Propolis and Its Combination with Boric Acid Protect Against Ischemia/Reperfusion-Induced Acute Kidney Injury by Inhibiting Oxidative Stress, Inflammation, DNA Damage, and Apoptosis in Rats.
Ischemia reperfusion (I/R) injury which causes kidney dysfunction is one of the most studied diseases directly linked to oxidative stress. In this regard, it is important to protect cells against damage by inducing antioxidant response. Herein, we aimed to evaluate the therapeutic roles and possible mechanisms of propolis and boric acid in kidney I/R injury based on relevant basic research and clinical studies. Sprague-Dawley rats were subjected to 50 min of ischemia followed by 3 h of reperfusion. Animals were randomly divided into a control group (the abdominal wall was just opened and closed), an I/R injury group, the propolis intervention group (200 mg/kg, intragastric administration, 1 h before ischemia), boric acid intervention group (14 mg/kg, intragastric administration 1 h before ischemia), and the propolis + boric acid intervention group (intragastric administration 1 h before ischemia). Kidney function, the antioxidant defensive system, and renal damage were assessed. In addition, the oxidative stress and inflammatory status were estimated in renal tissue. Furthermore, DNA damageand apoptosis were detected by immunohistochemistry. When compared with I/R group, propolis alone and especially propolis + boric acid groups significantly improved functional parameters. While the antioxidant response was increased, renal injury size and apoptosis were significantly decreased in both groups. Also, the MDA and TNF-α levels besides the 8-OHdG formation were downregulated. According to these outcomes, it can be said that especially propolis together with boric acid ameliorates kidney injury caused by I/R through acting as an antioxidant, anti-inflammatory, and antiapoptotic agent. In conclusion, propolis alone and its combination with boric acid could be developed as therapeutic agents against serious renal I/R injuries.


Rb2SeOCl4·H2O: a polar material among the alkali metal selenite halides with a strong SHG response.
An alkali metal selenite chloride, Rb2SeOCl4·H2O, has been hydrothermally synthesized and structurally characterized. It is the first example of an alkali metal selenite halide in the literature. The compound crystallizes in the noncentrosymmetric (NCS) space group, Cmc21(36), of the orthorhombic system with a = 10.342(3) Å, b = 10.124(3) Å, c = 9.158(3) Å, and α = β = γ = 90°. The anionic [SeOCl4]2- groups are arranged in the crystal in nearly the same direction, giving rise to a relatively large macroscopic dipole moment, causing the compound to display second harmonic generation (SHG) eight times as strong as that of KDP, measured using the Kurtz-Perry method on powders. First-principle density functional theory (DFT) calculations were carried out to interpret the relationship between the crystal structure and properties.


Spontaneous abortion and a diet drug containing caffeine and ephedrine: a study within the Danish national birth cohort.
Medications may be consumed periconceptionally before a woman knows she is pregnant. In this study, the authors evaluate the association of a prescription diet drug (Letigen) containing ephedrine (20 mg) and caffeine (200 mg) with spontaneous abortion (SAB) in the Danish National Birth Cohort. Women were recruited during their first prenatal visit from 1996-2002. Pre-conception and early pregnancy medication use was reported on the enrollment form, and pregnancy outcome was determined by linking the mother's Civil Registration Number to the Medical Birth Registry and the National Hospital Discharge Register. Of 97,903 eligible pregnancies, 4,443 ended in SAB between 5 and 20 completed gestational weeks, inclusive. Letigen use was reported for 565 pregnancies. Cox regression models accounting for left truncation were fit to estimate the effect of pre-conception and early pregnancy Letigen use on SAB. The estimated maternal age-adjusted hazard ratio for SAB was 1.1 (95% confidence interval 0.8-1.6) for any periconceptional Letigen use compared to no periconceptional use. Although Letigen has high levels of caffeine (the recommended 3 pills/day are approximately equivalent to caffeine from 6 cups of coffee), periconceptional use does not appear to be associated with an appreciably increased hazard of clinically recognized SAB.


The era of the wandering mind? Twenty-first century research on self-generated mental activity.
The first decade of the twenty-first century was characterized by renewed scientific interest in self-generated mental activity (activity largely generated by the individual, rather than in direct response to experimenters' instructions or specific external sensory inputs). To understand this renewal of interest, we interrogated the peer-reviewed literature from 2003 to 2012 (i) to explore recent changes in use of terms for self-generated mental activity; (ii) to investigate changes in the topics on which mind wandering research, specifically, focuses; and (iii) to visualize co-citation communities amongst researchers working on self-generated mental activity. Our analyses demonstrated that there has been a dramatic increase in the term "mind wandering" from 2006, and a significant crossing-over of psychological investigations of mind wandering into cognitive neuroscience (particularly in relation to research on the default mode and default mode network). If our article concludes that this might, indeed, be the "era of the wandering mind," it also calls for more explicit reflection to be given by researchers in this field to the terms they use, the topics and brain regions they focus on, and the research literatures that they implicitly foreground or ignore.


Using quantitative wastewater analysis to measure daily usage of conventional and emerging illicit drugs at an annual music festival.
Wastewater analysis provides a non-intrusive way of measuring drug use within a population. We used this approach to determine daily use of conventional illicit drugs [cannabis, cocaine, methamphetamine and 3,4-methylenedioxymethamphetamine (MDMA)] and emerging illicit psychostimulants (benzylpiperazine, mephedrone and methylone) in two consecutive years (2010 and 2011) at an annual music festival. Daily composite wastewater samples, representative of the festival, were collected from the on-site wastewater treatment plant and analysed for drug metabolites. Data over 2 years were compared using Wilcoxon matched-pair test. Data from 2010 festival were compared with data collected at the same time from a nearby urban community using equivalent methods. Conventional illicit drugs were detected in all samples whereas emerging illicit psychostimulants were found only on specific days. The estimated per capita consumption of MDMA, cocaine and cannabis was similar between the two festival years. Statistically significant (P < 0.05; Z = -2.0-2.2) decreases were observed in use of methamphetamine and one emerging illicit psychostimulant (benzyl piperazine). Only consumption of MDMA was elevated at the festival compared with the nearby urban community. Rates of substance use at this festival remained relatively consistent over two monitoring years. Compared with the urban community, drug use among festival goers was only elevated for MDMA, confirming its popularity in music settings. Our study demonstrated that wastewater analysis can objectively capture changes in substance use at a music setting without raising major ethical issues. It would potentially allow effective assessments of drug prevention strategies in such settings in the future.


Evidence of a large, international network of HCV transmission in HIV-positive men who have sex with men.
Since 2000, there has been a marked rise in acute hepatitis C virus (HCV) in human immunodeficiency virus (HIV)-positive men who have sex with men (MSM). We conducted an international phylogenetic study to investigate the existence of an HCV transmission network among MSM. HIV-positive MSM diagnosed with recent HCV (n = 226) in England (107), The Netherlands (58), France (12), Germany (25), and Australia (24) between 2000 and 2006 were enrolled into a molecular phylogenetic study. Using real-time polymerase chain reaction (PCR), the NS5B region of the HCV genome (436 base pair) was amplified, sequenced, and compared with unrelated NS5B sequences. NS5B sequences were obtained from 200 (89%) cases. Circulating HCV genotypes were 1a (59%), 4d (23%), 3a (11%), 1b (5%), and 2b/c (3%). Phylogenetic analysis revealed 156 (78%) sequences that formed 11 clusters (bootstrap value > 70%) containing between 4 and 37 individual sequences. Country mixing was associated with larger cluster size (17 vs 4.5 sequences; P = .03). "Molecular clock" analysis indicated that the majority (85%) of transmissions occurred since 1996. Phylogenetic analysis revealed a large international network of HCV transmission among HIV-positive MSM. The rapid spread of HCV among neighboring countries is supported by the large proportion (74%) of European MSM infected with an HCV strain co-circulating in multiple European countries, the low evolutionary distances among HCV isolates from different countries, and the trend toward increased country mixing with increasing cluster size. Temporally, this epidemic coincides with the introduction of highly active antiretroviral therapy and associated increases in sexual risk behaviors. International collaborative public health efforts are needed to mitigate HCV transmission among this population.


Lipoprotein hydrophobic core lipids are partially extruded to surface in smaller HDL: "Herniated" HDL, a common feature in diabetes.
Recent studies have shown that pharmacological increases in HDL cholesterol concentrations do not necessarily translate into clinical benefits for patients, raising concerns about its predictive value for cardiovascular events. Here we hypothesize that the size-modulated lipid distribution within HDL particles is compromised in metabolic disorders that have abnormal HDL particle sizes, such as type 2 diabetes mellitus (DM2). By using NMR spectroscopy combined with a biochemical volumetric model we determined the size and spatial lipid distribution of HDL subclasses in a cohort of 26 controls and 29 DM2 patients before and after two drug treatments, one with niacin plus laropiprant and another with fenofibrate as an add-on to simvastatin. We further characterized the HDL surface properties using atomic force microscopy and fluorescent probes to show an abnormal lipid distribution within smaller HDL particles, a subclass particularly enriched in the DM2 patients. The reduction in the size, force cholesterol esters and triglycerides to emerge from the HDL core to the surface, making the outer surface of HDL more hydrophobic. Interestingly, pharmacological interventions had no effect on this undesired configuration, which may explain the lack of clinical benefits in DM2 subjects.


Etiology and audiological outcomes at 3 years for 364 children in Australia.
Hearing loss is an etiologically heterogeneous trait with differences in the age of onset, severity and site of lesion. It is caused by a combination of genetic and/or environmental factors. A longitudinal study to examine the efficacy of early intervention for improving child outcomes is ongoing in Australia. To determine the cause of hearing loss in these children we undertook molecular testing of perinatal "Guthrie" blood spots of children whose hearing loss was either detected via newborn hearing screening or detected later in infancy. We analyzed the GJB2 and SLC26A4 genes for the presence of mutations, screened for the mitochondrial DNA (mtDNA) A1555G mutation, and screened for congenital CMV infection in DNA isolated from dried newborn blood spots. Results were obtained from 364 children. We established etiology for 60% of children. One or two known GJB2 mutations were present in 82 children. Twenty-four children had one or two known SLC26A4 mutations. GJB2 or SLC26A4 changes with unknown consequences on hearing were found in 32 children. The A1555G mutation was found in one child, and CMV infection was detected in 28 children. Auditory neuropathy spectrum disorder was confirmed in 26 children whose DNA evaluations were negative. A secondary objective was to investigate the relationship between etiology and audiological outcomes over the first 3 years of life. Regression analysis was used to investigate the relationship between hearing levels and etiology. Data analysis does not support the existence of differential effects of etiology on degree of hearing loss or on progressiveness of hearing loss.


Cost-Effectiveness of Sugammadex Versus Neostigmine to Reverse Neuromuscular Blockade in a University Hospital in Taiwan: A Propensity Score-Matched Analysis.
Sugammadex has several pharmacological advantages over neostigmine, including faster reversal of neuromuscular blockade and fewer adverse effects. However, the economic impact of sugammadex remains controversial due to the considerable heterogeneity of study designs and clinical settings in previous studies. In a post-hoc analysis of a randomized controlled trial, we evaluated patients who underwent elective surgeries and general anesthesia with endotracheal intubation in a medical center in Taiwan between March 2020 and August 2020. Patients were divided into either the sugammadex or neostigmine group based on the neuromuscular blocking drug used. Propensity score matching was used to balance the baseline patient characteristics between the two groups. The patient's recovery from anesthesia and the putative cost-effectiveness of sugammadex versus neostigmine was assessed. Derived cost-effectiveness using personnel costs in the operating room and the post-anesthesia care unit was estimated using multiple linear regression models. A total of 2587 and 1784 patients were included before and after matching, respectively. Time to endotracheal extubation was significantly shorter in the sugammadex group (mean 6.0 ± standard deviation 5.3 min) compared with the neostigmine group (6.6 ± 6.3 min; p = 0.0032). In addition, the incidence of bradycardia was significantly lower in the sugammadex group (10.2%) compared with the neostigmine group (16.9%; p < 0.001). However, the total costs were significantly lower in the neostigmine group (50.6 ± 21.4 United States dollars) compared with the sugammadex group (212.0 ± 49.5 United States dollars). Despite improving postoperative recovery, the benefits of sugammadex did not outweigh its higher costs compared with neostigmine, possibly due to the low costs of labor in Taiwan's healthcare system.


Energy audit in small wastewater treatment plants: methodology, energy consumption indicators, and lessons learned.
Energy audits in wastewater treatment plants (WWTPs) reveal large differences in the energy consumption in the various stages, depending also on the indicators used in the audits. This work is aimed at formulating a suitable methodology to perform audits in WWTPs and identifying the most suitable key energy consumption indicators for comparison among different plants and benchmarking. Hydraulic-based stages, stages based on chemical oxygen demand, sludge-based stages and building stages were distinguished in WWTPs and analysed with different energy indicators. Detailed energy audits were carried out on five small WWTPs treating less than 10,000 population equivalent and using continuous data for 2 years. The plants have in common a low designed capacity utilization (52% on average) and equipment oversizing which leads to waste of energy in the absence of controls and inverters (a common situation in small plants). The study confirms that there are several opportunities for reducing energy consumption in small WWTPs: in addition to the pumping of influent wastewater and aeration, small plants demonstrate low energy efficiency in recirculation of settled sludge and in aerobic stabilization. Denitrification above 75% is ensured through intermittent aeration and without recirculation of mixed liquor. Automation in place of manual controls is mandatory in illumination and electrical heating.


Effects of exercise, diet, and their combination on metabolic-syndrome-related parameters in OLETF rats.
This study was conducted to assess the effects of exercise, diet, and their combination on metabolic syndrome (MS) risk factors including visceral fat mass (VFM), glucose intolerance, and dyslipidemia in OLETF rats. Thirty-two male rats were assigned to exercise (OLETF-Ex), dietary treatment (-DT), combination (-Ex&DT), or sedentary (-Sed) groups. Daily voluntary exercise using a rotary wheel was performed in OLETF-Ex. Each treatment was conducted from 21 to 31 wk of age. An oral glucose tolerance test was performed before and after the treatment period. Absolute levels of VFM, subcutaneous fat mass (SFM), and serum lipids including triglyceride, total cholesterol, and LDL-cholesterol (LDL-C) were measured after the treatment period. All therapeutic treatments resulted in significantly lower levels of body weight, VFM, SFM, and serum lipids than in sedentary control rats. All therapeutic treatments were also found to improve indices of oral glucose tolerance. Of the 3 therapeutic treatments, serum LDL-C levels were significantly lower in OLETF-Ex and OLETF-Ex&DT than in OLETF-Sed. The data demonstrate that all therapeutic approaches tested were effective in improving a number of MS-related parameters in OLETF rats. However, exercise-based therapeutic intervention may provide additional benefits for improving fat metabolism in MS patients.


Nepenthesin from monkey cups for hydrogen/deuterium exchange mass spectrometry.
Studies of protein dynamics, structure and interactions using hydrogen/deuterium exchange mass spectrometry (HDX-MS) have sharply increased over the past 5-10 years. The predominant technology requires fast digestion at pH 2-3 to retain deuterium label. Pepsin is used almost exclusively, but it provides relatively low efficiency under the constraints of the experiment, and a selectivity profile that renders poor coverage of intrinsically disordered regions. In this study we present nepenthesin-containing secretions of the pitcher plant Nepenthes, commonly called monkey cups, for use in HDX-MS. We show that nepenthesin is at least 1400-fold more efficient than pepsin under HDX-competent conditions, with a selectivity profile that mimics pepsin in part, but also includes efficient cleavage C-terminal to "forbidden" residues K, R, H, and P. High efficiency permits a solution-based analysis with no detectable autolysis, avoiding the complication of immobilized enzyme reactors. Relaxed selectivity promotes high coverage of disordered regions and the ability to "tune" the mass map for regions of interest. Nepenthesin-enriched secretions were applied to an analysis of protein complexes in the nonhomologous end-joining DNA repair pathway. The analysis of XRCC4 binding to the BRCT domains of Ligase IV points to secondary interactions between the disordered C-terminal tail of XRCC4 and remote regions of the BRCT domains, which could only be identified with a nepenthesin-based workflow. HDX data suggest that stalk-binding to XRCC4 primes a BRCT conformation in these remote regions to support tail interaction, an event which may be phosphoregulated. We conclude that nepenthesin is an effective alternative to pepsin for all HDX-MS applications, and especially for the analysis of structural transitions among intrinsically disordered proteins and their binding partners.


The educational needs of staff grade doctors and dentists in Scotland.
Since its introduction in 1990, the Staff Grade has expanded to comprise almost 10% of the career grade establishment in Scotland. A study of this new grade was carried out to determine its progress and whether educational needs were being met. A questionnaire was sent to all doctors and dentists in the Staff Grade asking about reasons for applying; working environment; educational needs and perceptions of the grade. In Scotland 45% of Staff Grade doctors and dentists are male and 55% are female. The majority of posts are held by UK qualified women and overseas qualified men. Post holders are well qualified. 56% hold at least one full Membership or Fellowship qualification. The main reasons for applying for a Staff Grade post are domestic commitments and the desire for a permanent post. Staff Grade doctors are often used to strengthen 'middle grade' services and cover awkward times. The majority feel the educational content of their job is sufficient. Of those who were dissatisfied, most complained of a lack of formal education. In general the doctors and dentists feel they are viewed with respect by colleagues. Comments showed that senior staff are more positive towards the grade than juniors. 21% of Staff Grade doctors and dentists still hope to achieve Consultant status, although the greater majority do not think it likely they will reach this level. In the short term the introduction of the grade has been a success. The service needs which otherwise would be difficult to meet have been covered by the appointment of Staff Grade doctors and dentists. For the individual the Staff Grade has often been the answer to personal rather than professional aspirations. Some battle against colleagues' misconceptions that the grade is for 'failed Consultants'. Isolation is a problem for others. There is a desire to keep knowledge up to date, but heavy workload and problems in scheduling prevent many from attending educational activities. If the Staff Grade is to be an attractive option in the long term, there needs to be some form of career progression for the doctors and dentists within it.


Comparing inconsistent relationship configurations indicating UMLS errors.
The goal of this paper is to audit null-annotated parent-child pairs in the UMLS Metathesaurus. We have developed techniques for identifying suspicious pairs with high likelihood of errors by using inconsistencies between the hierarchical relationships of the Metathesaurus and the Semantic Network. Two formal conditions, called semantic inversion and lack of ancestry are investigated. Analyzing two corresponding samples shows that semantic inversion is significantly more likely to indicate an error than lack of ancestry, which in turn is more likely to indicate errors than a consistent configuration. We also discuss cases of parent-child pairs with semantic inversion that may be corrected by disambiguating the child.


Benefits of curcumin in brain disorders.
Curcumin is widely consumed in Asia either as turmeric directly or as one of the culinary ingredients in food recipes. The benefits of curcumin in different organ systems have been reported extensively in several neurological diseases and cancer. Curcumin has got its global recognition because of its strong antioxidant, anti-inflammatory, anti-cancer, and antimicrobial activities. Additionally, it is used in diabetes and arthritis as well as in hepatic, renal, and cardiovascular diseases. Recently, there is growing attention on usage of curcumin to prevent or delay the onset of neurodegenerative diseases. This review summarizes available data from several recent studies on curcumin in various neurological diseases such as Alzheimer's disease, Parkinson's disease, Multiple Sclerosis, Huntington's disease, Prions disease, stroke, Down's syndrome, autism, Amyotrophic lateral sclerosis, anxiety, depression, and aging. Recent advancements toward increasing the therapeutic efficacy of curcuma/curcumin formulation and the novel delivery strategies employed to overcome its minimal bioavailability and toxicity studies have also been discussed. This review also summarizes the ongoing clinical trials on curcumin for different neurodegenerative diseases and patent details of curcuma/curcumin in India.


Myo-Inositol Transporter SLC5A3 Associates with Degenerative Changes and Inflammation in Sporadic Inclusion Body Myositis.
Myo-inositol exerts many cellular functions, which include osmo-protection, membrane functioning, and secondary messaging. Its Na+/myo-inositol co-transporter SLC5A3 is expressed in muscle tissue and further accumulates in myositis. In this study we focused on the peculiar subgroup of sporadic inclusion body myositis (IBM), in which auto-inflammatory responses and degenerative changes co-exist. A cohort of nine patients was selected with clinically confirmed IBM, in which SLC5A3 protein was immune-localized to the different tissue constituents using immunofluorescence, and expression levels were evaluated using Western blotting. In normal muscle tissue, SLC5A3 expression was restricted to blood vessels and occasional low levels on muscle fiber membranes. In IBM tissues, SLC5A3 staining was markedly increased, with discontinuous staining of the muscle fiber membranes, and accumulation of SLC5A3 near inclusions and on the rims of vacuoles. A subset of muscle-infiltrating auto-aggressive immune cells was SLC5A3 positive, of which most were T-cells and M1 lineage macrophages. We conclude that SLC5A3 is overexpressed in IBM muscle, where it associates with protein aggregation and inflammatory infiltration. Based on our results, functional studies could be initiated to explore the possibilities of therapeutic osmolyte pathway intervention for preventing protein aggregation in muscle cells.


Simple to complex modeling of breathing volume using a motion sensor.
To compare simple and complex modeling techniques to estimate categories of low, medium, and high ventilation (VE) from ActiGraph™ activity counts. Vertical axis ActiGraph™ GT1M activity counts, oxygen consumption and VE were measured during treadmill walking and running, sports, household chores and labor-intensive employment activities. Categories of low (<19.3 l/min), medium (19.3 to 35.4 l/min) and high (>35.4 l/min) VEs were derived from activity intensity classifications (light <2.9 METs, moderate 3.0 to 5.9 METs and vigorous >6.0 METs). We examined the accuracy of two simple techniques (multiple regression and activity count cut-point analyses) and one complex (random forest technique) modeling technique in predicting VE from activity counts. Prediction accuracy of the complex random forest technique was marginally better than the simple multiple regression method. Both techniques accurately predicted VE categories almost 80% of the time. The multiple regression and random forest techniques were more accurate (85 to 88%) in predicting medium VE. Both techniques predicted the high VE (70 to 73%) with greater accuracy than low VE (57 to 60%). Actigraph™ cut-points for light, medium and high VEs were <1381, 1381 to 3660 and >3660 cpm. There were minor differences in prediction accuracy between the multiple regression and the random forest technique. This study provides methods to objectively estimate VE categories using activity monitors that can easily be deployed in the field. Objective estimates of VE should provide a better understanding of the dose-response relationship between internal exposure to pollutants and disease.


Identification and time dependence of quantitative trait loci for basal locomotor activity in the BXD recombinant inbred series and a B6D2 F2 intercross.
A complimentary two-phase strategy was used to detect and map quantitative trait loci (QTLs) associated with the basal locomotor response to a saline challenge (10 ml/kg). In phase 1, putative QTLs, significant at p < 0.01 or better, were identified by analysis of the strain means for 25 strains of the B x D recombinant inbred series. QTLs were identified on chromosomes 1, 3, 5, 9, 10, 16, and 18. Some of these QTLs were detected across the entire experimental period (0-20 min), while others were associated with specific 5-min blocks. Eighteen hundred C57BL/6J (B6) x DBA/2J (D2) F2 intercross animals were phenotyped for the basal locomotor response, and of this group, 500 to 700 individuals, pseudo-randomly selected, were used for a genomewide scan to confirm the RI-generated QTLs and to detect new QTLs. No new QTLs were detected but the QTLs on chromosome 1 were confirmed at p < 10(-5) to p < 10(-9), depending on the time interval. In addition, the QTLs on chromosomes 5 and 9 were confirmed at p < 0.001, providing a combined probability (RI + F2) which exceeds the threshold for a significant association. Two additional phenotypes which showed significant RI strain differences were examined--adaptation and thigmotaxis. Adaptation mapped to the same region of chromosome 9 and thigmotaxis to the same region of chromosome 1 as the distance-traveled QTL. Overall, the data presented here and elsewhere (Flint et al., 1995; Gershenfeld et al., 1997) illustrate that QTLs for basal activity are both robust and reliable.


Safety of autotransplants with high-dose melphalan in renal failure: a pharmacokinetic and toxicity study.
Melphalan (MEL) is probably the most effective chemotherapeutic agent in multiple myeloma (MM) with a clear dose-response effect. It can be escalated without excessive toxicity to 200 mg/m2, a myeloablative dose requiring hematopoietic stem cell support. Patients with marked renal insufficiency, not an infrequent finding in MM, have either received reduced doses or have been excluded from therapy with high-dose MEL. A prospective study was performed to evaluate the relationship between MEL pharmacokinetics and renal function in 20 patients with MM. Six patients had severe renal insufficiency (creatinine clearance, <40 ml/min), including five on chronic hemodialysis. Three patients with severe renal impairment first received a low test dose of MEL (16 mg/m2) for pharmacokinetic studies. All patients received 200 mg/m2 MEL divided into two equal doses of 100 mg/m2 i.v. on 2 consecutive days, followed by the administration of peripheral blood stem cells. MEL pharmacokinetics, performed after the first dose of 100 mg/m2, was not adversely affected by impaired renal function. The median half-life (t1/2), area under the concentration curve, and clearance of MEL were 1.1 h, 5.5 mg h/liter, and 27.5 liter/h, respectively, in patients with a creatinine clearance of <40 ml/min compared to 1.9, 7.9, and 23.6 for the others. Renal insufficiency also had no apparent negative impact on the quality of peripheral blood stem cell collections and did not adversely affect posttransplant engraftment, transfusion requirements, incidence of severe mucositis, or overall survival. However, it was associated with longer durations of fever (P = 0. 0005) and hospitalization (P = 0.004). No transplant-related deaths were observed. Plasma t1/2 and area under the concentration curve differed by a factor of 10 and MEL clearance by a factor of 5 between patients with the lowest and highest values. These large variations in MEL elimination could not be explained by patient or disease characteristics. We conclude that renal failure does not require dose reduction of MEL in autologous transplant. Due to marked interindividual variation in MEL elimination, pharmacokinetically guided dosing as well as cellular pharmacology studies may be helpful in achieving a more uniform antitumor effect.


Synthesis and Charactersiation of Chitosan conjugate; Design and Evaluation of Membrane Moderated Type Transdermal Drug Delivery System.
The purpose of the present research investigation was to synthesis, characterisation of chitosan conjugates and its effect on drug permeation from transdermal rate controlling membrane. Chitosan conjugate was synthesised by conjugation with thioglycolic acid. The prepared chitosan conjugate was characterised by determining the charring point, Fourier transmission-infrared and differential scanning calorimetric analysis. The rate controlling membranes were prepared by various proportions of chitosan and chitosan conjugate, to moderate drug permeation through rate controlling membrane. The membrane moderated transdermal system consists of reservoir to hold the drug gel was prepared by 20% w/v ethylcellulose with a cavity in its center. An impermeable backing layer was prepared by 2% w/v ethylcellulose. Gel consists of carvedilol was prepared by sodium alginate and sodium carboxymethylcellulose in ethanol:water solvent system The rate controlling membranes prepared were evaluated by various parameters like thickness, folding endurance, swelling index, moisture content, moisture uptake, water vapor transmission rate, tensile strength test, measurement of gel strength, in vitro permeation study, ex vivo permeation study, compatibility study using differential scanning calorimetry and stability studies. All physical parameters evident that prepared membranes have good folding endurance and sufficient tensile strength. As the proportion of chitosan conjugate increases in membrane swelling index, moisture content, moisture uptake and permeability coefficient increases. The gel strength of chitosan conjugate was considerable less compared with chitosan.


Glissonean approach for hepatic inflow control in minimally invasive anatomic liver resection: A systematic review.
The Glissonean approach has been widely validated for both open and minimally invasive anatomic liver resection (MIALR). However, the possible advantages compared to the conventional hilar approach are still under debate. The aim of this systematic review was to evaluate the application of the Glissonean approach in MIALR. A systematic review of the literature was conducted on PubMed and Ichushi databases. Articles written in English or Japanese were included. From 2,390 English manuscripts evaluated by title and abstract, 43 were included. Additionally, 23 out of 463 Japanese manuscripts were selected. Duplicates were removed, including the most recent manuscript. The Glissonean approach is reported for both major and minor MIALR. The 1st, 2nd and 3rd order divisions of both right and left portal pedicles can be reached following defined anatomical landmarks. Compared to the conventional hilar approach, the Glissonean approach is associated with shorter operative time, lower blood loss, and better peri-operative outcomes. Glissonean approach is safe and feasible for MIALR with several reported advantages compared to the conventional hilar approach. Clear knowledge of Laennec's capsule anatomy is necessary and serves as a guide for the dissection. However, the best surgical approach to be performed depends on surgeon experience and patients' characteristics. Standardization of the Glissonean approach for MIALR is important.


Modes of cell death induced by tetrahydroisoquinoline-based analogs in MDA-MB-231 breast and A549 lung cancer cell lines.
A and B rings of the steroidal microtubule disruptor, 2-methoxyestradiol, and its analogs can be mimicked with a tetrahydroisoquinoline (THIQ) core. THIQs are cytotoxic agents with potential anticancer activities. The aim of this in vitro study was to investigate the modes of cell death induced by four nonsteroidal THIQ-based analogs, such as STX 2895, STX 3329, STX 3451 and STX 3450, on MDA-MB-231 metastatic breast and A549 epithelial lung carcinoma cells. Cytotoxicity studies determined the half-maximal growth inhibitory concentration of the analogs to be at nanomolar concentrations without the induction of necrosis. Light and fluorescent microscopy determined that compounds caused microtubule depolymerization and displayed morphological hallmarks of apoptosis. Flow cytometric analyses confirmed apoptosis induction as well as an increased G2/M phase on cell cycle analysis. Furthermore, intrinsic pathway signaling was implicated due to increased cytochrome c release and a decrease in mitochondrial transmembrane potential. Potential involvement of autophagy was observed due to increased acidic vacuole formation and increased aggresome activation factor. Thus, it can be concluded that these four THIQ-based analogs exert anti-proliferative and antimitotic effects, induce apoptosis and involve autophagic processes. Further investigation into the efficacy of these potential anticancer drugs will be conducted in vitro and in vivo.


Inserted sequences in bovine satellite DNA's.
The nucleotide sequence of the 1413-base-pair repeat unit of bovine 1.711a satellite DNA (density in cesium chloride, 1.711 grams per cubic centimeter) has been determined. The repeat unit contains two segments consisting of variants of a basic 23-base-pair sequence that is closely related to sequences of bovine 1.706 satellite DNA. A third segment of the repeat unit contains an unrelated 611-base-pair sequence that is not internally repetitive. This segment is flanked by inverted repeats of 8 base pairs and, on one side, by a direct repeat of the terminal sequence. A related segment is present in bovine 1.711b satellite DNA and is inserted into sequences derived from the 1.715 satellite. These nucleotide sequences suggest the timing of some of the stages in the evolution of these complex, closely related satellite DNA's and indicate the mechanisms inherent in their divergence from a common ancestor.


A long noncoding RNA mediates both activation and repression of immune response genes.
An inducible program of inflammatory gene expression is central to antimicrobial defenses. This response is controlled by a collaboration involving signal-dependent activation of transcription factors, transcriptional co-regulators, and chromatin-modifying factors. We have identified a long noncoding RNA (lncRNA) that acts as a key regulator of this inflammatory response. Pattern recognition receptors such as the Toll-like receptors induce the expression of numerous lncRNAs. One of these, lincRNA-Cox2, mediates both the activation and repression of distinct classes of immune genes. Transcriptional repression of target genes is dependent on interactions of lincRNA-Cox2 with heterogeneous nuclear ribonucleoprotein A/B and A2/B1. Collectively, these studies unveil a central role of lincRNA-Cox2 as a broad-acting regulatory component of the circuit that controls the inflammatory response.


Identification of the primary caspase 3 cleavage site in alpha II-spectrin during apoptosis.
Alpha II-spectrin is one of the major proteins responsible for maintaining the cytoskeletal integrity of the cell. The caspase 3-mediated cleavage of alpha II-spectrin during apoptotic cell death may play an important role in altering membrane stability and the formation of apoptotic bodies. In this study, we identified the primary caspase 3 cleavage site in alpha II-spectrin. We found that the transcriptional inhibitor, actinomycin D, induced caspase 3 activation and that caspase 3 activation is coincident with the cleavage of alpha II-spectrin protein at a primary cleavage site. Deletion analysis and site directed mutagenesis identified the primary cleavage site in alpha II spectrin at amino acid 1185 (DETD). The primary caspase 3 cleavage site in alpha II spectrin is conserved in immature and mature B cells. Our results indicate that alpha II-spectrin is initially cleaved at a caspase 3 consensus site and this primary event likely alters the structural conformation of the protein exposing subsequent cleavage sites and altering cytoskeletal integrity. Identification of the primary cleavage site for caspase 3 may help to elucidate the role of alpha II-spectrin in membrane stability and apoptosis as well as provide new insights into alpha II-spectrin autoantibody formation associated with the autoimmune disease, Sjögren's syndrome.


'They aren't really black fellas but they are easy to talk to': Factors which influence Australian Aboriginal women's decision to disclose intimate partner violence during pregnancy.
intimate partner violence is a significant global health problem but remains largely hidden. Understanding decisions about whether or not to disclose violence in response to routine enquiry in health settings can inform safe and responsive systems. Elevated rates of violence and systematic disadvantage found among Indigenous women globally, can impact on their decisions to disclose violence. This study aimed to test, among Indigenous women, a model for decisions on whether to disclose intimate partner violence in the context of antenatal routine screening. we employed Qualitative Configurative Analysis, a method developed for the social sciences to study complex phenomena with intermediate sample sizes. Data were drawn from single semi- structured interviews with Indigenous women 28+ weeks pregnant attending antenatal care. Interviews addressed decisions to disclose recent intimate partner violence in the context of routine enquiry during the antenatal care. Interview transcripts were binary coded for conditions identified a priori from the model being tested and also from themes identified within the current study and analysed using Qualitative Configurative Analysis to determine causal conditions for the outcome of disclosure or non-disclosure of violence experienced. five Aboriginal and Maternal Infant Health Services (two urban and three regional), and one mainstream hospital, in New South Wales, Australia. indigenous women who had experienced partner violence in the previous year and who had been asked about this as part of an antenatal booking-in visit. Of the 12 participants six had elected to disclose their experience of violence to the midwife, and six had chosen not to do so. pathways to disclosure and non-disclosure were mapped using Qualitative Configurative Analysis. Conditions relevant to decisions to disclose were similar to the conditions for non-Aboriginal women found in our earlier study. Unique to Aboriginal women's decisions to disclose abuse was cultural safety. Cultural safety included elements we titled: Borrowed trust, Build the relationship first, Come at it slowly and People like me are here. The absence of cultural safety Its absence was also a factor in decisions not to disclose experiences of violence by this group of women. cultural safety was central to Indigenous women's decision to disclose violence and processes for creating safety are identified. Other forms of safety which influenced disclosure included: safety from detection by the abuser; safety from shame; and safety from institutional control. Disclosure was promoted by direct asking by the midwife and a perception of care. Non-disclosure was associated with a lack of care and a lack of all four types of safety. Experiences of institutional racism were associated with Indigenous women's perceived risk of control by others, particularly child protection services. policies to ask abuse questions at first visits and models where continuity of care is not maintained, are problematic for Aboriginal women, among whom relationship building is important as is ample warning about questions to be asked. Strategies are needed to build cultural safety to counter widespread racism and promote safe opportunities for Indigenous women to disclose intimate partner violence and receive support. Elements of cultural safety are necessary for vulnerable or marginalised populations to fully utilise available health services.


How risky are social networking sites? A comparison of places online where youth sexual solicitation and harassment occurs.
Recently, public attention has focused on the possibility that social networking sites such as MySpace and Facebook are being widely used to sexually solicit underage youth, consequently increasing their vulnerability to sexual victimization. Beyond anecdotal accounts, however, whether victimization is more commonly reported in social networking sites is unknown. The Growing up With Media Survey is a national cross-sectional online survey of 1588 youth. Participants were 10- to 15-year-old youth who have used the Internet at least once in the last 6 months. The main outcome measures were unwanted sexual solicitation on the Internet, defined as unwanted requests to talk about sex, provide personal sexual information, and do something sexual, and Internet harassment, defined as rude or mean comments, or spreading of rumors. Fifteen percent of all of the youth reported an unwanted sexual solicitation online in the last year; 4% reported an incident on a social networking site specifically. Thirty-three percent reported an online harassment in the last year; 9% reported an incident on a social networking site specifically. Among targeted youth, solicitations were more commonly reported via instant messaging (43%) and in chat rooms (32%), and harassment was more commonly reported in instant messaging (55%) than through social networking sites (27% and 28%, respectively). Broad claims of victimization risk, at least defined as unwanted sexual solicitation or harassment, associated with social networking sites do not seem justified. Prevention efforts may have a greater impact if they focus on the psychosocial problems of youth instead of a specific Internet application, including funding for online youth outreach programs, school antibullying programs, and online mental health services.


Geographic migration of black and white families over four generations.
This article analyzes patterns of geographic migration of black and white American families over four consecutive generations. The analysis is based on a unique set of questions in the Panel Study of Income Dynamics (PSID) asking respondents about the counties and states in which their parents and grandparents were raised. Using this information along with the extensive geographic information available in the PSID survey, the article tracks the geographic locations of four generations of family members and considers the ways in which families and places are linked together over the course of a family's history. The patterns documented in the article are consistent with much of the demographic literature on the Great Migration of black Americans out of the South, but they reveal new insights into patterns of black migration after the Great Migration. In the most recent generation, black Americans have remained in place to a degree that is unique relative to the previous generation and relative to whites of the same generation. This new geographic immobility is the most pronounced change in black Americans' migration patterns after the Great Migration, and it is a pattern that has implications for the demography of black migration as well as the literature on racial inequality.


Nitrate and human cancer: a review of the evidence.
Nitrites, derived mainly from ingested nitrates, may react in vivo with secondary nitrogen compounds occurring naturally in certain foods to form N-nitroso compounds, which are potent carcinogens in laboratory animals. This paper reviews the mechanism of their formation and the evidence from epidemiological studies that high nitrate ingestion is involved in the aetiology of human cancer.


Splicing Factor RBM20 Regulates Transcriptional Network of Titin Associated and Calcium Handling Genes in The Heart.
RNA binding motif 20 (RBM20) regulates pre-mRNA splicing of over thirty genes, among which titin is a major target. With RBM20 expression, titin expresses a larger isoform at fetal stage to a smaller isoform at adult resulting from alternative splicing, while, without RBM20, titin expresses exclusively a larger isoform throughout all ages. In addition to splicing regulation, it is unknown whether RBM20 also regulates gene expression. In this study, we employed Rbm20 knockout rats to investigate gene expression profile using Affymetrix expression array. We compared wild type to Rbm20 knockout at day1, 20 and 49. Bioinformatics analysis showed RBM20 regulates fewer genes expression at younger age and more at older age and commonly expressed genes have the same trends. GSEA indicated up-regulated genes are associated with heart failure. We examined titin binding partners. All titin direct binding partners are up-regulated and their increased expression is associated with dilated cardiomyopathy. Particularly, we found that genes involving calcium handling and muscle contraction are changed by RBM20. Intracellular calcium level measurement with individual cardiomyocytes further confirmed that changes of these proteins impact calcium handling. Selected genes from titin binding partners and calcium handling were validated with QPCR and western blotting. These data demonstrate that RBM20 regulates gene splicing as well as gene expression. Altered gene expression by RBM20 influences protein-protein interaction, calcium releasing and thus muscle contraction. Our results first reported gene expression impacted by RBM20 with heart maturation, and provided new insights into the role of RBM20 in the progression of heart failure.


Achieving the standard of the school health nursing process in elementary schools of Kerman, Iran.
Considering the school nursing standards, which is the most important and vital element of the school health team, can be a fundamental step toward solving the current and future problems of the school and society health. The present research was done with the goal of determining the current situation of the standard of the school health nursing process in elementary schools of Kerman, Iran. The present research is a quantitative, descriptive study and was done between the years 2009 and 2010 through conducting an opinion poll. In this study, first the international standards of school nursing were searched and extracted from informational sources. Then, a questionnaire was designed based on the standards of the school nursing process and its related indicators in 6 areas. This questionnaire had two parts. The first part had the respondents' demographic information, answering was optional, and the second part of the poll was about each of the indicators. After preparing the questionnaire and determining its validity and reliability, it was distributed among the 120 samples (60 health trainers and 60 of Kerman's elementary school staff), and their opinions were gathered and analyzed through statistical-descriptive analysis. The results of this research demonstrate that approximately all the above mentioned standard areas in the country were applied (98%). The rate of acquiring the standard of nursing process was high (90%) in some areas (Investigative area) and low (30%) in some other areas (diagnosis area). In total, the rate of acquiring the majority of indicators of nursing process standards has an average percentage. It is suggested to use schools health professionals to raise the indicators of the standard of the school nursing process (the indicators which had low or average acquiring rate), and to raise the performance quality.


Nucleolipid Acid-Based Nanocarriers Restore Neuronal Lysosomal Acidification Defects.
Increasing evidence suggests that lysosomal dysfunction has a pathogenic role in neurodegenerative diseases. In particular, an increase in lysosomal pH has been reported in different cellular models of Parkinson's disease. Thus, targeting lysosomes has emerged as a promising approach. More specifically, regulating its pH could play a central role against the neurodegeneration process. To date, only a few agents specifically targeting lysosomal pH are reported in the literature, partly due to the challenge of crossing the Blood-Brain-Barrier (BBB), preventing drug penetration into the central nervous system (CNS). To develop chronic treatments for neurodegenerative diseases, crossing the BBB is crucial. We report herein the conception and synthesis of an innovative DNA derivative-based nanocarrier. Nucleolipids, carrying a biocompatible organic acid as an active ingredient, were designed and synthesized as prodrugs. They were successfully incorporated into an oil-in-water nanoemulsion vehicle to cross biological membranes and then release effectively biocompatible acidic components to restore the functional lysosomal pH of neuronal cells. Biological assays on a genetic cell model of Parkinson's disease highlighted the non-toxicity of such nucleolipids after cellular uptake and their ability (at c = 40 µM) to fully restore lysosomal acidity.


An MRI compatible loading device for the reconstruction of clinically relevant plantar pressure distributions and loading scenarios of the forefoot.
The purpose of this study is to demonstrate a new MRI compatible loading device capable of reconstructing realistic loading scenarios of the human foot for research in the field of foot biomechanics. This device has two different configurations: one used to compress the forefoot and one to bend the metatarsophalangeal joints. Required plantar pressure distribution under the metatarsal heads can be achieved by modifying the distribution of the dorsally applied forces. To validate the device, subject-specific plantar pressures were measured and then reconstructed using the device. For quiet stance the peak pressure reconstruction error was 3% while for mid-stance phase of gait it was 8%. The device was also used to measure the passive bending stiffness of the metatarsophalangeal joints of one subject with low intra-subject variability. A series of preliminary MRI scans confirmed that the loading device can be used to produce static weight-bearing images of the foot (voxel size: 0.23 mm × 0.23 mm × 1.00 mm). The results indicate that the device presented here can accurately reconstruct subject specific plantar pressure distributions and measure the foot's metatarsophalangeal passive stiffness. Possible future applications include the validation of finite element models, the investigation of the relationship between plantar pressure and internal stresses/strains and the study of the foot's inter-segmental passive stiffness.


UFBP1, a Key Component of the Ufm1 Conjugation System, Is Essential for Ufmylation-Mediated Regulation of Erythroid Development.
The Ufm1 conjugation system is an ubiquitin-like modification system that consists of Ufm1, Uba5 (E1), Ufc1 (E2), and less defined E3 ligase(s) and targets. The biological importance of this system is highlighted by its essential role in embryogenesis and erythroid development, but the underlying mechanism is poorly understood. UFBP1 (Ufm1 binding protein 1, also known as DDRGK1, Dashurin and C20orf116) is a putative Ufm1 target, yet its exact physiological function and impact of its ufmylation remain largely undefined. In this study, we report that UFBP1 is indispensable for embryonic development and hematopoiesis. While germ-line deletion of UFBP1 caused defective erythroid development and embryonic lethality, somatic ablation of UFBP1 impaired adult hematopoiesis, resulting in pancytopenia and animal death. At the cellular level, UFBP1 deficiency led to elevated ER (endoplasmic reticulum) stress and activation of unfolded protein response (UPR), and consequently cell death of hematopoietic stem/progenitor cells. In addition, loss of UFBP1 suppressed expression of erythroid transcription factors GATA-1 and KLF1 and blocked erythroid differentiation from CFU-Es (colony forming unit-erythroid) to proerythroblasts. Interestingly, depletion of Uba5, a Ufm1 E1 enzyme, also caused elevation of ER stress and under-expression of erythroid transcription factors in erythroleukemia K562 cells. By contrast, knockdown of ASC1, a newly identified Ufm1 target that functions as a transcriptional co-activator of hormone receptors, led to down-regulation of erythroid transcription factors, but did not elevate basal ER stress. Furthermore, we found that ASC1 was associated with the promoters of GATA-1 and Klf1 in a UFBP1-dependent manner. Taken together, our findings suggest that UFBP1, along with ASC1 and other ufmylation components, play pleiotropic roles in regulation of hematopoietic cell survival and differentiation via modulating ER homeostasis and erythroid lineage-specific gene expression. Modulating the activity of this novel ubiquitin-like system may represent a novel approach to treat blood-related diseases such as anemia.


Digital polarized light dermoscopy of clinically nonpigmented dermal nevi.
Hand-held dermoscopy improves the malignant/benign excision ratio for melanocytic lesions. Much has been described about its use in pigmented lesions; however, the use of dermoscopy in clinically nonpigmented lesions is less well studied. Existing studies have used a combination of traditional immersion dermoscopy and polarized light dermoscopy. This is the first study, to our knowledge, to strictly use digital polarized light dermoscopy for the evaluation of clinically nonpigmented, biopsy-proven dermal nevi. The goal of this study was to describe the dermoscopic features of clinically nonpigmented, biopsy-proven dermal nevi using digital polarized light images. The dermoscopic features of 32 histopathologically confirmed, clinically nonpigmented, dermal nevi were evaluated. Images were obtained with a digital camera equipped with an epiluminescence microscopy attachment (polarized light); no liquid interface was used. RESULTS The most frequent dermoscopic feature of 32 clinically nonpigmented, biopsy-proven dermal nevi was brown pigment (78%) followed by white areas (53%), comma-shaped vessels (50%), hair (47%), hairpin vessels (22%), comedolike openings (22%), and dotted vessels, respectively (19%). The most common dermoscopic features (using polarized light) of clinically nonpigmented, biopsy-proven dermal nevi are brown pigment, white areas, comma-shaped vessels, and hair.


Case-control genome-wide association study of attention-deficit/hyperactivity disorder.
Although twin and family studies have shown attention-deficit/hyperactivity disorder (ADHD) to be highly heritable, genetic variants influencing the trait at a genome-wide significant level have yet to be identified. Thus additional genomewide association studies (GWAS) are needed. We used case-control analyses of 896 cases with DSM-IV ADHD genotyped using the Affymetrix 5.0 array and 2,455 repository controls screened for psychotic and bipolar symptoms genotyped using Affymetrix 6.0 arrays. A consensus SNP set was imputed using BEAGLE 3.0, resulting in an analysis dataset of 1,033,244 SNPs. Data were analyzed using a generalized linear model. No genome-wide significant associations were found. The most significant results implicated the following genes: PRKG1, FLNC, TCERG1L, PPM1H, NXPH1, PPM1H, CDH13, HK1, and HKDC1. The current analyses are a useful addition to the present literature and will make a valuable contribution to future meta-analyses. The candidate gene findings are consistent with a prior meta-analysis in suggesting that the effects of ADHD risk variants must, individually, be very small and/or include multiple rare alleles.


Per-attack reporting of prodromal symptoms concurrent with C1-inhibitor treatment of hereditary angioedema attacks.
Prodromal symptoms commonly precede hereditary angioedema (HAE) attacks. There is continuing interest in evaluating prodromes as treatment indicators, but a paucity of relevant data. This study was designed to prospectively identify prodomal characteristics in patients voluntarily reporting such information around the time of seeking treatment for an acute HAE attack. Twenty-eight patients with HAE were enrolled in this survey, which was conducted in the context of an open-label study of treatment of HAE attacks with plasma-derived C1-inhibitor concentrate. At the time of treatment, patients were encouraged to answer survey questions about prodromal symptoms preceding that particular HAE attack. Twenty-one patients provided prodromal information for 253 treated HAE attacks. Seventy-one percent of patients (15/21) reported prodromes. Three patients accounted for approximately 80% of the attacks and 89% of the reported prodromal symptoms. Prodromes were experienced before 67.6% (171/253) of attacks, with a mean of 1.4 prodromes per attack. Fatigue was the most frequent prodrome (42% of attacks), followed by nausea (26%), and flu-like symptoms (22%). The median duration of a prodrome before an attack was 12 h (range, 0.33-24 h). Despite many limitations in the study design, these findings confirm that prodromes are frequently associated with HAE attacks in many patients and occur sufficiently early to allow time for treatment initiation. The frequency of "false positive" prodromal symptoms remains undetermined, and the authors captured data only on attacks severe enough to warrant treatment. Additional well-designed prospective studies are clearly needed to continue investigating the potential clinical relevance of prodromes.


Aspects of the Taxonomic Relation in the Biomedical Domain.
Taxonomies are commonly used for organizing knowledge, particularly in biomedicine where the taxonomy of living organisms and the classification of diseases are central to the domain. The principles used to produce taxonomies are either intrinsic (properties of the partial ordering relation) or added to make knowledge more manageable (opposition of siblings and economy). The applicability of these principles in the biomedical domain is presented using the Unified Medical Language System (UMLS) and issues raised by the application of these principles are illustrated. While intrinsic principles are not challenged, we argue that the opposition of siblings brings to bear excessive constraints on a domain ontology and that the adverse effects of economy may outweigh its benefits. The two-level structure used in the UMLS is discussed.


Assessing Biases in the Evaluation of Classification Assays for HIV Infection Recency.
Identifying recent HIV infection cases has important public health and clinical implications. It is essential for estimating incidence rates to monitor epidemic trends and evaluate the effectiveness of interventions. Detecting recent cases is also important for HIV prevention given the crucial role that recently infected individuals play in disease transmission, and because early treatment onset can improve the clinical outlook of patients while reducing transmission risk. Critical to this enterprise is the development and proper assessment of accurate classification assays that, based on cross-sectional samples of viral sequences, help determine infection recency status. In this work we assess some of the biases present in the evaluation of HIV recency classification algorithms that rely on measures of within-host viral diversity. Particularly, we examine how the time since infection (TSI) distribution of the infected subjects from which viral samples are drawn affect performance metrics (e.g., area under the ROC curve, sensitivity, specificity, accuracy and precision), potentially leading to misguided conclusions about the efficacy of classification assays. By comparing the performance of a given HIV recency assay using six different TSI distributions (four simulated TSI distributions representing different epidemic scenarios, and two empirical TSI distributions), we show that conclusions about the overall efficacy of the assay depend critically on properties of the TSI distribution. Moreover, we demonstrate that an assay with high overall classification accuracy, mainly due to properly sorting members of the well-represented groups in the validation dataset, can still perform notoriously poorly when sorting members of the less represented groups. This is an inherent issue of classification and diagnostics procedures that is often underappreciated. Thus, this work underscores the importance of acknowledging and properly addressing evaluation biases when proposing new HIV recency assays.


Underutilization of mammography in older breast cancer survivors.
Annual mammography is recommended for all breast cancer survivors. To elucidate mammography use among older survivors of breast cancer and to explore determinants of such use. Retrospective cohort study using data from the Surveillance, Epidemiology, and End Results (SEER) registry linked to Medicare claims. A cohort of 3885 breast cancer survivors aged > or =65 years diagnosed with early-stage breast cancer in the United States in 1991. Medicare mammogram claims during the 2-year period following initial breast cancer treatment. Overall, 62% of the cohort underwent annual mammography, 23% underwent mammography in 1 of 2 years, and 15% had no mammography claim in the 2 years evaluated. Twenty-two percent of the women who underwent breast-conserving surgery (BCS) without radiotherapy had no mammogram in the 2-year period evaluated, compared with 17% of those who underwent mastectomy and 4% of those who underwent BCS with radiotherapy. In multivariate analyses controlling for age, cancer stage, and other patient factors, the use of annual mammography was significantly lower among women treated with mastectomy or BCS without radiotherapy than among women treated with BCS with radiotherapy. Mammography is underused in the follow-up care of older breast cancer survivors. Underuse is of particular concern in women treated with BCS without radiotherapy because of the high risk of local disease recurrence. It is unknown whether poorer follow-up care contributes to the previously described lower rate of long-term survival among women who received this therapy.


The Value of CT and MRI for Determining Thymoma in Patients With Myasthenia Gravis.
The aim of the study was to evaluate the usefulness of computed tomography (CT) and magnetic resonance imaging (MRI) for differentiating thymoma from nonthymoma abnormalities in patients with myasthenia gravis (MG). A cross-sectional study of 53 patients with MG, who had undergone surgical thymectomy, was conducted at 103 Hospital (Hanoi, Vietnam) and Cho Ray Hospital (Ho Chi Minh City, Vietnam) during August 2014 and January 2017. The CT and MRI images of patients with MG were qualitatively and quantitatively (radiodensity and chemical shift ratio [CSR]) analyzed to determine and compare their ability to distinguish thymoma from nonthymoma abnormalities. Logistic regression was used to identify the association between imaging parameters (eg, CSR) and the thymoma status. The receiver operating curve (ROC) analysis was used to determine the differentiating ability of CSR and radiodensity. As results, of the 53 patients with MG, 33 were with thymoma and 20 were with nonthymoma abnormalities. At qualitative assessment, MRI had significantly higher accuracy than did CT in differentiating thymoma from nonthymoma abnormalities (94.3% vs 83%). At quantitative assessment, both the radiodensity and CSR were significantly higher for thymoma compared with nonthymoma groups (P < .001). The ROC analysis showed that CSR had significantly higher sensitivity (Se) and specificity (Sp) than radiodensity in discriminating between the 2 groups (CSR: Se 100%, Sp 95% vs radiodensity: Se 90.9%, Sp 70%). When combining both qualitative and quantitative parameters, MRI had even higher accuracy than did CT in thymoma diagnosis (P = .031). In conclusion, chemical shift MRI was more accurate than CT for differentiating thymoma from nonthymoma in patients with MG.


Effects of low-level sarin and cyclosarin exposure and Gulf War Illness on brain structure and function: a study at 4T.
More than 100,000 US troops were potentially exposed to chemical warfare agents sarin (GB) and cyclosarin (GF) when an ammunition dump at Khamisiyah, Iraq was destroyed during the 1991 Persian Gulf War (GW). We previously found reduced total gray matter (GM) volume in 40 GW veterans with suspected GB/GF exposure relative to 40 matched, unexposed GW veterans on a 1.5T MR scanner. In this study, we reexamine the relationship between GB/GF exposure and volumetric measurements of gross neuroanatomical structures in a different cohort of GW veterans on a 4T MR scanner. Neuropsychological and magnetic resonance imaging (MRI) data from a cross sectional study on Gulf War Illness performed between 2005 and 2010 were used in this study. 4T MRI data were analyzed using automated image processing techniques that produced volumetric measurements of gray matter (GM), white matter (WM) and cerebrospinal fluid (CSF). Binary comparisons of 64 GB/GF exposed veterans and 64 'matched', unexposed veterans revealed reduced GM (p=0.03) and WM (p=0.03) volumes in the exposed veterans. Behaviorally, exposed veterans committed more errors of omission (p=0.02) and tended to have slower responses (p=0.05) than unexposed veterans on the Continuous Performance Test (CPT), a measure sustained and selective attention. Regression analyses confirmed that GB/GF exposure status predicted GM (β=-0.11, p=0.02) and WM (β=-0.14, p=0.03) volumes, and number of CPT omission errors (β=0.22, p=0.02) over and above potentially confounding demographic, clinical, and psychosocial variables. There was no dose-response relationship between estimated levels of GB/GF exposure and brain volume. However, we did find an effect of Gulf War Illness/Chronic Multisymptom Illness on both GM and WM volume in the GB/GF exposed veterans. These findings confirm previous reports by our group and others of central nervous system pathology in GW veterans with suspected exposure to low levels of GB/GF two decades after the exposure.


The fastclime Package for Linear Programming and Large-Scale Precision Matrix Estimation in R.
We develop an R package fastclime for solving a family of regularized linear programming (LP) problems. Our package efficiently implements the parametric simplex algorithm, which provides a scalable and sophisticated tool for solving large-scale linear programs. As an illustrative example, one use of our LP solver is to implement an important sparse precision matrix estimation method called CLIME (Constrained L1 Minimization Estimator). Compared with existing packages for this problem such as clime and flare, our package has three advantages: (1) it efficiently calculates the full piecewise-linear regularization path; (2) it provides an accurate dual certificate as stopping criterion; (3) it is completely coded in C and is highly portable. This package is designed to be useful to statisticians and machine learning researchers for solving a wide range of problems.


High-mobility three-atom-thick semiconducting films with wafer-scale homogeneity.
The large-scale growth of semiconducting thin films forms the basis of modern electronics and optoelectronics. A decrease in film thickness to the ultimate limit of the atomic, sub-nanometre length scale, a difficult limit for traditional semiconductors (such as Si and GaAs), would bring wide benefits for applications in ultrathin and flexible electronics, photovoltaics and display technology. For this, transition-metal dichalcogenides (TMDs), which can form stable three-atom-thick monolayers, provide ideal semiconducting materials with high electrical carrier mobility, and their large-scale growth on insulating substrates would enable the batch fabrication of atomically thin high-performance transistors and photodetectors on a technologically relevant scale without film transfer. In addition, their unique electronic band structures provide novel ways of enhancing the functionalities of such devices, including the large excitonic effect, bandgap modulation, indirect-to-direct bandgap transition, piezoelectricity and valleytronics. However, the large-scale growth of monolayer TMD films with spatial homogeneity and high electrical performance remains an unsolved challenge. Here we report the preparation of high-mobility 4-inch wafer-scale films of monolayer molybdenum disulphide (MoS2) and tungsten disulphide, grown directly on insulating SiO2 substrates, with excellent spatial homogeneity over the entire films. They are grown with a newly developed, metal-organic chemical vapour deposition technique, and show high electrical performance, including an electron mobility of 30 cm(2) V(-1) s(-1) at room temperature and 114 cm(2) V(-1) s(-1) at 90 K for MoS2, with little dependence on position or channel length. With the use of these films we successfully demonstrate the wafer-scale batch fabrication of high-performance monolayer MoS2 field-effect transistors with a 99% device yield and the multi-level fabrication of vertically stacked transistor devices for three-dimensional circuitry. Our work is a step towards the realization of atomically thin integrated circuitry.


Arms races and the evolution of big fierce societies.
The causes of biological gigantism have received much attention, but only for individual organisms. What selection pressures might favour the evolution of gigantic societies? Here we consider the largest single-queen insect societies, those of the Old World army ant Dorylus, single colonies of which can have 20 million workers. We propose that colony gigantism in Dorylus arises as a result of an arms race and test this prediction by developing a size-structured mathematical model. We use this model for exploring and potentially explaining differences in colony size, colony aggression and colony propagation strategies in populations of New World army ants Eciton and Old World army ants Dorylus. The model shows that, by determining evolutionarily stable strategies (ESSs), differences in the trophic levels at which these army ants live feed forwards into differences in their densities and collision rates and, hence, into different strategies of growth, aggression and propagation. The model predicts large colony size and the occurrence of battles and a colony-propagation strategy involving highly asymmetrical divisions in Dorylus and that Eciton colonies should be smaller, non-combative and exhibit equitable binary fission. These ESSs are in excellent agreement with field observations and demonstrate that gargantuan societies can arise through arms races.


In vitro free radical scavenging and antioxidant properties of ethanol extract of Terminalia glaucescens.
Reactive oxygen species (ROS) are implicated in various pathological conditions. Synthetic antioxidants have adverse health effects, while many medicinal plants have antioxidant components that can prevent the harmful effects of ROS. This study quantitatively determined the total phenolic content (TPC), total flavonoid content (TFC), and antioxidant properties of ethanol extract of the stem bark of Terminalia glaucescens (EESTG). The objectives were achieved based on in vitro assays. Data were analyzed by Sigma Plot (version 11.0). Using gallic acid as the standard compound, TPC value obtained was 596.57 μg GAE/mg extract. TFC content of EESTG, determined as quercetin equivalent was 129.58 μg QE/mg extract. Furthermore, EESTG significantly (P < 0.001) displayed higher reducing power activity than the standard compounds (ascorbic acid and butylated hydroxytoluene [BHT]). Total antioxidant capacity assay, measured by phosphomolybdate method, was 358.33 ± 5.77 μg butylated hydroxytoluene equivalents [BHTE]/mg extract. β-carotene-linoleate bleaching method affirmed the potency of EESTG because of its significantly (P < 0.001) higher anti-oxidant activity when compared with quercetin and BHT. Based on DPPH assay, EESTG displayed significantly (P < 0.001) higher activity than BHT, while the hydroxyl radical scavenging activities of BHT and quercetin significantly (P < 0.001) exceeded that of the extract, although EESTG still displayed a high level of activity obtained as 83.77% in comparison to 92.80% of the standard compounds. Findings from this study indicate the presence of promisingly potent phytoconstituents in EESTG that have the capability to act as antioxidants and free radical scavengers.


Evidence-based evaluation of physiological effects of standing and walking in individuals with spinal cord injury.
Spinal Cord Injury (SCI) is damage to spinal cord, which is categorized according to the extent of functional loss, sensation loss and inability of the subjects to stand and walk. The patients use two transportation systems including orthosis and wheelchair. It was claimed that standing and walking bring some benefits such as decreasing bone osteoporosis, prevention of pressure sores, and improvement of the function of the digestive system for SCI patients. Nevertheless, the question of wether or not there is enough evidence to support the effect of walking with orthosis on the health status of the subjects with SCI remains unanswered. In order to answer this question a review of the relevant literature was carried out. The review of the literature showed that evidence reported in the literature regarding the effectiveness of orthoses for improving the health condition of SCI patients was controversial. Many investigators had only used the comments of the users of orthoses. The benefits mentioned in various research studies regarding the use of orthosis included decreasing bone osteoprosis, preventing joint deformity, improving bowl and bladder function, improving digestive system function, decreasing muscle spasm, improving independent living, and improving respiratory and cardiovascular systems function. The findings of the studies reviewed also showed that improving the independent living and physiological health of the subjects were the only two benefits, which were supported by strong evidence. The review of the literature suggests that most published studies are in fact surveys, which collected questionnaire-based information from the users of orthosis.


Associations of maternal long-chain polyunsaturated fatty acids, methyl mercury, and infant development in the Seychelles Child Development Nutrition Study.
Fish consumption during gestation can provide the fetus with long-chain polyunsaturated fatty acids (LCPUFA) and other nutrients essential for growth and development of the brain. However, fish consumption also exposes the fetus to the neurotoxicant, methyl mercury (MeHg). We studied the association between these fetal exposures and early child development in the Seychelles Child Development Nutrition Study (SCDNS). Specifically, we examined a priori models of Omega-3 and Omega-6 LCPUFA measures in maternal serum to test the hypothesis that these LCPUFA families before or after adjusting for prenatal MeHg exposure would reveal associations with child development assessed by the BSID-II at ages 9 and 30 months. There were 229 children with complete outcome and covariate data available for analysis. At 9 months, the PDI was positively associated with total Omega-3 LCPUFA and negatively associated with the ratio of Omega-6/Omega-3 LCPUFA. These associations were stronger in models adjusted for prenatal MeHg exposure. Secondary models suggested that the MeHg effect at 9 months varied by the ratio of Omega-6/Omega-3 LCPUFA. There were no significant associations between LCPUFA measures and the PDI at 30 months. There were significant adverse associations, however, between prenatal MeHg and the 30-month PDI when the LCPUFA measures were included in the regression analysis. The BSID-II mental developmental index (MDI) was not associated with any exposure variable. These data support the potential importance to child development of prenatal availability of Omega-3 LCPUFA present in fish and of LCPUFA in the overall diet. Furthermore, they indicate that the beneficial effects of LCPUFA can obscure the determination of adverse effects of prenatal MeHg exposure in longitudinal observational studies.


Regulation of gap junctional conductance.
Gap junctional conductance is regulated by the number of channels between coupled cells (the balance between formation and loss of these channels) and by the fraction of these channels that are open (gating mechanisms). A variety of treatments are known to affect junction formation. Adenosine 3',5'-cyclic monophosphate (cAMP) is involved in some cases, and protein synthesis may be required but precursor molecules can also exist. Junction removal occurs both by dispersion of particles and by internalization of junctional membrane. Factors promoting removal are not well understood. A variety of gating mechanisms exist. Coupling may be controlled by changes in conductance of nonjunctional membranes. Several kinds of voltage dependence of junctional conductance are known, but rat ventricular junctions at least are electrically linear. Cytoplasmic acidification decreases conductance of most gap junctions. Sensitivity in rat ventricular myocytes allows modulation of coupling by moderate changes near normal internal pH. Increasing intracellular Ca also decreases junctional conductance, but in the better studied cases sensitivity is much lower to Ca than H. A few data support low sensitivity to Ca in cardiac cells, but quantitative studies are lacking. Higher alcohols such as octanol block junctional conductance in a wide range of tissues including rat ventricular myocytes. An antibody to liver gap junctions blocks junctions between rat ventricular myocytes. Cross reactivity indicates at least partial homology between many gap junctions. Although differences among gap junctions are known, a general physiology is being developed, which may have considerable relevance to normal cardiac function and also to conduction disorders of that tissue.


Neural mechanisms of sneeze.
Sneezes were induced in anestized cats by repetitive stimulation of the ethmoidal nerve. Activity of bulbar respiratory neurons during sneezing was recorded extracellularly through tungsten microelectrodes. Most expiratory neurons could be locked onto the stimulus pulses so that they responded either throughout inspiration as well as expiration or so that they began responding at some time during inspiration. As inspiration approached termination, multiple spiking occurred, finally to result in high-frequency bursts which just preceded active expiration. A fraction of expiratory neurons were activated only in bursts. Latent expiratory neurons were recruited in sneezing. Inspiratory neurons near nucleus ambiguus and most of those near fasciculus solitarius displayed similar response patterns consisting of silent periods followed by delayed smooth activations. Temporal characteristics of the silent periods, "inhibitory gaps," suggested that they resulted from inhibition whose source was the expiratory neurons which were driven throughout inspriation. Some inspiratory neurons in the area of fasciculus solitarius failed to exhibit inhibitory gaps.


Race/ethnic disparities in early childhood BMI, obesity and overweight in the United Kingdom and United States.
Racial/ethnic patterning in the risk of obesity and overweight has been observed in early childhood; however, little research has compared these disparities between the United Kingdom (UK) and United States (US) using detailed ethnic classifications. We use comparable nationally representative cohort studies to examine racial/ethnic disparities in mean body mass index (BMI) and in the odds of obesity/overweight in the UK and US. The contribution of sociodemographic, cultural and family routine factors are assessed. Data on BMI, obesity and overweight in 5-year-old children from the MCS (Millennium Cohort Study) and ECLS-B (Early Childhood Longitudinal Study, Birth Cohort) were examined. We investigated race/ethnic disparities in mean BMI and in the odds of obesity and overweight, as compared to normal weight. We assessed the independent contribution of sociodemographic, cultural and family routine factors to observed disparities. In the UK, after adjustment for sociodemographic, cultural and family routine factors and maternal BMI, we found Black Caribbean children to have higher odds ratio (OR=1.7, confidence interval (CI)=1.1-2.6), Pakistani children to have lower odds of obesity (OR=0.60, CI=0.37-0.96) and Black African children were more likely to be overweight (OR=1.40, CI=1.04-1.88). In the US, in fully adjusted models, there were no race/ethnic disparities in children's odds of obesity and overweight. Disparities for Bangladeshi children in the UK and Mexican, other Hispanic and American Indian children in the US can be explained by socioeconomic disadvantage, whereas a range of cultural and family characteristics partially explain disparities for other groups in the UK. Future public health initiatives focused on reducing risk of overweight and obesity should consider the diverse socioeconomic and cultural profiles of all race/ethnic groups.


Huntington's Disease and Striatal Signaling.
Huntington's Disease (HD) is the most frequent neurodegenerative disease caused by an expansion of polyglutamines (CAG). The main clinical manifestations of HD are chorea, cognitive impairment, and psychiatric disorders. The transmission of HD is autosomal dominant with a complete penetrance. HD has a single genetic cause, a well-defined neuropathology, and informative pre-manifest genetic testing of the disease is available. Striatal atrophy begins as early as 15 years before disease onset and continues throughout the period of manifest illness. Therefore, patients could theoretically benefit from therapy at early stages of the disease. One important characteristic of HD is the striatal vulnerability to neurodegeneration, despite similar expression of the protein in other brain areas. Aggregation of the mutated Huntingtin (HTT), impaired axonal transport, excitotoxicity, transcriptional dysregulation as well as mitochondrial dysfunction, and energy deficits, are all part of the cellular events that underlie neuronal dysfunction and striatal death. Among these non-exclusive mechanisms, an alteration of striatal signaling is thought to orchestrate the downstream events involved in the cascade of striatal dysfunction.


On-Orbit Performance of the Helioseismic and Magnetic Imager Instrument onboard the Solar Dynamics Observatory.
The Helioseismic and Magnetic Imager (HMI) instrument is a major component of NASA's Solar Dynamics Observatory (SDO) spacecraft. Since commencement of full regular science operations on 1 May 2010, HMI has operated with remarkable continuity, e.g. during the more than five years of the SDO prime mission that ended 30 September 2015, HMI collected 98.4% of all possible 45-second velocity maps; minimizing gaps in these full-disk Dopplergrams is crucial for helioseismology. HMI velocity, intensity, and magnetic-field measurements are used in numerous investigations, so understanding the quality of the data is important. This article describes the calibration measurements used to track the performance of the HMI instrument, and it details trends in important instrument parameters during the prime mission. Regular calibration sequences provide information used to improve and update the calibration of HMI data. The set-point temperature of the instrument front window and optical bench is adjusted regularly to maintain instrument focus, and changes in the temperature-control scheme have been made to improve stability in the observable quantities. The exposure time has been changed to compensate for a 20% decrease in instrument throughput. Measurements of the performance of the shutter and tuning mechanisms show that they are aging as expected and continue to perform according to specification. Parameters of the tunable optical-filter elements are regularly adjusted to account for drifts in the central wavelength. Frequent measurements of changing CCD-camera characteristics, such as gain and flat field, are used to calibrate the observations. Infrequent expected events such as eclipses, transits, and spacecraft off-points interrupt regular instrument operations and provide the opportunity to perform additional calibration. Onboard instrument anomalies are rare and seem to occur quite uniformly in time. The instrument continues to perform very well.


A Simple Thermoplastic Substrate Containing Hierarchical Silica Lamellae for High-Molecular-Weight DNA Extraction.
An inexpensive, magnetic thermoplastic nanomaterial is developed utilizing a hierarchical layering of micro- and nanoscale silica lamellae to create a high-surface-area and low-shear substrate capable of capturing vast amounts of ultrahigh-molecular-weight DNA. Extraction is performed via a simple 45 min process and is capable of achieving binding capacities up to 1 000 000 times greater than silica microparticles.


Overview of the randomized phase III trials in non-small cell lung cancer in North America.
Lung cancer is the leading cause of deaths due to cancer in the United States. Although surgery can be curative for the small group of patients with early stage disease, the majority of patients present with advanced disease, for which treatment is ineffective, resulting in a 5-year overall survival rate of only 13%. Research to discover and evaluate new treatment strategies that will result in a meaningful survival benefit for patients with lung cancer is constantly ongoing. However, the process is cumbersome and requires stringent evaluation of the candidate treatment during each phase of testing. The final step in this long process is to validate the benefit of a new treatment by comparing it with the current standard treatment in the setting of a randomized phase III clinical trial. The new promising treatments for non-small cell lung cancer that are currently in phase III testing in North America are reviewed, and upcoming phase III trials are discussed.


The Enemy within: Propagation of Aberrant Corticostriatal Learning to Cortical Function in Parkinson's Disease.
Motor dysfunction in Parkinson's disease is believed to arise primarily from pathophysiology in the dorsal striatum and its related corticostriatal and thalamostriatal circuits during progressive dopamine denervation. One function of these circuits is to provide a filter that selectively facilitates or inhibits cortical activity to optimize cortical processing, making motor responses rapid and efficient. Corticostriatal synaptic plasticity mediates the learning that underlies this performance-optimizing filter. Under dopamine denervation, corticostriatal plasticity is altered, resulting in aberrant learning that induces inappropriate basal ganglia filtering that impedes rather than optimizes cortical processing. Human imaging suggests that increased cortical activity may compensate for striatal dysfunction in PD patients. In this Perspective article, we consider how aberrant learning at corticostriatal synapses may impair cortical processing and learning and undermine potential cortical compensatory mechanisms. Blocking or remediating aberrant corticostriatal plasticity may protect cortical function and support cortical compensatory mechanisms mitigating the functional decline associated with progressive dopamine denervation.


Novel breast cancer susceptibility locus at 9q31.2: results of a genome-wide association study.
Genome-wide association studies have identified several common genetic variants associated with breast cancer risk. It is likely, however, that a substantial proportion of such loci have not yet been discovered. We compared 296,114 tagging single-nucleotide polymorphisms in 1694 breast cancer case subjects (92% with two primary cancers or at least two affected first-degree relatives) and 2365 control subjects, with validation in three independent series totaling 11,880 case subjects and 12,487 control subjects. Odds ratios (ORs) and associated 95% confidence intervals (CIs) in each stage and all stages combined were calculated using unconditional logistic regression. Heterogeneity was evaluated with Cochran Q and I(2) statistics. All statistical tests were two-sided. We identified a novel risk locus for breast cancer at 9q31.2 (rs865686: OR = 0.89, 95% CI = 0.85 to 0.92, P = 1.75 × 10(-10)). This single-nucleotide polymorphism maps to a gene desert, the nearest genes being Kruppel-like factor 4 (KLF4, 636 kb centromeric), RAD23 homolog B (RAD23B, 794 kb centromeric), and actin-like 7A (ACTL7A, 736 kb telomeric). We also identified two variants (rs3734805 and rs9383938) mapping to 6q25.1 estrogen receptor 1 (ESR1), which were associated with breast cancer in subjects of northern European ancestry (rs3734805: OR = 1.19, 95% CI = 1.11 to 1.27, P = 1.35 × 10(-7); rs9383938: OR = 1.18, 95% CI = 1.11 to 1.26, P = 1.41 × 10(-7)). A variant mapping to 10q26.13, approximately 300 kb telomeric to the established risk locus within the second intron of FGFR2, was also associated with breast cancer risk, although not at genome-wide statistical significance (rs10510102: OR = 1.12, 95% CI = 1.07 to 1.17, P = 1.58 × 10(-6)). These findings provide further evidence on the role of genetic variation in the etiology of breast cancer. Fine mapping will be needed to identify causal variants and to determine their functional effects.


Analysis of IL1B, TAP1, TAP2 and IKBL polymorphisms on susceptibility to tuberculosis.
Genetic determinants of human susceptibility to tuberculosis (TB) have not been completely elucidated. Interleukin-1 beta (IL-1beta) and the inhibitor of kB-like (IkBL) are important molecules that participate in the inflammatory response required for the immunological control of a broad spectrum of infectious agents. The transporter associated with antigen processing (TAP) is involved in the antigen processing via major histocompatibility complex class I molecules and in turn might regulate the T-cell response against Mycobacterium tuberculosis. To better characterize the host genetic factors determining the susceptibility to TB, we evaluated the influence of functional polymorphisms in IL1B, TAP and IKBL genes on the risk of developing pulmonary TB in a Northwestern Colombian population, an endemic area of M. tuberculosis infection. A total of 122 TB patients and 166 healthy controls (N = 166) negative for human immunodeficiency virus infection were examined for IL1B-511 and +3,953, TAP1 and TAP2 and IKBL+738 polymorphisms. Univariate analysis disclosed significant differences between patients and controls for IL1B+3,953 polymorphism. After unconditional logistic regression analysis, a strong protection conferred by IL1B+3,953 T-allele-carrying genotypes was observed. A trend between TAP2*0201 allele and disease was observed. Association between IL1B-511, TAP1 or IKBL polymorphisms and TB disease was not found. These results indicate that a functional polymorphism in the IL1B gene influences the susceptibility to TB and suggest a role for IL-1beta in the pathogenesis of mycobacterial infection.


S100a9 knockdown decreases the memory impairment and the neuropathology in Tg2576 mice, AD animal model.
Inflammation, insoluble protein deposition and neuronal cell loss are important features in the Alzheimer's disease (AD) brain. To investigate the regulatory genes responsible for the neuropathology in AD, we performed microarray analysis with APP(V717I)-CT100 transgenic mice, an animal model of AD, and isolated the S100a9 gene, which encodes an inflammation-associated calcium binding protein. In another AD animal model, Tg2576 mouse brain, and in human AD brain, induction of S100a9 was confirmed. The endogenous expression of S100a9 was induced by treatment with Abeta or CT peptides in a microglia cell line, BV2 cells. In these cells, silencing study of S100a9 showed that the induction of S100a9 increased the intracellular calcium level and up-regulated the inflammatory cytokines (IL-1beta and TNFalpha) and iNOS. S100a9 lentiviral short hairpin RNA (sh-S100a9) was injected into the hippocampus region of the brains of 13-month-old Tg2576 mice. At two months after injection, we found that knockdown of S100a9 expression had improved the cognition decline of Tg2576 mice in the water maze task, and had reduced amyloid plaque burden. These results suggest that S100a9 induced by Abeta or CT contributes to cause inflammation, which then affects the neuropathology including amyloid plaques burden and impairs cognitive function. Thus, the inhibition of S100a9 is a possible target for AD therapy.


AnnoTrack--a tracking system for genome annotation.
As genome sequences are determined for increasing numbers of model organisms, demand has grown for better tools to facilitate unified genome annotation efforts by communities of biologists. Typically this process involves numerous experts from the field and the use of data from dispersed sources as evidence. This kind of collaborative annotation project requires specialized software solutions for efficient data tracking and processing. As part of the scale-up phase of the ENCODE project (Encyclopedia of DNA Elements), the aim of the GENCODE project is to produce a highly accurate evidence-based reference gene annotation for the human genome. The AnnoTrack software system was developed to aid this effort. It integrates data from multiple distributed sources, highlights conflicts and facilitates the quick identification, prioritisation and resolution of problems during the process of genome annotation. AnnoTrack has been in use for the last year and has proven a very valuable tool for large-scale genome annotation. Designed to interface with standard bioinformatics components, such as DAS servers and Ensembl databases, it is easy to setup and configure for different genome projects. The source code is available at http://annotrack.sanger.ac.uk.