Non-mass breast lesions on ultrasound: final outcomes and predictors of malignancy.
Background Breast cancer can present as non-mass lesions (NMLs) on ultrasound. However, knowledge of and understanding about NMLs are scarce. Purpose To retrospectively investigate the final outcomes of sonographic breast NMLs and determine the clinical and radiologic variables associated with malignancy Material and Methods In our radiologic database of breast ultrasound examinations between 2011 and 2014, we found 119 women with 121 NMLs with available histopathologic or sonographic follow-up (over 2 years) data. We collected the clinical variables (patient's age, symptoms, and mammographic density) and histopathologic data as well as radiologic variables (mammographic and ultrasound findings) after retrospective review by two radiologists, the authors of the current paper, in consensus. We classified the ultrasound findings according to distribution (focal, linear or segmental, and regional) and associated features (calcification, architectural distortion, and ductal changes) and analyzed the associations between variables and malignancy using the t test and χ2 test. Results Of the 121 NMLs, 88 (72.7%) were benign and 33 (27.3%) were malignant. Ductal carcinoma in situ (DCIS) (17/33, 51.5%) and invasive ductal cancer with or without DCIS (13/33, 39.4%) comprised the main malignancies, and malignancy was significantly associated with palpability ( P = 0.000). Mammographic findings and sonographic distribution and associated features were significantly different between benign and malignant lesions ( P = 0.000, P = 0.004, and P = 0.001, respectively). Malignant lesions showed more frequent calcifications combined with asymmetry ( P = 0.000) on mammography and linear-segmental distributions ( P = 0.001) and associated calcifications ( P = 0.019) or architectural distortions ( P = 0.015) on ultrasound. Conclusion Breast NMLs on ultrasound showed high risk of malignancy. Symptoms and mammographic and ultrasound findings can be possible predictors of malignancy in NMLs.


Heterogeneity in mammography use across the nation: separating evidence of disparities from the disproportionate effects of geography.
Mammography is essential for early detection of breast cancer and both reduced morbidity and increased survival among breast cancer victims. Utilization is lower than national guidelines, and evidence of a recent decline in mammography use has sparked concern. We demonstrate that regression models estimated over pooled samples of heterogeneous states may provide misleading information regarding predictors of health care utilization and that comprehensive cancer control efforts should focus on understanding these differences and underlying causal factors. Our study population includes all women over age 64 with breast cancer in the Surveillance Epidemiology and End Results (SEER) cancer registries, linked to a nationally representative 5% reference sample of Medicare-eligible women located in 11 states that span all census regions and are heterogeneous in racial and ethnic mix. Combining women with and without cancer in the sample allows assessment of previous cancer diagnosis on propensity to use mammography. Our conceptual model recognizes the interplay between individual, social, cultural, and physical environments along the pathways to health care utilization, while delineating local and more distant levels of influence among contextual variables. In regression modeling, we assess individual-level effects, direct effects of contextual factors, and interaction effects between individual and contextual factors. Pooling all women across states leads to quite different conclusions than state-specific models. Commuter intensity, community acculturation, and community elderly impoverishment have significant direct impacts on mammography use which vary across states. Minorities living in isolated enclaves with others of the same race/ethnicity may be either advantaged or disadvantaged, depending upon the place studied. Careful analysis of place-specific context is essential for understanding differences across communities stemming from different causal factors. Optimal policy interventions to change behavior (improve screening rates) will be as heterogeneous as local community characteristics, so no "one size fits all" policy can improve population health. Probability modeling with correction for clustering of individuals within multilevel contexts can reveal important differences from place to place and identify key factors to inform targeting of specific communities for further study.


Quantitative characterization of androgen receptor protein expression and cellular localization in circulating tumor cells from patients with metastatic castration-resistant prostate cancer.
Many current therapies for metastatic castration-resistant prostate cancer (mCRPC) are aimed at AR signaling; however, resistance to these therapies is inevitable. To personalize CRPC therapy in an individual with clinical progression despite maximal AR signaling blockade, it is important to characterize the status of AR activity within their cancer. Biopsies of bone metastases are invasive and frequently fail to yield sufficient tissue for further study. Evaluation of circulating tumor cells (CTCs) offers an alternative, minimally invasive mechanism to characterize and study late-stage disease. The goal of this study was to evaluate the utility of CTC interrogation with respect to the AR as a potential novel therapeutic biomarker in patients with mCRPC. Fifteen mL of whole blood was collected from patients with progressive, metastatic mCRPC, the mononuclear cell portion was isolated, and fluorescence-activated cell sorting (FACS) was used to isolate and evaluate CTCs. A novel protocol was optimized to use ImageStreamX to quantitatively analyze AR expression and subcellular localization within CTCs. Co-expression of AR and the proliferation marker Ki67 was also determined using ImageStreamX. We found inter-patient and intra-patient heterogeneity in expression and localization of AR. Increased AR expression and nuclear localization are associated with elevated co-expression of Ki-67, consistent with the continued role for AR in castration-resistant disease. Despite intra-patient heterogeneity, CTCs from patients with prior exposure to abiraterone had increased AR expression compared to CTCs from patients who were abiraterone-naïve. As our toolbox for targeting AR function expands, our ability to evaluate AR expression and function within tumor samples from patients with late-stage disease will likely be a critical component of the personalized management of advanced prostate cancer. AR expression and nuclear localization varies within patients and between patients; however it remains associated with markers of proliferation. This supports a molecularly diverse AR-centric pathobiology imparting castration-resistance.


Evidence For Long-Lasting Transgenerational Antiviral Immunity in Insects.
Transgenerational immune priming (TGIP) allows memory-like immune responses to be transmitted from parents to offspring in many invertebrates. Despite increasing evidence for TGIP in insects, the mechanisms involved in the transfer of information remain largely unknown. Here, we show that Drosophila melanogaster and Aedes aegypti transmit antiviral immunological memory to their progeny that lasts throughout generations. We observe that TGIP, which is virus and sequence specific but RNAi independent, is initiated by a single exposure to disparate RNA viruses and also by inoculation of a fragment of viral double-stranded RNA. The progeny, which inherit a viral DNA that is only a fragment of the viral RNA used to infect the parents, display enriched expression of genes related to chromatin and DNA binding. These findings represent a demonstration of TGIP for RNA viruses in invertebrates, broadly increasing our understanding of the immune response, host genome plasticity, and antiviral memory of the germline.


Driver age and vehicle engine size effects on fault and severity in young motorcyclists accidents.
This paper reports a study of the combined effect of driver age and engine size on accident severity and at-fault risk of young riders of two-wheelers. Data from the national accident database of Greece are used to calculate accident severity and relative fault risk rates. The induced exposure technique is applied due to the lack of exposure data. A log-linear analysis is then used to examine first- and second-order effects within three-variable groups. Accident severity modelling revealed a significant second-order interaction between severity, driver age and two-wheeler engine size. On the contrary, no second-order effects were identified in fault risk modelling. Moreover, a significant effect of driver age on accident fault risk was identified. The effect of engine size was not significant.


Predicting skin sensitisation using a decision tree integrated testing strategy with an in silico model and in chemico/in vitro assays.
There is a pressing need for non-animal methods to predict skin sensitisation potential and a number of in chemico and in vitro assays have been designed with this in mind. However, some compounds can fall outside the applicability domain of these in chemico/in vitro assays and may not be predicted accurately. Rule-based in silico models such as Derek Nexus are expert-derived from animal and/or human data and the mechanism-based alert domain can take a number of factors into account (e.g. abiotic/biotic activation). Therefore, Derek Nexus may be able to predict for compounds outside the applicability domain of in chemico/in vitro assays. To this end, an integrated testing strategy (ITS) decision tree using Derek Nexus and a maximum of two assays (from DPRA, KeratinoSens, LuSens, h-CLAT and U-SENS) was developed. Generally, the decision tree improved upon other ITS evaluated in this study with positive and negative predictivity calculated as 86% and 81%, respectively. Our results demonstrate that an ITS using an in silico model such as Derek Nexus with a maximum of two in chemico/in vitro assays can predict the sensitising potential of a number of chemicals, including those outside the applicability domain of existing non-animal assays.


The PRICE study (Protection Rest Ice Compression Elevation): design of a randomised controlled trial comparing standard versus cryokinetic ice applications in the management of acute ankle sprain [ISRCTN13903946].
Cryotherapy (the application of ice for therapeutic purposes) is one of the most common treatment modalities employed in the immediate management of acute soft tissue injury. Despite its widespread clinical use, the precise physiological responses to therapeutic cooling have not been fully elucidated, and effective evidence-based treatment protocols are yet to be established. Intermittent ice applications are thought to exert a significant analgesic effect. This could facilitate earlier therapeutic exercise after injury, potentially allowing for a quicker return to activity. The primary aim of the forthcoming study is therefore to examine the safety and effectiveness of combining intermittent ice applications with periods of therapeutic exercise in the first week after an acute ankle sprain. The study is a randomised controlled trial. 120 subjects with an acute grade I or grade II ankle sprain will be recruited from Accident & Emergency and a University based Sports Injury Clinic. Subjects will be randomised under strict double-blind conditions to either a standard cryotherapy (intermittent ice applications with compression) or cryokinetic treatment group (intermittent ice applications with compression and therapeutic exercise). After the first week, treatment will be standardised across groups. Assessor blinding will be maintained throughout the trial. Primary outcome will be function, assessed using the Lower Extremity Functional Scale (LEFS). Additional outcomes will include pain (10 cm Visual Analogue Scale), swelling (modified figure-of-eight method) and activity levels (activPALtrade mark physical activity monitor, PAL Technologies, Glasgow, UK). Diagnostic Ultrasound (Episcan-1-200 high frequency ultrasound scanning system, Longport International Ltd, PA) will also be used to assess the degree of soft tissue injury. After baseline assessment subjects will be followed up at 1, 2, 3 & 4 weeks post injury. All data will be analysed using repeated measures analysis of co-variance (ANCOVA). This paper describes the rationale and design of a randomised controlled trial which will examine the effectiveness of two different cryotherapy protocols in the early management of acute ankle sprain. ISRCTN13903946.


Chronic Endocrinopathies in Traumatic Brain Injury Disease.
The aim of this review was to explain the role played by pituitary hormonal deficiencies in the traumatic brain injury (TBI) disease process. Chronic dysfunction of the pituitary axis is observed in approximately 35% of individuals who sustain a moderate-to-severe TBI. The most common deficiency is that of growth hormone, followed by gonadotropin, cortisol, and thyroid. The medical, psychological, and psychiatric consequences of untreated hypopituitarism are extensive and can be devastating. Many of the consequences of a chronic symptomatic TBI have, in the past, been solely attributed to the brain injury per se. Analysis of the signs and symptoms of pituitary axis dysfunction suggests that many of these consequences can be attributed to post-traumatic hypopituitarism (PTH). PTH may well play a significant role in the progressive signs and symptoms that follow a chronic TBI.


Calmodulin reduces ouabain-sensitive ATPase of cardiac sarcolemmal membranes: high reduction in spontaneously hypertensive rats.
Calmodulin and calcium effects on cardiac ouabain-sensitive adenosine triphosphatase (ATPase) activity were studied in young spontaneously hypertensive rats (SHR) and in their normotensive control Wistar-Kyoto rats (WKY). Cardiac sarcolemmal membranes from SHR showed significantly higher ouabain-sensitive ATPase activity than membranes from WKY rats. This activity was unaffected by calmodulin or calcium alone. However, when both calmodulin and calcium were added, ouabain-sensitive activity was significantly reduced without changes in the total ATPase activity. The calcium-dependent calmodulin effect was dose-dependent and greater in SHR than in WKY membranes. An altered interaction between the calcium-calmodulin system and sodium handling by the plasma membrane in SHR may play a role in the pathogenesis of hypertension.


An Arabidopsis mutant with high cyclic electron flow around photosystem I (hcef) involving the NADPH dehydrogenase complex.
Cyclic electron flow (CEFI) has been proposed to balance the chloroplast energy budget, but the pathway, mechanism, and physiological role remain unclear. We isolated a new class of mutant in Arabidopsis thaliana, hcef for high CEF1, which shows constitutively elevated CEF1. The first of these, hcef1, was mapped to chloroplast fructose-1,6-bisphosphatase. Crossing hcef1 with pgr5, which is deficient in the antimycin A-sensitive pathway for plastoquinone reduction, resulted in a double mutant that maintained the high CEF1 phenotype, implying that the PGR5-dependent pathway is not involved. By contrast, crossing hcef1 with crr2-2, deficient in thylakoid NADPH dehydrogenase (NDH) complex, results in a double mutant that is highly light sensitive and lacks elevated CEF1, suggesting that NDH plays a direct role in catalyzing or regulating CEF1. Additionally, the NdhI component of the NDH complex was highly expressed in hcef1, whereas other photosynthetic complexes, as well as PGR5, decreased. We propose that (1) NDH is specifically upregulated in hcef1, allowing for increased CEF1; (2) the hcef1 mutation imposes an elevated ATP demand that may trigger CEF1; and (3) alternative mechanisms for augmenting ATP cannot compensate for the loss of CEF1 through NDH.


Multimerization properties of PiggyMac, a domesticated piggyBac transposase involved in programmed genome rearrangements.
During sexual processes, the ciliate Paramecium eliminates 25-30% of germline DNA from its somatic genome. DNA elimination includes excision of ∼45 000 short, single-copy internal eliminated sequences (IESs) and depends upon PiggyMac (Pgm), a domesticated piggyBac transposase that is essential for DNA cleavage at IES ends. Pgm carries a core transposase region with a putative catalytic domain containing three conserved aspartic acids, and a downstream cysteine-rich (CR) domain. A C-terminal extension of unknown function is predicted to adopt a coiled-coil (CC) structure. To address the role of the three domains, we designed an in vivo complementation assay by expressing wild-type or mutant Pgm-GFP fusions in cells depleted for their endogenous Pgm. The DDD triad and the CR domain are essential for Pgm activity and mutations in either domain have a dominant-negative effect in wild-type cells. A mutant lacking the CC domain is partially active in the presence of limiting Pgm amounts, but inactive when Pgm is completely absent, suggesting that presence of the mutant protein increases the overall number of active complexes. We conclude that IES excision involves multiple Pgm subunits, of which at least a fraction must contain the CC domain.


Identification of Peptide lv, a novel putative neuropeptide that regulates the expression of L-type voltage-gated calcium channels in photoreceptors.
Neuropeptides are small protein-like signaling molecules with diverse roles in regulating neural functions such as sleep/wake cycles, pain modulation, synaptic plasticity, and learning and memory. Numerous drugs designed to target neuropeptides, their receptors, or relevant pathways have been developed in the past few decades. Hence, the discovery and characterization of new neuropeptides and their functions have received considerable attention from scientific research. Computational bioinformatics coupled with functional assays are powerful tools to address the difficulties in discovering new bioactive peptides. In this study, a new bioinformatic strategy was designed to screen full length human and mouse cDNA databases to search for novel peptides. One was discovered and named peptide Lv because of its ability to enhance L-type voltage-gated calcium channel (L-VGCC) currents in retinal photoreceptors. Using matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS), peptide Lv was detected in the culture media, which indicated that it was secreted from 661W cells transfected with the gene. In vitro treatments with either glutathione S-transferase (GST) fusion peptide Lv or synthesized peptide Lv enhanced L-VGCC channel activities in cone photoreceptors. At the molecular level, peptide Lv stimulated cAMP production, enhanced phosphorylation of extracellular signal-regulated kinase (ERK), and increased the protein expression of L-VGCCα1 subunits in cone photoreceptors. Therefore, the biological activities of peptide Lv may be very important in the modulation of L-VGCC dependent neural plasticity.


Efficacy of Kinesio Taping and McConnell Taping Techniques in the Management of Anterior Knee Pain.
Anterior knee pain also known as patellofemoral pain syndrome is a frequently encountered musculoskeletal disorder that worsens with activity. The multifactorial etiology of patellofemoral pain syndrome alters lower-extremity mechanics, increasing patellofemoral joint stresses during weight-bearing tasks. Kinesio and McConnell tapings are often incorporated into the treatment, but their efficacy is still unclear. To test the efficacy of Kinesio taping, McConnell taping, and sham taping in improving knee mechanics and reducing pain during activity. Cross-sectional design. Clinical biomechanics laboratory. Ten participants (age: 20.3 [1.5] y, height: 169.9 [10.4] cm, and mass: 70.17 [13.1] kg) with anterior knee pain and no history of trauma. Three trials each of squat, drop jump, and step-down tasks with 3 taping conditions in a counterbalanced order. Two-dimensional motion capture data of lower-extremities in frontal and sagittal planes were recorded and analyzed using 3 iPads and Spark Motion® application. Pooled effect sizes (Hedges' g), 95% confidence intervals, and repeated-measures analysis of variance (P < .05) compared baseline and taping conditions during exercises for pain Visual Analog Scale and knee flexion in all exercises, hip abduction during step-down and drop jump, frontal plane projection during step-downs, and knee translation in sagittal plane during squats. Significant reductions in Visual Analog Scale were recorded during squats between tapes (F2.505,12.867 = 3.407, P = .04, Hedges' g = -0.70). Pairwise comparison showed a decrease in Visual Analog Scale for sham taping (mean difference = 1.14 cm, P = .01) and Kinesio taping (mean difference = 1.54 cm, P = .02) compared with baseline during squats. A variety of taping methods can potentially reduce perceived pain in individuals with patellofemoral pain syndrome, allowing clinicians to perform rehabilitation exercises. Sensory effects associated with short-term taping may be sufficient enough to modify knee pain acutely by afferent input blocking nocioceptive pain before the participants could adapt. Most interestingly, the sham taping technique demonstrated promise for enhancing functional outcomes, depending on the length of the tape and area covered.


Nutrigenomic and Nutritional Analyses Reveal the Effects of Pelleted Feeds on Asian Seabass (Lates calcarifer).
As nutrition-related expenses constitute the majority of the costs for aquaculture farms, it is essential for them to use feeds that provide an ideal combination of nutrients for the species of choice. In this study, the relative effect of consuming three different pelleted feeds (B, C and D) in comparison to frozen baitfish (A; control) were compared on juvenile Asian seabass (77.3 ± 22.4g) that were selected for increased growth rate over two generations. Our objectives were: 1) to evaluate the effects of different pelleted feeds based on overall physiological changes and nutritional quality of fillets; 2) improve our understanding of the underlying mechanisms with transcriptomic analysis; 3) if possible, identify the feed type that supports the growth of these fishes without substantially reducing the nutritional quality of fillet. The growth performance, fatty acid composition of fillet, hepatic histology and transcriptome of the fishes (Groups A-D) were analyzed. The majority of fatty acids of the fillets, except γ-linolenic acid (GLA, C18:3n6), correlated significantly with the respective diets. Asian seabass fed Feed C showed highest specific growth rate (SGR) and feed conversion efficiency (FCE) with closest histology and transcriptomic profile to control, but their fillet contained the highest n6/n3 ratio. When the liver-based transcriptomes were analyzed, a complex set of differentially expressed genes were detected between groups fed pelleted feeds and controls as well as among the pellet-fed groups themselves. Significant enrichment of genes with growth-related function tallied with the morphological data measured. When compared with control (Group A), 'Biosynthesis of unsaturated fatty acids' and 'Steroid biosynthesis' pathways were significantly enriched in pellet-fed groups. Reduced goblet cell numbers were observed in the gut of pellet-fed fish compared to controls and fads6 was found to be a suitable candidate gene to separate wild-caught Asian seabass, from pellet-fed ones. These results provide insights for researchers on the various effects of feeds on the biochemistry and global gene expression of the fish and potentially for seabass farms to make more informed feed choices.


Occupational exposure to diesel engine exhaust: a literature review.
Diesel exhaust (DE) is classified as a probable human carcinogen. Aims were to describe the major occupational uses of diesel engines and give an overview of personal DE exposure levels and determinants of exposure as reported in the published literature. Measurements representative of personal DE exposure were abstracted from the literature for the following agents: elemental carbon (EC), particulate matter (PM), carbon monoxide (CO), nitrogen oxide (NO), and nitrogen dioxide (NO(2)). Information on determinants of exposure was abstracted. In total, 3528 EC, 4166 PM, 581 CO, 322 NO, and 1404 NO(2) measurements were abstracted. From the 10,001 measurements, 32% represented exposure from on-road vehicles and 68% from off-road vehicles (30% mining, 15% railroad, and 22% others). Highest levels were reported for enclosed underground work sites in which heavy equipment is used: mining, mine maintenance, and construction (EC: 27-658 microg/m(3)). Intermediate exposure levels were generally reported for above-ground (semi-) enclosed areas in which smaller equipment was run: mechanics in a shop, emergency workers in fire stations, distribution workers at a dock, and workers loading/unloading inside a ferry (generally: EC<50 microg/m(3)). Lowest levels were reported for enclosed areas separated from the source, such as drivers and train crew, or outside, such as surface mining, parking attendants, vehicle testers, utility service workers, surface construction and airline ground personnel (EC<25 microg/m(3)). The other agents showed a similar pattern. Determinants of exposure reported for enclosed situations were ventilation and exhaust after treatment devices. Reported DE exposure levels were highest for underground mining and construction, intermediate for working in above-ground (semi-) enclosed areas and lowest for working outside or separated from the source. The presented data can be used as a basis for assessing occupational exposure in population-based epidemiological studies and guide future exposure assessment efforts for industrial hygiene and epidemiological studies.


Prevalence of physical and mental non-communicable diseases in Europe: findings from the European Social Survey (2014) special module on the social determinants of health.
Previous studies examining physical and mental non-communicable diseases (NCDs) in Europe have so far largely either focused on limited numbers of countries or on fairly limited ranges of NCDs, with mental health in particular often being ignored. This article has three aims: (i) To provide a recent, comprehensive overview of a broad range of NCDs across a range of countries in all European regions; (ii) To give an overview of measures of physical and mental health in the new special rotating module in the European Social Survey (ESS); and (iii) To offer the first comprehensive comparison of estimates on physical and mental NCDs across European countries in this new promising data source. We use data from the 7th wave of the ESS. Results are presented separately for men and women. All results were age-standardized by weighting up or down the unstandardized (crude) prevalence rates for 5-year age groups in each country to a common standard. We present pooled estimates for the combined cross-national sample as well as country-specific results. Overall, 74.1% of men and 79.7% of women reported at least one physical NCD. Across the 21 countries were observed that these percentages varied between 45.2% (for men in Hungary) and 91.6% (women in Finland). Serious depressive symptoms were reported by 10.2% of men and 18.8% of women, with percentages ranging between 6.2% (men in Ireland) and 30.9% (women in Portugal). A substantial share of Europeans experience the burden of NCDs, and the extent to which people report these conditions varies across countries. However, all physical and mental NCDs in this rotating module are reported by considerable percentages in each of the 21 country samples, which emphasizes that these conditions are not marginal phenomena but public health concerns.


Disposition of Cannabidiol Metabolites in Serum and Urine from Healthy Individuals Treated with Pharmaceutical Preparations of Medical Cannabis.
The use of cannabis flowering tops with standardized amounts of active phytocannabinoids was recently authorized in several countries to treat several painful pathological conditions. The acute pharmacological effects and disposition of Δ-9-tetrahydrocannabinol (THC), cannabidiol (CBD), their acidic precursors and THC metabolites after oil and decoction administration have been already described. In this study, the disposition of CBD metabolites: 7-carboxy-cannabidiol (7-COOH-CBD), 7-hydroxycannabidiol (7-OH-CBD), 6-α-hydroxycannabidiol (6-α-OH-CBD), and 6-β-hydroxycannabidiol (6-β-OH-CBD) in the serum and urine of healthy volunteers was presented. Thirteen healthy volunteers were administered 100 mL of cannabis decoction in the first experimental session and, after 15 days of washout, 0.45 mL of oil. Serum and urine samples were collected at different time points, and the CBD metabolites were quantified by ultra-high-performance liquid chromatography-tandem mass spectrometry. The most abundant serum metabolite was 7-COOH-CBD, followed by 7-OH-CBD, 6-β-OH-CBD, and6-α-OH-CBD, after decoction and oil. Both 7-OH-CBD and the 6-α-OH-CBD showed similar pharmacokinetic properties following administration of both cannabis preparations, whereas 7-COOH and 6-α-OH-CBD displayed a significant higher bioavailability after decoction consumption. All CBD metabolites were similarly excreted after oil and decoction intake apart from 6-α-OH-CBD, which had a significantly lower excretion after oil administration. The pharmacokinetic characterization of CBD metabolites is crucial for clinical practice since the cannabis herbal preparations are increasingly used for several pathological conditions.


The collapse of gene complement following whole genome duplication.
Genome amplification through duplication or proliferation of transposable elements has its counterpart in genome reduction, by elimination of DNA or by gene inactivation. Whether loss is primarily due to excision of random length DNA fragments or the inactivation of one gene at a time is controversial. Reduction after whole genome duplication (WGD) represents an inexorable collapse in gene complement. We compare fifteen genomes descending from six eukaryotic WGD events 20-450 Mya. We characterize the collapse over time through the distribution of runs of reduced paralog pairs in duplicated segments. Descendant genomes of the same WGD event behave as replicates. Choice of paralog pairs to be reduced is random except for some resistant regions of contiguous pairs. For those paralog pairs that are reduced, conserved copies tend to concentrate on one chromosome. Both the contiguous regions of reduction-resistant pairs and the concentration of runs of single copy genes on a single chromosome are evidence of transcriptional co-regulation, dosage sensitivity or other functional interaction constraining the reduction process. These constraints and their evolution over time show a consistent pattern across evolutionary domains and a highly reproducible pattern, as replicates, for the several descendants of a single WGD.


A light responsive two-component supramolecular hydrogel: a sensitive platform for the fabrication of humidity sensors.
The supramolecular assembly of anionic azobenzene dicarboxylate and cationic cetyltrimethylammonium bromide (CTAB) formed a stimuli responsive hydrogel with a critical gelation concentration (CGC) of 0.33 wt%. This self-sustainable two-component system was able to repair damage upon light irradiation. Moreover, it was successfully employed in the fabrication of highly sensitive humidity sensors for the first time.


Constitutive NF-kappaB and NFAT activation leads to stimulation of the BLyS survival pathway in aggressive B-cell lymphomas.
B-lymphocyte stimulator (BLyS), a relatively recently recognized member of the tumor necrosis factor ligand family (TNF), is a potent cell-survival factor expressed in many hematopoietic cells. BLyS binds to 3 TNF-R receptors, TACI, BCMA, BAFF-R, to regulate B-cell survival, differentiation, and proliferation. The mechanisms involved in BLYS gene expression and regulation are still incompletely understood. In this study, we examined BLYS gene expression, function, and regulation in B-cell non-Hodgkin lymphoma (NHL-B) cells. Our studies indicate that BLyS is constitutively expressed in aggressive NHL-B cells, including large B-cell lymphoma (LBCL) and mantle cell lymphoma (MCL), playing an important role in the survival and proliferation of malignant B cells. We found that 2 important transcription factors, NF-kappaB and NFAT, are involved in regulating BLyS expression through at least one NF-kappaB and 2 NFAT binding sites in the BLYS promoter. We also provide evidence suggesting that the constitutive activation of NF-kappaB and BLyS in NHL-B cells forms a positive feedback loop associated with lymphoma cell survival and proliferation. Our findings indicate that constitutive NF-kappaB and NFAT activations are crucial transcriptional regulators of the BLyS survival pathway in malignant B cells that could be therapeutic targets in aggressive NHL-B.


Comparison of waist-to-hip ratio and other obesity indices as predictors of cardiovascular disease risk in people with type-2 diabetes: a prospective cohort study from ADVANCE.
The aim of this study was to compare the strength of associations and discrimination capability of body mass index (BMI), waist circumference (WC) and waist-to-hip ratio (WHR) with cardiovascular disease risk in individuals with type-2 diabetes. Eleven thousand, one hundred and forty men and women were followed for a mean of 4.8 years. The Cox proportional hazard models were used to compute the hazard ratios and 95% confidence intervals (95% CI) for one standard deviation (SD) increase in baseline BMI (SD: 5 kg/m2), WC (SD: 13 cm) and WHR (SD: 0.08) with cardiovascular disease risk. After adjustment, hazard ratio (95% CI) for WC were 1.10 (1.03–1.18) for cardiovascular events, 1.13 (1.03–1.24) for coronary events, and 1.08 (0.98–1.19) for cardiovascular deaths. Estimates for WHR were 1.12 (1.05–1.19), 1.17 (1.08–1.28) and 1.19 (1.09–1.31). BMI was not related to any of these outcomes. Although the receiver operating characteristic curve could not differentiate between anthropometric variables (P values 0.24), the relative integrated discrimination improvement statistic showed an enhancement in the discrimination capabilities of models using WHR for cardiovascular outcomes, except for cerebrovascular events. Strengths of associations and discrimination statistics suggested that WHR was the best predictor of cardiovascular events and mortality in patients with type-2 diabetes and BMI the worst.


Dental implants in geriatric patients: a retrospective study of 47 cases.
To determine the overall success of dental implants placed in geriatric patients. Dental implants were placed in 47 geriatric patients who were 79 or more years of age at the time of the procedure. The study group was composed of 27 men and 20 women, with a median age of 89 years and a range of 79 to 99 years of age at the time of implant surgery. A total of 73 dental implants were placed in the maxilla and 87 dental implants placed in the mandible. All implants were restored with fixed implant-supported prostheses or removable implant-supported prostheses. Eleven of the patients underwent maxillary sinus augmentation with porous hydroxyapatite and platelet-rich plasma. Seven patients had their implants immediately loaded. A total of 160 dental implants were placed in the 47 geriatric patients. One hundred fifty-nine integrated successfully. In the case of the failed implant, the site was grafted and another implant was placed 5 months subsequent to the initial failure. This replacement implant integrated and has been in function for 6 months. The survival rate for dental implants placed in the maxilla was 99% and in the mandible was 100% in our geriatric population. Treatment with dental implants can be predictable and safe for the rapidly growing geriatric population. Geriatric patients who are medically stable are suitable candidates for osseointegrated implant surgery, which facilitates oral function, comfort, and quality of life. A review of the 47 geriatric patients treated supports the conclusion that dental implants can be successfully placed and restored with fixed implant-supported or removable implant-supported prostheses.


Characterization of the IE110 gene of herpes simplex virus type 1.
We have determined the DNA sequence of the herpes simplex virus type 1 (HSV-1) gene encoding the immediate early protein IE110, which is involved in transcriptional activation of later virus genes. The locations of the 5' and 3' termini of IE110 mRNA together with the positions of two introns, were identified. Examination of the DNA sequence suggested that translation starts at the first ATG after the 5' terminus of the mRNA, and that both introns occur in protein-coding sequence. The predicted IE110 polypeptide contains 775 amino acids, and has a molecular weight of 78452. It contains a cysteine-rich region resembling regions found in several proteins which interact functionally with DNA. An antiserum was raised to the predicted C terminal amino acid sequence of the IE110 polypeptide and was shown to immunoprecipitate the native protein from HSV-1-infected cell extracts. The functional importance of regions of the protein was evaluated by construction of frameshift and deletion mutants of a plasmid-borne IE110 gene. The mutants were tested for IE110 function by short-term transfection assays, and the results were correlated with the DNA sequence and RNA mapping studies.


Structure-function analysis and therapeutic efficacy of antibodies to fungal melanin for melanoma radioimmunotherapy.
Metastatic melanoma remains difficult to treat despite recent approvals of several new drugs. Recently we reported encouraging results of Phase I clinical trial of radiolabeled with 188Re murine monoclonal IgM 6D2 to melanin in patients with Stage III/IV melanoma. Subsequently we generated a novel murine IgG 8C3 to melanin. IgGs are more amenable to humanization and cGMP (current Good Manufacturing Practice) manufacturing than IgMs. We performed comparative structural analysis of melanin-binding IgM 6D2 and IgG 8C3. The therapeutic efficacy of 213Bi- and 188Re-labeled 8C3 and its comparison with anti-CTLA4 immunotherapy was performed in B16-F10 murine melanoma model. The primary structures of these antibodies revealed significant homology, with the CDRs containing a high percentage of positively charged amino acids. The 8C3 model has a negatively charged binding surface and significant number of aromatic residues in its H3 domain, suggesting that hydrophobic interactions contribute to the antibody-melanin interaction. Radiolabeled IgG 8C3 showed significant therapeutic efficacy in murine melanoma, safety towards healthy melanin-containing tissues and favorable comparison with the anti-CTLA4 antibody. We have demonstrated that antibody binding to melanin relies on both charge and hydrophobic interactions while the in vivo data supports further development of 8C3 IgG as radioimmunotherapy reagent for metastatic melanoma.


High-mobility Group Box Protein-1, Matrix Metalloproteinases, and Vitamin D in Keloids and Hypertrophic Scars.
Keloids and hypertrophic scars represent excessive wound healing involving high production of collagen by skin fibroblasts. This review focuses on the role of high-mobility group box protein-1 (HMGB-1), matrix metalloproteinases (MMPs), and vitamin D in these conditions. Although the role of HMGB-1 in keloids and hypertrophic scars is unclear, the effect of HMGB-1 on fibroblasts suggests a profibrotic role and a potential contribution to excessive scarring. MMPs contribute extensively to wound healing and characteristically degrade the extracellular matrix. MMP-1 is decreased in keloids and hypertrophic scars. However, other MMPs, including MMP-2, have been found to be increased and are thought to possibly contribute to keloid expansion through peripheral extracellular matrix catabolism. Many novel therapeutic approaches to keloids and hypertrophic scars target MMPs and aim to increase their levels and catabolic activity. The higher prevalence of keloids in darker skin types may partially be due to a tendency for lower vitamin D levels. The physiologically active form of vitamin D, 1,25(OH)2D3, inhibits the proliferation of keloid fibroblasts, and correlations between vitamin D receptor polymorphisms, such as the TaqI CC genotype, and keloid formation have been reported. Additionally, vitamin D may exert an antifibrotic effect partially mediated by MMPs. Here, we critically discuss whether keloid and hypertrophic scar formation could be predicted based on vitamin D status and vitamin D receptor polymorphisms. Specifically, the findings identified HMGB-1, MMPs, and vitamin D as potential avenues for further clinical investigation and potentially novel therapeutic approaches to prevent the development of keloids and hypertrophic scars.


MiR-27a functions as a tumor suppressor in acute leukemia by regulating 14-3-3θ.
MicroRNAs (miRs) play major roles in normal hematopoietic differentiation and hematopoietic malignancies. In this work, we report that miR-27a, and its coordinately expressed cluster (miR-23a∼miR-27a∼miR-24-2), was down-regulated in acute leukemia cell lines and primary samples compared to hematopoietic stem-progenitor cells (HSPCs). Decreased miR-23a cluster expression in some acute leukemia cell lines was mediated by c-MYC. Replacement of miR-27a in acute leukemia cell lines inhibited cell growth due, at least in part, to increased cellular apoptosis. We identified a member of the anti-apoptotic 14-3-3 family of proteins, which support cell survival by interacting with and negatively regulating pro-apoptotic proteins such as Bax and Bad, as a target of miR-27a. Specifically, miR-27a regulated 14-3-3θ at both the mRNA and protein levels. These data indicate that miR-27a contributes a tumor suppressor-like activity in acute leukemia cells via regulation of apoptosis, and that miR-27a and 14-3-3θ may be potential therapeutic targets.


Ecological routes of avian influenza virus transmission to a common mesopredator: an experimental evaluation of alternatives.
Wild raccoons have been shown to be naturally exposed to avian influenza viruses (AIV). However, the mechanisms associated with these natural exposures are not well-understood. We experimentally tested three alternative routes (water, eggs, and scavenged waterfowl carcasses) of AIV transmission that may explain how raccoons in the wild are exposed to AIV. Raccoons were exposed to 1) water and 2) eggs spiked with an AIV (H4N6), as well as 3) mallard carcasses experimentally inoculated with the same virus. Three of four raccoons exposed to the high dose water treatment yielded apparent nasal shedding of >10(2.0) PCR EID50 equivalent/mL. Little to no shedding was observed from the fecal route. The only animals yielding evidence of serologic activity during the study period were three animals associated with the high dose water treatment. Overall, our results indicate that virus-laden water could provide a natural exposure route of AIV for raccoons and possibly other mammals associated with aquatic environments. However, this association appears to be related to AIV concentration in the water, which would constitute an infective dose. In addition, strong evidence of infection was only detected in three of four animals exposed to a high dose (e.g., 10(5.0) EID50/mL) of AIV in water. As such, water-borne transmission to raccoons may require repeated exposures to water with high concentrations of virus.


Comparison of two different types of heat and moisture exchangers in ventilated patients.
To compare the efficacy of two different types of Heat and Moisture Exchangers (HME filters) in reducing transmission of infection from the patient to ventilator and vice versa and also its cost effectiveness. Randomized, controlled, double blind, prospective study. 60 patients admitted to the ICU from May 1, 2007 to July 31, 2007 of either sex, age ranging between 20 and 60 years, requiring mechanical ventilation were screened for the study. Following intubation of the patients, the HME device was attached to the breathing circuit randomly by the chit-in-a box method. The patients were divided into two groups according to the HME filters attached. Both the groups were comparable with respect to age and sex ratio. In Type A HME filters, 80% showed growth on the patient end within 24 h and in 27% filters, culture was positive both on the patient and the machine ends. The organisms detected were Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa and co-related with the endotracheal aspirate culture. After 48 h, 87% filters developed organisms on the patient end, whereas 64% filters were culture positive both on the patient and the machine end. In Type B HME filters, 70% showed growth on patient's end after 24 h. Organisms detected were S. aureus, E. coli, P. aeruginosa and Acinetobacter. Thirty percent of filters were culture negative on both the patient and machine ends. No growth was found on the machine end in any of the filters after 24 h. After 48 h, 73% of the filters had microbial growth on the patient end, whereas only 3% filters had growth (S. aureus) on the machine end only. Seven percent had growth on both the patient as well as the machine ends. The microorganisms detected on the HME filters co-related with the endotracheal aspirate cultures. HME filter Type B (study group) was significantly better in reducing contamination of ventilator from the patient as compared to Type A (control group), which was routinely used in our ICU. Type B filter was found to be effective for at least 48 h. This study can also be applied to patients coming to emergency department (ED) and requiring emergency surgery and postoperative ventilation; and trauma patients like flail chest, head injury etc. requiring ventilatory support to prevent them from acquiring ventilator-associated pneumonia (VAP).


Beliefs About the Influence of Rest During Concussion Recovery May Predict Activity and Symptom Progression Within an Active Duty Military Population.
To evaluate relationships between beliefs about the impact of rest and the level of activities and symptoms over time among active duty Service members sustaining concussion, and whether these relationships vary by provision of concussion education. Longitudinal study using multilevel modeling to assess the relationship between beliefs about rest within 72 hours of concussion and change in activity and symptom level over time, as well as interaction by concussion education at the initial clinic visit. Three military treatment facilities. Study participants included active duty Service members diagnosed with a concussion (N=111; median age, 24 y). Individuals with previous history of concussion within 12 months of study enrollment were excluded. Not applicable. Activity questionnaire and the Neurobehavioral Symptom Inventory assessed within 72 hours of concussion; at 1 week; and at 1, 3, and 6 month(s) postinjury. Receipt of concussion education from providers was significantly associated with greater belief that rest influences concussion recovery. Greater belief that rest influences symptom recovery at the acute stage of concussion was associated with a greater increase in activities over time, but only among those who received education from their provider. Additionally, greater belief about the influence of rest was related to a more rapid decrease in symptoms over time. Concussed Service members who underestimate the influence of rest during acute recovery may be at risk for poorer recovery. Treatment of Service members with postconcussive symptoms should consider patient knowledge and/or beliefs about rest and recovery, which may influence prognosis. Our results support the provider's use of concussion education to correct potential misconceptions that may negatively impact symptom recovery.


Effects of ultrasound, shortwaves, and physical exertion on pregnancy outcome in physiotherapists.
The aim of the study was to investigate whether occupational exposure among physiotherapists is associated with spontaneous abortion or congenital malformation in the offspring. The study was a retrospective nested case-control study, where the pregnancy outcome data were based on the medical registers. All registered physiotherapists in Finland who had become pregnant during the study period were included in the study. Cases were defined as women who had been treated for spontaneous abortion during 1973-1983 or had delivered a malformed child during 1973-1982. One pregnancy per woman was randomly selected for the study. Three age matched (+/- 18 months) controls were selected for each abortion case and five for each malformation case. The final study population was 204 cases and 483 controls in the spontaneous abortion study, and 46 cases and 187 controls in the congenital malformation study. Exposure information was collected by mailed questionnaires from 1329 women. The response rate was 92% in the spontaneous abortion study, and 89% in the congenital malformation study. Heavy lifting (including patient transfers) was associated significantly with spontaneous abortion. Exposure to ultrasound and shortwaves showed about threefold odds ratios for spontaneous abortions occurring after the 10th week of gestation but in analysis where potential confounding variables were controlled, neither reached statistical significance. Deep heat therapies together, and shortwaves alone, were associated significantly with congenital malformations, but the increase was found in the lower exposure category only. From the potential confounding variables, previous abortion (spontaneous or induced) was associated significantly with spontaneous abortion, and febrile disease in early pregnancy was associated with congenital malformation. Physical exertion during early pregnancy seems to be a risk factor for spontaneous abortion. The findings raise suspicion of the potential harmful effect of shortwaves and ultrasound on the pregnancy, but no firm conclusion can be drawn on the bases of these results alone.


Agonists for the adenosine A1 receptor with tunable residence time. A Case for nonribose 4-amino-6-aryl-5-cyano-2-thiopyrimidines.
We report the synthesis and evaluation of previously unreported 4-amino-6-aryl-5-cyano-2-thiopyrimidines as selective human adenosine A1 receptor (hA1AR) agonists with tunable binding kinetics, this without affecting their nanomolar affinity for the target receptor. They show a very diverse range of kinetic profiles (from 1 min (compound 52) to 1 h (compound 43)), and their structure-affinity relationships (SAR) and structure-kinetics relationships (SKR) were established. When put in perspective with the increasing importance of binding kinetics in drug discovery, these results bring new evidence of the consequences of affinity-only driven selection of drug candidates, that is, the potential elimination of slightly less active compounds that may display preferable binding kinetics.


Local problems; local solutions: an innovative approach to investigating and addressing causes of maternal deaths in Zambia's Copperbelt.
Maternal mortality in developing countries is high and international targets for reduction are unlikely to be met. Zambia's maternal mortality ratio was 591 per 100,000 live births according to survey data (2007) while routinely collected data captured only about 10% of these deaths. In one district in Zambia medical staff reviewed deaths occurring in the labour ward but no related recommendations were documented nor was there evidence of actions taken to avert further deaths. The Investigate Maternal Deaths and Act (IMDA) approach was designed to address these deficiencies and is comprised of four components; identification of maternal deaths; investigation of factors contributing to the deaths; recommendations for action drawn up by multiple stakeholders and monitoring of progress through existing systems. A pilot was conducted in one district of Zambia. Maternal deaths occurring over a period of twelve months were identified and investigated. Data was collected through in-depth interviews with family, focus group discussions and hospital records. The information was summarized and presented at eleven data sharing meetings to key decision makers, during which recommendations for action were drawn up. An output indicator to monitor progress was included in the routine performance assessment tool. High impact interventions were identified using frequency analysis. A total of 56 maternal deaths were investigated. Poor communication, existing risk factors, a lack of resources and case management issues were the broad categories under which contributing factors were assigned. Sixty three recommendations were drawn up by key decision-makers of which two thirds were implemented by the end of the pilot period. Potential high impact actions were related to management of AIDS and pregnancy, human resources, referral mechanisms, birth planning at household level and availability of safe blood. In resource constrained settings the IMDA approach promotes the use of existing systems to reduce maternal mortality. In turn the capacity of local health officers to use data to determine, plan and implement relevant interventions that address the local factors contributing to maternal deaths is strengthened. Monitoring actions taken against the defined recommendations within the routine performance assessment ensures sustainability. Suggestions for further research are provided.


Lifetime history of indoor tanning in young people: a retrospective assessment of initiation, persistence, and correlates.
Despite educational and public health campaigns to convey the risks of indoor tanning, many individuals around the world continue to engage in this behavior. Few descriptive studies of indoor tanning have collected information pertaining to the lifetime history of indoor tanning, thereby limiting our ability to understand indoor tanning patterns and potentially target interventions for individuals who not only initiate, but continue to persistently engage in indoor tanning. In-person interviews elicited detailed retrospective information on lifetime history of indoor tanning among white individuals (n = 401) under age 40 seen by a dermatologist for a minor benign skin condition. These individuals were controls in a case-control study of early-onset basal cell carcinoma. Outcomes of interest included ever indoor tanning in both males and females, as well as persistent indoor tanning in females - defined as females over age 31 who tanned indoors at least once in the last three or all four of four specified age periods (ages 11-15, 16-20, 21-30 and 31 or older). Multivariate logistic regression was used to identify sociodemographic and lifestyle correlates of ever and persistent indoor tanning in females. Approximately three-quarters (73.3%) of females and 38.3% of males ever tanned indoors, with a median age of initiation of 17.0 and 21.5, respectively. Among indoor tanners, 39.3% of females and 21.7% of males reported being burned while indoor tanning. Female ever indoor tanners were younger, had darker color eyes, and sunbathed more frequently than females who never tanned indoors. Using unique lifetime exposure data, 24.7% of female indoor tanners 31 and older persistently tanned indoors starting as teenagers. Female persistent indoor tanners drank significantly more alcohol, were less educated, had skin that tanned with prolonged sun exposure, and sunbathed outdoors more frequently than non-persistent tanners. Indoor tanning was strikingly common in this population, especially among females. Persistent indoor tanners had other high-risk behaviors (alcohol, sunbathing), suggesting that multi-faceted behavioral interventions aimed at health promotion/disease prevention may be needed in this population.


Nonpharmacological interventions in long-term care: feasibility and recent trends.
Numerous studies have found excessive or in appropriate use of antipsychotic drugs in nursing home patients with cognitive impairment or perceived behavioral issues. Inappropriately medicating this vulnerable population can lead to several negative outcomes, including failure to have needs met, injury, illness, and even death. In response to recent literature and government reports highlighting this issue, in 2012, the Centers for Medicare and Medicaid Services (CMS) launched an initiative called the National Partnership to Improve Dementia Care. This article discusses the CMS initiative, as well as the feasibility and recent trends in the use of nonpharmacological interventions that could be implemented when working with patients with cognitive impairment and behavioral and psychological symptoms associated with dementia.


Nicotinamide adenine dinucleotide phosphate oxidase is differentially regulated in normal myometrium versus leiomyoma.
Uterine fibroids are the most common benign tumor in women. The goal of this study was to investigate whether nicotinamide adenine dinucleotide phosphate oxidase (NOX), a major source of superoxide and subsequent oxidative stress, was differentially regulated in myometrium versus leiomyoma. Expression levels of NOXs1-5, dual oxidase (DUOX), DUOX2, NOX organizer (NOXO) 1, NOX activator 1, p47(phox), p67(phox), and p22(phox) were determined in cells treated with hypoxia by real-time reverse transcription-polymerase chain reaction, Western blot, and immunohistochemistry in tissues. Expression of NOX4 increased in fibroid compared to myometrial tissues and cells. The NOX2, DUOX1, and p67(phox) were higher while p22(phox) was lower in fibroid than that in myometrial cells. Hypoxia increased NOX4, DUOX1, and NOXO1 and decreased p22(phox) in myometrial and reduced DUOX1 in fibroid cells. The NOX1, NOX3, NOX5, and DUOX2 were undetectable. Fibroid cells are characterized by a unique NOX profile, which promotes a severe prooxidant state that may be responsible for their development. Targeting these subunits may be beneficial for future therapeutic interventions.


Protective role of alpha-tocopherol and caffeic acid phenethyl ester on ischemia-reperfusion injury via nitric oxide and myeloperoxidase in rat kidneys.
The aim of this study was to determine the acute effects of antioxidant caffeic acid phenethyl ester (CAPE) and alpha-tocopherol (vitamin E) on nitric oxide (NO) production, neutrophil infiltration, and antioxidant enzyme activities on an in vivo model of renal ischemia-reperfusion injury. Rats were divided into five equal groups each consisting six rats: sham operation, ischemia, ischemia-reperfusion (I/R), I/R plus CAPE, and I/R plus vitamin E groups. CAPE or vitamin E was administered intraperitoneally before reperfusion. After experimental procedure, rats were sacrificed and both ipsilateral and contralateral kidneys were removed and prepared for NO concentrations, myeloperoxidase (MPO), catalase (CAT) and superoxide dismutase (SOD) activities. Acute administration of vitamin E decreased NO concentrations in both ipsilateral and contralateral renal tissues compared to I/R group. SOD activity was increased in I/R and I/R + CAPE groups compared to sham operation group. The most prominent results were encountered in MPO activities, which did not change in contralateral kidneys in both ischemia and I/R groups. There was a significant decrease in ipsilateral MPO activity in ischemia group and a significant increase in I/R group compared to sham operation group. Pretreatment with intraperitoneal CAPE significantly diminished the tissue MPO activity indicating the prevention of the neutrophil sequestration into the kidney. There is a role for CAPE in attenuation in renal damage after I/R injury of the kidney, in part at least by inhibition of neutrophil sequestration.


Admixture of hybrid swarms of native and introduced lizards in cities is determined by the cityscape structure and invasion history.
Introductions of non-native lineages increase opportunities for hybridization. Non-native lineages of the common wall lizard, Podarcis muralis, are frequently introduced in cities where they hybridize with native populations. We aimed at unravelling the invasion history and admixture of native and non-native wall lizards in four German cities using citywide, comprehensive sampling. We barcoded and genotyped 826 lizards and tested if gene flow in populations composed of admixed native and introduced lineages is facilitated by similar environmental factors to those in native populations by comparing fine-scale landscape genetic patterns. In cities with non-native lineages, lizards commonly occurred in numerous clusters of hybrid swarms, which showed variable lineage composition, consisting of up to four distinct evolutionary lineages. Hybrid swarms held vast genetic diversity and showed recent admixture with other hybrid swarms. Landscape genetic analyses showed differential effects of cityscape structures across cities, but identified water bodies as strong barriers to gene flow in both native and admixed populations. By contrast, railway tracks facilitated gene flow of admixed populations only. Our study shows that cities represent unique settings for hybridization, caused by multiple introductions of non-native taxa. Cityscape structure and invasion histories of cities will determine future evolutionary pathways at these novel hybrid zones.


Expanded ataxin-7 cause toxicity by inducing ROS production from NADPH oxidase complexes in a stable inducible Spinocerebellar ataxia type 7 (SCA7) model.
Spinocerebellar ataxia type 7 (SCA7) is one of nine inherited neurodegenerative disorders caused by polyglutamine (polyQ) expansions. Common mechanisms of disease pathogenesis suggested for polyQ disorders include aggregation of the polyQ protein and induction of oxidative stress. However, the exact mechanism(s) of toxicity is still unclear. In this study we show that expression of polyQ expanded ATXN7 in a novel stable inducible cell model first results in a concomitant increase in ROS levels and aggregation of the disease protein and later cellular toxicity. The increase in ROS could be completely prevented by inhibition of NADPH oxidase (NOX) complexes suggesting that ATXN7 directly or indirectly causes oxidative stress by increasing superoxide anion production from these complexes. Moreover, we could observe that induction of mutant ATXN7 leads to a decrease in the levels of catalase, a key enzyme in detoxifying hydrogen peroxide produced from dismutation of superoxide anions. This could also contribute to the generation of oxidative stress. Most importantly, we found that treatment with a general anti-oxidant or inhibitors of NOX complexes reduced both the aggregation and toxicity of mutant ATXN7. In contrast, ATXN7 aggregation was aggravated by treatments promoting oxidative stress. Our results demonstrates that oxidative stress contributes to ATXN7 aggregation as well as toxicity and show that anti-oxidants or NOX inhibition can ameliorate mutant ATXN7 toxicity.


Clinical Practice Guidelines From the AABB: Red Blood Cell Transfusion Thresholds and Storage.
More than 100 million units of blood are collected worldwide each year, yet the indication for red blood cell (RBC) transfusion and the optimal length of RBC storage prior to transfusion are uncertain. To provide recommendations for the target hemoglobin level for RBC transfusion among hospitalized adult patients who are hemodynamically stable and the length of time RBCs should be stored prior to transfusion. Reference librarians conducted a literature search for randomized clinical trials (RCTs) evaluating hemoglobin thresholds for RBC transfusion (1950-May 2016) and RBC storage duration (1948-May 2016) without language restrictions. The results were summarized using the Grading of Recommendations Assessment, Development and Evaluation method. For RBC transfusion thresholds, 31 RCTs included 12 587 participants and compared restrictive thresholds (transfusion not indicated until the hemoglobin level is 7-8 g/dL) with liberal thresholds (transfusion not indicated until the hemoglobin level is 9-10 g/dL). The summary estimates across trials demonstrated that restrictive RBC transfusion thresholds were not associated with higher rates of adverse clinical outcomes, including 30-day mortality, myocardial infarction, cerebrovascular accident, rebleeding, pneumonia, or thromboembolism. For RBC storage duration, 13 RCTs included 5515 participants randomly allocated to receive fresher blood or standard-issue blood. These RCTs demonstrated that fresher blood did not improve clinical outcomes. It is good practice to consider the hemoglobin level, the overall clinical context, patient preferences, and alternative therapies when making transfusion decisions regarding an individual patient. Recommendation 1: a restrictive RBC transfusion threshold in which the transfusion is not indicated until the hemoglobin level is 7 g/dL is recommended for hospitalized adult patients who are hemodynamically stable, including critically ill patients, rather than when the hemoglobin level is 10 g/dL (strong recommendation, moderate quality evidence). A restrictive RBC transfusion threshold of 8 g/dL is recommended for patients undergoing orthopedic surgery, cardiac surgery, and those with preexisting cardiovascular disease (strong recommendation, moderate quality evidence). The restrictive transfusion threshold of 7 g/dL is likely comparable with 8 g/dL, but RCT evidence is not available for all patient categories. These recommendations do not apply to patients with acute coronary syndrome, severe thrombocytopenia (patients treated for hematological or oncological reasons who are at risk of bleeding), and chronic transfusion-dependent anemia (not recommended due to insufficient evidence). Recommendation 2: patients, including neonates, should receive RBC units selected at any point within their licensed dating period (standard issue) rather than limiting patients to transfusion of only fresh (storage length: <10 days) RBC units (strong recommendation, moderate quality evidence). Research in RBC transfusion medicine has significantly advanced the science in recent years and provides high-quality evidence to inform guidelines. A restrictive transfusion threshold is safe in most clinical settings and the current blood banking practices of using standard-issue blood should be continued.


Screening for hepatitis C virus infection: a review of the evidence for the U.S. Preventive Services Task Force.
Hepatitis C virus (HCV) is the most common bloodborne pathogen in the United States and is an important cause of patient morbidity and mortality, but it is unclear whether screening to identify asymptomatic infected persons is appropriate. To synthesize the evidence on risks and benefits of screening for HCV infection. MEDLINE (through February 2003), Cochrane Clinical Trials Registry (2002, Issue 2), reference lists, and experts. Controlled studies of screening and antiviral therapy and observational studies on other interventions, risk factors, accuracy of antibody testing, work-up, harms of biopsy, and long-term outcomes. Using preset criteria, the authors assessed the quality of included studies and abstracted information about settings, patients, interventions, and outcomes. There are no published trials of screening for HCV infection. Approximately 2% of U.S. adults have HCV antibodies, with the majority having chronic infection. Risk factor assessment could identify adults at substantially higher risk. Antiviral treatment can result in a sustained virologic response rate of 54% to 56%, but no trials have been done specifically in asymptomatic patients likely to be identified by screening. Data are insufficient to determine whether treatment improves long-term outcomes. There are no data to estimate the benefit from counseling or immunizations. Although risks of biopsy and treatment appear minimal or self-limited, data on other adverse effects of screening, such as labeling or anxiety, are sparse. Antiviral treatment can successfully eradicate HCV, but data on long-term outcomes in populations likely to be identified by screening are lacking. Although the yield from targeted screening, particularly in intravenous drug users, would be substantially higher than in the general population, data are inadequate to accurately weigh the overall benefits and risks of screening in otherwise healthy asymptomatic adults.


Calonectria species associated with cutting rot of Eucalyptus.
Decline in the productivity of Eucalyptus hybrid cutting production in the Guangdong Province of China is linked to cutting rot associated with several Calonectria spp. The aim of this study was to identify these fungi using morphological and DNA sequence comparisons. Two previously undescribed Calonectria spp., Ca. pseudoreteaudii sp. nov. and Ca. cerciana sp. nov. were identified together with Ca. pauciramosa. Calonectria pseudoreteaudii resides in the Ca. reteaudii complex and Ca. cerciana is closely related to Ca. morganii. Connected to the discovery of Ca. pseudoreteaudii, species in the Ca. reteaudii complex were re-considered and the group is shown to accommodate two cryptic species. These originate from Australia and are described as Ca. queenslandica sp. nov. and Ca. terrae-reginae sp. nov.


Pleural Effusions After Congenital Cardiac Surgery Requiring Readmission: A Systematic Review and Meta-analysis.
Patients with congenital heart disease (CHD) are surviving longer thanks to improved surgical techniques and increasing knowledge of natural history. Pleural effusions continue to be a complication that affect many surgical patients and are associated with increased morbidity, many times requiring readmission and additional invasive procedures. The risks for development of pleural effusion after hospital discharge are ill-defined, which leads to uncertainty related to strategies for prevention. Our primary objective was to determine, in patients with CHD requiring cardiopulmonary bypass, the prevalence of post-surgical pleural effusions leading to readmission. The secondary objective was to identify risk factors associated with post-surgical pleural effusions requiring readmission. We identified 4417 citations; 10 full-text articles were included in the final review. Of the included studies, eight focused on single-ventricle palliation, one looked at Tetralogy of Fallot patients, and another on pleural effusion in the setting of post-pericardiotomy syndrome. Using a random-effect model, the overall prevalence of pleural effusion requiring readmission was 10.2% (95% CI 4.6; 17.6). Heterogeneity was high (I2 = 91%). In a subpopulation of patients after single-ventricle palliation, the prevalence was 13.0% (95% CI 6.0;21.0), whereas it was 3.0% (95% CI 0.4;6.75) in patients mostly with biventricular physiology. We were unable to accurately assess risk factors. A better understanding of this complication with a focus on single-ventricle physiology will allow for improved risk stratification, family counseling, and earlier recognition of pleural effusion in this patient population.


The moral bioenhancement of psychopaths.
We argue that the mandatory moral bioenhancement of psychopaths is justified as a prescription of social morality. Moral bioenhancement is legitimate when it is justified on the basis of the reasons of the recipients. Psychopaths expect and prefer that the agents with whom they interact do not have certain psychopathic traits. Particularly, they have reasons to require the moral bioenhancement of psychopaths with whom they must cooperate. By adopting a public reason and a Kantian argument, we conclude that we can justify to a psychopath being the recipient of mandatory moral bioenhancement because he has a reason to require the application of this prescription to other psychopaths.


The role(s) of lipophosphoglycan (LPG) in the establishment of Leishmania major infections in mammalian hosts.
The abundant cell surface glycolipid lipophosphoglycan (LPG) was implicated in many steps of the Leishmania infectious cycle by biochemical tests. The presence of other abundant surface or secreted glycoconjugates sharing LPG domains, however, has led to uncertainty about the relative contribution of LPG in vivo. Here we used an Leishmania major lpg1- mutant, which lacks LPG alone and shows attenuated virulence, to dissect the role of LPG in the establishment of macrophage infections in vivo. lpg1- was highly susceptible to human complement, had lost the ability to inhibit phagolysosomal fusion transiently, and was oxidant sensitive. Studies of mouse mutants defective in relevant defense mechanisms confirmed the role of LPG in oxidant resistance but called into question the importance of transient inhibition of phagolysosomal fusion for Leishmania macrophage survival. Moreover, the limited lytic activity of mouse complement appears to be an ineffective pathogen defense mechanism in vitro and in vivo, unlike human hosts. In contrast, lpg1- parasites bound C3b and resisted low pH and proteases normally, entered macrophages efficiently and silently, and continued to inhibit host-signaling pathways. These studies illustrate the value of mechanistic approaches focusing on both parasite and host defense pathways in dissecting the specific biological roles of complex virulence factors such as LPG.


Knowledge of wealth shapes social impressions.
Seven experiments conducted in India and the United States (N ∼7,000; 5 preregistered) examined the effects of wealth on warmth and competence, 2 fundamental dimensions of social impressions. Wealth causally influenced perceptions of a target's competence: high wealth increased perceived competence and low wealth decreased perceived competence (Experiments 1-3). Furthermore, both high and low wealth reduced perceived warmth compared with control conditions that provided no wealth-related information (Experiments 2 and 3). Attributing prosocial tendencies to the target in the form of charitable donations reversed wealth-induced reductions in warmth, while low levels of charitable donations lowered both perceived warmth and competence (Experiment 3). Reciprocally, information about the target's competence or warmth influenced how wealthy they were perceived to be (Experiment 4). Knowing the source of wealth (e.g., entrepreneurship, corporate fraud, inheritance) also affected perceptions of competence and warmth (Experiments 5 and 6). Moreover, participants expressed greater willingness to hire wealthier targets compared with poorer targets in hypothetical employment scenarios, a relationship mediated by perceived competence, suggesting that an individual's wealth may influence consequential assessments and decisions (Experiment 7). With rising economic inequality, it is crucial to understand how wealthy and poor individuals are perceived and the implications of these perceptions. The present experiments offer insight in this direction. (PsycInfo Database Record (c) 2022 APA, all rights reserved).


Valproic acid inhibits glioblastoma multiforme cell growth via paraoxonase 2 expression.
We studied the potential mechanisms of valproic acid (VPA) in the treatment of glioblastoma multiforme (GBM). Using the human U87, GBM8401, and DBTRG-05MG GBM-derived cell lines, VPA at concentrations of 5 to 20 mM induced G2/M cell cycle arrest and increased the production of reactive oxygen species (ROS). Stress-related molecules such as paraoxonase 2 (PON2), cyclin B1, cdc2, and Bcl-xL were downregulated, but p27, p21 and Bim were upregulated by VPA treatment. VPA response element on the PON2 promoter was localized at position -400/-1. PON2 protein expression was increased in GBM cells compared with normal brain tissue and there was a negative correlation between the expression of PON2 and Bim. These findings were confirmed by the public Bredel GBM microarray (Gene Expression Omnibus accession: GSE2223) and the Cancer Genome Atlas GBM microarray datasets. Overexpression of PON2 in GBM cells significantly decreased intracellular ROS levels, and PON2 expression was decreased after VPA stimulation compared with controls. Bim expression was significantly induced by VPA in GBM cells with PON2 silencing. These observations were further shown in the subcutaneous GBM8401 cell xenograft of BALB/c nude mice. Our results suggest that VPA reduces PON2 expression in GBM cells, which in turn increases ROS production and induces Bim production that inhibits cancer progression via the PON2-Bim cascade.


Antiangiogenic therapy: a universal chemosensitization strategy for cancer?
For more than 50 years, a major goal of research in cancer therapeutics has been to develop universally effective agents that render cancer cells more sensitive to cytotoxic chemotherapy without substantially increasing toxicity to normal cells. The results of recent clinical trials indicate that certain antiangiogenic drugs may produce this long-sought effect. Here, I describe three distinct mechanisms that may help to explain the chemosensitizing activity of these drugs: normalizing tumor vasculature, preventing rapid tumor cell repopulation, and augmenting the antivascular effects of chemotherapy. I then discuss how these potential mechanisms might be exploited to maximize therapeutic efficacy.


The Pharyngostomy Tube: Indications, Technique, Efficacy, and Safety in Modern Surgical Practice.
Long-term nasogastric tubes are uncomfortable and associated with complications such as impairment with speech and swallowing, septum trauma, epistaxis, alar necrosis, and intubation of the trachea among others. Pharyngostomy tubes (PTs) are an alternative for prolonged enteral feeding, transluminal drainage of collections, and gastric decompression in patients with an intestinal obstruction and an inoperable abdomen. This is a retrospective analysis of patients who had a PT placed at our institution from May 2005 to March 2015. The primary end point of the study was to establish the type and rate of complications and aspiration events related to PT use. During the specified period, a total of 84 PTs were placed. The most common indication for PT placement was enteric decompression in 65 (77.4%), followed by transluminal collection drainage in 12 (14.3%), and enteral access for nutrition in 7 (8.3%) patients. The mean time to tube removal was 17.8 days ± 17.1 (range, 2-119). We encountered 10 (11.2%) complications related to PT placement, including 7 cases of cellulitis, 2 superficial abscesses, and 1 patient with pharyngeal hemorrhage. PTs are a relatively simple, safe, and straightforward approach to achieve long-term enteral decompression, access for feeding or transluminal drainage, avoiding the complications associated with prolonged nasogastric tube placement. The complication rate is low and patient satisfaction and compliance appear to be higher than with nasogastric tubes. Modern surgeons should be familiar with the procedure and technique. PTs should be part of every surgeon's armamentarium.


The prolyl isomerase Pin1 restores the function of Alzheimer-associated phosphorylated tau protein.
One of the neuropathological hallmarks of Alzheimer's disease is the neurofibrillary tangle, which contains paired helical filaments (PHFs) composed of the microtubule-associated protein tau. Tau is hyperphosphorylated in PHFs, and phosphorylation of tau abolishes its ability to bind microtubules and promote microtubule assembly. Restoring the function of phosphorylated tau might prevent or reverse PHF formation in Alzheimer's disease. Phosphorylation on a serine or threonine that precedes proline (pS/T-P) alters the rate of prolyl isomerization and creates a binding site for the WW domain of the prolyl isomerase Pin1. Pin1 specifically isomerizes pS/T-P bonds and regulates the function of mitotic phosphoproteins. Here we show that Pin1 binds to only one pT-P motif in tau and copurifies with PHFs, resulting in depletion of soluble Pin1 in the brains of Alzheimer's disease patients. Pin1 can restore the ability of phosphorylated tau to bind microtubules and promote microtubule assembly in vitro. As depletion of Pin1 induces mitotic arrest and apoptotic cell death, sequestration of Pin1 into PHFs may contribute to neuronal death. These findings provide a new insight into the pathogenesis of Alzheimer's disease.


Effect of autoclave sterilization on the cyclic fatigue resistance of thermally treated Nickel-Titanium instruments.
To compare the cyclic fatigue resistance of HyFlex CM, Twisted Files (TF), K3XF, Race, and K3, and evaluate the effect of autoclave sterilization on the cyclic fatigue resistance of these instruments both before and after the files were cycled. Five types of NiTi instruments with similar size 30, .06 taper were selected: HyFlex CM, TF, K3XF, Race and K3. Files were tested in a simulated canal with a curvature of 60° and a radius of 3 mm. The number of cycles to failure of each instrument was determined to evaluate cyclic fatigue resistance. Each type of instruments was randomly divided into four experimental groups: group 1 (n = 20), unsterilized instruments; group 2 (n = 20), pre-sterilized instruments subjected to 10 cycles of autoclave sterilization; group 3 (n = 20), instruments tested were sterilized at 25%, 50% and 75% of the mean cycles to failure as determined in group 1, and then cycled to failure; group 4 (n = 20), instruments cycled in the same manner as group 3 but without sterilization. The fracture surfaces of instruments were examined by scanning electron microscopy (SEM). HyFlex CM, TF and K3XF had significantly higher cyclic fatigue resistance than Race and K3 in the unsterilized group 1 (P < 0.05). Autoclave sterilization significantly increased the MCF of HyFlex CM and K3XF (P < 0.05) both before and after the files were cycled. SEM examination revealed a typical pattern of cyclic fatigue fracture in all instruments. HyFlex CM, TF and K3XF instruments composed of new thermal-treated alloy were more resistant to fatigue failure than Race and K3. Autoclaving extended the cyclic fatigue life of HyFlex CM and K3XF.


Folding pathways of a knotted protein with a realistic atomistic force field.
We report on atomistic simulation of the folding of a natively-knotted protein, MJ0366, based on a realistic force field. To the best of our knowledge this is the first reported effort where a realistic force field is used to investigate the folding pathways of a protein with complex native topology. By using the dominant-reaction pathway scheme we collected about 30 successful folding trajectories for the 82-amino acid long trefoil-knotted protein. Despite the dissimilarity of their initial unfolded configuration, these trajectories reach the natively-knotted state through a remarkably similar succession of steps. In particular it is found that knotting occurs essentially through a threading mechanism, involving the passage of the C-terminal through an open region created by the formation of the native [Formula: see text]-sheet at an earlier stage. The dominance of the knotting by threading mechanism is not observed in MJ0366 folding simulations using simplified, native-centric models. This points to a previously underappreciated role of concerted amino acid interactions, including non-native ones, in aiding the appropriate order of contact formation to achieve knotting.


Prognostic significance of anaemia in patients with heart failure with preserved and reduced ejection fraction: results from the MAGGIC individual patient data meta-analysis.
Anaemia is common among patients with heart failure (HF) and is an important prognostic marker. We sought to determine the prognostic importance of anaemia in a large multinational pooled dataset of prospectively enrolled HF patients, with the specific aim to determine the prognostic role of anaemia in HF with preserved and reduced ejection fraction (HF-PEF and HF-REF, respectively). Individual person data meta-analysis. Patients with haemoglobin (Hb) data from the MAGGIC dataset were used. Anaemia was defined as Hb < 120 g/l in women and <130 g/l in men. HF-PEF was defined as EF ≥ 50%; HF-REF was EF < 50%. Cox proportional hazard modelling, with adjustment for clinically relevant variables, was undertaken to investigate factors associated with 3-year all-cause mortality. Thirteen thousand two hundred and ninety-five patients with HF from 19 studies (9887 with HF-REF and 3408 with HF-PEF). The prevalence of anaemia was similar among those with HF-REF and HF-PEF (42.8 and 41.6% respectively). Compared with patients with normal Hb values, those with anaemia were older, were more likely to have diabetes, ischaemic aetiology, New York Heart Association class IV symptoms, lower estimated glomerular filtration rate and were more likely to be taking diuretic and less likely to be taking a beta-blocker. Patients with anaemia had higher all-cause mortality (adjusted hazard ratio [aHR] 1.38, 95% confidence interval [CI] 1.25-1.51), independent of EF group: aHR 1.67 (1.39-1.99) in HF-PEF and aHR 2.49 (2.13-2.90) in HF-REF. Anaemia is an adverse prognostic factor in HF irrespective of EF. The prognostic importance of anaemia was greatest in patients with HF-REF.


Adaptive optics optical coherence tomography with dynamic retinal tracking.
Adaptive optics optical coherence tomography (AO-OCT) is a highly sensitive and noninvasive method for three dimensional imaging of the microscopic retina. Like all in vivo retinal imaging techniques, however, it suffers the effects of involuntary eye movements that occur even under normal fixation. In this study we investigated dynamic retinal tracking to measure and correct eye motion at KHz rates for AO-OCT imaging. A customized retina tracking module was integrated into the sample arm of the 2nd-generation Indiana AO-OCT system and images were acquired on three subjects. Analyses were developed based on temporal amplitude and spatial power spectra in conjunction with strip-wise registration to independently measure AO-OCT tracking performance. After optimization of the tracker parameters, the system was found to correct eye movements up to 100 Hz and reduce residual motion to 10 µm root mean square. Between session precision was 33 µm. Performance was limited by tracker-generated noise at high temporal frequencies.


Production and characterization of biosurfactant produced by a novel Pseudomonas sp. 2B.
Biosurfactant-producing bacteria were isolated from terrestrial samples collected in areas contaminated with petroleum compounds. Isolates were screened for biosurfactant production using Cetyl Tri Ammonium Bromide (CTAB)-Methylene blue agar selection medium and the qualitative drop-collapse test. An efficient bacterial strain was selected based on rapid drop collapse activity and highest biosurfactant production. The biochemical characteristics and partial sequenced 16S rRNA gene of isolate, 2B, identified the bacterium as Pseudomonas sp. Five different low cost carbon substrates were evaluated for their effect on biosurfactant production. The maximum biosurfactant synthesis (4.97 g/L) occurred at 96 h when the cells were grown on modified PPGAS medium containing 1% (v/v) molasses at 30 °C and 150 rpm. The cell free broth containing the biosurfactant could reduce the surface tension to 30.14 mN/m. The surface active compound showed emulsifying activity against a variety of hydrocarbons and achieved a maximum emulsion index of 84% for sunflower oil. Compositional analysis of the biosurfactant reveals that the extracted biosurfactant was a glycolipid type, which was composed of high percentages of lipid (∼65%, w/w) and carbohydrate (∼32%, w/w). Fourier transform infrared (FT-IR) spectrum of extracted biosurfactant indicates the presence of carboxyl, hydroxyl and methoxyl functional groups. The mass spectra (MS) shows that dirhamnolipid (l-rhamnopyranosyl-l-rhamnopyranosyl-3-hydroxydecanoyl-3-hydroxydecanoate, Rha-Rha-C(10)-C(10)) was detected in abundance with the predominant congener monorhamnolipid (l-rhamnopyranosyl-β-hydroxydecanoyl-β-hydroxydecanoate, Rha-C(10)-C(10)). The crude oil recovery studies using the biosurfactant produced by Pseudomonas sp. 2B suggested its potential application in microbial enhanced oil recovery and bioremediation.


Pressure losses across multiple fittings in ventilation ducts.
The accurate prediction of pressure losses across in-duct fittings is of significance in relation to the accurate sizing and good energy efficiency of air-delivery systems. Current design guides provide design methods and data for the prediction of pressure losses only for a single and isolated fitting. This study presents an investigation of pressure losses across multiple interactive in-duct fittings in a ventilation duct. A laboratory measurement of pressure losses across one fitting and multiple fittings in a ventilation duct is carried out. The pressure loss across multiple interactive fittings is lower than that across multiple similar individual fittings, while the percentage decrease is dependent on the configuration and combination of the fittings. This implies that the pressure loss across multiple closely mounted fittings calculated by summing the pressure losses across individual fittings, as provided in the ASHRAE handbook and the CIBSE guide, is overpredicted. The numerical prediction of the pressure losses across multiple fittings using the large-eddy simulation (LES) model shows good agreement with the measured data, suggesting that this model is a useful tool in ductwork design and can help to save experimental resources and improve experimental accuracy and reliability.


Automatic atlas-based three-label cartilage segmentation from MR knee images.
Osteoarthritis (OA) is the most common form of joint disease and often characterized by cartilage changes. Accurate quantitative methods are needed to rapidly screen large image databases to assess changes in cartilage morphology. We therefore propose a new automatic atlas-based cartilage segmentation method for future automatic OA studies. Atlas-based segmentation methods have been demonstrated to be robust and accurate in brain imaging and therefore also hold high promise to allow for reliable and high-quality segmentations of cartilage. Nevertheless, atlas-based methods have not been well explored for cartilage segmentation. A particular challenge is the thinness of cartilage, its relatively small volume in comparison to surrounding tissue and the difficulty to locate cartilage interfaces - for example the interface between femoral and tibial cartilage. This paper focuses on the segmentation of femoral and tibial cartilage, proposing a multi-atlas segmentation strategy with non-local patch-based label fusion which can robustly identify candidate regions of cartilage. This method is combined with a novel three-label segmentation method which guarantees the spatial separation of femoral and tibial cartilage, and ensures spatial regularity while preserving the thin cartilage shape through anisotropic regularization. Our segmentation energy is convex and therefore guarantees globally optimal solutions. We perform an extensive validation of the proposed method on 706 images of the Pfizer Longitudinal Study. Our validation includes comparisons of different atlas segmentation strategies, different local classifiers, and different types of regularizers. To compare to other cartilage segmentation approaches we validate based on the 50 images of the SKI10 dataset.


The asymptomatic outpatient with abnormal liver function tests.
Traditionally, the constellation of biochemistry tests including liver enzymes, total bilirubin, and hepatic synthetic measures (prothrombin time (PT) and serum albumin level) are referred to as liver function tests (LFTs). Abnormal LFTs can be encountered during primary health care visits, routine blood donation, and insurance screening. A reported 1% to 4% of asymptomatic patients exhibit abnormal LFTs, leading to a sizeable number of annual consultations to a gastroenterology and/or hepatology practice. A cost-effective and systematic approach is essential to the interpretation of abnormal LFTs. A review of pattern of abnormal LFTs, detailed medical history, and a comprehensive physical examination help establish a foundation for further individualized testing. Further investigation often involves biochemical testing for disease-specific markers, radiographic imaging, and even consideration of a liver biopsy. In the following account, markers of hepatic injury are reviewed followed by a discussion on an approach to various patterns of abnormal LFTs in an asymptomatic patient.


Omental infarction: preoperative diagnosis and laparoscopic management in children.
Omental infarction (OI) is an unusual, poorly characterized cause of abdominal pain in children and is often mistaken for appendicitis preoperatively. We present our experience with this disease process over a 5-year period to identify preoperative factors to aid in timely diagnosis and treatment. We retrospectively reviewed the medical records of all children that had OI and underwent laparoscopic omentectomy from November 2004 to June 2009. Ten patients with the diagnosis of OI were identified. OI occurred in 9 boys and 1 girl, with a median age at presentation of 8.5 years (range, 7-11). Median body mass index at presentation was 23.7 (range, 17-29), with 1 child categorized as healthy weight for age, 1 child as overweight for age, and 5 children as obese for age, based on Centers for Disease Control and Prevention criteria. All patients complained of right-sided abdominal pain; 4 patients complained of predominantly right-upper quadrant (RUQ) pain, 3 patients of right-lower quadrant (RLQ) pain, and 3 of combined RUQ/RLQ pain. On examination, 6 patients had RUQ tenderness and 4 patients had RLQ tenderness. The median duration of symptoms prior to seeking medical attention was 3 days (range, 2-7). All patients underwent computed tomography and the preoperative diagnosis of OI was established in 9 of 10 cases. Operative time was 48 ± 14 minutes. All patients underwent resection of the infarcted omentum; 2 patients underwent concurrent appendectomy. Median length of stay was 2 days (range, 2-4). OI occurs predominantly, but not exclusively, in obese preadolescent males. OI can be reliably distinguished from appendicitis on preoperative history, physical examination, laboratory analysis, and imaging. Laparoscopic omentectomy results in prompt resolution of symptoms and discharge.


Methods for first-order kernel estimation: simple-cell receptive fields from responses to natural scenes.
Recent studies have recovered receptive-field maps of simple cells in visual cortex from their responses to natural scene stimuli. Natural scenes have many theoretical and practical advantages over traditional, artificial stimuli; however, the receptive-field estimation methods are more complex than for white-noise stimuli. Here, we describe and justify several of these methods-spectral correction of the reverse correlation estimate, direct least-squares solution, iterative least-squares algorithms and regularized least-squares solutions. We investigate the pros and cons of the different methods, and evaluate them in a head-to-head comparison for simulated simple-cell data. This shows that, at least for quasilinear simulated simple cells, a regularized solution ('reginv') is most efficient, requiring fewer stimulus presentations for high-resolution reconstruction of the first-order kernel. We also investigate several practical issues that determine the success of this kind of experiment-the effects of neuronal nonlinearities, response variability and the choice of stimulus regime.


Differential modulation of TNF-alpha-induced apoptosis by Neisseria meningitidis.
Infections by Neisseria meningitidis show duality between frequent asymptomatic carriage and occasional life-threatening disease. Bacterial and host factors involved in this balance are not fully understood. Cytopathic effects and cell damage may prelude to pathogenesis of isolates belonging to hyper-invasive lineages. We aimed to analyze cell-bacteria interactions using both pathogenic and carriage meningococcal isolates. Several pathogenic isolates of the ST-11 clonal complex and carriage isolates were used to infect human epithelial cells. Cytopathic effect was determined and apoptosis was scored using several methods (FITC-Annexin V staining followed by FACS analysis, caspase assays and DNA fragmentation). Only pathogenic isolates were able to induce apoptosis in human epithelial cells, mainly by lipooligosaccharide (endotoxin). Bioactive TNF-alpha is only detected when cells were infected by pathogenic isolates. At the opposite, carriage isolates seem to provoke shedding of the TNF-alpha receptor I (TNF-RI) from the surface that protect cells from apoptosis by chelating TNF-alpha. Ability to induce apoptosis and inflammation may represent major traits in the pathogenesis of N. meningitidis. However, our data strongly suggest that carriage isolates of meningococci reduce inflammatory response and apoptosis induction, resulting in the protection of their ecological niche at the human nasopharynx.


Symptom reporting after the introduction of a new high-voltage power line: a prospective field study.
There is public concern about the potential health effects of exposure to extremely low frequency electromagnetic fields (ELF-EMF) of high-voltage power lines (HVPLs). Some residents living near HVPLs believe ELF-EMF might cause non-specific health complaints. The present study is the first to prospectively investigate whether self-reported health complaints and causal beliefs increase after the construction of a new power line. We used a quasi-experimental design with two pretests before and two posttests after a new HVPL was put into operation. Residents living near (0-300m, n=229; 300-500m, n=489) and farther away (500-2000m, n=536) participated in the study. Linear mixed models were fitted to test whether symptom reports and beliefs that power lines caused health complaints increased more in residents living close to the new line compared to residents living farther away. A significantly (p<.05) larger increase from baseline in symptom reports and causal beliefs was found in residents living within 300m from the new power line when compared to residents living farther away. While symptom reports did not differ at baseline, the belief that a power line could cause these symptoms was at baseline already stronger for residents living close compared to residents living farther away. We found a negative impact of a new HVPL on health perceptions of nearby residents, even before the line was put into operation.