Recognizing Hand-Printed Letters and Digits Using Backpropagation Learning.
We report on results of training backpropagation nets with samples of hand-printed digits scanned off of bank checks and hand-printed letters interactively entered into a computer through a stylus digitizer. Generalization results are reported as a function of training set size and network capacity. Given a large training set, and a net with sufficient capacity to achieve high performance on the training set, nets typically achieved error rates of 4-5% at a 0% reject rate and 1-2% at a 10% reject rate. The topology and capacity of the system, as measured by the number of connections in the net, have surprisingly little effect on generalization. For those developing hand-printed character recognition systems, these results suggest that a large and representative training sample may be the single, most important factor in achieving high recognition accuracy. Benefits of reducing the number of net connections, other than improving generalization, are discussed.


Economic value of norovirus outbreak control measures in healthcare settings.
Although norovirus is a significant cause of nosocomial viral gastroenteritis, the economic value of hospital outbreak containment measures following identification of a norovirus case is currently unknown. We developed computer simulation models to determine the potential cost-savings from the hospital perspective of implementing the following norovirus outbreak control interventions: (i) increased hand hygiene measures, (ii) enhanced disinfection practices, (iii) patient isolation, (iv) use of protective apparel, (v) staff exclusion policies, and (vi) ward closure. Sensitivity analyses explored the impact of varying intervention efficacy, number of initial norovirus cases, the norovirus reproductive rate (R(0)), and room, ward size, and occupancy. Implementing increased hand hygiene, using protective apparel, staff exclusion policies or increased disinfection separately or in bundles provided net cost-savings, even when the intervention was only 10% effective in preventing further norovirus transmission. Patient isolation or ward closure was cost-saving only when transmission prevention efficacy was very high (≥ 90%), and their economic value decreased as the number of beds per room and the number of empty beds per ward increased. Increased hand hygiene, using protective apparel or increased disinfection practices separately or in bundles are the most cost-saving interventions for the control and containment of a norovirus outbreak.


Evidence of health and safety in American members of a religion who use a hallucinogenic sacrament.
Ayahuasca is a South American hallucinogenic tea used as a sacrament by the Santo Daime Church, other religions, and traditional peoples. A recent U.S. Supreme Court decision indicates religious ayahuasca use is protected, but little is known about health consequences for Americans. 32 (out of 40) American members of one branch of the Santo Daime Church were interviewed providing demographic information, physical exam, drug use timeline, a variety of psychological measures, and data about childhood conduct disorder. Subjects were asked about extent of Church participation, what is liked least and most about ayahuasca, and what health benefits or harms they attribute to ayahuasca. Members usually attend services weekly (lifetime 269+/-314.7 ceremonies; range 20-1300). Physical exam and test scores revealed healthy subjects. Members claimed psychological and physical benefits from ayahuasca. 19 subjects met lifetime criteria for a psychiatric disorder, with 6 in partial remission, 13 in full remission, and 8 reporting induction of remission through Church participation. 24 subjects had drug or alcohol abuse or dependence histories with 22 in full remission, and all 5 with prior alcohol dependence describing Church participation as the turning point in their recovery. Conclusions should not be extrapolated to hallucinogen abusers of the general public. For those who have religious need for ingesting ayahuasca, from a psychiatric and medical perspective, these pilot results substantiate some claims of benefit, especially if subjects interviewed fully reflect general membership. Further research is warranted with blinded raters, matched comparison groups, and other measures to overcome present study limitations.


Circulating immonoglobulin M: increased concentrations in endemic and sporadic goiter.
Increased concentrations of immunoglobulin M have been found in the circulation of approximately half of patients with either endemic or sporadic nontoxic goiter. Blood was obtained from patients in several iodine-deficient goitrous areas; the patients with sporadic goiter resided in or about New York City. Concentrations of immunoglobulins G, A, and D were normal. Blood for control purposes was taken from patients residing in cities near the goiter areas where there was no iodine deficiency, and in New York City. Most of these samples came from hospitalized patients without known thyroid disease and were collected at random. Chi-square values for the difference between the number of goitrous patients with elevated concentrations of immunoglobulin M and those in the control patients were highly significant statistically.


Fizzy-Related dictates A cell cycle switch during organ repair and tissue growth responses in the Drosophila hindgut.
Ploidy-increasing cell cycles drive tissue growth in many developing organs. Such cycles, including endocycles, are increasingly appreciated to drive tissue growth following injury or activated growth signaling in mature organs. In these organs, the regulation and distinct roles of different cell cycles remains unclear. Here, we uncover a programmed switch between cell cycles in the Drosophila hindgut pylorus. Using an acute injury model, we identify mitosis as the response in larval pyloric cells, whereas endocycles occur in adult pyloric cells. By developing a novel genetic method, DEMISE (Dual-Expression-Method-for-Induced-Site-specific-Eradication), we show the cell cycle regulator Fizzy-related dictates the decision between mitosis and endocycles. After injury, both cycles accurately restore tissue mass and genome content. However, in response to sustained growth signaling, only endocycles preserve epithelial architecture. Our data reveal distinct cell cycle programming in response to similar stimuli in mature vs. developmental states and reveal a tissue-protective role of endocycles.


Genetic Relationship between Schizophrenia and Nicotine Dependence.
It is well known that most schizophrenia patients smoke cigarettes. There are different hypotheses postulating the underlying mechanisms of this comorbidity. We used summary statistics from large meta-analyses of plasma cotinine concentration (COT), Fagerström test for nicotine dependence (FTND) and schizophrenia to examine the genetic relationship between these traits. We found that schizophrenia risk scores calculated at P-value thresholds of 5 × 10(-3) and larger predicted FTND and cigarettes smoked per day (CPD), suggesting that genes most significantly associated with schizophrenia were not associated with FTND/CPD, consistent with the self-medication hypothesis. The COT risk scores predicted schizophrenia diagnosis at P-values of 5 × 10(-3) and smaller, implying that genes most significantly associated with COT were associated with schizophrenia. These results implicated that schizophrenia and FTND/CPD/COT shared some genetic liability. Based on this shared liability, we identified multiple long non-coding RNAs and RNA binding protein genes (DA376252, BX089737, LOC101927273, LINC01029, LOC101928622, HY157071, DA902558, RBFOX1 and TINCR), protein modification genes (MANBA, UBE2D3, and RANGAP1) and energy production genes (XYLB, MTRF1 and ENOX1) that were associated with both conditions. Further analyses revealed that these shared genes were enriched in calcium signaling, long-term potentiation and neuroactive ligand-receptor interaction pathways that played a critical role in cognitive functions and neuronal plasticity.


Rhinitis in children and adolescents with asthma: Ubiquitous, difficult to control, and associated with asthma outcomes.
Rhinitis and asthma are linked, but substantial knowledge gaps in this relationship exist. We sought to determine the prevalence of rhinitis and its phenotypes in children and adolescents with asthma, assess symptom severity and medication requirements for rhinitis control, and investigate associations between rhinitis and asthma. Seven hundred forty-nine children with asthma participating in the Asthma Phenotypes in the Inner-City study received baseline evaluations and were managed for 1 year with algorithm-based treatments for rhinitis and asthma. Rhinitis was diagnosed by using a questionnaire focusing on individual symptoms, and predefined phenotypes were determined by combining symptom patterns with skin tests and measurement of serum specific IgE levels. Analyses were done on 619 children with asthma who completed at least 4 of 6 visits. Rhinitis was present in 93.5%, and phenotypes identified at baseline were confirmed during the observation/management year. Perennial allergic rhinitis with seasonal exacerbations was most common (34.2%) and severe. Nonallergic rhinitis was least common (11.3%) and least severe. The majority of children remained symptomatic despite use of nasal corticosteroids with or without oral antihistamines. Rhinitis was worse in patients with difficult-to-control versus easy-to-control asthma, and its seasonal patterns partially corresponded to those of difficult-to-control asthma. Rhinitis is almost ubiquitous in urban children with asthma, and its activity tracks that of lower airway disease. Perennial allergic rhinitis with seasonal exacerbations is the most severe phenotype and most likely to be associated with difficult-to-control asthma. This study offers strong support to the concept that rhinitis and asthma represent the manifestations of 1 disease in 2 parts of the airways.


Designing A Pathogen-Focused Study To Address The High Unmet Medical Need Represented By Carbapenem-Resistant Gram-Negative Pathogens - The International, Multicenter, Randomized, Open-Label, Phase 3 CREDIBLE-CR Study.
Carbapenem-resistant (CR) Gram-negative infections, including those caused by Enterobacteriaceae and the non-fermenters, represent the greatest unmet need for new effective treatments. The clinical development of new antibiotics for the treatment of CR infections is challenging and should focus on the individual pathogens irrespective of the infection site. However, the drug approval pathway is generally infection-site specific and rarely includes such drug-resistant pathogens. To overcome this limitation, a streamlined clinical development program may include a pathogen-focused clinical study, such as the CREDIBLE-CR study, to meet the expectations of some health authorities (ie, the European Medicines Agency [EMA]) and the medical community. Cefiderocol is a novel siderophore cephalosporin designed to target CR pathogens, including CR strains of Enterobacteriaceae (CRE), Pseudomonas aeruginosa, Acinetobacter baumannii, and also Stenotrophomonas maltophilia, which is intrinsically CR. The CREDIBLE-CR study was planned to evaluate cefiderocol in patients with CR Gram-negative infections regardless of species or infection-site source. Rapid diagnostic testing and/or selective media were provided to facilitate detection of CR pathogens to rapidly enroll patients with nosocomial pneumonia, bloodstream infection/sepsis, or complicated urinary tract infection. Patients were randomized 2:1 to receive cefiderocol or best available therapy. There were no pre-specified statistical hypotheses for this study, as the sample size was driven by enrollment feasibility and not based on statistical power calculations. The objective of the CREDIBLE-CR study was to provide descriptive evidence of the efficacy and safety of cefiderocol for the target population of patients with CR infections, including the non-fermenters. The CREDIBLE-CR study is currently the largest pathogen-focused, randomized, open-label, prospective, Phase 3 clinical study to investigate a new antibiotic in patients with CR Gram-negative infections. Here we describe the design of this pathogen-focused study and steps taken to aid patient enrollment into the study within an evolving regulatory environment. NCT02714595. 2015-004703-23.


Gamma linolenic acid exerts anti-inflammatory and anti-fibrotic effects in diabetic nephropathy.
This study was undertaken to investigate the effects of gamma linolenic acid (GLA) on inflammation and extracellular matrix (ECM) synthesis in mesangial and tubular epithelial cells under diabetic conditions. Sprague-Dawley rats were intraperitoneally injected with either a diluent [n=16, control (C)] or streptozotocin [n=16, diabetes (DM)], and eight rats each from the control and diabetic groups were treated with evening primrose oil by gavage for three months. Rat mesangial cells and NRK-52E cells were exposed to medium containing 5.6 mM glucose and 30 mM glucose (HG), with or without GLA (10 or 100 μM). Intercellular adhesion molecule-1 (ICAM-1), monocyte chemoattractant protein-1 (MCP-1), and fibronectin (FN) mRNA and protein expression levels were evaluated. Twenty-four-hour urinary albumin excretion was significantly increased in DM compared to C rats, and GLA treatment significantly reduced albuminuria in DM rats. ICAM-1, MCP-1, FN mRNA and protein expression levels were significantly higher in DM than in C kidneys, and these increases were significantly abrogated by GLA treatment. In vitro, GLA significantly inhibited increases in MCP-1 mRNA expression and protein levels under high glucose conditions in HG-stimulated mesangial and tubular epithelial cells (p<0.05, respectively). ICAM-1 and FN expression showed a similar pattern to the expression of MCP-1. GLA attenuates not only inflammation by inhibiting enhanced MCP-1 and ICAM-1 expression, but also ECM accumulation in diabetic nephropathy.


Iron-catalysed tritiation of pharmaceuticals.
A thorough understanding of the pharmacokinetic and pharmacodynamic properties of a drug in animal models is a critical component of drug discovery and development. Such studies are performed in vivo and in vitro at various stages of the development process--ranging from preclinical absorption, distribution, metabolism and excretion (ADME) studies to late-stage human clinical trials--to elucidate a drug molecule's metabolic profile and to assess its toxicity. Radiolabelled compounds, typically those that contain (14)C or (3)H isotopes, are one of the most powerful and widely deployed diagnostics for these studies. The introduction of radiolabels using synthetic chemistry enables the direct tracing of the drug molecule without substantially altering its structure or function. The ubiquity of C-H bonds in drugs and the relative ease and low cost associated with tritium ((3)H) make it an ideal radioisotope with which to conduct ADME studies early in the drug development process. Here we describe an iron-catalysed method for the direct (3)H labelling of pharmaceuticals by hydrogen isotope exchange, using tritium gas as the source of the radioisotope. The site selectivity of the iron catalyst is orthogonal to currently used iridium catalysts and allows isotopic labelling of complementary positions in drug molecules, providing a new diagnostic tool in drug development.


Automated attenuation-based tube voltage selection for body CTA: Performance evaluation of 192-slice dual-source CT.
To assess radiation dose and image quality in body CT-angiography (CTA) with automated attenuation-based tube voltage selection (ATVS) on a 192-slice dual-source CT (DSCT). Forty patients (69.5 ± 9.6 years) who had undergone body CTA with ATVS (ref.kVp 100, ref.mAs 90) using a 2x192-slice CT in single-source mode were retrospectively included. All patients had undergone prior CTA with a 2x128-slice CT and ATVS with identical imaging and contrast media protocols, serving for comparison. Images were reconstructed with iterative reconstruction at similar strength levels. Radiation dose was determined. Image quality was assessed semi-quantitatively (1:excellent, 5:non-diagnostic), aortic attenuation, noise and CNR were determined. As compared to 128-slice DSCT, 192-slice DSCT selected tube voltages were lower in 30 patients (75 %), higher in 3 (7.5 %), and similar in 7 patients (17.5 %). CTDIvol was lower with 192-slice DSCT (4.7 ± 1.9 mGy vs. 5.8 ± 2.1 mGy; p < 0.001). Subjective image quality, mean aortic attenuation (342 ± 67HU vs. 268 ± 67HU) and CNR (9.8 ± 2.5 vs. 8.2 ± 2.9) were higher with 192-slice DSCT (all p < 0.01), all datasets being diagnostic. Our study suggests that ATVS of 192-slice DSCT for body CTA is associated with an improved image quality and further radiation dose reduction of 19 % compared to 128-slice DSCT. • 192-slice DSCT allows imaging from 70 kVp to 150 kVp at 10 kVp increments. • 192-slice DSCT allows for radiation-dose reduction in body-CTA with ATVS. • Subjective and objective image quality increase compared to 128-slice DSCT.


Survey of city ordinances and local enforcement regarding commercial availability of tobacco to minors in Minnesota, United States.
To determine the extent and nature of local ordinances to regulate tobacco sales to minors, the level of enforcement of local and state laws concerning tobacco availability to minors, and sanctions applied as a result of enforcement. Tobacco control ordinances were collected in 1993 from 222 of the 229 cities greater than or equal to 2000 population in Minnesota, United States. In addition a telephone survey with the head of the agency responsible for enforcement of the tobacco ordinances was conducted. Presence or absence of legislative provisions dealing with youth and tobacco, including licensure of tobacco retailers, sanctions for selling tobacco products to minors, and restrictions on cigarette vending machines, self-service merchandising, and point-of-purchase advertising; and enforcement of these laws (use of inspections and "sting" operations, and sanctions imposed on businesses and minors). Almost 94% of cities required tobacco licences for retailers. However, 57% of the cities specified licences for cigarettes only. Annual licence fees ranged from $10 to $250, with the higher fees adopted in the previous four years. More than 25% of the cities had adopted some kind of restriction on cigarette vending machines, but only six communities had banned self-service cigarette displays. Three cities specified a minimum age for tobacco sales staff. Fewer than 25% of police officials reported having conducted compliance checks with minors or in-store observations of tobacco sales to determine if minors were being sold tobacco during the current year. Police carrying out compliance checks with youth were almost four times as likely to issue citations as those doing in-store observations. More than 90% of police reported enforcement of the law against tobacco purchase or possession by minors, and nearly 40% reported application of penalties against minors. Almost 75% of the cities have done nothing to change policies or enforcement practices to encourage compliance with tobacco age-of-sale legislation, and only a few of the remaining cities have adopted optimal policies. In addition, officials in Minnesota cities are much more likely to use enforcement strategies against minors who buy tobacco than against merchants who sell tobacco.


Socioeconomic determinants of geographic disparities in campylobacteriosis risk: a comparison of global and local modeling approaches.
Socioeconomic factors play a complex role in determining the risk of campylobacteriosis. Understanding the spatial interplay between these factors and disease risk can guide disease control programs. Historically, Poisson and negative binomial models have been used to investigate determinants of geographic disparities in risk. Spatial regression models, which allow modeling of spatial effects, have been used to improve these modeling efforts. Geographically weighted regression (GWR) takes this a step further by estimating local regression coefficients, thereby allowing estimations of associations that vary in space. These recent approaches increase our understanding of how geography influences the associations between determinants and disease. Therefore the objectives of this study were to: (i) identify socioeconomic determinants of the geographic disparities of campylobacteriosis risk (ii) investigate if regression coefficients for the associations between socioeconomic factors and campylobacteriosis risk demonstrate spatial variability and (iii) compare the performance of four modeling approaches: negative binomial, spatial lag, global and local Poisson GWR. Negative binomial, spatial lag, global and local Poisson GWR modeling techniques were used to investigate associations between socioeconomic factors and geographic disparities in campylobacteriosis risk. The best fitting models were identified and compared. Two competing four variable models (Models 1 & 2) were identified. Significant variables included race, unemployment rate, education attainment, urbanicity, and divorce rate. Local Poisson GWR had the best fit and showed evidence of spatially varying regression coefficients. The international significance of this work is that it highlights the inadequacy of global regression strategies that estimate one parameter per independent variable, and therefore mask the true relationships between dependent and independent variables. Since local GWR estimate a regression coefficient for each location, it reveals the geographic differences in the associations. This implies that a factor may be an important determinant in some locations and not others. Incorporating this into health planning ensures that a needs-based, rather than a "one-size-fits-all", approach is used. Thus, adding local GWR to the epidemiologists' toolbox would allow them to assess how the impacts of different determinants vary by geography. This knowledge is critical for resource allocation in disease control programs.


Does the timing of comorbidity affect colorectal cancer survival? A population based study.
Comorbid conditions in colorectal cancer patients can influence both clinical eligibility for treatment and survival. We aimed to evaluate the effect of comorbidity on 1 year survival from colorectal cancer, and to assess whether this effect varied with the timing of the comorbidity in relation to the cancer diagnosis. A population based cohort of 29,563 colorectal cancer patients diagnosed between 1997 and 2004 in the North West of England was evaluated. The excess hazard of death up to 1 year after diagnosis was estimated using deprivation and region specific life tables to adjust for background mortality. Results were adjusted for age and stage at diagnosis. Comorbid conditions diagnosed during the period 18 to 6 months before the diagnosis of colorectal cancer were strongly associated with lower survival at 1 year. Stage and age remained the strongest predictors of cancer related mortality even after adjustment for comorbidity. Administrative data provide a good estimate of the prevalence of most comorbid conditions but may be biased for some comorbid conditions that can be contra-indicators for cancer treatment. The time window in which a comorbid condition occurs in relation to the cancer diagnosis should be taken into account. Adjustment should be carried out, where possible, to provide more robust and clinically appropriate comparisons of population based cancer patient survival.


Linkage analysis of two cloned DNA sequences, DXS197 and DXS207, in hypophosphatemic rickets families.
The human X-linked hypophosphatemic rickets gene locus (HYP, formerly HPDR) has been previously localized by linkage analysis to Xp22.31-Xp21.3 and the locus order Xpter-DXS43-HYP-DXS41-Xcen established. Recombination between HYP and these flanking markers is frequently observed and additional markers have been sought. The polymorphic loci DXS197 and DXS207 have been localized to Xpter-Xp11 and Xp22-Xp21, respectively. We have further localized DXS197 to Xpter-Xp21.3 by using a panel of rodent-human hybrid cells and have established the map positions of DXS197 and DXS207 in relation to HYP by linkage studies of hypophosphatemic rickets families. Linkage between DXS197 and the loci DXS43, DXS85, and DXS207 was established with peak lod score values of 6.19, 0 = 0.032; 4.14, 0 = 0.000; and 3.01, 0 = 0.000, respectively. Multilocus linkage analysis mapped the DXS197 and DXS207 loci distal to HYP and demonstrated the locus order Xpter-DXS85-(DXS207, DXS43, DXS197)-HYP-DXS41-Xcen. These additional genetic markers DXS197 and DXS207 will be useful as alternative markers in the genetic counseling of some families.


Kinetics of competitive Cd2+ binding pathways: the realistic structure of intrinsically disordered, partially metallated metallothioneins.
The 20-cysteine mammalian metallothioneins are considered to be central to the homeostatic control of the essential metals Zn(ii) and Cu(i) and, as part of their metal-loaded status, play a role in reversing oxidative stress. Native apo-MT does not adopt a well-known structural motif, being described as a random-coil or intrinsically-disordered. Conclusions reached from a combination of ESI-mass spectral charge states, As(iii) metallation of apo-MT at low pH, from molecular dynamic calculations and from metallation of the α-domain fragment, suggest that in fact the native apo-MT adopts a structure that is highly efficient towards metallation at physiological pH. The results in this paper show that the initial (M < 5) Cd(ii) metallation at physiological pH takes place to form structures based on isolated Cd(SCYS)4 units, beads. At pH 5, cysteine bridged Cd4(SCYS)11 clusters form. ESI-mass spectral profile of cysteine modification of apo-MT at physiological pH shows that it is folded, whereas in the presence of 3 M guandinium hydrochloride the apo-MT is unfolded. Stopped flow kinetic studies of the Cd(ii) metallation shows that the reaction is much slower for the unfolded vs. the folded apo-MT for formation of either beads or clusters. Metallation is also much slower for the formation of clusters than the formation of beads. These results are first to quantify the presence of structure in native apo-MT in terms of the critical metallation properties. The implications of this study suggest that oxidation of apo-MT due to ageing or other agent will negatively impact the metallation process for essential metals.


Tensin2 reduces intracellular phosphatidylinositol 3,4,5-trisphosphate levels at the plasma membrane.
Tensins are proposed cytoskeleton-regulating proteins. However, Tensin2 additionally inhibits Akt signalling and cell survival. Structural modelling of the Tensin2 phosphatase (PTPase) domain revealed an active site-like pocket receptive towards phosphoinositides. Tensin2-expressing HEK293 cells displayed negligible levels of plasma membrane phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P(3)) under confocal microscopy. However, mock-transfected cells, and Tensin2 cells harbouring a putative phosphatase-inactivating mutation, exhibited significant PtdIns(3,4,5)P(3) levels, which decreased upon phosphatidylinositol 3-kinase inhibition with LY294002. In contrast, wtTensin3, mock and mutant cells were identical in membrane PtdIns(3,4,5)P(3) and Akt phosphorylation. In vitro lipid PTPase activity was however undetectable in isolated recombinant PTPase domains of both Tensins, indicating a possible loss of structural stability when expressed in isolation. In summary, we provide evidence that Tensin2, in addition to regulating cytoskeletal dynamics, influences phosphoinositide-Akt signalling through its PTPase domain.


Germline BAP1 mutation predisposes to uveal melanoma, lung adenocarcinoma, meningioma, and other cancers.
To investigate the potential contribution of germline sequence alterations in the BAP1 gene in uveal melanoma (UM) patients with possible predisposition to hereditary cancer. A total of 53 unrelated UM patients with high risk for hereditary cancer and five additional family members of one proband were studied. Mutational screening was carried out by direct sequencing. Of the 53 UM patients studied, a single patient was identified with a germline BAP1 truncating mutation, c. 799 C→T (p.Q267X), which segregated in several family members and was associated with UM and other cancers. Biallelic inactivation of BAP1 and decreased BAP1 expression were identified in the UM, lung adenocarcinoma and meningioma tumours from three family members with this germline BAP1 mutation. Germline BAP1 variants of uncertain significance, likely non-pathogenic, were also identified in two additional UM patients. This study reports a novel hereditary cancer syndrome caused by a germline BAP1 mutation that predisposes patients to UM, lung carcinoma, meningioma, and possibly other cancers. The results indicate that BAP1 is the candidate gene in only a small subset of hereditary UM, suggesting the contribution of other candidate genes.


Noise-assisted data processing with empirical mode decomposition in biomedical signals.
In this paper, a methodology is described in order to investigate the performance of empirical mode decomposition (EMD) in biomedical signals, and especially in the case of electrocardiogram (ECG). Synthetic ECG signals corrupted with white Gaussian noise are employed and time series of various lengths are processed with EMD in order to extract the intrinsic mode functions (IMFs). A statistical significance test is implemented for the identification of IMFs with high-level noise components and their exclusion from denoising procedures. Simulation campaign results reveal that a decrease of processing time is accomplished with the introduction of preprocessing stage, prior to the application of EMD in biomedical time series. Furthermore, the variation in the number of IMFs according to the type of the preprocessing stage is studied as a function of SNR and time-series length. The application of the methodology in MIT-BIH ECG records is also presented in order to verify the findings in real ECG signals.


Analysis of the 19 Y-STR and 16 X-STR loci system in the Han population of Shandong province, China.
The sex-linked short tandem repeats (STR), Y-STR and X-STR, are important for autosomal STRs in forensic paternity testing. We evaluated the forensic parameters of 19 Y-STRs and 16 X-STRs in the Han population of Shandong province, China. A Goldeneye 20Y kit (DYS391, DYS389I, DYS390, DYS389II, DYS348, DYS456, Y-GATA-H4, DYS447, DYS19, DYS392, DYS393, DYS388, DYS439, DYS635, DYS448, DYS460, DYS458, DYS437, DYS385 a/b) was used to analyze the forensic parameters of 534 unrelated males. A Goldeneye17X system (DXS6795, DXS9902, DXS8378, HPRTB, GATA165B12, DXS7132, DXS7424, DXS6807, DXS6803, GATA172D05, DXS6800, DXS10134, GATA31E08, DXS10159, DXS6789, DXS6810, amelogenin) was used to analyze 97 unrelated males and 214 females. In addition, we used the kits to examine 5 cases with abnormal amelogenin test results, as well as a male child with agenosomia typed by autosomal STR. We found 203 Y-STR haplotypes with allele frequencies ranging from 0.0019 to 0.7959, and GD ranging from 0.3429 to 0.9667. Expect in DXS6803, the allele frequencies of the other 15 X-STR loci showed no differences between females and males. PDF ranged from 0.5504 to 0.9638, while PDM ranged from 0.3176 to 0.8377. With the exception of DXS6803 and DXS6810, the allele frequencies of other X-STR loci were in accordance with Hardy-Weinberg equilibrium in females. One amelogenin negative case was characterized as a deletion of Y-DYS458. This paper provided data regarding the genetic polymorphism of Y-STRs and X-STRs in the Han population, and demonstrated the importance of Y-STR and X-STR in forensic autosomal STR analysis.


Short-term clinical outcome of normotensive patients with acute PE and high plasma lactate.
Strategies for identifying normotensive patients with acute symptomatic PE at high risk of PE-related complications remain to be defined. This prospective cohort study aimed to determine the role of plasma lactate levels in the risk assessment of normotensive patients with acute PE. Outcomes assessed over the 7 days after the diagnosis of PE included PE-related mortality and haemodynamic collapse, defined as need for cardiopulmonary resuscitation, systolic blood pressure <90 mm Hg for at least 15 min, need for catecholamine administration, or need for mechanical ventilation. Between December 2012 and January 2014, the study enrolled 496 normotensive outpatients with acute symptomatic PE. PE-related complications occurred in 20 (4.0%; 95% CI 2.5% to 6.2%) of the 496 patients. These patients had higher baseline lactate levels (median 2.66 mmol/L; IQR 1.56-5.96 mmol/L) than patients without complications (1.20 mmol/L; IQR 1.20-2.00 mmol/L) (p<0.001). Overall, 135 patients (27.2%) had plasma lactate ≥2 mmol/L. Fourteen (10.4%) of them had PE-related complications versus 6 of 361 patients with low lactate (negative predictive value 98.3%; p<0.001). Patients with elevated plasma lactate had an increased rate of PE-related complications (adjusted OR 5.3; 95% CI 1.9 to 14.4; p=0.001) compared with those with low lactate. The combination of elevated plasma lactate with markers of right ventricular dysfunction (by echocardiogram) and myocardial injury (by cardiac troponin) was a particularly useful prognostic indicator (positive predictive value 17.9%; 95% CI 6.1% to 36.9%). Plasma lactate represents a powerful predictor of short-term PE-related complications and may provide guidance for decision-making in PE care.


Expanding beaver pond distribution in Arctic Alaska, 1949 to 2019.
Beavers were not previously recognized as an Arctic species, and their engineering in the tundra is considered negligible. Recent findings suggest that beavers have moved into Arctic tundra regions and are controlling surface water dynamics, which strongly influence permafrost and landscape stability. Here we use 70 years of satellite images and aerial photography to show the scale and magnitude of northwestward beaver expansion in Alaska, indicated by the construction of over 10,000 beaver ponds in the Arctic tundra. The number of beaver ponds doubled in most areas between ~ 2003 and ~ 2017. Earlier stages of beaver engineering are evident in ~ 1980 imagery, and there is no evidence of beaver engineering in ~ 1952 imagery, consistent with observations from Indigenous communities describing the influx of beavers over the period. Rapidly expanding beaver engineering has created a tundra disturbance regime that appears to be thawing permafrost and exacerbating the effects of climate change.


Making the financial case for a surgeon-directed critical care ultrasound program.
We sought to demonstrate that a well-staffed, surgeon-directed, critical care ultrasound program (CCUP) is financially sustainable and provides administrative and educational support for point-of-care ultrasound. The CCUP provides a clinical service and training as well as conducts research. Initial costs, annual costs (C), revenue (R), and savings (S) were prospectively recorded. Using data from the first 3 years, we calculated the projected C, R, and S at 5 years. We determined CCUP sustainability by C < R and C < R + S at 3 years and 5 years. During 36 months, the CCUP covered four surgical intensive care units (55 beds). Start-up costs included one basic and one cardiovascular device per 25 beds and a data storage system linking reports and images to the electronic medical record ($203,650). Billing increased threefold from Years 1 to 3, with a 21% increase between Years 2 to 3. Yearly costs included 0.5 full-time equivalent (FTE) sonographer and 0.2 FTE surgeon ($106,025); this was increased to 1 FTE and 0.25 FTE, respectively, for Years 4 and 5. The total 3-year cost was $521,725 and projected to be $863,325 by Year 5. The total 3-year revenue was $290,775 and projected to be $891,600 at 5 years. The total 3-year savings associated with the CCUP was $600,035 and is projected to be $1,194,220. With the use of the C < R, the CCUP meets operating expenses at Year 3 and covers overall cost at 5 years. If savings are included, then the CCUP is sustainable by its third year and is potentially profitable by Year 5. A surgeon-directed CCUP is financially sustainable, addresses administrative issues, and provides valuable training in point-of-care ultrasound.


Solving the full anisotropic liquid crystal waveguides by using an iterative pseudospectral-based eigenvalue method.
This study develops an efficient mode solver based on pseudospectral eigenvalue algorithm to analyze liquid crystal waveguides with full 3 × 3 anisotropic permittivity tensors. Present formulation yields a cubic eigenvalue matrix equation with an eigenvalue of the propagation constant, and they are solved using an iterative approach following the transformation of the matrix equation to a standard linear eigenvalue equation. The proposed scheme significantly reduces the memory storage and computational time by using only transverse magnetic field components. Although the proposed scheme requires an iterative procedure, the convergent eigenvalues are achieved after performing only four iterations. Therefore, for this scheme, computational efforts remain greatly lower than those for other reported schemes that used at least three field components. For solving the modes of nematic liquid crystal waveguides, the numerical results obtained by the proposed scheme are in good agreement with those calculated by using the finite-element and the finite-difference frequency-domain schemes, thus verifying the applicability of the proposed approach. Furthermore, the mode patterns of liquid crystal waveguides under arbitrary molecular orientations are also characterized in detail.


The Evolving Role of the Orthopaedic Surgeon in Combat Zones and Austere Deployed Locations Since the 2012 Troop Drawdown.
The purpose of this study was to evaluate the operative experience of orthopaedic surgeons in the various deployment locations since 2012. We also evaluated the implications of humanitarian surgical care and the impact of deployment on an orthopaedic practice. An emailed survey was sent to orthopaedic surgeons deployed after 2012. The survey was 48 questions. Most cases in Iraq, Afghanistan and Syria were emergent traumas. In other locations, however, most cases were elective/non-emergent cases. Of surgeons surveyed, 44% performed less than 10 cases during their deployment, and 50% considered humanitarian surgery part of their mission. Six weeks was needed to prepare for deployment, and 4.4 weeks to re-build a practice. Disparity exists in surgical case volume and types of cases performed by orthopaedic surgeons that is dependent on deployed location. This dichotomy in operative experience places surgeons deployed to such locations at risk of losing surgical skills. (Journal of Surgical Orthopaedic Advances 29(3):182-186, 2020).


Incorporation of the Multiple Barrier Approach in drinking water risk assessment tools.
A number of existing risk assessment tools make reference to, or incorporate, a Multiple Barrier Approach to drinking water safety. Three waterborne disease outbreaks that occurred in developed nations were used as case studies to test a selected set of risk assessment tools. The outbreaks were used to determine how well the risk assessment tools identify hazards and vulnerabilities associated with different barriers to drinking water contamination.


Anti-inflammatory efficiency of levobupivacaine in an experimental colitis model.
To investigate the efficiency of levobupivacaine in treating experimentally induced colitis in rats. Colitis was induced by trinitrobenzene sulfonic acid and ethanol in 30 rats under general anesthesia, and 10 rats were used as a sham group. Subsequent to induction of colitis, rats were divided into three groups; budesonide group received 0.1 mg/kg budesonide, levobupivacaine group received 10 mg/kg levobupivacaine and saline group received 1 mL saline solution via rectal route for 7 d. In the sham group, only routine rectal catheterization was performed without use of any material. At the end of 7 d, laparotomy and total colectomy were performed for histopathological examination in all rats and blood samples were drawn for measurement of tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 following cardiac puncture. Macroscopic and microscopic evaluations of the specimens were performed by a pathologist blinded to group assignment of the rats. Weight loss (P = 0.016) and macroscopic examination scores (P = 0.001) were significantly higher in saline group than others. Histopathological scoring was comparable between all colitis groups (P = 0.350). There was no significant difference in TNF-alpha levels and IL-6 levels (P = 0.150). The significant improvement in macroscopic scores suggests that levobupivacaine may have topical anti-inflammatory effects in an experimental colitis model; however, this finding was not supported by microscopic findings.


Cellular HIV-1 DNA load predicts HIV-RNA rebound and the outcome of highly active antiretroviral therapy.
To assess whether cellular HIV-1 DNA prior to highly active antiretroviral therapy (HAART) initiation predicts its outcome. Patients included all 51 hemophiliacs of the Greek component of the Multicenter Hemophilia Cohort Study who had initiated HAART and for whom cryopreserved lymphocyte samples before HAART initiation were available. Cellular HIV-1 DNA quantification was performed by a molecular beacon-based real-time PCR assay in multiple samples per patient with a median (interquartile range) follow-up of 76 (45-102) weeks. The median (range) baseline HIV-1 DNA load was 297 (< 10 to 3468) copies per 1 x 10(6) peripheral blood mononuclear cells. Baseline HIV-1 DNA load did not predict initial virological response (VR). None of the patients with initial VR and baseline HIV-1 DNA load at or below the median experienced a subsequent virological rebound, while the cumulative probability of virological rebound by week 104 was 55% among those with HIV-1 DNA load greater than the median (P < 0.008). Cellular HIV-1 DNA load was the only parameter associated with sustained virological response as shown by univariate or multivariate analyses [adjusted odds ratio (95% confidence interval) 0.197 (0.048-0.801) per 1 log10 increase in DNA copies, P = 0.023]. Low cellular HIV-1 DNA load is a marker of sustained virological response in patients with initial VR and it can reliably predict the long-term success of HAART.


Dopamine Regulates Approach-Avoidance in Human Sensation-Seeking.
Sensation-seeking is a trait that constitutes an important vulnerability factor for a variety of psychopathologies with high social cost. However, little is understood either about the mechanisms underlying motivation for intense sensory experiences or their neuropharmacological modulation in humans. Here, we first evaluate a novel paradigm to investigate sensation-seeking in humans. This test probes the extent to which participants choose either to avoid or self-administer an intense tactile stimulus (mild electric stimulation) orthogonal to performance on a simple economic decision-making task. Next we investigate in a different set of participants whether this behavior is sensitive to manipulation of dopamine D2 receptors using a within-subjects, placebo-controlled, double-blind design. In both samples, individuals with higher self-reported sensation-seeking chose a greater proportion of mild electric stimulation-associated stimuli, even when this involved sacrifice of monetary gain. Computational modelling analysis determined that people who assigned an additional positive economic value to mild electric stimulation-associated stimuli exhibited speeding of responses when choosing these stimuli. In contrast, those who assigned a negative value exhibited slowed responses. These findings are consistent with involvement of low-level, approach-avoidance processes. Furthermore, the D2 antagonist haloperidol selectively decreased the additional economic value assigned to mild electric stimulation-associated stimuli in individuals who showed approach reactions to these stimuli under normal conditions (behavioral high-sensation seekers). These findings provide the first direct evidence of sensation-seeking behavior being driven by an approach-avoidance-like mechanism, modulated by dopamine, in humans. They provide a framework for investigation of psychopathologies for which extreme sensation-seeking constitutes a vulnerability factor.


CRISPR Interference-Potential Application in Retinal Disease.
The treatment of dominantly inherited retinal diseases requires silencing of the pathogenic allele. RNA interference to suppress gene expression suffers from wide-spread off-target effects, while CRISPR-mediated gene disruption creates permanent changes in the genome. CRISPR interference uses a catalytically inactive 'dead' Cas9 directed by a guide RNA to block transcription of chosen genes without disrupting the DNA. It is highly specific and potentially reversible, increasing its safety profile as a therapy. Pre-clinical studies have demonstrated the versatility of CRISPR interference for gene silencing both in vivo and in ex vivo modification of iPSCs for transplantation. Applying CRISPR interference techniques for the treatment of autosomal dominant inherited retinal diseases is promising but there are few in vivo studies to date. This review details how CRISPR interference might be used to treat retinal diseases and addresses potential challenges for clinical translation.


Antiangiogenic properties of a nutrient mixture in a model of hemangioma.
The pathogenesis of hemangiomas is still largely unknown and the current therapy, such as systemic corticosteroid, vincristine, and interferon-alpha, is toxic and remains unsatisfactory. A nutrient mixture (NM) containing lysine, proline, ascorbic acid and green tea extract has shown significant anti-angiogenic and anti-tumor effect against a number of cancer cell lines. Using a mouse hemangioendothelioma model, we investigated the efficacy of NM. We also tested the effect of NM in vitro, evaluating cell viability, MMP secretion, invasion, morphology and apoptosis. Athymic nude mice, 5-6 weeks old, were inoculated with 3 x10(6) EOMA cells subcutaneously and randomly divided into two groups; group A was fed a regular diet and group B - a regular diet supplemented with 0.5% NM. Four weeks later, the mice were sacrificed and their tumors were excised, weighed and processed for histology. We also tested the effect of NM in vitro. NM inhibited the growth of tumors by 50%. In vitro, NM exhibited dose response cytotoxicity with 10%, 30% and 55% at 10, 100 and 1000 microg/ml. Invasion through Matrigel was inhibited at 50, 100 and 500 microg/ml by 25%, 30% and 100% respectively. NM induced dose-dependent apoptosis of EOMA cells. These results suggest that NM may have therapeutic potential in treating infantile hemangioendotheliomas and, perhaps, other cutaneous vascular tumors.


Sharing bodies: the impact of the biomedical model of pregnancy on women's embodied experiences of the transition to motherhood.
This paper explores how a medicalized view of pregnancy shapes the process of pregnant embodiment and women's experiences postpartum. Analyzing interviews with 42 pregnant women and new mothers, I show that while women's experiences of pregnant embodiment are shaped by biomedical notions of pregnancy, women also bring new meaning to the biomedical guidelines. Women view pregnancy as a process of sharing their bodies with their children, and they continue to share their bodies with their newborns during the postpartum period. I conclude the paper by reflecting on the role of the body in shaping our understanding of medicalized phenomena.


Insights into how nucleotide-binding domains power ABC transport.
The mechanism by which nucleotide-binding domains (NBDs) of ABC transporters power the transport of substrates across cell membranes is currently unclear. Here we report the crystal structure of an NBD, FbpC, from the Neisseria gonorrhoeae ferric iron uptake transporter with an unusual and substantial domain swap in the C-terminal regulatory domain. This entanglement suggests that FbpC is unable to open to the same extent as the homologous protein MalK. Using molecular dynamics we demonstrate that this is not the case: both NBDs open rapidly once ATP is removed. We conclude from this result that the closed structures of FbpC and MalK have higher free energies than their respective open states. This result has important implications for our understanding of the mechanism of power generation in ABC transporters, because the unwinding of this free energy ensures that the opening of these two NBDs is also powered.


Getting to the point: a case of a sewing needle retrieved from the thigh.
Foreign bodies are rarely retained in the skin after puncture wounds or impalement injuries and are even less commonly initially detected several months after penetration. Sewing needles are most frequently reported in the literature as foreign bodies in cases of ingestion, inoculation of the cranium and heart, and penetration of the knee. Herein we describe a case of a middle-aged man who presented to the outpatient dermatology clinic with an 8-month history of a nodule in his left thigh; he had noted recent onset of mild pain. On examination he was found to have a sharp needle-like point palpable below the skin of his left lateral thigh. Plain radiographs of the left thigh showed a fractured sewing needle overlying the same area. During local incision, two fragments of a sewing needle were removed from the lateral thigh.


Estimation of nasal shedding and seroprevalence of organisms known to be associated with bovine respiratory disease in Australian live export cattle.
The prevalence of organisms known to be associated with bovine respiratory disease (BRD) was investigated in cattle prior to export. A quantitative reverse transcription polymerase chain reaction assay was used to detect nucleic acids from the following viruses and bacteria in nasal swab samples: Bovine coronavirus (BoCV; Betacoronavirus 1), Bovine herpesvirus 1 (BoHV-1), Bovine viral diarrhea virus 1 (BVDV-1), Bovine respiratory syncytial virus (BRSV), Bovine parainfluenza virus 3 (BPIV-3), Histophilus somni, Mycoplasma bovis, Mannheimia haemolytica, and Pasteurella multocida. Between 2010 and 2012, nasal swabs were collected from 1,484 apparently healthy cattle destined for export to the Middle East and Russian Federation. In addition, whole blood samples from 334 animals were tested for antibodies to BoHV-1, BRSV, BVDV-1, and BPIV-3 using enzyme-linked immunosorbent assay. The nasal prevalence of BoCV at the individual animal level was 40.1%. The nasal and seroprevalence of BoHV-1, BRSV, BVDV-1, and BPIV-3 was 1.0% and 39%, 1.2% and 46%, 3.0% and 56%, and 1.4% and 87%, respectively. The nasal prevalence of H. somni, M. bovis, M. haemolytica, and P. multocida was 42%, 4.8%, 13.4%, and 26%, respectively. Significant differences in nasal and seroprevalence were detected between groups of animals from different geographical locations. The results of the current study provide baseline data on the prevalence of organisms associated with BRD in Australian live export cattle in the preassembly period. This data could be used to develop strategies for BRD prevention and control prior to loading.


Assessment of chronological lifespan dependent molecular damages in yeast lacking mitochondrial antioxidant genes.
The free radical theory of aging states that oxidative damage to biomolecules causes aging and that antioxidants neutralize free radicals and thus decelerate aging. Mitochondria produce most of the reactive oxygen species, but at the same time have many antioxidant enzymes providing protection from these oxidants. Expecting that cells without mitochondrial antioxidant genes would accumulate higher levels of oxidative damage and, therefore, will have a shorter lifespan, we analyzed oxidative damages to biomolecules in young and chronologically aged mutants lacking the mitochondrial antioxidant genes: GRX2, CCP1, SOD1, GLO4, TRR2, TRX3, CCS1, SOD2, GRX5, and PRX1. Among these mutants, ccp1Δ, trx3Δ, grx5Δ, prx1Δ, mutants were sensitive to diamide, and ccs1Δ and sod2Δ were sensitive to both diamide and menadione. Most of the mutants were less viable in stationary phase. Chronologically aged cells produced higher amount of superoxide radical and accumulated higher levels of oxidative damages. Even though our results support the findings that old cells harbor higher amount of molecular damages, no significant difference was observed between wild type and mutant cells in terms of their damage content.


Clustered regularly interspaced short palindromic repeats (CRISPRs): the hallmark of an ingenious antiviral defense mechanism in prokaryotes.
Many prokaryotes contain the recently discovered defense system against mobile genetic elements. This defense system contains a unique type of repetitive DNA stretches, termed Clustered Regularly Interspaced Short Palindromic Repeats (CRISPRs). CRISPRs consist of identical repeated DNA sequences (repeats), interspaced by highly variable sequences referred to as spacers. The spacers originate from either phages or plasmids and comprise the prokaryotes' 'immunological memory'. CRISPR-associated (cas) genes encode conserved proteins that together with CRISPRs make-up the CRISPR/Cas system, responsible for defending the prokaryotic cell against invaders. CRISPR-mediated resistance has been proposed to involve three stages: (i) CRISPR-Adaptation, the invader DNA is encountered by the CRISPR/Cas machinery and an invader-derived short DNA fragment is incorporated in the CRISPR array. (ii) CRISPR-Expression, the CRISPR array is transcribed and the transcript is processed by Cas proteins. (iii) CRISPR-Interference, the invaders' nucleic acid is recognized by complementarity to the crRNA and neutralized. An application of the CRISPR/Cas system is the immunization of industry-relevant prokaryotes (or eukaryotes) against mobile-genetic invasion. In addition, the high variability of the CRISPR spacer content can be exploited for phylogenetic and evolutionary studies. Despite impressive progress during the last couple of years, the elucidation of several fundamental details will be a major challenge in future research.


The relationship between paediatricians and commerce.
The interaction between doctors and commerce, particularly the pharmaceutical industry, has recently been subject to increasing scrutiny. Doctors are now exposed to mounting influence from industry as it spends large amounts of money on marketing, is heavily involved with continuing medical education and sponsors a major proportion of research. Conflicts of interest may exist on both sides of the relationship: doctors can be manipulated and companies need to be profitable. Paediatricians are just as open to this influence as are other members of the medical profession. There is evidence that clinical practice is altered by interaction with industry, although doctors appear to deny the likelihood of being influenced. There are significant concerns over the increasing involvement of the pharmaceutical industry with research, although the regulation of the industry continues to be strengthened and the process of research is becoming more transparent. Disclosure of conflicts of interest involving authorship is now common practice and should extend to all facets of the relationship. However, collaboration continues to be necessary in order to develop new therapies, maximise research and particularly in paediatrics, to test medications in children. Paediatricians need to be aware of the sources of influence and understand current guidelines so that interactions with industry continue to be appropriate.


Microbiome disturbance and resilience dynamics of the upper respiratory tract during influenza A virus infection.
Infection with influenza can be aggravated by bacterial co-infections, which often results in disease exacerbation. The effects of influenza infection on the upper respiratory tract (URT) microbiome are largely unknown. Here, we report a longitudinal study to assess the temporal dynamics of the URT microbiomes of uninfected and influenza virus-infected humans and ferrets. Uninfected human patients and ferret URT microbiomes have stable healthy ecostate communities both within and between individuals. In contrast, infected patients and ferrets exhibit large changes in bacterial community composition over time and between individuals. The unhealthy ecostates of infected individuals progress towards the healthy ecostate, coinciding with viral clearance and recovery. Pseudomonadales associate statistically with the disturbed microbiomes of infected individuals. The dynamic and resilient microbiome during influenza virus infection in multiple hosts provides a compelling rationale for the maintenance of the microbiome homeostasis as a potential therapeutic target to prevent IAV associated bacterial co-infections.


Results From Spain's 2016 Report Card on Physical Activity for Children and Youth.
The first Active Healthy Kids Spanish Report Card aims to gather the most robust information about physical activity (PA) and sedentary behavior of children and adolescents. A Research Working Group of experts on PA and sport sciences was convened. A comprehensive data search, based on a review of the literature, dissertations, gray literature, and experts' nonpublished data, was conducted to identify the best sources to grade each indicator following the procedures and methodology outlined by the Active Healthy Kids Canada Report Card model. Overall PA (based on objective and self-reported methods) was graded as D-, Organized Sports Participation as B, Active Play as C+, Active Transportation as C, Sedentary Behavior as D, School as C, and Family and Peers as Incomplete, Community and the Built Environment as Incomplete, and Government as Incomplete. Spanish children and adolescents showed low levels of adherence to PA and sedentary behavior guidelines, especially females and adolescents. There is a need to achieve consensus and harmonize methods to evaluate PA and sedentary behavior to monitor changes over time and to evaluate the effectiveness of policies to promote PA.


The impact of providing incentives for attendance at AIDS prevention sessions.
The research literature on AIDS prevention efforts contains many reports on the impact of intervention sessions. Little information is available, however, on the success of various strategies to recruit clients to attend these sessions. An assessment of the comparative impact of money and other types of incentives on group attendance in two AIDS risk reduction projects, in the Harlem area of New York City and in Cleveland, OH, was undertaken. In both projects, injecting drug users and the sex partners of injecting drug users were recruited to participate in group sessions that focused on the reduction of AIDS risk behaviors. Data on group attendance were analyzed for 838 people in the New York project and 1,168 in the Ohio project. After the projects were underway, attendance incentives at both were changed from money to food coupons or gift certificates. Results indicated that a nonmonetary incentive was associated with a significant decline in group attendance. Concerns regarding paying monetary incentives to injecting drug users are discussed.


DAF-18/PTEN locally antagonizes insulin signalling to couple germline stem cell proliferation to oocyte needs in C. elegans.
During development, stem cell populations rapidly proliferate to populate the expanding tissues and organs. During this phase, nutrient status, by systemically affecting insulin/IGF-1 signalling, largely dictates stem cell proliferation rates. In adults, however, differentiated stem cell progeny requirements are generally reduced and vary according to the spatiotemporal needs of each tissue. We demonstrate here that differential regulation of germline stem cell proliferation rates in Caenorhabditis elegans adults is accomplished through localized neutralization of insulin/IGF-1 signalling, requiring DAF-18/PTEN, but not DAF-16/FOXO. Indeed, the specific accumulation of oocytes, the terminally differentiated stem cell progeny, triggers a feedback signal that locally antagonizes insulin/IGF-1 signalling outputs in the germ line, regardless of their systemic levels, to block germline stem cell proliferation. Thus, during adulthood, stem cells can differentially respond within tissues to otherwise equal insulin/IGF-1 signalling inputs, according to the needs for production of their immediate terminally differentiated progeny.


PC6 acupoint stimulation for the prevention of postcardiac surgery nausea and vomiting: a protocol for a two-group, parallel, superiority randomised clinical trial.
Postoperative nausea and vomiting (PONV) are frequent but unwanted complications for patients following anaesthesia and cardiac surgery, affecting at least a third of patients, despite pharmacological treatment. The primary aim of the proposed research is to test the efficacy of PC6 acupoint stimulation versus placebo for reducing PONV in cardiac surgery patients. In conjunction with this we aim to develop an understanding of intervention fidelity and factors that support, or impede, the use of PC6 acupoint stimulation, a knowledge translation approach. 712 postcardiac surgery participants will be recruited to take part in a two-group, parallel, superiority, randomised controlled trial. Participants will be randomised to receive a wrist band on each wrist providing acupressure to PC six using acupoint stimulation or a placebo. Randomisation will be computer generated, use randomly varied block sizes, and be concealed prior to the enrolment of each patient. The wristbands will remain in place for 36 h. PONV will be evaluated by the assessment of both nausea and vomiting, use of rescue antiemetics, quality of recovery and cost. Patient satisfaction with PONV care will be measured and clinical staff interviewed about the clinical use, feasibility, acceptability and challenges of using acupressure wristbands for PONV. Ethics approval will be sought from appropriate Human Research Ethics Committee/s before start of the study. A systematic review of the use of wrist acupressure for PC6 acupoint stimulation reported minor side effects only. Study progress will be reviewed by a Data Safety Monitoring Committee (DSMC) for nausea and vomiting outcomes at n=350. Dissemination of results will include conference presentations at national and international scientific meetings and publications in peer-reviewed journals. Study participants will receive a one-page lay-summary of results. Australian New Zealand Clinical Trials Registry--ACTRN12614000589684.


Correlation of fatty acid composition of adipose tissue lipids and serum phosphatidylcholine and serum concentrations of micronutrients with disease duration in rheumatoid arthritis.
To establish the concentrations of micronutrients in serum, fatty acid composition in serum phosphatidylcholine and in adipose tissue, and their correlation with inflammation and disease duration in rheumatoid arthritis (RA), 21 consecutive patients with recently diagnosed disease (mean duration eight months), 21 patients with longstanding disease (mean duration 15 years), and 57 controls were examined. In the patients with RA low concentrations of the essential fatty acids, linoleic acid (18:2) and linolenic (18:3) acid, and high concentrations of total saturated fatty acids, both in serum phosphatidylcholine and in adipose tissue, were found, abnormalities that increased with disease duration. The proportion of 18:2 in serum phosphatidylcholine correlated inversely with such acute phase proteins as orosomucoid and C reactive protein. It is proposed that the decreases in essential fatty acids are related to increased activity in the desaturase/elongation enzymes, increased production of eicosanoids, or metabolic changes secondary to cytokine mediated inflammatory reaction. When the micronutrients were studied it was found that serum concentrations of selenium were lower in patients than in controls, but not those of ascorbic acid, alpha-tocopherol, retinol, folic acid, or cobalamine. Ascorbic acid concentrations tended to be lower in RA, however, and correlated inversely with those of haptoglobin, orosomucoid, and C reactive protein, indicating a relation between the ascorbic acid concentration and the degree of inflammation.


Beyond motor neurons: expanding the clinical spectrum in Kennedy's disease.
Kennedy's disease, or spinal and bulbar muscular atrophy (SBMA), is an X-linked neuromuscular condition clinically characterised by weakness, atrophy and fasciculations of the limb and bulbar muscles, as a result of lower motor neuron degeneration. The disease is caused by an abnormally expanded triplet repeat expansions in the ubiquitously expressed androgen receptor gene, through mechanisms which are not entirely elucidated. Over the years studies from both humans and animal models have highlighted the involvement of cell populations other than motor neurons in SBMA, widening the disease phenotype. The most compelling aspect of these findings is their potential for therapeutic impact: muscle, for example, which is primarily affected in the disease, has been recently shown to represent a valid alternative target for therapy to motor neurons. In this review, we discuss the emerging study of the extra-motor neuron involvement in SBMA, which, besides increasingly pointing towards a multidisciplinary approach for affected patients, deepens our understanding of the pathogenic mechanisms and holds potential for providing new therapeutic targets for this disease.


Hepatitis B virus nucleic acid testing in Chinese blood donors with normal and elevated alanine aminotransferase.
Nucleic acid testing (NAT) is currently not a routine donor test in China. The aim of this study was to evaluate the current residual risk of hepatitis B virus (HBV) transmission and the value of ALT testing in preventing HBV infection. From January 2008 to September 2009, a total of 5521 qualified donations by routine screening and 5034 deferred donations due to elevated ALT alone were collected from five blood centers. Samples were tested for HBV DNA by triplex individual-donation (ID)-NAT (ULTRIO assay, on the TIGRIS system, Novartis Diagnostics). HBV NAT-reactive samples were further analyzed by HBV serology, alternative NAT, and viral load and were diluted to simulate if they could be detected in a minipool-NAT. There was no significant difference in the HBV NAT-yield rate between the qualified donations group (5/5521) and the deferred donations group (4/5034). Of these nine potential HBV-yield cases, one donor (11%) was a possible HBV window-period donor, one (11%) was a chronic HBV carrier, and seven (78%) had probable or confirmed occult HBV infections. Of seven potential HBV-yield cases quantified, the viral loads were less than or equal to 70.0 IU/mL. Minipool testing (minipools of 4, 8, and 16 donations) would miss 43% to 79% of the nine HBV-yield donations. Based on our findings in qualified donations, we estimate that the nationwide implementation of ID-NAT testing for HBV DNA in China would detect an additional 9964 viremic donations per year. ALT testing seems to have no significant value in preventing transfusion-transmitted HBV infection. ID-NAT versus simulated minipool-NAT using the ULTRIO test demonstrates the benefit to implement a more sensitive NAT strategy in regions of high HBV endemicity.


Theophylline Pharmacokinetics in Foetal Sheep: Maternal Metabolic Capacity is the Principal Driver.
Understanding theophylline pharmacokinetics (PK) in the foetus is essential to prevent in utero toxicity and optimize prophylactic therapies. Previous studies in pregnancy have been obfuscated by maternal dosing and inadequate sampling in the foetus; both render modelling of foetal PK difficult. Six ewes carrying singleton foetuses received theophylline (60 mg) into the foetal jugular vein. Blood samples were drawn from the foetus and ewe over 36 hr. Serum concentrations were measured. Maternal and foetal pharmacokinetic parameters were estimated. Foetal non-compartmental pharmacokinetic parameters were as follows: half-life 7.37 ± 1.22 hr; volume of distribution 44.62 ± 11.45 L; area under the curve 14.82 ± 2.71 hr/(μg/mL); and clearance 4.15 ± 0.70 L/hr. Rapid theophylline distribution across the placenta was observed. Maternal non-compartmental pharmacokinetic parameters were as follows: half-life 6.54 ± 2.44 hr; volume of distribution 32.48 ± 9.99 L; area under the curve 16.28 ± 4.53 hr/(μg/mL); and clearance 3.69 ± 1.47 L/hr. Foetal and ewe serum concentration-time profiles were fit together into a 3-compartment population pharmacokinetic model, and parameters were as follows: central volume 1.38 ± 0.11 L; 2nd peripheral compartment volume 3.11 ± 0.29 L; 3rd peripheral compartment volume 60.14 ± 6.02 L; elimination clearance 9.89 ± 0.90 L/hr; distribution clearance between central and 2nd compartment 30.87 ± 2.31 L/hr; and distribution clearance between 2nd and 3rd compartments 13.89 ± 1.11 L/hr. Cytochrome P4501A expression was robust in maternal liver; negligible activities were observed in placenta, foetal liver and foetal kidney. In vitro protein binding of theophylline was 30% lower in foetal serum compared to maternal serum (29.7 ± 4.4 versus 42.0 ± 3.6%-bound). Free concentrations were lower in the foetus than in the ewe, suggesting active transport across placenta. In summary, foetal clearance of theophylline is attributable to rapid distribution into the maternal circulation across the placenta followed by greater maternal protein binding and metabolic activity.


Aging Gracefully.
At the Annual Meeting of the American Academy of Dermatology in 2016, I directed the symposium entitled 'Aging Gracefully' for the second time. The symposium's primary learning objective was to give the audience a framework for managing aesthetic patients. In the last decade, there has been a significant increase in the options for and availability of noninvasive and minimally invasive rejuvenation. With that has been an associated surge in interest by physicians and patients. And, as the number of procedures across the globe increases, so too do the number of aesthetically poor outcomes. Most come from practitioners doing paint-by-numbers treatment. As experts in skin biology and treatment, dermatologists should practice the highest-level cosmetic as well as general dermatology. The faculty presented information to aid practitioners how best to approach patients and formulate a cosmetic plan. The faculty discussed important considerations based on patient gender, age, and skin type. Updated information on the science of cosmeceuticals and the benefits of early noninvasive intervention was presented as were next generation devices and alternatives to standard therapies. The faculty have kindly condensed their AAD presentations for this supplement. I thank L'Oréal and the Journal of Drugs in Dermatology for giving us the opportunity to present this information to a wider audience in this e-supplement. Heidi A. Waldorf MD Director of Laser & Cosmetic Dermatology, The Mount Sinai Hospital, New York, NY Icahn School of Medicine of Mount Sinai, New York, NY Waldorf Dermatology Aesthetics, Nanuet, NY


A molecular-properties-based approach to understanding PDZ domain proteins and PDZ ligands.
PDZ domain-containing proteins and their interaction partners are mutated in numerous human diseases and function in complexes regulating epithelial polarity, ion channels, cochlear hair cell development, vesicular sorting, and neuronal synaptic communication. Among several properties of a collection of documented PDZ domain-ligand interactions, we discovered embedded in a large-scale expression data set the existence of a significant level of co-regulation between PDZ domain-encoding genes and these ligands. From this observation, we show how integration of expression data, a comparative genomics catalog of 899 mammalian genes with conserved PDZ-binding motifs, phylogenetic analysis, and literature mining can be utilized to infer PDZ complexes. Using molecular studies we map novel interaction partners for the PDZ proteins DLG1 and CARD11. These results provide insight into the diverse roles of PDZ-ligand complexes in cellular signaling and provide a computational framework for the genome-wide evaluation of PDZ complexes.


Coronavirus infection induces DNA replication stress partly through interaction of its nonstructural protein 13 with the p125 subunit of DNA polymerase δ.
Perturbation of cell cycle regulation is a characteristic feature of infection by many DNA and RNA viruses, including Coronavirus infectious bronchitis virus (IBV). IBV infection was shown to induce cell cycle arrest at both S and G(2)/M phases for the enhancement of viral replication and progeny production. However, the underlying mechanisms are not well explored. In this study we show that activation of cellular DNA damage response is one of the mechanisms exploited by Coronavirus to induce cell cycle arrest. An ATR-dependent cellular DNA damage response was shown to be activated by IBV infection. Suppression of the ATR kinase activity by chemical inhibitors and siRNA-mediated knockdown of ATR reduced the IBV-induced ATR signaling and inhibited the replication of IBV. Furthermore, yeast two-hybrid screens and subsequent biochemical and functional studies demonstrated that interaction between Coronavirus nsp13 and DNA polymerase δ induced DNA replication stress in IBV-infected cells. These findings indicate that the ATR signaling activated by IBV replication contributes to the IBV-induced S-phase arrest and is required for efficient IBV replication and progeny production.


Rhinolithiasis: a retrospective study and review of the literature.
We conducted a retrospective analysis of 18 cases of rhinolithiasis treated in our clinic between 1990 and 2004. Age, sex, locations, diagnostic methods, and surgical technique were analyzed. Diagnosis was made by clinical examination and radiologic methods. Anterior rhinoscopy was performed in all patients and endoscopic evaluation in 14 patients. Plain-film x-rays of the paranasal sinus were taken in all patients, and computed tomography was performed in 5 patients. All rhinoliths were in the inferior meatus-11 right and 7 left. Patients' complaints were unilateral, foul-smelling rhinorrhea and nasal obstruction. Five patients also had headache, and 2 had cleft lip and palate. Rhinoliths were removed under local anesthesia in 12 patients and under general anesthesia in 6. An anterior rhinoscopic approach was used in 4 patients and an endoscopic approach in 14. Four of the patients underwent additional procedures, such as septoplasty, endoscopic sinus surgery, and adenoidectomy. Rhinolithiasis should be suspected in every case with unilateral, foul-smelling rhinorrhea and nasal obstruction. The treatment of choice is surgical removal under local or general anesthesia.


Optimization of biomass, total carotenoids and astaxanthin production in Haematococcus pluvialis Flotow strain Steptoe (Nevada, USA) under laboratory conditions.
The microalga Haematococcus pluvialis Flotow is one of the natural sources of astaxanthin, a pigment widely used in salmon feed. This study was made to discover optimal conditions for biomass and astaxanthin production in H. pluvialis from Steptoe, Nevada (USA), cultured in batch mode. Growth was carried out under autotrophic (with NaNO3, NH4Cl and urea) and mixotrophic conditions (with 4, 8, 12 mM sodium acetate) under two photon flux densities (PFD) (35 and 85 mumol m-2 s-1). The carotenogenesis was induced by 1) addition of NaCl (0.2 and 0.8%), 2) N-deprivation and 3) high PFD (150 mumol m-2 s-1). Total carotenoids were estimated by spectrophotometry and total astaxanthin by HPLC. Ammonium chloride was the best N-source for growth (k = 0.7 div day-1, 228-258 mg l-1 and 2.0 x 10(5)-2.5 x 10(5) cells ml-1 at both PFD, respectively). With increasing acetate concentration, a slight increment in growth occurred only at 85 mumol m-2 s-1. Light was the best inductive carotenogenic factor, and the highest carotenoid production (4.9 mg l-1, 25.0 pg cell-1) was obtained in cultures pre-grown in nitrate at low light. The NaCl caused an increase in carotenoid content per cell at increasing salt concentrations, but resulted in a high cell mortality and did not produce any increment in carotenoid content per volume compared to cultures grown at 150 mumol m-2 s-1. The highest carotenoid content per cell (22 pg) and astaxanthin content per dry weight (10.3 mg g-1) (1% w/w) were obtained at 85 mumol m-2 s-1 with 0.8% NaCl.


Epigenetics for ecologists.
There is now mounting evidence that heritable variation in ecologically relevant traits can be generated through a suite of epigenetic mechanisms, even in the absence of genetic variation. Moreover, recent studies indicate that epigenetic variation in natural populations can be independent from genetic variation, and that in some cases environmentally induced epigenetic changes may be inherited by future generations. These novel findings are potentially highly relevant to ecologists because they could significantly improve our understanding of the mechanisms underlying natural phenotypic variation and the responses of organisms to environmental change. To understand the full significance of epigenetic processes, however, it is imperative to study them in an ecological context. Ecologists should therefore start using a combination of experimental approaches borrowed from ecological genetics, novel techniques to analyse and manipulate epigenetic variation, and genomic tools, to investigate the extent and structure of epigenetic variation within and among natural populations, as well as the interrelations between epigenetic variation, phenotypic variation and ecological interactions.


Multi-feature based Benchmark for Cervical Dysplasia Classification Evaluation.
Cervical cancer is one of the most common types of cancer in women worldwide. Most deaths due to the disease occur in less developed areas of the world. In this work, we introduce a new image dataset along with expert annotated diagnoses for evaluating image-based cervical disease classification algorithms. A large number of Cervigram® images are selected from a database provided by the US National Cancer Institute. For each image, we extract three complementary pyramid features: Pyramid histogram in L*A*B* color space (PLAB), Pyramid Histogram of Oriented Gradients (PHOG), and Pyramid histogram of Local Binary Patterns (PLBP). Other than hand-crafted pyramid features, we investigate the performance of convolutional neural network (CNN) features for cervical disease classification. Our experimental results demonstrate the effectiveness of both our hand-crafted and our deep features. We intend to release this multi-feature dataset and our extensive evaluations using seven classic classifiers can serve as the baseline.


Marcos Zapata's "Last Supper": a feast of European religion and Andean culture.
In Marcos Zapata's 1753 painting of the Last Supper in Cuzco, Peru, Christian symbolism is filtered through Andean cultural tradition. Zapata was a late member of the Cuzco School of Painting, a group comprised of few European immigrants and handfuls of mestizo and Indian artists. The painters in Cuzco learned mostly from prints of European paintings, and their style tends to blend local culture into the traditional painting of their conquistadors. Imagery was the most successful tool used by the Spaniards in their quest to Christianize the Andean population. By teaching locals to paint Christian subjects, they were able to infuse Christianity into Andean traditions. Zapata's rendering of the Last Supper utilizes this cultural blending while staying true to the Christian symbolism within the subject. Instead of the traditional lamb, Zapata's Last Supper features a platter of cuy, or guinea pig, an Andean delicacy stocked with protein as well as cultural significance. Cuy was traditionally a sacrificial animal at Inca agricultural festivals and in this way it offers poignant parallel to the lamb, as a traditional Christian sacrificial animal.


Determinants of influenza transmission in South East Asia: insights from a household cohort study in Vietnam.
To guide control policies, it is important that the determinants of influenza transmission are fully characterized. Such assessment is complex because the risk of influenza infection is multifaceted and depends both on immunity acquired naturally or via vaccination and on the individual level of exposure to influenza in the community or in the household. Here, we analyse a large household cohort study conducted in 2007-2010 in Vietnam using innovative statistical methods to ascertain in an integrative framework the relative contribution of variables that influence the transmission of seasonal (H1N1, H3N2, B) and pandemic H1N1pdm09 influenza. Influenza infection was diagnosed by haemagglutination-inhibition (HI) antibody assay of paired serum samples. We used a Bayesian data augmentation Markov chain Monte Carlo strategy based on digraphs to reconstruct unobserved chains of transmission in households and estimate transmission parameters. The probability of transmission from an infected individual to another household member was 8% (95% CI, 6%, 10%) on average, and varied with pre-season titers, age and household size. Within households of size 3, the probability of transmission from an infected member to a child with low pre-season HI antibody titers was 27% (95% CI 21%-35%). High pre-season HI titers were protective against infection, with a reduction in the hazard of infection of 59% (95% CI, 44%-71%) and 87% (95% CI, 70%-96%) for intermediate (1∶20-1∶40) and high (≥1∶80) HI titers, respectively. Even after correcting for pre-season HI titers, adults had half the infection risk of children. Twenty six percent (95% CI: 21%, 30%) of infections may be attributed to household transmission. Our results highlight the importance of integrated analysis by influenza sub-type, age and pre-season HI titers in order to infer influenza transmission risks in and outside of the household.


Low B12 levels in chronic idiopathic urticaria.
Recent studies suggest that autoimmune mechanisms may be involved in the etiology of chronic idiopathic urticaria (CIU). There is a higher prevalence of B12 deficiency in autoimmune diseases and possibly in gastric Helicobacter pylori (H. pylori) infection. The frequency of B12 deficiency in CIU is unknown. Our objective in this study was to determine the prevalence of B12 deficiency in patients with CIU and also its relationship to gastric H. pylori infection and serologic markers of autoimmunity in these groups. Thirty-three patients with CIU and 27 healthy controls were included in the study. Serum vitamin B12 levels, H. pylori infection and serological markers of autoimmunity (anti-thyroglobulin, thyroid microsomal, gastric parietal cell and antinuclear autoantibodies) were investigated. H. pylori infection was determined according to serology and gastric biopsy in 19 patients, serology and urea breath test in 4 patients and serology alone in the remaining 10 patients. Serum B12 levels were below the normal reference range in 11/33 (33.3%) patients with CIU. The mean serum B12 levels among patients with CIU and the controls were 281+/-127.5 pg/ml and 465.1+/-140.3 pg/ml (p=0.0001), respectively. Anti-thyroid antibodies were positive in 6 of 11 patients (54.5%) with low B12 levels, but only in 4 of 27 (14.8%) healthy controls (p=0.019). Anti-GPC antibodies were positive in 4 of 11 (36.4%) patients with CIU and low B12 levels, but only in 2 of 27 (7.4%) healthy controls (p=0.047). In CIU patients, there was no difference in the frequency of IgG H. pylori antibodies between those with low B12 levels and normal B12 levels. Among the 19 patients who had been performed gastric endoscopy, 15 patients (78.9%) had chronic antral gastritis, 2 patients (10.5%) had atrophic gastritis and there were normal findings in 2 patients (10.5%). In conclusion, serum B12 levels were found to be below the normal reference range in 33% of the patients with CIU. An association between low B12 levels and H. pylori could not be shown. The higher frequency of antithyroid and anti-GPC antibodies in patients with low B12 levels suggest that low B12 levels in CIU may be autoimmune in nature.


Comparative effectiveness of linezolid and vancomycin among a national cohort of patients infected with methicillin-resistant Staphylococcus aureus.
While newer antibiotics play a key role in treating methicillin-resistant Staphylococcus aureus (MRSA) infections, knowledge of their real-world clinical impact is limited. We sought to quantify the effectiveness of linezolid compared to that of vancomycin among MRSA-infected patients. This national retrospective cohort study included adult patients admitted to all Veterans Affairs hospitals between January 2002 and June 2008, infected with MRSA, and treated with either linezolid (oral or intravenous [i.v.]) or vancomycin (i.v.). Patients were followed from their treatment initiation date until the event of interest, discharge, death, or December 2008. Utilizing propensity score methods, we estimated the treatment effects of linezolid primarily on time to discharge and secondarily on time to all-cause in-hospital mortality, therapy discontinuation, and all-cause 90-day readmission with Cox proportional-hazard models. We identified 20,107 patients treated with linezolid (3.2%) or vancomycin (96.8%). Baseline covariates were well balanced by treatment group within propensity score quintiles and between propensity score matched patients (626 pairs). The discharge rate was significantly higher among patients treated with linezolid, representing a decreased length of stay, in both the propensity score adjusted (hazard ratio [HR], 1.38; 95% confidence interval [95% CI], 1.27 to 1.50) and matched (HR, 1.70; 95% CI, 1.44 to 2.00) analyses. A significantly decreased rate of therapy discontinuation, indicating longer therapy duration, was observed in the linezolid group (adjusted HR, 0.64; 95% CI, 0.54 to 0.75; matched HR, 0.49; 95% CI, 0.36 to 0.65). In this clinical population of MRSA-infected patients, linezolid therapy was as effective as vancomycin therapy with respect to in-hospital survival and readmission.


Bleeding Efficiency and Meat Oxidative Stability and Microbiological Quality of New Zealand White Rabbits Subjected to Halal Slaughter without Stunning and Gas Stun-killing.
A study was conducted to compare the effect of halal slaughter without stunning and gas stun killing followed by bleeding on residual blood content and storage stability of rabbit meat. Eighty male New Zealand white rabbits were divided into two groups of 40 animals each and subjected to either halal slaughter without stunning (HS) or gas stun-kill (GK). The volume of blood lost during exsanguination was measured. Residual blood was further quantified by determination of haemoglobin content in Longissimus lumborum (LL) muscle. Storage stability of the meat was evaluated by microbiological analysis and measuring lipid oxidation in terms of thiobarbituric acid reactive substances (TBARS). HS resulted in significantly higher blood loss than GK. HS had significantly lower residual haemoglobin in LL muscle compared to GK. Slaughter method had no effect on rabbit meat lipid oxidation at 0, 1, and 3 d postmortem. However, at 5 and 8 days of storage at 4°C, significant differences (p<0.05) were found, with meat from the GK group exhibiting significantly higher levels of MDA than that from HS. At day 3, greater growth of Pseudomonas aeroginosa and E. coli were observed in the GK group (p<0.05) with B. thermosphacta and total aerobic counts remained unaffected by slaughter method. At days 5 and 7 postmortem, bacterial counts for all tested microbes were affected by slaughter method, with GK exhibiting significantly higher growth than HS. It can be concluded that slaughter method can affect keeping quality of rabbit meat, and HS may be a favourable option compared to GK due to high bleed out.


Sex and death in birds: a model of dosage compensation that predicts lethality of sex chromosome aneuploids.
Birds show female heterogamety, with ZZ males and ZW females. It is still not clear whether the W is female-determining, or whether two doses of the Z chromosomes are male-determining, or both. This question could easily be settled by the sexual phenotypes of ZZW and ZO birds, in the same way that the sexual phenotypes of XXY and XO showed that the Y is male determining in humans, but that the dosage of an X-borne gene determines sex in Drosophila. However, despite extensive searches, no ZZW or ZO diploid birds have been satisfactorily documented, so we must assume that these genotypes are embryonic lethals. Given that ZW and ZZ are viable and the W contains few genes it is not clear why this should be so. Here I propose that sex chromosome aneuploids are lethal in chicken because, to achieve dosage compensation, a locus on the W chromosome controls the upregulation of genes on the Z in ZW females. ZO birds would therefore have only half the normal dose of Z-linked gene product and ZZW would have twice the amount, both of which would undoubtedly be incompatible with life. Reports of other aneuploids and triploids are also consistent with this hypothesis.


Potential c-myc antisense oligonucleotide carriers: PCl/PEG/PEI and PLL/PEG/PEI.
In this work, positively charged, micelle-forming polymers were synthesized and used as a model vector to deliver antisense oligodeoxynucleotide (ASODN) into melanoma cells. Polymers and polymer/ASODN complexes were characterized by DLS according to size, charge, and critical micelle concentration. Nanosize and spherical complexes were observed by AFM. Complexes did not reveal significant toxicity to melanoma cells. Antiproliferative effect of the complexes was observed by immunocytochemical staining and estimated as 56.8% with N/P:9. High amount of apoptosis and very small amount of necrosis were estimated. According to the results, these positively charged polymers forming micelle-like structures seem promising as ASODN carriers.


When Diabetes Confronts HIV: Biological Sub-citizenship at a Public Hospital in Nairobi, Kenya.
This article investigates how international donor policies cultivate a form of biological sub-citizenship for those with diabetes in Kenya. We interviewed 100 patients at a public hospital clinic in Nairobi, half with a diabetes diagnosis. We focus on three vignettes that illustrate how our study participants differentially perceived and experienced living with and seeking treatment and care for diabetes compared to other conditions, with a special focus on HIV. We argue that biological sub-citizenship, where those with HIV have consistent and comprehensive free medical care and those with diabetes must pay out-of-pocket for testing and treatment, impedes diabetes testing and treatment. Once diagnosed, many are then systematically excluded from the health care system due to their own inability to pay. We argue that the systematic exclusion from international donor money creates a form of biological sub-citizenship based on neoliberal economic policies that undermine other public health protections, such as universal primary health care.


Contact structures in the poultry industry in Great Britain: exploring transmission routes for a potential avian influenza virus epidemic.
The commercial poultry industry in United Kingdom (UK) is worth an estimated 3.4 billion pounds sterling at retail value, producing over 174 million birds for consumption per year. An epidemic of any poultry disease with high mortality or which is zoonotic, such as avian influenza virus (AIV), would result in the culling of significant numbers of birds, as seen in the Netherlands in 2003 and Italy in 2000. Such an epidemic would cost the UK government millions of pounds in compensation costs, with further economic losses through reduction of international and UK consumption of British poultry. In order to better inform policy advisers and makers on the potential for a large epidemic in GB, we investigate the role that interactions amongst premises within the British commercial poultry industry could play in promoting an AIV epidemic, given an introduction of the virus in a specific part of poultry industry in Great Britain (GB). Poultry premises using multiple slaughterhouses lead to a large number of premises being potentially connected, with the resultant potential for large and sometimes widespread epidemics. Catching companies can also potentially link a large proportion of the poultry population. Critical to this is the maximum distance traveled by catching companies between premises and whether or not between-species transmission could occur within individual premises. Premises closely linked by proximity may result in connections being formed between different species and or sectors within the industry. Even quite well-contained epidemics have the potential for geographically widespread dissemination, potentially resulting in severe logistical problems for epidemic control, and with economic impact on a large part of the country. Premises sending birds to multiple slaughterhouses or housing multiple species may act as a bridge between otherwise separate sectors of the industry, resulting in the potential for large epidemics. Investment into further data collection and analyses on the importance of industry structure as a determinant for spread of AIV would enable us to use the results from this study to contribute to policy on disease control.


The replication capacity of intact mammalian nuclei in Xenopus egg extracts declines with quiescence, but the residual DNA synthesis is independent of Xenopus MCM proteins.
In eukaryotes, the initiation of DNA synthesis requires the assembly of a pre-replicative complex (pre-RC) at origins of replication. This involves the sequential binding of ORC (origin-recognition-complex), Cdc6 and MCM proteins, a process referred to as licensing. After origin firing, the Cdc6 and MCM proteins dissociate from the chromatin, and do not rebind until after the completion of mitosis, thereby restricting replication to a single round in each cell cycle. Although nuclei normally become licensed for replication as they enter G(1), the extent to which the license is retained when cells enter the quiescent state (G(0)) is controversial. Here we show that the replication capacity of nuclei from Swiss 3T3 cells, in Xenopus egg extracts, is not lost abruptly with the onset of quiescence, but instead declines gradually. The decline in replication capacity, which affects both the number of nuclei induced to replicate and their subsequent rate of DNA synthesis, is accompanied by a fall in the level of chromatin-bound MCM2. When quiescent nuclei are incubated in egg extracts, they do not bind further MCMs unless the nuclei are first permeabilized. The residual replication capacity of intact nuclei must therefore be dependent on the remaining endogenous MCMs. Although high levels of Cdk activity are known to block MCM binding, we show that the failure of intact nuclei in egg extracts to increase their bound MCMs is not due to their uptake and accumulation of Cdk complexes. Instead, the failure of binding must be due to exclusion of some other binding factor from the nucleus, or to the presence within nuclei of an inhibitor of binding other than Cdk activity. In contrast to the situation in Xenopus egg extracts, following serum stimulation of intact quiescent cells, the level of bound MCMs does increase before the cells reach S phase, without any disruption of the nuclear envelope.


A real-time PCR array for hierarchical identification of Francisella isolates.
A robust, rapid and flexible real-time PCR assay for hierarchical genetic typing of clinical and environmental isolates of Francisella is presented. Typing markers were found by multiple genome and gene comparisons, from which 23 canonical single nucleotide polymorphisms (canSNPs) and 11 canonical insertion-deletion mutations (canINDELs) were selected to provide phylogenetic guidelines for classification from genus to isolate level. The specificity of the developed assay, which uses 68 wells of a 96-well real-time PCR format with a detection limit of 100 pg DNA, was assessed using 62 Francisella isolates of diverse genetic and geographical origins. It was then successfully used for typing 14 F. tularensis subsp. holarctica isolates obtained from tularemia patients in Sweden in 2008 and five more genetically diverse Francisella isolates of global origins. When applied to human ulcer specimens for direct pathogen detection the results were incomplete due to scarcity of DNA, but sufficient markers were identified to detect fine-resolution differences among F. tularensis subsp. holarctica isolates causing infection in the patients. In contrast to other real-time PCR assays for Francisella, which are typically designed for specific detection of a species, subspecies, or strain, this type of assay can be easily tailored to provide appropriate phylogenetic and/or geographical resolution to meet the objectives of the analysis.