Role of chloride ions in modulation of the interaction between von Willebrand factor and ADAMTS-13

The degradation of von Willebrand factor (VWF) depends on the activity of a zinc protease (referred to as ADAMTS-13), which cleaves VWF at the Tyr(1605)-Met(1606) peptide bond. Little information is available on the physiological mechanisms involved in regulation of AD-AMTS-13 activity. In this study, the role of ions on the ADAMTS-13/VWF interaction was investigated. In the presence of 1.5 m urea, the protease cleaved multimeric VWF in the absence of NaCl at pH 8.00 and 37 degrees C, with an apparent k(cat)/K(m) congruent with 3.4 x 10(4) M(-1) s(-1), but this value decreased by approximately 10-fold in the presence of 0.15 M NaCl. Using several monovalent salts, the inhibitory effect was attributed mostly to anions, whose potency was inversely related to the corresponding Jones-Dole viscosity B coefficients (ClO(4)(-) > Cl(-) > F(-)). The specific inhibitory effect of anions was due to their binding to VWF, which caused a conformational change responsible for quenching the intrinsic fluorescence of the protein and reducing tyrosine exposition to bulk solvent. Ristocetin binding to VWF could reduce the apparent affinity and reverse the inhibitory effect of chloride. We hypothesize that, after secretion into the extracellular compartment, VWF is bound by chloride ions abundantly present in this milieu, becoming unavailable to proteolysis by AD-AMTS-13. Shear forces, which facilitate GpIbalpha binding (this effect being artificially obtained by ristocetin), can reverse the inhibitory effect of chloride, whose concentration gradient across the cell membrane may represent a simple but efficient strategy to regulate the enzymatic activity of ADAMTS-13.     

Trends in First-Line Antiretroviral Therapy in Asia: Results from the TREAT Asia HIV Observational Database

Background

Antiretroviral therapy (ART) has evolved rapidly since its beginnings. This analysis describes trends in first-line ART use in Asia and their impact on treatment outcomes.

Methods

Patients in the TREAT Asia HIV Observational Database receiving first-line ART for ≥6 months were included. Predictors of treatment failure and treatment modification were assessed.

Results

Data from 4662 eligible patients was analysed. Patients started ART in 2003–2006 (n = 1419), 2007–2010 (n = 2690) and 2011–2013 (n = 553). During the observation period, tenofovir, zidovudine and abacavir use largely replaced stavudine. Stavudine was prescribed to 5.8% of ART starters in 2012/13. Efavirenz use increased at the expense of nevirapine, although both continue to be used extensively (47.5% and 34.5% of patients in 2012/13, respectively). Protease inhibitor use dropped after 2004. The rate of treatment failure or modification declined over time (22.1 [95%CI 20.7–23.5] events per 100 patient/years in 2003–2006, 15.8 [14.9–16.8] in 2007–2010, and 11.6 [9.4–14.2] in 2011–2013). Adjustment for ART regimen had little impact on the temporal decline in treatment failure rates but substantially attenuated the temporal decline in rates of modification due to adverse event. In the final multivariate model, treatment modification due to adverse event was significantly predicted by earlier period of ART initiation (hazard ratio 0.52 [95%CI 0.33–0.81], p = 0.004 for 2011–2013 versus 2003–2006), older age (1.56 [1.19–2.04], p = 0.001 for ≥50 years versus <30years), female sex (1.29 [1.11–1.50], p = 0.001 versus male), positive hepatitis C status (1.33 [1.06–1.66], p = 0.013 versus negative), and ART regimen (11.36 [6.28–20.54], p<0.001 for stavudine-based regimens versus tenofovir-based).

Conclusions

The observed trends in first-line ART use in Asia reflect changes in drug availability, global treatment recommendations and prescriber preferences over the past decade. These changes have contributed to a declining rate of treatment modification due to adverse event, but not to reductions in treatment failure.     

Apparent survival rates of a long-lived partial migrant: the Yellow-legged Gull Larus michahellis

Capsule: In Yellow-legged Gull Larus michahellis populations from the eastern Adriatic Sea, there are considerable differences in the ratio of migratory birds and apparent survival among the colonies. Survival was dependent on age, colony and area of dispersal.

Aims: To identify the ratio of migratory birds within populations of Yellow-legged Gulls, and to compare apparent survival of gulls during migration in central and northern Europe and around the Adriatic Sea.

Methods: We analysed 15 years of resighting data of Yellow-legged Gulls using a MARK multi-state model to calculate survival rates. The effects of age, natal colony and area of dispersal were examined.

Results: Almost 60% of Adriatic Yellow-legged Gulls were migratory but the ratio varied among colonies (10.3–78.3%). Survival was dependent on age, colony and area of dispersal, with average values per group ranging between 0.599 (se 0.093) and 0.684 (se 0.084).

Conclusion: The ratio of migratory and dispersive Yellow-legged Gulls from different Adriatic colonies might be affected by both inheritance and food availability.     

Relationship between push phase and final race time in skeleton performance

The aim of this study was to examine the relationship between push-time and final race time in skeleton participants during a series of major international competitions to determine the importance of the push phase in skeleton performance. Correlations were computed from the first and second heat split data measured during 24 men and 24 women skeleton competitions. Body mass, height, age, and years of experience of the first 30 men and women athletes of the skeleton, bobsleigh and luge 2003-2004 World Cup ranking were used for the comparison between sliding sports. Moderate but significant correlations (p < 0.05) were found between push-time and final race time in men (r(mean) = 0.48) and women (r(mean) = 0.63). No correlations were found between changes in the individual push-time between the first and second heat with the corresponding changes in final race time. The bobsleigh sliders are heavier than the athletes of the other sliding disciplines. Luge athletes have more experience and are younger than bobsleigh and skeleton sliders. The results of this study suggest that a fast push phase is a prerequisite to success in competition and confirms that the selection of skeleton athletes based on the ability to accelerate to a maximum speed quickly could be valid. However, a good or improved push-time does not ensure a placement in the top finishing positions. On the basis of these results, we suggest that strength and power training is necessary to maintain a short push-time but additional physical training aimed to enhance the push phase might not reflect performance improvements. The recruitment of younger athletes and an increase of youthful competitive activity may be another effective way to reach international competitive results.     

EVA regulates thymic stromal organisation and early thymocyte development

Epithelial V-like antigen (EVA) is an immunoglobulin-like adhesion molecule identified in a screen for molecules developmentally regulated at the DN to DP progression in thymocyte development. We show that EVA is expressed during the early stages of thymus organogenesis in both fetal thymic epithelia and T cell precursors, and is progressively downregulated from day 16.5 of embryonic development. In the postnatal thymus, EVA expression is restricted to epithelial cells and is distributed throughout both cortical and medullary thymic regions. Transgenic overexpression of EVA in the thymus cortex resulted in a modified stromal environment, which elicited an increase in organ size and absolute cell number. Although peripheral T lymphocyte numbers are augmented throughout life, no imbalance either in the repertoire, or in the different T cell subsets was detected. Collectively, these data suggest a role for EVA in structural organisation of the thymus and early lymphocyte development.     

Salivary cortisol concentration after high-intensity interval exercise: Time of day and chronotype effect

Due to personal and working necessities, the time for exercise is often short, and scheduled early in the morning or late in the afternoon. Cortisol plays a central role in the physiological and behavioral response to a physical challenge and can be considered as an index of exercise stress. Therefore, the aim of this study was to evaluate the influence of the circadian phenotype classification on salivary cortisol concentration in relation to an acute session of high-intensity interval exercise (HIIE) performed at different times of the day. Based on the morningness–eveningness questionnaire, 12 M-types (N = 12; age 21 ± 2 years; height 179 ± 5 cm; body mass 74 ± 12 kg, weekly training volume 8 ± 1 hours) and 11 E-types (N = 11; age 21 ± 2 years; height 181 ± 11 cm; body mass 76 ± 11 kg, weekly training volume 7 ± 2 hours) were enrolled in a randomized crossover study. All subjects underwent measurements of salivary cortisol secretion before (PRE), immediately after (POST), and 15 min (+15 min), 30 min (+30 min), 45 min (+45 min) and 60 min (+60 min) after the completion of both morning (08.00 am) and evening (08.00 p.m.) high-intensity interval exercise. Two-way analysis of variance with Tuckey’s multiple comparisons test showed significant increments over PRE-cortisol concentrations in POSTcondition both in the morning (4.88 ± 1.19 ng · mL^?1 vs 6.60 ± 1.86 ng · mL^?1, +26.1%, P < 0.0001, d > 0.8) and in the evening (1.56 ± 0.48 ng · mL^?1 vs 2.34 ± 0.37, +33.4%, P = 0.034, d > 0.6) exercise in all the 23 subject that performed the morning and the evening HIIE. In addition, during morning exercise, significant differences in cortisol concentration between M-types and E-types at POST (5.49 ± 0.98 ng · mL^?1 versus 8.44 ± 1.08 ng · mL^?1, +35%, P < 0.0001, d > 0.8), +15 min (4.52 ± 0.42 ng · mL^?1 versus 6.61 ± 0.62 ng · mL^?1, +31.6%, P < 0.0001, d > 0.8), +30 min (4.10 ± 1.44 ng · mL^?1 versus 6.21 ± 1.60 ng · mL^?1, +34.0%, P < 0.0001, d = 0.7), + 45 min (3.78 ± 0.55 ng · mL^?1 versus 5.80 ± 0.72 ng · mL^?1, +34.9%, P < 0.0001, d = 0.7), and + 60 min condition(3.53 ± 0.45 ng · mL^?1 versus 5.78 ± 1.13 ng · mL^?1, 38.9%, P = 0.0008, d = 0.7) were noted. No statistical significant differences between M-types and E-types during evening HIIE on post-exercise cortisol concentration were detected. E-types showed a higher morning peak of salivary cortisol respect to M-types when performing a HIIE early in the morning and produced higher salivary cortisol concentrations after the cessation of the exercise. Practical applications suggest that it is increasingly important for the exercise professionals to identify the compatibility between time of day for exercising and chronotype to find the individual’s favorable circadian time to perform a HIIE.     

Structure–cytotoxic activity relationship of sesquilignan,morinol A

The cytotoxic activities of sesquilignans, (7S,8S,7′R,8′R)- and (7R,8R,7′S,8′S)-morinol A and (7S,8S,7′S,8′S)- and (7R,8R,7′R,8′R)-morinol B were compared, showing no significant difference between stereoisomers (IC₅₀ = 24–35 μM). As a next stage, the effect of substituents at 7, 7′, and 7″-aromatic ring on the activity was evaluated to find out the higher activity of (7S,8S,7′R,8′R)-7,7′,7″-phenyl derivative 18 (IC₅₀ = 6–7 μM). In the research on the structure–activity relationship of 7″-position of (7S,8S,7′R,8′R)-7,7′,7″-phenyl derivative 18, the most potent compounds were 7,7′,7″-phenyl derivative 18 (IC₅₀ = 6 μM) against HeLa cells. Against HL-60 cells, 7″-(4-nitrophenyl)-7,7′-phenyl derivative 33 and 7″-hexyl-7,7′-phenyl derivative 37 (IC₅₀ = 5 μM) showed highest activity. We discovered the compounds showed four to sevenfold potent activity than that of natural (7S,8S,7′R,8′R)-morinol A. It was also confirmed that the 7′-benzylic hydroxy group have an important role for exhibiting activity, on the other hand, the resonance system of cinnamyl structure is not crucial for the potent activity.     

The Diagnostic and Prognostic Value of Dengue Non-Structural 1 Antigen Detection in a Hyper-Endemic Region in Indonesia

As dengue fever is undifferentiated from other febrile illnesses in the tropics and the clinical course is unpredictable, early diagnosis is important. Several commercial assays to detect dengue NS1 antigen have been developed; however, their performances vary and data is lacking from hyper-endemic areas where all four serotypes of dengue are equally represented. To assess the sensitivity of the Bio-Rad platelia Dengue NS1 antigen assay according to virus serotype, immune status, gender, and parameters of severe disease, acute sera from 220 individuals with confirmed dengue and 55 individuals with a non-dengue febrile illness were tested using the Bio-Rad platelia Dengue NS1 antigen assay. The overall sensitivity of the NS1 ELISA was 46.8% and the specificity was 100%. The sensitivity in primary infections was significantly higher than in secondary infections (100% vs. 35.7%). In secondary infections, the sensitivity of NS1 detection was highest in DENV-3 (47.1%), followed by DENV-1 (40.9%), DENV-2 (30%) and DENV-4 (27%) infections. NS1 was less frequently detected in sera with high titers of HI antibodies or in acute samples from patients whose pre-illness sera showed neutralizing antibodies to more than one serotype. The detection of NS1 was higher in females, severe cases, and individuals with lower platelet counts (<100,000/mm³). While the overall sensitivity of this NS1 ELISA is poor, our data suggest that in secondary infections, detection may be predictive of a more severe illness.     

Antioxidant Activity of Ubiquinone-3 in Human Low Density Lipoprotein

The ability of ubiquinone-3, a short chain ubiquinone homologue, to prevent Cu²⁺ induced oxidation of human low density lipoprotein was investigated. The results are as follows: in the presence of ubiquinone-3 the extent of peroxidation, as determined by the formation of thiobarbituric acid reactive substances, was only one third of that found in its absence; the quinone can also prevent the fragmentation of apolipo-protein B-100 and the increase of the net negative surface charge of the particle.     

Sleep quality and high intensity interval training at two different times of day: A crossover study on the influence of the chronotype in male collegiate soccer players

The influence of the chronotype on the sleep quality in male collegiate soccer players in response to acute high intensity interval training (HIIT) performed at two different times of day was evaluated. The sleep quality was poorer in the morning-type than in the evening-type players after the evening HIIT session, whereas no significant changes in the sleep quality of the two chronotypes after the morning HIIT session was observed. The results suggest that an athlete’s chronotype should be taken into account when scheduling training sessions and to promote faster recovery processes.