Fisetin Inhibited Growth and Metastasis of Triple-Negative Breast Cancer by Reversing Epithelial-to-Mesenchymal Transition via PTEN/Akt/GSK3β Signal Pathway.
Triple negative breast cancer (TNBC), characterized by its highly aggressive and metastatic features, is associated with poor prognosis and high mortality partly due to lack of effective treatment. Fisetin, a natural flavonoid compound, has been demonstrated to possess anti-cancer effects in various cancers. However, the effects and mechanisms of fisetin on metastasis of TNBC remain uncovered. In this study, we found that fisetin dose-dependently inhibited cell proliferation, migration and invasion in TNBC cell lines MDA-MB-231 and BT549 cells. In addition, fisetin reversed epithelial to mesenchymal transition (EMT) as evaluated by cell morphology and EMT markers in MDA-MB-231 and BT549 cells. Furthermore, fisetin suppressed phosphoinositol 3-kinase (PI3K)-Akt-GSK-3β signaling pathway but upregulated the expression of PTEN mRNA and protein in a concentration-dependent manner. Further, silence of PTEN by siRNA abolished these benefits of fisetin on proliferation and metastasis of TNBCs. In vivo, using the metastatic breast cancer xenograft model bearing MDA-MB-231 cells, we found that fisetin dramatically inhibited growth of primary breast tumor and reduced lung metastasis, meanwhile, the expression of EMT molecules and PTEN/Akt/GSK-3β in primary and metastatic tissues changed in the same way as those in vitro experiments. In conclusion, all these results indicated that fisetin could effectively suppress proliferation and metastasis of TNBC and reverse EMT process, which might be mediated by PTEN/Akt/GSK-3β signaling pathway.


Branching and intercellular communication in the Section V cyanobacterium Mastigocladus laminosus, a complex multicellular prokaryote.
The filamentous Section V cyanobacterium Mastigocladus laminosus is one of the most morphologically complex prokaryotes. It exhibits cellular division in multiple planes, resulting in the formation of true branches, and cell differentiation into heterocysts, hormogonia and necridia. Here, we investigate branch formation and intercellular communication in M. laminosus. Monitoring of membrane rearrangement suggests that branch formation results from a randomized direction of cell growth. Transmission electron microscopy reveals cell junction structures likely to be involved in intercellular communication. We identify a sepJ gene, coding for a potential key protein in intercellular communication, and show that SepJ is localized at the septa. To directly investigate intercellular communication, we loaded the fluorescent tracer 5-carboxyfluorescein diacetate into the cytoplasm, and quantified its intercellular exchange by fluorescence recovery after photobleaching. Results demonstrate connectivity of the main trichome and branches, enabling molecular exchange throughout the filament network. Necridia formation inhibits further molecular exchange, determining the fate of a branch likely to become a hormogonium. Cells in young, narrow trichomes and hormogonia exhibited faster exchange rates than cells in older, wider trichomes. Signal transduction to co-ordinate movement of hormogonia might be accelerated by reducing cell volume.


Experimental demonstration of 30 Gb/s direct-detection optical OFDM transmission with blind symbol synchronisation using virtual subcarriers.
The paper investigates the performance of a blind symbol synchronisation technique for optical OFDM systems based on virtual subcarriers. The test-bed includes a real-time 16-QAM OFDM transmitter operating at a net data rate of 30.65 Gb/s using a single OFDM band with a single FPGA-DAC subsystem and demonstrates transmission over 23.3 km SSMF with direct detection at a BER of 10(-3). By comparing the performance of the proposed synchronisation scheme with that of the Schmidl and Cox algorithm, it was found that the two approaches achieve similar performance for large numbers of averaging symbols, but the performance of the proposed scheme degrades as the number of averaging symbols is reduced. The proposed technique has lower complexity and bandwidth overhead as it does not rely on training sequences. Consequently, it is suitable for implementation in high speed optical OFDM transceivers.


Hyperbaric oxygen therapy for late radiation-induced tissue toxicity: prospectively patient-reported outcome measures in breast cancer patients.
This study examines patient reported outcome measures of women undergoing hyperbaric oxygen treatment (HBOT) after breast-conserving therapy. Included were 57 women treated with HBOT for late radiation-induced tissue toxicity (LRITT) referred in the period January 2014-December 2015. HBOT consisted of (on average) 47 sessions. In total, 80 min of 100 % O2 was administered under increased pressure of 2.4 ATA. Quality of life was assessed before and after treatment using the European Organization for Research and Treatment of Cancer (EORTC) QLQ-BR23, and a NRS pain score. Fifty-seven women were available for evaluation before and after treatment. Before HBOT, patients had severe complaints of pain in the arm/shoulder (46 %), swollen arm/hand (14 %), difficulty to raise arm or move it sideways (45 %), pain in the area of the affected breast (67 %), swollen area of the affected breast (45 %), oversensitivity of the affected breast (54 %), and skin problems on/in the area of the affected breast (32 %); post HBOT, severe complaints were still experienced in 17, 7, 22, 15, 13, 15, and 11 % of the women, respectively. Differences were all significant. The NRS pain score improved at least 1 point (range 0-10) in 81 % of the patients (p < 0.05). In these breast cancer patients treated with HBOT for LRITT, the patient-reported outcomes were positive and improvements were observed. HBOT was a well-tolerated treatment for LRITT and its side-effects were both minimal and reversible.


Direct and indirect effects of simulated calcareous dredge material on eggs and larvae of pink snapper Pagrus auratus.
The direct and indirect effects of a simulated, calcarenite-based dredge material on eggs and larvae of pink snapper Pagrus auratus were assessed. Direct effects were assessed by measuring hatch rate or survival of eggs and pre-feeding larvae, respectively, over a range of concentrations and exposure durations. Exposure of eggs to suspended solid concentrations up to 10 000 mg l(-1) for 24 h did not affect egg buoyancy or hatch rate, despite sediment adherence occurring at the two highest concentrations tested. Newly hatched larvae, whose mouths were still closed, were relatively tolerant of suspended solids, with a 12 h lethal concentration resulting in 50% mortality, LC(50), of 2020 mg l(-1) and a first observable effect concentration of 150 mg l(-1). Once the larvae's mouths opened, tolerance was significantly reduced, with a 12 h LC(50) of 157 mg l(-1) and a first observable effect concentration of 4 mg l(-1). Tolerance of larvae to suspended solids was negatively correlated with suspended solids concentration and exposure time, with exposure durations of <or=6 h being significantly less detrimental than those of 9 h or more. Indirect effects to larvae were assessed by measuring ingestion of copepod nauplii by 10 and 15 days post-hatch (dph) larvae at sediment concentrations from 0 to 200 mg l(-1) in 50 mg l(-1) increments over 4 h. Ingestion was not significantly affected by sediment for 10 dph larvae, but by 15 dph, sediment had a far greater impact on ingestion, with larvae in all sediment treatments eating significantly fewer copepods than those in the control.


Empowering targeted therapy: lessons from rituximab.
Rituximab, a monoclonal antibody directed against the B cell-specific protein CD20, has revolutionized lymphoma treatment by providing a highly effective form of therapy with relatively mild toxic side effects. Effective as a single agent against some forms of B cell lymphoma, rituximab also has a chemosensitizing effect, enhancing the efficacy of chemotherapy against other forms of the disease. Although the mechanisms whereby rituximab achieves its effects remain incompletely understood, these seem to involve at least three distinct phenomena: (i) antibody-dependent cell-mediated cytotoxicity, (ii) complement-mediated cell lysis, and (iii) stimulation of apoptosis in target cells. The latter occurs through interaction of complexes of rituximab and CD20 in lipid rafts, with elements of a signaling pathway involving Src kinases. Effector molecules trigger various gene expression events, leading to sensitization of malignant cells to proapoptotic stimuli. Lessons learned from the research on rituximab may be applied to the rational development of antibody-based therapies against other forms of cancer.


Comparison of kNN and k-means optimization methods of reference set selection for improved CNV callers performance.
There are over 25 tools dedicated for the detection of Copy Number Variants (CNVs) using Whole Exome Sequencing (WES) data based on read depth analysis. The tools reported consist of several steps, including: (i) calculation of read depth for each sequencing target, (ii) normalization, (iii) segmentation and (iv) actual CNV calling. The essential aspect of the entire process is the normalization stage, in which systematic errors and biases are removed and the reference sample set is used to increase the signal-to-noise ratio. Although some CNV calling tools use dedicated algorithms to obtain the optimal reference sample set, most of the advanced CNV callers do not include this feature. To our knowledge, this work is the first attempt to assess the impact of reference sample set selection on CNV detection performance. We used WES data from the 1000 Genomes project to evaluate the impact of various methods of reference sample set selection on CNV calling performance of three chosen state-of-the-art tools: CODEX, CNVkit and exomeCopy. Two naive solutions (all samples as reference set and random selection) as well as two clustering methods (k-means and k nearest neighbours (kNN) with a variable number of clusters or group sizes) have been evaluated to discover the best performing sample selection method. The performed experiments have shown that the appropriate selection of the reference sample set may greatly improve the CNV detection rate. In particular, we found that smart reduction of reference sample size may significantly increase the algorithms' precision while having negligible negative effect on sensitivity. We observed that a complete CNV calling process with the k-means algorithm as the selection method has significantly better time complexity than kNN-based solution.


The database for aggregate analysis of ClinicalTrials.gov (AACT) and subsequent regrouping by clinical specialty.
The ClinicalTrials.gov registry provides information regarding characteristics of past, current, and planned clinical studies to patients, clinicians, and researchers; in addition, registry data are available for bulk download. However, issues related to data structure, nomenclature, and changes in data collection over time present challenges to the aggregate analysis and interpretation of these data in general and to the analysis of trials according to clinical specialty in particular. Improving usability of these data could enhance the utility of ClinicalTrials.gov as a research resource. The purpose of our project was twofold. First, we sought to extend the usability of ClinicalTrials.gov for research purposes by developing a database for aggregate analysis of ClinicalTrials.gov (AACT) that contains data from the 96,346 clinical trials registered as of September 27, 2010. Second, we developed and validated a methodology for annotating studies by clinical specialty, using a custom taxonomy employing Medical Subject Heading (MeSH) terms applied by an NLM algorithm, as well as MeSH terms and other disease condition terms provided by study sponsors. Clinical specialists reviewed and annotated MeSH and non-MeSH disease condition terms, and an algorithm was created to classify studies into clinical specialties based on both MeSH and non-MeSH annotations. False positives and false negatives were evaluated by comparing algorithmic classification with manual classification for three specialties. The resulting AACT database features study design attributes parsed into discrete fields, integrated metadata, and an integrated MeSH thesaurus, and is available for download as Oracle extracts (.dmp file and text format). This publicly-accessible dataset will facilitate analysis of studies and permit detailed characterization and analysis of the U.S. clinical trials enterprise as a whole. In addition, the methodology we present for creating specialty datasets may facilitate other efforts to analyze studies by specialty groups.


Ambient GABA responsible for age-related changes in multistable perception.
Multistable perception is a psychophysical phenomenon in which one unique interpretation alternates spontaneously every few seconds between two or more interpretations of the same sensory input. Well-known examples include the Necker cube and face-vase illusions in vision. Interestingly, young adults generally see more perceptual switches than do elderly people. To understand the underlying neuronal mechanism of age-related multistable perception, we simulated a cortical neural network model that consists of multiple cell assemblies. In the network, a specific population of noncore cells and a common population of core cells form a cell assembly that represents a single object (or event). Every dynamic cell assembly, activated by a given sensory input, involves the common (overlapping) population of core cells. Ambient GABA-mediated intracortical tonic inhibition via extrasynaptic GABAa receptors destabilized the currently appearing dynamic cell assembly and terminated its burst firing. This allowed another dynamic cell assembly to emerge one after the other. Namely, multistable perception took place. Transporters, which were embedded in axon terminal membranes of interneurons, regulated levels of ambient GABA. For elderly people, we assumed a decline in transporter. This decelerated GABA augmentation and resulted in prolonging the durations of burst firing and thus in slowing perceptual switches. We suggest that poor control of ambient GABA levels due to age-related decline in GABA transporter may be responsible for the slowing of perceptual switches in elderly people.


The UK Diabetes Research Network--an opportunity and a challenge.
The Department of Health has funded a national diabetes network to support clinical research. The network will facilitate recruitment into clinical trials and has been widely welcomed by clinicians. However, if the network is to reach its full potential, all those involved will need to advocate a change in attitude towards clinical trials and research, encouraging participation and contribution of data. Clinicians need to be willing to take a proactive view about research studies, and to encourage patients to adopt a positive and altruistic attitude towards trial participation. The future of trials and other important clinical research in the UK may depend on it.


Parental perceptions in egg allergy: does egg challenge make a difference?
The aim of the study was to determine the effect of an oral egg challenge in egg sensitized children on parental perceptions relating to their child's allergy. A questionnaire was completed by parents for 167 children attending a tertiary paediatric clinic with egg sensitization. The questionnaires included 10 questions concerning parental perceptions of their child's egg allergy. Parental perceptions of those children who had not had an egg challenge (n = 83) were compared with those whose children had a positive (n = 27) and those with a negative (n = 57) egg challenge. A significant difference (p = < or =0.02) was observed between challenge positive(CP) and challenge negative (CN) subjects in reported changes to lifestyle and the fact that more parents in the CN group expected little or no future inconvenience for the child. The responses of parents whose child had undergone an egg challenge differed significantly (p = < or =0.005) from those not challenged with a significant reduction in the following parameters; the effect on out-of-home care arrangements, the perception of being more severe as compared to other common childhood illnesses, whether they found egg allergy to be moderately or very stressful, whether their lifestyle was changed, the expectation of little or no future discomfort for the child and whether others treated the child differently. The performance of an egg challenge was associated with reduced adverse parental concerns. For 6/10 parameters, expectations concerning egg allergy in children who had been challenged were significantly better than those who had never been challenged irrespective of the challenge outcome. The greater certainty provided by the performance of a food challenge may be a positive outcome in both CP and CN children.


Significance of proteinuria on the outcome of renal function in patients with focal segmental glomerulosclerosis.
Kidney survival analysis was performed for 64 patients with focal segmental sclerosis to ascertain whether the degree of proteinuria and other factors determined at the time of renal biopsy might be associated with progression to end-stage renal failure. On the basis of urinary excretion of protein, which was measured in 63 of the 64 patients, three groups of patients were identified: 15 patients (group A) had asymptomatic proteinuria (less than 3.5 g/24 h), 38 patients (group B) had nephrotic proteinuria (3.5 to 14 g/24 h), and 10 patients (group C) had massive proteinuria (more than 14 g/24 h). Kidney survival curves showed that the median time from biopsy to end-stage renal failure was more than 11, 7, and 3 years for groups A, B, and C, respectively. Thus, patients with massive proteinuria had an accelerated course to renal failure as compared with other nephrotic patients who had a lesser degree of proteinuria (P = 0.014) and patients who had asymptomatic proteinuria (P less than 0.001). Higher initial serum creatinine levels and severe tubulointerstitial damage were associated with a shorter time to end-stage renal failure. Age at onset and at biopsy, systolic and diastolic blood pressure, serum albumin and cholesterol, percentage of sclerotic glomeruli, mesangial proliferation, hyalinosis, vascular sclerosis, and initial response to prednisone were not associated with the time to end-stage renal failure when each of these variables was considered separately.


Design of Assembled Systems Based on Conjugated Polyphenylene Derivatives and Carbon Nanohorns.
Promising materials have been designed and fully characterised by an effective interaction between versatile platforms such as carbon nanohorns (CNHs) and conjugated molecules based on thiophene derivatives. Easy and non-aggressive methods have been described for the synthesis and purification of the final systems. Oligothiophenephenylvinylene (OTP) systems with different geometries and electron density are coupled to the CNHs. A wide range of characterization techniques have been used to confirm the effective interaction between the donor (OTP) and the acceptor (CNH) systems. These hybrid materials show potential for integration into solar cell devices. Importantly, surface-enhanced Raman spectroscopy (SERS) effects are observed without the presence of any metal surface in the system. Theoretical calculations have been performed to study the optimised geometries of the noncovalent interaction between the surface and the organic molecule. The calculations allow information on the monoelectronic energies of HOMO-LUMO orbitals and band gap of different donor systems to be extracted.


Immune activation by a multigene family of lectins with variable tandem repeats in oriental river prawn (Macrobrachium nipponense).
Genomic regions with repeated sequences are unstable and prone to rapid DNA diversification. However, the role of tandem repeats within the coding region is not fully characterized. Here, we have identified a new hypervariable C-type lectin gene family with different numbers of tandem repeats (Rlecs; R means repeat) in oriental river prawn (Macrobrachium nipponense). Two types of repeat units (33 or 30 bp) are identified in the second exon, and the number of repeat units vary from 1 to 9. Rlecs can be classified into 15 types through phylogenetic analysis. The amino acid sequences in the same type of Rlec are highly conservative outside the repeat regions. The main differences among the Rlec types are evident in exon 5. A variable number of tandem repeats in Rlecs may be produced by slip mispairing during gene replication. Alternative splicing contributes to the multiplicity of forms in this lectin gene family, and different types of Rlecs vary in terms of tissue distribution, expression quantity and response to bacterial challenge. These variations suggest that Rlecs have functional diversity. The results of experiments on sugar binding, microbial inhibition and clearance, regulation of antimicrobial peptide gene expression and prophenoloxidase activation indicate that the function of Rlecs with the motif of YRSKDD in innate immunity is enhanced when the number of tandem repeats increases. Our results suggest that Rlecs undergo gene expansion through gene duplication and alternative splicing, which ultimately leads to functional diversity.


Temperature change in pig rib bone during implant site preparation by low-speed drilling.
The purpose of this study was to evaluate the temperature change during low-speed drilling using infrared thermography. Pig ribs were used to provide cortical bone of a similar quality to human mandible. Heat production by three implant drill systems (two conventional drilling systems and one low-speed drilling system) was evaluated by measuring the bone temperature using infrared thermography. Each system had two different bur sizes. The drill systems used were twist drill (2.0 mm/2.5 mm), which establishes the direction of the implant, and finally a 3.0 mm-pilot drill. Thermal images were recorded using the IRI1001 system (Infrared Integrated Systems Ltd.). Baseline temperature was 31±1ºC. Measurements were repeated 10 times, and a static load of 10 kg was applied while drilling. Data were analyzed using descriptive statistics. Statistical analysis was conducted with two-way ANOVA. Mean values (n=10 drill sequences) for maximum recorded temperature (Max TºC), change in temperature (ΔTºC) from baseline were as follows. The changes in temperature (ΔTºC) were 1.57ºC and 2.46ºC for the lowest and the highest values, respectively. Drilling at 50 rpm without irrigation did not produce overheating. There was no significant difference in heat production between the 3 implant drill systems (p>0.05). No implant drill system produced heat exceeding 47ºC, which is the critical temperature for bone necrosis during low-speed drilling. Low-speed drilling without irrigation could be used during implant site preparation.


Towards virtual doctor consultations: A call for the scale-up of telemedicine in sub-Saharan Africa during COVID-19 lockdowns and beyond.
The outbreak of COVID-19 has resulted in adoption and implementation of mitigatory policies, including movement restrictions (lockdowns) to curb its spread. These lockdowns have brought unintended consequences such as increasing the inequalities in health delivery. In the context of these restrictions, telemedicine provides an opportunity for continuation of essential health care provision. This review aimed to map available literature on the current status of telemedicine in sub-Saharan Africa to proffer recommendations for scale up during COVID-19 and beyond. Our review highlighted the lack of meaningful investment in the area. The literature identified resistance to telemedicine, infrastructural barriers, and the lack of policy and budgetary support as main deterrents to current implementation. We recommend the region to leverage on the rapid expansion of internet and telecommunication in addition to adopting a mix of strategies to set up an infrastructure for providing scale up of telemedicine and overcome barriers to implementation. There is an urgent need for policy formulation and the provision of budgetary support through sustainable business models.


The Development of Expanded Snack Product Made from Pumpkin Flour-Corn Grits: Effect of Extrusion Conditions and Formulations on Physical Characteristics and Microstructure.
Pumpkin products confer natural sweetness, desirable flavours and β-carotene, a vitamin A precursor when added as ingredients to extruded snacks. Therefore, a potential use for dried pumpkin flour is as an ingredient in ready-to-eat (RTE) snack foods. Growth in this market has driven food manufacturers to produce a variety of new high value snack foods incorporating diverse ingredients to enhance the appearance and nutritional properties of these foods. Ready-to-eat snacks were made by extruding corn grits with 5%, 10%, 15% and 20% of pumpkin flour. Snacks made from 100% corn grits were used as control products for this work. The effect of formulation and screw speeds of 250 rpm and 350 rpm on torque and specific mechanical energy (SME, kWh/kg), physical characteristics (expansion ratio, bulk density, true density and hardness) and the microstructure of the snacks were studied. Increasing the screw speed resulted in a decrease of torque for all formulations. When pumpkin flour was added the specific mechanical energy (SME) decreased by approximately 45%. Increasing the percentage of pumpkin flour at the higher screw speed resulted in a harder texture for the extruded products. X-ray tomography of pumpkin flour-corn grit snacks showed that increased levels of pumpkin flour decreased both the bubble area and bubble size. However, no significant differences (p > 0.05) in bubble wall thickness were measured. By understanding the conditions during extrusion, desirable nutritional characteristics can be incorporated while maximizing expansion to make a product with low bulk density, a fine bubble structure and acceptable organoleptic properties.


Sulfonylureas in NIDDM.
Sulfonylureas have represented the backbone of oral therapy in non-insulin-dependent diabetes mellitus for greater than 30 yr. Despite this, our knowledge about the mode of actions of these agents is limited, and the use of them is far from rational. Sulfonylureas lower blood glucose concentrations primarily by stimulating insulin secretion. The evidence for clinically significant extrapancreatic effects is scanty. Therefore, the effect of sulfonylurea is limited to patients with preserved beta-cell function, with the best effect observed in the early stages of the disease. Sulfonylurea treatment is often started relatively late and is continued when the agents can no longer achieve the treatment goals. Drug dosages are increased to maximum recommended doses, although there is no evidence for a dose-response relationship between the sulfonylurea dose and its biological effect. To rationalize the use of sulfonylureas, we should ask the questions to whom, how much, and for how long? The decision to stop treatment is as important as the decision to start treatment.


Anti-Inflammatory Nutrition and Successful Ageing in Elderly Individuals: The Multinational MEDIS Study.
The role of diet and inflammation in successful ageing is not transparent, and as such, is still being investigated. The aim of the present work was to evaluate the inflammatory potential of dietary habits in the successful ageing of a random sample of older adults living in the Mediterranean basin and who participated in the MEDIS (MEDiterranean ISlands) study. During 2005-2016, 3,128 older adults (aged 65-100 years) from 24 Mediterranean islands and the rural Mani region (Peloponnesus) of Greece were enrolled in the study. A multidimensional successful ageing index consisting of 10 components was employed. A validated and reproducible Food Frequency Questionnaire (FFQ) was used to evaluate the dietary habits of the older adults. A nutrition anti-inflammatory (NAI) score based on the participants' specific dietary habits was assessed. Participants with high NAI scores (proinflammatory nutrition) had a higher prevalence of hypercholesterolemia and lower levels of successful ageing. After adjusting for several confounders, the NAI score was associated with successful ageing (-0.03, 95% CI -0.5 to -0.006). Stratified analysis by gender and advanced age revealed heterogeneity in the NAI score, predicting successful ageing. The inflammatory potential of nutrition was reported as an important factor for successful ageing, suggesting that further research is needed on the role of anti- and proinflammatory dietary habits in healthy and successful ageing.


Cannabinoids for the Treatment of Chronic Non-Cancer Pain: An Updated Systematic Review of Randomized Controlled Trials.
An updated systematic review of randomized controlled trials examining cannabinoids in the treatment of chronic non-cancer pain was conducted according to PRISMA guidelines for systematic reviews reporting on health care outcomes. Eleven trials published since our last review met inclusion criteria. The quality of the trials was excellent. Seven of the trials demonstrated a significant analgesic effect. Several trials also demonstrated improvement in secondary outcomes (e.g., sleep, muscle stiffness and spasticity). Adverse effects most frequently reported such as fatigue and dizziness were mild to moderate in severity and generally well tolerated. This review adds further support that currently available cannabinoids are safe, modestly effective analgesics that provide a reasonable therapeutic option in the management of chronic non-cancer pain.


A functional survey of the enhancer activity of conserved non-coding sequences from vertebrate Iroquois cluster gene deserts.
Recent studies of the genome architecture of vertebrates have uncovered two unforeseen aspects of its organization. First, large regions of the genome, called gene deserts, are devoid of protein-coding sequences and have no obvious biological role. Second, comparative genomics has highlighted the existence of an array of highly conserved non-coding regions (HCNRs) in all vertebrates. Most surprisingly, these structural features are strongly associated with genes that have essential functions during development. Among these, the vertebrate Iroquois (Irx) genes stand out on both fronts. Mammalian Irx genes are organized in two clusters (IrxA and IrxB) that span >1 Mb each with no other genes interspersed. Additionally, a large number of HCNRs exist within Irx clusters. We have systematically examined the enhancer activity of HCNRs from the IrxB cluster using transgenic Xenopus and zebrafish embryos. Most of these HCNRs are active in subdomains of endogenous Irx expression, and some are candidates to contain shared enhancers of neighboring genes, which could explain the evolutionary conservation of Irx clusters. Furthermore, HCNRs present in tetrapod IrxB but not in fish may be responsible for novel Irx expression domains that appeared after their divergence. Finally, we have performed a more detailed analysis on two IrxB ultraconserved non-coding regions (UCRs) duplicated in IrxA clusters in similar relative positions. These four regions share a core region highly conserved among all of them and drive expression in similar domains. However, inter-species conserved sequences surrounding the core, specific for each of these UCRs, are able to modulate their expression.


Nonrandom spatial clustering of spontaneous anterior fossa cerebrospinal fluid fistulas and predilection for the posterior cribriform plate.
OBJECTIVE The anterior skull base is a common site for the spontaneous development of meningoceles, encephaloceles, and meningoencephaloceles that can lead to cerebrospinal fluid (CSF) fistula formation, particularly in association with idiopathic intracranial hypertension. In some circumstances the lesions are difficult to localize. Whether all sites in the anterior skull base are equally prone to fistula formation or whether they are distributed randomly throughout the anterior skull base is unknown, although the anterior cribriform plate has been proposed as the most frequent location. The purpose of this study was to identify sites of predilection in order to provide assistance for clinicians in finding occult leaks and increase the understanding of the etiology of this pathology. METHODS The authors performed a retrospective review of a prospectively acquired surgical database of all endonasal endoscopic surgeries performed at Weill Cornell Medical College by the senior authors. Spontaneous CSF fistulas of the anterior skull base were identified. The anatomical sites of the defects were located on radiographic images and normalized to a theoretical 4 × 2 grid representing the anterior midline skull base. Data from the left and right skull base were combined to increase statistical power. This grid was then used to analyze the distribution of defects. Frequency analysis was performed by means of a chi-square test, with a subsequent Monte Carlo simulation to further strengthen the statistical support of the conclusions. RESULTS Nineteen cases of spontaneous CSF fistulas were identified. Frequency analysis using chi-square indicated a nonrandom distribution of sites (p = 0.035). Monte Carlo simulation supported this conclusion (p = 0.034). Seventy-four percent of cases occurred in the cribriform plate (p = 0.086). Moreover, 37% of all defects occurred in the posterior third of the cribriform plate. CONCLUSIONS Anterior skull base spontaneous CSF leaks are distributed in a nonrandom fashion. The most likely site of origin of the spontaneous CSF leaks of the anterior midline skull base is the cribriform plate, particularly the posterior third of the plate, likely because of the lack of significant thick bony buttressing. Clinicians searching for occult spontaneous leaks of the anterior skull base should examine the cribriform plate, especially the posterior third with particularly close scrutiny.


Prognostic importance of late gadolinium enhancement cardiovascular magnetic resonance in cardiomyopathy.
Cardiovascular magnetic resonance has revolutionised the diagnosis of cardiomyopathy, particularly through the use of late gadolinium enhancement imaging which provides the unique opportunity to assess myocardial fibrosis in vivo. More recently, the prognostic capability of cardiovascular magnetic resonance to predict outcomes has been assessed. Traditional risk markers do not at present adequately predict outcomes in either dilated cardiomyopathy or hypertrophic cardiomyopathy, which are the two most common causes of primary heart muscle disease. Many of these existing markers reflect underlying disease severity. Given the important role fibrosis is thought to play in the pathogenesis and sequelae of these cardiomyopathies, the presence and amount of fibrosis has been proposed as a potential novel risk factor for adverse events. This paper reviews the evidence for late gadolinium enhancement as a prognostic marker in dilated and hypertrophic cardiomyopathy and highlights the challenges ahead.


Nutritional composition of the diets of South Asian, black African-Caribbean and white European children in the United Kingdom: the Child Heart and Health Study in England (CHASE).
In the UK, South Asian adults have increased risks of CHD, type 2 diabetes and central obesity. Black African-Caribbeans, in contrast, have increased risks of type 2 diabetes and general obesity but lower CHD risk. There is growing evidence that these risk differences emerge in early life and that nutritional factors may be important. We have therefore examined the variations in nutritional composition of the diets of South Asian, black African-Caribbean and white European children, using 24 h recalls of dietary intake collected during a cross-sectional survey of cardiovascular health in eighty-five primary schools in London, Birmingham and Leicester. In all, 2209 children aged 9-10 years took part, including 558 of South Asian, 560 of black African-Caribbean and 543 of white European ethnicity. Compared with white Europeans, South Asian children reported higher mean total energy intake; their intakes of total fat, polyunsaturated fat and protein (both absolute and as proportions of total energy intake) were higher and their intakes of carbohydrate as a proportion of energy (particularly sugars), vitamin C and D, Ca and haem Fe were lower. These differences were especially marked for Bangladeshi children. Black African-Caribbean children had lower intakes of total and saturated fat (both absolute and as proportions of energy intake), NSP, vitamin D and Ca. The lower total and saturated fat intakes were particularly marked among black African children. Appreciable ethnic differences exist in the nutritional composition of children's diets, which may contribute to future differences in chronic disease risk.


Dysfunctional beliefs in bipolar disorder: hypomanic vs. depressive attitudes.
To date the effect of cognitive behavioural therapy modified for bipolar disorder has been inconsistent and sometimes disappointing. However studies exploring cognitive style in bipolar disorder have not identified the unique patterns of beliefs specific to bipolar disorder. The current study examines whether Mansell's hypomania-related dysfunctional belief scale specifically identifies bipolar disorder patients. Forty remitted bipolar patients, twenty remitted unipolar patients and twenty healthy controls completed the Hypomanic Attitudes and Positive Prediction Inventory (HAPPI) and the Dysfunctional Attitude Scale (DAS). The remitted bipolar group scored higher than the unipolar and healthy control groups on the HAPPI scale overall score and on three subscales that measured self-catastrophic beliefs, beliefs related to negative responses from other people when in elevated mood and beliefs related the response style to activation and elevation. The study finds evidence of unique dysfunctional beliefs elevated only in remitted bipolar patients. Such findings could be used to inform the development of a specific cognitive behavioural therapy for bipolar disorder.


Bone marrow-derived mesenchymal stem cells improve diabetes-induced cognitive impairment by exosome transfer into damaged neurons and astrocytes.
The incidence of dementia is higher in diabetic patients, but no effective treatment has been developed. This study showed that rat bone marrow mesenchymal stem cells (BM-MSCs) can improve the cognitive impairments of STZ-diabetic mice by repairing damaged neurons and astrocytes. The Morris water maze test demonstrated that cognitive impairments induced by diabetes were significantly improved by intravenous injection of BM-MSCs. In the CA1 region of the hippocampus, degeneration of neurons and astrocytes, as well as synaptic loss, were prominent in diabetes, and BM-MSC treatment successfully normalized them. Since a limited number of donor BM-MSCs was observed in the brain parenchyma, we hypothesized that humoral factors, especially exosomes released from BM-MSCs, act on damaged neurons and astrocytes. To investigate the effectiveness of exosomes for treatment of diabetes-induced cognitive impairment, exosomes were purified from the culture media and injected intracerebroventricularly into diabetic mice. Recovery of cognitive impairment and histological abnormalities similar to that seen with BM-MSC injection was found following exosome treatment. Use of fluorescence-labeled exosomes demonstrated that injected exosomes were internalized into astrocytes and neurons; these subsequently reversed the dysfunction. The present results indicate that exosomes derived from BM-MSCs might be a promising therapeutic tool for diabetes-induced cognitive impairment.


DLD pillar shape design for efficient separation of spherical and non-spherical bioparticles.
Particle sorting methods in microfluidic platforms are gaining momentum for various biomedical applications. Bioparticles are found in different shapes and sizes. However, conventional separation techniques are mainly designed for separation of spherical particles. Thus, there is a need to develop new methods for effective separation of spherical and non-spherical bioparticles for various applications. Deterministic lateral displacement (DLD) microfluidic methods have become popular for high separation resolution, simplicity, and predictability. However, shape sorting in the DLD separation methods is not well researched. Recently, we explored this area and found that pillar shapes in DLD significantly affect bioparticle separation. In this work, we designed a group of different pillar shapes with protrusions and groove structures with the hypothesis that pillar protrusions will induce particle rotation while pillar grooves will confine the particle rotational movement in a directed path for effective separation in a DLD pillar array. Using combinations of protrusions and grooves, 3-dimensional spherical particles, 2-dimensional planar disc-shaped red blood cells and 1-dimensional rod-shaped bacteria were separated and two interesting phenomena were observed. Firstly, the arrangement of pillar protrusions and grooves induces inertial movements, enhancing the separation of spherical particles. Secondly, non-spherical particles experience dominant rotational movements due to the protrusions and grooves which help in changing their orientations. This gives an opportunity to perform efficient separation based on the desired orientation (the longest dimension of the particles) by restricting or containing their movement within a specific DLD path.


Adolescent idiopathic scoliosis: a new classification to determine extent of spinal arthrodesis.
The lack of a reliable, universally acceptable system for classification of adolescent idiopathic scoliosis has made comparisons between various types of operative treatment an impossible task. Furthermore, long-term outcomes cannot be determined because of the great variations in the description of study groups. We developed a new classification system with three components: curve type (1 through 6), a lumbar spine modifier (A, B, or C), and a sagittal thoracic modifier (-, N, or +). The six curve types have specific characteristics, on coronal and sagittal radiographs, that differentiate structural and nonstructural curves in the proximal thoracic, main thoracic, and thoracolumbar/lumbar regions. The lumbar spine modifier is based on the relationship of the center sacral vertical line to the apex of the lumbar curve, and the sagittal thoracic modifier is based on the sagittal curve measurement from the fifth to the twelfth thoracic level. A minus sign represents a curve of less than +10 degrees, N represents a curve of 10 degrees to 40 degrees, and a plus sign represents a curve of more than +40 degrees. Five surgeons, members of the Scoliosis Research Society who had developed the new system and who had previously tested the reliability of the King classification on radiographs of twenty-seven patients, measured the same radiographs (standing coronal and lateral as well as supine side-bending views) to test the reliability of the new classification. A randomly chosen independent group of seven surgeons, also members of the Scoliosis Research Society, tested the reliability and validity of the classification as well. The interobserver and intraobserver kappa values for the curve type were, respectively, 0.92 and 0.83 for the five developers of the system and 0.740 and 0.893 for the independent group of seven scoliosis surgeons. In the independent group, the mean interobserver and intraobserver kappa values were 0.800 and 0.840 for the lumbar modifier and 0.938 and 0.970 for the sagittal thoracic modifier. These kappa values were all in the good-to-excellent range (>0.75), except for the interobserver reliability of the independent group for the curve type (kappa = 0.74), which fell just below this level. This new two-dimensional classification of adolescent idiopathic scoliosis, as tested by two groups of surgeons, was shown to be much more reliable than the King system. Additional studies are necessary to determine the versatility, reliability, and accuracy of the classification for defining the vertebrae to be included in an arthrodesis.


Polymerization stress of dental resin composite continues to develop 12 hours after irradiation.
This study assessed the development of stress from polymerization of light-cured dental resin composites for 24 hours after irradiation. Initial cracks were made near the edge of a cylindrical hole in glass, and crack lengths were measured. Revolution Formula 2, Kalore and Venus Diamond were polymerized in the hole. Crack lengths were measured at several intervals after irradiation up to 24 hours. Stresses at the composite-glass interface were calculated using the crack lengths. Elastic moduli of the composites were measured at the same time intervals. Interfacial stress and elastic modulus were significantly related to material and time. Stress continued to increase up to 12 hours after irradiation. Significantly lower stresses were measured in Kalore and Venus Diamond than Revolution Formula 2 throughout 24 hours. Stress at 24 hours was two times greater than the stress at 30 minutes. The increase in elastic modulus from 30 minutes to 24 hours ranged from 8 to 24%, which was less than the increase in stress over the same time period. Interfacial stress and elastic modulus of the composites demonstrated the average increases of 155% and 14%, respectively, from 30 minutes to 24 hours after irradiation. Since the elastic modulus is a measure of stiffness and resistance to load, clinicians might consider advising their patients to avoid heavy occlusal function until the elastic modulus has reached a plateau, which would be 60 minutes for Venus Diamond, 12 hours for Kalore, and 24 hours for Revolution Formula 2.


Special topic section: linkages among cerebrovascular, cardiovascular, and cognitive disorders: Preventing dementia by preventing stroke: The Berlin Manifesto.
The incidence of stroke and dementia are diverging across the world, rising for those in low-and middle-income countries and falling in those in high-income countries. This suggests that whatever factors cause these trends are potentially modifiable. At the population level, neurological disorders as a group account for the largest proportion of disability-adjusted life years globally (10%). Among neurological disorders, stroke (42%) and dementia (10%) dominate. Stroke and dementia confer risks for each other and share some of the same, largely modifiable, risk and protective factors. In principle, 90% of strokes and 35% of dementias have been estimated to be preventable. Because a stroke doubles the chance of developing dementia and stroke is more common than dementia, more than a third of dementias could be prevented by preventing stroke. Developments at the pathological, pathophysiological, and clinical level also point to new directions. Growing understanding of brain pathophysiology has unveiled the reciprocal interaction of cerebrovascular disease and neurodegeneration identifying new therapeutic targets to include protection of the endothelium, the blood-brain barrier, and other components of the neurovascular unit. In addition, targeting amyloid angiopathy aspects of inflammation and genetic manipulation hold new testable promise. In the meantime, accumulating evidence suggests that whole populations experiencing improved education, and lower vascular risk factor profiles (e.g., reduced prevalence of smoking) and vascular disease, including stroke, have better cognitive function and lower dementia rates. At the individual levels, trials have demonstrated that anticoagulation of atrial fibrillation can reduce the risk of dementia by 48% and that systolic blood pressure lower than 140 mmHg may be better for the brain. Based on these considerations, the World Stroke Organization has issued a proclamation, endorsed by all the major international organizations focused on global brain and cardiovascular health, calling for the joint prevention of stroke and dementia. This article summarizes the evidence for translation into action. © 2019 the Alzheimer's Association and the World Stroke Organisation. Published by Elsevier Inc. All rights reserved.


Microduplication of Xq24 and Hartsfield syndrome with holoprosencephaly, ectrodactyly, and clefting.
The combination of holoprosencephaly and ectrodactyly, also known as Hartsfield syndrome, represents a unique genetic entity. An X-linked recessive mode of transmission has been suggested for this condition based on the observation that male patients have preferentially been affected. Thus far, no candidate genes have been suggested on the X chromosome. We report a male patient with a full-blown Hartsfield syndrome phenotype who had microduplication at Xq24 involving four genes. He presented with bilateral ectrodactyly of the hands (both hands had four fingers with a deep gap between the 2nd and 3rd digits), cleft lip and palate, and a depressed nasal bridge. Magnetic resonance imaging of the brain revealed lobar holoprosencephaly. His G-banded karyotype was normal. Array comparative genomic hybridization (CGH) using the Agilent 244K Whole Human Genome CGH array revealed a microduplication at Xq24 of 210 kb. Parental testing revealed that the deletion was derived from the asymptomatic mother. Of the genes on the duplicated interval, the duplications of SLC25A43 and SLC25A5 appeared to be the most likely to explain the patient's phenotype. From a clinical standpoint, it is important to point out that the propositus, who performs relatively well with holoprosencephaly and has a developmental quotient around 70, has survived multiple life-threatening episodes of hypernatremia. Awareness of the risk of hypernatremia is of great importance for the anticipatory management of patients with ectrodactyly and an oral cleft, even in the absence of overt hypotelorism.


Differential equation for normal glass dispersion and evaluation of the secondary spectrum.
Some of the questions concerning secondary chromatic aberration at both sides of the visible band of the spectrum are the following: (1) What is the bandwidth at different wavelengths, given the permissible chromatic aberration circle and the lens aperture? (2) What is the size of the chromatic aberration circle, given the wavelength, the bandwidth, and the lens aperture? The answers to these and other questions may be found with the new definitions of V-number and relative partial dispersion P based on infinitesimal bandwidths that we propose. In addition, an alignment chart for the secondary color of a normal glass doublet is presented, so fast answers to the questions posed above and to other questions concerned with secondary color can be found. In addition, a continual challenge in computer-aided lens design is the use of optical glasses as design parameters in simultaneous optimization of lens systems over various regions of the spectrum. This problem could be solved if we could find an ideal glass family, not too different from real glasses, such that, given the refractive index n and the V-number at any wavelength, the indices at all wavelengths could be determined. Therefore we derive a differential equation for normal glass dispersion and present a recursive solution.


The ghosts of predators past: population cycles and the role of maternal programming under fluctuating predation risk.
Maternal effects may be a major factor influencing the demography of populations. In mammals, the transmission of stress hormones between mother and offspring may play an important role in these effects. Laboratory studies have shown that stressors during pregnancy and lactation result in lifelong programming of the offspring phenotype. However, the relevance of these studies to free-living mammals is unclear. The 10-year snowshoe hare (Lepus americanus) cycle is intimately linked to fluctuating predation pressure and predation risk. The enigma of these cycles is the lack of population growth following the decline phase, when the predators have virtually all disappeared and the food supply is ample. We have shown that a predator-induced increase in maternal stress hormone levels resulted in a decline in reproduction. Here we examine population and hormone changes over a four-year period from the increase (2005) to the decline (2008). We report (1) that an index of maternal stress (fecal corticosteroid metabolite [FCM] concentrations) fluctuates in synchrony with predator density during the breeding season; (2) that maternal FCM levels are echoed in their offspring, and this occurs at a population-wide level; and (3) that higher maternal FCM levels at birth are correlated with an increased responsiveness of the hypothalamic-pituitary-adrenal (HPA) axis in their progeny. Our results show an intergenerational inheritance of stress hormones in a free-ranging population of mammals. We propose that the lack of recovery of reproductive rates during the early low phase of the hare cycle may be the result of the impacts of intergenerational, maternally inherited stress hormones caused by high predation risk during the decline phase.


A Thyroid Hormone-Independent Molecular Fingerprint of 3,5-Diiodothyronine Suggests a Strong Relationship with Coffee Metabolism in Humans.
Background: In numerous studies based predominantly on rodent models, administration of 3,5-diiodo-L-thyronine (3,5-T2), a metabolite of the thyroid hormones (TH) thyroxine (T4) and triiodo-L-thyronine (T3), was reported to cause beneficial health effects, including reversal of steatohepatosis and prevention of insulin resistance, in most instances without adverse thyrotoxic side effects. However, the empirical evidence concerning the physiological relevance of endogenously produced 3,5-T2 in humans is comparatively poor. Therefore, to improve the understanding of 3,5-T2-related metabolic processes, we performed a comprehensive metabolomic study relating serum 3,5-T2 concentrations to plasma and urine metabolite levels within a large general population sample. Methods: Serum 3,5-T2 concentrations were determined for 856 participants of the population-based Study of Health in Pomerania-TREND (SHIP-TREND). Plasma and urine metabolome data were generated using mass spectrometry and nuclear magnetic resonance spectroscopy, allowing quantification of 613 and 578 metabolites in plasma and urine, respectively. To detect thyroid function-independent significant 3,5-T2-metabolite associations, linear regression analyses controlling for major confounders, including thyrotropin and free T4, were performed. The same analyses were carried out using a sample of 16 male healthy volunteers treated for 8 weeks with 250 μg/day levothyroxine to induce thyrotoxicosis. Results: The specific molecular fingerprint of 3,5-T2 comprised 15 and 73 significantly associated metabolites in plasma and urine, respectively. Serum 3,5-T2 concentrations were neither associated with classical thyroid function parameters nor altered during experimental thyrotoxicosis. Strikingly, many metabolites related to coffee metabolism, including caffeine and paraxanthine, formed the clearest positively associated molecular signature. Importantly, these associations were replicated in the experimental human thyrotoxicosis model. Conclusion: The molecular fingerprint of 3,5-T2 demonstrates a clear and strong positive association of the serum levels of this TH metabolite with plasma levels of compounds indicating coffee consumption, therefore pointing to the liver as an organ, the metabolism of which is strongly affected by coffee. Furthermore, 3,5-T2 serum concentrations were found not to be directly TH dependent. Considering the beneficial health effects of 3,5-T2 administration observed in animal models and those of coffee consumption demonstrated in large epidemiological studies, one might speculate that coffee-stimulated hepatic 3,5-T2 production or accumulation represents an important molecular link in this connection.


Enhanced dewaterability of sewage sludge with zero-valent iron-activated persulfate oxidation system.
The potential benefits of zero-valent iron-activated persulfate (Na2S2O8) oxidation in enhanced dewaterability of sludge, along with the associated mechanisms were investigated in this study. The sludge dewaterability was evaluated in terms of specific resistance to filtration (SRF) and water content. Based on these indexes, it was observed that ZVI-S2O8(2) oxidation effectively improved sludge dewaterability. The optimal conditions to give preferable dewaterability were found when the molar ratio of ZVI/S2O8(2-) was 5:1 and pH value was 3.0. The most important mechanism was proposed to be the degradation of extracellular polymeric substances (EPS) incorporated in sludge flocs and rupture of microbial cells. Three-dimensional excitation-emission matrix fluorescence spectra revealed that the powerful SO4- and ·OH generated from ZVI-S2O8(2-) system destroyed the particular functional groups of fluorescing substances (aromatic protein-like and tryptophan protein-like substances), resulting in the release of bound water and the subsequent enhancement of dewaterability. Therefore, ZVI/S2O8(2-) oxidation is an alternative approach showing great potential to be applied in sludge treatment plants.


'Worth the test?' Pragmatism, pill testing and drug policy in Australia.
Recent deaths of young Australian music festival attendees from 'party-drug' overdoses have sparked debate about the effectiveness of drug policies. Australia is widely lauded for its harm minimisation approach to drugs, and yet, over the last 30 years, it can be argued its policies have been fragmented, sometimes inconsistent and contradictory. The present article examines the root of this inconsistency, using it as a foundation to advocate for drug policy reform. In keeping with the goals of the National Drug Strategy to promote policy innovation, there is an opportunity to learn from international studies which have shown promising findings in the reduction of party-drug use and its harms through application of pill testing. This paper evaluates Australia's National Drug Strategy and pill testing through a lens of pragmatism, to determine whether there is space for testing practices in contemporary policy. Specifically, the paper analyses current drug policy literature and research studies, examining a range of key drug use indicators, social and political debate and research evidence. The need for policy reform, attitudinal and cultural shifts and development of stronger cross-sectoral partnerships is highlighted, to ensure a rational and logical approach that genuinely tackles drug policy-making and strategy from a broad public health perspective. Using a theoretical frame of pragmatism and drawing from national and international research evidence, this paper recommends the integration of pill testing into Australia's harm minimisation strategy.


Molecular evolution of Vibrio pathogenicity island-2 (VPI-2): mosaic structure among Vibrio cholerae and Vibrio mimicus natural isolates.
Vibrio cholerae is a Gram-negative rod that inhabits the aquatic environment and is the aetiological agent of cholera, a disease that is endemic in much of Southern Asia. The 57.3 kb Vibrio pathogenicity island-2 (VPI-2) is confined predominantly to toxigenic V. cholerae O1 and O139 serogroup isolates and encodes 52 ORFs (VC1758 to VC1809), which include homologues of an integrase (VC1758), a restriction modification system, a sialic acid metabolism gene cluster (VC1773-VC1783), a neuraminidase (VC1784) and a gene cluster that shows homology to Mu phage. In this study, a 14.1 kb region of VPI-2 comprising ORFs VC1773 to VC1787 was identified by PCR and Southern blot analyses in all 17 Vibrio mimicus isolates examined. The VPI-2 region in V. mimicus was inserted adjacent to a serine tRNA similar to VPI-2 in V. cholerae. In 11 of the 17 V. mimicus isolates examined, an additional 5.3 kb region encoding VC1758 and VC1804 to VC1809 was present adjacent to VC1787. The evolutionary history of VPI-2 was reconstructed by comparative analysis of the nanH (VC1784) gene tree with the species gene tree, deduced from the housekeeping gene malate dehydrogenase (mdh), among V. cholerae and V. mimicus isolates. Both gene trees showed an overall congruence; on both gene trees V. cholerae O1 and O139 serogroup isolates clustered together, whereas non-O1/non-O139 serogroup isolates formed separate divergent branches with similar clustering of strains within the branches. One exception was noted: on the mdh gene tree, V. mimicus sequences formed a distinct divergent lineage from V. cholerae sequences; however, on the nanH gene tree, V. mimicus clustered with V. cholerae non-O1/non-O139 isolates, suggesting horizontal transfer of this region between these species.


The economics of primary prevention of cardiovascular disease - a systematic review of economic evaluations.
In the quest for public and private resources, prevention continues to face a difficult challenge in obtaining tangible public and political support. This may be partly because the economic evidence in favour of prevention is often said to be largely missing. The overall aim of this paper is to examine whether economic evidence in favour of prevention does exist, and if so, what its main characteristics, weaknesses and strengths are. We concentrate on the evidence regarding primary prevention that targets cardiovascular disease event or risk reduction. We conducted a systematic literature review of journal articles published during the period 1995-2005, based on a comprehensive key-word based search in generic and specialized electronic databases, accompanied by manual searches of expert databases. The search strategy consisted of combinations of freetext and keywords related to economic evaluation, cardiovascular diseases, and primary preventive interventions of risk assessment or modification. A total of 195 studies fulfilled all of the relevant inclusion criteria. Overall, a significant amount of relevant economic evidence in favour of prevention does exist, despite important remaining gaps. The majority of studies were cost-effectiveness-analyses, expressing benefits as "life years gained", were conducted in a US or UK setting, assessed clinical prevention, mainly drugs targeted at lowering lipid levels, and referred to subjects aged 35-64 years old with at least one risk factor. First, this review has demonstrated the obvious lack of economic evaluations of broader health promotion interventions, when compared to clinical prevention. Second, the clear role for government to engage more actively in the economic evaluation of prevention has become very obvious, namely, to fill the gap left by private industry in terms of the evaluation of broader public health interventions and regarding clinical prevention, in light of the documented relationship between study funding and reporting of favourable results. Third, the value of greater adherence to established guidelines on economic evaluation cannot be emphasised enough. Finally, there appear to be certain methodological features in the practice of economic evaluations that might bias the choice between prevention and cure in favour of the latter.


Division of labor among oxidoreductases: TMX1 preferentially acts on transmembrane polypeptides.
The endoplasmic reticulum (ER) is the site of maturation for secretory and membrane proteins in eukaryotic cells. The lumen of the mammalian ER contains >20 members of the protein disulfide isomerase (PDI) superfamily, which ensure formation of the correct set of intramolecular and intermolecular disulfide bonds as crucial, rate-limiting reactions of the protein folding process. Components of the PDI superfamily may also facilitate dislocation of misfolded polypeptides across the ER membrane for ER-associated degradation (ERAD). The reasons for the high redundancy of PDI family members and the substrate features required for preferential engagement of one or the other are poorly understood. Here we show that TMX1, one of the few transmembrane members of the family, forms functional complexes with the ER lectin calnexin and preferentially intervenes during maturation of cysteine-containing, membrane-associated proteins while ignoring the same cysteine-containing ectodomains if not anchored at the ER membrane. As such, TMX1 is the first example of a topology-specific client protein redox catalyst in living cells.


Parallel and competitive pathways for substrate desaturation, hydroxylation, and radical rearrangement by the non-heme diiron hydroxylase AlkB.
A purified and highly active form of the non-heme diiron hydroxylase AlkB was investigated using the diagnostic probe substrate norcarane. The reaction afforded C2 (26%) and C3 (43%) hydroxylation and desaturation products (31%). Initial C-H cleavage at C2 led to 7% C2 hydroxylation and 19% 3-hydroxymethylcyclohexene, a rearrangement product characteristic of a radical rearrangement pathway. A deuterated substrate analogue, 3,3,4,4-norcarane-d(4), afforded drastically reduced amounts of C3 alcohol (8%) and desaturation products (5%), while the radical rearranged alcohol was now the major product (65%). This change in product ratios indicates a large kinetic hydrogen isotope effect of ∼20 for both the C-H hydroxylation at C3 and the desaturation pathway, with all of the desaturation originating via hydrogen abstraction at C3 and not C2. The data indicate that AlkB reacts with norcarane via initial C-H hydrogen abstraction from C2 or C3 and that the three pathways, C3 hydroxylation, C3 desaturation, and C2 hydroxylation/radical rearrangement, are parallel and competitive. Thus, the incipient radical at C3 either reacts with the iron-oxo center to form an alcohol or proceeds along the desaturation pathway via a second H-abstraction to afford both 2-norcarene and 3-norcarene. Subsequent reactions of these norcarenes lead to detectable amounts of hydroxylation products and toluene. By contrast, the 2-norcaranyl radical intermediate leads to C2 hydroxylation and the diagnostic radical rearrangement, but this radical apparently does not afford desaturation products. The results indicate that C-H hydroxylation and desaturation follow analogous stepwise reaction channels via carbon radicals that diverge at the product-forming step.


Medium pH-dependent redistribution of the urease of Helicobacter pylori.
Helicobacter pylori is an aetiological agent of gastric disease. Although the role of urease in gastric colonization of H. pylori has been shown, it remains unclear as to where urease is located in this bacterial cell. The purpose of this study was to define the urease-associated apparatus in the H. pylori cytoplasm. H. pylori was incubated at both a neutral and an acidic pH in the presence or absence of urea and examined by double indirect immunoelectron microscopy. The density of gold particles for UreA was greatest in the inner portion of the wild-type H. pylori cytoplasm at neutral pH but was greatest in the outer portion at acidic pH. This difference was independent of the presence of urea and was not observed in the ureI-deletion mutant. Also, the eccentric shift of urease in acidic pH was not observed in UreI. After a 2 day incubation period at acidic pH, it was observed that the urease gold particles in H. pylori assembled and were associated with UreI gold particles. Urease immunoreactivity shifted from the inner to the outer portion of H. pylori as a result of an extracellular decrease in pH. This shift was urea-independent and UreI-dependent, suggesting an additional role of UreI in urease-dependent acid resistance. This is the first report of the intracellular transport of molecules in bacteria in response to changes in the extracellular environment.


Safety of combination interferon alfa-2b/ribavirin therapy in chronic hepatitis C-relapsed and treatment-naive patients.
The coadministration of ribavirin with recombinant interferon alfa-2b (rIFN-alpha 2b) compared with rIFN-alpha 2b alone markedly enhanced sustained virologic response rates in relapsed and treatment-naive chronic hepatitis C patients. The potential for ribavirin to likewise exacerbate the adverse events associated with the alpha interferons is reviewed. The overall safety and tolerability of combination rIFN-alpha 2b/ribavirin therapy was evaluated in 2,089 patients treated in phase III clinical studies conducted in the United States and internationally. Serious adverse events were also evaluated on an interim basis in > 25,000 patients--a majority of whom were treated with combination therapy (open label)--treated worldwide in investigator-initiated studies. Patients in the phase III studies received 3 million International Units rIFN-alpha 2b three times per week by subcutaneous injection plus either ribavirin or placebo orally in divided daily doses of 1,000 or 1,200 mg for patients weighing < or = 75 or > 75 kg, respectively. Adverse event frequency and severity and dose modifications were recorded throughout the 24-week (relapse) or 48-week (naive) treatment period and 24-week follow-up period. Clinically significant adverse events included anemia and depression. There was no evidence that the adverse effects of alpha interferon (e.g., fatigue, depression, neutropenia) were exacerbated by ribavirin. Severe adverse events were limited due to strict adherence to dose-modification criteria; approximately 6% to 9% of patients discontinued combination therapy because of an adverse event. Clinically serious adverse events, dose reductions and discontinuations, and potential mechanisms of toxicity associated with rIFN-alpha 2b and ribavirin are examined.


Carbonylation of myosin heavy chains in rat heart during diabetes.
Cardiac inotropy progressively declines during diabetes mellitus. To date, the molecular mechanisms underlying this defect remain incompletely characterized. This study tests the hypothesis that ventricular myosin heavy chains (MHC) undergo carbonylation by reactive carbonyl species (RCS) during diabetes and these modifications contribute to the inotropic decline. Male Sprague-Dawley rats were injected with streptozotocin (STZ). Fourteen days later the animals were divided into two groups: one group was treated with the RCS blocker aminoguanidine for 6 weeks, while the other group received no treatment. After 8 weeks of diabetes, cardiac ejection fraction, fractional shortening, left ventricular pressure development (+dP/dt) and myocyte shortening were decreased by 9%, 16%, 34% and 18%, respectively. Ca(2+)- and Mg(2+)-actomyosin ATPase activities and peak actomyosin syneresis were also reduced by 35%, 28%, and 72%. MHC-alpha to MHC-beta ratio was 12:88. Mass spectrometry and Western blots revealed the presence of carbonyl adducts on MHC-alpha and MHC-beta. Aminoguanidine treatment did not alter MHC composition, but it blunted formation of carbonyl adducts and decreases in actomyosin Ca(2+)-sensitive ATPase activity, syneresis, myocyte shortening, cardiac ejection fraction, fractional shortening and +dP/dt induced by diabetes. From these new data it can be concluded that in addition to isozyme switching, modification of MHC by RCS also contributes to the inotropic decline seen during diabetes.


Safety trial of high-intensity focused ultrasound therapy for pancreatic cancer.
To evaluate the safety and clinical application of high-intensity focused ultrasound (HIFU) therapy for unresectable pancreatic cancer (PC). Thirty PC patients (16 cases in stage III and 14 cases in stage IV) with visualized pancreatic tumors were admitted for HIFU therapy as an optional local therapy in addition to systemic chemotherapy or chemoradiotherapy. Informed consent was obtained. This study began at the end of 2008 and was approved by the ethics committee of our hospital [Institutional Review Board (IRB): 890]. The HIFU device used was the FEP-BY02 (Yuande Bio-Medical Engineering, Beijing, China). The mean tumor size after HIFU therapy changed to 30.9 ± 1.7 mm from 31.7 ± 1.7 mm at pre-therapy. There were no significant changes in tumor size, mean number of treatment sessions (2.7 ± 0.1 mm), or mean total treatment time (2.4 ± 0.1 h). The rate of symptom relief effect was 66.7%. The effectiveness of primary lesion treatment was as follows: complete response, 0; partial response, 4; stable disease, 22; progressive disease, 4. Treatment after HIFU therapy included 2 operations, 24 chemotherapy treatments, and 4 best supportive care treatments. Adverse events occurred in 10% of cases, namely pseudocyst formation in 2 cases and mild pancreatitis development in 1. However, no severe adverse events occurred in this study. We suggest that HIFU therapy is safe and has the potential to be a new method of combination therapy for PC.


Altered gene expression in morphologically normal epithelial cells from heterozygous carriers of BRCA1 or BRCA2 mutations.
We hypothesized that cells bearing a single inherited "hit" in a tumor suppressor gene express an altered mRNA repertoire that may identify targets for measures that could delay or even prevent progression to carcinoma. We report here on the transcriptomes of primary breast and ovarian epithelial cells cultured from BRCA1 and BRCA2 mutation carriers and controls. Our comparison analyses identified multiple changes in gene expression, in both tissues for both mutations, which were validated independently by real-time reverse transcription-PCR analysis. Several of the differentially expressed genes had been previously proposed as cancer markers, including mammaglobin in breast cancer and serum amyloid in ovarian cancer. These findings show that heterozygosity for a mutant tumor suppressor gene can alter the expression profiles of phenotypically normal epithelial cells in a gene-specific manner; these detectable effects of "one hit" represent early molecular changes in tumorigenesis that may serve as novel biomarkers of cancer risk and as targets for chemoprevention.


PAM50 and Risk of Recurrence Scores for Interval Breast Cancers.
Breast cancers detected after a negative breast screening examination and prior to the next screening are referred to as interval cancers. These cancers generally have poor clinical characteristics compared with screen-detected cancers, but associations between interval cancer and genomic cancer characteristics are not well understood. Mammographically screened women diagnosed with primary invasive breast cancer from 1993 to 2013 (n = 370) were identified by linking the Carolina Breast Cancer Study and the Carolina Mammography Registry. Among women with a registry-identified screening mammogram 0 to 24 months before diagnosis, cancers were classified as screen-detected (N = 165) or interval-detected (N = 205). Using logistic regression, we examined the association of mode of detection with cancer characteristics (clinical, IHC, and genomic), overall, and in analyses stratified on mammographic density and race. Interval cancer was associated with large tumors [>2 cm; OR, 2.3; 95% confidence interval (CI), 1.5-3.7], positive nodal status (OR, 1.8; 95% CI, 1.1-2.8), and triple-negative subtype (OR, 2.5; 95% CI, 1.1-5.5). Interval cancers were more likely to have non-Luminal A subtype (OR, 2.9; 95% CI, 1.5-5.7), whereas screen-detected cancers tended to be more indolent (96% had low risk of recurrence genomic scores; 71% were PAM50 Luminal A). When stratifying by mammographic density and race, associations between interval detection and poor prognostic features were similar by race and density status. Strong associations between interval cancers and poor-prognosis genomic features (non-Luminal A subtype and high risk of recurrence score) suggest that aggressive tumor biology is an important contributor to interval cancer rates. Cancer Prev Res; 11(6); 327-36. ©2018 AACR.


Minimum five-year wear rate of metal-on-highly cross-linked polyethylene in primary total hip arthroplasty.
Highly cross-linked polyethylenes (PE) have been developed with encouraging results in terms of wear. Another body of the literature has indicated potential catastrophic failures related to reduced fatigue properties and oxidation. Each PE available on the market has its own processing characteristics. The aim of this retrospective study was to evaluate the minimum five-year wear properties of an original highly cross-linked PE in a consecutive series of primary THAs. Between August 2005 and December 2007, 80 patients with a mean age of 62.7 years were included. All patients had a 28-mm CoCr femoral head articulating with a highly cross-linked insert (Highcross®, Medacta SA) that was 100 Mrads gamma radiated, remelted at 150 °C, and ethylene oxide sterilized. The primary criterion for evaluation was the femoral head penetration, as measured by Hip Analysis Suite software. The steady state wear was also calculated. Functional results were evaluated according to the WOMAC score. Complete data were available for analysis in 67 patients at a mean follow-up of 5.5 years. The mean femoral head penetration was 0.128 ± 0.62 mm and the steady state wear was-0.025 ± 0.22 mm/year. The WOMAC score significantly decreased from 16.5 ± 5.93 pre-operatively to 4.12 ± 5.5 at the latest follow-up (p <0.001). The minimal five-year results of this retrospective study indicate that this particular highly cross-linked and remelted polyethylene had a low wear rate. Longer-term results are needed to warrant that these mid-term data will generate less osteolysis and resultant aseptic loosening.


Predicting growth conditions from internal metabolic fluxes in an in-silico model of E. coli.
A widely studied problem in systems biology is to predict bacterial phenotype from growth conditions, using mechanistic models such as flux balance analysis (FBA). However, the inverse prediction of growth conditions from phenotype is rarely considered. Here we develop a computational framework to carry out this inverse prediction on a computational model of bacterial metabolism. We use FBA to calculate bacterial phenotypes from growth conditions in E. coli, and then we assess how accurately we can predict the original growth conditions from the phenotypes. Prediction is carried out via regularized multinomial regression. Our analysis provides several important physiological and statistical insights. First, we show that by analyzing metabolic end products we can consistently predict growth conditions. Second, prediction is reliable even in the presence of small amounts of impurities. Third, flux through a relatively small number of reactions per growth source (∼10) is sufficient for accurate prediction. Fourth, combining the predictions from two separate models, one trained only on carbon sources and one only on nitrogen sources, performs better than models trained to perform joint prediction. Finally, that separate predictions perform better than a more sophisticated joint prediction scheme suggests that carbon and nitrogen utilization pathways, despite jointly affecting cellular growth, may be fairly decoupled in terms of their dependence on specific assortments of molecular precursors.


Textual practices in crafting bioethics cases.
Bioethics case reports generally treat aspects of moral fathomability, characterised and addressed in different ways. This paper reads the case as a textual model of scenarios and draws attention to its structure, narrative shape, linguistic register, and the effects of tone and temporality on reader expectation and responsiveness. Such textual elements of case composition reflect authorial purpose and influence the interpretation, including moral and ethical interpretation, of bioethics cases.


Effects of infection with Anguillicola crassus and simultaneous exposure with Cd and 3,3',4,4',5-pentachlorobiphenyl (PCB 126) on the levels of cortisol and glucose in European eel ( Anguilla anguilla ).
To investigate whether the stress response of European eels infected with Anguillicola crassus is influenced by environmental pollutants, experimentally infected eels were exposed to Cd and/or to 3,3', 4,4', 5-pentachlorobiphenyl (PCB 126). Serum cortisol and glucose concentrations of these eels were monitored over a period of 103 days and were compared with data from infected, unexposed eels as well as with data from uninfected eels. Additionally, the levels of cortisol were correlated with concentrations of Anguillicola-specific antibodies. All eels showed an initial increase of the cortisol levels until day 63. This general elevation of plasma cortisol is most likely due to handling stress, as all eels were repeatedly netted and afterwards inoculated with a feeding tube. At the end of the exposure period eels which were infected and those which were infected and simultaneously exposed to Cd and PCB showed significantly higher levels than the controls. The general course of serum glucose levels in eels resembled that of cortisol. Accordingly, Spearman correlation analysis revealed that an increase in serum cortisol concentrations is correlated with rising levels of glucose. With respect to immune-endocrine interactions a significant negative correlation between cortisol and anti-A. crassus antibodies was found. Our data show that A. crassus is the most potent stressor for European eels among the treatments tested within this study. This is important in terms of ecotoxicological studies as the main effects are caused by parasites rather than chemicals. Accordingly, effects of parasites on the physiological homeostasis of organisms must be considered in ecotoxicology. From the parasitological point of view our results suggest that probably as part of an unbalanced host-parasite interaction A. crassus evokes a strong cortisol response in A. anguilla, thereby suppressing the immune response which in turn enables the parasite to establish. The parasite-induced stress response in the newly adopted European eel might be one of the factors which contributes to the extremely effective colonizing strategy of A. crassus.


Deep sequencing reveals differences in the transcriptional landscapes of fibers from two cultivated species of cotton.
Cotton (Gossypium) fiber is the most prevalent natural product used in the textile industry. The two major cultivated species, G. hirsutum (Gh) and G. barbadense (Gb), are allotetraploids with contrasting fiber quality properties. To better understand the molecular basis for their fiber differences, EST pyrosequencing was used to document the fiber transcriptomes at two key development stages, 10 days post anthesis (dpa), representing the peak of fiber elongation, and 22 dpa, representing the transition to secondary cell wall synthesis. The 617,000 high quality reads (89% of the total 692,000 reads) from 4 libraries were assembled into 46,072 unigenes, comprising 38,297 contigs and 7,775 singletons. Functional annotation of the unigenes together with comparative digital gene expression (DGE) revealed a diverse set of functions and processes that were partly linked to specific fiber stages. Globally, 2,770 contigs (7%) showed differential expression (>2-fold) between 10 and 22 dpa (irrespective of genotype), with 70% more highly expressed at 10 dpa, while 2,248 (6%) were differentially expressed between the genotypes (irrespective of stage). The most significant genes with differential DGE at 10 dpa included expansins and lipid transfer proteins (higher in Gb), while at 22 dpa tubulins, cellulose, and sucrose synthases showed higher expression in Gb. DGE was compared with expression data of 10 dpa-old fibers from Affymetrix microarrays. Among 543 contigs showing differential expression on both platforms, 74% were consistent in being either over-expressed in Gh (242 genes) or in Gb (161 genes). Furthermore, the unigene set served to identify 339 new SSRs and close to 21,000 inter-genotypic SNPs. Subsets of 88 SSRs and 48 SNPs were validated through mapping and added 65 new loci to a RIL genetic map. The new set of fiber ESTs and the gene-based markers complement existing available resources useful in basic and applied research for crop improvement in cotton.


Simultaneous detection of recombinant DNA segments introduced into genetically modified crops with multiplex ligase chain reaction coupled with multiplex polymerase chain reaction.
We developed a multiplex polymerase chain reaction (PCR)-multiplex ligase chain reaction (LCR) (MPCR-MLCR) technique as a novel approach for the simultaneous detection of recombinant DNA segments (e.g., promoters, trait genes, and terminators) of genetically modified (GM) crops. With this technique, target DNA regions were amplified by multiplex PCR, the PCR products were then subjected to multiplex LCR as template DNAs, and the LCR products were then analyzed by polyacrylamide gel electrophoresis and subsequent fluorescent scanning. Seven recombinant DNA segments commonly introduced into some GM crop lines were selected as target DNA regions. In addition, another MPCR-MLCR system for the simultaneous detection of three endogenous DNA segments was designed as a positive control test. The specificity and sensitivity of the method were examined. The method allowed us to detect GM crops comprehensively and is expected to be utilized for efficient screening of GM crops into which any one of the seven recombinant DNA segments have been introduced, and for profiling the segments.


Strong polarization dependence in the optical transmission through a bull's eye with an elliptical sub-wavelength aperture.
Strong polarization dependence in the optical transmission through a bull's eye with a central elliptical aperture in a thin Au film is analyzed numerically by finite difference time domain (FDTD) method. Focusing on the impacts of the structural anisotropy, detailed investigation of polarization dependent enhanced optical transmission (EOT) of light is discussed in terms of the resonance intensity variations caused by the incident light polarization and the geometrical parameters of bull's eye. We found that the light polarized along the minor axis of the elliptic aperture has significantly larger EOT by more than three orders of magnitude than the other orthogonal polarization, which can be further utilized in polarized EOT devices.


Dialysis arthropathy: a clinical, biochemical, radiological and histological study of 36 patients.
Out of a population of 97 haemodialysis patients, 36 patients with dialysis arthropathy were identified. Dialysis arthropathy is a chronic symmetrical polyarthritis which affected 97 per cent of the patients who had been undergoing cuprophane haemodialysis for more than 10 years. It commonly affected the shoulders, hips, hands, knees and wrists, worsening with time and extending to other joints. Fifty-eight per cent of the patients complained of morning stiffness and 47 per cent complained of exacerbation of shoulder pain during or after haemodialysis. Half of the patients also suffered from carpal tunnel syndrome, which recurred and was associated with a long-lasting disability. The most common radiological abnormality was periarticular bone cysts, followed by articular erosions and a destructive spondyloarthropathy, but clinical symptoms were more common than radiological signs. Patients with dialysis arthropathy had a higher C-reactive protein level than patients without arthropathy (18.6 mg/l versus 11.4 mg/l), indicative of an inflammatory process. Some of the clinical manifestations of the disease correlated with levels of C-reactive protein and ferritin. Serum ferritin levels correlated strongly with the units of blood transfused in the past five years (RS = 0.83), and the logarithm of ferritin level correlated weakly with C-reactive protein (r = 0.32). Haemarthroses were documented in 19 per cent of patients. Mean serum beta 2-microglobulin was elevated in the patients with (57.3 mg/l) and without arthropathy (50.7 mg/l), and there was no difference in the parathormone or aluminium levels between these groups. Articular tissue was obtained in 25 patients; beta 2-microglobulin amyloid was present in 24. Larger deposits were present in the capsular tissue, and these appeared to replace collagen bundles in eight cases. Amyloid deposits replaced the lining layer in six cases. It is likely therefore that amyloid disrupts normal joint function by replacing normal joint tissue. Mild chronic synovitis with haemosiderin deposition were found in approximately 60 per cent of cases. These findings suggest that amyloid derived from beta 2-microglobulin has a primary role in the pathogenesis of dialysis arthropathy, but there was also evidence of inflammatory processes. It is suggested that iron overload or haemarthroses might contribute to the inflammation, but other factors, such as dialysis-related bioincompatibility reactions, may also have a role.


Performance of creatinine-based equations to estimate glomerular filtration rate with a methodology adapted to the context of drug dosage adjustment.
The Cockcroft-Gault (CG) creatinine-based equation is still used to estimate glomerular filtration rate (eGFR) for drug dosage adjustment. Incorrect eGFR may lead to hazardous over- or underdosing. In a cross-sectional analysis, CG was validated against measured GFR (mGFR) in 14 804 participants and compared with the Modification-of-Diet-in-Renal-Diseases (MDRD), Chronic-Kidney-Disease-Epidemiology (CKD-EPI), Lund-Malmö-Revised (LMR) and European-Kidney-Function-Consortium (EKFC) equations. Validation focused on bias, imprecision and accuracy (percentage of estimates within ±30% of mGFR, P30), overall and stratified for mGFR, age and body mass index at mGFR <60 mL/min, as well as classification in mGFR stages. The CG equation performed worse than the other equations, overall and in mGFR, age and BMI subgroups in terms of bias (systematic overestimation), imprecision and accuracy except for patients ≥65 years where bias and P30 were similar to MDRD and CKD-EPI, but worse than LMR and EKFC. In subjects with mGFR <60 mL/min and at BMI 18.5-25 kg/m2 , all equations performed similarly, and for BMI < 18.5 kg/m2 CG and LMR had the best results though all equations had poor P30-accuracy. At BMI ≥ 25 kg/m2 the bias of the CG increased with increasing BMI (+17.2 mL/min at BMI ≥ 40 kg/m2 ). The four more recent equations also classified mGFR stages better than CG. The CG equation showed poor ability to estimate GFR overall and in analyses stratified for mGFR, age and BMI. CG was inferior to correctly classify the patients in the mGFR staging compared to more recent creatinine-based equations.


The effects of the stereoisomers of the alpha 2-adrenergic agonist medetomidine on systemic and coronary hemodynamics in conscious dogs.
The alpha 2-adrenergic agonist medetomidine produces systemic hemodynamic effects that are mediated by both peripheral and central nervous system actions. The current investigation was designed to characterize coronary and systemic hemodynamic effects of the D- and L-stereoisomers of medetomidine in conscious, chronically instrumented dogs with and without autonomic nervous system blockade. Dogs were instrumented for measurement of aortic pressure, coronary blood flow velocity, cardiac output, left ventricular pressure, rate of change in pressure (dP/dt), and subendocardial systolic shortening. Administration of the D-isomer of medetomidine (doses of 1.25, 2.5, and 5.0 micrograms/kg, each administered over 10 min, with 60 min between doses) significantly altered systemic hemodynamics, in a biphasic fashion. A decrease in respiratory rate without change in arterial blood gas tensions occurred. With the 5 micrograms/kg dose of D-medetomidine, an initial pressor response was followed by secondary, significant (P less than 0.05), and dose-related decreases in heart rate (74 +/- 3 to 57 +/- 4 beats per min), mean arterial pressure (109 +/- 2 to 100 +/- 3 mmHg) and the rate-pressure product (10.5 +/- 0.4 to 7.0 +/- 0.5 beats.min-1.mmHg.10(3] accompanied by a reduction in plasma concentrations of norepinephrine. No changes in left ventricular end diastolic pressure or coronary blood flow velocity occurred. In contrast to the D-isomer, the L-isomer (1.25, 2.5 and 5.0 micrograms/kg) produced no changes in hemodynamics or plasma concentrations of norepinephrine. In dogs pretreated with hexamethonium (20 mg/kg), propranolol (2 mg/kg), and atropine methylnitrate (3 mg/kg) to produce autonomic nervous system blockade, D-medetomidine also produced an initial pressor response, but no secondary reduction in heart rate or arterial pressure occurred. The results indicate that the D-isomer of medetomidine is stereospecific for alterations in hemodynamics: the active D-isomer produces decreases in heart rate, arterial pressure, and the rate-pressure product via diminished sympathetic and/or augmented parasympathetic tone. This conclusion is supported by the absence of these changes after pharmacologic blockade of the autonomic nervous system.


Early [18F]FET-PET in Gliomas after Surgical Resection: Comparison with MRI and Histopathology.
The precise definition of the post-operative resection status in high-grade gliomas (HGG) is crucial for further management. We aimed to assess the feasibility of assessment of the resection status with early post-operative positron emission tomography (PET) using [18F]O-(2-[18F]-fluoroethyl)-L-tyrosine ([18F]FET). 25 patients with the suspicion of primary HGG were enrolled. All patients underwent pre-operative [18F]FET-PET and magnetic resonance imaging (MRI). Intra-operatively, resection status was assessed using 5-aminolevulinic acid (5-ALA). Imaging was repeated within 72 h after neurosurgery. Post-operative [18F]FET-PET was compared with MRI, intra-operative assessment and clinical follow-up. [18F]FET-PET, MRI and intra-operative assessment consistently revealed complete resection in 12/25 (48%) patients and incomplete resection in 6/25 cases (24%). In 7 patients, PET revealed discordant findings. One patient was re-resected. 3/7 experienced tumor recurrence, 3/7 died shortly after brain surgery. Early assessment of the resection status in HGG with [18F]FET-PET seems to be feasible.


Kawasaki disease presented with status epilepticus and diffusion MRI abnormalities in the subcortical white matter.
Kawasaki disease (KD) is an acute, self-limited vasculitis of unknown etiology that occurs predominantly in infants and young children. Encephalitis/encephalopathy is an extremely rare complication of KD. A previously healthy 8-month-old Japanese boy had a prolonged seizure after febrile illness for one day. On the fourth day, he had bilateral nonexudative conjunctivitis, changes in the extremities, rash and induration at the Bacillus Calmette-Guerin inoculation site. He was diagnosed with incomplete KD and treated with immunoglobulin. On the fifth day, he had cluster seizures. Brain magnetic resonance imaging (MRI) showed restricted diffusion in the left subcortical white matter, which was consistent with acute encephalopathy with biphasic seizures and late reduced diffusion (AESD). He was treated with controlled normothermia, pulseddose methylprednisolone, continuous infusion of midazolam, and edaravone. On the tenth day, he had a recurrent fever and was treated with a second course of immunoglobulin. Subsequently, he had defervescence, and the abnormal signal detected in the MRI disappeared. At the age of 11 months, he had normal growth and development for his age by the Denver Developmental Screening Test. It is necessary to consider AESD as the differential diagnosis of prolonged seizure in infants with KD. Brain MRI led to early diagnosis and intervention in our patient. The neurological prognosis of our patient was relatively good, but the prognosis of KD with AESD is unknown. To clarify this, further case accumulation is warranted.


Binary and ternary new water soluble copper(II) complexes of l-tyrosine and substituted 1,10-phenanthrolines: effect of substitution on DNA interactions and cytotoxicities.
Binary and ternary water soluble copper(II) complexes - [Cu(nphen)2(H2O)](NO3)2·H2O (1), [Cu(phen)2(H2O)](NO3)2 (2), [Cu(nphen)(l-tyr)(H2O)]NO3·2H2O (3), [Cu(phen)(tyr)(H2O)] NO3·2H2O (4) - and diquarternary salts of nphen and phen (nphen=5-nitro-1,10-phenanthroline, phen=1,10-phenanthroline and tyr=l-tyrosine) have been synthesized and characterized by CHN analysis, (1)H NMR, (13)C NMR and IR spectroscopy, thermal analysis and single crystal X-ray diffraction techniques. The CT-DNA binding properties of these compounds have been investigated by thermal denaturation measurements, absorption and emission spectroscopy. The supercoiled pUC19 plasmid DNA cleavage activity of these compounds has been explored by agarose gel electrophoresis. The cytotoxicity of these compounds against MCF-7, Caco-2, A549 cancer cells and BEAS-2B healthy cells was also studied by using XTT method. The complexes 1-4 exhibit significant high cytotoxicity with low IC50 values in compared with cisplatin. The effect of the substituents of phen and coordinated amino acid in the above complexes are presented and discussed.


Hartmann wave-front scanner.
A wave-front sensor is described that uses a programmable moving aperture to scan an incoming wave front. The position of the diffraction spot is recorded behind an objective lens with a two-dimensional sensor and gives an estimate of the local slope at the aperture position. Then the wave front is reconstructed by processing of the slope data. The device is basically a programmable Hartmann wave-front sensor. Compared with a microlens Shack-Hartmann wave-front sensor, its much longer focal length provides higher resolution, although real-time operation is lost. A practical implementation of the new scanner with a liquid-crystal television as the programmable aperture is presented.