Combination of MEK-ERK inhibitor and hyaluronic acid has a synergistic effect on anti-hypertrophic and pro-chondrogenic activities in osteoarthritis treatment

We hypothesised that a potentially disease-modifying osteoarthritis (OA) drug such as hyaluronic acid (HA) given in combination with anti-inflammatory signalling agents such as mitogen-activated protein kinase kinase–extracellular signal-regulated kinase (MEK-ERK) signalling inhibitor (U0126) could result in additive or synergistic effects on preventing the degeneration of articular cartilage. Chondrocyte differentiation and hypertrophy were evaluated using human OA primary cells treated with either HA or U0126, or the combination of HA + U0126. Cartilage degeneration in menisectomy (MSX) induced rat OA model was investigated by intra-articular delivery of either HA or U0126, or the combination of HA + U0126. Histology, immunostaining, RT-qPCR, Western blotting and zymography were performed to assess the expression of cartilage matrix proteins and hypertrophic markers. Phosphorylated ERK (pERK)1/2-positive chondrocytes were significantly higher in OA samples compared with those in healthy control suggesting the pathological role of that pathway in OA. It was noted that HA + U0126 significantly reduced the levels of pERK, chondrocyte hypertrophic markers (COL10 and RUNX2) and degenerative markers (ADAMTs5 and MMP-13), however, increased the levels of chondrogenic markers (COL2) compared to untreated or the application of HA or U0126 alone. In agreement with the results in vitro, intra-articular delivery of HA + U0126 showed significant therapeutic improvement of cartilage in rat MSX OA model compared with untreated or the application of HA or U0126 alone. Our study suggests that the combination of HA and MEK-ERK inhibition has a synergistic effect on preventing cartilage degeneration.

The effect of post-exercise hydrotherapy on subsequent exercise performance and heart rate variability

We investigated the effect of hydrotherapy on time-trial performance and cardiac parasympathetic reactivation during recovery from intense training. On three occasions, 18 well-trained cyclists completed 60 min high-intensity cycling, followed 20 min later by one of three 10-min recovery interventions: passive rest (PAS), cold water immersion (CWI), or contrast water immersion (CWT). The cyclists then rested quietly for 160 min with R-R intervals and perceptions of recovery recorded every 30 min. Cardiac parasympathetic activity was evaluated using the natural logarithm of the square root of mean squared differences of successive R-R intervals (ln rMSSD). Finally, the cyclists completed a work-based cycling time trial. Effects were examined using magnitude-based inferences. Differences in time-trial performance between the three trials were trivial. Compared with PAS, general fatigue was very likely lower for CWI (difference [90% confidence limits; -12% (-18; -5)]) and CWT [-11% (-19; -2)]. Leg soreness was almost certainly lower following CWI [-22% (-30; -14)] and CWT [-27% (-37; -15)]. The change in mean ln rMSSD following the recovery interventions (ln rMSSD(Post-interv)) was almost certainly higher following CWI [16.0% (10.4; 23.2)] and very likely higher following CWT [12.5% (5.5; 20.0)] compared with PAS, and possibly higher following CWI [3.7% (-0.9; 8.4)] compared with CWT. The correlations between performance, ln rMSSD(Post-interv) and perceptions of recovery were unclear. A moderate correlation was observed between ln rMSSD(Post-interv) and leg soreness [r = -0.50 (-0.66; -0.29)]. Although the effects of CWI and CWT on performance were trivial, the beneficial effects on perceptions of recovery support the use of these recovery strategies.

The effect of screen size on mission commander's situation awareness

Situation awareness lost is a common factor leading to human error in the aviation industry. However, few studies have investigated the effect on situation awareness where the control interface is a touch-screen device that supports simultaneous multi-touch input and information output. This research aims to conduct an experiment to evaluate the difference in situation awareness on a large screen device, DiamondTouch (DT107), and a small screen device, iPad, both with multi-touch interactive functions. The Interface Operation and Situation Awareness Testing Simulator (IOSATS), is a simulator to test the three basis interface operations (Search Target, Information Reading, and Change Detection) by implementing a simplified search and rescue scenario. The result of this experiment will provide reliable data for future research for improving operator's situation awareness in the avionic domain.

The effect of Tenofovir on vitamin D metabolism in HIV-infected adults is dependent on sex and ethnicity

Background: Tenofovir has been associated with renal phosphate wasting, reduced bone mineral density, and higher parathyroid hormone levels. The aim of this study was to carry out a detailed comparison of the effects of tenofovir versus non-tenofovir use on calcium, phosphate and, vitamin D, parathyroid hormone (PTH), and bone mineral density. Methods: A cohort study of 56 HIV-1 infected adults at a single centre in the UK on stable antiretroviral regimes comparing biochemical and bone mineral density parameters between patients receiving either tenofovir or another nucleoside reverse transcriptase inhibitor. Principal Findings: In the unadjusted analysis, there was no significant difference between the two groups in PTH levels (tenofovir mean 5.9 pmol/L, 95% confidence intervals 5.0 to 6.8, versus non-tenofovir; 5.9, 4.9 to 6.9; p = 0.98). Patients on tenofovir had significantly reduced urinary calcium excretion (median 3.01 mmol/24 hours) compared to non-tenofovir users (4.56; p,0.0001). Stratification of the analysis by age and ethnicity revealed that non-white men but not women, on tenofovir had higher PTH levels than non-white men not on tenofovir (mean difference 3.1 pmol/L, 95% CI 5.3 to 0.9; p = 0.007). Those patients with optimal 25-hydroxyvitamin D (.75 nmol/L) on tenofovir had higher 1,25-dihydroxyvitamin D [1,25(OH)2D] (median 48 pg/mL versus 31; p = 0.012), fractional excretion of phosphate (median 26.1%, versus 14.6;p = 0.025) and lower serum phosphate (median 0.79 mmol/L versus 1.02; p = 0.040) than those not taking tenofovir. Conclusions: The effects of tenofovir on PTH levels were modified by sex and ethnicity in this cohort. Vitamin D status also modified the effects of tenofovir on serum concentrations of 1,25(OH)2D and phosphate.

Client adaptiveness in entrepreneurship and its effect on sustained competitive advantage in project-orientated service firms

Important differences exist in how service firms operate in comparison with manufacturing firms (c.f. Johne & Storey, 1998; Tether, 2002). Despite these significant differences, not much is known whether these differences extrapolate to entrepreneurship in the services industry. This study seeks to address this gap by investigating how value creation occurs when project-oriented firms1 adopt client adaptiveness as part of their entrepreneurial posture. Specifically, we examine the effect of client adaptiveness on sustained competitive advantage. Client adaptiveness is conceptualized as the extent to which an organization engages in identifying and responding to perceived client needs and wants which reflects the service firm’s propensity to dynamically synchronize with the project/client requirements.

Effect of lipopolysaccharide from periodontal pathogens on the production of tissue plasminogen activator and plasminogen activator inhibitor 2 by human gingival fibroblasts.

Both tissue plasminogen activator (t-PA) and plasminogen activator inhibitor 2 (PAI-2) are important proteolysis factors present in inflamed human periodontal tissues. The aim of the present study was to investigate the effect of lipopolysaccharide (LPS) on the synthesis of t-PA and PAI-2 by human gingival fibroblasts (HGF). LPS from different periodontal pathogens including Actinobacillus actinomycetemcomitans, Porphyromonas gingivalis and Fusobacterium nucleatum were extracted by the hot phenol water method. The levels of t-PA and PAI-2 secreted into the cell culture media were measured by enzyme-linked immunosorbent assays (ELISA). The mRNA for t-PA and PAI-2 were measured by RT-PCR. The results showed t-PA synthesis was increased in response to all types of LPS studied and PAI-2 level was increased by LPS from A. actinomycetemcomitans and F. nucleatum, but not P. gingivalis. When comparing the effects of LPS from non-periodontal bacteria (Escherichia coli and Salmonella enteritidis) with the LPS from periodontal pathogens, we found that the ratio of t-PA to PAI-2 was greater following exposure of the cells to LPS from periodontal pathogens. The highest ratio of t-PA to PAI-2 was found in those cells exposed to LPS from P. gingivalis. These results indicate that LPS derived from periodontal pathogens may cause unbalanced regulation of plasminogen activator and plasminogen activator inhibitor by HGF and such an effect may, in part, contribute to the destruction of periodontal connective tissue through dysregulated pericellular proteolysis.

The effect of charge on ultrafine particle deposition : an experimental pilot study

Eepidemiological studies have linked exposure to ultrafine particles (UFPs, <100 nm) to a variety of adverse health effects. To understand the mechanisms behind these effects, it is essential to measure aerosol deposition in the human respiratory tract. Electrical charge is a very important property as it may increase the particle deposition in human respiratory tract (Melanderi et al., 1983). However, the effect of charge on UFP deposition has seldom been investigated. The aim of this study is to investigate the effect of charge on UFP deposition in human lung, by conducting a pilot study using a tube-based experimental system.

Performance evaluation of onsite wastewater treatment : field sampling and preliminary evaluation of results

Background The onsite treatment of sewage and effluent disposal within the premises is widely prevalent in rural and urban fringe areas due to the general unavailability of reticulated wastewater collection systems. Despite the seemingly low technology of the systems, failure is common and in many cases leading to adverse public health and environmental consequences. Therefore it is important that careful consideration is given to the design and location of onsite sewage treatment systems. It requires an understanding of the factors that influence treatment performance. The use of subsurface effluent absorption systems is the most common form of effluent disposal for onsite sewage treatment and particularly for septic tanks. Additionally in the case of septic tanks, a subsurface disposal system is generally an integral component of the sewage treatment process. Therefore location specific factors will play a key role in this context. The project The primary aims of the research project are: • to relate treatment performance of onsite sewage treatment systems to soil conditions at site; • to identify important areas where there is currently a lack of relevant research knowledge and is in need of further investigation. These tasks were undertaken with the objective of facilitating the development of performance based planning and management strategies for onsite sewage treatment. The primary focus of the research project has been on septic tanks. Therefore by implication the investigation has been confined to subsurface soil absorption systems. The design and treatment processes taking place within the septic tank chamber itself did not form a part of the investigation. In the evaluation to be undertaken, the treatment performance of soil absorption systems will be related to the physico-chemical characteristics of the soil. Five broad categories of soil types have been considered for this purpose. The number of systems investigated was based on the proportionate area of urban development within the Brisbane region located on each soil types. In the initial phase of the investigation, though the majority of the systems evaluated were septic tanks, a small number of aerobic wastewater treatment systems (AWTS) were also included. This was primarily to compare the effluent quality of systems employing different generic treatment processes. It is important to note that the number of different types of systems investigated was relatively small. As such this does not permit a statistical analysis to be undertaken of the results obtained. This is an important issue considering the large number of parameters that can influence treatment performance and their wide variability. The report This report is the second in a series of three reports focussing on the performance evaluation of onsite treatment of sewage. The research project was initiated at the request of the Brisbane City Council. The work undertaken included site investigation and testing of sewage effluent and soil samples taken at distances of 1 and 3 m from the effluent disposal area. The project component discussed in the current report formed the basis for the more detailed investigation undertaken subsequently. The outcomes from the initial studies have been discussed, which enabled the identification of factors to be investigated further. Primarily, this report contains the results of the field monitoring program, the initial analysis undertaken and preliminary conclusions. Field study and outcomes Initially commencing with a list of 252 locations in 17 different suburbs, a total of 22 sites in 21 different locations were monitored. These sites were selected based on predetermined criteria. To obtain house owner agreement to participate in the monitoring study was not an easy task. Six of these sites had to be abandoned subsequently due to various reasons. The remaining sites included eight septic systems with subsurface effluent disposal and treating blackwater or combined black and greywater, two sites treating greywater only and six sites with AWTS. In addition to collecting effluent and soil samples from each site, a detailed field investigation including a series of house owner interviews were also undertaken. Significant observations were made during the field investigations. In addition to site specific observations, the general observations include the following: • Most house owners are unaware of the need for regular maintenance. Sludge removal has not been undertaken in any of the septic tanks monitored. Even in the case of aerated wastewater treatment systems, the regular inspections by the supplier is confined only to the treatment system and does not include the effluent disposal system. This is not a satisfactory situation as the investigations revealed. • In the case of separate greywater systems, only one site had a suitably functioning disposal arrangement. The general practice is to employ a garden hose to siphon the greywater for use in surface irrigation of the garden. • In most sites, the soil profile showed significant lateral percolation of effluent. As such, the flow of effluent to surface water bodies is a distinct possibility. • The need to investigate the subsurface condition to a depth greater than what is required for the standard percolation test was clearly evident. On occasion, seemingly permeable soil was found to have an underlying impermeable soil layer or vice versa. The important outcomes from the testing program include the following: • Though effluent treatment is influenced by the physico-chemical characteristics of the soil, it was not possible to distinguish between the treatment performance of different soil types. This leads to the hypothesis that effluent renovation is significantly influenced by the combination of various physico-chemical parameters rather than single parameters. This would make the processes involved strongly site specific. • Generally the improvement in effluent quality appears to take place only within the initial 1 m of travel and without any appreciable improvement thereafter. This relates only to the degree of improvement obtained and does not imply that this quality is satisfactory. This calls into question the value of adopting setback distances from sensitive water bodies. • Use of AWTS for sewage treatment may provide effluent of higher quality suitable for surface disposal. However on the whole, after a 1-3 m of travel through the subsurface, it was not possible to distinguish any significant differences in quality between those originating from septic tanks and AWTS. • In comparison with effluent quality from a conventional wastewater treatment plant, most systems were found to perform satisfactorily with regards to Total Nitrogen. The success rate was much lower in the case of faecal coliforms. However it is important to note that five of the systems exhibited problems with regards to effluent disposal, resulting in surface flow. This could lead to possible contamination of surface water courses. • The ratio of TDS to EC is about 0.42 whilst the optimum recommended value for use of treated effluent for irrigation should be about 0.64. This would mean a higher salt content in the effluent than what is advisable for use in irrigation. A consequence of this would be the accumulation of salts to a concentration harmful to crops or the landscape unless adequate leaching is present. These relatively high EC values are present even in the case of AWTS where surface irrigation of effluent is being undertaken. However it is important to note that this is not an artefact of the treatment process but rather an indication of the quality of the wastewater generated in the household. This clearly indicates the need for further research to evaluate the suitability of various soil types for the surface irrigation of effluent where the TDS/EC ratio is less than 0.64. • Effluent percolating through the subsurface absorption field may travel in the form of dilute pulses. As such the effluent will move through the soil profile forming fronts of elevated parameter levels. • The downward flow of effluent and leaching of the soil profile is evident in the case of podsolic, lithosol and kransozem soils. Lateral flow of effluent is evident in the case of prairie soils. Gleyed podsolic soils indicate poor drainage and ponding of effluent. In the current phase of the research project, a number of chemical indicators such as EC, pH and chloride concentration were employed as indicators to investigate the extent of effluent flow and to understand how soil renovates effluent. The soil profile, especially texture, structure and moisture regime was examined more in an engineering sense to determine the effect of movement of water into and through the soil. However it is not only the physical characteristics, but the chemical characteristics of the soil also play a key role in the effluent renovation process. Therefore in order to understand the complex processes taking place in a subsurface effluent disposal area, it is important that the identified influential parameters are evaluated using soil chemical concepts. Consequently the primary focus of the next phase of the research project will be to identify linkages between various important parameters. The research thus envisaged will help to develop robust criteria for evaluating the performance of subsurface disposal systems.

The effect of a high fat meal on postprandial arterial stiffness in men with obesity and type 2 diabetes

Context: Postprandial dysmetabolism is emerging as an important cardiovascular risk factor. Augmentation index (AIx) is a measure of systemic arterial stiffness and independently predicts cardiovascular outcome. Objective: The objective of this study was to assess the effect of a standardized high-fat meal on metabolic parameters and AIx in 1) lean, 2) obese nondiabetic, and 3) subjects with type 2 diabetes mellitus (T2DM). Design and Setting: Male subjects (lean, n = 8; obese, n = 10; and T2DM, n = 10) were studied for 6 h after a high-fat meal and water control. Glucose, insulin, triglycerides, and AIx (radial applanation tonometry) were measured serially to determine the incremental area under the curve (iAUC). Results: AIx decreased in all three groups after a high-fat meal. A greater overall postprandial reduction in AIx was seen in lean and T2DM compared with obese subjects (iAUC, 2251 +/- 1204, 2764 +/- 1102, and 1187 +/- 429% . min, respectively; P < 0.05). The time to return to baseline AIx was significantly delayed in subjects with T2DM (297 +/- 68 min) compared with lean subjects (161 +/- 88 min; P < 0.05). There was a significant correlation between iAUC AIx and iAUC triglycerides (r = 0.50; P < 0.05). Conclusions: Obesity is associated with an attenuated overall postprandial decrease in AIx. Subjects with T2DM have a preserved, but significantly prolonged, reduction in AIx after a high-fat meal. The correlation between AIx and triglycerides suggests that postprandial dysmetabolism may impact on vascular dynamics. The markedly different response observed in the obese subjects compared with those with T2DM was unexpected and warrants additional evaluation.

Aging and its effect on inflammation in skeletal muscle at rest and following exercise-induced muscle injury

Aging and its effects on inflammation in skeletal muscle at rest and following exercise-induced muscle injury. Am J Physiol Regul Integr Comp Physiol 298: R1485-R1495, 2010. First published April 14, 2010; doi:10.1152/ajpregu.00467.2009.-The world's elderly population is expanding rapidly, and we are now faced with the significant challenge of maintaining or improving physical activity, independence, and quality of life in the elderly. Counteracting the progressive loss of muscle mass that occurs in the elderly, known as sarcopenia, represents a major hurdle in achieving these goals. Indirect evidence for a role of inflammation in sarcopenia is that markers of systemic inflammation correlate with the loss of muscle mass and strength in the elderly. More direct evidence is that compared with skeletal muscle of young people, the number of macrophages is lower, the gene expression of several cytokines is higher, and stress signaling proteins are activated in skeletal muscle of elderly people at rest. Sarcopenia may also result from inadequate repair and chronic maladaptation following muscle injury in the elderly. Macrophage infiltration and the gene expression of certain cytokines are reduced in skeletal muscle of elderly people compared with young people following exercise-induced muscle injury. Further research is required to identify the cause(s) of inflammation in skeletal muscle of elderly people. Additional work is also needed to expand our understanding of the cells, proteins, and transcription factors that regulate inflammation in the skeletal muscle of elderly people at rest and after exercise. This knowledge is critical for devising strategies to restrict sarcopenia, and improve the health of today's elderly population.

Effect of outdoor site location on calculated I/O ratios

Motor vehicle emissions have been identified as one of the major contributors of fine and ultrafine particles (UFP) in urban areas. Schools located near major roads could potentially be exposed to high levels of UPFs and school classroom is an important microenvironment where significant exposure to UFPs is likely to occur. Most of the research conducted to date has investigated the relationship between indoor and outdoor particle number concentration (PNC) in schools based on one outdoor location, which may introduce a level of error when calculating the variation of total UPFs, and can result in the underestimation or overestimation of indoor to outdoor (I/O) ratio values.

Experimental study of the effect of charge on ultrafine particle deposition

The health effects of ultrafine particles (UFPs, <100 nm) have received increasing attention in recent years and particles from a variety of indoor sources, such as combustion or printer emissions, fall within this size range. Since people spend most of their time indoors, knowledge on aerosol deposition in the human respiratory tract is essential to minimise the health risks associated with environmental or occupational exposure to aerosol particles. Among the factors that could alter particle deposition, electrical charge is important as it may increase particle deposition in human respiratory tract (Melanderi et al., 1983), even when particles carry only a few charges. However, evidence showing such an increase in particle deposition for UFPs is sparse. The aim of this study was to investigate the effect of charge on the deposition of UFPs in the human lung by studying the deposition of charged particles in the conductive tubing of an experimental laboratory system.

The effect of exercise on sleep quality in heart failure

Purpose The primary objective of this study was to examine the effect of exercise on subjective sleep quality in heart failure patients. Methods This study used a randomised, controlled trial design with blinded end-point analysis. Participants were randomly assigned to a 12-week programme of education and self-management support (control) or to the same programme with the addition of a tailored physical activity programme designed and supervised by an exercise specialist (intervention). The intervention consisted of 1 hour of aerobic and resistance exercise twice a week. Participants included 108 patients referred to three hospital heart failure services in Queensland, Australia. Results Patients who participated in supervised exercise classes showed significant improvement in subjective sleep quality, sleep latency, sleep disturbance and global sleep quality scores after 12 weeks of supervised hospital based exercise. Secondary analysis showed that improvements in sleep quality were correlated with improvements in geriatric depression score (p=0.00) and exercise performance (p=0.03). General linear models were used to examine whether the changes in sleep quality following intervention occurred independently of changes in depression, exercise performance and weight. Separate models adjusting for each covariate were performed. Results suggest that exercise significantly improved sleep quality independent of changes in depression, exercise performance and weight. Conclusion This study supports the hypothesis that a 12 week program of aerobic and resistance exercise improves subjective sleep quality in patients with heart failure. This is the first randomised controlled trial to examine the role of exercise in the improvement of sleep quality for patients with this disease. While this study establishes exercise as a therapy for poor sleep quality, further research is needed to investigate exercise as a treatment for other parameters of sleep in this population. Study investigators plan to undertake a more in-depth examination within the next 12 months

Effect of engine backpressure on the performance and emissions of a CI engine

This study investigated the effect of engine backpressure on the performance and emissions of a CI engine under different speed and load conditions. A 4-stroke single cylinder naturally aspirated direct injection (DI) diesel engine was used for the investigation with the backpressure of 0, 40, 60 and 80 mm of Hg at engine speed of 600, 950 and 1200 rpm. Two parameters were measured during the engine operation: one is engine performance (brake thermal efficiency and brake specific fuel consumption), and the other is the exhaust emissions (NOx, CO and odor). NOx and CO emission were measured by flue gas analyzer (IMR 1400). The engine backpressure produced by the flow regulating valve in the exhaust line was measured by Hg (mercury) manometer. The result showed that, the brake thermal efficiency and brake specific fuel consumption (bsfc) are almost unchanged with increasing backpressure up to 40 mm of Hg pressure for all engine speed and load conditions. The NOx emission became constant or a little decreased with increasing backpressure. The formation of CO was slightly higher with increase of load and back pressure at low engine speed condition. However, under high speed conditions, CO reduced significantly with increasing backpressure for all load conditions. The odor level was similar or a little higher with increasing backpressure for all engine speed and load conditions. Hence, backpressure up to a certain level is not detrimental for a CI engine.

The effect of silicate ions on proliferation, osteogenic differentiation and cell signalling pathways (WNT and SHH) of bone marrow stromal cells

Silicon (Si) is a trace element, which plays an important role in human bone growth. Si has been incorporated into biomaterials for bone regeneration in order to improve their osteogenic potential, both in vitro and in vivo. Little is known, however, as to how Si ions elicit their biological response on bone-forming cells. The aim of this study was to investigate the effect of Si ions on the proliferation, differentiation, bone-related gene expression and cell signalling pathways of bone marrow stromal cells (BMSCs) by comparing the BMSC responses to different concentrations of NaCl and Na2SiO3, while taking into account and excluding the effect of Na ions. Our study showed that Si ions at a concentration of 0.625 mM significantly enhanced the proliferation, mineralization nodule formation, bone-related gene expression (OCN, OPN and ALP) and bone matrix proteins (ALP and OPN) of BMSCs. Furthermore, Si ions at 0.625 mM could counteract the effect of the WNT inhibitor (W.I.) cardamonin on the osteogenic genes expression, (OPN, OCN and ALP), WNT and SHH signalling pathway-related genes in BMSCs. These results suggest that Si ions by themselves play an important role in regulating the proliferation and osteogenic differentiation of BMSCs, with the involvement of WNT and SHH signalling pathways. Our study provides evidence to explain possible molecular mechanisms whereby Si ions released from Si-containing biomaterials can acquire enhanced bioactivity at desired concentration.