients found resectable by conventional US, 9 (47%) were considered inoperable using PIUS supported by biopsies. Biopsies of additional findings were performed in 17 of 18 patients. All biopsies of additional findings confirmed malignancy. PIUS with an IV contrast agent increased the ability to detect liver metastases compared to conventional US scanning. The technique had a high impact on patient management. The results showed that PIUS-guided biopsy was possible. PIUS with IV contrast will undoubtedly become an important diagnostic tool in the evaluation of patients with metastatic liver disease.


Clinical Experience with Chitosan Matrix and Cultured Fibroblasts for Burns.
Burns are an important public health challenge due to the frequency of getting burns in day-to-day life, occupational hazards, and catastrophes. Treatment of burns is complex and is associated with high morbidity and mortality. Duration and complexity of burn treatment require finding new ways of curing and rehabilitating burns. The result of burn treatment plays a significant role in post-traumatic status of a patient and his or her consequent adaptation in society. Chitosan is a natural safe non-toxic product compatible with human tissues, characterized by hydrosorbid, anticoagulant, antibacterial, and wound healing features. The study aims to show a clinical application of chitosan-pectin scaffold with cultured human skin fibroblasts in the treatment of deep burns. The substrate was prepared by dissolving 3% chitosan in 0.5N acetic acid, which was then mixed with 3% solution of pectin dissolved in distillated water. Chitosan film was formed in a Petri dish for 20-24 hours at 20-25 °C. After drying the film, cultured allogeneic fibroblasts (patent number RK-25091) were seeded on its surface. The results from an in vitro culture study showed that human allogeneic fibroblasts could adhere well and grow on the selected scaffold with a typical morphology. During autodermoplasty surgery, cultured allogeneic fibroblasts were applied on granulating wounds of 9 patients with IIIA to IVB degree burns and limited donor resources. Wounds treated with the fibroblastseeded scaffold among all patients provided the highest level of re-epithelialization (day 5), in comparison to cell-free scaffold (day 7) and untreated surface of wounds (day 10). Our results indicate the potential use of chitosan for wound healing due to its allogenic fibroblast adherence to scaffolding as well as high epithelization. This warrants further studies on chitosan for use in wounds resulting from third and fourth degree burns.


Microinjection wound assay and in vivo localization of epidermal wound response reporters in Drosophila embryos.
The Drosophila embryo develops a robust epidermal layer that serves both to protect the internal cells from a harsh external environment as well as to maintain cellular homeostasis. Puncture injury with glass needles provides a direct method to trigger a rapid epidermal wound response that activates wound transcriptional reporters, which can be visualized by a localized reporter signal in living embryos or larvae. Puncture or laser injury also provides signals that promote the recruitment of hemocytes to the wound site. Surprisingly, severe (through and through) puncture injury in late stage embryos only rarely disrupts normal embryonic development, as greater than 90% of such wounded embryos survive to adulthood when embryos are injected in an oil medium that minimizes immediate leakage of hemolymph from puncture sites. The wound procedure does require micromanipulation of the Drosophila embryos, including manual alignment of the embryos on agar plates and transfer of the aligned embryos to microscope slides. The Drosophila epidermal wound response assay provides a quick system to test the genetic requirements of a variety of biological functions that promote wound healing, as well as a way to screen for potential chemical compounds that promote wound healing. The short life cycle and easy culturing routine make Drosophila a powerful model organism. Drosophila clean wound healing appears to coordinate the epidermal regenerative response, with the innate immune response, in ways that are still under investigation, which provides an excellent system to find conserved regulatory mechanisms common to Drosophila and mammalian epidermal wounding.


Cannabinoids mediate opposing effects on inflammation-induced intestinal permeability.
Activation of cannabinoid receptors decreases emesis, inflammation, gastric acid secretion and intestinal motility. The ability to modulate intestinal permeability in inflammation may be important in therapy aimed at maintaining epithelial barrier integrity. The aim of the present study was to determine whether cannabinoids modulate the increased permeability associated with inflammation in vitro. Confluent Caco-2 cell monolayers were treated for 24 h with IFNγ and TNFα (10 ng·mL(-1) ). Monolayer permeability was measured using transepithelial electrical resistance and flux measurements. Cannabinoids were applied either apically or basolaterally after inflammation was established. Potential mechanisms of action were investigated using antagonists for CB(1) , CB(2) , TRPV1, PPARγ and PPARα. A role for the endocannabinoid system was established using inhibitors of the synthesis and degradation of endocannabinoids. Δ(9) -Tetrahydrocannabinol (THC) and cannabidiol accelerated the recovery from cytokine-induced increased permeability; an effect sensitive to CB(1) receptor antagonism. Anandamide and 2-arachidonylglycerol further increased permeability in the presence of cytokines; this effect was also sensitive to CB(1) antagonism. No role for the CB(2) receptor was identified in these studies. Co-application of THC, cannabidiol or a CB(1) antagonist with the cytokines ameliorated their effect on permeability. Inhibiting the breakdown of endocannabinoids worsened, whereas inhibiting the synthesis of endocannabinoids attenuated, the increased permeability associated with inflammation. These findings suggest that locally produced endocannabinoids, acting via CB(1) receptors play a role in mediating changes in permeability with inflammation, and that phytocannabinoids have therapeutic potential for reversing the disordered intestinal permeability associated with inflammation. This article is part of a themed section on Cannabinoids in Biology and Medicine. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-8. To view Part I of Cannabinoids in Biology and Medicine visit http://dx.doi.org/10.1111/bph.2011.163.issue-7.


Rewriting the regulations: how the World Trade Organisation could accelerate privatisation in health-care systems.
The World Trade Organisation (WTO) is drawing up regulatory proposals which could force governments to open up their public services to foreign Investors and markets. As part of the General Agreement on Trade in Services (GATS) negotiations, the WTO working party on reform of domestic regulation is developing a regulatory reform agenda which could mark a new era of compulsion in international trade law. Article VI.4 of the GATS is being strengthened with the aim of requiring member states to show that they are employing least trade-restrictive policies. The legal tests under consideration would outlaw the use of non-market mechanisms such as cross-subsidisation, universal risk pooling, solidarity, and public accountability in the design, funding, and delivery of public services as being anti-competitive and restrictive to trade. The domestic policies of national governments will be subject to WTO rules, and if declared illegal, could lead to trade sanctions under the WTO disputes panel process. The USA and European Union, with the backing of their own multinational corporations, believe that these new powers will advantage their own economies. Health-care professionals and public-health activists must ensure that this secretive regulatory reform process is opened up for public debate.


Agreement between patient-reported symptoms and their documentation in the medical record.
To determine the agreement between patient-reported symptoms of chest pain, dyspnea, and cough and the documentation of these symptoms by physicians in the electronic medical record. Symptoms reported on patient-provided information forms between January 1, 2006, and June 30, 2006, were compared with those identified by natural language processing of the text of clinical notes from care providers. Terms that represent the 3 symptoms were used to search clinical notes electronically with subsequent manual identification of the context (eg, affirmative, negated, family history) in which they occurred. Results were reported using positive and negative agreement, and kappa statistics. Symptoms reported by 1119 patients age 18 years or older were compared with the nonnegated terms identified in their clinical notes. Positive agreement was 74, 70, and 63 for chest pain, dyspnea, and cough, while negative agreement was 78, 76, and 75, respectively. Kappa statistics were 0.52 (95% confidence interval [CI] = 0.44, 0.60) for chest pain, 0.46 (95% CI = 0.37, 0.54) for dyspnea, and 0.38 (95% CI = 0.28, 0.48) for cough. Positive agreement was higher for older men (P >.05), and negative agreement was higher for younger women (P >.05). We found discordance between patient self-report and documentation of symptoms in the medical record. This discordance has important implications for research studies that rely on symptom information for patient identification and may have clinical implications that must be evaluated for potential impact on quality of care, patient safety, and outcomes.


NDRG2 expression decreases with tumor stages and regulates TCF/beta-catenin signaling in human colon carcinoma.
NDRG (N-Myc downstream-regulated gene)-2 is a member of the NDRG family. Although it has been suggested that NDRG2 is involved in cellular differentiation and tumor suppression, its intracellular signal and regulatory mechanism are not well known. Here, we show the differential expression of NDRG2 in human colon carcinoma cell lines and tissues by reverse transcription-polymerase chain reaction and immunohistochemical analyses with monoclonal antibody against NDRG2. NDRG2 was strongly expressed in normal colonic mucosa and colonic adenomatous tissues (25 of 25) but not in all invasive cancer tissues [44 of 99 (44%)]. Most distinctive results indicated that the high expression level of NDRG2 has a positive correlation with tumor differentiation and inverse correlation with tumor invasion depth and Dukes' stage of colon adenocarcinoma. To investigate the roles of NDRG2 in tumorigenesis, we used in vitro cell culture system. SW620 colon cancer cell line with a low level of intrinsic NDRG2 protein was transfected with NDRG2-expressing plasmid. TOPflash luciferase reporter assay showed that the transcriptional activity of T-cell factor (TCF)/lymphoid enhancer factor (LEF) was reduced by NDRG2 introduction, but not by the introduction of mutant NDRG2 generated by deletion or site-directed mutagenesis. Intracellular beta-catenin levels were slightly reduced in the NDRG2-transfected SW620 cells and this regulation of beta-catenin stability and TCF/LEF activity were mediated through the modulation of glycogen synthase kinase-3beta activity by NDRG2 function. Our results suggest that NDRG2 might play a pivotal role as a potent tumor suppressor by the attenuation of TCF/beta-catenin signaling for the maintenance of healthy colon tissues.


What Orthopaedic Operating Room Surfaces Are Contaminated With Bioburden? A Study Using the ATP Bioluminescence Assay.
Contaminated operating room surfaces can increase the risk of orthopaedic infections, particularly after procedures in which hardware implantation and instrumentation are used. The question arises as to how surgeons can measure surface cleanliness to detect increased levels of bioburden. This study aims to highlight the utility of adenosine triphosphate (ATP) bioluminescence technology as a novel technique in detecting the degree of contamination within the sterile operating room environment. What orthopaedic operating room surfaces are contaminated with bioburden? When energy is required for cellular work, ATP breaks down into adenosine biphosphate (ADP) and phosphate (P) and in that process releases energy. This process is inherent to all living things and can be detected as light emission with the use of bioluminescence assays. On a given day, six different orthopaedic surgery operating rooms (two adult reconstruction, two trauma, two spine) were tested before surgery with an ATP bioluminescence assay kit. All of the cases were considered clean surgery without infection, and this included the previously performed cases in each sampled room. These rooms had been cleaned and prepped for surgery but the patients had not been physically brought into the room. A total of 13 different surfaces were sampled once in each room: the operating room (OR) preparation table (both pre- and postdraping), OR light handles, Bovie machine buttons, supply closet countertops, the inside of the Bair Hugger™ hose, Bair Hugger™ buttons, right side of the OR table headboard, tourniquet machine buttons, the Clark-socket attachment, and patient positioners used for total hip and spine positioning. The relative light units (RLUs) obtained from each sample were recorded and data were compiled and averaged for analysis. These values were compared with previously published ATP benchmark values of 250 to 500 RLUs to define cleanliness in both the hospital and restaurant industries. All surfaces had bioburden. The ATP RLUs (mean ± SD) are reported for each surface in ascending order: the OR preparation table (postdraping; 8.3 ± 3.4), inside the sterilized pan (9.2 ± 5.5), the inside of the Bair Hugger™ hose (212.5 ± 155.7), supply closet countertops (281.7 ± 236.7), OR light handles (647.8 ± 903.7), the OR preparation table (predraping; 1054 ± 387.5), the Clark-socket attachment (1135.7 ± 705.3), patient positioners used for total hip and spine positioning (1201.7 ± 1144.9), Bovie machine buttons (1264.5 ± 638.8), Bair Hugger™ buttons (1340.8 ± 1064.1), tourniquet machine buttons (1666.5 ± 2144.9), computer keyboard (1810.8 ± 929.6), and the right side of the OR table headboard (2539 ± 5635.8). ATP bioluminescence is a novel method to measure cleanliness within the orthopaedic OR and can help identify environmental trouble spots that can potentially lead to increased infection rates. Future studies correlating ATP bioluminescence findings with microbiology cultures could add to the clinical utility of this technology. Surfaces such as the undersurface of the OR table headboard, Bair Hugger™ buttons, and tourniquet machine buttons should be routinely cleansed as part of an institutional protocol. Although correlation between ATP bioluminescence and clinical infection was not evaluated in this study, it is the subject of future research. Specifically, evaluating microbiology samples taken from these environmental surfaces and correlating them with increased bioburden found with ATP bioluminescence technology can help promote improved surgical cleaning practices.


Resolving complex research data management issues in biomedical laboratories: Qualitative study of an industry-academia collaboration.
This paper describes a distributed collaborative effort between industry and academia to systematize data management in an academic biomedical laboratory. Heterogeneous and voluminous nature of research data created in biomedical laboratories make information management difficult and research unproductive. One such collaborative effort was evaluated over a period of four years using data collection methods including ethnographic observations, semi-structured interviews, web-based surveys, progress reports, conference call summaries, and face-to-face group discussions. Data were analyzed using qualitative methods of data analysis to (1) characterize specific problems faced by biomedical researchers with traditional information management practices, (2) identify intervention areas to introduce a new research information management system called Labmatrix, and finally to (3) evaluate and delineate important general collaboration (intervention) characteristics that can optimize outcomes of an implementation process in biomedical laboratories. Results emphasize the importance of end user perseverance, human-centric interoperability evaluation, and demonstration of return on investment of effort and time of laboratory members and industry personnel for success of implementation process. In addition, there is an intrinsic learning component associated with the implementation process of an information management system. Technology transfer experience in a complex environment such as the biomedical laboratory can be eased with use of information systems that support human and cognitive interoperability. Such informatics features can also contribute to successful collaboration and hopefully to scientific productivity.


'An uneasy compromise': strategies and dilemmas in realizing a permissive abortion law in Ethiopia.
At the turn of the century, when the Millennium Development Goals placed maternal mortality reduction high on the global agenda, Ethiopia relaxed its restrictive abortion law to expand grounds on which a woman could legally obtain an abortion. This radical policy shift took place within a context of predominant anti-abortion public opinion shaped by strong religious convictions. Drawing upon Walt and Gilson's policy analysis framework, this paper explores the tension between public policy and religious dogma for the strategies chosen by the Ethiopian Ministry of Health and its partners implementing the new policy, and for access to safe abortion services. The study employed a qualitative research methodology. It targeted organizations that are key stakeholders in the field of reproductive health. These included policy makers and policy implementers like ministries, UN agencies and international and national NGOs as well as religious organizations as key opinion leaders. The data collection took place in Addis Ababa between 2016 and 2018. A total of 26 interviews were conducted, transcribed, and analyzed using the principles of qualitative content analysis. Our analysis showed that the implementing organizations adopted a strategy of silence not to provoke anti-abortion sentiments and politicization of the abortion issue which was seen as a threat to the revised law and policy. This strategy has facilitated a rollout of services and has improved access to safe abortion care. Nevertheless informants were concerned that the silence strategy has prevented dissemination of knowledge about the revised law to the general public, to health workers and to the police. In turn this has caused confusion about eligibility to legal and safe abortion procedures. While silence as a strategy works to protect the law enhancing the health and survival of young women, it may at the same time prevent the law from being fully effective. As a long term strategy, silence fails to expand awareness and access to safe abortion services, and may not sufficiently serve to fulfill the potential of the law to prevent abortion related maternal deaths.


Variation in tissue-specific gene expression among natural populations.
Variation in gene expression is extensive among tissues, individuals, strains, populations and species. The interactions among these sources of variation are relevant for physiological studies such as disease or toxic stress; for example, it is common for pathologies such as cancer, heart failure and metabolic disease to be associated with changes in tissue-specific gene expression or changes in metabolic gene expression. But how conserved these differences are among outbred individuals and among populations has not been well documented. To address this we examined the expression of a selected suite of 192 metabolic genes in brain, heart and liver in three populations of the teleost fish Fundulus heteroclitus using a highly replicated experimental design. Half of the genes (48%) were differentially expressed among individuals within a population-tissue group and 76% were differentially expressed among tissues. Differences among tissues reflected well established tissue-specific metabolic requirements, suggesting that these measures of gene expression accurately reflect changes in proteins and their phenotypic effects. Remarkably, only a small subset (31%) of tissue-specific differences was consistent in all three populations. These data indicate that many tissue-specific differences in gene expression are unique to one population and thus are unlikely to contribute to fundamental differences between tissue types. We suggest that those subsets of treatment-specific gene expression patterns that are conserved between taxa are most likely to be functionally related to the physiological state in question.


Expression and function of FGF10 in mammalian inner ear development.
We have investigated the expression of FGF10 during ear development and the effect of an FGF10 null mutation on ear development. Our in situ hybridization data reveal expression of FGF10 in all three canal crista sensory epithelia and the cochlea anlage as well as all sensory neurons at embryonic day 11.5 (E11.5). Older embryos (E18.5) displayed strong graded expression in all sensory epithelia. FGF10 null mutants show complete agenesis of the posterior canal crista and the posterior canal. The posterior canal sensory neurons form initially and project rather normally by E11.5, but they disappear within 2 days. FGF10 null mutants have no posterior canal system at E18.5. In addition, these mutants have deformations of the anterior and horizontal cristae, reduced formation of the anterior and horizontal canals, as well as altered position of the remaining sensory epithelia with respect to the utricle. Hair cells form but some have defects in their cilia formation. No defects were detected in the organ of Corti at the cellular level. Together these data suggest that FGF10 plays a major role in ear morphogenesis. Most of these data are consistent with earlier findings on a null mutation in FGFR2b, one of FGF10's main receptors.


Thermally reversible surface morphology transition in thin diblock copolymer films.
Many phase transitions exhibit ordering transitions at the boundary of the material that are distinct from its interior where intermolecular interactions can be significantly different. The present work considers the existence of a surface thermodynamic order-order transition between two distinct morphologies in thin block copolymer (BCP) films that are of interest in nanomanufacturing applications. Specifically, we find a thermally reversible interfacial transition between sphere-like structures and cylinders in flow-coated films of poly(styrene-block-methyl methacrylate) (PS-b-PMMA), where the BCP forms a cylinder microphase in the bulk. We present direct evidence from atomic force microscopy (AFM) of ion-etched films and grazing-incidence small-angle X-ray scattering (GISAXS) on films without etching, which shows that the order-order transition is restricted to the outer layer of the film, while the film interior remains in the cylinder state. Moreover, we find this order-order transition to be insensitive to film thickness over the range investigated (40-170 nm). This morphological transition is of importance in characterizing the thermodynamics and dynamics of thin BCP films used as templates in nanomanufacturing applications.


Traditional Chinese medication for cardiovascular disease.
Traditional Chinese medication (TCM) is increasingly used to treat cardiovascular disease (CVD) in China and some other Asian countries. However, therapeutic efficacy and adverse effects of TCM are difficult to evaluate because few large-scale, randomized controlled trials (RCTs) enrolling patients with CVD have been performed. In this Review, we critically examine the current evidence on the cardiovascular effects of TCM. We reviewed 68 RCTs that included a total of 16,171 patients. The methodological quality of the trials was generally low. Only three reports described adverse cardiovascular events specifically, although in most studies TCM was associated with significant improvements in surrogate end points for hypertension, coronary heart disease, cardiac arrhythmias, and heart failure. The risk of adverse effects was not increased compared with no intervention, placebo, or Western medications. However, whether TCM is effective in reducing the all-cause or cardiovascular mortality in patients with CVD remains unknown and must be tested in large-scale RCTs with adverse cardiovascular events as primary end points.


Thymic B cells of pig fetuses and germ-free pigs spontaneously produce IgM, IgG and IgA: detection by ELISPOT method.
The aim of this study was to investigate spontaneous immunoglobulin production and a pattern of isotype switching by thymic B lymphocytes (TBL) as compared with cells isolated from spleen during early ontogeny using a pig model in which B-cell development is not influenced by maternal regulatory factors. A sensitive ELISPOT assay was therefore employed to detect immunoglobulins in pig fetuses, colostrum-deprived germ-free (GF) piglets as well as conventionally (CONV) reared pigs. The first spontaneously immunoglobulin-secreting cells in the thymus were detected in 67-day-old fetuses (the length of gestation period in pigs is 114 days), their number increasing during fetal ontogeny. In contrast to fetal splenic cells, which secrete exclusively IgM, fetal thymic immunoglobulin-secreting cells were determined to undergo spontaneous isotype switching to IgG and IgA. In 28-day-old GF piglets and 3-month-old CONV pigs the number of thymic immunoglobulin-secreting cells of all isotypes was comparable to the number of thymic immunoglobulin-secreting cells detected in the newborn thymus. Considerable augmentation of IgG and IgA production by splenic immunoglobulin-secreting cells in CONV pigs was observed as compared to GF newborns and GF piglets, in which IgG- and IgA-secreting cells were detected occasionally. Our results indicate that TBL represent the first B-cell population in early fetal ontogeny spontaneously undergoing isotype switching to IgG and IgA; in the postnatal period the TBL population does not appear to be influenced by external antigenic stimuli of conventional microflora.


Targeting the TS dimer interface in bifunctional Cryptosporidium hominis TS-DHFR from parasitic protozoa: Virtual screening identifies novel TS allosteric inhibitors.
Effective therapies are lacking to treat gastrointestinal infections caused by the genus Cryptosporidium, which can be fatal in the immunocompromised. One target of interest is Cryptosporidium hominis (C. hominis) thymidylate synthase-dihydrofolate reductase (ChTS-DHFR), a bifunctional enzyme necessary for DNA biosynthesis. Targeting the TS-TS dimer interface is a novel strategy previously used to identify inhibitors against the related bifunctional enzyme in Toxoplasma gondii. In the present study, we target the ChTS dimer interface through homology modeling and high-throughput virtual screening to identifying allosteric, ChTS-specific inhibitors. Our work led to the discovery of methylenedioxyphenyl-aminophenoxypropanol analogues which inhibit ChTS activity in a manner that is both dose-dependent and influenced by the conformation of the enzyme. Preliminary results presented here include an analysis of structure activity relationships and a ChTS-apo crystal structure of ChTS-DHFR supporting the continued development of inhibitors that stabilize a novel pocket formed in the open conformation of ChTS-TS.


SF2/ASF autoregulation involves multiple layers of post-transcriptional and translational control.
SF2/ASF is a prototypical serine- and arginine-rich protein, with important roles in splicing and other aspects of mRNA metabolism. Splicing factor, arginine/serine-rich 1 (SFRS1), the gene encoding SF2/ASF, is a potent proto-oncogene with abnormal expression in many tumors. We found that SF2/ASF negatively autoregulates its expression to maintain homeostatic levels. We characterized six alternatively spliced SF2/ASF mRNA isoforms: the major isoform encodes full-length protein, whereas the others are either retained in the nucleus or degraded by nonsense-mediated mRNA decay. Unproductive splicing accounts for only part of the autoregulation, which occurs primarily at the translational level. The effect is specific to SF2/ASF and requires RNA recognition motif 2 (RRM2). The ultraconserved 3' untranslated region (UTR) is necessary and sufficient for downregulation. SF2/ASF overexpression shifts the distribution of target mRNA toward monoribosomes, and translational repression is partly independent of Dicer and a 5' cap. Thus, multiple post-transcriptional and translational mechanisms are involved in fine-tuning the expression of SF2/ASF.


What information do physicians receive from pharmaceutical representatives?
To assess the information pharmaceutical sales representatives provide to physicians. A MEDLINE search from January 1966 to May 1996 was done using combinations of the terms pharmaceutical industry, drug information services, drug utilization, physician's practice patterns and prescriptions, and drugs. Studies identified from this search were supplemented by material from my personal library. Studies had to be conducted in industrialized countries, based on direct observations of actual physician and sales representative contacts, and reporting quantitative results on the quality of information transmitted. Four studies were included. Representatives usually mentioned the indications for their drugs, but omitted safety information. Representatives' information frequently contained inaccuracies. Sales representatives present only selected, usually positive, information about their products. Canadian doctors should not be passive recipients of information provided by sales representatives. Physicians who choose to continue to see representatives must critically compare the information they get from them with that contained in scientific publications.


Visual long-term memory has a massive storage capacity for object details.
One of the major lessons of memory research has been that human memory is fallible, imprecise, and subject to interference. Thus, although observers can remember thousands of images, it is widely assumed that these memories lack detail. Contrary to this assumption, here we show that long-term memory is capable of storing a massive number of objects with details from the image. Participants viewed pictures of 2,500 objects over the course of 5.5 h. Afterward, they were shown pairs of images and indicated which of the two they had seen. The previously viewed item could be paired with either an object from a novel category, an object of the same basic-level category, or the same object in a different state or pose. Performance in each of these conditions was remarkably high (92%, 88%, and 87%, respectively), suggesting that participants successfully maintained detailed representations of thousands of images. These results have implications for cognitive models, in which capacity limitations impose a primary computational constraint (e.g., models of object recognition), and pose a challenge to neural models of memory storage and retrieval, which must be able to account for such a large and detailed storage capacity.


mRNA Vaccine Effectiveness Against Coronavirus Disease 2019 Hospitalization Among Solid Organ Transplant Recipients.
The study objective was to evaluate 2- and 3-dose coronavirus disease 2019 (COVID-19) mRNA vaccine effectiveness (VE) in preventing COVID-19 hospitalization among adult solid organ transplant (SOT) recipients. We conducted a 21-site case-control analysis of 10 425 adults hospitalized in March to December 2021. Cases were hospitalized with COVID-19; controls were hospitalized for an alternative diagnosis (severe acute respiratory syndrome coronavirus 2-negative). Participants were classified as follows: SOT recipient (n = 440), other immunocompromising condition (n = 1684), or immunocompetent (n = 8301). The VE against COVID-19-associated hospitalization was calculated as 1-adjusted odds ratio of prior vaccination among cases compared with controls. Among SOT recipients, VE was 29% (95% confidence interval [CI], -19% to 58%) for 2 doses and 77% (95% CI, 48% to 90%) for 3 doses. Among patients with other immunocompromising conditions, VE was 72% (95% CI, 64% to 79%) for 2 doses and 92% (95% CI, 85% to 95%) for 3 doses. Among immunocompetent patients, VE was 88% (95% CI, 87% to 90%) for 2 doses and 96% (95% CI, 83% to 99%) for 3 doses. Effectiveness of COVID-19 mRNA vaccines was lower for SOT recipients than immunocompetent adults and those with other immunocompromising conditions. Among SOT recipients, vaccination with 3 doses of an mRNA vaccine led to substantially greater protection than 2 doses.


Risk and patterns of bacteraemia after splenectomy: a population-based study.
During a period in which vaccination of splenectomized patients has been recommended, we analysed the patterns of severe post-splenectomy infections (i.e. bacteraemia or meningitis) in a defined population-based cohort. A total of 561 patients undergoing splenectomy were identified during 1984-93 in a Danish county, and the 538 eligible patients were followed for 1731 person-years. After splenectomy, 38 patients contracted a bacteraemia, of which 45% occurred within 30 d (i.e. during the postoperative period). No cases of meningitis were found. Among splenectomized patients the incidence rate of bacteraemia was 2.3 per 100 person-years at risk. Beyond the postoperative period we found an 8-fold increased risk of bacteraemia. Enterobacteria were the predominant cause (45%), and only 1 case due to Streptococcus pneumoniae was recorded. 89 (17%) died during the postoperative period, and the overall mortality rate was 18.4 per 100 person-years at risk. In all, 60% of the patients had been given a pneumococcal vaccination, and a Cox proportional hazard regression model showed that vaccination significantly reduced the risk of bacteraemia of any cause beyond the postoperative period. We conclude that splenectomy increases the risk of severe infections, and that vaccinated patients carry a lower risk of infection than non-vaccinated ones.


Predictors of long-term compliance with continuous positive airway pressure.
There are very few data on objectively assessed long-term compliance with continuous positive airway pressure (CPAP). No single factor has been consistently identified as predictive of continued CPAP use. Adherence to and associations with objective CPAP use were examined in 639 of 3900 patients in whom CPAP treatment was started between 1994 and 2005. Kaplan-Meier survival analyses were used to estimate the proportion of patients still on CPAP. Cox regression models were used to explore the effects of covariates on continued use of CPAP. The median (IQR) follow-up time after initiating CPAP therapy was 3.9 (1.5-6.9) years and the average use of CPAP was 6.2 (4.5-7.3) h/night. The percentage of patients adherent to CPAP after 5 and 10 years was 81% and 70%, respectively. Multivariate analysis, including gender, age, neck circumference, Epworth Sleepiness Score, oxygen desaturation index (ODI) and research study participation, indicated that ODI was the only clinical variable independently associated with long-term adherence to CPAP (HR per 1 event=0.97, p<0.001, 95% CI 0.96 to 0.98). ODI categories were significantly associated with the risk for stopping CPAP in multivariate analysis (using ODI group 0-15/h as reference, HR for ODI group >15-30/h=0.68, p=0.100, 95% CI 0.43 to 1.08; for ODI group >30-60/h=0.37, p<0.001, 95% CI 0.22 to 0.60; and for ODI group >60/h=0.17, p=0.001, 95% CI 0.06 to 0.48). The majority of patients with sleep-disordered breathing are using CPAP in the long term and the severity of sleep-disordered breathing rather than sleepiness determines long-term adherence to CPAP therapy.


Adsorption of PAHs on interstellar ice viewed by classical molecular dynamics.
Polycyclic Aromatic Hydrocarbons (PAHs) are a family of molecules which represent the best candidates to explain the observation of one set of features in the Interstellar Medium (ISM): the Aromatic Interstellar Bands (AIBs). They could also contribute to the Diffuse Interstellar Bands (DIBs). In dense molecular clouds, PAHs may condense onto interstellar grains, contributing to the complex chemistry occurring in their icy mantles, composed essentially of water. In this context, the adsorption of various aromatic molecules, from benzene to ovalene, on different ices - both amorphous and crystalline - is investigated by means of classical molecular dynamics simulations. Initially, a systematic parametrization of the electronic charges on the chosen PAHs in these environments is carried out, and benchmarked with reference to free energies of solvation in liquid water. Then we propose a new, rigorous methodology, transferable to any other PAH or molecular species, to evaluate the charges to be applied to the molecule in the gas phase, at interfaces, or in liquid water. Ultimately, the adsorption energies calculated for the various PAHs are used to derive a function predicting the adsorption energy of any PAH on a given ice surface as a function of the number of C and H atoms it contains. For all PAHs studied, the largest adsorption energies are found on the crystalline hexagonal ice surface (Ih). Binding energy maps constructed for each PAH-ice pair give valuable insight into adsorption site densities and the barriers to surface diffusion. One key result is that the amorphous surface offers a smaller number of adsorption sites compared to that of hexagonal ice. A direct correlation between the location of energetically favourable adsorption sites and the presence of dangling H-bonds is also demonstrated using these maps, showing that PAHs adsorb preferentially on sites offering dangling H-bonds. The present work represents a complete description of PAH-ice interaction in the ground electronic state and at low temperature, providing the binding energies and barrier heights necessary to the ongoing improvement of astrochemical models.


Flexible minerals: self-assembled calcite spicules with extreme bending strength.
Silicatein-α is responsible for the biomineralization of silicates in sponges. We used silicatein-α to guide the self-assembly of calcite "spicules" similar to the spicules of the calcareous sponge Sycon sp. The self-assembled spicules, 10 to 300 micrometers (μm) in length and 5 to 10 μm in diameter, are composed of aligned calcite nanocrystals. The spicules are initially amorphous but transform into calcite within months, exhibiting unusual growth along [100]. They scatter x-rays like twinned calcite crystals. Whereas natural spicules evidence brittle failure, the synthetic spicules show an elastic response, which greatly enhances bending strength. This remarkable feature is linked to a high protein content. With nano-thermogravimetric analysis, we measured the organic content of a single spicule to be 10 to 16%. In addition, the spicules exhibit waveguiding properties even when they are bent.


ISG15 in Host Defense Against Candida albicans Infection in a Mouse Model of Fungal Keratitis.
ISG15, a di-ubiquitin-like protein, is critical for controlling certain viral and bacterial infections. We sought to determine if ISG15 plays a role in corneal innate immunity against Candida albicans (C. albicans) using a C57BL/6 (B6) mouse model of human fungal keratitis. Scarified corneas of adult B6 mice were pretreated with TLR5 ligand flagellin and then inoculated with C. albicans. The expression of ISG15 and other genes involved in ISG15 conjugation (ISGylation) was determined by real-time PCR. ISG15 expression and distribution in infected corneas were assessed by immunohistochemistry. ISGylation was examined by Western blotting. siRNA knockdown and recombinant ISG15 were used to elucidate the effects of ISG15 on controlling fungal keratitis by clinical scoring, fungal number plate counting, ELISA cytokine determination, and polymorphonuclear leukocytes (PMN) infiltration measurement. Heat-killed C. albicans induced expression of ISG15, and hBD2 was markedly enhanced by flagellin-pretreatment in cultured human primary corneal epithelial cells (CECs). In vivo, C. albicans infection induced the expression of ISG15, ISGylation-associated genes (UBE1L, UBCH8, and HERC5), and ISGylation in mouse CECs, all of which were enhanced by flagellin-pretreatment. siRNA knockdown of ISG15 increased keratitis severity, dampened flagellin-induced protection, and greatly suppressed the expressions of ISGylation enzymes, IFN-γ, but not CXCL2 in B6 mouse CECs. Recombinant ISG15, on the other hand, enhanced corneal innate immunity against C. albicans and suppressed infection-induced IL-1β, but not IL-Ra expression. ISG15 alone induced the expression of IL-1Ra, CXCL10, and CRAMP in mouse CECs. ISG15 was upregulated and secreted in cultured human CECs in response to challenge in a type 1 IFN-dependent manner. Our data, for the first time, demonstrate that ISG15 acts as an immunomodulator in the cornea and plays a critical role in controlling fungal keratitis.


Antimicrobial Susceptibility of Persister Biofilm Cells of Bacillus cereus and Pseudomonas fluorescens.
The present study evaluates the antimicrobial susceptibility of persister cells of Bacillus cereus and Pseudomonas fluorescens after their regrowth in suspension and as biofilms. Two conventional (benzalkonium chloride-BAC and peracetic acid-PAA) and two emerging biocides (glycolic acid-GA and glyoxal-GO) were selected for this study. Persister cells resulted from biofilms subjected to a critical treatment using the selected biocides. All biocide treatments developed B. cereus persister cells, except PAA that effectively reduced the levels of vegetative cells and endospores. P. fluorescens persister cells comprise viable and viable but non-culturable cells. Afterwards, persister cells were regrown in suspension and in biofilms and were subjected to a second biocide treatment. In general, planktonic cultures of regrown persister cells in suspension lost their antimicrobial tolerance, for both bacteria. Regrown biofilms of persister cells had antimicrobial susceptibility close to those regrown biofilms of biocide-untreated cells, except for regrown biofilms of persister P. fluorescens after BAC treatment, which demonstrated increased antimicrobial tolerance. The most active biocide against persister cells was PAA, which did not promote changes in susceptibility after their regrowth. In conclusion, persister cells are ubiquitous within biofilms and survive after critical biocide treatment. The descendant planktonic and biofilms populations showed similar properties as the original ones.


Alpha-1-antitrypsin interacts with gp41 to block HIV-1 entry into CD4+ T lymphocytes.
Study of a clinic case reveals that alpha-1-antitrypsin (AAT) deficiency is related to CD4+ T cell count decline and AIDS progression, suggesting that AAT might be an endogenous inhibitor of HIV/AIDS. Previous study shows that AAT inhibits HIV-1 replication in infected host cells and the C-terminus fragment of AAT, VIRIP, interferes with HIV-1 infection. However, it is still unclear whether and how intact AAT inhibits HIV-1 infection. It is also unknown what the mechanism of AAT is and which critical step(s) are involved. In the present study, the C-terminus of AAT (C) was synthesized. C terminus-truncated AAT (ΔAAT) was also prepared by digesting AAT with metalloproteinase. Primary CD4+ T cells were then co-cultured with HIV-1 with the presence or absence of AAT/C/ΔAAT to detect cis-infection of HIV-1. The interaction between AAT/C/ΔAAT and gp120/gp41 was also measured. Meanwhile, HIV-1 reverse transcriptase activity and viral DNA integration were also detected in these lymphocytes. The results demonstrated that AAT and C, not ΔAAT, inhibited HIV-1 entry by directly interacting with gp41. Meanwhile, AAT, C and ΔAAT could not directly interfere with the steps of viral RNA reverse transcription and viral DNA integration. AAT inhibits HIV-1 entry by directly interacting with gp41 through its C-terminus and thereby inhibits HIV-1 infection.


Angiogenic protein expression in advanced epithelial ovarian cancer.
We set out to determine whether advanced epithelial ovarian cancer (EOC) is associated with elevated serum and ascitic concentrations of the angiogenic factors angiogenin (ANG), basic fibroblastic growth factor (bFGF), and vascular endothelial growth factor (VEGF), and whether the expression of angiogenic factors was associated with tumor vascularity. Serum and ascitic samples were collected from previously untreated patients with FIGO stage III and IV EOC and stored at -70 degreesC. Levels of the three factors were determined by enzyme-linked immunoassay. Histological sections from paraffin blocks of ovarian cancers were stained immunochemically for factor VIII, CD34, and VEGF. Thirty-nine patients were studied, although not all had paired serum and ascitic samples. For each angiogenic factor, the following findings were noted: (a) there was a wide range in serum and ascitic fluid concentrations; (b) the mean serum concentration was higher (P < 0.05) than the mean concentration in normal serum; and (c) the mean serum concentration was lower (P < 0. 05) than the mean ascitic concentration. Overall, the most consistent pattern of elevated serum and ascitic concentrations was with bFGF. With serum samples, 38.9% of patients had a normal VEGF concentration, as did 15.3% for ANG and 7.7% for bFGF. In ascites, the VEGF concentration was in the range for normal serum in 24.5% of samples, compared to 39.4% for ANG and 2.8% for bFGF. In paired samples, both VEGF and bFGF showed higher ascitic concentrations in 100 and 88.3% of samples, compared to 53.3% for ANG. There was no correlation between the serum and/or ascitic concentration of one factor and that of another, suggesting that these factors are independently regulated. Staining with anti-CD34 was more sensitive and reliable than with anti-factor VIII. VEGF staining was most prominent in poorly differentiated tumors and was observed only on tumor cells. There was no correlation between the serum or ascitic concentrations of angiogenic factors and tumor vascularity. Advanced EOC is associated with raised serum and ascitic bFGF concentrations and with markedly elevated ascitic VEGF in most cases. Serum VEGF and serum and ascitic ANG are less often elevated. There was no correlation between the angiogenic profile in serum and ascites and tumor vascularity.


Anti-inflammatory effect of Prunus armeniaca L. (Apricot) extracts ameliorates TNBS-induced ulcerative colitis in rats.
Prunus armeniaca L. (Apricot) is a tree cultivated in different parts of the world. Apricot kernel as a good dietary supplement has shown antioxidant, anti-inflammatory and other pharmacologic properties which suggest that it may be functional as an anticolitis agent. In this study we evaluated the effects of apricot kernel extract and oil on ulcerative colitis in rats. Rats were fasted for 36 h before the experiment. Colitis was induced by intra-rectal instillation of 50 mg/kg trinitrobenzene sulfonic acid in male Wistar rats. Treatments were started 6 h after colitis induction and continued every 24 h for 5 days. Apricot kernel extract (100, 200, 400 mg/kg p.o. and 100, 400 mg/kg i.p.) and apricot kernel extract/oil (100, 200, 400 mg/kg p.o.) were used as experimental treatments and prednisolone (4 mg/kg p.o. or i.p.) was used as reference drug. On the day 6, colon tissue was removed and macroscopic and pathologic parameters were evaluated. Ulcer index and total colitis index as representative of macroscopic and histologic parameters respectively showed ameliorating effects in experimental groups especially those treated by intraperitoneal administration route. Results also demonstrated that oil fraction was not able to potentiate the effects of extract. These data suggest that apricot kernel extracts (with or without oil) can be introduced for further mechanistic and clinical studies as a complementary medicine for inflammatory bowel disorders.


Survival motor neuron affects plastin 3 protein levels leading to motor defects.
The actin-binding protein plastin 3 (PLS3) has been identified as a modifier of the human motoneuron disease spinal muscular atrophy (SMA). SMA is caused by decreased levels of the survival motor neuron protein (SMN) and in its most severe form causes death in infants and young children. To understand the mechanism of PLS3 in SMA, we have analyzed pls3 RNA and protein in zebrafish smn mutants. We show that Pls3 protein levels are severely decreased in smn(-/-) mutants without a reduction in pls3 mRNA levels. Moreover, we show that both pls3 mRNA and protein stability are unaffected when Smn is reduced. This indicates that SMN affects PLS3 protein production. We had previously shown that, in smn mutants, the presynaptic protein SV2 is decreased at neuromuscular junctions. Transgenically driving human PLS3 in motoneurons rescues the decrease in SV2 expression. To determine whether PLS3 could also rescue function, we performed behavioral analysis on smn mutants and found that they had a significant decrease in spontaneous swimming and turning. Driving PLS3 transgenically in motoneurons rescued both of these defects. These data show that PLS3 protein levels are dependent on SMN and that PLS3 is able to rescue the neuromuscular defects and corresponding movement phenotypes caused by low levels of Smn suggesting that decreased PLS3 contributes to SMA motor phenotypes.


15-Epi-LXA4 and MaR1 counter inflammation in stromal cells from patients with Achilles tendinopathy and rupture.
Resolution of inflammation is poorly understood in Achilles tendon disorders. Herein, we investigated the bioactive lipid mediator profiles of tendon-derived stromal cells isolated from patients with Achilles tendinopathy (AT) or Achilles rupture (AR) under baseline and IL-1β-stimulated conditions. We also determined whether incubating these cells with 2 of the mediators produced by tendon-derived stromal cells, 15-epi-Lipoxin A4 (15-epi-LXA4) or maresin (MaR)-1, moderated their proinflammatory phenotype. Under baseline conditions, AT cells showed concurrent increased levels of proinflammatory eicosanoids and proresolving mediators compared with AR cells. IL-1β treatment induced profound prostaglandin E2 release in AR compared with AT cells. Incubation of IL-1β treated AT and AR tendon-derived stromal cells in 15-epi-LXA4 or MaR1 reduced proinflammatory eicosanoids and potentiated the release of proresolving mediators. These mediators also induced specialized proresolving mediator (SPM) biosynthetic enzymes arachidonate lipoxygenase (ALOX) 12 and ALOX15 and up-regulated the proresolving receptor ALX compared with vehicle-treated cells. Incubation in 15-epi-LXA4 or MaR1 also moderated the proinflammatory phenotype of AT and AR cells, regulating podoplanin, CD90, signal transducer and activator of transcription (STAT)-1, IL-6, IFN regulatory factor (IRF) 5, and TLR4 and suppressed c-Jun N-terminal kinase 1/2/3, Lyn, STAT-3, and STAT-6 phosphokinase signaling. In summary, we identify proresolving mediators that are active in AT and AR and propose SPMs, including 15-epi-LXA4 or MaR1, as a potential strategy to counterregulate inflammatory processes in these cells.-Dakin, S. G., Colas, R. A., Newton, J., Gwilym, S., Jones, N., Reid, H. A. B., Wood, S., Appleton, L., Wheway, K., Watkins, B., Dalli, J., Carr, A. J. 15-Epi-LXA4 and MaR1 counter inflammation in stromal cells from patients with Achilles tendinopathy and rupture.


A pharmacogenomic method for individualized prediction of drug sensitivity.
Identifying the best drug for each cancer patient requires an efficient individualized strategy. We present MATCH (Merging genomic and pharmacologic Analyses for Therapy CHoice), an approach using public genomic resources and drug testing of fresh tumor samples to link drugs to patients. Valproic acid (VPA) is highlighted as a proof-of-principle. In order to predict specific tumor types with high probability of drug sensitivity, we create drug response signatures using publically available gene expression data and assess sensitivity in a data set of >40 cancer types. Next, we evaluate drug sensitivity in matched tumor and normal tissue and exclude cancer types that are no more sensitive than normal tissue. From these analyses, breast tumors are predicted to be sensitive to VPA. A meta-analysis across breast cancer data sets shows that aggressive subtypes are most likely to be sensitive to VPA, but all subtypes have sensitive tumors. MATCH predictions correlate significantly with growth inhibition in cancer cell lines and three-dimensional cultures of fresh tumor samples. MATCH accurately predicts reduction in tumor growth rate following VPA treatment in patient tumor xenografts. MATCH uses genomic analysis with in vitro testing of patient tumors to select optimal drug regimens before clinical trial initiation.


Systems biology approaches to finding novel pain mediators.
Chronic pain represents a major health burden; this maladaptive pain state occurs as a consequence of hypersensitivity within the peripheral and central components of the somatosensory system. High throughput technologies (genomics, transciptomics, lipidomics, and proteomics) are now being applied to tissue derived from pain patients as well as experimental pain models to discover novel pain mediators. The use of clustering, meta-analysis and other techniques can help refine potential candidates. Of particular importance are systems biology methods, such as co-expression network generating algorithms, which infer potential associations/interactions between molecules and build networks based on these interactions. Protein-protein interaction networks allow the lists of potential targets generated by these different platforms to be analyzed in their biological context. Outputs from these different methods must also be related to the clinical pain phenotype. The improved and standardized phenotyping of pain symptoms and sensory signs enables much better subject stratification. Our hope is that, in the future, the use of computational approaches to integrate datasets including sensory phenotype as well as the outputs of high throughput technologies will help define novel pain mediators and provide insights into the pathogenesis of chronic pain.


An optimal proportion of mixing broad-leaved forest for enhancing the effective productivity of moso bamboo.
Moso bamboos (Phyllostachys edulis) are important forestry plants in southern China, with substantial roles to play in regional economic and ecological systems. Mixing broad-leaved forests and moso bamboos is a common management practice in China, and it is fundamental to elucidate the interactions between broad-leaved trees and moso bamboos for ensuring the sustainable provision of ecosystem services. We examine how the proportion of broad-leaved forest in a mixed managed zone, topology, and soil profile affects the effective productivity of moso bamboos (i.e., those with significant economic value), using linear regression and generalized additive models. Bamboo's diameter at breast height follows a Weibull distribution. The importance of these variables to bamboo productivity is, respectively, slope (25.9%), the proportion of broad-leaved forest (24.8%), elevation (23.3%), gravel content by volume (16.6%), slope location (8.3%), and soil layer thickness (1.2%). Highest productivity is found on the 25° slope, with a 600-m elevation, and 30% broad-leaved forest. As such, broad-leaved forest in the upper slope can have a strong influence on the effective productivity of moso bamboo, ranking only after slope and before elevation. These factors can be considered in future management practice.


Transabdominal Redo Ileal Pouch Surgery for Failed Restorative Proctocolectomy: Lessons Learned Over 500 Patients.
The purpose of this study was to report our large, single-center experience of transabdominal ileal pouch-anal anastomoses (IPAA) redo surgery for a failed initial IPAA. IPAA fail from 3% to 15% of the times, mainly due to technical or inflammatory conditions. There is limited information about the surgical, functional, and quality-of-life (QOL) outcomes of redo surgery for failed IPAA, especially in large series of patients. Patients undergoing transabdominal redo surgery for failed IPAA between 1983 and 2014 were evaluated. Primary endpoints were morbidity of the surgery, the proportion of patients with a functioning pouch, frequency of defecation and incidence of incontinence, and the patients' perception of QOL. There were 502 (43% males) patients with a median age of 38 years and median body mass index 24 kg/m at the time of revision surgery. A new pouch was created in 41% of patients whereas 59% had their original pouch revised and retained. Postoperative mortality was 0% and morbidity was 53%. The short-term anastomotic leak rate was 8%. At a median follow-up of 7 years after redo surgery, 101 (n = 20%) patients had redo IPAA failure. Pelvic sepsis developing after redo ileal pouch surgery was the primary indicator of pouch failure (hazard ratio, 3.691; 95% confidence interval, 2.411-5.699; P < 0.0001). Overall functional outcomes and QOL scores were acceptable. Patients with a failed ileoanal pouch may be offered redo pouch surgery with a high likelihood of success in terms of function and QOL.


Inhibition of HIV-1 multiplication by a modified U7 snRNA inducing Tat and Rev exon skipping.
The HIV-1 regulatory proteins Tat and Rev are encoded by multiply spliced mRNAs that differ by the use of alternative 3' splice sites at the beginning of the internal exon. If these internal exons are skipped, the expression of these genes, and hence HIV-1 multiplication, should be inhibited. We have previously developed a strategy, based on antisense derivatives of U7 small nuclear RNA, that allows us to induce the skipping of an internal exon in virtually any gene. Here, we have successfully applied this approach to induce a partial skipping of the Tat, Rev (and Nef) internal exons. Three functional U7 constructs were subcloned into a lentiviral vector. Two of them strongly reduced the efficiency of lentiviral particle production compared to vectors carrying either no U7 insert or unrelated U7 cassettes. This defect could be partly or fully compensated by coexpressing Rev from an unspliced mRNA in the producing cell line. Upon stable transduction into CEM-SS or CEM T-lymphocytes, the most efficient of these constructs inhibits HIV-1 multiplication. Although the inhibition is not complete, it is more efficient in combination with another mechanism inhibiting HIV multiplication. Therefore, this new approach targeting HIV-1 regulatory genes at the level of pre-mRNA splicing, in combination with other antiviral strategies, may be a useful new tool in the fight against HIV/AIDS.


Nasal patency as a factor for successful transnasal endoscopy.
In recent years, transnasal endoscopy had been more widely accepted for its safety and convenience, and although it can lead to a weaker pharyngeal reflex, compared with the effects of transoral endoscopy, examinees often suffer intolerable pain and discomfort during passage of the endoscope through the nasal cavity. The aim of this study was to estimate the relationship between the uncomfortable factors during transnasal endoscopy and nasal patency. The subjects comprised 23 consecutive patients who underwent transnasal endoscopy from October 2007 to April 2009 at our Gastroenterology and Otorhinolaryngology Departments. Immediately prior to endoscopy, the left and right nasal resistance was measured with an active anterior rhinomanometer; a value of 100 Pa was determined as nasal resistance. The transnasal endoscope was inserted in the subjectively preferred side by the examinee. Thereafter, the subjects were asked to fill in a questionnaire on physical tolerance during the procedure, to quantify the sensations of nasal pain, nausea, and choking on a 10-point visual analogue scale. The mean scores were 3.0 ± 2.7 for nasal pain, 1.7 ± 2.0 for choking, and 1.6 ± 1.9 for nausea. The most intolerable factor among the complaints was pain (45%), which was followed by nausea (18%) and choking (9%). Unilateral nasal resistance was significantly related with nasal pain only (P = 0.0135). In conclusion, the most difficult problem during transnasal endoscopy was pain, which was related to nasal patency. We successfully demonstrated the clinical significance of nasal patency in determining the side of insertion for transnasal endoscopy.


Comprehensive overview of recent preparation and application trends of various open tubular capillary columns in separation science.
Open tubular (OT) capillary columns have been increasingly used in a variety of fields of separation science such as CEC, LC, and SPE. Especially their application in CEC has attracted a lot of attention for their outstanding separation performance. Various forms of OT stationary phase materials have been employed such as in-situ prepared polymers, molecular imprinted polymers (MIPs), brush ligands, host ligands, block copolymers, aptamers, carbon nanotubes, polysaccharides, proteins, tentacles, nanoparticles, monoliths, and polyelectrolyte multi-layers. They have been prepared either in the chemically bound format or physically adsorbed format. Sol-gel technologies and nanoparticles have been sometimes involved in their preparation. There have been also some unique miscellaneous studies, for example, adopting preferentially adsorbed mobile phase components as stationary phases. In this review, recent progresses since mostly 2007 will be critically discussed in detail with some summarized descriptions for the work before the date.


Correlation of the Bruininks-Oseretsky Test of Motor Proficiency with the Southern California Sensory Integration Tests.
Correlations between the Bruininks-Oseretsky Test of Motor Proficiency (BOTMP) and the Southern California Sensory Integration Tests (SCSIT) were studied by using test results obtained from a sample of 49 learning-disabled children. It was found that those SCSIT tests with a motor component correlated significantly with the BOTMP battery composite scores. The fine motor composite scores of the BOTMP reflected the greatest percentage of significant correlation with SCSIT tests. These results suggested that the BOTMP would be useful for screening children for referral to occupational therapy by educators. In addition, the high correlation of the BOTMP with the SCSIT motor tests indicated that the BOTMP may be appropriate for use in clinical research to evaluate the effectiveness of sensory integrative procedures in relation to motor function.


Ischemia-induced spreading depolarization in the retina.
Cortical spreading depolarization is a metabolically costly phenomenon that affects the brain in both health and disease. Following severe stroke, subarachnoid hemorrhage, or traumatic brain injury, cortical spreading depolarization exacerbates tissue damage and enlarges infarct volumes. It is not known, however, whether spreading depolarization also occurs in the retina in vivo. We report now that spreading depolarization episodes are generated in the in vivo rat retina following retinal vessel occlusion produced by photothrombosis. The properties of retinal spreading depolarization are similar to those of cortical spreading depolarization. Retinal spreading depolarization waves propagate at a velocity of 3.0 ± 0.1 mm/min and are associated with a negative shift in direct current potential, a transient cessation of neuronal spiking, arteriole constriction, and a decrease in tissue O2 tension. The frequency of retinal spreading depolarization generation in vivo is reduced by administration of the NMDA antagonist MK-801 and the 5-HT(1D) agonist sumatriptan. Branch retinal vein occlusion is a leading cause of vision loss from vascular disease. Our results suggest that retinal spreading depolarization could contribute to retinal damage in acute retinal ischemia and demonstrate that pharmacological agents can reduce retinal spreading depolarization frequency after retinal vessel occlusion. Blocking retinal spreading depolarization generation may represent a therapeutic strategy for preserving vision in branch retinal vein occlusion patients.