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23259589 | Compression of coated drug beads for sustained release tablet of glipizide: formulation, and dissolution. | A promising glipizide formulation comprising compression of four-layer coated beads into tablets was prepared. The tablet offered the advantages of: a two-hour lag time before drug release, retaining sustained release characteristics and providing approximately zero-order drug release. Drug release was nearly independent of paddle speeds of 50 and 100 rpm releasing 80% over 14 h similar to the commercial glipizide osmotic pump tablet during dissolution testing while keeping the benefits of multiparticular dosage forms. The tablets contain beads with four layers: (1) the innermost layer consists of 2.5 g glipizide and 3.75 g solid ethylcellulose (Surelease®) coated onto 71.25 g of sugar beads; (2) next a hardening layer of 5 g of hypromellose; (3) the controlled release layer of 7.5 g of Surelease®:lactose at a solids ratio of 100:7 and (4) an outermost layer of 20 g of lactose:sodium starch glycolate (Explotab®) at a 2:1 ratio. Then, beads were compressed into tablets containing 11 mg of glipizide using 1500 lbs of compression pressure. The dissolution test similarity factor (f2) was above 50 for all test conditions for formulation F13 and Glucotrol® with a high of 69.9. The two Surelease® layers both aid controlling drug release, with the Surelease®-drug layer affecting drug release to a greater extent. |
23259588 | Hypertriglyceridemia is a practical biomarker of metabolic syndrome in individuals with abdominal obesity. | Individuals with the metabolic syndrome have a significantly higher risk of type 2 diabetes mellitus (T2DM) and cardiovascular disease. Body mass index (BMI) and waist circumference are inaccurate methods for assessing abdominal obesity; in addition, some obese individuals are metabolically healthy while some normal weight individuals have metabolic syndrome. The methods used to visualize intra-abdominal fat, such as computed tomography (CT) scan and magnetic resonance imaging (MRI), are not available to primary care practitioners as screening methods for the primary care patient. The present study examined commonly used biomarkers to assess which of them would be most predictive of metabolic syndrome to assess the feasibility of using indicators other than BMI in the assessment of obesity-associated disease risk in the primary care setting. We examined 169 (118 females, 51 males) obese individuals with increased waist circumference (>102 cm for men and >85 cm for women), who were patients at the UCLA Risk Factor Obesity Clinic. Of these, 59 had three or more criteria associated with metabolic syndrome. In a multivariate linear regression model including body weight, BMI, waist circumference, waist-to-hip ratio, systolic blood pressure, diastolic blood pressure, glucose, high-density lipoprotein, and triglycerides (TG), only log TG and glucose values were significantly associated with the presence of metabolic syndrome (p<0.001). Both TG and fasting glucose levels were significantly and positively correlated with fasting insulin (p<0.001), homeostasis model assessment (HOMA) (p<0.001). TG were correlated negatively with adiponectin (p<0.01) and positively with high-sensitivity C-reactive protein. We conclude that the presence of elevated TG is independently associated with metabolic syndrome and is a likely predictor for insulin resistance in individuals with increased waist circumference. This finding has significant implications for screening obese and normal weight individuals in the general population for clinically significant metabolic syndrome and prediabetes, which has a major public health impact given the common occurrence of metabolic syndrome and the need for early intervention to prevent T2DM. |
23259587 | High prevalence of metabolic syndrome in young Hispanic women: findings from the national Sister to Sister campaign. | Hispanics are the fastest growing segment of the U.S. population and have a higher prevalence of cardiometabolic risk factors as compared with non-Hispanic whites. Further data suggests that Hispanics have undiagnosed complications of metabolic syndrome, namely diabetes mellitus, at an earlier age. We sought to better understand the epidemiology of metabolic syndrome in Hispanic women using data from a large, community-based health screening program. Using data from the Sister to Sister: The Women's Heart Health Foundation community health fairs from 2008 to 2009 held in 17 U.S. cities, we sought to characterize how cardiometabolic risk profiles vary across age for women by race and ethnicity. Metabolic syndrome was defined using the updated National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) guidelines, which included three or more of the following: Waist circumference ≥35 inches, triglycerides ≥150 mg/dL, high-density lipoprotein (HDL) <50 mg/dL, systolic blood pressure ≥130 mmHg or diastolic blood pressure ≥85 mmHg, or a fasting glucose ≥100 mg/dL. A total of 6843 community women were included in the analyses. Metabolic syndrome had a prevalence of 35%. The risk-adjusted odds ratio for metabolic syndrome in Hispanic women versus white women was 1.7 (95% confidence interval, 1.4, 2.0). Dyslipidemia was the strongest predictor of metabolic syndrome among Hispanic women. This disparity appeared most pronounced for younger women. Additional predictors of metabolic syndrome included black race, increasing age, and smoking. In a large, nationally representative sample of women, we found that metabolic syndrome was highly prevalent among young Hispanic women. Efforts specifically targeted to identifying these high-risk women are necessary to prevent the cardiovascular morbidity and mortality associated with metabolic syndrome. |
23259586 | Development of functionalised polyelectrolyte capsules using filamentous Escherichia coli cells. | Escherichia coli is one of the best studied microorganisms and finds multiple applications especially as tool in the heterologous production of interesting proteins of other organisms. The heterologous expression of special surface (S-) layer proteins caused the formation of extremely long E. coli cells which leave transparent tubes when they divide into single E. coli cells. Such natural structures are of high value as bio-templates for the development of bio-inorganic composites for many applications. In this study we used genetically modified filamentous Escherichia coli cells as template for the design of polyelectrolyte tubes that can be used as carrier for functional molecules or particles. Diversity of structures of biogenic materials has the potential to be used to construct inorganic or polymeric superior hybrid materials that reflect the form of the bio-template. Such bio-inspired materials are of great interest in diverse scientific fields like Biology, Chemistry and Material Science and can find application for the construction of functional materials or the bio-inspired synthesis of inorganic nanoparticles. Genetically modified filamentous E. coli cells were fixed in 2% glutaraldehyde and coated with alternating six layers of the polyanion polyelectrolyte poly(sodium-4styrenesulfonate) (PSS) and polycation polyelectrolyte poly(allylamine-hydrochloride) (PAH). Afterwards we dissolved the E. coli cells with 1.2% sodium hypochlorite, thus obtaining hollow polyelectrolyte tubes of 0.7 μm in diameter and 5-50 μm in length. For functionalisation the polyelectrolyte tubes were coated with S-layer protein polymers followed by metallisation with Pd(0) particles. These assemblies were analysed with light microscopy, scanning electron microscopy, energy dispersive X-ray spectroscopy and transmission electron microscopy. The thus constructed new material offers possibilities for diverse applications like novel catalysts or metal nanowires for electrical devices. The novelty of this work is the use of filamentous E. coli templates and the use of S-layer proteins in a new material construct. |
23259585 | Assessing biodiversity of a freshwater benthic macroinvertebrate community through non-destructive environmental barcoding of DNA from preservative ethanol. | Characterizing biodiversity in a habitat or in targeted taxonomically or socioeconomically important groups remains a challenge. Standard DNA-based biodiversity identification tools such as DNA barcoding coupled with high-throughput Next-Generation Sequencing (NGS) technologies are rapidly changing the landscape of biodiversity analysis by targeting various habitats and a wide array of organisms. However, effective use of these technological advances requires optimized protocols and benchmarking against traditional tools. Here we investigate the use of commonly used preservative ethanol as a non-destructive and inexpensive source of DNA for NGS biodiversity analysis of benthic macroinvertebrates. We used the preservative ethanol added to field collected organisms (live sorted bulk benthic samples) as a source of community DNA for NGS environmental barcoding. We directly compare this approach with a DNA barcode library generated using Sanger sequencing of all individuals separated from abenthic sample as well as with NGS environmental barcoding of DNA extracted from mixed/homogenized tissue specimens of the same benthic sample. We also evaluate a multiplex PCR strategy, as compared to commonly used single amplicon workflow, using three newly designed primer sets targeting a wide array of benthic macroinvertebrate taxa. Our results indicate the effectiveness of ethanol-based DNA in providing sequence information from 87% of taxa identified individually from mixture as compared to 89% in conventional tissue extracted DNA. Missing taxa in both DNA sources were from species with the lowest abundance (e.g. 1 individual) in the benthic mixture. Interestingly, we achieved 100% detection for taxa represented with more than 1% individuals in the mixture in both sources of DNA. Our multiplex amplification regime increased the detection as compared to any single primer set indicating the usefulness of using multiple primer sets in initial amplification of target genes. Although NGS approaches have significantly increased the potential of using DNA information in biodiversity analysis, robust methods are needed to provide reliable data and alleviate sample-processing bottlenecks. Here we coupled non-destructive DNA access and a multiplex PCR approach in NGS environmental barcoding for effective data generation from benthic live-sorted samples collected in bulk and preserved in ethanol. Our study provides a possible solution to sampling and vouchering challenges in using benthic samples through next-generation environmental barcoding and facilitates wider utility of DNA information, especially species-specific DNA barcodes, in ecological and environmental studies and real-world applications such as biomonitoring programs. |
23259582 | Drugging topoisomerases: lessons and challenges. | Topoisomerases are ubiquitous enzymes that control DNA supercoiling and entanglements. They are essential during transcription and replication, and topoisomerase inhibitors are among the most effective and most commonly used anticancer and antibacterial drugs. This review consists of two parts. In the first part ("Lessons"), it gives background information on the catalytic mechanisms of the different enzyme families (6 different genes in humans and 4 in most bacteria), describes the "interfacial inhibition" by which topoisomerase-targeted drugs act as topoisomerase poisons, and describes clinically relevant topoisomerase inhibitors. It generalizes the interfacial inhibition principle, which was discovered from the mechanism of action of topoisomerase inhibitors, and discusses how topoisomerase inhibitors kill cells by trapping topoisomerases on DNA rather than by classical enzymatic inhibition. Trapping protein-DNA complexes extends to a novel mechanism of action of PARP inhibitors and could be applied to the targeting of transcription factors. The second part of the review focuses on the challenges for discovery and precise use of topoisomerase inhibitors, including targeting topoisomerase inhibitors using chemical coupling and encapsulation for selective tumor delivery, use of pharmacodynamic biomarkers to follow drug activity, complexity of the response determinants for anticancer activity and patient selection, prospects of rational combinations with DNA repair inhibitors targeting tyrosyl-DNA-phosphodiesterases 1 and 2 (TDP1 and TDP2) and PARP, and the unmet need to develop inhibitors for type IA enzymes. |
23259584 | Limitations of surface enhanced Raman scattering in sensing DNA hybridization demonstrated by label-free DNA oligos as molecular rulers of distance-dependent enhancement. | This article presents a critical evaluation of silver nanorod arrays as substrates for assaying nucleic acid hybridization by surface enhanced Raman scattering (SERS). SERS spectra acquired on complementary oligos, alone or in combination, contain the known spectral signatures of the nucleotides that comprise the oligo; however, no signature bands characteristic of the hybrid were observed. Spectra acquired on an oligo with a 5'- or 3'-thiol were distinctly different from that acquired on the identical oligo without a thiol pendant group suggesting a degree of control over the orientation of the oligo on the nanorod surface. A set of oligos consisting of adenine tracts in a polycytosine chain served as molecular rulers to probe the distance dependence of the SERS enhancement. Using these, we have identified the point at which the characteristic bands for the nucleotides that comprise the oligo disappear from the spectrum. These findings suggest that the applicability of SERS for label-free detection of nucleic acid hybridization is limited to short oligos of less than nine nucleotides. |
23259583 | A mediator model to predict workplace influenza vaccination behaviour--an application of the health action process approach. | Applying the health action process approach (HAPA) to vaccination behaviour as a single-event health behaviour to study vaccination adherence and its predictors in a worksite flu vaccination programme. A total of N = 823 employees participated in a longitudinal survey. Predictors (risk perception, self-efficacy, positive and negative outcome expectancies, intention and planning) were assessed at Time 1, and behaviour was assessed five months later at Time 2. Intention and planning were specified as mediators in a path analytical logistic regression model. Risk perception, self-efficacy and positive as well as negative outcome expectancies predicted intention (R² = .76). Intention and planning predicted subsequent behaviour, and planning mediated the relation between intention and vaccination behaviour (R² = .67). In addition, results suggested the adjustment of the theoretical model: risk perception and negative outcome expectancies showed direct effects on behaviour resulting in a significantly better model fit. Findings support the general applicability of the HAPA to vaccination behaviour and the importance of planning for translating intentions into behaviour. However, the adjusted model was superior and underlined the particular role of risk perception and negative outcome expectancies for vaccination behaviour to explain underlying mechanisms in vaccination behaviour. |
23259581 | Regulation of enhanced cerebrovascular expression of proinflammatory mediators in experimental subarachnoid hemorrhage via the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase pathway. | Subarachnoid hemorrhage (SAH) is associated with high morbidity and mortality. It is suggested that the associated inflammation is mediated through activation of the mitogen-activated protein kinase (MAPK) pathway which plays a crucial role in the pathogenesis of delayed cerebral ischemia after SAH. The aim of this study was first to investigate the timecourse of altered expression of proinflammatory cytokines and matrix metalloproteinase in the cerebral arteries walls following SAH. Secondly, we investigated whether administration of a specific mitogen-activated protein kinase kinase (MEK)1/2 inhibitor, U0126, given at 6 h after SAH prevents activation of the MEK/extracellular signal-regulated kinase 1/2 pathway and the upregulation of cerebrovascular inflammatory mediators and improves neurological function. SAH was induced in rats by injection of 250 μl of autologous blood into basal cisterns. U0126 was given intracisternally using two treatment regimens: (A) treatments at 6, 12, 24 and 36 h after SAH and experiments terminated at 48 h after SAH, or (B) treatments at 6, 12, and 24 h after SAH and terminated at 72 h after SAH. Cerebral arteries were harvested and interleukin (IL)-6, IL-1β, tumor necrosis factor α (TNF)α, matrix metalloproteinase (MMP)-9 and phosphorylated ERK1/2 (pERK1/2) levels investigated by immunohistochemistry. Early activation of pERK1/2 was measured by western blot. Functional neurological outcome after SAH was also analyzed. Expression levels of IL-1β, IL-6, MMP-9 and pERK1/2 proteins were elevated over time with an early increase at around 6 h and a late peak at 48 to 72 h post-SAH in cerebral arteries. Enhanced expression of TNFα in cerebral arteries started at 24 h and increased until 96 h. In addition, SAH induced sensorimotor and spontaneous behavior deficits in the animals. Treatment with U0126 starting at 6 h after SAH prevented activation of MEK-ERK1/2 signaling. Further, U0126 significantly decreased the upregulation of inflammation proteins at 48 and 72 h following SAH and improved neurological function. We found no differences between treatment regimens A and B. These results show that SAH induces early activation of the MEK-ERK1/2 pathway in cerebral artery walls, which is associated with upregulation of proinflammatory cytokines and MMP-9. Inhibition of the MEK-ERK1/2 pathway by U0126 starting at 6 h post-SAH prevented upregulation of cytokines and MMP-9 in cerebral vessels, and improved neurological outcome. |
23259580 | Tracking the mechanical dynamics of human embryonic stem cell chromatin. | A plastic chromatin structure has emerged as fundamental to the self-renewal and pluripotent capacity of embryonic stem (ES) cells. Direct measurement of chromatin dynamics in vivo is, however, challenging as high spatiotemporal resolution is required. Here, we present a new tracking-based method which can detect high frequency chromatin movement and quantify the mechanical dynamics of chromatin in live cells. We use this method to study how the mechanical properties of chromatin movement in human embryonic stem cells (hESCs) are modulated spatiotemporally during differentiation into cardiomyocytes (CM). Notably, we find that pluripotency is associated with a highly discrete, energy-dependent frequency of chromatin movement that we refer to as a 'breathing' state. We find that this 'breathing' state is strictly dependent on the metabolic state of the cell and is progressively silenced during differentiation. We thus propose that the measured chromatin high frequency movements in hESCs may represent a hallmark of pluripotency and serve as a mechanism to maintain the genome in a transcriptionally accessible state. This is a result that could not have been observed without the high spatial and temporal resolution provided by this novel tracking method. |
23259579 | Retraction: cigarette smoke-induced oxidative/nitrosative stress impairs VEGF- and fluid shear stress-mediated signaling in endothelial cells. Edirisinghe I, Arunachalam G, Wong C, Yao H, Rahman A, Phipps RP, Jin ZG, and Rahman I. Antioxid Redox Signal 12: 1355-1369, 2010. | The corresponding author has sought retraction of this work from ARS. The author statement is copied below: We, the authors, wish to retract "Cigarette Smoke-Induced Oxidative/Nitrosative Stress Impairs VEGF- and Fluid Shear Stress-Mediated Signaling in Endothelial Cells" by Edirisinghe et al. (Antioxid Redox Signal 12: 1355-1369; DOI:10.1089/ars.2009.2874) because we are not satisfied with the quality of some of the data presented in the article. Overall, however, the data are reproducible and the conclusions drawn were not affected. We apologize for any inconvenience this may have caused to the readers. |
23259578 | cnvHiTSeq: integrative models for high-resolution copy number variation detection and genotyping using population sequencing data. | Recent advances in sequencing technologies provide the means for identifying copy number variation (CNV) at an unprecedented resolution. A single next-generation sequencing experiment offers several features that can be used to detect CNV, yet current methods do not incorporate all available signatures into a unified model. cnvHiTSeq is an integrative probabilistic method for CNV discovery and genotyping that jointly analyzes multiple features at the population level. By combining evidence from complementary sources, cnvHiTSeq achieves high genotyping accuracy and a substantial improvement in CNV detection sensitivity over existing methods, while maintaining a low false discovery rate. cnvHiTSeq is available at http://sourceforge.net/projects/cnvhitseq. |
23259577 | Experimental measurement and theoretical assessment of fast lanthanide electronic relaxation in solution with four series of isostructural complexes. | The rates of longitudinal relaxation for ligand nuclei in four isostructural series of lanthanide(III) complexes have been measured by solution state NMR at 295 K at five magnetic fields in the range 4.7-16.5 T. The electronic relaxation time T(le) is a function of both the lanthanide ion and the local ligand field. It needs to be considered when relaxation probes for magnetic resonance applications are devised because it affects the nuclear relaxation, especially over the field range 0.5 to 4.7 T. Analysis of the data, based on Bloch-Redfield-Wangsness theory describing the paramagnetic enhancement of the nuclear relaxation rate has allowed reliable estimates of electronic relaxation times, T(1e), to be obtained using global minimization methods. Values were found in the range 0.10-0.63 ps, consistent with fluctuations in the transient ligand field induced by solvent collision. A refined theoretical model for lanthanide electronic relaxation beyond the Redfield approximation is introduced, which accounts for the magnitude of the ligand field coefficients of order 2, 4, and 6 and their relative contributions to the rate 1/T(le). Despite the considerable variation of these contributions with the nature of the lanthanide ion and its fluctuating ligand field, the theory explains the modest change of measured T(le) values and their remarkable statistical ordering across the lanthanide series. Both experiment and theory indicate that complexes of terbium and dysprosium should most efficiently promote paramagnetic enhancement of the rate of nuclear relaxation. |
23259576 | Quantized conductance in an InSb nanowire. | Ballistic one-dimensional transport in semiconductor nanowires plays a central role in creating topological and helical states. The hallmark of such one-dimensional transport is conductance quantization. Here we show conductance quantization in InSb nanowires at nonzero magnetic fields. Conductance plateaus are studied as a function of source-drain bias and magnetic field, enabling extraction of the Landé g factor and the subband spacing. |
23259574 | Comparison of surgical stress in patients undergoing open versus laparoscopic radical prostatectomy by measuring perioperative serum cytokine levels. | We evaluated the perioperative serum levels of inflammatory cytokines in patients with prostate cancer (PCa) treated with open or laparoscopic radical prostatectomy (RP) and assessed the surgical stress based on the cytokine levels in addition to conventional clinical stress markers after surgery. One hundred sixty-five patients who received RP for clinically localized PCa were enrolled. Serum levels of interleukin (IL)-10, IL-6, tumor necrosis factor-α, IL-1β, IL-8, and IL-12p70 were quantitatively measured using a multiplex bead array at three time points (i.e., before the operation [pre-OP], immediately after the operation [post-OP], and on postoperative Day 1 [POD1]). The perioperative changes in serum stress markers, including cytokines, were compared between patients who underwent open and laparoscopic RP, and the predictors for high levels of postoperative cytokines were assessed. The median age and estimated blood loss were significantly lower in the laparoscopic RP group than in the open RP group (P=.003 and P<.01, respectively). In all patients, body temperature, white blood cell count, and serum IL-10 and IL-6 levels were significantly higher at post-OP and POD1 than at pre-OP. Patients who underwent laparoscopic RP had significantly lower levels of serum IL-10, IL-6, and IL-1β at post-OP and POD1 than those who underwent open RP. Multivariate regression analyses showed that the surgical group (open versus laparoscopic) was an independent influencing factor on the levels of serum IL-6 and IL-10 at POD1 (P=.031 and P<.004, respectively) among various clinical perioperative parameters. Several inflammatory cytokines, particularly IL-6 and IL-10, are potential surgical stress markers in patients with PCa treated with RP. Based on cytokine production, our data support the view that laparoscopic RP is less invasive than open RP. |
23259573 | HuR cytoplasmic expression is associated with increased cyclin A expression and poor outcome with upper urinary tract urothelial carcinoma. | HuR is an RNA-binding protein that post-transcriptionally modulates the expressions of various target genes implicated in carcinogenesis, such as CCNA2 encoding cyclin A. No prior study attempted to evaluate the significance of HuR expression in a large cohort with upper urinary tract urothelial carcinomas (UTUCs). In total, 340 cases of primary localized UTUC without previous or concordant bladder carcinoma were selected. All of these patients received ureterectomy or radical nephroureterectomy with curative intents. Pathological slides were reviewed, and clinical findings were collected. Immunostaining for HuR and cyclin A was performed and evaluated by using H-score. The results of cytoplasmic HuR and nuclear cyclin A expressions were correlated with disease-specific survival (DSS), metastasis-free survival (MeFS), urinary bladder recurrence-free survival (UBRFS), and various clinicopathological factors. HuR cytoplasmic expression was significantly related to the pT status, lymph node metastasis, a higher histological grade, the pattern of invasion, vascular and perineurial invasion, and cyclin A expression (p = 0.005). Importantly, HuR cytoplasmic expression was strongly associated with a worse DSS (p < 0.0001), MeFS (p < 0.0001), and UBRFS (p = 0.0370) in the univariate analysis, and the first two results remained independently predictive of adverse outcomes (p = 0.038, relative risk [RR] = 1.996 for DSS; p = 0.027, RR = 1.880 for MeFS). Cyclin A nuclear expression was associated with a poor DSS (p = 0.0035) and MeFS (p = 0.0015) in the univariate analysis but was not prognosticatory in the multivariate analyses. High-risk patients (pT3 or pT4 with/without nodal metastasis) with high HuR cytoplasmic expression had better DSS if adjuvant chemotherapy was performed (p = 0.015). HuR cytoplasmic expression was correlated with adverse phenotypes and cyclin A overexpression and also independently predictive of worse DSS and MeFS, suggesting its roles in tumorigenesis or carcinogenesis and potentiality as a prognostic marker of UTUC. High HuR cytoplasmic expression might identify patients more likely to be beneficial for adjuvant chemotherapy. |
23259572 | Defining bacterial species in the genomic era: insights from the genus Acinetobacter. | Microbial taxonomy remains a conservative discipline, relying on phenotypic information derived from growth in pure culture and techniques that are time-consuming and difficult to standardize, particularly when compared to the ease of modern high-throughput genome sequencing. Here, drawing on the genus Acinetobacter as a test case, we examine whether bacterial taxonomy could abandon phenotypic approaches and DNA-DNA hybridization and, instead, rely exclusively on analyses of genome sequence data. In pursuit of this goal, we generated a set of thirteen new draft genome sequences, representing ten species, combined them with other publically available genome sequences and analyzed these 38 strains belonging to the genus. We found that analyses based on 16S rRNA gene sequences were not capable of delineating accepted species. However, a core genome phylogenetic tree proved consistent with the currently accepted taxonomy of the genus, while also identifying three misclassifications of strains in collections or databases. Among rapid distance-based methods, we found average-nucleotide identity (ANI) analyses delivered results consistent with traditional and phylogenetic classifications, whereas gene content based approaches appear to be too strongly influenced by the effects of horizontal gene transfer to agree with previously accepted species. We believe a combination of core genome phylogenetic analysis and ANI provides an appropriate method for bacterial species delineation, whereby bacterial species are defined as monophyletic groups of isolates with genomes that exhibit at least 95% pair-wise ANI. The proposed method is backwards compatible; it provides a scalable and uniform approach that works for both culturable and non-culturable species; is faster and cheaper than traditional taxonomic methods; is easily replicable and transferable among research institutions; and lastly, falls in line with Darwin's vision of classification becoming, as far as is possible, genealogical. |
23259571 | Lipids and non-cardiac vascular disease: a lecture overview. | The lecture covered the role of lipids in the pathogenesis and treatment of non-cardiac vascular disease. The following conditions were considered: abdominal aortic aneurysms (AAAs), peripheral arterial disease (PAD), carotid artery disease and atherosclerotic renal artery stenosis (ARAS). |
23259570 | Hypertension: quo vadis? | High blood pressure (BP) along with smoking habit and lipid disorders are the most important and modifiable risk factors for cardiovascular diseases. However, the prevalence of high BP has grown progressively over time with a progressive increase not only in the absolute number of patients but in the proportion of those showing BP values out of control. The increasing world-wide prevalence of hypertension and the related increase in burden of the disease due to diagnosis, treatment and management of the complications mandates both Health Authorities and research institutions to find out new strategies to improve the BP control. So, one of the main questions is which are the possible perspectives for the future of high BP management, and in particular how can we face the problem of hypertension in the near future? Four main points will be shortly discussed: the genetic contribution to hypertension development and control, the availability of effective preventive strategies, the improvement of disease management, and the role of extensive control of concomitant risk factors. It is relatively easy to suppose that the integration of the best available knowledge with the more recent diagnostic and therapeutic achievements will improve the management of hypertension through a more effective detection of subjects at risk who will undergo an earlier diagnosis leading to a more tailored, tolerated and effective treatment of the hypertensive disease. This means that the future direction of the hypertension management is the simpler: the patient instead of the disease. |
23259569 | Treatment of carotid stenosis. | Carotid stenosis is frequent in the general population, especially in elderly people and is associated with a high risk of stroke and vascular events. In patients with asymptomatic carotid stenosis the overall annual risk of ipsilateral stroke has dramatically decreased over the past decades, due to improvement in medical management. Asymptomatic carotid stenosis is probably a better indicator of generalized atherosclerotic disease than of stroke risk, with an average risk of nonstroke death (mainly due to ischemic heart disease) generally higher than the risk of ipsilateral stroke. Management of risk factors, antiplatelet therapy, and statins are highly beneficial in these patients. Carotid surgery in patients with asymptomatic carotid stenosis is associated with a small absolute benefit compared to medical treatment. The prognosis of patients with symptomatic carotid stenosis is dramatically different from that of patients with asymptomatic carotid stenosis because the risk of stroke on medical treatment alone is very high and highest during the first few days and weeks. In these patients, endarterectomy is highly beneficial and the absolute benefit of is increased in patients with 70- 99% stenosis, men, patients over 75 years, and in those treated within 2 weeks after the last event. The meta-analysis of the 3 major European trials comparing endarterectomy to stenting in symptomatic stenosis has shown an increased risk of perioperative risk of any stroke or death in the stenting group (74% increase in risk in patients treated with stenting). However, the risk of stroke or death after stenting and surgery were equivalent below the age of 70 whereas there was a two-fold increase in risk of stenting over endarterectomy above this age. Thus, surgery remains the first line method in most cases but stenting is potentially an alternative in young patients. |
23259568 | Management of patients with poly-vascular disease: priorities for revascularization procedures. | Multisite artery disease (MSAD) affects 15% to 30% of patients with clinically manifest atherosclerosis, and has a relevant negative impact on prognosis. However, studies specifically focused on MSAD are very few, and available evidence is scarce. Importantly, patients with MSAD require an integrated management, possibly by a "Vascular Team" composed of the different specialists involved in the treatment of atherosclerosis. A multi-disciplinary, patient-centered approach is mandatory to deal with the variety of clinical scenarios and comorbidities found in MSAD patients. The risk/benefit ratio for multi-site arterial revascularization should always be carefully assessed in MSAD patients, taking into account the additional risks of interventions in this subset of patients. Many therapeutic options have been proposed for multisite revascularization, but little evidence is currently available to support specific recommendations. Percutaneous revascularization of the different arterial districts, when feasible, appears promising because of the lower operative morbidity and mortality. |
23259567 | How to identify subjects with poly-vascular disease? | Multisite artery or polyvascular disease is common. In the REACH registry, 15.9% of patients with either established atherosclerotic arterial disease or at least 3 risk factors for atherothrombosis had symptomatic polyvascular disease. History of risk factors and known co-morbidities, as well as a thorough physical examination, are mandatory in the initial screening and diagnostic work-up. Various non-invasive imaging techniques (duplex ultrasound, computed tomography angiography, magnetic resonance angiography) can be used for the identification of the polyvascular patient. Digital subtraction angiography is now used almost exclusively in association with endovascular procedures. Appropriate implementation of each technique is based on international guidelines and a multidisciplinary discussion for each case. The presence of co-existing disease in a different vascular bed is associated with a higher risk of recurrent symptoms and complications in the first site. In this context, accumulating evidence suggests that arterial biomarkers, such as arterial stiffness (pulse wave velocity), central blood pressures, wave reflections indices, ankle-brachial index, carotid intimamedia thickness, as well as vasculogenic erectile dysfunction, can predict cardiovascular morbidity and mortality beyond classical risk factors and prediction models. An important pending question is whether identification of multisite arterial disease may improve clinical outcomes in patients who are already in secondary prevention programs. Such screening of asymptomatic multisite artery disease in patients with known CVD would be of paramount importance if it is ultimately proven with hard evidence that it should lead to a different management from the one proposed for CVD patients without multisite artery disease. |
23259566 | Lessons from the REACH Registry in Europe. | Among patients with atherothrombosis, including coronary artery disease (CAD), cerebrovascular disease (CVD), and peripheral arterial disease (PAD), patients with PAD generally have the worse prognosis. The Reduction of Atherothrombosis for Continued Health (REACH) Registry characterized the atherothrombotic risk factor profile, and evaluated treatment intensity and cardiovascular events among different atherothrombotic patient populations worldwide. Two thirds of PAD patients had polyvascular disease, defined as symptomatic involvement of more than one vascular bed. The risk factor profile in patients with CAD, CVD and PAD was very much similar. However, optimal risk factor control by medical treatment and lifestyle interventions was least accomplished in PAD patients. Furthermore, PAD patients and patients with polyvascular disease showed the highest cardiovascular event rates. Of note, therapeutic strategies are similar for all atherothrombotic disease categories, irrespective of the presence of polyvascular disease. Therefore, it is of the utmost importance to achieve optimal risk factor control, particularly for PAD patients and for those with polyvascular disease, in order to prevent future cardiovascular events. |
23259565 | Therapeutic targets to raise HDL in patients at risk or with coronary artery disease. | The plasma levels of high-density lipoprotein (HDL) cholesterol are inversely related to cardiovascular risk. Traditional HDL-raising therapies, like fibrates, PPAR-γ agonists, and nicacin, among others, are associated with undesirable side effects, limited efficacy, or have not yet been shown to improve morbidity and mortality on top of statins in clinical outcome trials. A novel pharmacological target for raising circulating HDL-C levels is the cholesterol ester transfer protein (CETP), an enzyme that facilitates the transport of cholesteryl esters and triglycerides between the lipoproteins. Four pharmacological small-molecule inhibitors of CETP, i.e. torcetrapib (Pfizer), dalcetrapib (JTT-705; Roche), anacetrapib (Merck), and evacetrapib (Eli Lilly) have been developed. Notwithstanding a marked increase in HDL, torcetrapib was associated with an increase in all-cause mortality in the ILLUMINATE trial and raised safety concerns related to the off-target effects of CETP inhibition. Most recently, development of dalcetrapib was abruptly stopped due to a lack of clinically meaningful efficacy. Thus, it will be of utmost importance to demonstrate that the remaining CETP inhibitors in development not only increase HDL-C levels in plasma, but also improve HDL-function in patients with coronary disease or an acute coronary syndrome. |
23259564 | High density lipoprotein - should we raise it? | Low high-density lipoprotein (HDL) cholesterol levels are associated with an increased risk of coronary artery disease and myocardial infarction. Experimental studies have identified several potential anti-atherogenic properties of HDL, including promotion of macrophage cholesterol efflux, endothelial nitric oxide stimulation, anti-inflammatory and anti-thrombotic effects. These observations have lead to the important question of whether raising of HDL can reduce cardiovacular risk. Notably, recent studies have suggested that vascular effects of HDL can be highly heterogenous and are altered in patients with coronary disease or diabetes, that has been referred to as "HDL dysfunction". Moreover, studies using gene-targeted mice have indicated that genetic modifications leading to a similar increase of HDL cholesterol levels can either reduce (i.e. apoA1 transgene overexpression) or accelerate (i.e. SR-B1 deficiency) atherosclerosis, depending on the molecular target. These findings therefore suggest that HDL cholesterol levels alone are likely not sufficient as a readout for the vascular effects of HDL-targeted therapeutic interventions, since both, the vascular effects of on-treatment HDL as well as the underlying molecular mechanism used to elevate HDL cholesterol levels may represent critical determinants of the overall vascular effects of therapeutic interventions raising HDL-cholesterol levels. In summary, low HDL cholesterol plasma levels remain associated with an increased cardiovascular risk. However, the above findings suggest that careful clinical trial programms are needed to determine, which HDL raising therapeutic interventions may indeed exert vasoprotective effects. |
23259563 | Getting patients to target- implementing the guidelines. | All coronary patients should be advised and have the opportunity to access a comprehensive cardiovascular prevention and rehabilitation programme, addressing all aspects of lifestyle - smoking cessation, healthy eating and being physically active - together with more effective management of blood pressure, lipids and glucose. To achieve the clinical benefits of a multidisciplinary and multifactorial prevention programme we need to integrate professional lifestyle interventions with effective risk factor management, and evidence based drug therapies, appropriately adapted to the medical, cultural, and economic setting of a country. The challenge is to engage and motivate cardiologists, physicians and health professionals to routinely practice high quality preventive cardiology in hospital and community, and a health care system which invests in prevention. |
23259562 | The utility of emerging biomarkers and imaging for assessment of cardiovascular risk. | The need of early, preclinical detection of disease is given by the fact that in 50% of patients dying due to coronary death, mortality is neither heralded by cardiac symptoms nor diagnosis make .The risk during life of suffering of consequences of atherosclerosis can be efficiently assessed through the Framingham risk score (among several other global risk scores). Global risk scores although originally formulated to give a numerical estimate of the risk, give generally a rough categorization of the patient into a low, (0-10%) intermediate (10%-20%) or high ( > 20%) risk. Furthermore the boarders between intermediate and low or high risk are frequently not uniform. Although global risk score evaluation are considered efficient tools in medical practice, over- or underestimation of risk has been reported in several studies. These are the mean reason why many investigators embarked during the last two decades in an effort to discover newer predictive markers. Among them few have passed the threshold of a rigorous assessment of their predictive power including analysis not only of statistical association but also of calibration, discrimination, and reclassification. |
23259561 | Global cardiovascular risk management in primary prevention. | Although the impressive progression of modern diagnostic opportunities and therapeutic options, cardiovascular diseases still represent the leading causes of morbidity and mortality, worldwide. Beyond the effective pharmacological treatment of major cardiovascular disease or sequelae, however, cardiovascular diseases developing in adult individuals are largely preventable. The substantial failure to prevent cardiovascular disease in the 20th century generation is mostly linked to the ineffective use, as well as to the underuse of available preventive strategies. As a consequence, preventive strategies should be encouraged at both individual and population level, to substantially improve healthy status of the general population and reduce the burden of cardiovascular diseases in Western and Developing Countries. |
23259560 | Tetrahydrobiopterin: a vascular redox target to improve endothelial function. | Loss of normal endothelial function and bioactivity of nitric oxide (NO), associated with increased production of reactive oxygen species (ROS), are characteristics of cardiovascular disease states. There is good experimental evidence that these abnormalities are causally related to cardiovascular disease pathogeneses, and are amenable to therapeutic intervention. However, simple attempts to increase NO levels or reduce "oxidative stress", for example using nonselective anti-oxidant drugs, have shown no benefit as treatments of cardiovascular disease. Increasing evidence highlights the need to better understand NO and ROS mediated signaling mechanisms in endothelial function, in order to identify more rational and selective therapeutic targets. The NO synthase co-factor, tetrahydrobiopterin (BH4) is a redox active molecule which regulates NO and ROS production by NO synthase and provides an exemplar of redox dependent signaling in the endothelium, with relevance to cardiovascular disease. Loss of endothelial cell BH4 is observed in cardiovascular disease states and results in loss of NO, but increased ROS production by endothelial NO synthase. Genetic mouse models of augmented endothelial cell BH4 synthesis have shown proof of concept that endothelial cell BH4 can alter cardiovascular disease pathogenesis, but clinical trials of BH4 therapy in vascular disease have been limited by systemic oxidation and limited endothelial cell uptake of BH4. In contrast, some existing therapies such as statins appear to exert favourable effects on endothelial cell BH4 and endothelial NO synthase function. Identifying specific redox mechanisms and targets in the endothelium will provide new potential targets for future drug treatments. |
23259559 | Decreasing arterial aging by controlling blood pressure levels and hypertension: a step forward. | Arterial aging, characterized by arterial stiffening that is clinically evaluable as aortic pulse wave velocity, is risky for CV events, disability, and loss of cognitive function. Today the only adopted strategy to decrease arterial aging/ arterial stiffness is represented by decreasing BP. Selective antihypertensive drug classes (calcium channel blockers, converting enzyme inhibitors, angiotensin type 1 receptor antagonists) showed a beneficial effect on the arterial wall and on both large and small arteries over and above the reduction in BP levels. Still, the lower the better paradigm seems only to expose older subjects to higher rate of side effects, that via hypotension result in even transient organ hypoperfusion. This vicious circle may be particularly detrimental for cerebral district and, thus, for cognitive impairment onset and progression until dementia. |
23259558 | Genetic and environmental determinants of early vascular ageing (EVA). | Cardiovascular disease is multidimensional and new ideas are needed to develop the conventional risk factor paradigm that has been based on the Framingham Heart Study since more than 30 years. Traditional risk factors such as hypertension, smoking, hyperlipidemia and diabetes can only explain about 50% of the distribution of coronary heart disease whereas the inclusion of new risk markers or protective markers may increase the explained proportion up to 80% of myocardial infarction risk according to the INTERHEART study. Still there are substantial differences in cardiovascular risk between regions and populations that are hard to explain. Findings in the former Soviet Union geographical area in Eastern Europe could contribute to new and better understanding of cardiovascular risk as a reflection of ageing in general, as populations in these areas not only run a very high cardiovascular risk but also have a shorter mean life expectancy in general. New understanding of the interaction between genes and the environment in prediction of cardiovascular ageing could contribute to the development of more effective preventive strategies. |
23259557 | p66 Shc as the engine of vascular aging. | The present work is addressing the latest advances made in understanding the molecular mechanisms of vascular aging. Increased production of reactive oxygen species (ROS) is the common denominator of vascular aging, endothelial dysfunction and atherosclerosis. ROS are generated by different intracellular molecular pathways. In view of its role in determining the redox state of the cells and their responses to free radicals, mitochondrial p66Shc protein has been regarded as part of a putative transduction pathway relevant to endothelial integrity. Future efforts should translate our knowledge of the mechanisms of aging and its interaction with risk factors into the development of new therapeutic strategies to prevent age-associated cardiovascular disease. |
23259556 | SIRT1 - an anti-inflammatory pathway at the crossroads between metabolic disease and atherosclerosis. | Atherosclerosis is a chronic inflammatory disease that is based on the interaction between inflammatory cell subsets and specific cells in the arterial wall. SIRT1 deacetylates histone and non-histone proteins and has been implicated in protective effects of caloric restriction on lifespan and metabolic pathways in yeast, nematodes, and mice. In the vasculature of rodents, SIRT1 mediates vasodilatation through the release of endothelial nitric oxide synthase-derived nitric oxide and scavenges reactive oxygen species. Using a genetic loss-of-function approach, SIRT1 has been shown to interfere with crucial steps of endothelial activation and atherogenesis by suppressing NFκB signaling: Partial SIRT1 deletion in ApoE-/- mice prevented expression of endothelial adhesion molecules thereby hampering the extravasation of circulating monocytes. In monocyte-derived macrophages SIRT1 deletion reduced the expression of the scavenger receptor lectin-like oxidized low-density lipoprotein receptor 1 (Lox-1) resulting in reduced foam cell formation and atherosclerosis. Moreover, it was reported that SIRT1 regulates the activity of liver X-receptor, thereby promoting ABCA1-driven reverse cholesterol transport in plaque-resident macrophages slowing foam cell formation. Finally, SIRT1 suppressed the expression of endothelial tissue factor, and thus exerted anti-thrombotic properties during induced carotid thrombosis in mice. These findings indicate protective effects of SIRT1 in atherogenesis and thrombosis at an experimental level and highlight the opportunity to translate this concept from bench to bedside. Indeed, SIRT1 activators are available and have been shown to exert beneficial effects at the preclinical level in obesity and type 2 diabetes mellitus (T2DM). SIRT1 activators are currently being evaluated in phase II clinical trials in patients with T2DM. The concept of SIRT1 activation appears a promising strategy for novel therapeutic approaches in patients with atherothrombosis. |
23259555 | Joint ESC/EASD guidelines on diabetes, where are we now and where should we go? | Patients with diabetes and prediabetes are at high risk for micro- and macrovascular complications. A multifactorial management strategy improves their prognosis considerably. Of concern is that these patients often fall between two specialties: cardiovascular medicine and diabetology. Practice guidelines for this patient category have been issued in collaboration between the European Society of Cardiology and the European Association for the Study of Diabetes to ascertain management according to the best available evidence. This article discusses why and for whom such guidelines are important. |
23259554 | Glucose and LDL lowering: the need for intensive therapy. | In almost every epidemiological analysis so far performed a strong correlation always emerges between degree of hyperglycemia and risk of both micro- and macrovascular complications. However, whereas lowering plasma glucose levels by intensive treatment has proven to reduce the risk of development of retinopathy, nephropathy and neuropathy, the effect on macrovascular complications has remained quite doubtful. Multiple factors may have concurred to this negative findings including long duration of diabetes, poor pre-existing glycaemic control, potentially inadequate anti-diabetes drugs. Another potential explanation is that, given the high cardiovascular risk of the diabetic patients they were already aggressively treated as far as their cardiovascular risk factors are concerned. The annual mortality in these diabetic cohorts was, indeed, incredibly close to that of the non-diabetic population. These considerations along with the results of multiintervention studies, such as the Steno-2, supports the need for multifactorial intensive needs, definitely including glucose and lipid lowering. |
23259553 | Mechanisms of diabetic dyslipidemia: relevance for atherogenesis. | Diabetic dyslipidemia is due to a multiple array of metabolic abnormalities determining a typical phenotype characterized by increased plasma triglycerides, reduced HDL and a preponderance of small, dense LDL. This dyslipidemia, defined as atherogenic dyslipidemia, is thought to be highly responsible for the increased cardiovascular risk in diabetes mellitus. Several lines of evidence indicate that the increased liver production of VLDL is the main underlying defect in atherogenic dyslipidemia. This review will recapitulate the pathophysiological aspects of diabetic dyslipidemia with special focus on the molecular mechanism causing increased liver production of VLDL in diabetic patients. The consequences of atherogenic dyslipidemia on mechanisms of atherogenesis will be also reviewed. |
23259552 | Impact of pre-diabetes and diabetes on cardiovascular outcomes. | The present paper examines major evidences on the correlation between pre-diabetes, diabetes and cardiovascular risk, especially focusing on early and multifactorial treatment strategies holding the potential to delay the occurrence of micro- and macro-vascular complications causing impaired quality of life and reduced survival. |
23259551 | Dysglycemia and abdominal obesity. | Dysglycemia as a pre-stage of diabetes mellitus and abdominal obesity are closely interrelated at multiple levels and by a whole array of complex mechanisms, many of which seem to have the potential of causing harm to large blood vessels, in particular to coronary and peripheral vascular segments. Both conditions are associated with elevated circulating concentrations of free fatty acids in conjunction with insulin resistance, oxidative stress, mitochondrial dysfunction, disordered nitric oxide release, and endothelial dysfunction. Oscillating glucose levels seem to be associated with the most of the injury burden to endothelial cells of large blood vessels and also generate some kind of metabolic memory. In addition, the multiple effects of insulin also on the regulation of the vasculature are shifted towards vasoconstriction and proliferation in the context of insulin resistance and the excessively high levels. |
23259549 | Determination of stanozolol and 3'-hydroxystanozolol in rat hair, urine and serum using liquid chromatography tandem mass spectrometry. | Anabolic androgenic steroids, such as stanozolol, are typically misused by athletes during preparation for competition. Out-of-competition testing presents a unique challenge in the current anti-doping detection system owing to logistic reasons. Analysing hair for the presence of a prohibited drug offers a feasible solution for covering the wider window in out-of-competition testing. To assist in vivo studies aiming to establish a relationship between drug levels detected in hair, urine and blood, sensitive methods for the determination of stanozolol and its major metabolite 3'-hydroxystanozolol were developed in pigmented hair, urine and serum, using brown Norway rats as a model system and liquid chromatography tandem mass spectrometry (LC-MS/MS). For method development, spiked drug free rat hair, blood and urine samples were used. The newly developed method was then applied to hair, urine and serum samples from five brown Norway rats after treatment (intraperitoneal) with stanozolol for six consecutive days at 5.0 mg/kg/day. The assay for each matrix was linear within the quantification range with determination coefficient (r2) values above 0.995. The respective assay was capable of detecting 0.125 pg/mg stanozolol and 0.25 pg/mg 3'-hydroxystanozolol with 50 mg hair; 0.063 ng/mL stanozolol and 0.125 ng/mL 3'-hydroxystanozolol with 100 μL of urine or serum. The accuracy, precision and extraction recoveries of the assays were satisfactory for the detection of both compounds in all three matrices. The average concentrations of stanozolol and 3'-hydroxystanozolol, were as follows: hair = 70.18 ± 22.32 pg/mg and 13.01 ± 3.43 pg/mg; urine = 4.34 ± 6.54 ng/mL and 9.39 ± 7.42 ng/mL; serum = 7.75 ± 3.58 ng/mL and 7.16 ± 1.97 ng/mL, respectively. The developed methods are sensitive, specific and reproducible for the determination of stanozolol and 3'-hydroxystanozolol in rat hair, urine and serum. These methods can be used for in vivo studies further investigating stanozolol metabolism, but also could be extended for doping testing. Owing to the complementary nature of these tests, with urine and serum giving information on recent drug use and hair providing retrospective information on habitual use, it is suggested that blood or urine tests could accompany hair analysis and thus avoid false doping results. |
23259548 | Radiographic and clinical outcome of syringomyelia in patients treated for tethered cord syndrome without other significant imaging abnormalities. | The surgical management of patients with symptoms of tethered cord syndrome (TCS) who lack significant radiographic abnormalities is controversial. One potential MRI marker for TCS is a spinal cord syrinx or syringomyelia. Alternatively, a syrinx may be a benign and incidental finding. In this report the authors evaluated a highly selected cohort of patients with symptoms of TCS with minimal radiographic abnormalities other than syringomyelia. They analyzed clinical and radiographic outcomes after tethered cord release (TCR). A retrospective review of data from 16 children who met the study inclusion criteria was performed. All patients had been surgically treated at Riley Hospital for Children in Indianapolis, Indiana, between 2006 and 2011. All children had clinical symptoms of TCS as well as available pre- and postoperative MRI data. The most common presentation (12 [75%] of 16 patients) was urinary dysfunction, defined as symptoms of urgency or incontinence with abnormal urodynamic studies. Clinical follow-up data were available in 11 of these 12 patients. All 11 had improvement in symptoms at an average follow-up of 17 months. Seven (87.5%) of 8 patients presenting with back or leg pain had improvement. Three patients had progressive scoliosis; 2 had stabilization of the curve or mild improvement, and 1 patient had worsening deformity. Radiographic follow-up data were obtained an average of 14.5 months after surgery. Twelve patients (75%) had stable syringomyelia after TCR. Four patients showed improvement, with 2 having complete radiographic resolution. Highly selected patients with symptoms of TCS did very well clinically. Patients with abnormal urodynamic studies, pain, and gait disturbances showed a high rate of symptomatic improvement. However, a smaller percentage of patients had radiographic improvement of the syrinx. Therefore, the authors suggest that the decision to perform TCR should be based on clinical symptoms in this population. Symptomatic improvement was not necessarily related to radiographic resolution of the syrinx. |
23259547 | Positive genetic interactors of HMG2 identify a new set of genetic perturbations for improving sesquiterpene production in Saccharomyces cerevisiae. | Terpenoids and isoprenoids are an important class of natural products, which includes currently used drugs, high value bioactive and industrial compounds, and fuel candidates. Due to their industrial application, there is increasing interest in the development of S. cerevisiae strains capable of producing high levels of terpenoids. Aiming to identify new gene targets which can be manipulated to increase sesquiterpene production, a set of HMG2 positive genetic interactors were assessed as single and digenic heterozygous deletions in the presence or absence of stable HMG2(K6R) overexpression. Upon single allele deletion, most genes examined led to increased sesquiterpene production in yeast cells. Tandem heterozygous deletion of a set of three genes, the ubiquitin ligases ubc7 and ssm4/doa10, and the ER resident protein pho86, led to an 11-fold increase in caryophyllene yields (125 mg/L in shake flasks) compared to cells lacking these modifications. The effect of the heterozygous deletions appears to be due to Hmg1p and Hmg2p stabilization. Heterozygous deletions cause significant reductions in protein levels but do not lead to growth impediments frequently seen in haploid strains. By exploiting desirable haploinsufficiencies in yeast, we identified a new set of genes that can be disrupted in tandem and cause significant stabilization of Hmgp and a substantial increase in sesquiterpene production. The approach presented here allows new genetic perturbations to be compiled on yeast cell factory strains without negatively impacting cell growth and viability. |
23259546 | Examining direct and indirect pathways to health behaviour: the influence of cognitive and affective probability beliefs. | This study aimed to extricate the influence of rational (e.g., 'I think …') and intuitive (e.g., 'I feel …') probability beliefs in the behavioural decision-making process regarding skin cancer prevention practices. Structural equation modelling was used in two longitudinal surveys (sun protection during winter sports [N = 491]; sun protection during summer [N = 277]) to examine direct and indirect behavioural effects of affective and cognitive likelihood (i.e. unmediated or mediated by intention), controlled for attitude, social influence and self-efficacy. Affective likelihood was directly related to sun protection in both studies, whereas no direct effects were found for cognitive likelihood. After accounting for past sun protective behaviour, affective likelihood was only directly related to sun protection in Study 1. No support was found for the indirect effects of affective and cognitive likelihood through intention. The findings underscore the importance of feelings of (cancer) risk in the decision-making process and should be acknowledged by health behaviour theories and risk communication practices. Suggestions for future research are discussed. |
23259545 | Replacement of hematopoietic system by allogeneic stem cell transplantation in myelofibrosis patients induces rapid regression of bone marrow fibrosis. | Bone marrow fibrosis is a hallmark of primary and post ET/PV myelofibrosis. To investigated the impact of replacement of the hematopoietic system in myelofibrosis patients by allogeneic stem cell transplantation on bone marrow fibrosis, we studied bone marrow fibrosis on bone marrow samples from 24 patients with myelofibrosis before and after dose-reduced conditioning followed by allogeneic stem cell transplantation from related or unrelated donor. Using the European Consensus on Grading Bone Marrow Fibrosis, before allografting all patients had advanced fibrosis MF-2 (n = 13) or MF-3 (n = 11). After transplantation, a complete (MF-0) or nearly complete (MF-1) regression of bone marrow fibrosis was seen in 59 % at day +100, in 90 % at day +180, and in 100 % at day +360. No correlation between occurrence of acute graft-versus-host disease, and fibrosis regression on day +180 was seen. We conclude that dose-reduced conditioning, followed by allogeneic stem cell transplantation, resulted in a rapid resolution of bone-marrow fibrosis suggesting the bone marrow fibrogenesis is a highly dynamic rather than static process in patients with myelofibrosis. |
23259543 | Analysis of lumbar plexopathies and nerve injury after lateral retroperitoneal transpsoas approach: diagnostic standardization. | The minimally invasive lateral transpsoas approach has become an increasingly popular means of fusion. The most frequent complication is related to lumbar plexus nerve injuries; these can be diagnosed based on distribution of neurological deficit following the motor and/or sensory nerve injury. However, the literature has failed to provide a clinically relevant description of these complications. With accurate clinical diagnosis, spine practitioners can provide more precise prognostic and management recommendations to include observation, nerve blocks, neurodestructive procedures, medications, or surgical repair strategies. The purpose of this study was to standardize the clinical findings of lumbar plexopathies and nerve injuries associated with minimally invasive lateral retroperitoneal transpsoas lumbar fusion. A thorough literature search of the MEDLINE database up to June 2012 was performed to identify studies that reported lumbar plexus and nerve injuries after the minimally invasive lateral retroperitoneal transpsoas approach. Included studies were assessed for described neurological deficits postoperatively. Studies that did attempt to describe nerve-related complications clinically were excluded. A clinically relevant assessment of lumbar plexus nerve injury was derived to standardize early diagnosis and outline prognostic implications. A total of 18 studies were selected with a total of 2310 patients; 304 patients were reported to have possible plexus-related complications. The incidence of documented nerve and/or root injury and abdominal paresis ranged from 0% to 3.4% and 4.2%, respectively. Motor weakness ranged from 0.7% to 33.6%. Sensory complications ranged from 0% to 75%. A lack of consistency in the descriptions of the lumbar plexopathies and/or nerve injuries as well as a lack of diagnostic paradigms was noted across studies reviewed. Sensory dermal zones were established and a standardized approach was proposed. There is underreporting of postoperative lumbar plexus nerve injury and a lack of standardization of clinical findings of neural complications related to the minimally invasive lateral retroperitoneal transpsoas approach. The authors provide a diagnostic paradigm that allows for an efficient and accurate classification of postoperative lumbar plexopathies and nerve injuries. |
23259542 | A novel animal model of human breast cancer metastasis to the spine: a pilot study using intracardiac injection and luciferase-expressing cells. | Metastatic spine disease is prevalent in cancer victims; 10%-30% of the 1.2 million new patients diagnosed with cancer in the US exhibit spinal metastases. Unfortunately, treatments are limited for these patients, as disseminated disease is often refractory to chemotherapy and is difficult to treat with surgical intervention alone. New animal models that accurately recapitulate the human disease process are needed to study the behavior of metastases in real time. In this study the authors report on a cell line that reliably generates bony metastases following intracardiac injection and can be tracked in real time using optical bioluminescence imaging. This line, RBC3, was derived from a metastatic breast adenocarcinoma lesion arising in the osseous spine of a rat following intracardiac injection of MDA-231 human breast cancer cells. Upon culture and reinjection of RBC3, a statistically significantly increased systemic burden of metastatic tumor was noted. The resultant spine lesions were osteolytic, as demonstrated by small animal CT scanning. This cell line generates spinal metastases that can be tracked in real time and may serve as a useful tool in the study of metastatic disease in the spine. |
23259540 | Perioperative complications in patients undergoing open transforaminal lumbar interbody fusion as a revision surgery. | Transforaminal lumbar interbody fusion (TLIF) has been increasingly used to treat degenerative spine disease, including that in patients in whom earlier decompressive procedures have failed. Reexploration in these cases is always challenging and is thought to pose a higher risk of complications. To the best of the authors' knowledge, there are no current studies specifically analyzing the effects of previous lumbar decompressive surgeries on the complication rates of open TLIF. The authors performed a retrospective study of surgeries performed by a single surgeon. A total of 187 consecutive patients, in whom the senior author (A.N.) had performed open TLIF between January 2007 and January 2011, met the inclusion criteria. The patients were divided into two groups (primary and revision TLIF) for the comparison of perioperative complications. Overall, the average age of the patients was 49.7 years (range 18-80 years). Of the 187 patients, 73 patients had no history of lumbar surgery and 114 were undergoing revision surgery. Fifty-four patients (28.9%) had a documented complication intraoperatively or postoperatively. There was no difference in the rate on perioperative complications between the two groups (overall, medical, wound related, inadvertent dural tears [DTs], or neural injury). Patients who had undergone more than one previous lumbar surgery were, however, more likely to have suffered from DTs (p = 0.054) and neural injuries (p = 0.007) compared with the rest. In the hands of an experienced surgeon, revision open TLIF does not necessarily increase the risk of perioperative complications compared with primary TLIF. Two or more previous lumbar decompressive procedures, however, increase the risk of inadvertent DTs and neural injury. |
23259539 | Balantidium coli: an unrecognized cause of vertebral osteomyelitis and myelopathy. | Balantidium coli is a ciliated protozoan parasite that primarily infects primates and pigs. It is the largest protozoan to infect humans and is a well-known cause of diarrhea and dysentery. Extraintestinal disease is uncommon, and extraintestinal spread to the peritoneal cavity, appendix, genitourinary tract, and lung has rarely been reported. The authors describe a case of vertebral osteomyelitis with secondary cervical cord compression caused by B. coli. The patient was a 60-year-old immunocompetent man presenting with quadriplegia of short duration. Magnetic resonance imaging of the cervical spine showed extradural and prevertebral abscess at the C3-4 level. Drainage of the abscess, C3-4 discectomy, and iliac bone grafting were performed. Histologically B. coli was confirmed in an abscess sample. To the best of the authors' knowledge, involvement of bone by B. coli has never been reported, and this case is the first documented instance of cervical cord compression due to B. coli osteomyelitis of the spine in the literature. |
23259538 | Evaluation of efficacy of iodine prophylaxis in Poland based on the examination of schoolchildren living in Opoczno Town (Lodz Voivodship). | In 1997 a currently obligatory model of iodine prophylaxis, based on mandatory iodization of household salt with 30 mg KI/kg, was introduced. The aim of our study was to assess the iodine intake among school-age children living in Opoczno in 3 subsequent time points - in 1994, before establishment of currently operating model of iodine prophylaxis, in 1999 - 2 years after implementation of iodine prophylaxis and in 2010, - 14 years after its implementation. We assessed goitre incidence and urine iodine concentration (UIC) in 104 children in 1994, 207 children in 1999 and 174 children in 2012. Age of examined children ranged from 6 to 15 years. The thyroid volumes evaluated by ultrasound were compared to reference values for thyroid volume proposed by Zimmermann at al. Moreover, we have introduced a new index - V/BSA ratio (comparison of thyroid volume to the body surface area), which to our belief allows for more accurate assessment of thyroid volume. The median of UICs was 45.5 μg/L (1994), 101.1 μg/L (1999) and 100.6 μg/L (2010). The distribution of obtained results has changed as well - iodine concentrations below 50 μg/L were present in 59.1% children in 1994, in 12.6% children - in 1999 and in 7.1% children - in 2010.Although a significant decrease in goitre incidence with regard to age - 92.6% (1994) vs 18.5% (1999) and 15.8% (2010), as well as with regard to BSA - 95.4% (1994) vs 15.2% (1999) and 11.6% (2010) was observed, it still points to the iodine deficiency, which is in contradiction with UICs as they are within normal limits. V/BSA ratio avoids such discrepancy. The values of ratio V/BSA were higher in 1994 (7.079 ± 2.775) than in 1999 (2.935 ± 1.112) (p<0.05) and in 2010 (2.846 ± 1.029) (p<0.05). Hitherto model of iodine prophylaxis has proved to be effective in eliminating the iodine deficiency. The iodine intake is now more even, homogenous, which translates into smaller scatter of UICs and less percentage of children, in whom UIC is less than 50 μg/L. However, the iodine intake only slightly exceeds the recommended values, so median of UICs oscillates around the lower limit of references values. |
23259537 | Management of unusual genital lymphedema complication after Fournier's gangrene: a case report. | Fournier's gangrene is a bacterial infection characterized by necrotizing fasciitis, skin and soft tissue involvement, and eventually myositis of the perineal region. Aggressive debridement of devitalized tissue and overlying skin is of paramount importance, but often leaves large defects to be reconstructed. The present case reports successful extensive perineal defects coverage following Fournier's gangrene and management of subsequent penile lymphoedema impairing sexual function in a young patient. Following perianal abscess drainage, a healthy young man presented with scrotal pain. Fournier's gangrene was diagnosed and treated with multiple surgical debridements. Tissue excision extended through the entire perineal area, base of the penile shaft, lower abdominal region, the inner thighs, and gluteal region, corresponding to 12% of the total body surface area. After serial debridements and negative pressure dressings, the defect was covered by two stages of skin grafting. Graft take was 90%. Healing was achieved without hypertrophic or retractile scar. However, chronic penile lymphedema remained and was first treated with compressive garments for 2 years. Upon failure of this conservative approach, we performed a circumcision, but only a "penile lift" allowed a satisfactory esthetical and functional result. Fournier's gangrene can be complicated by a chronic lymphedema of the penis. Conservative treatment is likely to fail in severe cases and can be treated surgically by "penile lift". |
23259534 | Mutation spectrum of Drosophila CNVs revealed by breakpoint sequencing. | The detailed study of breakpoints associated with copy number variants (CNVs) can elucidate the mutational mechanisms that generate them and the comparison of breakpoints across species can highlight differences in genomic architecture that may lead to lineage-specific differences in patterns of CNVs. Here, we provide a detailed analysis of Drosophila CNV breakpoints and contrast it with similar analyses recently carried out for the human genome. By applying split-read methods to a total of 10x coverage of 454 shotgun sequence across nine lines of D. melanogaster and by re-examining a previously published dataset of CNVs detected using tiling arrays, we identified the precise breakpoints of more than 600 insertions, deletions, and duplications. Contrasting these CNVs with those found in humans showed that in both taxa CNV breakpoints fall into three classes: blunt breakpoints; simple breakpoints associated with microhomology; and breakpoints with additional nucleotides inserted/deleted and no microhomology. In both taxa CNV breakpoints are enriched with non-B DNA sequence structures, which may impair DNA replication and/or repair. However, in contrast to human genomes, non-allelic homologous-recombination (NAHR) plays a negligible role in CNV formation in Drosophila. In flies, non-homologous repair mechanisms are responsible for simple, recurrent, and complex CNVs, including insertions of de novo sequence as large as 60 bp. Humans and Drosophila differ considerably in the importance of homology-based mechanisms for the formation of CNVs, likely as a consequence of the differences in the abundance and distribution of both segmental duplications and transposable elements between the two genomes. |
23259536 | Photonic modulation of electron transfer with switchable phase inversion. | Photochromes may be reversibly photoisomerized between two metastable states and their properties can influence, and be influenced by, other chromophores in the same molecule through energy or electron transfer. In the photochemically active molecular tetrad described here, a porphyrin has been covalently linked to a fullerene electron acceptor, a quinoline-derived dihydroindolizine photochrome, and a dithienylethene photochrome. The porphyrin first excited singlet state undergoes photoinduced electron transfer to the fullerene to generate a charge-separated state. The quantum yield of charge separation is modulated by the two photochromes: one isomer of each quenches the porphyrin excited state, reducing the quantum yield of electron transfer to near zero. Interestingly, when the molecule is illuminated with white light, the quantum yield decreases as the white light intensity is increased, generating an out-of-phase response of the quantum yield to white light. However, when the same experiment is performed in the presence of additional, steady-state UV illumination, a phase inversion occurs. The quantum yield of electron transfer now increases with increasing white light intensity. Such effects illustrate emergent complexity in a relatively simple system and could find applications in molecular logic, photochemical labeling and drug delivery, and photoprotection for artificial photosynthetic molecules. The photochemistry leading to this behavior is discussed. |
23259535 | Evidence from neuroimaging to explore brain plasticity in humans during an ultra-endurance burden. | Physical activity, likely through induction of neuroplasticity, is a promising intervention to promote brain health. In athletes it is clear that training can and does, by physiological adaptations, extend the frontiers of performance capacity. The limits of our endurance capacity lie deeply in the human brain, determined by various personal factors yet to be explored. The human brain, with its vast neural connections and its potential for seemingly endless behaviors, constitutes one of the final frontiers of medicine. In a recent study published in BMC Medicine, the TransEurope FootRace Project followed 10 ultra-endurance runners over around 4,500 km across Europe and recorded a large data collection of brain imaging scans. This study indicates that the cerebral atrophy amounting to a reduction of approximately 6% throughout the two months of the race is reversed upon follow-up. While this study will contribute to advances in the limits of human performance on the neurophysiological processes in sports scientists, it will also bring important understanding to clinicians about cerebral atrophy in people who are vulnerable to physical and psychological stress long term.See related research article http://www.biomedcentral.com/1741-7015/10/170. |
23259533 | Probing the bonding and electronic structure of single atom dopants in graphene with electron energy loss spectroscopy. | A combination of scanning transmission electron microscopy, electron energy loss spectroscopy, and ab initio calculations reveal striking electronic structure differences between two distinct single substitutional Si defect geometries in graphene. Optimised acquisition conditions allow for exceptional signal-to-noise levels in the spectroscopic data. The near-edge fine structure can be compared with great accuracy to simulations and reveal either an sp(3)-like configuration for a trivalent Si or a more complicated hybridized structure for a tetravalent Si impurity. |
23259530 | Iron-sulfur cluster binding by mitochondrial monothiol glutaredoxin-1 of Trypanosoma brucei: molecular basis of iron-sulfur cluster coordination and relevance for parasite infectivity. | Monothiol glutaredoxins (1-C-Grxs) are small proteins linked to the cellular iron and redox metabolism. Trypanosoma brucei brucei, model organism for human African trypanosomiasis, expresses three 1-C-Grxs. 1-C-Grx1 is a highly abundant mitochondrial protein capable to bind an iron-sulfur cluster (ISC) in vitro using glutathione (GSH) as cofactor. We here report on the functional and structural analysis of 1-C-Grx1 in relation to its ISC-binding properties. An N-terminal extension unique to 1-C-Grx1 from trypanosomatids affects the oligomeric structure and the ISC-binding capacity of the protein. The active-site Cys104 is essential for ISC binding, and the parasite-specific glutathionylspermidine and trypanothione can replace GSH as the ligands of the ISC. Interestingly, trypanothione forms stable protein-free ISC species that in vitro are incorporated into the dithiol T. brucei 2-C-Grx1, but not 1-C-Grx1. Overexpression of the C104S mutant of 1-C-Grx1 impairs disease progression in a mouse model. The structure of the Grx-domain of 1-C-Grx1 was solved by nuclear magnetic resonance spectroscopy. Despite the fact that several residues--which in other 1-C-Grxs are involved in the noncovalent binding of GSH--are conserved, different physicochemical approaches did not reveal any specific interaction between 1-C-Grx1 and free thiol ligands. Parasite Grxs are able to coordinate an ISC formed with trypanothione, suggesting a new mechanism of ISC binding and a novel function for the parasite-specific dithiol. The first 3D structure and in vivo relevance of a 1-C-Grx from a pathogenic protozoan are reported. T. brucei 1-C-Grx1 is indispensable for mammalian parasitism and utilizes a new mechanism for ISC binding. |
23259532 | High-resolution length fractionation of surfactant-dispersed carbon nanotubes. | Length fractionation of colloidal single-wall carbon nanotube (SWCNT) dispersions is required for many studies. Size-exclusion chromatography (SEC) has been developed as a reliable method for high-resolution length fractionation of DNA-dispersed SWCNTs but has not been applied to surfactant-dispersed SWCNTs due to their lower dispersion stability and tendency to adsorb onto SEC stationary phases. Here, we report that SEC length fractionation can be achieved for bile salt dispersed SWCNTs by using porous silica-based beads as the stationary phase and bile salt solution as the mobile phase. We demonstrate that the SEC length sorting method can be combined with existing ultracentrifugation SWCNT sorting methods to produce "orthogonally sorted" samples, including length sorted semiconducting SWCNTs, which are important for electronics applications as well as length sorted empty-core SWCNTs. Importantly, we show that unlike simple length fractionation by SEC or any other method, orthogonal sorting produces samples of consistent quality for different length fractions, with similar UV-vis-nearIR absorption and Raman spectral features. |
23259531 | CTGF is a central mediator of tissue remodeling and fibrosis and its inhibition can reverse the process of fibrosis. | CTGF is a secreted matricellular protein with very complex biology. It has been shown to modulate many signaling pathways leading to cell adhesion and migration, angiogenesis, myofibroblast activation, and extracellular matrix deposition and remodeling, which together lead to tissue remodeling and fibrosis. It has been reported in the literature that inhibition of CTGF expression by siRNA prevents CCl4-induced liver fibrosis and can reverse fibrosis when administered after significant collagen deposition is observed. A monoclonal antibody to CTGF that is currently in clinical development (FG-3019) has demonstrated the ability to reverse vascular stiffening and improve cardiac function in a rat model of diabetic complications. FG-3019 has also exhibited activity in a murine radiation-induced pulmonary fibrosis model. When FG-3019 was administered to mice after a significant radiation-induced increase in lung density could be observed by CT imaging, the density of the lungs was observed to decrease over the period during which the antibody was administered and to remain stable after therapy had ceased. When considered together, these data indicate that inhibition of CTGF can prevent and reverse the process of fibrosis. |
23259529 | Angiotensin II type 1 and type 2 receptor expression in circulating monocytes of diabetic and hypercholesterolemic patients over 3-month rosuvastatin treatment. | In diabetes, a variety of pro-inflammatory cellular changes has been found in various cell types, including monocytes which are known to be involved in all the phases of atherogenesis. Angiotensin II (Ang II) type 1 receptor (AT1R) mediates the pro-atherogenic effects of Ang II whereas the type 2 receptor (AT2R) seems associated with atheroprotection. We sought to investigate the potential changes of AT1R-AT2R expression in human monocytes of type 2 diabetic- hypercholesterolemic patients and in hypercholesterolemic subjects, upon clinical treatment with rosuvastatin. The AT1R membrane protein and mRNA AT1R and AT2R expression in monocytes were investigated in 10 type 2 diabetic-hypercholesterolemic patients and in 10 hypercholesterolemic subjects, before and after 3-month rosuvastatin treatment. Moreover, the serum cytokine levels of interferon-γ (IFN-γ) and interleukin-4 (IL-4) were detected. As expected, rosuvastatin was associated with a change in the lipid profile in the two groups. Both the membrane protein (P = 0.008) and the AT1R mRNA expression (P = 0.038) were significantly reduced during treatment in the absence of AT2R expression change in diabetic-hypercholesterolemic patients whereas no significant difference was observed in hypercholesterolemic subjects. The serum IL-4 levels were increased during treatment whereas no change was observed in IFN-γ in diabetic-hypercholesterolemic patients. No cytokine change was observed in hypercholesterolemic subjects. Our study on monocytes of diabetic-hypercholesterolemic patients, showing a reduced AT1R but not AT2R expression during rosuvastatin treatment, suggests that statin therapy may modulate favorably the AT1-AT2 receptor balance in subjects with coexistent type 2 diabetes. |
23259527 | Insights into the CRISPR/Cas system of Gardnerella vaginalis. | Gardnerella vaginalis is identified as the predominant colonist of the vaginal tracts of women diagnosed with bacterial vaginosis (BV). G. vaginalis can be isolated from healthy women, and an asymptomatic BV state is also recognised. The association of G. vaginalis with different clinical phenotypes could be explained by different cytotoxicity of the strains, presumably based on disparate gene content. The contribution of horizontal gene transfer to shaping the genomes of G. vaginalis is acknowledged. The CRISPR loci of the recently discovered CRISPR/Cas microbial defence system provide a historical view of the exposure of prokaryotes to a variety of foreign genetic elements. The CRISPR/Cas loci were analysed using available sequence data from three G. vaginalis complete genomes and 18 G. vaginalis draft genomes in the NCBI database, as well as PCR amplicons of the genomic DNA of 17 clinical isolates. The cas genes in the CRISPR/Cas loci of G. vaginalis belong to the E. coli subtype. Approximately 20% of the spacers had matches in the GenBank database. Sequence analysis of the CRISPR arrays revealed that nearly half of the spacers matched G. vaginalis chromosomal sequences. The spacers that matched G. vaginalis chromosomal sequences were determined to not be self-targeting and were presumably neither constituents of mobile-element-associated genes nor derived from plasmids/viruses. The protospacers targeted by these spacers displayed conserved protospacer-adjacent motifs. The CRISPR/Cas system has been identified in about one half of the analysed G. vaginalis strains. Our analysis of CRISPR sequences did not reveal a potential link between their presence and the virulence of the G. vaginalis strains. Based on the origins of the spacers found in the G. vaginalis CRISPR arrays, we hypothesise that the transfer of genetic material among G. vaginalis strains could be regulated by the CRISPR/Cas mechanism. The present study is the first attempt to determine and analyse the CRISPR loci of bacteria isolated from the human vaginal tract. |
23259528 | Seroprevalence of Toxoplasma gondii infection in Norwegian dairy goats. | Toxoplasma gondii is a major problem for the sheep industry as it may cause reproduction problems. The importance of T. gondii in Norwegian goat herds is uncertain, but outbreaks of toxoplasmosis in dairy goat farms have been recorded. The aim of this study was to describe the prevalence of T. gondii infection in Norwegian dairy goats by using serology. Goat serum originally collected as part of two nationwide surveillance and control programmes between 2002 and 2008 were examined for T. gondii antibodies by using direct agglutination test. In total, 55 of 73 herds (75%) had one or more serologically positive animals, while 377 of 2188 (17%) of the individual samples tested positive for T. gondii antibodies. This is the first prevalence study of T. gondii infection in Norwegian goats. The results show that Norwegian goat herds are commonly exposed to T. gondii. Nevertheless, the majority of goat herds have a low prevalence of antibody positive animals, which make them vulnerable to infections with T. gondii during the gestation period. |
23259526 | The role of phosphoinositide 3-kinase subunits in chronic thyroiditis. | The risk of neoplastic transformation in patients with chronic thyroiditis (Hashimoto's thyroiditis - HT) is slightly increased. Genetic background of this observation is still unclear. PI3K isoforms are linked with inflammatory and neoplastic processes, thus they appear to be interesting subjects of a research in this respect. The aim of our study was to assess the PIK3CA, PIK3CB, PIK3CD and PIK3CG genes expression levels in HT. Following conventional cytological examination, 67 thyroid FNAB specimens, received from patients with HT, were quantitatively evaluated regarding PIK3CA, PIK3CB, PIK3CD and PIK3CG expression levels by real-time PCR in the ABI PRISM ®7500 Sequence Detection System. The performed analysis has revealed significantly higher expression levels (RQ) of PIK3CD, PIK3CG and PIK3CA genes in comparison with PIK3CB gene (p<0.05) and significantly higher gene expression level of PIK3CD in comparison with PIK3CA (p<0.05). The observed increased PIK3CD, PIK3CG genes expression in HT is probably related to lymphocyte infiltration commonly seen in this condition, however, the role of increased PIK3CA gene expression in the multi-step carcinogenesis process cannot be excluded. |
23259525 | Truck drivers' opinion on road safety in Tanzania--a questionnaire study. | Even though the traffic fatality risk (fatalities per 100,000 inhabitants) in Tanzania is quite low, the fatality rate (fatalities per 10,000 vehicles) is one of the highest in the world. With increasing vehicle density this means that the number of people dying in traffic will increase dramatically in the near future. Therefore, it is important to implement measures to increase traffic safety as soon as possible, and in order to be able to do this in an efficient way, it is important to investigate where the main problems lie. Within the European Union (EU) project ASSET-Road a questionnaire study on road safety was conducted with 250 truck drivers in Tanzania. The study was done to increase the knowledge about the situation of the Tanzanian truckers, who are the most frequent road users in the country. The drivers were interviewed in 3 different towns in southern Tanzania, and participation was voluntary. The questionnaire treated demographics, the state of the drivers' vehicles, the frequency of breakdowns, and the maintenance of the vehicles. Further questions concerned driver behavior, crash involvement, crash risk, and crash mitigation. The drivers who participated in the study were predominantly male and their average age was 36 years. Truck drivers reported driving 10.6 h without a break on average, with several drivers reporting that they had to drive 24 h without rest. Around 40 percent of the trucks did not have any seat belts installed, with a larger share of older trucks lacking belts. Most of the drivers who had seat belts reported using them, however. Almost 40 percent of the drivers reported being involved in at least one crash, and 45 percent of those drivers had experienced fatal crashes. This underlines that the crash frequency per vehicle is very high, and the results are often severe, especially when heavy vehicles are involved. When asked what the 3 most common crash causations were, driver-related causes were named frequently. Drivers were said to be reckless, and further crash causations named were drunkenness, inattention, and sleepiness. One of the most frequently mentioned crash mitigation strategies was driver education, followed by improvement of the roads and the vehicles. The results indicate that countermeasures should be implemented in an integrated fashion, taking into account aspects such as driver, vehicle, infrastructure, legislature, and other road users. |
23259524 | Kinematics of child volunteers and child anthropomorphic test devices during emergency braking events in real car environment. | The objective of this study was to present, compare, and discuss the kinematic response of children and child anthropomorphic test devices (ATDs) during emergency braking events in different restraint configurations in a passenger vehicle. A driving study was conducted on a closed-circuit test track comprising 16 children aged 4 to 12 years old and the Q3, Hybrid III (HIII) 3-year-old, 6-year-old, and 10-year-old ATDs restrained on the right rear seat of a modern passenger vehicle. The children were exposed to one braking event in each of the 2 restraint systems and the ATDs were exposed to 2 braking events in each restraint system. All events had a deceleration of 1.0 g. Short children (stature 107-123 cm) and the Q3, HIII 3-year-old, and 6-year-old were restrained on booster cushions as well as high-back booster seats. Tall children (stature 135-150 cm) and HIII 10-year-old were restrained on booster cushions or restrained by 3-point belts directly on the car seat. Vehicle data were collected and synchronized with video data. Forward trajectories for the forehead and external auditory canal (ear) were determined as well as head rotation and shoulder belt force. A total of 40 trials were analyzed. Child volunteers had greater maximum forward displacement of the head and greater head rotation compared to the ATDs. The average maximum displacement for children ranged from 165 to 210 mm and 155 to 195 mm for the forehead and ear target, respectively. Corresponding values for the ATDs were 55 to 165 mm and 50 to 160 mm. The change in head angle was greater for short children than for tall children. Shoulder belt force was within the same range for short children when restrained on booster cushions or high-back booster seats. For tall children, the shoulder belt force was greater when restrained on booster cushions compared to being restrained by seat belts directly on the car seat. The forward displacement was within the same range for all children regardless of stature and restraint system. However, the maximum forward position depended on the initial seated posture and shoulder belt position on the shoulder. Differences could also be seen in the curvature of the neck and spine. Short children exhibited a greater flexion motion of the head, whereas a more upright posture at maximum forward position was exhibited by the tall children. The ATDs displayed less forward displacement compared to the children. |
23259523 | Traffic crashes and alcohol outlets in a Brazilian state capital. | Restricting alcohol outlets is being considered as a measure for preventing alcohol-related crashes. However, in many developing countries, alcohol availability is not regulated and its influence on motor vehicle traffic crashes is unknown. This study explores the association between traffic crashes and alcohol outlets in a Brazilian city. Data were geocoded and exploratory analysis was conducted using the kernel density estimator. Two generalized additive models (GAMs) were implemented to predict the factors associated with alcohol-related crashes. For 78 percent of the 3840 traffic crashes where the driver was a victim, there was at least one bar located within a 300-m radius. The median distances between an outlet were 124.4 and 130.7 m for a non-alcohol- and alcohol-related crashes, respectively (P =.13). The GAMs did not make evident any significant association between the outlet locations and alcohol-related crashes: the presence of at least one outlet was associated with alcohol-related crashes with an odds ratio (OR) of 0.94 (95% confidence interval [CI] = 0.75-1.17). Alcohol crashes are more likely to be observed among males (OR = 1.58; 95% CI = 1.21-2.06), young drivers vs. those aged 50 years+ (OR = 3.4; 95% CI = 1.79-6.43), and crashes with fatalities (OR = 1.73; 95% CI = 0.98-3.04). Density of alcohol outlets was high all over the city and both alcohol- and non-alcohol-related crashes occurred near an outlet. The study helps to better understand the relationship between alcohol availability and traffic crashes in a middle-income country where licensing/zoning is absent and suggests that measures for restricting the physical availability of alcohol are necessary, even though further studies are still needed. |
23259522 | All-terrain vehicles (ATVs) on the road: a serious traffic safety and public health concern. | On-road all-terrain vehicle (ATV) crashes are frequent occurrences that disproportionately impact rural communities. These crashes occur despite most states having laws restricting on-road ATV use. A number of overall risk factors for ATV-related injuries have been identified (e.g., lack of helmet, carrying passengers). However, few studies have determined the relative contribution of these and other factors to on-road crashes and injuries. The objective of our study was to determine whether there were differences between on- and off-road ATV crashes in their demographics and/or mechanisms and outcomes of injuries. Data were derived from our statewide ATV injury surveillance database (2002-2009). Crash location and crash and injury mechanisms were coded using a modification of the Department of Transportation (DOT) coding system. Descriptive analyses and statistical comparisons (chi-square test) of variables were performed. Multivariate logistic regression analysis was used to determine relative risk. 976 records were included in the final analysis, with 38 percent of the injured individuals from on-road crashes. Demographics were similar for crashes at each location, with approximately 80 percent males, 30 percent under the age of 16, and 15 percent passengers. However, females and youths under 16 were over 4 times more likely to be passengers (P ≤ 0.0001), regardless of crash location. Compared to those off-road, on-road crash victims were approximately 10 times more likely to be involved in a vehicle-vehicle collision (P < 0.001), 3 times more likely to have a severe brain injury (P < 0.001), and twice as likely to have suffered major trauma (P < 0.001). Adult operators in on-road crashes were also twice as likely to test positive for alcohol as those off-road (P < 0.05). Helmet use significantly reduced the odds of sustaining a brain injury and on-road victims were only half as likely to be helmeted (P < 0.01). More than 1 in 3 on-road crashes involved a collision with another vehicle, suggesting that ATVs on the road represent a potential traffic safety concern. Of note, helmets were associated with reduced risk for the number and severity of brain injuries, providing further support for the importance of helmet use. Finally, even controlling for helmet use, on-road crash victims suffered more major trauma and severe brain injuries than those off-road. Overall, our data reinforce the importance of laws restricting ATV road use and the need for effective enforcement, as well as the need to increase user education about ATV road-use laws and the dangers of riding on the roads. |
23259521 | Situations of car-to-pedestrian contact. | To reduce the severity of injuries and the number of pedestrian deaths in traffic accidents, active safety devices providing pedestrian detection are considered effective countermeasures. The features of car-to-pedestrian collisions need to be known in detail to develop such safety devices. Because information on real-world accidents is limited, this study investigated near-miss situations captured by drive recorders installed in passenger cars. We showed similarities of the contact situation between near-miss incidents and real-world fatal pedestrian accidents in Japan. We analyzed the near-miss incident data via video capturing pedestrians crossing the road in front of forward-moving cars. Using a video frame captured by a drive recorder, the time to collision (TTC) was calculated from the car velocity and the distance between the car and pedestrian at the moment that the pedestrian initially appeared. The average TTC in the cases where pedestrians were not using a pedestrian crossing was shorter than that in the cases where pedestrians were using a pedestrian crossing. The average TTC in the cases where pedestrians emerged from behind obstructions was shorter than that in the cases where drivers had unobstructed views of the pedestrians. We propose that the specifications of the safety device for pedestrian detection and automatic braking should reflect the severe approach situation for a pedestrian and car including the TTC observed for near-miss incidents. |
23259520 | Analysis of the frequency and severity of rear-end crashes in work zones. | The objective of this study was to identify the factors that influence the frequency and severity of rear-end crashes in work zones because rear-end crashes represent a significant proportion of crashes that occur in work zones. Truncated count data models were developed to identify influencing factors on the frequency of read-end crashes in work zones and ordered probit models were developed to evaluate influencing factors on the severity of rear-end crashes in work zones. Most of the variables identified in this study for these 2 models were significant at the 95 percent level. The statistics for models indicate that the 2 developed models are appropriate compared to alternative models. Major findings related to the frequency of rear-end crashes include the following: (1) work zones for capacity and pavement improvements have the highest frequency compared to other types of work zones; (2) work zones controlled by flaggers are associated with more rear-end crashes compared to those controlled by arrow boards; and (3) work zones with alternating one-way traffic tended to have more rear-end crashes compared to those with lane shifts. Major findings related to the severity of the rear-end crashes include the following: (1) rear-end crashes associated with alcohol, night, pedestrians, and roadway defects are more severe, and those associated with careless backing, stalled vehicles, slippery roadways, and misunderstanding flagging signals are less severe; (2) truck involvement and a large number of vehicles in a crash are both associated with increased severity, and (3) rear-end crashes that happened in work zones for bridge, capacity, and pavement are likely to be more severe than others. |
23259519 | Bicyclist-bicyclist crashes--a medical and technical crash analysis. | The purpose of this study was to analyze the actual injury situation of bicyclists focusing on accidents involving more than one bicyclist. A medical and technical analysis was performed as a basis for preventive measures. Technical and medical data were collected at the scene, shortly after the accident. Technical analysis included speed at crash, type of collision, impact angle, environment, lane used, and relative velocity. Medical analysis included injury patterns and severity (Abbreviated Injury Scale [AIS], Injury Severity Score [ISS]). Five hundred seventy-eight injured bicyclists in 289 accidents from 1999 to 2008 were included into the study. Sixty-one percent were male (n = 350) and 39 percent were female (n = 228). Sixty-seven percent ranged between 18 and 64 years of age, 12 percent each between 13 and 17 years of age and older than 65 years, 8 percent between 6 and 12 years, and 1 percent between 2 and 5 years. Ninety-two percent of crashes took place in urban areas and 8 percent in rural areas. Ninety-seven percent of crashes occurred in dry conditions and 3 percent in wet conditions. Eighty-three percent of all accidents occurred during the daytime, 10 percent at night, and 7 percent at dawn. The helmet use rate was only 7.5 percent for all involved bicyclists. The mean Abbreviated Injury Scale (AIS) score was 1.31. The prevalence of bicycle-to-bicycle crashes is high. Most of these accidents occur in urban areas. Bicyclists should be considered as minimally or unprotected road users, with an unsatisfactorily low rate of helmet use. Though the average level and patterns of injuries is moderate, most of the severe injuries involved the head and extremities. However, there was no significant correlation between frequent helmet use and sustained injuries to the head of major AIS. |
23259518 | Secondary collisions revisited: real-world crash data and relationship to crash test criteria. | Previous research conducted in the late 1980s suggested that vehicle impacts following an initial barrier collision increase severe occupant injury risk. Now over 25 years old, the data are no longer representative of the currently installed barriers or the present US vehicle fleet. The purpose of this study is to provide a present-day assessment of secondary collisions and to determine if current full-scale barrier crash testing criteria provide an indication of secondary collision risk for real-world barrier crashes. To characterize secondary collisions, 1,363 (596,331 weighted) real-world barrier midsection impacts selected from 13 years (1997-2009) of in-depth crash data available through the National Automotive Sampling System (NASS) / Crashworthiness Data System (CDS) were analyzed. Scene diagram and available scene photographs were used to determine roadside and barrier specific variables unavailable in NASS/CDS. Binary logistic regression models were developed for second event occurrence and resulting driver injury. To investigate current secondary collision crash test criteria, 24 full-scale crash test reports were obtained for common non-proprietary US barriers, and the risk of secondary collisions was determined using recommended evaluation criteria from National Cooperative Highway Research Program (NCHRP) Report 350. Secondary collisions were found to occur in approximately two thirds of crashes where a barrier is the first object struck. Barrier lateral stiffness, post-impact vehicle trajectory, vehicle type, and pre-impact tracking conditions were found to be statistically significant contributors to secondary event occurrence. The presence of a second event was found to increase the likelihood of a serious driver injury by a factor of 7 compared to cases with no second event present. The NCHRP Report 350 exit angle criterion was found to underestimate the risk of secondary collisions in real-world barrier crashes. Consistent with previous research, collisions following a barrier impact are not an infrequent event and substantially increase driver injury risk. The results suggest that using exit-angle based crash test criteria alone to assess secondary collision risk is not sufficient to predict second collision occurrence for real-world barrier crashes. |
23259517 | Feasibility of a computer-delivered driver safety behavior screening and intervention program initiated during an emergency department visit. | Injuries from motor vehicle crashes are a significant public health problem. The emergency department (ED) provides a setting that may be used to screen for behaviors that increase risk for motor vehicle crashes and provide brief interventions to people who might otherwise not have access to screening and intervention. The purpose of the present study was to (1) assess the feasibility of using a computer-assisted screening program to educate ED patients about risky driving behaviors, (2) evaluate patient acceptance of the computer-based traffic safety educational intervention during an ED visit, and (3) assess postintervention changes in risky driving behaviors. Pre/posteducational intervention involving medically stable adult ED patients in a large urban academic ED serving over 100,000 patients annually. Patients completed a self-administered, computer-based program that queried patients on risky driving behaviors (texting, talking, and other forms of distracted driving) and alcohol use. The computer provided patients with educational information on the dangers of these behaviors and data were collected on patient satisfaction with the program. Staff called patients 1 month post-ED visit for a repeat query. One hundred forty-nine patients participated, and 111 completed 1-month follow up (75%); the mean age was 39 (range: 21-70), 59 percent were Hispanic, and 52 percent were male. Ninety-seven percent of patients reported that the program was easy to use and that they were comfortable receiving this education via computer during their ED visit. All driving behaviors significantly decreased in comparison to baseline with the following reductions reported: talking on the phone, 30 percent; aggressive driving, 30 percent; texting while driving, 19 percent; drowsy driving, 16 percent; driving while multitasking, 12 percent; and drinking and driving, 9 percent. Overall, patients were very satisfied receiving educational information about these behaviors via computer during their ED visits and found the program easy to use. We found a high prevalence of self-reported risky driving behaviors in our ED population. At 1-month follow-up, patients reported a significant decrease in these behaviors. This study indicates that a low-intensity, computer-based educational intervention during an ED visit may be a useful approach to educate patients about safe driving behaviors and safe drinking limits and help promote behavior change. |
23259516 | Can patients receiving opioid maintenance therapy safely drive? A systematic review of epidemiological and experimental studies on driving ability with a focus on concomitant methadone or buprenorphine administration. | To perform a systematic review of the present scientific literature on the treatment with methadone or buprenorphine related to (1) traffic accident risk in epidemiological studies and (2) their effects on cognitive and psychomotor functions of relevance to driving in experimental studies. Searches for corresponding literature were conducted in MEDLINE, EMBASE, and PsycINFO throughout March and June of 2010. The search strategy consisted of words colligated to accident risk and culpability, in addition to cognitive and psychomotor functions of relevance to driving, all in relation to methadone or buprenorphine administration. In total, 59 studies were included. Early epidemiological studies found no substantial difference in motor vehicle accident risk between methadone maintenance therapy patients (MMPs) and control groups. However, more recent studies have found an increased risk of traffic accident involvement for both MMPs and buprenorphine maintenance therapy patients (BMPs). In experimental studies, impairments of cognitive and psychomotor functions have been observed among both MMPs and BMPs when compared to control groups. When comparing MMPs with BMPs, the latter appeared to be less impaired than MMPs, but this difference may be unrelated to the maintenance therapy. Further impairments have been observed among MMPs after single doses, after an additional versus regular daily dosing, in multiple versus single dosing, and after long-term treatment compared to baseline levels. All studies showed impairments among opioid-naïve subjects after the administration of a comparatively low and single dose of either methadone or buprenorphine. Both methadone and buprenorphine were confirmed as having impairing potentials in opioid-naïve subjects. At least some opioid maintenance therapy patients are observed having only slight impairments of relevance to driving. Knowing this when approaching the question of ability to drive, an individual evaluation of the driving performance, pertaining to the opioid maintained patient, may be the most useful and conclusive procedure. |
23259515 | Hospital outpatients' responses to taking medications with driving warnings. | The study investigates the knowledge, intentions, and driving behavior of persons prescribed medications that display a warning about driving. It also examines their confidence that they can self-assess possible impairment, as is required by the Australian labeling system. We surveyed 358 outpatients in an Australian public hospital pharmacy, representing a well-advised group taking a range of medications including those displaying a warning label about driving. A brief telephone follow-up survey was conducted with a subgroup of the participants. The sample had a median age of 53.2 years and was 53 percent male. Nearly three quarters (73.2%) had taken a potentially impairing class of medication and more than half (56.1%) had taken more than one such medication in the past 12 months. Knowledge of the potentially impairing effects of medication was relatively high for most items; however, participants underestimated the possibility of increased impairment from exceeding the prescribed dose and at commencing treatment. Participants' responses to the safety implications of taking drugs with the highest level of warning varied. Around two thirds (62.8%) indicated that they would consult a health practitioner for advice and around half would modify their driving in some way. However, one fifth (20.9%) would drive when the traffic was thought to be less heavy and over a third (37.7%) would modify their medication regime so that they could drive. The findings from the follow-up survey of a subsample taking target drugs at the time of the first interview were also of concern. Only just over half (51%) recalled seeing the warning label on their medications and, of this group, three quarters (78%) reported following the warning label advice. These findings indicated that there remains a large proportion of people who either did not notice or did not consider the warning when deciding whether to drive. There was a very high level of confidence in this group that they could determine whether they were personally affected by the medication, which may be a problem from a safety perspective. This study involved persons who should have had a very high level of knowledge and awareness of medication warning labeling. Even in this group there was a lack of informed response to potential impairment. A review of the Australian warning system and wider dissemination of information on medication treatment effects would be useful. Clarifying the importance of potential risk in the general community context is recommended for consideration and further research. |
23259514 | Does a medicinal dose of kava impair driving? A randomized, placebo-controlled, double-blind study. | Increasing concerns over the potentially impairing effects of prescriptive sedative drugs such as benzodiazepines on driving have been raised. However, other alternatives such as natural medicines may also carry similar risks with respect to driving safety. Kava (Piper methysticum) is a psychotropic plant commonly used both recreationally and medicinally in the United States, Australia, and the South Pacific to elicit a physically tranquilizing effect. To date no controlled study has tested a medicinal dose of kava versus placebo and a standard sedative drug on driving ability and driving safety. Due to the need to establish the safety of kava in operating a motor vehicle, we compared the acute effects of the plant extract versus the benzodiazepine oxazepam and placebo using a driving simulator. A driving simulator (AusEd) was used by 22 adults aged between 18 and 65 years after being randomly administered an acute medicinal dose of kava (180 mg of kavalactones), oxazepam (30 mg), or placebo one week apart in a crossover design trial. No impairing effects on driving outcomes were found after kava administration compared to placebo. Results on specific driving outcome domains revealed that the oxazepam condition had significantly slower braking reaction time compared to the placebo condition (p =.002) and the kava condition (p =.003). The kava condition had significantly fewer lapses of concentration compared to the oxazepam condition (p =.033). No significant differences were found between conditions for steering deviation, speed deviation, and number of crashes. Results were not modified by driving experience. On the Bond-Lader visual analogue sub-scale of alertness, a significant Treatment × Time interaction (p =.032) was found, with a significant reduction over time for oxazepam decreasing alertness (p <.001), whereas no significant reduction was found in the kava or placebo conditions. The results indicate that a medicinal dose of kava containing 180 mg of kavalactones does not impair driving ability, whereas 30 mg of oxazepam shows some impairment. Research assessing larger recreational doses of kava on driving ability should now be conducted. |
23259513 | A preliminary estimation of motorcyclist fatal injury risk by BAC level relative to car/van drivers. | This study sought to quantify the fatal injury risks for motorcyclists associated with the riders' blood alcohol concentrations (BACs). Using a case-control study design with New Zealand data, fatal injury risk curves for motorcyclists and car drivers were modeled. A total of 142 fatally injured drivers/riders (cases) and 58,000 control drivers/riders were studied. For motorcyclists, there were 13 cases and 194 controls. The rate of increase in fatal injury risk with increasing BAC was not found to be different for motorcyclists compared to car/van drivers. However, because the baseline risk for motorcyclists was already considerably higher than for car/van drivers, even modest amounts of alcohol were associated with very high risks for motorcyclists compared to sober car/van drivers. It was estimated that, relative to their sober risk, motorcycle riders at BAC = 0.03 percent have 3 times the fatality risk (95% confidence interval [CI] = 2.8-3.5) and, at BAC = 0.08, 20 times the fatality risk (95% CI = 15.0-27.3). Interventions focused on reducing the alcohol consumption of motorcycle riders are clearly required when the degree of risk even at low alcohol levels is as disturbingly high as estimated in the current study. |
23259512 | Characteristics of DUI offenders with a high versus low perceived risk of arrest. | To compare offenders with high versus low perceptions of risk for being stopped by police for drinking and driving using measures of beliefs, behaviors, social context of drinking, and perceived influence from a significant other in their social network. Telephone interviews were conducted with 161 individuals who received a first-time driving under the influence (DUI) citation in Maryland. They were divided into 2 groups: those who felt that it was almost certain or very likely that they would be stopped by the police if they drove after having too much to drink (n = 56) and those who felt that it was only somewhat likely or unlikely (n = 105). The 2 groups did not differ in terms of age, gender, race/ethnicity, education, employment, or marital status. Offenders with a low perceived risk of being stopped were less likely to believe that they would be convicted if they were stopped and arrested. They were more likely to report having an encounter with an aggressive driver, running through a stop sign or traffic light, drinking in a context of social facilitation, knowing someone in their social network who had received a DUI citation, and having a member of their social network suggest that they had had too much to drink and could not drive safely. The social context of drinking and the relationship they have to their social network have important implications for influencing first DUI offenders and preventing them from recidivating. |
23259511 | The biology/disease-driven human proteome project (B/D-HPP): enabling protein research for the life sciences community. | The biology and disease oriented branch of the Human Proteome Project (B/D-HPP) was established by the Human Proteome Organization (HUPO) with the main goal of supporting the broad application of state-of the-art measurements of proteins and proteomes by life scientists studying the molecular mechanisms of biological processes and human disease. This will be accomplished through the generation of research and informational resources that will support the routine and definitive measurement of the process or disease relevant proteins. The B/D-HPP is highly complementary to the C-HPP and will provide datasets and biological characterization useful to the C-HPP teams. In this manuscript we describe the goals, the plans, and the current status of the of the B/D-HPP. |
23259510 | Prognosis by tumor location for pediatric spinal cord ependymomas. | Ependymoma is a common CNS tumor in children, with spinal cord ependymomas making up 13.1% of all ependymomas in this age group. The clinical features that affect prognosis in pediatric spinal cord ependymomas are not well understood. A comprehensive literature review was performed to determine whether a tumor location along the spinal cord is prognostically significant in children undergoing surgery for spinal cord ependymomas. A PubMed search was performed to identify all papers that contained data on patients with spinal cord ependymomas. Only pediatric patients (age < 18 years) who underwent resection with a clearly reported tumor location were included in the analysis. Myxopapillary tumors were excluded from study. Tumor location was subdivided into 6 regions: cervicomedullary, cervical, cervicothoracic, thoracic, thoracolumbar, and conus medullaris. Kaplan-Meier survival and Cox regression analyses were performed to determine the effects of tumor location on progression-free survival (PFS) and overall survival (OS). Fifty-eight patients who underwent resection of spinal cord ependymomas were identified. Ependymomas were located all along the spinal cord but occurred with the highest frequency in the cervical region (29.3%). Progression-free survival was significantly better in patients with tumors arising in the upper portion of the spinal cord (p = 0.031), which remained significant in the multivariate Cox regression analysis (p < 0.05). Moreover, OS was significantly better in patients with upper spinal cord ependymomas than in those harboring ependymomas in the lower spinal cord (p = 0.048). Although more common in adults, spinal ependymomas can occur anywhere along the spinal cord in the pediatric population; however, tumors occurring in the lower half of the spinal cord carry a worse prognosis with shorter PFS and OS. By comparison, ependymomas in the upper spinal cord recur later and less frequently, with little or no mortality in this patient group. |
23259508 | Vitamin D receptor gene (VDR) transcripts in bone, cartilage, muscles and blood and microarray analysis of vitamin D responsive genes expression in paravertebral muscles of juvenile and adolescent idiopathic scoliosis patients. | VDR may be considered as a candidate gene potentially related to idiopathic scoliosis susceptibility and natural history. Transcriptional profile of VDR mRNA isoforms might be changed in the structural tissues of the scoliotic spine and potentially influence the expression of VDR responsive genes. The purpose of the study was to determine differences in mRNA abundance of VDR isoforms in bone, cartilage and paravertebral muscles between tissues from curve concavity and convexity, between JIS and AIS and to identify VDR responsive genes differentiating juvenile and adolescent idiopathic scoliosis in paravertebral muscles. In a group of 29 patients with JIS and AIS, specimens of bone, cartilage, paravertebral muscles were harvested at the both sides of the curve apex together with peripheral blood samples. Extracted total RNA served as a matrix for VDRs and VDRl mRNA quantification by QRT PCR. Subsequent microarray analysis of paravertebral muscular tissue samples was performed with HG U133A chips (Affymetrix). Quantitative data were compared by a nonparametric Mann Whitney U test. Microarray results were analyzed with GeneSpring 11GX application. Matrix plot of normalized log-intensities visualized the degree of differentiation between muscular tissue transcriptomes of JIS and AIS group. Fold Change Analysis with cutoff of Fold Change ≥2 identified differentially expressed VDR responsive genes in paravertebral muscles of JIS and AIS. No significant differences in transcript abundance of VDR isoforms between tissues of the curve concavity and convexity were found. Statistically significant difference between JIS and AIS group in mRNA abundance of VDRl isoform was found in paravertebral muscles of curve concavity. Higher degree of muscular transcriptome differentiation between curve concavity and convexity was visualized in JIS group. In paravertebral muscles Tob2 and MED13 were selected as genes differentially expressed in JIS and AIS group. In Idiopathic Scolioses transcriptional activity and alternative splicing of VDR mRNA in osseous, cartilaginous, and paravertebral muscular tissues are tissue specific and equal on both sides of the curve. The number of mRNA copies of VDRl izoform in concave paravertebral muscles might be one of the factors differentiating JIS and AIS. In paravertebral muscles Tob2 and Med13 genes differentiate Adolescent and Juvenile type of Idiopathic Scoliosis. |
23259509 | P(CH)P pincer rhodium(I) complexes: the key role of electron-poor imidazoliophosphine extremities. | The coordination chemistry of a potentially pincer-type dicationic meta-phenylene-bis(imidazoliophosphine) ligand 3 to neutral and cationic carbonylrhodium(I) centers has been investigated. Similarly to what was observed previously for its ortho-phenylene counterpart, 3 was found to bind to the RhCl(CO) fragment in a trans-chelating manner that makes possible a weak Rh-C(H) interaction, inferred from the nonbonding but relatively short Rh-C and Rh-H contacts observed in the solid state structure of the dicationic adduct (3)RhCl(CO) (5). Formation of the target PCP-type pincer complex could not be triggered despite multiple attempts to deprotonate the central C-H moiety in the initial dicationic adduct 5, or in the tricationic species [(3)Rh(CO)](+) (8) generated by abstraction of the chloride ion from 5. Complex 8 was identified on the basis of NMR and IR analyses as a Rh(I)-stabilized P(CH)P-intermediate en route to the anticipated classical PCP-type pincer complex. Analysis of the electronic structure of this intermediate computed at the density functional level of theory (DFT level) revealed a bonding overlap between a Rh d-orbital and π-orbitals of the m-phenylene ring. NBO analyses and calculated Wiberg indices confirm that this interaction comprises an η(1)-C-Rh bonding mode, with only secondary contributions from the geminal C and H atoms. Although the target PCP-type pincer complex could not be generated, treatment of the tricationic intermediate with methanol induced a P-CN(2) bond cleavage at both imidazoliophosphine moieties, resulting in the formation of a dicationic "open pincer" species, that is, a nonchelated bis((MeO)PPh(2))-stabilized aryl-Rhodium complex that is the κC-only analogue of the putative κP,κC,κP-PCP complex sought initially. Theoretical studies at the DFT level of experimental or putative species relevant to the final C-H activation process ruled out the oxidative addition pathway. Two alternative pathways are proposed to explain the formation of the "open pincer" complex, one based on an organometallic α-elimination step, the other based on an organic aromatization-driven β-elimination process. |
23259507 | Substantial and reversible brain gray matter reduction but no acute brain lesions in ultramarathon runners: experience from the TransEurope-FootRace Project. | During the extremely challenging 4,487 km ultramarathon TransEurope-FootRace 2009, runners showed considerable reduction of body weight. The effects of this endurance run on brain volume changes but also possible formation of brain edema or new lesions were explored by repeated magnetic resonance imaging (MRI) studies. A total of 15 runners signed an informed consent to participate in this study of planned brain scans before, twice during, and about 8 months after the race. Because of dropouts, global gray matter volume analysis could only be performed in ten runners covering three timepoints, and in seven runners who also had a follow-up scan. Scanning was performed on three identical 1.5 T Siemens MAGNETOM Avanto scanners, two of them located at our university. The third MRI scanner with identical sequence parameters was a mobile MRI unit escorting the runners. Volumetric 3D datasets were acquired using a magnetization prepared rapid acquisition gradient echo (MPRAGE) sequence. Additionally, diffusion-weighted (DWI) and fluid attenuated inversion recovery (FLAIR) imaging was performed. Average global gray matter volume as well as body weight significantly decreased by 6% during the race. After 8 months, gray matter volume returned to baseline as well as body weight. No new brain lesions were detected by DWI or FLAIR imaging. Physiological brain volume reduction during aging is less than 0.2% per year. Therefore a volume reduction of about 6% during the 2 months of extreme running appears to be substantial. The reconstitution in global volume measures after 8 months shows the process to be reversible. As possible mechanisms we discuss loss of protein, hypercortisolism and hyponatremia to account for both substantiality and reversibility of gray matter volume reductions. Reversible brain volume reduction during an ultramarathon suggests that extreme running might serve as a model to investigate possible mechanisms of transient brain volume changes. However, despite massive metabolic load, we found no new lesions in trained athletes participating in a multistage ultramarathon.See related commentary http://www.biomedcentral.com/1741-7015/10/171. |
23259504 | Microevolutionary analysis of Clostridium difficile genomes to investigate transmission. | The control of Clostridium difficile infection is a major international healthcare priority, hindered by a limited understanding of transmission epidemiology for these bacteria. However, transmission studies of bacterial pathogens are rapidly being transformed by the advent of next generation sequencing. Here we sequence whole C. difficile genomes from 486 cases arising over four years in Oxfordshire. We show that we can estimate the times back to common ancestors of bacterial lineages with sufficient resolution to distinguish whether direct transmission is plausible or not. Time depths were inferred using a within-host evolutionary rate that we estimated at 1.4 mutations per genome per year based on serially isolated genomes. The subset of plausible transmissions was found to be highly associated with pairs of patients sharing time and space in hospital. Conversely, the large majority of pairs of genomes matched by conventional typing and isolated from patients within a month of each other were too distantly related to be direct transmissions. Our results confirm that nosocomial transmission between symptomatic C. difficile cases contributes far less to current rates of infection than has been widely assumed, which clarifies the importance of future research into other transmission routes, such as from asymptomatic carriers. With the costs of DNA sequencing rapidly falling and its use becoming more and more widespread, genomics will revolutionize our understanding of the transmission of bacterial pathogens. |
23259506 | Ultraviolet electroluminescence from nitrogen-doped ZnO-based heterojuntion light-emitting diodes prepared by remote plasma in situ atomic layer-doping technique. | Remote plasma in situ atomic layer doping technique was applied to prepare an n-type nitrogen-doped ZnO (n-ZnO:N) layer upon p-type magnesium-doped GaN (p-GaN:Mg) to fabricate the n-ZnO:N/p-GaN:Mg heterojuntion light-emitting diodes. The room-temperature electroluminescence exhibits a dominant ultraviolet peak at λ ≈ 370 nm from ZnO band-edge emission and suppressed luminescence from GaN, as a result of the decrease in electron concentration in ZnO and reduced electron injection from n-ZnO:N to p-GaN:Mg because of the nitrogen incorporation. The result indicates that the in situ atomic layer doping technique is an effective approach to tailoring the electrical properties of materials in device applications. |
23259503 | Molecular epidemiology and public health relevance of Campylobacter isolated from dairy cattle and European starlings in Ohio, USA. | Dairy cattle serve as a potential source for Campylobacter infection in humans. Outbreaks associated with consumption of either Campylobacter contaminated raw milk or contaminated milk after treatment were previously recorded in the United States. Further, starlings have been implicated in the spread of bacterial pathogens among livestock. Here, we determined the prevalence, genotypic, and phenotypic properties of Campylobacter isolated from fecal samples of dairy cattle and starlings found on the same establishment in northeastern Ohio. Campylobacter were detected in 83 (36.6%) and 57 (50.4%) out of 227 dairy and 113 starling fecal samples, respectively. Specifically, 79 C. jejuni, five C. coli, and two other Campylobacter spp. were isolated from dairy feces, while all isolates from starlings (n=57) were C. jejuni. Our results showed that the prevalence of C. jejuni in birds was significantly (p<0.01) higher than that in dairy cattle. The pulsed-field gel electrophoresis analysis showed that C. jejuni were genotypically diverse and host restricted; however, there were several shared genotypes between dairy cattle and starling isolates. Likewise, many shared clonal complexes (CC) between dairy cattle and starlings were observed by multilocus sequence typing (MLST) analysis. As in humans, both in cattle and starlings, the CC 45 and CC 21 were the most frequently represented CCs. As previously reported, CC 177 and CC 682 were restricted to the bird isolates, while CC 42 was restricted to dairy cattle isolates. Further, two new sequence types (STs) were detected in C. jejuni from dairy cattle. Interestingly, cattle and starling C. jejuni showed high resistance to multiple antimicrobials, including ciprofloxacin, erythromycin, and gentamicin. In conclusion, our results highlight starlings as potential reservoirs for C. jejuni, and they may play an important role in the epidemiology of clinically important C. jejuni in dairy population. |
23259502 | Phenotypic and molecular antibiotic resistance profile of Enterococcus faecalis and Enterococcus faecium isolated from different traditional fermented foods. | A collection of 55 enterococci (41 Enterococcus faecium and 14 E. faecalis strains) isolated from various traditional fermented foodstuffs of both animal and vegetable origins, and water was evaluated for resistance against 15 antibiotics. Lower incidence of resistance was observed with gentamicin, ampicillin, penicillin and teicoplanin. However, a high incidence of antibiotic resistance was detected for rifampicin (12 out of 14 of isolates), ciprofloxacin (9/14), and quinupristin/dalfopristin (8/14) in E. faecalis strains. Enterococcus faecium isolates were resistant to rifampicin (25/41), ciprofloxacin (23/41), erythromycin (18/41), levofloxacin (16/41), and nitrofurantoin (15/41). One Enterococcus faecalis and two E. faecium strains were resistant to vancomycin (MIC>16 μg/mL). Among 55 isolates, 27 (19 E. faecium and eight E. faecalis) were resistant to at least three antibiotics. High level of multidrug resistance to clinically important antibiotics was detected in E. faecalis strains (57% of E. faecalis versus 46% of E. faecium), which showed resistance to six to seven antibiotics, especially those isolated from foods of animal origin. So, it is necessary to re-evaluate the use of therapeutic antibiotics in stock farms at both regional and international levels due to the high number of multiple resistant (MR) bacteria. Fifty-six MR E. faecalis and E. faecium strains selected from this and previous studies (Valenzuela et al., 2008, 2010) were screened by polymerase chain reaction for antibiotic resistance genes, revealing the presence of tet(L), tet(M), ermB, cat, efrA, efrB, mphA, or msrA/B genes. The ABC Multidrug Efflux Pump EfrAB was detected in 96% of E. faecalis strains and also in 13% of E. faecium strains; this is the first report describing EfrAB in this enterococcal species. The efflux pump-associated msrA/B gene was detected in 66.66% of E. faecium strains, but not in E. faecalis strains. |
23259501 | Number of rare germline CNVs and TP53 mutation types. | The Li-Fraumeni syndrome (LFS), an inherited rare cancer predisposition syndrome characterized by a variety of early-onset tumors, is caused by different highly penetrant germline mutations in the TP53 gene; each separate mutation has dissimilar functional and phenotypic effects, which partially clarifies the reported heterogeneity between LFS families. Increases in copy number variation (CNV) have been reported in TP53 mutated individuals, and are also postulated to contribute to LFS phenotypic variability. The Brazilian p.R337H TP53 mutation has particular functional and regulatory properties that differ from most other common LFS TP53 mutations, by conferring a strikingly milder phenotype. We compared the CNV profiles of controls, and LFS individuals carrying either p.R337H or DNA binding domain (DBD) TP53 mutations by high resolution array-CGH. Although we did not find any significant difference in the frequency of CNVs between LFS patients and controls, our data indicated an increased proportion of rare CNVs per genome in patients carrying DBD mutations compared to both controls (p=0.0002***) and p.R337H (0.0156*) mutants. The larger accumulation of rare CNVs in DBD mutants may contribute to the reported anticipation and severity of the syndrome; likewise the fact that p.R337H individuals do not present the same magnitude of rare CNV accumulation may also explain the maintenance of this mutation at relatively high frequency in some populations. |
23259499 | Single nucleotide polymorphism discovery in cutthroat trout subspecies using genome reduction, barcoding, and 454 pyro-sequencing. | Salmonids are popular sport fishes, and as such have been subjected to widespread stocking throughout western North America. Historically, stocking was done with little regard for genetic variation among populations and has resulted in genetic mixing among species and subspecies in many areas, thus putting the genetic integrity of native salmonid populations at risk and creating a need to assess the genetic constitution of native salmonid populations. Cutthroat trout is a salmonid species with pronounced geographic structure (there are 10 extant subspecies) and a recent history of hybridization with introduced rainbow trout in many populations. Genetic admixture has also occurred among cutthroat trout subspecies in areas where introductions have brought two or more subspecies into contact. Consequently, management agencies have increased their efforts to evaluate the genetic composition of cutthroat trout populations to identify populations that remain uncompromised and manage them accordingly, but additional genetic markers are needed to do so effectively. Here we used genome reduction, MID-barcoding, and 454-pyrosequencing to discover single nucleotide polymorphisms that differentiate cutthroat trout subspecies and can be used as a rapid, cost-effective method to characterize the genetic composition of cutthroat trout populations. Thirty cutthroat and six rainbow trout individuals were subjected to genome reduction and next-generation sequencing. A total of 1,499,670 reads averaging 379 base pairs in length were generated by 454-pyrosequencing, resulting in 569,060,077 total base pairs sequenced. A total of 43,558 putative SNPs were identified, and of those, 125 SNP primers were developed that successfully amplified 96 cutthroat trout and rainbow trout individuals. These SNP loci were able to differentiate most cutthroat trout subspecies using distance methods and Structure analyses. Genomic and bioinformatic protocols were successfully implemented to identify 125 nuclear SNPs that are capable of differentiating most subspecies of cutthroat trout from one another. The ability to use this suite of SNPs to identify individuals of unknown genetic background to subspecies can be a valuable tool for management agencies in their efforts to evaluate the genetic structure of cutthroat trout populations prior to constructing and implementing conservation plans. |
23259498 | Cost-effectiveness of a health-social partnership transitional program for post-discharge medical patients. | Readmissions are costly and have implications for quality of care. Studies have been reported to support effects of transitional care programs in reducing hospital readmissions and enhancing clinical outcomes. However, there is a paucity of studies executing full economic evaluation to assess the cost-effectiveness of these transitional care programs. This study is therefore launched to fill this knowledge gap. Cost-effectiveness analysis was conducted alongside a randomized controlled trial that examined the effects of a Health-Social Transitional Care Management Program (HSTCMP) for medical patients discharged from an acute regional hospital in Hong Kong. The cost and health outcomes were compared between the patients receiving the HSTCMP and usual care. The total costs comprised the pre-program, program, and healthcare utilization costs. Quality of life was measured with SF-36 and transformed to utility values between 0 and 1. The readmission rates within 28 (control 10.2%, study 4.0%) and 84 days (control 19.4%, study 8.1%) were significantly higher in the control group. Utility values showed no difference between the control and study groups at baseline (p = 0.308). Utility values for the study group were significantly higher than in the control group at 28 (p < 0.001) and 84 days (p = 0.002). The study group also had a significantly higher QALYs gain (p < 0.001) over time at 28 and 84 days when compared with the control group. The intervention had an 89% chance of being cost-effective at the threshold of £20000/QALY. Previous studies on transitional care focused mainly on clinical outcomes and not too many included cost as an outcome measure. Studies examining the cost-effectiveness of the post-discharge support services are scanty. This study is the first to examine the cost-effectiveness of a transitional care program that used nurse-led services participated by volunteers. Results have shown that a health-social partnership transitional care program is cost-effective in reducing healthcare costs and attaining QALY gains. Economic evaluation helps to inform funders and guide decisions for the effective use of competing healthcare resources. |
23259497 | Mechanisms of pulmonary fibrosis: role of activated myofibroblasts and NADPH oxidase. | A common feature of pathological fibrosis involving the lung and other organs is the persistent activation of myofibroblasts in injured tissues. Recent evidence supports the role of a member of the NADPH oxidase (NOX) gene family, NOX4, in myofibroblast differentiation, matrix synthesis and contractility. Additionally, NOX4 may contribute directly or indirectly to alveolar epithelial cell death, while myofibroblasts themselves acquire an apoptosis-resistant phenotype. Thus, NOX4 may be responsible for the cardinal features of progressive fibrosis - myofibroblast activation and epithelial cell dysrepair. Therapeutic targeting of NOX4 is likely to be effective in progressive cases of fibrosis involving multiple organs. |
23259496 | The chromosome-centric human proteome project: a call to action. | The grand vision of the human proteome project (HPP) is moving closer to reality with the recent announcement by HUPO of the creation of the HPP consortium in charge of the development of a two-part HPP, one focused on the description of proteomes of biological samples or related to diseases (B/D-HPP) and the other dedicated to a systematic description of proteins as gene products encoded in the human genome (the C-HPP). This new initiative of HUPO seeks to identify and characterize at least one representative protein from every gene, create a protein distribution atlas and a protein pathway or network map. This vision for proteomics can be the roadmap of biological and clinical research for years to come if it delivers on its promises. The Industrial Advisory Board (IAB) to HUPO shares the visions of C-HPP. The IAB will support and critically accompany the overall project goals and the definitions of the critical milestones. The member companies are in a unique position to develop hardware and software, reagents and standards, procedures, and workflows to ensure a reliable source of tools available to the proteomics community worldwide. In collaboration with academia, the IAB member companies can and must develop the tools to reach the ambitious project goals. We offer to partner with and challenge the academic groups leading the C-HPP to define both ambitious and obtainable goals and milestones to make the C-HPP a real and trusted resource for future biology. |
23259495 | The influence of liver and pancreas surgery on the thyroid function. | Nowadays, the increasing number of oncologic patients with liver or pancreatic tumours are subjected to surgical treatment, as it can provide a long-term survival or sometimes cure. As a result, numerous new clinical questions regarding metabolic disturbances in these patients have been arisen. Among others, the impact of the pancreas and liver surgery extent in relation to the thyroid function remains to be elucidated. The study comprised 51 patients (25 men and 26 women, mean age ± SD 61.6 ± 10.4 yrs, mean ± SD) with pancreatic or liver tumours, qualified for abdominal operation. Serum levels of FT3, FT4 and TSH were measured on the day before (time "0") and on the 1st, 3rd and 5th day after surgery in two (2) subgroups reflecting the extent of surgery: twenty seven (27) patients (14 men and 13 women, mean age ± SD 61.5 ± 11.8 yrs) after major surgery (Whipple's surgery, right and left hemihepatectomy, segmentectomy of the liver, distal pancreatectomy, total duodenopancreatectomy) and twenty four (24) patients (11 men and 13 women, mean age ± SD 61.8 ± 8.9 yrs) after minor, palliative surgery (exploratory laparotomy, gastroenterostomy, triple by-pass, liver tumour embolization, hepaticojejunostomy). Additionally, the obtained results were analyzed in relation to the type of the disease (pancreatic surgery vs liver surgery). Mean serum FT3 level decreased significantly during the study in major and minor surgery subgroups (p<0.001, in both) in comparison to the baseline values, accompanied by stable serum concentrations of TSH (NS) and FT4 (NS). The above decreasing tendency in FT3 concentrations was similar in both subgroups (NS), the same as were unchanged levels of TSH (NS) and FT4 (NS). Mean FT4 concentration on the 3rd and 5th day after major surgery was lower in pancreatic tumour patients in comparison to liver tumour patients (p=0.002, p=0.032, respectively). Similarly, mean FT3 concentration on the 3rd day in minor surgery subgroup was lower in pancreatic tumour patients in comparison to liver tumour patients (p=0.015). Our findings have confirmed essential reduction of FT3 values after abdominal surgery, independently of surgery extent. Additionally, pancreatic tumour patients are more likely to have lower FT3 and FT4 levels after surgery when compared to liver tumour patients. |
23259491 | Impact of a surfactant on the electroactivity of proteins at an aqueous-organogel microinterface array. | The impact of surfactant addition to the organic phase on the electroactivity of proteins at the aqueous-organogel interface was examined by voltammetry. The presence of bis(2-ethylhexyl)sulfosuccinate (AOT) in the organogel phase, as the sodium salt, caused marked changes in the peak currents for myoglobin detection. The protein desorption voltammetric peak exhibited a 6-fold increase in the current compared to the corresponding experiment without surfactant. Interfacial coverage showed a 17-fold increase in the adsorbed protein at the interface, from 50 pmol cm(-2), in the absence of surfactant, to 850 pmol cm(-2), in the presence of 10 mM surfactant. Additionally, the presence of the surfactant resulted in a second pair of adsorption/desorption peaks at lower potentials and in a change in the capacitance of the system. The formation of surfactant-protein and surfactant-protein-organic anion deposits is proposed on the basis of these features, leading to increased voltammetric signals for myoglobin, hemoglobin, and cytochrome c. The mechanism of protein-surfactant interaction was probed by using the surfactant as the anion in the organic phase electrolyte salt. Repetitive cyclic voltammetry of cytochrome c showed that in the presence of surfactant there was an enhancement of the signal, caused by a buildup of the protein-surfactant-electrolyte anion assembly at the interface. These findings provide the basis for surfactant-modified interfaces to enhance the electroanalytical performance for protein detection. |
23259489 | Hypertension and the development of new onset chronic kidney disease over a 10 year period: a retrospective cohort study in a primary care setting in Malaysia. | Little is known about the rate of progression to chronic kidney disease (CKD) among hypertensive patients, particularly at the primary care level. This study aims to examine risk factors associated with new onset CKD among hypertensive patients attending a primary care clinic. This is a 10-year retrospective cohort study of 460 patients with hypertension who were on treatment. Patient information was collected from patient records. CKD was defined as a glomerular filtration rate <60 ml/min per 1.73 m2 (Cockcroft-Gault equation). Multiple logistic regression statistics was used to test the association in newly diagnosed CKD. The incidence of new CKD was 30.9% (n = 142) with an annual rate of 3%. In multivariate logistic regression analysis, factors associated with development of new onset of CKD among hypertensive patients were older age (odds ratio [OR] 1.123, 95% confidence interval [CI] 1.078-1.169), presence of diabetes (OR 2.621, 95% CI 1.490-4.608), lower baseline eGFR (OR 1.041, 95% CI 0.943-0.979) and baseline hyperuricaemia (OR 1.004, 95% CI 1.001-1.007). The progression to new onset CKD is high among urban multiethnic hypertensive patients in a primary care population. Hence every effort is needed to detect the presence of new onset CKD earlier. Hypertensive patients who are older, with underlying diabetes, hyperuricaemia and lower baseline eGFR are associated with the development of CKD in this population. |
23259488 | Challenge in pathologic diagnosis of Alport syndrome: evidence from correction of previous misdiagnosis. | Pathologic studies play an important role in evaluating patients with Alport syndrome besides genotyping. Difficulties still exist in diagnosing Alport syndrome (AS), and misdiagnosis is a not-so-rare event, even in adult patient evaluated with renal biopsy. We used nested case-control study to investigate 52 patients previously misdiagnosed and 52 patients initially diagnosed in the China Alport Syndrome Treatments and Outcomes Registry e-system. We found mesangial proliferative glomerulonephritis (MsPGN, 26.9%) and focal and segmental glomerulosclerosis (FSGS, 19.2%) were the most common misdiagnosis. FSGS was the most frequent misdiagnosis in female X-linked AS (fXLAS) patients (34.8%), and MsPGN in male X-linked AS (mXLAS) patients (41.2%). Previous misdiagnosed mXLAS patients (13/17, 76.5%) and autosomal recessive AS (ARAS) patients (8/12, 66.7%) were corrected after a second renal biopsy. While misdiagnosed fXLAS patients (18/23, 78.3%) were corrected after a family member diagnosed (34.8%) or after rechecking electronic microscopy and/or collagen-IV alpha-chains immunofluresence study (COL-IF) (43.5%) during follow-up. With COL-IF as an additional criterion for AS diagnosis, we found that patients with less than 3 criteria reached have increased risk of misdiagnosis (3.29-fold for all misdiagnosed AS patients and 3.90-fold for fXLAS patients). We emphasize timely and careful study of electronic microscopy and COL-IF in pathologic evaluation of AS patients. With renal and/or skin COL-IF as additional criterion, 3 diagnosis criteria reached are the cutoff for diagnosing AS pathologically. |
23259487 | Iron L-edge X-ray absorption spectroscopy of oxy-picket fence porphyrin: experimental insight into Fe-O2 bonding. | The electronic structure of the Fe-O(2) center in oxy-hemoglobin and oxy-myoglobin is a long-standing issue in the field of bioinorganic chemistry. Spectroscopic studies have been complicated by the highly delocalized nature of the porphyrin, and calculations require interpretation of multideterminant wave functions for a highly covalent metal site. Here, iron L-edge X-ray absorption spectroscopy, interpreted using a valence bond configuration interaction multiplet model, is applied to directly probe the electronic structure of the iron in the biomimetic Fe-O(2) heme complex [Fe(pfp)(1-MeIm)O(2)] (pfp ("picket fence porphyrin") = meso-tetra(α,α,α,α-o-pivalamidophenyl)porphyrin or TpivPP). This method allows separate estimates of σ-donor, π-donor, and π-acceptor interactions through ligand-to-metal charge transfer and metal-to-ligand charge transfer mixing pathways. The L-edge spectrum of [Fe(pfp)(1-MeIm)O(2)] is further compared to those of [Fe(II)(pfp)(1-MeIm)(2)], [Fe(II)(pfp)], and [Fe(III)(tpp)(ImH)(2)]Cl (tpp = meso-tetraphenylporphyrin) which have Fe(II)S = 0, Fe(II)S = 1, and Fe(III)S = 1/2 ground states, respectively. These serve as references for the three possible contributions to the ground state of oxy-pfp. The Fe-O(2) pfp site is experimentally determined to have both significant σ-donation and a strong π-interaction of the O(2) with the iron, with the latter having implications with respect to the spin polarization of the ground state. |
23259486 | Low-spin hexacoordinate Mn(III): synthesis and spectroscopic investigation of homoleptic tris(pyrazolyl)borate and tris(carbene)borate complexes. | Three complexes of Mn(III) with "scorpionate" type ligands have been investigated by a variety of physical techniques. The complexes are [Tp(2)Mn]SbF(6) (1), [Tp(2)*Mn]SbF(6) (2), and [{PhB(MeIm)(3)}(2)Mn](CF(3)SO(3)) (3a), where Tp(-) = hydrotris(pyrazolyl)borate anion, Tp*(-) = hydrotris(3,5-dimethylpyrazolyl)borate anion, and PhB(MeIm)(3)(-) = phenyltris(3-methylimidazol-2-yl)borate anion. The crystal structure of 3a is reported; the structures of 1 and 2 have been previously reported, but were reconfirmed in this work. The synthesis and characterization of [{PhB(MeIm)(3)}(2)Mn]Cl (3b) are also described. These complexes are of interest in that, in contrast to many hexacoordinate (pseudo-octahedral) complexes of Mn(III), they exhibit a low-spin (triplet) ground state, rather than the high-spin (quintet) ground state. Solid-state electronic absorption spectroscopy, SQUID magnetometry, and high-frequency and -field electron paramagnetic resonance (HFEPR) spectroscopy were applied. HFEPR, in particular, was useful in characterizing the S = 1 spin Hamiltonian parameters for complex 1, D = +19.97(1), E = 0.42(2) cm(-1), and for 2, D = +15.89(2), E = 0.04(1) cm(-1). In addition, frequency domain Fourier-transform THz-EPR spectroscopy, using coherent synchrotron radiation, was applied to 1 only and gave results in good agreement with HFEPR. Variable-temperature dc magnetic susceptibility measurements of 1 and 2 were also in good agreement with the HFEPR results. This magnitude of zero-field splitting (zfs) is over 4 times larger than that in comparable hexacoordinate Mn(III) systems with S = 2 ground states. Complexes 3a and 3b (i.e., regardless of counteranion) have a yet much larger magnitude zfs, which may be the result of unquenched orbital angular momentum so that the spin Hamiltonian model is not appropriate. The triplet ground state is rationalized in each complex by ligand-field theory (LFT) and by quantum chemistry theory, both density functional theory and unrestricted Hartree-Fock methods. This analysis also shows that spin-crossover behavior is not thermally accessible for these complexes as solids. The donor properties of the three different scorpionate ligands were further characterized using the LFT model that suggests that the tris(carbene)borate is a strong σ-donor with little or no π-bonding. |
23259485 | Organic silicone sol-gel polymer as a noncovalent carrier of receptor proteins for label-free optical biosensor application. | Optical biosensing techniques have become of key importance for label-free monitoring of biomolecular interactions in the current proteomics era. Together with an increasing emphasis on high-throughput applications in functional proteomics and drug discovery, there has been demand for facile and generally applicable methods for the immobilization of a wide range of receptor proteins. Here, we developed a polymer platform for microring resonator biosensors, which allows the immobilization of receptor proteins on the surface of waveguide directly without any additional modification. A sol-gel process based on a mixture of three precursors was employed to prepare a liquid hybrid polysiloxane, which was photopatternable for the photocuring process and UV imprint. Waveguide films were prepared on silicon substrates by spin coating and characterized by atomic force microscopy for roughness, and protein adsorption. The results showed that the surface of the polymer film was smooth (rms = 0.658 nm), and exhibited a moderate hydrophobicity with the water contact angle of 97°. Such a hydrophobic extent could provide a necessary binding strength for stable immobilization of proteins on the material surface in various sensing conditions. Biological activity of the immobilized Staphylococcal protein A and its corresponding biosensing performance were demonstrated by its specific recognition of human Immunoglobulin G. This study showed the potential of preparing dense, homogeneous, specific, and stable biosensing surfaces by immobilizing receptor proteins on polymer-based optical devices through the direct physical adsorption method. We expect that such polymer waveguide could be of special interest in developing low-cost and robust optical biosensing platform for multidimensional arrays. |
23259483 | Genome-guided analysis of physiological and morphological traits of the fermentative acetate oxidizer Thermacetogenium phaeum. | Thermacetogenium phaeum is a thermophilic strictly anaerobic bacterium oxidizing acetate to CO(2) in syntrophic association with a methanogenic partner. It can also grow in pure culture, e.g., by fermentation of methanol to acetate. The key enzymes of homoacetate fermentation (Wood-Ljungdahl pathway) are used both in acetate oxidation and acetate formation. The obvious reversibility of this pathway in this organism is of specific interest since syntrophic acetate oxidation operates close to the energetic limitations of microbial life. The genome of Th. phaeum is organized on a single circular chromosome and has a total size of 2,939,057 bp. It comprises 3.215 open reading frames of which 75% could be assigned to a gene function. The G+C content is 53.88 mol%. Many CRISPR sequences were found, indicating heavy phage attack in the past. A complete gene set for a phage was found in the genome, and indications of phage action could also be observed in culture. The genome contained all genes required for CO(2) reduction through the Wood-Ljungdahl pathway, including two formyl tetrahydrofolate ligases, three carbon monoxide dehydrogenases, one formate hydrogenlyase complex, three further formate dehydrogenases, and three further hydrogenases. The bacterium contains a menaquinone MQ-7. No indications of cytochromes or Rnf complexes could be found in the genome. The information obtained from the genome sequence indicates that Th. phaeum differs basically from the three homoacetogenic bacteria sequenced so far, i.e., the sodium ion-dependent Acetobacterium woodii, the ethanol-producing Clostridium ljungdahlii, and the cytochrome-containing Moorella thermoacetica. The specific enzyme outfit of Th. phaeum obviously allows ATP formation both in acetate formation and acetate oxidation. |
23259484 | Evaluation of the tuberculosis programme in Ningxia Hui Autonomous region, the People's Republic of China: a retrospective case study. | Tuberculosis is a devastating disease due to its rapid transmission and high rate of mortality. Ningxia Hui Autonomous Region (NHAR), located in the North-west, is one of the poorest provinces in China and national surveys have shown TB has been hyper endemic in NHAR for several decades. As no active surveys had been undertaken since the initiation of the DOTS control program across all of NHAR. A retrospective study was undertaken of all clinical records of TB patients registered from January 2005 to September 2009. Poisson regression was performed to investigate the change in incidence over time and accounted for age, sex and county. Length of time on treatment, disease severity and patient delay were assessed by county. More than 30% of patients had been on treatment for over 12 months and 10% for over 3 years, reflecting drug-resistance or failure of DOTS. More than 93% of patients had grade III disease at time of diagnosis and >15% of patients had severe disease grade IV-V in some NHAR counties. Further, 8.8% of patients were not diagnosed for over 6 months from the onset of symptoms; this was as high as 20% in some counties. The reported incidence of TB is most likely grossly underestimated and the data indicate TB is a major public health concern in NHAR. It is clear that active surveillance is necessary to determine the full extent of the burden of TB in NHAR. New control and treatment strategies for TB are required that increase awareness in the health-care system and at the individual and community level. |
23259482 | All black people are not alike: differences in HIV testing patterns, knowledge, and experience of stigma between U.S.-born and non-U.S.-born blacks in Massachusetts. | Non-U.S.-born black individuals comprise a significant proportion of the new diagnoses of HIV in the United States. Concurrent diagnosis (obtaining an AIDS diagnosis in close proximity to an initial diagnosis of HIV) is common in this subpopulation. Although efforts have been undertaken to increase HIV testing among African Americans, little is known about testing patterns among non-U.S.-born black people. A cross-sectional survey was self-administered by 1060 black individuals in Massachusetts (57% non-U.S.-born) to assess self-reported rates of HIV testing, risk factors, and potential barriers to testing, including stigma, knowledge, immigration status, and access to health care. Bivariate analysis comparing responses by birthplace and multivariate logistic regression assessing correlates of recent testing were completed. Non-U.S.-born individuals were less likely to report recent testing than U.S.-born (41.9% versus 55.6%, p<0.0001). Of those who recently tested, the majority did so for immigration purposes, not because of perceived risk. Stigma was significantly higher and knowledge lower among non-U.S.-born individuals. In multivariate analysis, greater length of time since immigration was a significant predictor of nontesting among non-U.S.-born (adjusted odds ratio [AOR] 0.56, 95% confidence interval [CI] 0.36-0.87). Poor health care access and older age were correlated to nontesting in both U.S.- and non-U.S.-born individuals. Our findings indicate that differences in HIV testing patterns exist by nativity. Efforts addressing unique factors limiting testing in non-U.S.-born black individuals are warranted. |
23259480 | Nanosensor electrical immunoassay for quantitative detection of NT-pro brain natriuretic peptide. | To demonstrate a label-free electrical immunoassay for profiling vascular biomarker N-terminal pro-brain natriuretic peptide (NT-proBNP) associated with improved cardiac risk prediction. A high-density nanowell-based electrical immunoassay has been designed by integrating nanoporous aluminum oxide onto printed circuit board chips for the detection of NT-proBNP. The concentration of the biomarker is quantitatively determined by measuring impedance changes to the electrical double layer within the nanowells using electrochemical impedance spectroscopy. Detection sensitivity in the fg/ml range was obtained due to spatial confinement of the target biomarkers in size-matched nanowells. Electrical immunoassay performance was determined for the detection of NT-proBNP in phosphate-buffered saline (PBS) and human serum (HS). The lower limit of detection for the sensor was observed to be 10 fg/ml in PBS and 500 fg/ml in HS. The upper limit of detection was observed to be 500 fg/ml in PBS and 500 ng/ml in HS. A label-free technique for detection of NT-proBNP at clinically relevant concentrations for evaluating cardiac risk is demonstrated. High sensitivity and specificity, robust detection and low volume (100 µl) per assay project the technology to be a successful competitor to traditional ELISA-based techniques. |
23259477 | Cysteine protease cathepsins and matrix metalloproteinases in the development of abdominal aortic aneurysms. | Both cysteine protease cathepsins and matrix metalloproteinases are implicated in the pathogenesis of abdominal aortic aneurysms (AAAs) in humans and animals. Blood and aortic tissues from humans or animals with AAAs contain much higher levels of these proteases, and often lower levels of their endogenous inhibitors, than do blood and aortic tissues from healthy subjects. Protease- and protease inhibitor-deficient mice and synthetic protease inhibitors have affirmed that cysteinyl cathepsins and matrix metalloproteinases both participate directly in AAA development in several experimental model systems. Here, we summarize our current understanding of how proteases contribute to the pathogenesis of AAA, and discuss whether proteases or their inhibitors may serve as diagnostic biomarkers or potential therapeutic targets for this common human arterial disease. |