L-Carnitine Combined with Leucine Supplementation Does Not Improve the Effectiveness of Progressive Resistance Training in Healthy Aged Women.

OBJECTIVES: To evaluate the effect of L-carnitine (LC) in combination with leucine supplementation on muscle strength and muscle hypertrophy in aged women participating in a resistance exercise training (RET) program. DESIGN/SETTING/PARTICIPANTS: Thirty-seven out of sixty (38.3% dropout) healthy women aged 60-75 years (mean 67.6 ± 0.7 years) completed the intervention in one of three groups. One of the supplemented groups received 1 g of L-carnitine-L-tartrate in combination with 3 g of L-leucine per day (LC+L group; n = 12), and the second supplemented group received 4 g of L-leucine per day (L group; n = 13). The control group (CON group; n = 12) received no supplementation. INTERVENTION: All three groups completed the same RET protocol involving exercise sessions twice per week for 24 weeks. MEASUREMENTS: Before and after the experiment, participants performed isometric and isokinetic muscle strength testing on the Biodex dynamometer. The cross-sectional areas of the major knee extensors and total thigh muscles were assessed using magnetic resonance imaging. Fasting serum levels of insulin-like growth factor-1 (IGF-1), myostatin and decorin, and plasma levels of total carnitine (TC) and trimethylamine-N-oxide (TMAO) levels were measured. RESULTS: The 24-week RET significantly increased muscle strength and muscle volume, but the group and time interactions were not significant for the muscle variables analyzed. Plasma total carnitine increased only in the LC+L group (p = 0.009). LC supplementation also caused a significant increase in plasma TMAO, which was higher after the intervention in the LC+L group than in the L (p < 0.001), and CON (p = 0.005) groups. The intervention did not change plasma TMAO concentration in the L (p = 0.959) and CON (p = 0.866) groups. After the intervention serum decorin level was higher than before in both supplemented groups combined (p = 0.012), still not significantly different to post intervention CON (p = 0.231). No changes in serum IGF-1 and myostatin concentrations and no links between the changes in blood markers and muscle function or muscle volume were observed. CONCLUSIONS: LC combined with leucine or leucine alone does not appear to improve the effectiveness of RET.

Influence of surface modification of Ti6Al7Nb alloy on adhesion of poly (lactide-co-glycolide) coating (PLGA).

The paper presents the results of studies on the influence of surface topography and wettability of a Ti6Al7Nb alloy substrate on the adhesion of a PLGA coating. The alloy surface was modified using a mechanical pre-treatment including: grinding, vibration treatment, mechanical polishing, sandblasting and anodic oxidation. The polymer coating was applied to the metal substrate by a dip-coating method. The scope of the research included microscopic observations of the substrate and polymer coating using SEM and acoustic microscopy. In addition, studies on the wettability and topography of the polymer coating and the metal substrate, the thickness of the polymer coating as well as qualitative and quantitative testing of the adhesion of the polymer coating to the substrate were carried out. Coating adhesion tests were conducted for samples in the initial state and after 6 weeks exposure to Ringer's solution. Analysis of the results indicates the influence of the method used to modify the metal substrate on its topography and wettability. These parameters affect the thickness of the obtained polymer coating. Regardless the parameters of the metal substrate, a qualitative analysis of the adhesion of the coating applied to the substrate of the Ti6Al7Nb alloy did not show any delamination for both samples exposed and non-exposed to Ringer's solution. On the other hand, quantitative scratch-test studies showed different adhesion of the polymer coating to the substrate depending on the surface topography obtained by various modification methods. The cytotoxicity test conducted by the indirect method using extracts confirmed that the surface modification does not affect cell growth. The complex methods of surface pre-treatment of the alloy together with the kind of polymer selected for the study allowed to develop well adhered PLGA layers on Ti6Al7Nb intended for short term implants. The lack of delamination of the layer during 6 weeks was proved, what allows for maintaining the protection function of the layer during this period and contribute to improving biocompatibility.

Expression of proinflammatory cytokines IL-1ß, IL-6 and TNFα in the retained placenta of mares.

Retained fetal membranes (RFM) is a prevalent postpartum disease in mares. During parturition, various proinflammatory cytokines are released in the placenta, which further facilitates uterine contractions, expulsion of the fetus and fetal membranes. We hypothesized that an altered inflammatory response in mares results in retained fetal membranes. Samples of the endometrium and the allantochorion were collected from 15 mares with RFM and from 29 control mares within 2 h of foal delivery. Next, the mRNA expression of IL-1ß, IL-6 and TNFα proteins was analyzed by Real Time PCR and Western blot. These cytokines were also localized by immunocytochemistry. In mares with RFM, the mRNA expression of IL-1ß in the endometrium (p < 0.05) and IL-6 in the allantochorion (p < 0.0001) was higher than in mares that expelled fetal membranes physiologically. Higher expression of IL-6 in the allantochorion was confirmed by Western blot. In contrast, no changes in TNFα mRNA and protein expression were observed between the 2 groups of mares. Moreover, TNFα mRNA was barely detectable. The presence of all studied cytokine proteins in the allantochorion was confirmed by immunocytochemistry. The results suggest that the outbreak of inflammation is involved in the mechanism of placenta release in mares. Increased expression of IL-6 in the allantochorion and IL-1ß in the endometrium could reflect a local immune response which leads to the detachment of fetal membranes. The low expression of TNFα mRNA might suggest that this cytokine is not involved in the expulsion of fetal membranes. Further work is needed to determine the exact role and timing of inflammatory activation in fetal membranes during equine parturition.

Improvement of cognitive functions in response to a regular Nordic walking training in elderly women - A change dependent on the training experience.

Although regular physical activity is known to benefit health of aging populations, there are still many factors, which regulate exercise-induced adaptive changes. Among many vitamin D and myokines are under consideration. We, therefore, evaluated the influence of a single session of and regular Nordic Walking (NW) training combined with vitamin D supplementation on cognitive functions and muscle strength and some elements of the amino-acid profile. Thirty-five healthy elderly women (68 ±â€¯5 years old) from health promotion programmes took part in the study. At baseline they were divided into two groups: women, who participated in NW training for the first time (Beginners Group: BG) and women, who continued regular NW training longer than four years (Advance Group: AG). All women had a similar concentration of vitamin D (above 20 ng·ml-1) at baseline. The 12 weeks of NW training was supported by supplementation of vitamin D3 (4000 IU/day). Muscle strength, serum concentrations of myokines (irisin and IL-6), brain derived neurotrophic factor (BDNF), inflammation marker, glucose, branched amino acids and tryptophan were all assessed at baseline, 1 h after the first single training session and adequately at the end of the training programme. In addition, iron and ferritin were measured. The concentration of vitamin D3 as well as psychological (Quality-of-Life Assessment, The Beck Depression Inventory-2) and cognitive evaluations (D2 test of attention, Trial Making Test A&B) were also performed before and after the 12-week training programme. Data were interpreted using magnitude-based inferences. According to data obtained in this study, regular NW training resulted in improvement of cognitive functions in aged women. These positive changes were accompanied by an increase of irisin and BDNF concentration (adjusted effect moderate and likely). Our data also revealed that observed reductions of glucose and tryptophan concentrations might have positively contributed to the amelioration of cognitive functions. Still, obtained results indicated that it was not the level vitamin D that modulated exercise-induced changes, but rather the long-lasting experience and being more advanced in training.

The impact of a single bout of high intensity circuit training on myokines' concentrations and cognitive functions in women of different age.

The study aimed to assess effect of a single bout of high-intensity circuit training (HICT) on myokines concentration: interleukin-6 and irisin, inteleukin-10, brain-derived neurotrophic factor (BDNF), heat shock proteins (HSP27, HSP70) and cognitive functions among women participated in HICT. It also attempted evaluating whether vitamin D could have modified the effect of HICT. Fourteen healthy, non-active women participating in the experiment were assigned to a young or middle-aged group. They performed a single session HICT using body weight as a resistance, based on the ACSM recommendations. Blood samples were taken before, one and 24h after training. Cognitive functions were assessed before and 1h after the HICT session. Simple statistics and effects of changes for dependent variables were determined using mixed linear modeling, and evaluated by means of magnitude-based inference (MBI). Following a single session of HICT the young group exhibited improved concentration and spatial memory, whereas in middle-aged women these functions were attenuated. A varied tendency was also observed in the levels of myokine IL-6 and cytokine IL-10. Vitamin D was covariate for changes in cognitive functions and myokines' levels after exercise. Its concentration modified the anti-inflammatory effect of HICT, expressed in decreasing HSP70.

Skin hydration analysis by experiment and computer simulations and its implications for diapered skin.

BACKGROUND: Experimental work on skin hydration is technologically challenging, and mostly limited to observations where environmental conditions are constant. In some cases, like diapered baby skin, such work is practically unfeasible, yet it is important to understand potential effects of diapering on skin condition. To overcome this challenge, in part, we developed a computer simulation model of reversible transient skin hydration effects. METHODS: Skin hydration model by Li et al. (Chem Eng Sci, 138, 2015, 164) was further developed to simulate transient exposure conditions where relative humidity (RH), wind velocity, air, and skin temperature can be any function of time. Computer simulations of evaporative water loss (EWL) decay after different occlusion times were compared with experimental data to calibrate the model. Next, we used the model to investigate EWL and SC thickness in different diapering scenarios. RESULTS: Key results from the experimental work were: (1) For occlusions by RH=100% and free water longer than 30 minutes the absorbed amount of water is almost the same; (2) Longer occlusion times result in higher water absorption by the SC. The EWL decay and skin water content predictions were in agreement with experimental data. Simulations also revealed that skin under occlusion hydrates mainly because the outflux is blocked, not because it absorbs water from the environment. Further, simulations demonstrated that hydration level is sensitive to time, RH and/or free water on skin. In simulated diapering scenarios, skin maintained hydration content very close to the baseline conditions without a diaper for the entire duration of a 24 hours period. CONCLUSION: Different diapers/diaper technologies are known to have different profiles in terms of their ability to provide wetness protection, which can result in consumer-noticeable differences in wetness. Simulation results based on published literature using data from a number of different diapers suggest that diapered skin hydrates within ranges considered reversible.

Changes in pro-inflammatory markers and leucine concentrations in response to Nordic Walking training combined with vitamin D supplementation in elderly women.

Mechanisms underpinning age-related decreases in muscle strength and muscle mass relate to chronic inflammation. Physical activity induces an anti-inflammatory effect, but it is modulated by additional factors. We hypothesized that vitamin D, which has also anti-inflammatory activity will modify adaptation to exercise and reduce inflammation in elderly women. Twenty-seven women aged 67 ± 8 years were included and divided into groups with baseline vitamin D concentration more than 20 ng mL-1 (MVD) and less than 20 ng mL-1 (LVD). Both groups performed 1 h Nordic Walking (NW) training combined with vitamin D supplementation for 12 weeks. Serum concentrations of inflammation markers, branched amino acids, vitamin D, muscle strength and balance were assessed at the baseline and three days after intervention. The training caused the significant decrease in concentration of pro-inflammatory proteins HMGB1 (30 ± 156%; 90% CI) and IL-6 (-10 ± 66%; 90% CI) in MVD group. This effects in group MVD were moderate, indicating vitamin D as one of the modifiers of these exercise-induced changes. Rise of myokine irisin induced by exercise correlated inversely with HMGB1 and the correlation was more pronounced at the baseline as well as after training among MVD participants. Although the intervention caused the leucine level to rise, a comparison of the recorded response between groups and the adjusted effect indicated that the effect was 20% lower in the LVD group. Overall the applied training program was effective in reducing HMGB1 concentration. This drop was accompanied by the rise of myokine irisin and better uptake of leucine among women with higher baseline vitamin D.

Myokines in Response to a Tournament Season among Young Tennis Players.

The study investigated changes in myokines, heat shock proteins, and growth factors in highly ranked, young, male tennis players in response to physical workload during the competitive season and their potential correlations with match scores. Blood collections were carried out at the beginning, the midpoint, and the end of the tournament season. Data analysis revealed a significant increase in interleukin 6 and its inverse correlation with the number of lost games (r = -0.45; 90% CI -0.06 to 0.77). Neither the irisin nor BDNF level changed notably, yet delta changes of irisin across the season significantly correlated with the number of games won. The concentration of HSP27 recorded a small increase (31.2%; 90% CI 10.7 to 55.5, most likely). A negative correlation was noted between IGF-1 and HSP27 concentration at baseline (-0.70 very high; 90% CI -0.89 to -0.31, very likely). At the end of the season IGF-1 correlated positively with the number of games won (r = 0.37 moderate, 90% CI -0.16 to 0.73, likely) but negatively with the number of games lost (r = -0.39, 90% CI -0.14 to -0.74, likely). In conclusion our data indicated that Il-6, irisin, and growth factor IGF-1 may modify overall performance during a long lasting season, expressed in the amount of games won or lost.

The effect of the competitive season in professional basketball on inflammation and iron metabolism.

Following acute physical activity, blood hepcidin concentration appears to increase in response to exercise-induced inflammation, but the long-term impact of exercise on hepcidin remains unclear. Here we investigated changes in hepcidin and the inflammation marker interleukin-6 to evaluate professional basketball players' response to a season of training and games. The analysis also included vitamin D (25(OH)D3) assessment, owing to its anti-inflammatory effects. Blood samples were collected for 14 players and 10 control non-athletes prior to and after the 8-month competitive season. Athletes' performance was assessed with the NBA efficiency score. At the baseline hepcidin correlated with blood ferritin (r = 0.61; 90% CL ±0.31), but at the end of the season this correlation was absent. Compared with the control subjects, athletes experienced clear large increases in hepcidin (50%; 90% CI 15-96%) and interleukin-6 (77%; 90% CI 35-131%) and a clear small decrease in vitamin D (-12%; 90% CI -20 to -3%) at the season completion. Correlations between change scores of these variables were unclear (r = -0.21 to 0.24, 90% CL ±0.5), but their uncertainty generally excluded strong relationships. Athletes were hence concluded to have experienced acute inflammation at the beginning but chronic inflammation at the end of the competitive season. At the same time, the moderate correlation between changes in vitamin D and players' performance (r = 0.43) was suggestive of its beneficial influence. Maintaining the appropriative concentration of vitamin D is thus necessary for basketball players' performance and efficiency. The assessment of hepcidin has proven to be useful in diagnosing inflammation in response to chronic exercise.

Multifunctional PLGA/Parylene C Coating for Implant Materials: An Integral Approach for Biointerface Optimization.

Functionalizing implant surfaces is critical for improving their performance. An integrated approach was employed to develop a multifunctional implant coating based on oxygen plasma-modified parylene C and drug-loaded, biodegradable poly(dl-lactide-co-glycolide) (PLGA). The key functional attributes of the coating (i.e., anti-corrosion, biocompatible, anti-infection, and therapeutic) were thoroughly characterized at each fabrication step by spectroscopic, microscopic, and biologic methods and at different scales, ranging from molecular, through the nano- and microscales to the macroscopic scale. The chemistry of each layer was demonstrated separately, and their mutual affinity was shown to be indispensable for the development of versatile coatings for implant applications.

Understanding genetic toxicity through data mining: the process of building knowledge by integrating multiple genetic toxicity databases.

ABSTRACT Genetic toxicity data from various sources were integrated into a rigorously designed database using the ToxML schema. The public database sources include the U.S. Food and Drug Administration (FDA) submission data from approved new drug applications, food contact notifications, generally recognized as safe food ingredients, and chemicals from the NTP and CCRIS databases. The data from public sources were then combined with data from private industry according to ToxML criteria. The resulting "integrated" database, enriched in pharmaceuticals, was used for data mining analysis. Structural features describing the database were used to differentiate the chemical spaces of drugs/candidates, food ingredients, and industrial chemicals. In general, structures for drugs/candidates and food ingredients are associated with lower frequencies of mutagenicity and clastogenicity, whereas industrial chemicals as a group contain a much higher proportion of positives. Structural features were selected to analyze endpoint outcomes of the genetic toxicity studies. Although most of the well-known genotoxic carcinogenic alerts were identified, some discrepancies from the classic Ashby-Tennant alerts were observed. Using these influential features as the independent variables, the results of four types of genotoxicity studies were correlated. High Pearson correlations were found between the results of Salmonella mutagenicity and mouse lymphoma assay testing as well as those from in vitro chromosome aberration studies. This paper demonstrates the usefulness of representing a chemical by its structural features and the use of these features to profile a battery of tests rather than relying on a single toxicity test of a given chemical. This paper presents data mining/profiling methods applied in a weight-of-evidence approach to assess potential for genetic toxicity, and to guide the development of intelligent testing strategies.

Intranasal delivery of whole influenza vaccine prevents subsequent allergen-induced sensitization and airway hyper-reactivity in mice.

BACKGROUND: Infection with influenza virus has been associated with seemingly opposing effects on the development of asthma. However, there are no data about the effects of mucosal vaccination with inactivated influenza on the inception of allergic asthma. OBJECTIVE: To assess the immunological effects of inhaled inactivated influenza vaccine, using two different types of flu vaccines, on the inception of allergic sensitization and allergen-mediated airway disease in a mouse model. METHODS: BALB/c mice were intranasally or intratracheally vaccinated with whole or split influenza virus vaccine (days -1 or -1, 27) before systemic sensitization with ovalbumin (OVA) (days 1, 14) and repeated airway allergen challenges (days 28-30). Allergen sensitization (IgE serum levels), airway inflammation (differential cells in bronchoalveolar lavage fluid) and airway hyper-reactivity (AHR) (in vivo lung function) were analysed. RESULTS: The intranasal instillation of whole influenza vaccine before allergen sensitization significantly reduced the serum levels of total and OVA-specific IgE as well as allergen-induced AHR. Prevention was due to an allergen-specific shift from a predominant T helper (Th)2- towards a Th1-immune response. Application of split influenza vaccine did not show the same preventive effect. CONCLUSION: Intranasal administration of inactivated whole influenza vaccine reduced subsequent allergen sensitization and prevented allergen-induced AHR. Our results show that the composition of the influenza vaccine has a major influence on subsequent development of allergen-induced sensitization and AHR, and suggest that mucosal inactivated whole influenza vaccination may represent a step towards the development of a preventive strategy for atopic asthma.

How can structural similarity analysis help in category formation?

Chemical category is a regulatory concept facilitating filling safety data gaps. Practically, all chemical management programs like the OECD HPV Program, EU REACH, or the Canadian DSL Categorization are planning to use or are already using categorization approaches to reduce resources including animal testing. The aim of the study was to discuss the feasibility to apply computational structural similarity methods to augment formation of a category. The article discusses also how this understanding can be translated into computer readable format, an ultimate need for practical, broad scope applications. We conclude that for the skin sensitization endpoint, used as a working example, mechanistic understanding expressed as chemical reactivity can be exploited by computational structural similarity methods to augment category formation process. We propose a novel method, atom environments ranking (AER), to assess similarity to a reference training set representing a common mechanism of action, as a potential method for grouping chemicals into reactivity domains.

Probiotic-induced suppression of allergic sensitization and airway inflammation is associated with an increase of T regulatory-dependent mechanisms in a murine model of asthma.

BACKGROUND: Microbial intestinal colonization in early in life is regarded to play a major role for the maturation of the immune system. Application of non-pathogenic probiotic bacteria during early infancy might protect from allergic disorders but underlying mechanisms have not been analysed so far. OBJECTIVE: The aim of the current study was to investigate the immune effects of oral application of probiotic bacteria on allergen-induced sensitization and development of airway inflammation and airway hyper-reactivity, cardinal features of bronchial asthma. METHODS: Newborn Balb/c mice received orally 10(9) CFU every second day either Lactobacillus rhamnosus GG or Bifidobacterium lactis (Bb-12) starting from birth for consecutive 8 weeks, during systemic sensitization (six intraperitoneal injections, days 29-40) and airway challenge (days 54-56) with ovalbumin. RESULTS: The administration of either Bb-12 or LGG suppressed all aspects of the asthmatic phenotype: airway reactivity, antigen-specific immunoglobulin E production and pulmonary eosinophilia (mean: 137 vs. 17 and 13 cellsx10(3)/mL, respectively). Antigen-specific recall proliferation by spleen cells and T-helper type 2 cytokine production (IL-4, IL-5 and IL-10) by mesenteric lymph node cells also showed significant reduction, while TGF production remained unchanged. Oral LGG administration particularly suppressed allergen-induced proliferative responses and was associated with an increase in numbers of TGF-beta-secreting CD4+/CD3+ T cells in mesenteric lymph nodes (6.5, 16.7%) as well as nearly 2-fold up-regulation of Foxp3-expressing cells in peribronchial lymph nodes. CONCLUSIONS: Neonatal application of probiotic bacteria inhibits subsequent allergic sensitization and airway disease in a murine model of asthma by induction of T regulatory cells associated with increased TGF-beta production.

Geo-referencing of probabilistic risk of new chemicals in rivers.

The characterisation of the risk of (new) chemicals to species/communities, when both the exposure/environmental concentration and effects (species sensitivity) are variable and uncertain, is the central issue in Probabilistic Environmental Risk Assessment. The spatial variability is one of the largest components of the total variability. This paper tries to explicitly account for this spatial variability by geo-referencing the exposure, effect and finally probabilistic risk. Geo-referencing makes the risk assessment more refined and realistic. In addition, it is also highlighted that geo-referencing the effects of chemicals (species sensitivity distribution) is still a large unexplored area but has large potential to improve probabilistic ecological risk assessments.

Probabilistic assessment of biodegradability based on metabolic pathways: catabol system.

A novel mechanistic modeling approach has been developed that assesses chemical biodegradability in a quantitative manner. It is an expert system predicting biotransformation pathway working together with a probabilistic model that calculates probabilities of the individual transformations. The expert system contains a library of hierarchically ordered individual transformations and matching substructure engine. The hierarchy in the expert system was set according to the descending order of the individual transformation probabilities. The integrated principal catabolic steps are derived from set of metabolic pathways predicted for each chemical from the training set and encompass more than one real biodegradation step to improve the speed of predictions. In the current work, we modeled O2 yield during OECD 302 C (MITI I) test. MITI-I database of 532 chemicals was used as a training set. To make biodegradability predictions, the model only needs structure of a chemical. The output is given as percentage of theoretical biological oxygen demand (BOD). The model allows for identifying potentially persistent catabolic intermediates and their molar amounts. The data in the training set agreed well with the calculated BODs (r2 = 0.90) in the entire range i.e. a good fit was observed for readily, intermediate and difficult to degrade chemicals. After introducing 60% ThOD as a cut off value the model predicted correctly 98% ready biodegradable structures and 96% not ready biodegradable structures. Crossvalidation by four times leaving 25% of data resulted in Q2 = 0.88 between observed and predicted values. Presented approach and obtained results were used to develop computer software for biodegradability prediction CATABOL.

Bayesian analysis and inference from QSAR predictive model results.

QSAR models have been under development for decades but acceptance and utilization of model results have been slow, in part, because there is no widely accepted metric for assessing their reliability. We reapply a method commonly used in quantitative epidemiology and medical decision-making for evaluating the results of screening tests to assess reliability of a QSAR model. It quantifies the accuracy (expressed as sensitivity and specificity) of QSAR models as conditional probabilities of correct and incorrect classification of chemical characteristic, given a true characteristic. Using Bayes formula, these conditional probabilities are combined with prior information to generate a posterior distribution to determine the probability a specific chemical has a particular characteristic, given a model prediction. As an example, we apply this approach to evaluate the predictive reliability of a CATABOL model and base on it a "ready" and "not ready" biodegradability classification. Finally, we show how predictive capability of the model can be improved by sequential use of two models, the first one with high sensitivity and the second with high specificity.