Nucleic acids for ultra-sensitive protein detection.
Major advancements in molecular biology and clinical diagnostics cannot be brought about strictly through the use of genomics based methods. Improved methods for protein detection and proteomic screening are an absolute necessity to complement to wealth of information offered by novel, high-throughput sequencing technologies. Only then will it be possible to advance insights into clinical processes and to characterize the importance of specific protein biomarkers for disease detection or the realization of "personalized medicine". Currently however, large-scale proteomic information is still not as easily obtained as its genomic counterpart, mainly because traditional antibody-based technologies struggle to meet the stringent sensitivity and throughput requirements that are required whereas mass-spectrometry based methods might be burdened by significant costs involved. However, recent years have seen the development of new biodetection strategies linking nucleic acids with existing antibody technology or replacing antibodies with oligonucleotide recognition elements altogether. These advancements have unlocked many new strategies to lower detection limits and dramatically increase throughput of protein detection assays. In this review, an overview of these new strategies will be given.


Interaction effects on counting statistics and the transmission distribution.
We investigate the effect of weak interactions on the full counting statistics of charge transfer through an arbitrary mesoscopic conductor. We show that the main effect can be incorporated into an energy dependence of the transmission eigenvalues and study this dependence in a nonperturbative approach. An unexpected result is that all mesoscopic conductors behave at low energies such as either a single or a double tunnel junction, which divides them into two broad classes.


The cyclin-dependent kinase activator, Spy1A, is targeted for degradation by the ubiquitin ligase NEDD4.
Spy1A is a cyclin-like protein required for progression through the G(1)/S phase of the cell cycle. Elevated Spy1A protein levels have been implicated in tumorigenesis and are attributed to overriding the DNA damage response and enhancing cell proliferation. Understanding how Spy1A is produced and degraded is essential in resolving how it contributes to normal and abnormal growth processes. Herein, we demonstrate that Spy1A is degraded in a cell cycle-dependent manner during mitosis via the ubiquitin-proteasome system. We have resolved the E3 ligase and essential phosphorylation sites mediating Spy1A degradation. Furthermore, we have determined that non-degradable forms of Spy1A do not trigger cell cycle arrest but, rather, contribute to uncontrolled cell growth. Further investigation into the regulation of Spy1A may reveal novel strategies for understanding the etiology and progression of specific growth disorders.


Small airways, lung function and aviation.
The anatomy, physiology and functional assessment of small airways and their relevance to aviation is reviewed. Small airways normally contribute little to lung function, and they can become extensively and irreversibly damaged, or even closed, before clinical deterioration is evident. Small airways disease does, however, produce typical and reproducible changes in spirogram, flow volume, and closing volume measurements. Minor abnormalities of respiratory function, inconsequential at sea level, can substantially reduce arterial oxygen saturation at high altitude. Aircrew with pulmonary disease could also be severely affected by loss of pressure, causing significant hypoxia. Stress during flight may exacerbate airways obstruction, especially in asthmatics. The hypoxia resulting from these situations could seriously compromise in-flight performance. Peak flow, FEV1, and FVC measurements are recommended for civilian air crew prior to employment and at routine intervals thereafter.


Evaluation of the Degree of Conversion, Residual Monomers and Mechanical Properties of Some Light-Cured Dental Resin Composites.
The novelty of this study consists in the formulation and characterization of three experimental dental composites (PM, P14M, P2S) for cervical dental lesion restoration compared to the commercial composites Enamel plus HRi® - En (Micerium S.p.A, Avengo, Ge, Italy), G-ænial Anterior® - Ge, (GC Europe N.V., Leuven, Belgium), Charisma® - Ch (Heraeus Kulzer, Berkshire, UK). The physio-chemical properties were studied, like the degree of conversion and the residual monomers in cured samples using FTIR-ATR (attenuated total reflectance) and HPLC-UV (ultraviolet detection), as well as the evaluation of the mechanical properties of the materials. The null hypothesis was that there would be no differences between experimental and commercial resin composites regarding the evaluated parameters. Statistical analysis revealed that water and saliva storage induced significant modifications of all mechanical parameters after three months for all tested materials, except for a few comparisons for each type of material. Storage medium seemed not to alter the values of mechanical parameters in comparison with the initial ones for: diametral tensile strength (DTS-saliva for Ge and PM, compressive strength (CS)-water for Ch, DTS-water and Young's modulus YM-saliva for P14M and YM-water/ saliva for P2S (p > 0.05). Two of the experimental materials showed less than 1% residual monomers, which sustains good polymerization efficiency. Experimental resin composites have good mechanical properties, which makes them recommendable for the successful use in load-bearing surfaces of posterior teeth.


Transformation of Unsaturated Fatty Acids/Esters to Corresponding Keto Fatty Acids/Esters by Aerobic Oxidation with Pd(II)/Lewis Acid Catalyst.
Utilization of renewable biomass to partly replace the fossil resources in industrial applications has attracted attention due to the limited fossil feedstock with the increased environmental concerns. This work introduced a modified Wacker-type oxidation for transformation of unsaturated fatty acids/esters to the corresponding keto fatty acids/esters, in which Cu2+ cation was replaced with common nonredox metal ions, that is, a novel Pd(II)/Lewis acid (LA) catalyst. It was found that adding nonredox metal ions can effectively promote Pd(II)-catalyzed oxidation of unsaturated fatty acids/esters to the corresponding keto fatty acids/esters, even much better than Cu2+, and the promotional effect is highly dependent on the Lewis acidity of added nonredox metal ions. The improved catalytic efficiency is attributed to the formation of heterobimetallic Pd(II)/LA species, and the oxidation mechanism of this Pd(II)/LA catalyst is also briefly discussed.


Occurrence and Molecular Characteristics of Extended-Spectrum Beta-Lactamase-Producing Enterobacterales Recovered From Chicken, Chicken Meat, and Human Infections in Sao Paulo State, Brazil.
This study aimed to investigate the phylogenetic diversity and epidemiology of extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli and Klebsiella pneumoniae from chicken, chicken meat, and human clinical isolates in Sao Paolo, Brazil, and characterize their respective ESBL-encoding plasmids. Three hundred samples from chicken cloaca, chicken meat, and clinical isolates were phenotypically and genotypically assessed for ESBL resistance. Isolates were identified by MALDI TOF-MS and further characterized by MLST analysis and phylogenetic grouping. ESBL genes were characterized and their location was determined by I-Ceu-I-PFGE and Southern blot, conjugation, transformation, and PCR-based replicon typing experiments. Thirty-seven ESBL-producing isolates (28 E. coli and 9 K. pneumoniae) that were positive for the bla CTX-M-1 or bla CTX-M-2 gene groups were obtained. Two isolates were negative in the transformation assay, and the chromosomal location of the genes was deduced by Southern blot. The bla CTX-M genes identified were carried on plasmid replicon-types X1, HI2, N, FII-variants, I1 and R. The E. coli isolates belonged to nine sequence types, while the K. pneumoniae isolates belonged to four sequence types. The E. coli isolates belonged to phylotype classification groups A, B1, D, and F. This study demonstrated that isolates from cloacal swabs, chicken meat, and human feces had genetic diversity, with a high frequency of bla CTX-M-15 among chickens, chicken meat, and human feces. Thus, this reinforces the hypothesis that chickens, as well as their by-products, could be an important source of transmission for ESBL-producing pathogens to humans in South America.


Engineered antibody fragments for immuno-PET imaging of endogenous CD8+ T cells in vivo.
The noninvasive detection and quantification of CD8(+) T cells in vivo are important for both the detection and staging of CD8(+) lymphomas and for the monitoring of successful cancer immunotherapies, such as adoptive cell transfer and antibody-based immunotherapeutics. Here, antibody fragments are constructed to target murine CD8 to obtain rapid, high-contrast immuno-positron emission tomography (immuno-PET) images for the detection of CD8 expression in vivo. The variable regions of two anti-murine CD8-depleting antibodies (clones 2.43 and YTS184.108.40.206) were sequenced and reformatted into minibody (Mb) fragments (scFv-CH3). After production and purification, the Mbs retained their antigen specificity and bound primary CD8(+) T cells from the thymus, spleen, lymph nodes, and peripheral blood. Importantly, engineering of the parental antibodies into Mbs abolished the ability to deplete CD8(+) T cells in vivo. The Mbs were subsequently conjugated to S-2-(4-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid for (64)Cu radiolabeling. The radiotracers were injected i.v. into antigen-positive, antigen-negative, immunodeficient, antigen-blocked, and antigen-depleted mice to evaluate specificity of uptake in lymphoid tissues by immuno-PET imaging and ex vivo biodistribution. Both (64)Cu-radiolabeled Mbs produced high-contrast immuno-PET images 4 h postinjection and showed specific uptake in the spleen and lymph nodes of antigen-positive mice.


The Relationship Between Crackle Characteristics and Airway Morphology in COPD.
Crackles in COPD are believed to be generated by the re-opening of collapsed airways, which result from chronic inflammation, secretions, and loss of cartilaginous support through inflammation. However, it is unclear whether crackle characteristics can be used to identify COPD. This is the first study to examine the relationship between specific added lung sounds (crackles) and measurements of conductive airways and emphysema score obtained from high-resolution computed tomography (HRCT) in vivo in humans. A predictive relationship might permit the use of lung sounds as a biomarker for COPD. A convenience sample of 26 subjects was recruited into the study and consisted of 9 healthy non-smokers, 9 healthy smokers, and 8 subjects with mild or moderate COPD. Lung sound data were recorded using a digital stethoscope connected to a laptop computer. Airway diameter, emphysema score, and percentage of wall area were measured from HRCT scans. The analysis showed that there were no statistically significant differences in crackle characteristics (the number of crackles per breathing cycle and crackle 2-cycle duration) between the 3 subject groups. Both crackle 2-cycle duration and crackle number showed some significant correlation with airway parameters at some branch generations, but due to the large number of correlations performed, these were consistent with chance findings. Although there were some significant correlations between crackle characteristics and measurements of the conductive airways and emphysema score, the possibility that these correlations have occurred by chance cannot be ruled out. Therefore, this study provides no conclusive evidence that crackle characteristics are related to HRCT variables in COPD.


Solvatochromic sensors detect proteome aggregation in stressed liver tissues with hepatic cancer and cirrhosis.
Protein misfolding and aggregation involve complex cellular processes with clinical implications in various diseases. However, the detection of aggregated proteomes without defined 3-D structures in a complex biological milieu is challenging. This study utilizes chromone scaffold-based environment-sensitive fluorophores P1 and P2 to detect misfolded and aggregated proteome in stressed liver cells and the liver tissues diseased patients. The reported crystallization induced emission probes (P1 and P2) exhibit both polarity and viscosity sensitivity, with emission intensity and wavelength linearly correlated to viscosity and polarity. Meanwhile, P1 and P2 selectively and generally fluoresce upon binding to various aggregated proteins. In hepatic cells, P2 outperforms P1 in detecting stress-induced global proteome aggregation. In mouse liver tissue upon drug-induced injury, the fluorescence intensity of P2 correlated with the severity of liver injury, serving as an earlier indicator for liver stress prior to ALT/AST increase. The quantification of emission wavelength reveals lower micro-environmental polarity in liver-injury tissue. In patient-derived tissues with hepatic cancer and cirrhosis, P1 and P2 also report on the presence of aggregated proteome. Together, the reported solvatochromic proteome aggregation sensors can detect hepatic proteome aggregation and analyze its local polarity in cultured cell lines, animal model tissues, and human clinical samples.


Suppression of the activity of arbuscular mycorrhizal fungi by the soil microbiota.
Arbuscular mycorrhizal fungi (AMF) colonise roots of most plants; their extra-radical mycelium (ERM) extends into the soil and acquires nutrients for the plant. The ERM coexists with soil microbial communities and it is unresolved whether these communities stimulate or suppress the ERM activity. This work studied the prevalence of suppressed ERM activity and identified main components behind the suppression. ERM activity was determined by quantifying ERM-mediated P uptake from radioisotope-labelled unsterile soil into plants, and compared to soil physicochemical characteristics and soil microbiome composition. ERM activity varied considerably and was greatly suppressed in 4 of 21 soils. Suppression was mitigated by soil pasteurisation and had a dominating biotic component. AMF-suppressive soils had high abundances of Acidobacteria, and other bacterial taxa being putative fungal antagonists. Suppression was also associated with low soil pH, but this effect was likely indirect, as the relative abundance of, e.g., Acidobacteria decreased after liming. Suppression could not be transferred by adding small amounts of suppressive soil to conducive soil, and thus appeared to involve the common action of several taxa. The presence of AMF antagonists resembles the phenomenon of disease-suppressive soils and implies that ecosystem services of AMF will depend strongly on the specific soil microbiome.


Measuring transport of water across the peritoneal membrane.
Mechanisms of water flow across the peritoneal membrane include diffusion, convection, and reabsorption. To understand these processes more clearly we have developed a method to measure transport of water across the peritoneal membrane. An artificial gradient of deuterated water (HDO) between blood and dialysate compartments was created in five subjects who took 0.3g per kg of body weight of D2O, which was allowed to equilibrate with total body water. During a test dwell (2 L, bicarbonate:lactate buffer, 1.36% glucose to minimize convection), frequent dialysate samples were drawn to determine the abundance of deuterium and other solutes and to calculate their time constants. Dialysate deuterium abundance was measured using flowing afterglow mass spectrometry (FA-MS). The method was combined with 125iodine-labeled albumin (RISA) to enable simultaneous estimates of intraperitoneal volume and thus calculation of the mass transfer area coefficient (MTAC) for small solutes using the Garred equation. The appearance of HDO in dialysate in four subjects is described by a single exponential fit with residuals of <1%, similar to method precision. In a fifth subject, the resolution of this method demonstrated that the best fit was a double exponential. When compared to other solutes, the time constant for water was as predicted by its molecular weight, with a MTAC of 38.7 +/- 4.4 mL/min. Total body water could also be estimated from the equilibrated dialysate deuterium abundance, with repeat estimates within 0.5%. Transport of water across the peritoneum can be measured with remarkable accuracy and when combined with an intraperitoneal volume estimation can be used to determine mass transfer. In conditions of low convection, the relative rate of deuterium appearance and mass transfer compared to other solutes suggests that water diffuses predominantly through the intercellular small pores.


Cross-sectional structure evolution of phase-separated spin-coated ethylcellulose/hydroxypropylcellulose films during solvent quenching.
Porous phase-separated ethylcellulose/hydroxypropylcellulose (EC/HPC) films are used to control drug transport out of pharmaceutical pellets. The films are applied on the pellets using fluidized bed spraying. The drug transport rate is determined by the structure of the porous films that are formed as the water-soluble HPC leaches out. However, a detailed understanding of the evolution of the phase-separated structure during production is lacking. Here, we have investigated EC/HPC films produced by spin-coating, which mimics the industrial manufacturing process. This work aimed to understand the structure formation and film shrinkage during solvent evaporation. The cross-sectional structure evolution was characterized using confocal laser scanning microscopy (CLSM), profilometry and image analysis. The effect of the EC/HPC ratio on the cross-sectional structure evolution was investigated. During shrinkage of the film, the phase-separated structure undergoes a transition from 3D to nearly 2D structure evolution along the surface. This transition appears when the typical length scale of the phase-separated structure is on the order of the thickness of the film. This was particularly pronounced for the bicontinuous systems. The shrinkage rate was found to be independent of the EC/HPC ratio, while the initial and final film thickness increased with increasing HPC fraction. A new method to estimate part of the binodal curve in the ternary phase diagram for EC/HPC in ethanol has been developed. The findings of this work provide a good understanding of the mechanisms responsible for the morphology development and allow tailoring of thin EC/HPC films structure for controlled drug release.


Initial investigation of the corrosion stability of craniofacial implants.
Although craniofacial implants have been used for retention of facial prostheses, failures are common. Titanium undergoes corrosion in the oral cavity, but the corrosion of craniofacial implants requires evaluation. The purpose of this in vitro study was to investigate the corrosion stability of commercially pure titanium (CP Ti) exposed to simulated human perspiration at 2 different pH levels (5.5 and 8). Fifteen titanium disks were divided into 3 groups (n=5 per group). The control group was subjected to simulated body fluid (SBF) (control). Disks from the 2 experimental groups were immersed in simulated alkaline perspiration (SAKP) and simulated acidic perspiration (SACP). Electrochemical tests, including open circuit potential (3600 seconds), electrochemical impedance spectroscopy, and potentiodynamic tests were performed according to the standardized method of 3-cell electrodes. Data were analyzed by 1-way ANOVA and the Tukey honestly significant difference tests (α=.05). Simulated human perspiration reduced the corrosion stability of CP Ti (P<.05). The SBF group presented the lowest capacitance values (P<.05). SAKP and SACP groups showed increased values of capacitance and showed no statistically significant differences (P>.05) from each other. The increase in capacitance suggests that the acceleration of the ionic exchanges between the CP Ti and the electrolyte leads to a lower corrosion resistance. SAKP reduced the oxide layer resistance of CP Ti (P<.05), and an increased corrosion rate was noted in both simulated human perspiration groups. Craniofacial implants can corrode when in contact with simulated human perspiration, whereas alkaline perspiration shows a more deleterious effect. Perspiration induces a more corrosive effect than simulated body fluid.


The Effect of a Receding Saline Lake (The Salton Sea) on Airborne Particulate Matter Composition.
The composition of ambient particulate matter (PM) and its sources were investigated at the Salton Sea, a shrinking saline lake in California. To investigate the influence of playa exposure on PM composition, PM samples were collected during two seasons and at two sites around the Salton Sea. To characterize source composition, soil samples were collected from local playa and desert surfaces. PM and soil samples were analyzed for 15 elements using mass spectrometry and X-ray diffraction. The contribution of sources to PM mass and composition was investigated using Al-referenced enrichment factors (EFs) and source factors resolved from positive matrix factorization (PMF). Playa soils were found to be significantly enriched in Ca, Na, and Se relative to desert soils. PMF analysis resolved the PM10 data with four source factors, identified as Playa-like, Desert-like, Ca-rich, and Se. Playa-like and desert-like sources were estimated to contribute to a daily average of 8.9% and 45% of PM10 mass, respectively. Additionally, playa sources were estimated to contribute to 38-68% of PM10 Na. PM10 Se concentrations showed strong seasonal variations, suggesting a seasonal cycle of Se volatilization and recondensation. These results support the importance of playas as a source of PM mass and a controlling factor of PM composition.


A Maximum Likelihood Approach for Depth Field Estimation Based on Epipolar Plane Images.
In this paper, a multi-resolution method for depth estimation from dense image arrays is presented. Recent progress in consumer electronics has enabled the development of low cost hand-held plenoptic cameras. In these systems, multiple views of a scene are captured in a single shot by means of a micro-lens array placed on the focal point of the first camera lens, in front of the imaging sensor. These views can be processed jointly to obtain accurate depth maps. In this contribution, to reduce the computational complexity associated to global optimization schemes based on match cost functions, we make a local estimate based on the maximization of the total log-likelihood spatial density aggregated along the epipolar lines corresponding to each view pair. This method includes the local maximum likelihood estimation of the depth field based on epipolar plane images. To face the potential accuracy losses associated to the ambiguity problem that arises in flat surface regions while preserving bandwidth in correspondence of the edges, we adopt a multi-resolution scheme. In practice, the depth map resolution is reduced in regions where maximizing the higher resolution functional is ill-conditioned. The main benefits of the proposed system are in a reduced computational complexity and a high accuracy of the estimated depth. Experimental results show that the proposed scheme represents a good tradeoff among accuracy, robustness, and discontinuities handling.


Micronuclei Frequency in Tumors Is a Predictive Biomarker for Genetic Instability and Sensitivity to the DNA Repair Inhibitor AsiDNA.
Therapeutic strategies targeting DNA repair pathway defects have been widely explored, but often only benefit small numbers of patients. Here we characterized potential predictive biomarkers for treatment with AsiDNA, a novel first-in-class DNA repair inhibitor. We evaluated genetic instability and DNA repair defects by direct and indirect assays in 12 breast cancer cell lines to estimate the spontaneous occurrence of single-strand and double-strand breaks (DSB). For each cell line, we monitored constitutive PARP activation, spontaneous DNA damage by alkaline comet assay, basal micronuclei levels, the number of large-scale chromosomal rearrangements (LST), and the status of several DNA repair pathways by transcriptome and genome analysis. Sensitivity to AsiDNA was associated with a high spontaneous frequency of cells with micronuclei and LST and specific alterations in DNA repair pathways that essentially monitor DSB repair defects. A high basal level of micronuclei as a predictive biomarker for AsiDNA treatment was validated in 43 tumor cell lines from various tissues and 15 models of cell- and patient-derived xenografts. Micronuclei quantification was also possible in patient biopsies. Overall, this study identified genetic instability as a predictive biomarker for sensitivity to AsiDNA treatment. That micronuclei frequency can be measured in biopsies and does not reveal the same genetic instability as conventional genome assays opens new perspectives for refining the classification of tumors with genetic instability. Cancer Res; 77(16); 4207-16. ©2017 AACR.


The Association of the Average Epinephrine Dosing Interval and Survival With Favorable Neurologic Status at Hospital Discharge in Out-of-Hospital Cardiac Arrest.
For patients with out-of-hospital cardiac arrest, the recommended dosing interval of epinephrine is 3 to 5 minutes, but this recommendation is based on expert opinion without data to guide optimal management. We seek to evaluate the association between the average epinephrine dosing interval and patient outcomes. In a secondary analysis of the Resuscitation Outcomes Consortium continuous chest compression trial, we identified consecutive patients treated with greater than or equal to 2 doses of epinephrine. We defined average epinephrine dosing interval as resuscitation duration after the first dose of epinephrine divided by the total administered epinephrine, and categorized the dosing interval in minutes as less than 3, 3 to less than 4, 4 to less than 5, and greater than or equal to 5. We fit a logistic regression model to estimate the association of the average epinephrine dosing interval category with survival with favorable neurologic status (modified Rankin Scale score ≤3) at hospital discharge. We included 15,909 patients (median age 68 years [interquartile range 56 to 80 years], 35% women, 13% public location, 46% bystander cardiopulmonary resuscitation, and 19% initial shockable rhythm). The median epinephrine dosing interval was 4.3 minutes (interquartile range 3.5 to 5.3 minutes). Survival with favorable neurologic status occurred in 4.7% of patients. Compared with the reference dosing interval of less than 3 minutes, longer epinephrine dosing intervals were associated with lower survival with favorable neurologic status: dosing interval 3 to less than 4 minutes, adjusted odds ratio 0.44 (95% confidence interval 0.32 to 0.60); 4 to less than 5 minutes, adjusted odds ratio 0.26 (95% confidence interval 0.18 to 0.36); and greater than or equal to 5 minutes, adjusted odds ratio 0.21 (95% confidence interval 0.15 to 0.30). In this out-of-hospital cardiac arrest series, a shorter average epinephrine dosing interval was associated with improved survival with favorable neurologic status.


Network spandrels reflect ecological assembly.
Ecological networks that exhibit stable dynamics should theoretically persist longer than those that fluctuate wildly. Thus, network structures which are over-represented in natural systems are often hypothesised to be either a cause or consequence of ecological stability. Rarely considered, however, is that these network structures can also be by-products of the processes that determine how new species attempt to join the community. Using a simulation approach in tandem with key results from random matrix theory, we illustrate how historical assembly mechanisms alter the structure of ecological networks. We demonstrate that different community assembly scenarios can lead to the emergence of structures that are often interpreted as evidence of 'selection for stability'. However, by controlling for the underlying selection pressures, we show that these assembly artefacts-or spandrels-are completely unrelated to stability or selection, and are instead by-products of how new species are introduced into the system. We propose that these network-assembly spandrels are critically overlooked aspects of network theory and stability analysis, and we illustrate how a failure to adequately account for historical assembly can lead to incorrect inference about the causes and consequences of ecological stability.


Cardiac arrest in a child following cranioplasty.
Craniofacial surgery in paediatric patients is associated with several complications, including severe bleeding and venous air embolism. We present a case of an 18 months, 10 kilogramme weight child who had cardiac arrest after completion of surgery, but before extubation. Possibility of both haemorrhage and venous air embolism is discussed.


DNA polymorphism of HLA class II genes in alopecia areata.
We investigated the DNA restriction polymorphism (RFLP) of the Major Histocompatibility Complex (MHC) class II genes: HLA-DQA, -DQB, -DPA, and -DPB in 20 Danish patients with alopecia areata (AA) and in healthy Danes. The frequency in AA of the DQB1*0301 and DQw7 associated DQB Bgl/II 4.2 kb fragment was increased to 65.0 per cent compared to 23.2 per cent in controls (RR = 6.1; p less than 10(-3)) suggesting that the previously reported associations between AA and both DR4 and DR5 is secondary to an association between AA and DQB1*0301, which codes for the beta-chain of the HLA-DQ molecule of the serologically defined HLA-DQw7 specificity. Individuals who carried both DQA1*0501 and DQB1*0301 seemed to have a further increased risk of developing AA compared to individuals carrying only one of these HLA class II genes. Analysis of the combined presence of DQB1*0301 and DPA1*0103 in AA suggests that an additive risk effect (synergism or interaction) exists between the DQB1*0301 and DPA1*0103 alleles which are situated at different HLA class II loci.


Clinical value of next-generation sequencing compared to cytogenetics in patients with suspected myelodysplastic syndrome.
Next-generation sequencing (NGS) increasingly influences diagnosis, prognosis and management of myelodysplastic syndrome (MDS). In addition to marrow morphology and flow cytometry, our institution performs cytogenetics (CG) and NGS-based testing routinely in patients with suspected MDS. We evaluated the relative value of NGS in the assessment of patients with suspected MDS. We initially compared the diagnostic and prognostic information derived from CG and NGS in 134 patients. NGS enhanced the diagnostic yield compared to CG for clonal myeloid disorders (sensitivity 77% vs. 42·2%; specificity 90·2% vs. 78%; positive predictive value 92·8% vs. 76%; and negative predictive value 70·8% vs. 45·5%). The identification of poor prognosis mutations by NGS altered risk category in 27/39 (69·2%) patients with MDS with good/intermediate risk CG. Subsequently, we prospectively evaluated 70 patients with suspected MDS using an 'NGS-first approach' with CG restricted to samples with morphological abnormalities. We rarely identified mutations or CG abnormalities in patients without dysplastic features. NGS has a superior diagnostic performance compared to CG in patients with suspected MDS. We estimate that by using an 'NGS-first approach' we could reduce karyotyping by approximately 30%.


Guideline-adherence in the treatment of symptomatic urolithiasis in children and adolescents in southwestern Germany.
Approximately 1% of urolithiasis cases in Germany affect children. Interdisciplinary groups have agreed on national and international guidelines for children to recommend appropriate treatment pathways. The aim of this retrospective and preliminary study is to analyze whether adherence to current guidelines for pediatric stone disease in southwestern Germany is feasible. During 2014 to 2017 24 children and adolescents (nine female, 15 male, median age 9.7 years), were treated for symptomatic urolithiasis in our institutions. We retrospectively collected clinical and operative courses. Clinical pathways were compared to previous guideline recommendations of the EAU 2014 and the German S2k guideline 2015. 17 of the 24 patients were treated according to guideline recommendations (71%). Non-adherency was based on parental decisions in two and technical/medical considerations in five cases. In 11 children (45.8%) secondary or adjunctive treatments were necessary, in three of the seven non-adherently treated (43%) and in eight of the 17 adherently treated children (47%). Our daily treatment approach seems to comply well with current pediatric stone guidelines. Nevertheless, guideline-non-adherent decision making emphasizes their strength and limitations, as specific clinical situations in children may require an individual treatment plan, as non-predictable conditions may occur.


Cumulative risk and asthma outcomes in inner-city African-American youth.
A cumulative risk framework was used to examine the impact of the presence of multiple risk factors on key asthma outcomes (i.e., health-related quality of life [HRQoL], severity) for a sample of 149 inner-city African-American youth with asthma. The presence of a greater number of risk factors was associated with lower HRQoL and greater severity, regardless of age or gender. Cumulative risk methodology, in combination with selection of risk factors based on theoretical and empirical work, is a viable option for researchers and clinicians who are interested in examining the impact of multiple risk factors on disease functioning and status.


Environmental impacts of a reduced flow stretch on hydropower plants.
In Brazil, given its privileged hydrology, the unexplored economic use of water resources has many dimensions, such as hydroelectric power. This energy will face increasingly rigorous social and environmental impact assessments (40% of potential is located in the Amazon region). Hydropower inventory studies conducted over decades, with solutions such as ecological river flows, that flood smaller areas and reduce natural river flows modifications, are being reviewed. The river extension from dam to the point where the waters are returned after the powerhouse is known as the Reduced Flow Stretch (RFS). Even mega-projects, such as the 11.3 GW Belo Monte dam, are designed with deviating flows reaching an astounding 13,000 m 3/s (excavated material higher than Panama Canal). RFS requires to be carefully studied to achieve appropriate ecological flows, since RFS flows increased reduces the plant's electricity production to the same installed capacity. Balancing RFS requirements and hydroelectric power remains a challenge and, clearly, there is no consensus. Here, we performed an analysis of the main environmental impacts caused by RFS requirements, considering the multiple water use specific for each dam site. The natural variability of river flows provides diversity of habitats and maintains the richness and complexity of biological communities. Therefore, the present study has great ecological, social and economic relevance, since proper evaluation of the RFS requirements avoids potential destabilization of biological communities and even loss of biodiversity. This type of arrangement was more common in dams located in headwaters of rivers, as in the slopes of the Andes mountain range, and in regions like the Alps. There are many hydroelectric plants in South America and Europe that have this type of arrangement of engineering works. But the times are different and the environmental impacts have to be better evaluated. A final aspect also involves the maintenance of ecological flows downstream of dams. Regularization reservoirs need to keep downstream, even if they do not have a TVR, adequate flows that represent minimally the seasonality of the river, with floods and droughts, that propitiate the maintenance of the ecosystems downstream. There are cases such as the Sobradinho Plant in the São Francisco River that has been much questioned in this regard, especially when the climate is changing in the basin, with long periods of drought, and with increasing water use. So this is a very important and increasingly current issue.


Childhood absence epilepsy: Elctroclinical features and diagnostic criteria.
To analyze the electroclinical features of children with childhood absence epilepsy (CAE) and discuss the diagnostic criteria for CAE. The video-electroencephalogram (VEEG) database in our hospital was searched using "absence seizures" and "3-Hz generalized spike and waves (GSW)" as key-words. Other epileptic syndromes with typical absence seizures were carefully excluded. Children meeting the CAE diagnostic criteria of the International League Against Epilepsy (ILAE) in 1989 were further evaluated with the diagnostic criteria proposed by Panayiotopoulos in 2005. Totally 37 children met the 1989 ILAE criteria of CAE. The onset age of absence seizures ranged from 3 to 11 years. All patients had frequent absence seizures (5-60 times per day). Two patients (5.4%) had generalized tonic-clonic seizures. Hyperventilation induced absences in all patients. VEEG confirmed that 7 patients (18.9%) had only simple absences, 25 patients (67.6%) had only complex absences, and 5 patients (13.5%) had both simple and complex absences. Ictal EEG showed 3Hz GSW discharges in all patients. The seizure duration ranged from 3 to 40s. Four patients (10.8%) had two spikes per wave in ictal EEG. GSW fragments were found in 29 patients (78.4%) during sleep. Interictal polyspikes and waves were present in 17 patients (45.9%). Focal discharges predominantly in the anterior regions, were found in 22 patients (56.8%). Only 7 patients (18.9%) met the diagnostic criteria proposed by Panayiotopoulos in 2005. Few patients meeting the 1989 ILAE diagnostic criteria for CAE meet the new diagnostic criteria proposed by Panayiotopoulos in 2005. The new criteria for CAE are too strict to appropriately classify some patients.


Immunohistological features in the synovium obtained from clinically uninvolved knee joints of patients with rheumatoid arthritis.
The spectrum of immunohistological change in the affected joints of patients with rheumatoid arthritis has been well described. In this study, the immunohistological features in synovial membrane obtained from apparently uninvolved knee joints of 16 patients with active untreated rheumatoid arthritis were examined and compared to tissue from control subjects. Synovial tissue was obtained by needle biopsy. Hyperplasia of the synovial lining layer, present in 69%, was the most frequently observed abnormality in synovium obtained from uninvolved joints. Perivascular mononuclear cell infiltration was present in 31% and consisted predominantly of helper T-cells. Increased vascularity and fibrin deposition were not notable features. Clinically overt synovitis emerged in only two patients during a follow-up period of up to 36 months. In conclusion, a considerable degree of histological change was observed in the apparently uninvolved knee joints of patients with active rheumatoid arthritis. The presence of subclinical synovitis challenges current concepts of disease activity and clinical remission. Further study is required to determine whether the features described may be associated with progressive joint erosion.


Simulation study on compressive laminar optical tomography for cardiac action potential propagation.
To measure the activity of tissue at the microscopic level, laminar optical tomography (LOT), which is a microscopic form of diffuse optical tomography, has been developed. However, obtaining sufficient recording speed to determine rapidly changing dynamic activity remains major challenges. For a high frame rate of the reconstructed data, we here propose a new LOT method using compressed sensing theory, called compressive laminar optical tomography (CLOT), in which novel digital micromirror device-based illumination and data reduction in a single reconstruction are applied. In the simulation experiments, the reconstructed volumetric images of the action potentials that were acquired from 5 measured images with random pattern featured a wave border at least to a depth of 2.5 mm. Consequently, it was shown that CLOT has potential for over 200 fps required for the cardiac electrophysiological phenomena.


Prevalence and risk factors for postpartum anovulatory condition in dairy cows.
The objectives of this research were to determine the prevalence of the anovulatory condition within a temperate region of North America and identify cow-level and herd-level risk factors for this condition. A total of 1,341 cows from 18 herds were classified as cycling or anovular based on skim milk progesterone concentration determined at 46 and 60 +/- 7 d in milk. Calving history, periparturient disease incidence, body condition score, milk ketone concentration in the first 2 wk of lactation, and first 305-d mature-equivalent milk projections were recorded. Reproductive and culling information was retrieved monthly from the Dairy Herd Improvement Association. The cow-level prevalence of anovulation was 19.5%, with a herd-specific range from 5 to 45%. Accounting for the effect of clustering at the herd level, cows experiencing a difficult calving, cows with twin calvings, displaced abomasum, and cows with subclinical ketosis in the first week after calving were at greater risk for diagnosis of anovulation. Anovular cows within herds using ovulation synchronization programs were inseminated at the same time postpartum with a 6-percentage point reduction in the probability of pregnancy relative to cycling herdmates (29.7 vs. 35.9%, respectively), whereas anovular cows in herds breeding based on observed estrus were inseminated 8 d later and suffered a 10-percentage point reduction in the probability of pregnancy at first insemination (20.3 vs. 30.5). Time to pregnancy was delayed in anovular cows by 30 d (156 vs. 126 d). Using survival analysis, the impact of anovulation decreased with time. The daily probability of pregnancy (hazard ratio) was similar to cycling cows by 165 d in milk. The results underline the important associations of peripartum health with reproductive function and performance.


Use of woven glass fibres to reinforce a composite veneer. A fracture resistance and acoustic emission study.
The aim of this study was to investigate the possibility to reinforce the mechanically interlocked veneer of a porcelain-fused-to-metal (PFM) crown by woven glass fibre. A simulated situation to repair a fractured porcelain veneer was used in the experimental test set-up. A brass jig made into the shape of a framework of PFM maxillary central incisor crown with a retentive area at the palatal side of the incisal edge was used. A veneer were made with a restorative hybrid composite on the brass jig (control group). In the test groups, one or two layers of woven polymer pre-impregnated glass fibres (thickness: 0.06 mm/layer) were used by pressing the fibre weaves to the surface of the brass jig. Restorative hybrid composite was applied on the glass fibre weaves. Five veneers were made for all groups and the veneers were not cemented on the test jig. The veneers were loaded from the incisal edge until fracture occurred. The force was measured simultaneously with an acoustic emission analysis (AE) of the fracture propagation. Fracture force values for control veneers were 121 N and for those reinforced with one layer of glass fibres 399 N and for those reinforced with two layers of glass fibres 744 N ANOVA revealed significant difference between the mean values (P=0.003). The AE analysis showed different fracture propagation for the unreinforced and glass fibre reinforced veneers. The results of this study suggests that by placing two layers of woven glass fibres on the retentively shaped metal framework of the PFM crown before applying the restorative composite, considerably higher fracture resistance for the veneer could be obtained.


Molecular dissection of the response of the rice Systemic Acquired Resistance Deficient 1 (SARD1) gene to different types of ionizing radiation.
Exposure to ionizing radiation induces plant defenses by regulating the expression of response genes. The systemic acquired resistance deficient 1 (SARD1) is a key gene in plant defense response. In this study, the function of Oryza sativa SARD1 (OsSARD1) was investigated after exposure of seeds/plants to ionizing radiation, jasmonic acid (JA) or salicylic acid (SA). Rice seeds exposed to two types of ionizing radiations (gamma ray [GR] and ion beam [IB]) were analyzed by quantitative reverse transcription PCR (qRT-PCR) to identify the genes that are altered in response to ionizing radiation. Then, OsSARD1-overexpressing homozygous Arabidopsis plants were generated to assess the effects of OsSARD1 in the response to irradiation. The phenotypes of these transgenic plants, as well as control plants, were monitored after GR irradiation at doses of 200 and 300 Gray (Gy). The OsSARD1 transcript was strongly downregulated after exposure to GR and IB irradiation. Previous phylogenetic analysis showed that the Arabidopsis SARD1 (AtSARD1) protein is closely related to Arabidopsis calmodulin-binding protein 60g (AtCBP60g), which is known to be required for activation of SA biosynthesis. In this study, phylogenetic analysis showed that OsSARD1 was grouped with AtSARD1. The OsSARD1 gene was induced after exposure to SA and JA. The biological phenotype of OsSARD1-overexpressing Arabidopsis plants was examined. OsSARD1-overexpressing plants displayed resistance to GR; in comparison with wild-type plants, the height and weight of OsSARD1-overexpressing plants were significantly greater after GR irradiation. In addition, OsSARD1 protein was abundantly accumulated in the nucleus. The results indicate that OsSARD1 plays an important role in the regulation of the defense responses to GR and IB irradiation and exhibits phytohormone induced expression.


The Impact of Lens Opacity on SD-OCT Retinal Nerve Fiber Layer and Bruch's Membrane Opening Measurements Using the Anatomical Positioning System (APS).
To evaluate the impact of lens opacity on retinal nerve fiber layer thickness (RNFLT) and Bruch's membrane opening (BMO) measurements. Fifty-nine randomly selected patients without any other relevant ocular pathology undergoing elective routine cataract surgery in two specialized eye clinics were enrolled. RNFLT, BMO area, and BMO minimum rim width (BMO-MRW) were assessed with the Heidelberg Engineering Spectralis OCT using the anatomical positioning system (APS) prior to and 1 day after cataract surgery using a ring scan at different eccentricities of the disc (3.5, 4.1 and 4.7 mm). Lens opacity was quantified using densitometry based on Scheimpflug images (Oculus Pentacam AXL). RNFLT, BMO area, and BMO-MRW were virtually identical before and following removal of the cataractous lens. This held when assessed overall, within the six sectors for the 3.5-mm scan, or at any other eccentricity. Baseline RNFLT was not associated with lens opacity. Using the APS, RNFLT remained unchanged following cataract surgery, contrary to results reported by previous studies. Our results imply that the APS may have contributed to more precise spectral-domain optical coherence measurements, minimizing the influence of cataract on RNFLT and BMO assessments in our cohort.


Eradication of HPV post-surgical treatments, its correlation with specific types, types of surgery and the physical status.
Low-risk human papillomaviruses (HPVs) will be completely eradicated as long as most visible lesions are treated. However, it is uncertain whether this is also the case for high-risk HPVs that are capable of causing cervical cancer. Many recent studies have demonstrated a high incidence of HPV persistence during post-conization or loop electrosurgical excision (LEEP) due to high-grade cervical intraepithelial neoplasia (CIN). In this report, we correlated the post-operative HPV status with pre-operative HPV type, types of surgery and HPV's physical status. Post-operative HPV E6 amplification by nested PCR was carried out for 157 female patients with positive pre-operative HPV. They underwent LEEPs, therapeutic laser conizations, and simple or radical hysterectomies. We found that high-risk types of HPVs were eradicated in 26.4% (42/159) of patients after extirpation of the lesions. The clearance rate of HPVs increased to 39.2% (40/102), excluding patients with other high-risk (OHR) kinds of type 31, 52b and 58, since OHR persisted after almost all surgeries. Eradication of HPV after radical hysterectomies are highly expected for patients with invasive cancer (70.0%, when excluding OHR), while more than half of them with CIN continue to carry pre-operative types of HPV or some different types from before treatment. Type 33 is most frequently persistent among types 16, 18 and 33. Persistent high-risk HPVs increase the risk for recurrence of post-surgical treatments of CIN, but the incidence is not high as long as the lesion is completely removed.


Phenomics in sport: Can emerging methodology drive advanced insights?
Methodologies in applied sport science have predominantly driven a reductionist grounding to component-specific mechanisms to drive athlete training and care. While linear mechanistic approaches provide useful insights, they have impeded progress in the development of more complex network physiology models that consider the temporal and spatial interactions of multiple factors within and across systems and subsystems. For this, a more sophisticated approach is needed and the development of such a methodological framework can be considered a Sport Grand Challenge. Specifically, a transdisciplinary phenomics-based scientific and modeling framework has merit. Phenomics is a relatively new area in human precision medicine, but it is also a developed area of research in the plant and evolutionary biology sciences. The convergence of innovative precision medicine, portable non-destructive measurement technologies, and advancements in modeling complex human behavior are central for the integration of phenomics into sport science. The approach enables application of concepts such as phenotypic fitness, plasticity, dose-response dynamics, critical windows, and multi-dimensional network models of behavior. In addition, profiles are grounded in indices of change, and models consider the athlete's performance or recovery trajectory as a function of their dynamic environment. This new framework is introduced across several example sport science domains for potential integration. Specific factors of emphasis are provided as potential candidate fitness variables and example profiles provide a generalizable modeling approach for precision training and care. Finally, considerations for the future are discussed, including scaling from individual athletes to teams and additional factors necessary for the successful implementation of phenomics.


Pathology of opportunistic infections in children with acquired immune deficiency syndrome.
Opportunistic infections (OI) were diagnosed by histology and culture of biopsy and autopsy material in 15 children with the acquired immune deficiency syndrome (AIDS). The opportunistic pathogens included Pneumocystic carinii, Toxoplasma gondii, Candida species, Aspergillus species, Mycobacterium avium-intracellulare, cytomegalovirus, and herpes simplex virus. Seven of 15 patients also had multiple systemic infections with common pathogenic bacteria. Accurate diagnosis of OI in AIDS is of importance in the decision regarding the choice of appropriate antimicrobial therapy. Careful histologic assessment of the biopsy specimens; awareness of unusual features such as paucity of organisms and inflammatory reaction, "histoid" variety of reaction, lack of granuloma formation, and resemblance to Whipple's disease in certain OI; and demonstration of causative organisms by appropriate special stains and/or culture are essential in the evaluation of these patients.


Serum cytokine profiles in patients with pancreatic cancer and chronic pancreatitis.
Chronic pancreatitis (CP) may cause tumor-like lesions, creating a challenge in distinguishing between CP and pancreatic ductal adenocarcinoma (PDAC) in a patient. Given that invasive surgery is a standard cancer treatment, we aimed to examine whether a noninvasive diagnostic tool utilizing serum cytokines could safely differentiate between PDAC and CP. A pre-operative serum panel comprising 48 inflammatory cytokines, CA19-9, and C-reactive protein (CRP) was analyzed, consisting of 231 patients, 186 with stage I-III PDAC and 45 with CP. We excluded PDAC patients who underwent neoadjuvant therapy and those CP patients with other active malignancies. The laboratory variables most associated with PDAC diagnosis were assessed using logistic regression and selected using the lasso method. The cytokines CTACK, GRO-α, and β-NGF were selected alongside CA19-9 and CRP for our differential diagnostic model. The area under the curve (AUC) for our differential diagnostic model was 0.809 (95% confidence interval [CI] 0.738-0.880), compared with 0.791 (95% CI 0.728-0.854) for CA19-9 alone (not significant). We found that inflammatory cytokines CTACK, GRO-α, and β-NGF alongside CA19-9 and CRP may help distinguish PDAC from CP.


Sprouty genes regulate proliferation and survival of human embryonic stem cells.
Sprouty (Spry) genes encode negative regulators of receptor tyrosine kinase (RTK) signaling, which plays important roles in human embryonic stem cells (hESCs). SPRY2 and SPRY4 are the two most highly expressed Sprouty family members in hESCs, suggesting that they may influence self-renewal. To test this hypothesis, we performed siRNA-mediated knock down (KD) studies. SPRY2 KD resulted in increased cell death and decreased proliferation, whereas SPRY4 KD enhanced survival. In both cases, after KD the cells were able to differentiate into cells of the three germ layers, although after SPRY2 KD there was a tendency toward increased ectodermal differentiation. SPRY2 KD cells displayed impaired mitochondrial fusion and cell membrane damage, explaining in part the increased cell death. These data indicate that Sprouty genes regulate pathways involved in proliferation and cell death in hESCs.


Contemporary denture base resins: Part 2.
Provision of partial and complete dentures constructed from resin is commonplace and a satisfactory outcome requires the consideration of the properties of the resin, the oral tissues and prosthodontic principles. This second of a two-part series examines the advantages and disadvantages of flexible nylon denture base resins, which have found popularity for the provision of partial dentures. Adverse effects of denture base resins are examined and the benefits and shortcomings of softliners are explored. Chairside adjustment and polishing, and denture hygiene are also discussed. Knowledge of contemporary denture base resin systems will help to achieve optimal outcomes in removable prosthodontics.


Elevated IL-16 levels in patients with systemic lupus erythematosus are associated with disease severity but not with genetic susceptibility to lupus.
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by several immunological abnormalities. The pathogenic importance of T cells in this disease is well established. Interleukin-16 (IL-16) is a cytokine which is mainly produced by CD8+ T cells and induces chemotaxis of CD4+ T cells and monocytes. IL-16 levels have been shown to be elevated in SLE patients in a cross-sectional study, but the mechanism is unknown. To explore whether the increased IL-16 levels are associated with genetic background or the disease itself, we investigated the IL-16 level in healthy first-degree family members of SLE patients and SLE patients who were followed over time with regard to disease activity. We observed high IL-16 levels in SLE patients with severe disease compared to SLE patients with non-severe disease and healthy controls. Furthermore, IL-16 levels in first-degree relatives were not different from those in healthy controls. These results suggest that high IL-16 levels are associated with severity of SLE, but not with genetic susceptibility to SLE. Finally, we followed the disease activity of SLE patients over time, which showed significant correlation between the SLE disease activity index and IL-16, ESR and the complement components C3, C4 and CH50. In conclusion, these results implicate an association of IL-16 with SLE.


A novel approach for modelling and classifying sit-to-stand kinematics using inertial sensors.
Sit-to-stand transitions are an important part of activities of daily living and play a key role in functional mobility in humans. The sit-to-stand movement is often affected in older adults due to frailty and in patients with motor impairments such as Parkinson's disease leading to falls. Studying kinematics of sit-to-stand transitions can provide insight in assessment, monitoring and developing rehabilitation strategies for the affected populations. We propose a three-segment body model for estimating sit-to-stand kinematics using only two wearable inertial sensors, placed on the shank and back. Reducing the number of sensors to two instead of one per body segment facilitates monitoring and classifying movements over extended periods, making it more comfortable to wear while reducing the power requirements of sensors. We applied this model on 10 younger healthy adults (YH), 12 older healthy adults (OH) and 12 people with Parkinson's disease (PwP). We have achieved this by incorporating unique sit-to-stand classification technique using unsupervised learning in the model based reconstruction of angular kinematics using extended Kalman filter. Our proposed model showed that it was possible to successfully estimate thigh kinematics despite not measuring the thigh motion with inertial sensor. We classified sit-to-stand transitions, sitting and standing states with the accuracies of 98.67%, 94.20% and 91.41% for YH, OH and PwP respectively. We have proposed a novel integrated approach of modelling and classification for estimating the body kinematics during sit-to-stand motion and successfully applied it on YH, OH and PwP groups.


Surface Mobility and Ordered Rearrangement of Immobilized DNA Origami.
The immobilization of DNA nanostructures on a surface is a key step for the integration of DNA-based material in nanotechnology for electronic or sensorial applications. Thereby the arrangement and distribution at the substrate surface is of growing interest. Top-down approaches such as lithography have been reported, but show certain limitations regarding costs and/or throughput. Here we present a self-assembly effect observed when already immobilized and dried origami preparations were again rehydrated under certain conditions, resulting in a certain ordering of densely packed origami structures. We investigate the influence of different parameters in order to reveal the underlying mechanisms, and find that subsequent droplet formation and interfacial tension during the droplet drying play a role. Further adjustment of these parameters could develop the introduced effect to an additional tool for controlled integration of DNA nanostructures.


Increased lymphocyte adherence to human arterial endothelial cell monolayers in the context of allorecognition.
The interactions of alloreactive T lymphocytes with the vascular endothelium were studied in an in vitro model of lymphocyte adherence to cultured human arterial endothelial cell (HAEC) monolayers. Donor-primed lymphocytes (DPL) were shown to have significantly greater adherence to donor HAEC than were third-party primed lymphocytes. Limiting dilution analysis of adherent DPL showed an enrichment of donor-reactive lymphocytes compared with nonadherent DPL. This study examines the allospecific nature of this increased lymphocyte adherence. HAEC constitutively express class I HLA Ag and can be induced by IFN-gamma to express class II Ag. DPL adherence to class I+ HAEC was inhibited only in the presence of mAb directed against class I Ag. DPL adherence to class I+ and class II+ HAEC was inhibited in the presence of mAb directed against class I and class II Ag. Class I- and class II-specific adherence was also shown to involve CD8 and CD4 molecules, respectively, whereas lymphocyte function-associated Ag do not appear to play a major role in long term alloreactive lymphocyte adherence to HAEC. These findings suggest that alloreactive lymphocyte adherence to HAEC is mediated by two mechanisms. One is based on allorecognition, primarily of HLA Ag, and the other is related to presumably non-Ag-specific interactions between activated lymphocytes and the vascular endothelium. The studies presented provide evidence to suggest that HLA-specific lymphocyte adherence to endothelium may significantly contribute to the development of alloreactive lymphocyte infiltrates within the allograft.


The item position effects in international examinations: the roles of gender.
The goal of the present study was to evaluate the roles of item position in terms of item difficulty levels in the assessment of aptitude. Using data from a National Examination in Saudi Arabia, the item position effect was evaluated as a teacher licensure test (GTLT) was administered using five different forms with the same items appearing in a different order. Results indicated minuscule in magnitude position effects estimates, overall, with initially 11.1% of the tests being significant but all of them failing to reach significance using the Holm-Bonferroni's and Sidak corrective procedures. With regard to gender, item position effects emerged in 47.6% of the tests after adjusting the level of significance using the Sidak correction. Interestingly, the direction of effect was consistent so that in 87% of the significant gender comparisons, item position effects were in the direction where females were spending more time on items when they appeared in later positions on the test compared to males. Assuming that items appearing later on the test are likely more difficult, the present findings suggest a profile of deep processing and active engagement in females when facing achievement tests.


Metabolic syndrome and periodontal disease.
It is important for a dentist to be well informed and updated on the latest research on the association of oral and systemic health. Of late, the metabolic syndrome has gained importance in dental literature, and metabolic syndrome and periodontal disease have been linked. Metabolic syndrome (MeS) is a group of three or more (up to five) interrelated metabolic abnormalities, which increases the risk of cardiovascular morbidity and mortality. Also, both MeS and periodontal disease may be linked through a common pathophysiological pathway. Some studies have been conducted to show such an association and additional studies are required to establish this association. A dental surgeon can play a major role in evaluating patients with MeS and thus prevent the development of overt cardiovascular disease.


Asymmetric anti-resonant reflecting optical waveguides (arrow) as chemical sensors.
Anti-resonant reflecting optical waveguides (ARROW) are described which trap light in a low index layer between a lower, high-index confining layer and an upper total internal reflection boundary. In this configuration, most of the light (greater than 80%) travels in the low index porous polymer layer, the refractive index of which is monitored by examining the angle at which light is coupled out of the waveguide. It is shown that asymmetric ARROW sensors can be constructed using conventional chemical vapour deposition and spin-coating techniques and their sensitivity is as predicted by theoretical modelling.


Determination of Peroxide Explosive TATP and Related Compounds by Dielectric Barrier Discharge Ionization-Mass Spectrometry (DBDI-MS).
Dielectric barrier discharge ionization-mass spectrometry (DBDI-MS), which is based on the use of a low temperature helium plasma as ionization source, is used for the determination of trace amounts of triacetone triperoxide (TATP) and its homologue diacetone diperoxide (DADP) from surfaces. TATP is observed as [M+NH4]+ adduct, whereas DADP is observed as [M+O+NH4]+. Measurement of DADP with varying deuteration degrees (DADP, DADP-d6, and DADP-d12) indicates that DADP undergoes oxidation when ionized by DBDI. If acetonitrile is used as deposition solvent, TATP tends to show fragmentation and is not only detected as [M+NH4]+ but as [M-CH4+NH4]+ and [M-C2H4+NH4]+ as well. Quantification of TATP solutions from glass surfaces by DBDI-MS, using TATP-3,6,9-13C as internal standard, was done and validated using an LC/APCI-MS method. Achievable limits of detection (LOD) for TATP are equivalent to the deposition of 15 ng TATP and are comparable with other ambient desorption/ionization mass spectrometric techniques like desorption electrospray ionization (DESI).


A robust and high-capacity [(35)S]GTPgammaS binding assay for determining antagonist and inverse agonist pharmacological parameters of histamine H(3) receptor ligands.
Guanosine 5'-O-(3-[(35)S]thio)triphosphate ([(35)S]GTPgammaS) binding assays were established and utilized as a reliable and high-capacity functional assay for determining antagonist and inverse agonist pharmacological parameters of novel histamine H(3) ligands, at the recombinant human H(3) receptor. [(35)S]GTPgammaS binding assays were performed with membranes prepared from human embryonic kidney 293 cells stably expressing the full-length (445 amino acids) human H(3) receptor isoform, at approximately 1 pmol/mg of protein. Utilizing robotic liquid handling, assay filtration, and scintillation counting in a 96-well format, concentration-response curves were determined for up to 40 compounds per assay. The imidazole-containing H(3) receptor antagonist ciproxifan and the non-imidazole antagonist ABT-239 inhibited (R)-alpha-methylhistamine (RAMH)-stimulated [(35)S]GTPgammaS binding in a competitive manner, and negative logarithm of the dissociation equilibrium constant (pK(b)) values determined for nearly 200 structurally diverse H(3) antagonists were very similar to the respective negative logarithm of the equilibrium inhibition constant values from N-alpha-[(3)H]methylhistamine competition binding assays. H(3) antagonists also concentration-dependently decreased basal [(35)S]GTPgammaS binding, thereby displaying inverse agonism at the constitutively active H(3) receptor. At maximally effective concentrations, non-imidazole H(3) antagonists inhibited basal [(35)S]GTPgammaS binding by approximately 20%. For over 100 of these antagonists, negative logarithm of the 50% effective concentration values for inverse agonism were very similar to the respective pK(b) values. Both H(3) receptor agonist-dependent and -independent (constitutive) [(35)S]GTPgammaS binding were sensitive to changes in assay concentrations of sodium, magnesium, and the guanine nucleotide GDP; however, the potency of ABT-239 for inhibition of RAMH-stimulated [(35)S]GTPgammaS binding was not significantly affected. These robust and reliable [(35)S]GTPgammaS binding assays have become one of the important tools in our pharmacological analysis and development of novel histamine H(3) receptor antagonists/inverse agonists.


Coup-TF1 and Coup-TF2 control subtype and laminar identity of MGE-derived neocortical interneurons.
Distinct cortical interneuron (CIN) subtypes have unique circuit functions; dysfunction in specific subtypes is implicated in neuropsychiatric disorders. Somatostatin- and parvalbumin-expressing (SST+ and PV+) interneurons are the two major subtypes generated by medial ganglionic eminence (MGE) progenitors. Spatial and temporal mechanisms governing their cell-fate specification and differential integration into cortical layers are largely unknown. We provide evidence that Coup-TF1 and Coup-TF2 (Nr2f1 and Nr2f2) transcription factor expression in an arc-shaped progenitor domain within the MGE promotes time-dependent survival of this neuroepithelium and the time-dependent specification of layer V SST+ CINs. Coup-TF1 and Coup-TF2 autonomously repress PV+ fate in MGE progenitors, in part through directly driving Sox6 expression. These results have identified, in mouse, a transcriptional pathway that controls SST-PV fate.


A new lymphocyte surface protein present in normal urine. I. Isolation and physicochemical properties.
A lymphocyte surface glycoprotein designated urinary acidic antigen (UA) has been isolated from normal urine by a combination of preparative isoelectric focusing and ammonium sulfate precipitation. It has an m.w. of 14,000 to 17,500 daltons, and is approximately 60% carbohydrate and 40% amino acid in content. The protein exhibited the following physical properties: S20,omega = 1.24; v = 0.693 ml/g; E1%1 cm, 278 nm = 2.08; and pI-2.5. It appears to be unrelated to beta 2-microglobulin, protein HC, urinary proteose, microglobulin, or any previously described normal urine or human serum protein.


A Comparison of Patient History- and EKG-based Cardiac Risk Scores.
Patient-specific risk scores are used to identify individuals at elevated risk for cardiovascular disease. Typically, risk scores are based on patient habits and medical history - age, sex, race, smoking behavior, and prior vital signs and diagnoses. We explore an alternative source of information, a patient's raw electrocardiogram recording, and develop a score of patient risk for various outcomes. We compare models that predict adverse cardiac outcomes following an emergency department visit, and show that a learned representation (e.g. deep neural network) of raw EKG waveforms can improve prediction over traditional risk factors. Further, we show that a simple model based on segmented heart beats performs as well or better than a complex convolutional network recently shown to reliably automate arrhythmia detection in EKGs. We analyze a large cohort of emergency department patients and show evidence that EKG-derived scores can be more robust to patient heterogeneity.


[Prognostic value of cytokines and neurohormones in severe heart failure].
The screening of candidates for heart transplantation continues to present difficulties. High plasma levels of cytokines and neurohormones have been associated with a poor prognosis in heart failure but their usefulness for identifying candidates for heart transplantation is still not established. In 83 patients (59 11 years old), with systolic left ventricular dysfunction and New York Heart Association functional class III-IV, we assessed levels of aldosterone, atrial natriuretic peptide, plasma renin activity, angiotensin II, norepinephrine, endothelin, interleukin-6 and tumor necrosis factor-alpha. Over the following year, 13 patients died and 26 received heart transplantation. Mean ejection fraction was 23 6%, end-diastolic and end-systolic diameters were 73 10 and 60 10 mm, respectively. Univariate analysis identified the following variables to be associated with poor prognosis: angiotensin II (p = 0.001), norepinephrine (p = 0.003), plasma renin activity (p = 0.02), systolic blood pressure (p = 0.006), end-diastolic diameter (p = 0.02) and end-systolic diameter (p = 0.04). Multivariate regression analysis identified the following variables to be independent predictors of death or need for heart transplantation: a low cardiac index (p = 0.007), plasma angiotensin II (p = 0.001) and pulmonary capillary wedge pressure (p = 0.04) The sensitivity and specificity of angiotensin II for predicting poor outcome was only moderate according to interpretation of the receiver operating curves. Although plasma angiotensin II was the best neurohormone for identifying patients with severe heart failure and the worst prognosis, its sensitivity and specificity for predicting death or the need for heart transplantation was limited. The decision to transplant should continue to be based on clinical and hemodynamic parameters.


[Birth Cohort Technical Specification Part 2: Long Term Follow-up (T/CPMA 015.2-2020)].
The long-term follow-up is an important content of birth cohort, which focus on the dynamic cohort data collection at different stages including the pre-pregnancy, pregnancy, postpartum and fetal growth period. This document establishes specifications for the follow-up, the management of refusal to follow up and loss to follow-up, compliance maintenance and quality control in the long-term follow-up of birth cohort research.


An immunocytochemical study of changes in the human erythrocyte membrane skeleton produced by stretching examined by the quick-freezing and deep-etching method.
A quick-freezing and deep-etching method in combination with erythrocyte splitting was used to examine the cytoplasmic aspect of whole-mount human erythrocyte membranes. Various external forces induced alterations in membrane skeletal organisation during the splitting procedure. The initial change was elongation in the peripheral part of the membrane skeleton, examined by immunostaining with a monoclonal antispectrin antibody. Under severe stretching conditions, a linear rearrangement of filamentous components was evident; these were disposed parallel to the rim of the erythrocyte, while the central part of the concavity exhibited a more compacted structure. These changes resulted in a different distribution of membrane skeletal components between central rigid and peripheral flexible areas in biconcave erythrocytes. It is suggested that the reversible membrane skeletal changes in the flexible areas which resist the external forces are important for maintaining the normal framework of biconcave human erythrocytes.


Within-family selection at an otherwise unselected locus in dairy cattle.
Identification of allelic variants with economic importance is feasible via molecular genetic techniques. This information can be used to increase the frequency of favourable alleles in dairy cattle. The effect of selection on the genotype within families in the early stages of life is examined. Three different strategies are considered: (1) random mating of bull sires with bull dams and with cows, with embryo selection of young bulls and all cows; (2) random mating of bull sires with bull dams, with embryo selection of young bulls only; (3) minimizing or avoiding matings between homozygotes for the unfavourable allele, with embryo selection of young bulls. Selection strategies assume the use of reproductive technologies such as embryo transfer to produce large family sizes for within-family selection to be practiced. All the three strategies increase the frequency of the favourable allele rapidly. Strategy 1 gives the fastest increase in the frequency of the favourable allele. The increase in the frequency of the favourable allele is slower under random mating (strategy 2) than under a negative assortative mating (strategy 3). This is a novel example of increased selection response with negative assortative mating.


Rationalising the effects of ionic liquids on a nucleophilic aromatic substitution reaction.
The nucleophilic aromatic substitution reaction between 1-fluoro-2,4-dinitrobenzene and ethanol was examined in a series of ionic liquids across a range of mole fractions. Temperature-dependent kinetic analyses were undertaken to determine the activation parameters for this reaction at the highest mole fraction. As the mole fraction of ionic liquid was increased, the rate constant of the reaction also increased, however the microscopic origin of the rate enhancement was shown to be different between different ionic liquids and also between different solvent compositions. These results indicate a balance between microscopic interactions that result in the observed solvent effects and a qualitative method for analysing such interactions is introduced.


Surface enhanced anti-Stokes one-photon luminescence from single gold nanorods.
Anti-Stokes one-photon luminescence from a single gold nanorod is experimentally investigated. The anti-Stokes emission of gold nanorods is enhanced and strongly modulated by localized surface plasmon resonance (LSPR). It is found that the polarization dependence of the anti-Stokes emission is in strong correlation with that of the Stokes emission. Further experiments provide evidence that LSPR significantly enhanced both excitation and emission processes. Moreover, the line shape of the anti-Stokes emission is dependent on the surface temperature, which is related to the distribution of free electrons near the Fermi level. This discovery provides an effective method in principle to probe localized temperature at nanoscale dimension. Here, the reported results about the anti-Stokes emission provide more understanding for the photoemission process from the plasmonic nanostructures.


Molecular characterisation of Giardia intestinalis assemblages from human isolates at a tertiary care centre of India.
The aim of the study was to determine the genetic heterogeneity of Giardia intestinalis isolates detected in stool samples of the study population using polymerase chain reaction assay and restriction fragment length polymorphism. We also tried to correlate the association/differences between the clinical symptomatology and infection by different assemblages (genotypes) of G. intestinalis. This cross-sectional study was conducted from April 2008 to June 2010. A total of 40 adults (n = 40) and 42 children (n = 42) below the age of 12 years with the clinical suspicion of giardiasis and with the onset of one or more of the following five symptoms, i.e., loose stool, nausea, weight loss, fatigue and foul smelling faeces and confirmed laboratory diagnosis of giardiasis at least once during the current episode of diarrhoea were included in this study. Of the 82 patients (males 66) enrolled in the study, 70 (85%) presented with diarrhoea (56 males) and 12 (15%) without diarrhoea (10 males). Out of 70 diarrheic patients, 61 (87%) had chronic diarrhoea, 8 (11.5%) had acute diarrhoea and 1 (1.5%) had persistent diarrhoea. Of the total patients, 63 (77%) were clinically assessed and were apparently immunocompetent, whereas, 19 (23%) immunocompromised patients had different underlying conditions besides giardiasis. Genotyping identified all 82 (100%) isolates as assemblage B. We found that assemblage B of G. intestinalis presents with all kinds of clinical features ranging from asymptomatic carriage to acute, persistent or chronic diarrhoea.


Delivery strategies and potential targets for siRNA in major cancer types.
Small interfering RNA (siRNA) has gained attention as a potential therapeutic reagent due to its ability to inhibit specific genes in many genetic diseases. For many years, studies of siRNA have progressively advanced toward novel treatment strategies against cancer. Cancer is caused by various mutations in hundreds of genes including both proto-oncogenes and tumor suppressor genes. In order to develop siRNAs as therapeutic agents for cancer treatment, delivery strategies for siRNA must be carefully designed and potential gene targets carefully selected for optimal anti-cancer effects. In this review, various modifications and delivery strategies for siRNA delivery are discussed. In addition, we present current thinking on target gene selection in major tumor types.


A Report of a Case of Segmental Zoster Paresis Demonstrated by Limb Paralysis and a Review of the Literature.
Varicella zoster virus (VZV) lies dormant in our spinal dorsal root ganglia until reactivation occurs and causes herpes zoster. VZV can spread from the dorsal root to the neighboring ventral root and cause subsequent segmental paresis. In this case report, we present the case of a 78-year-old female who was hospitalized after she developed right upper extremity paresis and altered mental status four days after the eruption of a vesicular rash involving the same dermatome. The patient received intravenous acyclovir, gabapentin, and inpatient rehabilitation. She was found to have made a full recovery one year later. Pain and a vesicular rash is the most common presentation of VZV infection in the elderly. However, segmental zoster paresis should be suspected in any patient with paralysis and a recent diagnosis of herpes zoster.


Punicalagin protects against impaired skeletal muscle function in high-fat-diet-induced obese mice by regulating TET2.
The function of skeletal muscles can be markedly hampered by obesity. Ten-eleven translocation 2 (TET2) is an important therapeutic target for ameliorating skeletal muscle dysfunction. Our previous study revealed that punicalagin (PUN) regulated TET2 in obese mice; however, whether PUN can prevent obesity-induced skeletal muscle dysfunction by regulating TET2 remains unclear. In the present study, 40 male C57BL/6J mice were divided into four groups (n = 10 per group): the control (CON) group, the high-fat-diet (HFD, negative control) group, the resveratrol (positive control) group, and the PUN group. The ratio of gastrocnemius weight to body weight (0.0097 ± 0.0016 vs. 0.0080 ± 0.0011), the grip strength (120.04 g ± 11.10 vs. 98.89 g ± 2.79), and the muscle fiber count (314.56 per visual field ± 92.73 vs. 236.44 per visual field ± 50.58) in the PUN group were higher than those in the HFD group. Moreover, the levels of the TET2 protein, 5-hydroxymethylcytosine (5hmC), and 5-formylcytosine (5fC) in skeletal muscles were significantly lower in the HFD group than those in the CON group; these levels increased after PUN treatment. Compared with the HFD group, the phosphorylation level of AMP-activated protein kinase (AMPK) α in the PUN group was higher, which effectively enhanced the stability of the TET2 protein. Besides, the ratio of (succinic acid + fumaric acid)/α-ketoglutarate in the PUN group was lower than that in the HFD group (43.21 ± 12.42 vs. 99.19 ± 37.07), and a lower ratio led to a higher demethylase activity of TET2 in the PUN group than in the HFD group. This study highlights that PUN supplementation protects against obesity-induced impairment of the skeletal muscle function via regulating the protein stability of TET2 and the enzymatic activity of TET2 demethylation.


Patterns and levels of halogenated volatile compounds in Portuguese surface waters.
The present study focused on monitoring the concentration of 14 halogenated volatile organic compounds in surface waters, including sea, estuarine, river water and industrial effluents in order to determine the most ubiquitous compounds and their concentration levels, which were used to establish their geographical and temporal distribution. EPA Method 502, based on purge and trap techniques, was used. In this method volatile organic pollutants are extracted (purged) from the water sample by bubbling inert gas through the aqueous sample. Purged sample components are trapped in a cartridge containing the polymeric sorbent Tenax and, thereafter, the cartridge is heated and backflushed with helium to desorb the trapped sample components directly into a gas chromatograph with electron capture detector (GC-ECD). The linearity range of the method varied from 0.1 to 4 microg L(-1) with a limit of detection at the low microg L(-1) level. The present study consisted of a monthly monitoring of 46 points throughout Portugal, during 14 months. Chloroform was found in 50% of the samples analyzed, its presence being correlated to both agricultural and industrial activities. Other compounds detected were tetrachloroethylene, trichloroethylene, carbon tetrachloride and 1,2,4 trichlorobenzene, which were present in 10-20% of the samples at concentrations up to 18 microg L(-1). 1,1,2,2-Tetrachloroethane and its degradation product 1,1,2-trichloroethane were found in 5% of the samples, the levels of the latter being higher than those of the parent compound in most samples. Sporadic high concentrations of some volatile halogenated organic compounds were attributed to local uses as solvents.


Reciprocal influence of protein domains in the cold-adapted acyl aminoacyl peptidase from Sporosarcina psychrophila.
Acyl aminoacyl peptidases are two-domain proteins composed by a C-terminal catalytic α/β-hydrolase domain and by an N-terminal β-propeller domain connected through a structural element that is at the N-terminus in sequence but participates in the 3D structure of the C-domain. We investigated about the structural and functional interplay between the two domains and the bridge structure (in this case a single helix named α1-helix) in the cold-adapted enzyme from Sporosarcina psychrophila (SpAAP) using both protein variants in which entire domains were deleted and proteins carrying substitutions in the α1-helix. We found that in this enzyme the inter-domain connection dramatically affects the stability of both the whole enzyme and the β-propeller. The α1-helix is required for the stability of the intact protein, as in other enzymes of the same family; however in this psychrophilic enzyme only, it destabilizes the isolated β-propeller. A single charged residue (E10) in the α1-helix plays a major role for the stability of the whole structure. Overall, a strict interaction of the SpAAP domains seems to be mandatory for the preservation of their reciprocal structural integrity and may witness their co-evolution.


FuMeGA Criteria for Visual Assessment of Postoperative 18F-Fluorocholine PET in Patients With Glioma.
Postoperative assessment is crucial in the imaging follow-up and prognosis in patients with glioma. Whereas grade of resection is defined attending to the gadolinium enhancement in early postoperative MRI, no metabolical criteria exist for postoperative PET interpretation. Based on our prospective and multicenter FuMeGA (Functional and Metabolic Glioma Analysis) ongoing study, we propose criteria for the visual interpretation of F-fluorocholine PET scans in patients undergoing brain tumor resection. The different imaging characteristics between MRI and PET may explain the discordances regarding to the postresection status with both techniques.


Direct regulation of the proglucagon gene by insulin, leptin, and cAMP in embryonic versus adult hypothalamic neurons.
The proglucagon gene is expressed not only in the pancreas and intestine but also in the hypothalamus. Proglucagon-derived peptides have emerged as potential regulators of energy homeostasis. Whether leptin, insulin, or cAMP activation controls proglucagon gene expression in the hypothalamus is not known. A key reason for this has been the inaccessibility of hypothalamic proglucagon-expressing neurons and the lack of suitable neuronal cell lines. Herein we describe the mechanisms involved in the direct regulation of the proglucagon gene by insulin, leptin, and cAMP in hypothalamic cell models. Insulin, through an Akt-dependent manner, significantly induced proglucagon mRNA expression by 70% in adult-derived mHypoA-2/10 neurons and significantly suppressed it by 45% in embryonic-derived mHypoE-39 neurons. Leptin, via the Janus kinase-2/ signal transducer and activator of transcription-3 pathway, caused an initial increase by 66 and 43% at 1 h followed by a decrease by 45 and 34% at 12 h in mHypoA-2/10 and mHypoE-39 cells, respectively. Furthermore, cAMP activation by forskolin up-regulated proglucagon expression by 87% in mHypoE-39 neurons and increased proglucagon mRNA, through Epac activation, in the mHypoE-20/2 neurons. Specific regions of the proglucagon promoter were regulated by cAMP signaling, as determined by transient transfections, whereas mRNA stability assays demonstrate that insulin and leptin increase proglucagon mRNA stability in the adult cells. These findings suggest that insulin, leptin, and cAMP act directly, but differentially, on specific hypothalamic neurons to regulate proglucagon gene expression. Because proglucagon-derived peptides are potential regulators of energy homeostasis, an understanding of hypothalamic proglucagon neurons is important to further expand our knowledge of alternative feeding circuits.


Comparison of ixekizumab with ustekinumab in moderate-to-severe psoriasis: 24-week results from IXORA-S, a phase III study.
It has been shown that the interleukin (IL)-23/IL-17 axis is critical in the pathogenesis of psoriasis. To present the primary end point (week 12) and safety and efficacy data up to week 24 from a head-to-head trial (IXORA-S) of the IL-17A inhibitor ixekizumab (IXE) vs. the IL-12/23 inhibitor ustekinumab (UST). Randomized patients received IXE (160-mg starting dose, then 80 mg every 2 weeks for 12 weeks, then 80 mg every 4 weeks, n = 136) or UST (45 mg or 90 mg weight-based dosing per label, n = 166). The primary end point was the proportion of patients reaching ≥ 90% Psoriasis Area and Severity Index improvement (PASI 90). Hommel-adjusted key secondary end points at week 12 included PASI 75, PASI 100, static Physician's Global Assessment (sPGA) score of 0 or 1, sPGA score of 0, Dermatology Life Quality Index (DLQI) score of 0 or 1, ≥ 4-point reduction on the itch numerical rating scale (NRS) and changes in itch NRS and skin pain visual analogue scale. At week 12, IXE (n = 99, 72·8%) was superior to UST (n = 70, 42·2%) in PASI 90 response (response difference 32·1%, 97·5% confidence interval 19·8-44·5%, P < 0·001). Response rates for PASI 75, PASI 100 and sPGA (0,1) were significantly higher for IXE than for UST (adjusted P < 0·05). At week 24, IXE-treated patients had significantly higher response rates than UST-treated patients for PASI, sPGA and DLQI (unadjusted P < 0·05). No deaths were reported, and the treatments did not differ with regard to overall incidences of adverse events (P = 0·299). The superior efficacy of IXE demonstrated at week 12 persisted up to week 24. The safety profiles were consistent with those previously reported for both treatments.


Malignant pleural mesothelioma: a survival study.
Ninety-four patients with malignant pleural mesothelioma were treated at Southern California Permanente Medical Group Facilities between 1965 and 1988. This retrospective analysis of survival in these patients is compared according to surgical and/or supportive management. Group I patients received supportive care only, including pleurodesis as needed. This group included the majority of patients. Group II patients were managed largely with debulking procedures including decortication and pleurectomy. Group III patients received extrapleural pneumonectomy. This group included the two long-term survivors of the entire group. This study of survival points out the need for a cooperative protocol as well as the consistent use of proper modern preoperative staging in an attempt to select patients who benefit from extrapleural pneumonectomy.


Prevalence of macular abnormalities assessed by optical coherence tomography in patients with Usher syndrome.
To investigate the prevalence of macular abnormalities in patients affected by Usher syndrome (USH), by comparing the clinical findings between two types (i.e., USH1 and USH2). A retrospective study was performed by reviewing optical coherence tomography (OCT) in 134 USH patients to determine the presence of macular abnormalities, including cystoid macular edema (CME), epiretinal membrane (ERM), vitreo-macular traction syndrome (VMT), and macular hole (MH). Macular abnormalities were observed in 126/268 (47.0%) examined eyes. The most frequent abnormality was ERM observed in 51 eyes (19%), followed by CME observed in 42 eyes (15.7%). Moreover, CME was significantly (p < 0.05) associated with younger age (CME: 30.1 ± 11.1 years; without CME: 36.9 ± 14.9 years), whereas VMT and full thickness MH were associated with older age (p < 0.05). Moreover, a significantly (p < 0.05) decreased best-corrected visual acuity was associated with MH compared to eyes without MH. Finally, CME was more frequent in USH1 compared to USH2. Our study, for the first time in the literature, showed the distribution of all macular abnormalities assessed by SD-OCT in a large USH cohort, comparing USH1 and USH2 patients. We observed that ocular abnormalities are highly prevalent in USH patients compared to general population, with ERM and CME being the most common alterations. Based on these findings, OCT screening in USH patients is recommended for early detection of macular changes and early treatment.


Distribution of enantiomers of methadone and its main metabolite EDDP in human tissues and blood of postmortem cases.
Knowledge concerning the distribution of methadone in postmortem human tissue and the effect of postmortem redistribution on methadone is today limited making the choice of a suitable substitute for femoral blood difficult when this is not available. Cardiac blood, femoral blood, muscle, and brain tissue concentrations of the enantiomers of methadone and its metabolite 2-ethyl-1,5-dimethyl-3,3-diphenylpyrrolinium were recorded for 155 postmortem cases. Brain and muscle tissue concentrations exceeded the femoral blood concentrations with a median fold of 2.3 and 1.6, respectively, but both had a better correlation than cardiac blood to femoral blood concentrations. The Kruskal-Wallis test showed a significant dependency on time and body mass index for some of the matrix ratios over femoral blood. We conclude brain or muscle tissue may constitute a better alternative for measurement of methadone than cardiac blood for situations in which femoral blood is not available, despite concentrations in both matrices being systematically higher.


Effect of intermittent carbon monoxide inhalation on erythropoiesis and organ weights in rats.
Sprague-Dawley rats were exposed to 450 ppm carbon monoxide (CO) for 6 h per day, 5 days per week for 33 days. The effect of CO on reticulocyte count, hematocrit, hemoglobin concentration, body weight and selected organ weights was measured. Exposure to CO caused a three-fold increase in the youngest reticulocyte population, concomitant with an increase in the total reticulocyte count. Despite continued CO exposure, reticulocyte number and distribution returned to normal by day 9, suggesting that reticulocyte response of the organism to CO had changed. Both hematocrit and hemoglobin concentrations began to increase 16 days after CO exposure and remained at the increased level for the duration of the exposure period. There were no changes in kidney, liver and adrenal weights throughout the course of study. However, spleen weight was increased after 5 days of CO exposure. Left and right ventricular organ weight ratios increased equally at the same time during the study. These results indicate that the increase in the young reticulocyte population and the subsequent increase in total reticulocyte count are the earliest erythropoietic responses to intermittent CO exposure and that CO-induced polycythemia is associated with cardiac hypertrophy in rats.


Rat alveolar macrophage-derived platelet-derived growth factor is chemotactic for rat lung fibroblasts.
Alveolar macrophages and their products are thought to be important mediators of the inflammatory lesions and consequent interstitial fibrosis caused by inhalation of inorganic particles. Identification of a homolog of platelet-derived growth factor (PDGF) produced by rat alveolar macrophages that were stimulated with carbonyl iron particles and asbestos fibers motivated our studies on the biologic activity of this potent cytokine. Macrophage-derived PDGF (MD-PDGF) competes for specific membrane receptors on rat lung fibroblasts, initiating DNA synthesis and cell replication. The present report demonstrates that purified human PDGF and the MD-PDGF are chemotactic for early passage rat lung fibroblasts, but not for lung macrophages. Rat lung fibroblasts exhibit a typical bell-shaped, dose-related curve and respond optimally between 2 and 4 ng/ml PDGF. We found that alveolar macrophage-conditioned medium (AMCM), fractionated by gel filtration in 1 M acetic acid, induced a clear chemotactic response in the same fractions (20 to 22 ml) where PDGF was identified by enzyme immunoassay. In contrast, AMCM fractionated by gel filtration in phosphate-buffered saline did not induce any chemotactic activity unless the fractions were treated further with 1 M acetic acid. In this case, chemotactic activity was observed in those fractions with molecular weights of 150 and greater than 200 kD. All chemotactic activity observed with fractionated AMCM was blocked greater than 90% by an anti-PDGF antibody. These observations demonstrate that MD-PDGF is chemotactic for rat lung fibroblasts if it first is released from its binding protein, alpha-macroglobulin (alpha-M), which is secreted into the medium along with PDGF.(ABSTRACT TRUNCATED AT 250 WORDS)


The StrongWomen Change Clubs: engaging residents to catalyze positive change in food and physical activity environments.
The epidemic of obesity is a multifaceted public health issue. Positive policy and environmental changes are needed to support healthier eating and increased physical activity. StrongWomen Change Clubs (SWCCs) were developed through an academic-community research partnership between researchers at Cornell University and Tufts University and community partners (cooperative extension educators) in rural towns in seven U.S. states. Extension educators served as the local leader and each recruited 10-15 residents to undertake a project to improve some aspect of the nutrition or physical activity environment. Most residents had limited (or no) experience in civic engagement. At 6 and 12 months after implementation, the research team conducted key informant interviews with SWCC leaders to capture their perceptions of program process, benchmark achievement, and self-efficacy. At 12 months, each SWCC had accomplished one benchmark; the majority had completed three or more benchmarks. They described common processes for achieving benchmarks such as building relationships and leveraging stakeholder partnerships. Barriers to benchmark achievement included busy schedules and resistance to and slow pace of change. Findings suggest that community change initiatives that involve stakeholders, build upon existing activities and organizational resources, and establish feasible timelines and goals can successfully catalyze environmental change.