Disentangling the direct and indirect effects of agricultural runoff on freshwater ecosystems subject to global warming: A microcosm study.
Aquatic ecosystems are exposed to multiple stressors such as agricultural run-off (ARO) and climate-change related increase of temperature. We aimed to determine how ARO and the frequency of its input can affect shallow lake ecosystems through direct and indirect effects on primary producers and primary consumers, and whether warming can mitigate or reinforce the impact of ARO. We performed a set of microcosm experiments simulating ARO using a cocktail of three organic pesticides (terbuthylazine, tebuconazole, pirimicarb), copper and nitrate. Two experiments were performed to determine the direct effect of ARO on primary producers (submerged macrophytes, periphyton and phytoplankton) and on the grazing snail Lymnaea stagnalis, respectively. Three different ARO concentrations added as single doses or as multiple pulses at two different temperatures (22°C and 26°C) were applied. In a third experiment, primary producers and consumers were exposed together to allow trophic interactions. When functional groups were exposed alone, ARO had a direct positive effect on phytoplankton and a strong negative effect on L. stagnalis. When exposed together, primary producer responses were contrasting, as the negative effect of ARO on grazers led to an indirect positive effect on periphyton. Periphyton in turn exerted a strong control on phytoplankton, leading to an indirect negative effect of ARO on phytoplankton. Macrophytes showed little response to the stressors. Multiple pulse exposure increased the effect of ARO on L. stagnalis and periphyton when compared with the same quantity of ARO added as a single dose. The increase in temperature had only limited effects. Our results highlight the importance of indirect effects of stressors, here mediated by grazers and periphyton, and the frequency of the ARO input in aquatic ecosystems.


Mechanistic studies of substrate-assisted inhibition of ubiquitin-activating enzyme by adenosine sulfamate analogues.
Ubiquitin-activating enzyme (UAE or E1) activates ubiquitin via an adenylate intermediate and catalyzes its transfer to a ubiquitin-conjugating enzyme (E2). MLN4924 is an adenosine sulfamate analogue that was identified as a selective, mechanism-based inhibitor of NEDD8-activating enzyme (NAE), another E1 enzyme, by forming a NEDD8-MLN4924 adduct that tightly binds at the active site of NAE, a novel mechanism termed substrate-assisted inhibition (Brownell, J. E., Sintchak, M. D., Gavin, J. M., Liao, H., Bruzzese, F. J., Bump, N. J., Soucy, T. A., Milhollen, M. A., Yang, X., Burkhardt, A. L., Ma, J., Loke, H. K., Lingaraj, T., Wu, D., Hamman, K. B., Spelman, J. J., Cullis, C. A., Langston, S. P., Vyskocil, S., Sells, T. B., Mallender, W. D., Visiers, I., Li, P., Claiborne, C. F., Rolfe, M., Bolen, J. B., and Dick, L. R. (2010) Mol. Cell 37, 102-111). In the present study, substrate-assisted inhibition of human UAE (Ube1) by another adenosine sulfamate analogue, 5'-O-sulfamoyl-N(6)-[(1S)-2,3-dihydro-1H-inden-1-yl]-adenosine (Compound I), a nonselective E1 inhibitor, was characterized. Compound I inhibited UAE-dependent ATP-PP(i) exchange activity, caused loss of UAE thioester, and inhibited E1-E2 transthiolation in a dose-dependent manner. Mechanistic studies on Compound I and its purified ubiquitin adduct demonstrate that the proposed substrate-assisted inhibition via covalent adduct formation is entirely consistent with the three-step ubiquitin activation process and that the adduct is formed via nucleophilic attack of UAE thioester by the sulfamate group of Compound I after completion of step 2. Kinetic and affinity analysis of Compound I, MLN4924, and their purified ubiquitin adducts suggest that both the rate of adduct formation and the affinity between the adduct and E1 contribute to the overall potency. Because all E1s are thought to use a similar mechanism to activate their cognate ubiquitin-like proteins, the substrate-assisted inhibition by adenosine sulfamate analogues represents a promising strategy to develop potent and selective E1 inhibitors that can modulate diverse biological pathways.


Electronic medical records: a path forward.
Health systems are moving to implement comprehensive electronic medical record (EMR) systems, or significant pieces of them, in the belief that EMR can be integrated into clinical practice and lead to improved patient outcomes and enhanced safety. There are substantial roadblocks to implementing EMR, including significant cost, the competency needed to implement, the political environment, organization infrastructure and culture, and how organization leaders understand return on investment. Complicating factors include the drive to implement EMR to meet meaningful use standards to qualify for a federal incentive program and recently publicized studies that question the value equation of the EMR as it relates to patient care improvements. We offer our experiences on the successful implementation of the EMR across the large health systems we lead. We offer practical advice and tips on how to achieve successful implementation, evidence that successful implementations improve patient care and safety, and a glimpse of how EMR is a significant foundation in a future of collaborative models that provide continuum-based care.


Genetical genomics identifies the genetic architecture for growth and weevil resistance in spruce.
In plants, relationships between resistance to herbivorous insect pests and growth are typically controlled by complex interactions between genetically correlated traits. These relationships often result in tradeoffs in phenotypic expression. In this study we used genetical genomics to elucidate genetic relationships between tree growth and resistance to white pine terminal weevil (Pissodes strobi Peck.) in a pedigree population of interior spruce (Picea glauca, P. engelmannii and their hybrids) that was growing at Vernon, B.C. and segregating for weevil resistance. Genetical genomics uses genetic perturbations caused by allelic segregation in pedigrees to co-locate quantitative trait loci (QTLs) for gene expression and quantitative traits. Bark tissue of apical leaders from 188 trees was assayed for gene expression using a 21.8K spruce EST-spotted microarray; the same individuals were genotyped for 384 SNP markers for the genetic map. Many of the expression QTLs (eQTL) co-localized with resistance trait QTLs. For a composite resistance phenotype of six attack and oviposition traits, 149 positional candidate genes were identified. Resistance and growth QTLs also overlapped with eQTL hotspots along the genome suggesting that: 1) genetic pleiotropy of resistance and growth traits in interior spruce was substantial, and 2) master regulatory genes were important for weevil resistance in spruce. These results will enable future work on functional genetic studies of insect resistance in spruce, and provide valuable information about candidate genes for genetic improvement of spruce.


A new technique to evaluate the ability of cryoprotectors to prevent premature acrosome reaction in human spermatozoa.
Acrosome reaction (AR) induced by low temperature has been used to evaluate sperm function; it correlates adequately with the fertilization percentages in vitro. In this study, the technique of AR induction by low temperature was used to evaluate the effect in the protection of the acrosome by cryopreservatives normally used in human semen cryopreservation. Donor sperm selected by use of the migration sedimentation technique was incubated in human tubal fluid medium, added to dimethyl sulphoxide 1 m, ethylene glycol 0.75 m, glycerol 1 m, incubated at 4 degrees C and 20 degrees C (as a control) for 18 h, and then for 3 h at 37 degrees C in a cell incubator. The AR was evaluated by triple stain in 100 viable spermatozoa. The effect of cryopreservatives on acrosome preservation in samples incubated for 18 h at 4 degrees C was as follows: 78% intact acrosome for glycerol, 77.8% intact acrosome for dimethyl sulphoxide and 96.2% intact acrosome for ethylene glycol (P < 0.0025 compared with glycerol and dimethyl-sulphoxide). The sperm samples incubated with cryopreservatives for 18 h at 20 degrees C did not show an increase in the percentage of AR in samples incubated with glycerol and ethylene glycol, while a significant variation was observed in the sample incubated with dimethyl sulphoxide (P < 0.001). Additional incubation for 3 h at 37 degrees C significantly increased the AR only in the sample incubated with glycerol (P < 0.001). Acrosome preservation is essential in the fertilization process and the evaluation of acrosome reaction induction by low temperature test was satisfactory. This test proves that ethylene glycol presents a greater protective effect on the acrosome preservation of human spermatozoa.


Operational vector-borne disease surveillance and control: closing the capabilities gap through research at overseas military laboratories.
Malaria, dengue fever, chikungunya virus, leishmaniasis, and a myriad of other vector-borne diseases pose significant threats to the warfighter and to the overall combat effectiveness of units. Military preventive medicine (PM) assets must accurately evaluate the vector-borne disease threat and then implement and/or advise the commander on countermeasures to reduce a particular threat. The success of these measures is contingent upon the biology of the disease vector and on the tools or methods used to conduct vector/pathogen surveillance and vector control. There is a significant gap between the tools available and those required for operational PM assets to provide real-time, effective surveillance and control. A network of US Army and US Navy overseas laboratories is focused on closing the current capabilities gap. Their mission is to develop and field test tools and methods to enhance the combatant commander's ability to identify and mitigate the threat posed by these vector-borne diseases.


Vitamin D status and circulating biomarkers of endothelial dysfunction and inflammation in non-diabetic obese individuals: a pilot study.
Obesity and inadequate vitamin D status are associated with endothelial dysfunction and cardiovascular disease. We evaluated the associations between vitamin D status (i.e. serum levels of 25-hydroxyvitamin D (25(OH)D)), biomarkers of endothelial dysfunction (i.e. serum concentrations of soluble intercellular adhesion molecule 1 (sICAM-1) and soluble E-selectin (sE-selectin)), inflammatory markers (i.e. high-sensitivity C-reactive protein (hsCRP) and fibrinogen) and cardiometabolic risk factors. Fifty obese (body mass index (BMI) ≥ 30 kg/m2) non-diabetic adults (mean age: 36.2 ±5.4 years) without pre-existing cardiovascular abnormalities and 25 clinically healthy, normal weight and age-matched individuals were included. Anthropometric parameters, markers of glucose and lipid metabolism, and serum levels of inflammatory and endothelial dysfunction biomarkers were assessed in all subjects. The mean serum 25(OH)D level was significantly lower in the obese group than in controls (33.5 ±15.2 vs. 60.1 ±23.1 nmol/l; p < 0.001). In the obese group, sE-selectin (36.4 (32.1-47.2) vs. 32.4 (24.6-35.5) ng/ml, p < 0.05) and hsCRP (6.0 ±3.4 vs. 3.5 ±1.0 mg/l, p < 0.05) were significantly higher in individuals with lower than median vitamin D levels (i.e. 31 nmol/l) compared with those with higher vitamin D levels. In multivariable linear regression analysis, hsCRP (β = -0.43; p < 0.001) and sE-selectin (β = -0.30; p = 0.03) were independently and significantly associated with serum 25(OH)D levels in the obese group. Vitamin D levels may be related to increased levels of biomarkers of endothelial dysfunction and inflammation in obese non-diabetic individuals.


Reflectance, Solar Absorptivity, and Thermal Emissivity of SiO(2)-Coated Aluminum.
The reflectance, solar absorptivity (alpha), and the total normal and hemispherical emissivity (epsilonNu and epsilon) of evaporated aluminum coated with SiO(2) films of various thicknesses were determined. High vacuum evaporation with an electron gun was used for preparing uv transparent undecomposed films of SiO(2) up to thicknesses of more than 3.5 micro Because of their hardness, chemical stability, and excellent adherence, evaporated SiO(2) films were found to be very suitable as protective layers for aluminum front surface mirrors, especially if high reflectance in the uv is required. alpha of SiO(2)-coated Al was determined to be about 11 % and to be essentially independent of the SiO(2) thickness, whereas epsilonNu and epsilon increased with increasing oxide thickness, and reached values of 0.62 and 0.55, respectively, for a SiO(2) thickness of 3.75 micro. Films of this type are, therefore, suitable as surface layers for controlling the temperature of satellites in orbit. Ultraviolet irradiation in vacuum at one and five times the equivalent solar energy decreased the uv and visible reflectance of SiO(2)-coated Al. The effect of this reflectance decrease on alpha/epsilon and on the temperature of an orbiting satellite is discussed.


Predictors and Moderators Two Treatments of Oppositional Defiant Disorder in Children.
The aim of this study was to examine predictors and moderators of behavioral improvement in children with Oppositional Defiant Disorder (ODD) following treatment with Parent Management Training (PMT) and Collaborative and Proactive Solutions (CPS). Initial problem severity, inconsistent discipline, parental attributions of child misbehavior, and child lagging cognitive skills were examined. One hundred and forty-five children aged between 7 and 14 (103 males, M = 8.88 years, ethnicity representative of the wider Australian population) were randomly assigned to PMT and CPS. Assessment was conducted at baseline, post-intervention, and at 6-month follow-up, using independently rated semi-structured diagnostic interviews and parent-ratings of ODD symptoms. Using an intent-to-treat sample in this secondary analysis (Murrihy et al., 2022), linear regressions and PROCESS (Hayes, 2017) were used to examine these predictors and possible moderators of treatment. Higher pre-treatment levels of conduct problems, lagging skills, and inconsistent discipline predicted poorer behavioral outcomes following both treatments. The only characteristic that moderated treatment outcome was child-responsible attributions - mothers who were more likely to attribute their child's problematic behaviors to factors in the child had significantly poorer outcomes in PMT than CPS at 6-month follow-up. CPS may be a more beneficial treatment than PMT for families who have been identified as having higher levels of child-responsible attributions before commencing treatment for ODD. While tentative, this provides promising insights as to how treatment outcomes for children with ODD may be improved.


Kinetics of Hydrogen Radical Reactions with Toluene Including Chemical Activation Theory Employing System-Specific Quantum RRK Theory Calibrated by Variational Transition State Theory.
Pressure-dependent reactions are ubiquitous in combustion and atmospheric chemistry. We employ a new calibration procedure for quantum Rice-Ramsperger-Kassel (QRRK) unimolecular rate theory within a chemical activation mechanism to calculate the pressure-falloff effect of a radical association with an aromatic ring. The new theoretical framework is applied to the reaction of H with toluene, which is a prototypical reaction in the combustion chemistry of aromatic hydrocarbons present in most fuels. Both the hydrogen abstraction reactions and the hydrogen addition reactions are calculated. Our system-specific (SS) QRRK approach is adjusted with SS parameters to agree with multistructural canonical variational transition state theory with multidimensional tunneling (MS-CVT/SCT) at the high-pressure limit. The new method avoids the need for the usual empirical estimations of the QRRK parameters, and it eliminates the need for variational transition state theory calculations as a function of energy, although in this first application we do validate the falloff curves by comparing SS-QRRK results without tunneling to multistructural microcanonical variational transition state theory (MS-μVT) rate constants without tunneling. At low temperatures, the two approaches agree well with each other, but at high temperatures, SS-QRRK tends to overestimate falloff slightly. We also show that the variational effect is important in computing the energy-resolved rate constants. Multiple-structure anharmonicity, torsional-potential anharmonicity, and high-frequency-mode vibrational anharmonicity are all included in the rate computations, and torsional anharmonicity effects on the density of states are investigated. Branching fractions, which are both temperature- and pressure-dependent (and for which only limited data is available from experiment), are predicted as a function of pressure.


Eye movement desensitization and reprocessing for mental health problems: a systematic review and meta-analysis.
There is no comprehensive meta-analysis of randomised trials examining the effects of Eye Movement Desensitization and Reprocessing (EMDR) on post-traumatic stress disorder (PTSD) and no systematic review at all of the effects of EMDR on other mental health problems. We conducted a systematic review and meta-analysis of 76 trials. Most trials examined the effects on PTSD (62%). The effect size of EMDR compared to control conditions was g = 0.93 (95% CI: 0.67-.18), with high heterogeneity (I2= 72%). Only four of 27 studies had low risk of bias, and there were indications for publication bias. EMDR was more effective than other therapies (g = 0.36; 95% CI: 0.14-0.57), but not in studies with low risk of bias. Significant results were also found for EMDR in phobias and test anxiety, but the number of studies was small and risk of bias was high. EMDR was examined in several other mental health problems, but for none of these problems, sufficient studies were available to pool outcomes. EMDR may be effective in the treatment of PTSD in the short term, but the quality of studies is too low to draw definite conclusions. There is not enough evidence to advise it for the use in other mental health problems.


Identification of molecular sites on factor VII which mediate its assembly and function in the extrinsic pathway activation complex.
Factor VII-VIIa, in association with tissue factor, participates in the complex which initiates blood coagulation through the extrinsic pathway. To identify functional domains on factor VII which mediate the activation of factor X, 16 synthetic peptides corresponding to 55% of the primary structure were assayed for their ability to inhibit factor VII function. Factor Xa formation was inhibited by eight of the peptides in a dose-dependent manner. Kinetic analyses indicated noncompetitive inhibition of factor X activation by seven of these peptides. Peptide-(347-361) inhibited factor Xa cleavage of a chromogenic substrate by a competitive mechanism and was excluded from further analysis in this study. Among the seven inhibitory peptides which have the ability to prevent the factor VIIa-tissue factor-mediated conversion of factor X to factor Xa, peptide-(285-305) was most inhibitory, with a Ki value of 2.4 microM. The Ki values were in the range of 42-65 microM for peptides-(44-50), -(194-214), -(208-229), and -(376-390). The least inhibitory peptides were at positions 170-178 and 330-340, with a Ki value greater than 200 microM. Polyclonal antibodies were raised against four of these peptides; and when antisera were assayed by a solid-phase radioimmunoassay, they bound not only to their respective immunizing peptides, but also to factor VII. The Fab fragments of specific IgG preparations, affinity-purified on a factor VII-agarose column, inhibited the rate of factor X activation in a dose-dependent manner. Six of the seven inhibitory peptides represent amino acid sequences within the heavy chain of factor VII, and the remaining one corresponds to a sequence within the light chain. The corresponding regions in the x-ray crystal structure of chymotrypsin represented by the six heavy chain inhibitory peptides are found to be located in three distinct regions, one region located spatially distal to the active site and the other two regions located relatively closer to the active site and the substrate-binding pocket. The results suggest that at least three specific regions in the heavy chain and one region in the light chain of factor VII mediate its interaction with the factor X activation complex.


Dehydrogenative cross-coupling reaction by cooperative transition-metal and Brønsted acid catalysis for the synthesis of β-quinolinyl α-amino acid esters.
A novel dehydrogenative cross-coupling (DCC) reaction between methylquinoline derivatives and N-aryl glycine esters was developed by a cooperative catalysis of copper salt and Brønsted acid, affording an efficient synthesis of β-quinolinyl α-amino acid esters. A plausible mechanism using a proton to activate the methylquinoline derivative and copper(II) to activate N-aryl glycine ester has been proposed.


Differences across Playing Levels for Match-Play Physical Demands in Women's Professional and Collegiate Soccer: A Narrative Review.
Advancements in sport technology have made quantifying match-play external load (e.g., total distance, sprint distance, number of sprints) a popular option for athletics personnel. These variables of volume and intensity are useful for both objectively monitoring training in field-based sports and for designing training programs. As physical abilities differ across playing levels, match-play demands likely also differ. This narrative review compiles and compares the match-play external load data for women's soccer at the professional and collegiate levels. Databases were searched through July 2022, yielding 13 primary articles that assessed the match-play demands of women's soccer (3 professional, 8 Division I, 1 Division II, and 1 Division III). The results indicate that the average total distance covered were similar between the professional, Division I and Division III levels, but the variability was greater among Division III compared to professional and Division I players. Data for Division II are scarce, but the total distance covered appears to be less than for professional, Division I and Division III. There was also large variability for sprint distance and number of sprints across data at all playing levels. Considering the lack of studies of Division II and Division III players, more research is necessary to determine how playing level may affect external load profiles, as isolated studies likely only reflect data from isolated teams.


Comparison of manual and power toothbrushing, with and without adjunctive oral irrigation, for controlling plaque and gingivitis.
We compared the effects of four oral hygiene methods (manual tooth-brushing, power toothbrushing, manual toothbrushing plus irrigation, and power toothbrushing plus irrigation) on plaque and periodontal disease. These methods were tested both when used alone and when used in conjunction with professional mechanical oral hygiene. 108 subjects were clinically assessed for plaque, stain, gingival inflammation, bleeding to probing, probing depth and attachment loss, and randomly assigned to one of the 4 oral hygiene groups. Subjects were carefully instructed in the use of their assigned method and asked to discontinue all other forms of oral hygiene. After 3-months, subjects returned for re-examination and full-month professional mechanical oral hygiene care. 3 months later, subjects returned for a final oral examination. All subjects kept a diary of use of their assigned method and were called every 2 weeks to monitor discomfort, provide reinforcement and answer questions. Results showed that all the oral hygiene methods were equally effective in reducing plaque and stain accumulation, gingival bleeding, bleeding to probing ratio and the % of pockets 4 mm or deeper. None of the oral hygiene methods was associated with injury to soft or hard tissues.


New kaurene diterpenoid glycosides from fenugreek seeds.
Two new kaurene diterpenoid glycosides, named Graecumoside A (1) and B (2), were isolated from fenugreek seeds, along with three known flavonoid-C-glycosides, isoorientin (3), isovitexin (4) and vitexin (5). By combined analyses of 1D- and 2D-NMR, and MS spectroscopy, the structures of two new compounds were elucidated as 3-O-β- D-glucopyranosyl kaur-5, 16-dien-3β, 6, 13β-trihydroxy-7-oxo-18-oic acid methyl ester and 3-O-β-neohesperidosyl kaur-5, 16-dien-3β, 6, 13β-trihydroxy-7-oxo-18-oic acid methyl ester, respectively. The kaurene diterpenoid glycosides were first isolated and identified from fenugreek seeds.


In memoriam: Lauri Saxén (1927-2005).
Dr. Lauri "Tupu" Saxen died last October (2005) at the age of 78. He was a physician, a scientist, a photographer, a naturalist, a great story-teller and a man who enjoyed science enormously. His name has become synonymous with the Finnish school of Developmental Biology, a school that focuses on reciprocal inductive interactions during vertebrate organogenesis. But many biologists probably don't know the full extent of his importance to the field. A few years ago, I had the occasion to outline some of his contributions which are so varied and important that it is difficult to believe that they are the work of one person, and I have included them in this brief eulogy. One could divide his scientific contributions into five categories: (1) the threshold hypothesis of amphibian metamorphosis; (2) the double-gradient hypothesis of primary embryonic induction; (3) the analysis of reciprocal induction during kidney development; (4) the integration of developmental biology with epidemiology and (5) the maintenance of a national infrastructure for science.


Enhancing the current evidence on endoscopist-directed propofol-based sedation.
During the last years, there is more and more scientific evidence about the safety and feasibility of non-anesthesiologist administration of propofol (NAAP) in gastrointestinal endoscopy, reducing sedation induction and recovery time as well as increasing patient and endoscopist satisfaction. Furthermore, a similar risk of adverse events compared with traditional agents or anesthesiologist administration of propofol (AAP) has been described. The present special issue of the Spanish Journal of Gastroenterology (Revista Española de Enfermedades Digestivas) focusses on NAAP in different settings, including complex endoscopic procedures.


Development of an annual drought classification system based on drought severity indexes.
In order to characterize the occurrence and intensity of droughts in the Doce River Basin, as well as to develop a system for its classification, four different drought indexes were evaluated: Percent of Normal Precipitation (PNP), Deciles Method (DM), Rainfall Anomaly Index (RAI) and Standardized Precipitation Index (SPI). The indices were calculated annually, based on precipitation data from 89 rainfall stations of the Brazilian National Water Agency (ANA). Nine analysis units (AUs) were determined in the basin and the Thiessen Polygons method was used to obtain the average precipitation in the respective drainage areas. The indices were calculated for each AU and then related to the drought intensity classes. An overall classification of the indices was proposed for the drought classification system for a 30-year base period, from 1985 to 2015. The most critical hydrological years of the Doce River Basin in relation to the drought were 1994/1995, 2000/2001 and 2014/2015, the latter being the most critical of the last 30 years. The results show that the annual drought classification system proved to be efficient in the identification of events, allowing to verify that the Doce River Basin presents a severe climatic drought condition, on average, every seven years.


A successful treatment of an intrarenal arteriovenous fistula by percutaneous embolization.
A 37-year-old woman patient, known to have poorly controlled arterial hypertension that was diagnosed following a cerebrovascular accident at the age of 15 years, was referred to our outpatient clinic for investigation in 1987. An intrarenal arteriovenous fistula was diagnosed by selective renal angiography. Embolization of the fistula was performed using four 15-mm/5-cm coils, which induced thrombosis and obstructed the fistula. The vascularization of the affected kidney improved immediately. During the following 4 months, the antihypertensive treatment was stopped gradually, and the patient remained normotensive. This is an unusual case of a large intrarenal arteriovenous fistula, whose etiology was not clear, that was successfully treated by percutaneous embolization.


Bioinformatics for protein biomarker panel classification: what is needed to bring biomarker panels into in vitro diagnostics?
A large number of biomarkers have been discovered over the past few years using proteomics techniques. Unfortunately, most of them are neither specific nor sensitive enough to be translated into in vitro diagnostics and routine clinical practice. From this observation, the idea of combining several markers into panels to improve clinical performances has emerged. In this article, we present a discussion of the bioinformatics aspects of biomarker panels and the concomitant challenges, including high dimensionality and low patient number and reproducibility.


One thousand centuries of climatic record from cAMP century on the greenland ice sheet.
A correlation of time with depth has been evaluated for the Camp Century, Greenland, 1390 meter deep ice core. Oxygen isotopes in approximately 1600 samples throughout the core have been analyzed. Long-term variations in the isotopic composition of the ice reflect the climatic changes during the past nearly 100,000 years. Climatic oscillations with periods of 120, 940, and 13,000 years are observed.


Detection of very early antibody to native HIV antigens by HIV neutralization and live-cell immunofluorescence assays.
Very early detection of HIV infection could help decrease the spread of HIV, improve safety of the blood supply, and permit earlier treatment. Early detection was reported when native gp41 antigen was used to detect antibodies that occurred 2-6 weeks earlier than detection of antibodies to denatured antigens by the current EIA or WB tests or detection by the HIV RNA test. We hypothesized that early antibodies to native gp41/160 could be detected, not only by the reported live-cell immunofluorescence (IFA) but also by a neutralization test, since virions as well as HIV-infected cells contain native gp41/160. To test this hypothesis, we did an initial test of concept study to compare the neutralization test with other tests, using sera from 12 high-risk patients. The neutralization test reproducibly detected early antibodies (characterized) in the sera of 10 of 12 (83%) high-risk subjects. Importantly, the EIA and WB tests that use denatured antigens missed the early diagnosis in 12 of the 13 subjects (92%). The findings support the concept that native HIV antigens can detect polyclonal HIV neutralizing antibodies and live-cell IFA antibodies earlier than currently available tests that use denatured antigens.


Optical fiber modes using stimulated four photon mixing.
Stimulated four photon mixing has been used to excite separately all the modes of a ten-mode optical fiber. Photographs were taken and the mode intensities scanned with a moving pinhole. Measured intensities were found to agree well with the intensities calculated for an ideal guide with an abrupt core-cladding interface. In addition a locking effect was observed in which two separate Stokes:anti-Stokes pairs, which normally occur at slightly different frequency shifts from the pump, locked together at the same frequency.


An Investigation on the Therapeutic Effect of Thymosin β4 and Its Expression Levels in Streptozotocin-Induced Diabetic Mice.
Thymosin β4 (Tβ4) treatment was known to show the potential therapeutic effects on diabetic complications. This study was performed to determine if Tβ4 expression is changed in both serum and tissues under diabetic conditions and can be a serum biomarker. Type 1 diabetic mice were induced in C57/BL6J mice by intraperitoneal injection of streptozotocin (STZ) at a dose of 50 mg/kg body weight. The mice were sacrificed at 16 weeks after STZ injection. Tissues and plasmas were obtained to determine the expression levels of Tβ4 using ELISA, real time RT-PCR, and immunohistochemistry. The average serum glucose level was increased to approximately 400 mg/dL beginning 2 weeks after the five injections of STZ and lasting for at least 13 weeks until sacrifice. The plasma and tissue levels of Tβ4 in the age-matched control mice were not significantly different from those of the diabetic mice. In conclusion, the Tβ4 expression level in the plasmas and tissues of diabetic mice was not affected by diabetic conditions. It indirectly suggests that the therapeutic effect of Tβ4 on diabetic complications is due to its regenerative effects on damaged tissue but not to the changed expression level of Tβ4 in plasma and tissues of diabetes.


Epigenetic and Proteomic Biomarkers of Elevated Alcohol Use Predict Epigenetic Aging and Cell-Type variation Better Than Self-Report.
Excessive alcohol consumption (EAC) has a generally accepted effect on morbidity and mortality, outcomes thought to be reflected in measures of epigenetic aging (EA). As the association of self-reported EAC with EA has not been consistent with these expectations, underscoring the need for readily employable non-self-report tools for accurately assessing and monitoring the contribution of EAC to accelerated EA, newly developed alcohol consumption DNA methylation indices, such as the Alcohol T Score (ATS) and Methyl DetectR (MDR), may be helpful. To test that hypothesis, we used these new indices along with the carbohydrate deficient transferrin (CDT), concurrent as well as past self-reports of EAC, and well-established measures of cigarette smoking to examine the relationship of EAC to both accelerated EA and immune cell counts in a cohort of 437 young Black American adults. We found that MDR, CDT, and ATS were intercorrelated, even after controlling for gender and cotinine effects. Correlations between EA and self-reported EAC were low or non-significant, replicating prior research, whereas correlations with non-self-report indices were significant and more substantial. Comparing non-self-report indices showed that the ATS predicted more than four times as much variance in EA, CDT4 cells and B-cells as for both the MDR and CDT, and better predicted indices of accelerated EA. We conclude that each of the non-self-report indices have differing predictive capacities with respect to key alcohol-related health outcomes, and that the ATS may be particularly useful for clinicians seeking to understand and prevent accelerated EA. The results also underscore the likelihood of substantial underestimates of problematic use when self-report is used and a reduction in correlations with EA and variance in cell-types.


Reproductive Outcome of Transcervical Uterine Incision in Unicornuate Uterus.
The pregnancy outcome of the unicornuate uterus is associated with an increased risk of miscarriage, cervical incompetence, and a number of obstetric complications. However, at present, there is no accepted treatment method for women with unicornuate uterus, other than expectant measures. The aim of this study was to evaluate the reproductive outcome of transcervical uterine incision (TCUI) in patients with unicornuate uterus. Thirty-three patients with unicornuate uterus presented to our tertiary center for infertility or miscarriage. All 33 patients underwent TCUI and were followed up for 10-52 months. The pregnancy outcomes ( first-trimester miscarriage, second-trimester miscarriage, preterm, term, intrauterine death, ongoing pregnancy, and live birth) before and after TCUI were compared by t- test. Among 31 patients who attempted to conceive after TCUI, twenty conceived including one termination of pregnancy, one second-trimester miscarriage, one ectopic pregnancy, five preterm deliveries, 11 term delivery, and one ongoing pregnancy. There were 16 live births in total. There was significant reduction in the first-trimester miscarriage rate (t = 4.890; P< 0.001), increase in term delivery (t = -3.288; P = 0.002), and live birth rates (t = -4.073; P< 0.001) after TCUI. TCUI appeared to improve the pregnancy outcome in women with unicornuate uterus presenting with infertility or miscarriage.


Can the costs of critical care be controlled?
Critical care medicine (CCM) is expensive. CCM costs have continued to rise since they were first calculated in the 1970s. By 2005, CCM costs in the US were estimated to be $81.7 billion accounting for 13.4% of hospital costs, 4.1% of the national health expenditures and 0.66% of the gross domestic product. This review first addresses the methodology and inherent limitations of calculating global CCM costs using the Russell equation and the challenges of defining critical care in the US when universal definitions of intensive care unit (ICU) bed types do not exist. Studies and concepts recently put forth to control CCM costs are then discussed. These include rationing ICU care, caring for patients in non-ICU locations, regionalizing care, changing the ICU workforce, imposing care protocols and bundles, and adjusting long-term ICU traditions. Many of these programs have benefits but may also have unintended expenses. Even documenting ICU costs themselves may be quite challenging as costs are frequently shifted between the ICU and its supporting clinical and hospital services. Cost containment is difficult to attain in critical care as the programs proposed to achieve cost control may be so pricey, that potential cost savings are offset. Some CCM cost saving methodologies may benefit patient care, whereas others may be detrimental to society. CCM cost containment may prove as illusory in the future as it has been in the past.


Establishment of Carotid Artery Dissection and MRI Findings in a Swine Model.
Carotid artery dissection (CAD) is the leading cause of ischemic stroke in young patients; however, the etiology and pathophysiology of CAD remain largely unknown. In our study, two types of dissections (length × width: 1.5 cm × 1/3 circumference of intima, Group I, n = 6; or 1.5 cm × 2/3 circumference of intima, Group II, n = 6) were created between the media and intima. Ultrasound (within 2 h after dissection) showed a dissociated intima in the lumen and obstructed blood flow in the surgical area. Digital subtraction angiography (DSA, 72 h after dissection), magnetic resonance imaging (MRI, 72 h after dissection), and hematoxylin-eosin (H&E, 7 days after dissection) staining confirmed stenosis (33.67 ± 5.66%) in Group I and total occlusion in Group II. In 10 out of 12 swine, the CAD model was established using a detacher and balloon dilation, and morphological outcomes (stenosis or occlusion) after CAD were determined by the size of intimal incision.


Evaluation of a visualization assay for blood on forensic evidence.
In forensics, bloodstains on dark fabrics might be invisible for the naked eye. Although several visualization, presumptive, and confirmatory blood tests have been developed, all have one or more disadvantages, especially on DNA analysis. We report here the use of a visualization assay that can visually detect blood drops up to 1/20 dilution. In this assay, the fabric is placed between two wet filter papers and covered by glass surfaces on both sides. Pressure is applied on the glass surfaces in which bloodstains transfer onto the filter papers through capillary forces. Detected stains can be tested with other more sensitive presumptive blood tests performed on the filter paper. Even more, DNA analysis can be performed on the transferred bloodstains. The presented visualization assay is easy to perform, extremely cheap, requires little hands on time, and does not affect bloodstain pattern analysis.


An anatomic-arthrographic study of the relationships of the lateral meniscus and the popliteus tendon.
The anatomy of the posterior lateral knee joint is studied through photography and radiography of plastic corrosion casts of the knee joint. The images thus obtained are compared to in vivo arthrograms. This anatomic-arthrographic correlation clearly demonstrates how the bursal extensions of the joint space about the popliteus tendon dictate the location and arthrographic appearance of the peripheral attachments of the posterior lateral meniscus. The casts also serve to illustrate a discussion of anatomic variation, embryology, and function of the popliteus apparatus. The largely unappreciated direct action of the popliteus muscle on the lateral meniscus is emphasized.


Certain surfactants show promise in the therapy of pulmonary tuberculosis.
The aim of the present study was to develop the basis for the use of surfactants in the treatment of pulmonary tuberculosis (TB). Bacteria are surrounded by a thick lipid coat primarily consisting of trehalose dimycolate (TDM) and, consequently, are well shielded from the immune system's response and antibiotics. This protective barrier was removed by exposing the bacteria to certain surfactants. Dodecyl maltoside (DDM) and octyl glucoside (OG) were utilized as non-toxic surfactants. Electron microscopy (EM) studies revealed that aggregated bacteria were also covered with excessive TDM which exacerbate the treatment efforts. Light and EM studies demonstrated that DDM and OG disperse the aggregated bacteria and are bactericidal. The studies presented here establish that certain surfactants are proficient in removing MTB's shield and, because they are well known as cell permeabilizing agents, they may also enhance the effectiveness of antibiotics and the immune system's response in the treatment of pulmonary TB.


Pre-operative screening for excessive alcohol consumption among patients scheduled for elective surgery.
Pre-operative intervention for excessive alcohol consumption among patients scheduled for elective surgery has been shown to reduce complications of surgery. However, successful intervention depends upon an effective and practical screening procedure. This study examines current screening practices for excessive alcohol consumption amongst patients scheduled for elective surgery in general hospitals. It also examines the appropriateness of potential sites and staff for pre-operative screening. Forms used routinely to assess alcohol consumption in the pre-admission clinics (PAC) of eight Sydney hospitals were examined. In addition, the appropriateness of six staff categories (surgeons, surgeons' secretaries, junior medical officer, anaesthetists, nurses and a research assistant) and of two sites (surgeons' office and PAC) in conducting additional screening was assessed at two hospitals. Outcomes included observed advantages and disadvantages of sites and personnel, and number of cases with excessive drinking identified. There was duplication in information collected routinely on alcohol use in the PACs in eight Sydney Hospitals. Questions on alcohol consumption in patient self-completion forms were not validated. The PAC provided for efficient screening but time to surgery was typically too short for successful intervention in many cases. A validated tool and efficient screening procedure is required to detect excessive drinking before elective surgery. Patients often present to the PAC too close to the time of surgery for any change in drinking to reverse alcohol's effects. The role of the referring general practitioner and of printed advice from the surgeon in preparing patients for surgery needs further investigation.


Lead induction of crop dysfunction in pigeons through a direct action on neural or smooth muscle components of crop tissue.
Lead acetate solutions administered p.o. to pigeons produce crop stasis. Crop dysfunction may be an indirect effect on crop activity by a direct interaction with the cerebellum or some other site associated with lead-induced ataxia. Alternatively, crop stasis may be due to the direct interaction of lead with sites on the smooth muscle or neural elements in crop tissue. A behavioral test for ataxia was performed on pigeons given lead by crop intubation or i.m. injection. Blood lead concentrations were also monitored. Lead-induced ataxia was separable from lead-induced crop dysfunction depending on the route of lead administration, suggesting that lead-induced crop stasis is not secondary to toxicity at a site associated with ataxia. Intramuscular treatment produced crop stasis more readily than did crop intubation. This probably reflects different mechanisms of absorption and metabolism. A Tris-succinate medium was devised which accommodated the solubility characteristics of lead, permitting studies of crop tissue in vitro. Lead chloride added to crop tissue in tris-succinate medium caused a concentration-related reversible relaxation. Crop circular muscle was more sensitive to Pb++ than was longitudinal muscle, in agreement with the effects of other agonists. The EC30 of crop circular smooth muscle in plasma was 1000 microM PbCl2 compared to 3 microM in Tris-succinate medium. The results suggest that lead induces crop dysfunction by acting either directly on crop smooth muscle or on neural elements in crop tissue.


[Study on serum proteome of rat endotoxemia treated by figwort root].
To study the serum proteome of rat endotoxemia treated by figwort root (FR). The differences of serum proteome among rats treated with lipopolysaccharide (LPS), FR, LPS + FR and saline respectively were analyzed by two-dimensional electrophoresis (2DE) assay. The volumes of sixteen serum proteins (xPr) in LPS induced-endotoxemia group were greatly changed compared with those of the control group. Among them, the volumes of xPr 16, 19 were significantly decreased, and the volumes of xPr 1, 2, 3, 4, 5, 6, 7, 8, 9, 11, 12, 14, 18, 23 were significantly increased. When treated with FR, the volumes of xPr 1, 6, 7, 8, 9, 11, 12, 14, 18, 23 were significantly decreased, and the volumes of xPr 8, 9, 11, 12, 23, 14 were back to normal level. Two factors statistic analysis showed that FR had interaction with LPS for xPr 1, 5, 8, 10, 11, 12, 18, 19, 20, 21, 22, and FR might be the functional antagonist of LPS. We also observed that the volumes of xPr 10, 13, 15, 20, 21, 22 were found to change significantly only in FR treated group but not in LPS treated group or control group. Interestingly, the volume of xPr 13, 20, 21, 22 were increased and the volume of xPr 10, 15 were decreased. The molecular basis of therapeutic effect of FR on endotoxemia might be through the regulation of xPr 1, 6, 7, 8, 9, 11, 12, 14, 18, 23. We can use proteomic techniques to study the molecular mechanisms of diseases treated by functional Chinese herbs and the combination of different herbs is necessary for the treatment of endotoxemia, as FR can not regulated all the changed proteins induced by LPS.


[Neutrophils and immunity: is it innate or acquired?].
The neutrophil has long been considered a phagocytic cell with a short life-span whose major role is to destroy intruders to the body. Toll receptors and anti-infectious factors such as defensin, perforin and granzymes are newly discovered mechanisms used by neutrophils for the first line of defense against invaders. Moreover, subpopulations of neutrophils share specific functions like the synthesis of certain cytokines and chemokines, as well as the expression of immunoreceptors like the T cell receptor. A primary consequence of inflammation on neutrophils is a delay in their spontaneous programmed cell death. Hence, this multifunctional cell is also a necessary actor of the acquired immune response. Neutrophils have the capacity to degrade and process antigens as well as efficiently present antigenic peptides to lymphocytes. Neutrophil interactions with immune cells, in particular dendritic cells, lead to the formation of IL-12 and TNF-alpha deviating the immune response towards a Th1 phenotype. Thus, the neutrophil exhibits a cellular plasticity that explains its capacity to transdifferentiate depending on the local requirements of the immune response. The neutrophil is probably the most underappreciated immune cell among hematopoietic leukocytes, and many neutrophil functions remain to be unraveled.


18F-Choline PET/mpMRI for Detection of Clinically Significant Prostate Cancer: Part 2. Cost-Effectiveness Analysis.
The objective of this study was to evaluate the cost-effectiveness of 18F-choline PET/multiparametric MRI (mpMRI) versus mpMRI alone for the detection of primary prostate cancer with a Gleason score of greater than or equal to 3 + 4 in men with elevated prostate-specific antigen levels. Methods: A Markov model of prostate cancer onset and progression was used to estimate the health and economic consequences of 18F-choline PET/mpMRI for the detection of primary prostate cancer with a Gleason score of greater than or equal to 3 + 4 in men with elevated prostate-specific antigen levels. Multiple simultaneous hybrid 18F-choline PET/mpMRI strategies were evaluated using Likert or Prostate Imaging Reporting and Data System version 2 (PI-RADSv2) scoring; the first was biopsy for Likert 5 mpMRI lesions or Likert 3-4 lesions with 18F-choline target-to-background ratios of greater than or equal to 1.58, and the second was biopsy for PI-RADSv2 5 mpMRI lesions or PI-RADSv2 3-4 mpMRI lesions with 18F-choline target-to-background ratios of greater than or equal to 1.58. These strategies were compared with universal standard biopsy, mpMRI alone with biopsy only for PI-RADSv2 3-5 lesions, and mpMRI alone with biopsy only for Likert 4-5 lesions. For each mpMRI strategy, either no biopsy or standard biopsy could be performed after negative mpMRI results were obtained. Deaths averted, quality-adjusted life years (QALYs), cost, and incremental cost-effectiveness ratios were estimated for each strategy. Results: When the results of 18F-choline PET/mpMRI were negative, performing a standard biopsy was more expensive and had lower QALYs than performing no biopsy. The best screening strategy among those considered in this study performed hybrid 18F-choline PET/mpMRI with Likert scoring on men with elevated PSA, performed combined biopsy (targeted biopsy and standard 12-core biopsy) for men with positive imaging results, and no biopsy for men with negative imaging results ($22,706/QALY gained relative to mpMRI alone); this strategy reduced the number of biopsies by 35% in comparison to mpMRI alone. When the same policies were compared using PI-RADSv2 instead of Likert scoring, hybrid 18F-choline PET/mpMRI cost $46,867/QALY gained relative to mpMRI alone. In a threshold analysis, the best strategy among those considered remained cost-effective when the sensitivity and specificity of PET/mpMRI and combined biopsy (targeted biopsy and standard 12-core biopsy) were simultaneously reduced by 20 percentage points. Conclusion:18F-choline PET/mpMRI for the detection of primary prostate cancer with a Gleason score of greater than or equal to 3 + 4 is cost-effective and can reduce the number of unneeded biopsies in comparison to mpMRI alone.


Sexual activity before marriage in sub-Saharan Africa.
Throughout sub-Saharan Africa there is notable concern about the consequences of premarital sexual intercourse, such as illegal abortions and pregnancy-related school dropouts, and the potential risk of HIV infection. Using data from the Demographic and Health Surveys, the authors investigated sexual activity among never-married women aged 15-24 in Botswana, Burundi, Ghana, Kenya, Liberia, and Zimbabwe. While there are important cross-country differentials, in most countries the majority of unmarried adolescents have been sexually active. Contrary to the common belief that teenage premarital sexual activity is a new phenomenon caused by socioeconomic development, particularly Western education, the data show that in most countries sexual activity among unmarried adolescents was also common in the past, and that increases across cohorts have occurred mostly in countries where the prevalence was already high. For most countries, there is little support for theories claiming that education is associated with loose morals and high levels of premarital sexual activity. The findings highlight the importance of family-planning services for unmarried adolescents and of family-life education in primary schools to reach children before they become sexually active.


[Prevalence of peptic ulcer in smokers and non-smokers in Aragon].
The present study has attempted to determine the prevalence of peptic ulcer (UP) in smokers and nonsmokers in the geographic region of Aragon (Spain) using a sample of 10,000 subjects, 1,897 with ulcer, 1,708 of them diagnosed by endoscopy. The prevalence of smokers is 42.4% (63% of males and 14% of females). The prevalence of peptic ulcer in smokers (26.87%) is double that of nonsmokers (13.38%) (p less than 0.05). In males, all of the locations (duodenal, duodenal + gastric and gastric) are more common among smokers than among nonsmokers. These differences do not exist in women, gastric ulcer being more common among nonsmokers. Complications were more frequent among smokers with ulcer (60%) than among nonsmokers with ulcer (40%).


Detection of saponins in extracts from the rhizomes of Paris species and prepared Chinese medicines by high performance liquid chromatography-electrospray ionization mass spectrometry.
A highly sensitive and specific method, based on high performance liquid chromatography-electrospray ionization mass spectrometry (HPLC-ESI-MS), was developed for simultaneous detection of eleven steroidal saponins and one phytoecdysone in extracts from the rhizomes of thirteen PARIS species and four prepared Chinese medicines (PCMs). The HPLC experiments were performed by means of a reversed-phase C18 column (4.6 mm x 150 mm, 5 microm) and mobile phase system consisting of 0.1 % aqueous formic acid and acetonitrile under gradient elution conditions. The most intensive electrospray ionization signals were found in the negative ion spectra due to HCOO- adducts. The limits of detection (LODs) for the saponins were lower than 40 ng/mL in selected ion monitoring (SIM) mode. The identification of the saponins in the extracts of PARIS species and PCMs was confirmed using their retention times and mass spectral comparisons to standard compounds. The validated method was successfully applied for simultaneous detection of twelve standard compounds in the analytes so that it provided a new means for quality evaluation of Rhizoma Paridis and Chinese multiherb remedies that contain Rhizoma Paridis. The results showed that most species of PARIS contain steroidal saponins, which provided evidence for expanding the botanical origin of Rhizoma Paridis.


Benchmark performance of low-cost Sb2Se3 photocathodes for unassisted solar overall water splitting.
Determining cost-effective semiconductors exhibiting desirable properties for commercial photoelectrochemical water splitting remains a challenge. Herein, we report a Sb2Se3 semiconductor that satisfies most requirements for an ideal high-performance photoelectrode, including a small band gap and favourable cost, optoelectronic properties, processability, and photocorrosion stability. Strong anisotropy, a major issue for Sb2Se3, is resolved by suppressing growth kinetics via close space sublimation to obtain high-quality compact thin films with favourable crystallographic orientation. The Sb2Se3 photocathode exhibits a high photocurrent density of almost 30 mA cm-2 at 0 V against the reversible hydrogen electrode, the highest value so far. We demonstrate unassisted solar overall water splitting by combining the optimised Sb2Se3 photocathode with a BiVO4 photoanode, achieving a solar-to-hydrogen efficiency of 1.5% with stability over 10 h under simulated 1 sun conditions employing a broad range of solar fluxes. Low-cost Sb2Se3 can thus be an attractive breakthrough material for commercial solar fuel production.


Microstructure and Mechanical Properties of NiTi-Based Eutectic Shape Memory Alloy Produced via Selective Laser Melting In-Situ Alloying by Nb.
This paper presents the results of selective laser melting (SLM) process of a nitinol-based NiTiNb shape memory alloy. The eutectic alloy Ni45Ti45Nb10 with a shape memory effect was obtained by SLM in-situ alloying using a powder mixture of NiTi and Nb powder particles. Samples with a high relative density (>99%) were obtained using optimized process parameters. Microstructure, phase composition, tensile properties, as well as martensitic phase transformations temperatures of the produced alloy were investigated in as-fabricated and heat-treated conditions. The NiTiNb alloy fabricated using the SLM in-situ alloying featured the microstructure consisting of the NiTi matrix, fine NiTi+β-Nb eutectics, as well as residual unmelted Nb particles. The mechanical tests showed that the obtained alloy has a yield strength up to 436 MPa and the tensile strength up to 706 MPa. At the same time, in-situ alloying with Nb allowed increasing the hysteresis of martensitic transformation as compared to the alloy without Nb addition from 22 to 50 °C with an increase in Af temperature from -5 to 22 °C.


The effects of florfenicol on lymphocyte subsets and humoral immune response in mice.
Florfenicol is a broad-spectrum bacteriostatic antibiotic used in domestic animals. The aim of the study was to determine the effect of florfenicol on the total number of lymphocytes in the thymus, spleen and mesenteric lymph nodes and the percentage and the absolute number of T cell subsets (CD4+CD8+, CD4-CD8-, CD4+, CD8+) in the thymus and T (CD3+, CD4+, CD8+) and B (CD19+) lymphocytes in the peripheral lymphatic organs in non-immunized mice and humoral immune response in sheep red blood cells (SRBC)-immunized mice. Florfenicol was administered orally at a dose of 30 mg/kg six times at 24 h intervals to non-immunized mice and four or seven times at 24 h intervals to SRBC-immunized mice. SRBC was injected 2 hours prior to the first dose of the drug. Florfenicol increased the percentage of CD4CD8- thymocytes and the absolute number of CD4+ and CD8+ thymocytes on day 7. The increased percentage and absolute number of CD3+, CD4+ and CD8+ lymphocytes in mesenteric lymph nodes and decreased percentage of lymphocytes B were also observed 24 hours from the last administration of florfenicol. Florfenicol administered after SRBC immunization reduced the number of plaque forming cells (PFC) and the production of anti-SRBC antibodies on days 4 and 7 after priming.


C-jun N-terminal kinase mediates tumor necrosis factor-alpha suppression of differentiation in myoblasts.
The stress kinase c-jun N-terminal kinase (JNK) was recently shown to be involved in the pathophysiology of major inflammatory conditions, including Alzheimer's disease, stroke, obesity, and type II diabetes. However, the role of JNK in regulating inflammatory events in skeletal muscle is only beginning to be explored. IGF-I is the major hormone that promotes muscle growth and development. Here we used a novel, JNK interacting protein (JIP)-derived JNK peptide inhibitor to establish that JNK suppresses the biological activity of IGF-I in skeletal muscle progenitor cells. In these myoblasts, TNFalpha and its downstream receptor substrates, neutral-sphingomyelinase (N-SMase) and N-acetyl-d-sphingosine (C2-ceramide), induce JNK kinase activity in a time-dependent manner. Consistent with these results, TNFalpha induces JNK binding to insulin receptor substrate 1 (IRS-1) but is unable to inhibit IGF-I-induced IRS-1 tyrosine phosphorylation in myoblasts that are treated with the JNK peptide inhibitor. More importantly, JNK activation induced by TNFalpha, C2-ceramide, and N-SMase is associated with reduced expression of the critical muscle transcription factor myogenin as well as the differentiation marker myosin heavy chain (MHC). The JNK peptide inhibitor, but not the control peptide, completely reverses this inhibition of both myogenin and MHC. In the absence of IGF-I, TNFalpha, C2-ceramide, N-SMase and the JNK inhibitor are inactive, as shown by their inability to affect IRS tyrosine phosphorylation and protein expression of myogenin and MHC. These results establish that the resistance of muscle progenitor cells to IGF-I, which is caused by inflammatory stimuli, is mediated by the JNK stress kinase pathway.


[Treatment of Metacarpal and Phalangeal Fractures].
Metacarpal and phalangeal fractures are the second most frequent fractures of the upper extremity. Treatment goal is to restore the function of the injured hand. Due to better understanding of anatomy and biomechanics as well as the development of locking and low-profile implants for osteosynthesis of such fractures, there is a growing safety when choosing the operative treatment for the correct indication. Nevertheless, conservative treatment of these injuries still plays an important role.


Designing a brief behaviour change intervention to reduce sexually transmitted infections: a discrete choice experiment.
To understand whether people attending sexual health (SH) clinics are willing to participate in a brief behavioural change intervention (BBCI) to reduce the likelihood of future sexually transmitted infections (STIs) and to understand their preferences for different service designs, we conducted a discrete choice experiment (DCE) with young heterosexual adults (aged 16-25 years), and men who have sex with men (MSM) aged 16 or above, attending SH clinics in England. Data from 368 participants showed that people particularly valued BBCIs that involved talking (OR 1.45; 95%CI 1.35, 1.57 compared with an 'email or text'-based BBCIs), preferably with a health care professional rather than a peer. Findings also showed that 26% of respondents preferred 'email/texts' to all other options; the remaining 14% preferred not to participate in any of the offered BBCIs. These results suggest that most people attending SH clinics in England are likely to participate in a BBCI if offered, but the type/format of the BBCI is likely to be the single important determinant of uptake rather than characteristics such as the length and the number of sessions. Moreover, participants generally favoured 'talking'-based options rather than digital alternatives, which are likely to require the most resources to implement.


A technical note on emerging combination approach involved in the onconanotherapeutics.
Cancer is the second cause of mortality worldwide, and the currently available conventional treatment approach is associated with serious side effects and poor clinical outcomes. Based on the outcome of the exploratory preclinical and clinical studies, it was found that therapeutic response increases multiple folds when anticancer drugs are used in combination. However, the conventional combination of anticancer drugs was associated with various limitations such as increased cost of treatment, systemic toxicity, drug resistance, and reduced pharmacokinetic attributes. Hence, attempts were made to formulate nanocarrier fabricated combinatorial drugs (NFCDs) to effectively manage and treat cancer. This approach offers several advantages, such as improved stability, lower drug exposure, targeted drug delivery, low side effects, and improved clinical outcome. Hence, in this review, first time, we have discussed the recent advancement and various types of nano carrier-based combinatorial drug delivery systems in a different type of cancer and highlighted the personalized combinatorial theranostic medicine as a futuristic anticancer treatment approach.


Utilization of mercaptoethylgluconamide for depleting human cystinotic fibroblasts of their accumulated lysosomal cystine.
Human cystinotic fibroblasts were completely depleted of their accumulated intracellular free cystine within a 2-h time interval when exposed to culture medium containing between 1 and 5 mM mercaptoethylgluconamide. This cystine-depleting action of mercaptoethylgluconamide was observed with three different human cystinotic fibroblast cell lines and with all three cell lines, 2 mM mercaptoethylgluconamide was as effective as 1 mM cysteamine in depleting cells of their intracellular free cystine. Cell viability was excellent for cystinotic fibroblasts exposed to 2 mM mercaptoethylgluconamide for up to 6 days in duration. Mercaptoethylgluconamide (2 mM) was sufficiently stable under cell culture conditions such that a single addition of mercaptoethylgluconamide maintained cystine depletion in human cystinotic fibroblasts for at least a 4-day period. In contrast to cysteamine, 2 mM mercaptoethylgluconamide was not capable of depleting the cystine content of isolated cystinotic lysosomes, implying that cellular integrity is necessary to achieve cystine depletion by mercaptoethylgluconamide. The efficient cystine-depleting action of mercaptoethylgluconamide coupled with its lack of offensive odor encourage further investigation of this agent to possibly complement or supplant the use of cysteamine in the treatment of nephropathic cystinosis.


Microwave-developed three-dimensional real-time holography.
A new technique capable of enhancing optical nonlinearity is proposed. In the suggested scheme, weak optical fields create a three-dimensional real-time hologram written as a carrier distribution, and then an applied microwave field develops the hologram by heating the carriers and increasing the nonlinear refractive index locally. As an example, we have calculated the diffraction efficiency for the case of four-wave mixing. A value as high as 1% can be achieved in a 5-mm sample of CdS microcrystallites in glass.


[Hepatic resection as necessary in liver injuries].
The fact that experience has been gained during four successive episodes since 1940 emphasizes the progress accomplished in the fields of therapeutic indications and surgical techniques for these lesions. Resection "on request" is effective both as therapy of hemorrhage and escape of bile: conducted under the control of regional hemostasis it is the most sparing of healthy parenchyma while being effective and complete. It can be adapted for emergency cases, or used as first intention surgery as well as in delayed cases or previously operated patients. Results are particularly interesting in the absence of associated lesions.


Short Wavelength Inner Filter Technique (SWIFT) in Designing Reactive Fluorescent Molecular Probes.
Here, we present a conceptually novel and experimentally straightforward technique for selective analyte detection that uses a combination of commercial fluorophores and simple chemicals. The technique utilizes the well-known inner filter effect (IFE); however, the fluorophore's excitation is performed at wavelengths significantly shorter than its absorption maximum. In the presence of the analyte, the "filter" appears or disappears at the excitation wavelength resulting in the fluorescence turning OFF or ON, respectively. Unlike common probes, our technique allows real-time monitoring of a fluorophore's stability as well as its recycling. We further demonstrate the applicability of this technique in continuing analyte detection as well as vapor analysis.


Gene expression profiling of rat pheochromocytoma.
Sporadic and syndrome-associated human pheochromocytomas exhibit a spectrum of common and distinctive phenotypic markers. Animal models may contribute to understanding of common denominators leading to development and progression of pheochromocytoma, and to mechanisms that underlie distinctive phenotypes. Rat pheochromocytomas are common, in contrast to their human counterparts, and their frequency is increased by a variety of genotoxic or nongenotoxic agents. Toxicological studies of rats are therefore a potentially rich source of information on pheochromocytoma biology. To compare the molecular profiles of rat and human pheochromocytomas and to identify pathways potentially involved in pathogenesis of rat pheochromocytomas, we conducted a gene expression profiling study comparing 31 pheochromocytomas obtained from the National Toxicology Program to normal adult rat adrenal medulla. The microarray chips were generated from 31,769-oligomer set representing over 27,200 unique Mouse Ensembl genes. The analysis showed over 1,900 genes that were up- or downregulated in the tumors. More than half of the former are involved in protein synthesis and signal transduction, including oncogenes of the RAS family and several heat shock proteins and chaperones. Downregulated genes included receptors and tumor-suppressor genes, including NF2 and Dmbt1. Specific genes related to neuroendocrine function were either upregulated or downregulated in subsets of tumors. Cross-comparison with a human pheochromocytoma database showed greater than 60% correlation. Results of this study reveal both generic and specific parallels between rat and human pheochromocytomas.


Detection and clinical relevance of BCR-ABL fusion gene in childhood T-lineage acute lymphoblastic leukemia: a report on 4 cases.
The bcr-abl rearrangement has rarely been reported in T-lineage acute lymphoblastic leukemia and the clinical significance of this translocation is currently unknown. We screened 28 children with T-lineage acute lymphoblastic leukemia at diagnosis by reverse transcription polymerase chain reaction for major and minor break point regions of bcr-abl fusion gene. Four out of 28 patients (14.2%) were bcr-abl positive for the minor breakpoint transcript. One of these patients was refractory to therapy, whereas the other 3 relapsed on therapy.


Post-Translational Modifications of BRD4: Therapeutic Targets for Tumor.
Bromodomain-containing protein 4 (BRD4), a member of the bromodomain and extraterminal (BET) family, is considered to be a major driver of cancer cell growth and a new target for cancer therapy. Over 30 targeted inhibitors currently in preclinical and clinical trials have significant inhibitory effects on various tumors, including acute myelogenous leukemia (AML), diffuse large B cell lymphoma, prostate cancer, breast cancer and so on. However, resistance frequently occurs, revealing the limitations of BET inhibitor (BETi) therapy and the complexity of the BRD4 expression mechanism and action pathway. Current studies believe that when the internal and external environmental conditions of cells change, tumor cells can directly modify proteins by posttranslational modifications (PTMs) without changing the original DNA sequence to change their functions, and epigenetic modifications can also be activated to form new heritable phenotypes in response to various environmental stresses. In fact, research is constantly being supplemented with regards to that the regulatory role of BRD4 in tumors is closely related to PTMs. At present, the PTMs of BRD4 mainly include ubiquitination and phosphorylation; the former mainly regulates the stability of the BRD4 protein and mediates BETi resistance, while the latter is related to the biological functions of BRD4, such as transcriptional regulation, cofactor recruitment, chromatin binding and so on. At the same time, other PTMs, such as hydroxylation, acetylation and methylation, also play various roles in BRD4 regulation. The diversity, complexity and reversibility of posttranslational modifications affect the structure, stability and biological function of the BRD4 protein and participate in the occurrence and development of tumors by regulating the expression of tumor-related genes and even become the core and undeniable mechanism. Therefore, targeting BRD4-related modification sites or enzymes may be an effective strategy for cancer prevention and treatment. This review summarizes the role of different BRD4 modification types, elucidates the pathogenesis in the corresponding cancers, provides a theoretical reference for identifying new targets and effective combination therapy strategies, and discusses the opportunities, barriers, and limitations of PTM-based therapies for future cancer treatment.


Gene expression profiles in anatomically and functionally distinct regions of the normal aged human brain.
In this article, we have characterized and compared gene expression profiles from laser capture microdissected neurons in six functionally and anatomically distinct regions from clinically and histopathologically normal aged human brains. These regions, which are also known to be differentially vulnerable to the histopathological and metabolic features of Alzheimer's disease (AD), include the entorhinal cortex and hippocampus (limbic and paralimbic areas vulnerable to early neurofibrillary tangle pathology in AD), posterior cingulate cortex (a paralimbic area vulnerable to early metabolic abnormalities in AD), temporal and prefrontal cortex (unimodal and heteromodal sensory association areas vulnerable to early neuritic plaque pathology in AD), and primary visual cortex (a primary sensory area relatively spared in early AD). These neuronal profiles will provide valuable reference information for future studies of the brain, in normal aging, AD and other neurological and psychiatric disorders.


Assay of estrogens in human feces.
A radioimmunological method for the determination of unconjugated and conjugated estrone (E1), estradiol (E2) and estriol (E3) in feces of women and men is described and validated. Positive proof of specificity was obtained by GC/MS identification of the three estrogens in feces of a non-pregnant woman. In addition estradiol-17 alpha was detected in the estradiol fraction and an unknown tetrol in the E3 fraction. It is shown that the method fulfills the reliability criteria and that it is possible to measure these estrogens in 1 g feces samples. Estrogen excretion varies during the menstrual cycle with the greatest excretion around ovulation time. The relative amount of E2 is much higher in feces than in urine and bile reflecting reductive metabolism in the gut. About 10-15% of E1, E2 and E3 occurs in the conjugated form in feces. Quantitative data for young women during the menstrual cycle, for postmenopausal women and for men are presented. Men and postmenopausal women excrete similar amounts of estrogen in feces, but during the menstrual cycle much higher concentrations are found. Calculations reveal that fecal excretion of these estrogens represents about 5-10% of total excretion of estrogens in urine and feces. It is concluded that estrogen metabolism in the intestinal tract may be of similar biological significance to that in the liver.


Rethinking Clinical Trials and Personalized Medicine with Placebogenomics and Placebo Dose.
Pharmacogenomics, nutrigenomics, vaccinomics, and the nascent field of plant omics are examples of variability science. They are embedded within an overarching framework of personalized medicine. Across these public health specialties, the significance and biology of the placebo response have been historically neglected. A placebo is any substance such as a sugar pill administered in the guise of medication, but one that does not have pharmacological activity. Placebos do have clinical effects, however, that can be substantive in magnitude and vary markedly from person-to-person depending, for example, on the type of disease, symptoms, or clinical trial design. Research over the past several decades attests to a genuine neurobiological basis for placebo effects. All drugs have placebo components that contribute to their overall treatment effect. Placebos are used in clinical trials as control groups to ascertain the net pharmacological effect of a drug candidate. Not only less well known but also relevant to rational therapeutics and personalized medicine is the nocebo. A nocebo effect occurs when an inert substance is administered in a context that induces negative expectations, worsening patients' symptoms. With the COVID-19 pandemic, there are high public expectations for new vaccines and medicines to end the contagion, while at the same time antiscience, post-truth, and antivaccine movements are worrisomely on the rise. These social movements, changes in public health cultures, and conditioned behavioral responses can trigger both placebo and nocebo effects. Hence, in clinical trials, forecasting and explaining placebo and nocebo variability are more important than ever for robust science and personalized health care. Against this overarching context, this article provides (1) a brief history of placebo and (2) a discussion on biology, mechanisms, and variability of placebo effects, and (3) discusses three emerging new concepts: placebogenomics, nocebogenomics, and augmented placebo, that is, the notion of a "placebo dose." We conclude with a roadmap for placebogenomics, its synergies with the nascent field of social pharmacology, and the ways in which a new taxonomy of drug and placebo variability can be anticipated in the next decade.


Aromatic DNA adducts in larynx biopsies and leukocytes.
Larynx cancer is strongly associated with tobacco smoking. The objective of this work was an analysis of aromatic DNA adducts in tumour and non-tumour larynx cells by means of the 32P-postlabelling method. Peripheral blood leukocytes were used as a reference tissue. The presence of aromatic DNA adducts was demonstrated in all the studied tissues obtained after surgery of larynx tumours. The highest level of DNA adducts was found in larynx tumour cells, followed by non-tumour larynx cells, which exceeded that found in leukocytes almost 2.5 times. Large interindividual differences were detected between subjects. The adduct level in tumour/non-tumour correlated only moderately. However a high correlation was found between the level of DNA adducts in larynx (tumour and non-tumour) cells and that in leukocytes.


PRP-paradigm provides evidence for a perceptual origin of the negative compatibility effect.
Visual stimuli (primes) that are made invisible by masking can affect motor responses to a subsequent target stimulus. When a prime is followed by a mask which is followed by a target stimulus, an inverse priming effect (or negative compatibility effect) has been found: Responses are slow and frequently incorrect when prime and target stimuli are congruent, but fast and accurate when prime and target stimuli are incongruent. To functionally localize the origins of inverse priming effects, we applied the psychological refractory period (PRP-) paradigm which distinguishes a perceptual level, a central bottleneck, and a level of motor execution. Two dual-task experiments were run with the PRP-paradigm to localize the inverse priming effect relative to the central bottleneck. Together, results of the Effect-Absorption and the Effect-Propagation Procedure suggest that inverse priming effects are generated by perceptual mechanisms. We suggest two perceptual mechanisms as the source of inverse priming effects.


[Idiopathic intracranial hypertension: clinical features and outcome].
Idiopathic intracranial hypertension in children is rare. We analyzed clinical presentation and outcome in eight patients (six girls and two boys) diagnosed with idiopathic intracranial hypertension. The mean age was 11.1 years. The most common clinical features were headache, papilledema and visual disturbance (visual loss and diplopia). Response to treatment was satisfactory in all patients except one who presented almost complete bilateral amaurosis requiring extracranial shunting and who later developed optic atrophy. Outcome is usually is benign, but given the possibility of severe loss of visual function, close ophthalmic follow-up is recommended until complete resolution.


[Ocular Syphilis May Lead to Persistent Visual Dysfunction].
The spectrum of intraocular and systemic findings in patients with ocular syphilis is described. Persistent visual dysfunction and structural abnormality, in spite of targeted antibiotic therapy, were identified and analysed. Patients with ocular syphilis who were treated at University Hospital Zurich (USZ) between 2010 and 2018 were included in this study. General characteristics, ocular manifestation and visual function (best-corrected visual acuity [BCVA], visual field) before and after treatment were analysed retrospectively. Ocular syphilis was diagnosed in one female and 16 male patients (median age 42 years, range 22 to 53 years). A bilateral infection was present in 11 cases, and 28 of 34 eyes were affected (82%). Manifestations included anterior (n = 3), intermediate (n = 4), posterior (n = 10) uveitis, as well as panuveitis (n = 5) and papillitis (n = 6). Abnormal liquor findings were present in 8 patients (47%). Six patients were human immunodeficiency virus (HIV) positive. In all patients, intravenous benzyl penicillin was initiated and led to inactivation of intraocular inflammation. Before the initial intravenous treatment, all patients received one dose of steroids orally (Prednisone [PDN] 50 to 70 mg). Seven patients had systemic steroids added over the course of the antibiotic treatment being gradually decreased during and after the antibiotic treatment. The initial median BCVA of all affected eyes (n = 28) of 17 patients was 0.1 logMAR (0.8 decimal), range 2.8 to - 0.1 logMAR (light perception to 1.25 decimal). At the last visit, the median BCVA was 0 logMAR, range 0.4 to - 0.1 logMAR (0.4 to 1.25 decimal). Median follow-up time was 11 months (range 3 to 60 months). At the last visit, BCVA of 4 eyes (3 patients) was ≤ 0.6. Six eyes of 5 patients had a persisting scotoma with central visual field defects. Morphologically, disintegration and irregularities of outer retinal layers after central retinitis (5 eyes) and atrophy of the peripapillary retinal nerve fibre layer (4 eyes) after papillitis correlated with abnormal vision. The spectrum of ocular manifestations in syphilis is broad. Despite targeted antibiotic therapy, more than a third of affected eyes had lasting abnormal vision. Patients with papillitis and retinitis were at an increased risk for persistent visual dysfunction.


Purification of a jojoba embryo wax synthase, cloning of its cDNA, and production of high levels of wax in seeds of transgenic arabidopsis.
Wax synthase (WS, fatty acyl-coenzyme A [coA]: fatty alcohol acyltransferase) catalyzes the final step in the synthesis of linear esters (waxes) that accumulate in seeds of jojoba (Simmondsia chinensis). We have characterized and partially purified this enzyme from developing jojoba embryos. A protein whose presence correlated with WS activity during chromatographic fractionation was identified and a cDNA encoding that protein was cloned. Seed-specific expression of the cDNA in transgenic Arabidopsis conferred high levels of WS activity on developing embryos from those plants. The WS sequence has significant homology with several Arabidopsis open reading frames of unknown function. Wax production in jojoba requires, in addition to WS, a fatty acyl-CoA reductase (FAR) and an efficient fatty acid elongase system that forms the substrates preferred by the FAR. We have expressed the jojoba WS cDNA in Arabidopsis in combination with cDNAs encoding the jojoba FAR and a beta-ketoacyl-CoA synthase (a component of fatty acid elongase) from Lunaria annua. (13)C-Nuclear magnetic resonance analysis of pooled whole seeds from transgenic plants indicated that as many as 49% of the oil molecules in the seeds were waxes. Gas chromatography analysis of transmethylated oil from individual seeds suggested that wax levels may represent up to 70% (by weight) of the oil present in those seeds.


Tritoroidal particle rings formation in open microfluidics induced by standing surface acoustic waves.
In this paper, the particle movements in a sessile droplet induced by standing surface acoustic waves (SSAWs) are studied. Tritoroidal particle rings are formed under the interaction of acoustic field and electric field. The experimental results demonstrate that the electric field plays an important role in patterning nanoparticles. The electric field can define the droplet shape due to electrowetting. When the droplet approximates a hemisphere, the acoustic radiation force induced by SSAWs drives the particles to form tritoroidal particle rings. When the droplet approximates a convex plate, the drag force induced by acoustic steaming drives the particle to move. The results will be useful for better understanding the nanoparticle movements in a sessile droplet, which is important to explain the mechanism that SSAWs enhance reaction and crystallization in droplet.


Neurotrophin receptors TrkA and TrkB in retinoblastoma are differentially expressed depending on cellular differentiation.
Retinoblastoma is the most common primary intraocular malignancy in children. With the progression of retinoblastoma, retinoblastoma cells lose their ability to differentiate. Regardless of many attempts to identify prognostic factors in retinoblastoma, further investigation for prognostic factors of retinoblastoma progression is still required because of the lack of sensitivity and specificity of these prognostic factors in predicting disease progression. We demonstrated that the differential expression of the neurotrophin receptors TrkA and TrkB is closely related to the differentiation of retinoblastoma cells. While retinoblastoma cells expressed TrkA as well as TrkB, their growth rates were not influenced by the addition of nerve growth factor to the culture medium. In experimental animal models of retinoblastoma, TrkA expression was primarily detected in more differentiated areas with high nm23 immunoreactivity whereas TrkB expression was apparent in more proliferative areas with high Ki67 immunoreactivity. With retinoic-acid-induced differentiation of retinoblastoma cells, TrkA expression significantly increased whereas TrkB significantly decreased. The differential expression of TrkA and TrkB with differentiation of retinoblastoma cells was mediated by extracellular-signal-regulated kinase 1/2 activation, which was confirmed by immunocytochemistry of TrkA. Therefore, our results suggest that the differential expression of TrkA and TrkB could be valuable as a therapeutic target, for instance using specific inhibitors.


Emerging issues in the Pacific Basin.
This review provides a snapshot of some key environmental health issues that will provide ongoing challenges for the Pacific Basin region in the coming decades. It is clear that climate change as well as the rapidly increasing production of environmental pollutants are significant emerging environmental health issues. To date, research in these areas is limited, and the consequences of potential changes in disease vector distribution, disease outbreaks associated with climate change-induced severe weather events, and the consequences of chronic exposure to engineered nanoparticles and persistent organic pollutants (POPs), particularly in children, remain to be determined. Clearly, any progress in (i) predicting the outcomes of potential environmental health issues in the future, (ii) identifying subpopulations (at local, national, and international levels) that are at risk, and (iii) establishing measures to limit the impact of these issues in terms of public health, will require a coordinated effort from scientists, epidemiologists, monitoring agencies, governments, and aid agencies.


Deregulation of apoptosis-related genes is associated with PRV1 overexpression and JAK2 V617F allele burden in Essential Thrombocythemia and Myelofibrosis.
Essential Thrombocythemia (ET) and Primary Myelofibrosis (PMF) are Chronic Myeloproliferative Neoplasms (MPN) characterized by clonal myeloproliferation/myeloaccumulation without cell maturation impairment. The JAK2 V617F mutation and PRV1 gene overexpression may contribute to MPN physiopathology. We hypothesized that deregulation of the apoptotic machinery may also play a role in the pathogenesis of ET and PMF. In this study we evaluated the apoptosis-related gene and protein expression of BCL2 family members in bone marrow CD34+ hematopoietic stem cells (HSC) and peripheral blood leukocytes from ET and PMF patients. We also tested whether the gene expression results were correlated with JAK2 V617F allele burden percentage, PRV1 overexpression, and clinical and laboratory parameters. By real time PCR assay, we observed that A1, MCL1, BIK and BID, as well as A1, BCLW and BAK gene expression were increased in ET and PMF CD34+ cells respectively, while pro-apoptotic BAX and anti-apoptotic BCL2 mRNA levels were found to be lower in ET and PMF CD34+ cells respectively, in relation to controls. In patients' leukocytes, we detected an upregulation of anti-apoptotic genes A1, BCL2, BCL-XL and BCLW. In contrast, pro-apoptotic BID and BIMEL expression were downregulated in ET leukocytes. Increased BCL-XL protein expression in PMF leukocytes and decreased BID protein expression in ET leukocytes were observed by Western Blot. In ET leukocytes, we found a correlation between JAK2 V617F allele burden and BAX, BIK and BAD gene expression and between A1, BAX and BIK and PRV1 gene expression. A negative correlation between PRV1 gene expression and platelet count was observed, as well as a positive correlation between PRV1 gene expression and splenomegaly. Our results suggest the participation of intrinsic apoptosis pathway in the MPN physiopathology. In addition, PRV1 and JAK2 V617F allele burden were linked to deregulation of the apoptotic machinery.


Phase shift and penetration depth of metal mirrors in a microcavity structure.
Optical properties of metal films, such as phase shift on reflection or penetration depth of electromagnetic waves into mirrors, play an important role in determining the resonance wavelength of a microcavity. We created a series of lambda/2 cavities with a symmetrical structure of glass/Ag/lithium fluoride/Ag by changing the thickness of the Ag film. The penetration depth at different thicknesses of Ag film was obtained from the transmittance peaks of the cavities. Phase shift on reflection at the lithium fluoride-Ag interface was calculated based on the measured optical constants. The formulation between phase shift and penetration depth was proved by experimental results, which are in good agreement with the theoretical calculations.


HRAS1 minisatellite alleles in colorectal carcinoma: relationship to microsatelite instability.
To further evaluate sporadic colon carcinoma risk associated with rare HRAS1 VNTR alleles, the relationship with microsatellite instability and with HRAS1 VNTR instability. The HRAS1 VNTR was genotyped in 121 tumors and normal samples from sporadic colon carcinoma patients (47 right and 74 left colon) and in 109 samples from healthy individuals. The HRAS1 alleles were identified using PCR and automatic fluorescent electrophoresis detection combined with MVR-PCR (Minisatellite Variant Repeat-Polymerase Chain Reaction). Microsatellite Instability (MI) was analysed with 10 microsatellite markers. A relative risk of 3.04 (95% CI: 1.16-4.92) associated with rare alleles was obtained. No HRAS1 minisatellite instability was present in the tumors. Samples with MI were equally distributed between the common and rare HRAS1 allele groups, while the distribution of HRAS1 alleles in samples with MI was similar in right and left colorectal carcinoma. Rare HRAS1 VNTR alleles are associated with colorectal carcinoma risk independent of the tumor location. MI is not likely to be involved in the same underlying defect that generates rare HRAS1 alleles in colorectal carcinoma.


Studies on experimentally induced hyperphenylalaninemia.
The administration of several compounds that can increase plasma phenylalanine levels and/or inhibit phenylalanine hydroxylase in rats was studied in order to determine their usefulness in inducing a phenylketonuria-like state. The results of this investigation revealed that 4.5 microns/10 g p-chlorophenylalanine is more effective than L-phenylalanine, alpha-methylphenylalanine, trimethoprim, Bactrim and Septra, since the former compound produced both adequate hyperphenylalaninemia and marked inhibition of hepatic phenylalanine hydroxylase activity. In addition, a 24-h study provided important insights into the changing diurnal patterns of specified biochemical parameters.


The SOBANE strategy for the management of risk, as applied to whole-body or hand-arm vibration.
The objective was to develop a coherent set of methods to be used effectively in industry to prevent and manage the risks associated with exposure to vibration, by coordinating the progressive intervention of the workers, their management, the occupational health and safety (OHS) professionals and the experts. The methods were developed separately for the exposure to whole-body and hand-arm vibration. The SOBANE strategy of risk prevention includes four levels of intervention: level 1, Screening; level 2, Observation; level 3, Analysis and; level 4, Expertise. The methods making it possible to apply this strategy were developed for 14 types of risk factors. The article presents the methods specific to the prevention of the risks associated with the exposure to vibration. The strategy is similar to those published for the risks associated with exposure to noise, heat and musculoskeletal disorders. It explicitly recognizes the qualifications of the workers and their management with regard to the work situation and shares the principle that measuring the exposure of the workers is not necessarily the first step in order to improve these situations. It attempts to optimize the recourse to the competences of the OHS professionals and the experts, in order to come more rapidly, effectively and economically to practical control measures.


Intravitreous high expression level of netrin-1 in patients with proliferative diabetic retinopathy.
To investigate the significance of netrin-1 and vascular endothelial growth factor (VEGF) in the pathogenesis of retinal angiogenesis, the levels of netrin-1 and VEGF in the vitreous fluid and serum of the proliferative diabetic retinopathy (PDR) and non-proliferative diabetic retinopathy (non-PDR) patients were measured. We then determined the netrin-1 and VEGF expression in the oxygen induced retinopathy (OIR) mice retinas. A total of 18 eyes from 18 patients were included in our study and 10 of them were collected from PDR patients and 8 from non-PDR patients. Undiluted vitreous fluid samples were collected during pars plana vitrectomy. Appropriate blood samples were collected if possible. Netrin-1 and VEGF levels in the vitreous fluid and plasma were determined by Enzyme-linked Immunosorbent Assays. OIR mice models were established, and netrin-1 and VEGF levels were determined by immunohistochemistry analysis. The levels of netrin-1 and VEGF in the vitreous of PDR patients were significantly higher than those in the controls (Mediannetrin-1=509.94 vs. 85.91 pg/ml, P<0.001 and Median VEGF=762.60 vs. 77.52 pg pg/ml, P<0.001). Netrin-1 was mainly expressed in GCL and INL of the retina in mice. Both netrin-1 and VEGF were up-regulated in OIR mice. Netrin-1 and VEGF levels were elevated in vitreous fluid of the PDR patients and the OIR mice retinas. Therefore, netrin-1 may play important roles in pathological retinal angiogenesis.


The index of ideality of correlation: QSAR studies of hepatitis C virus NS3/4A protease inhibitors using SMILES descriptors.
Robust and reliable QSAR models were developed to predict half-maximal inhibitory concentration (IC50) values of hepatitis C virus NS3/4A protease inhibitors from the Monte Carlo technique. 524 HCV NS3/4A protease inhibitors were extracted from the scientific literature to create a reasonably large set. The models were developed using CORAL software by using two target functions namely target function 1 (TF1) without applying the index of ideality of correlation (IIC) and target function 2 (TF2) that uses IIC. The constructed models based on TF2 were statistically more significant and robust than the models based on TF1. The determination coefficients (r2) of training and test sets were 0.86 and 0.88 for the best split based on TF2. The promoters of the increase/decrease of activity were also extracted and interpreted in detail. The model interpretation results explain the role of different structural attributes in predicting the pIC50 values of hepatitis C virus NS3/4A protease inhibitors. Based on the mechanistic model interpretation results, eight new compounds were designed and their pIC50 values were predicted based on the average prediction of ten models.


Effects of drift gas on collision cross sections of a protein standard in linear drift tube and traveling wave ion mobility mass spectrometry.
There has been a significant increase in the use of ion mobility mass spectrometry (IM-MS) to investigate conformations of proteins and protein complexes following electrospray ionization. Investigations which employ traveling wave ion mobility mass spectrometry (TW IM-MS) instrumentation rely on the use of calibrants to convert the arrival times of ions to collision cross sections (CCS) providing "hard numbers" of use to structural biology. It is common to use nitrogen as the buffer gas in TW IM-MS instruments and to calibrate by extrapolating from CCS measured in helium via drift tube (DT) IM-MS. In this work, both DT and TW IM-MS instruments are used to investigate the effects of different drift gases (helium, neon, nitrogen, and argon) on the transport of multiply charged ions of the protein myoglobin, frequently used as a standard in TW IM-MS studies. Irrespective of the drift gas used, recorded mass spectra are found to be highly similar. In contrast, the recorded arrival time distributions and the derived CCS differ greatly. At low charge states (7 ≤ z ≤ 11) where the protein is compact, the CCS scale with the polarizability of the gas; this is also the case for higher charge states (12 ≤ z ≤ 22) where the protein is more unfolded for the heavy gases (neon, argon, and nitrogen) but not the case for helium. This is here interpreted as a different conformational landscape being sampled by the lighter gas and potentially attributable to increased field heating by helium. Under nanoelectrospray ionization (nESI) conditions, where myoglobin is sprayed from an aqueous solution buffered to pH 6.8 with 20 mM ammonium acetate, in the DT IM-MS instrument, each buffer gas can yield a different arrival time distribution (ATD) for any given charge state.