Do Disease-Modifying Anti-rheumatic Drugs and Exercise Therapy Have a Combined Effect on Disease Activity in Patients with RA? A Scoping Review.

PURPOSE OF REVIEW: In addition to disease-modifying anti-rheumatic drug (DMARD) treatment, exercise is increasingly promoted in patients with rheumatoid arthritis (RA). Although both are known to reduce disease activity, few studies have investigated the combined effects of these interventions on disease activity. The aim of this scoping review was to provide an overview of the reported evidence on whether a combined effect-i.e., a greater reduction in disease activity outcome measures-can be detected in studies where an exercise intervention was performed in addition to the DMARD treatment in patients with RA. This scoping review followed the PRISMA guidelines. A literature search was performed for exercise intervention studies in patients with RA treated with DMARDs. Studies without a non-exercise control group were excluded. Included studies reported on (components of) DAS28 and DMARD use and were assessed for methodological quality using version 1 of the Cochrane risk-of-bias tool for randomized trials. For each study, comparisons between groups (i.e., exercise + medication vs. medication only) were reported on disease activity outcome measures. Study data related to the exercise intervention, medication use, and other relevant factors were extracted to assess what may have influenced disease activity outcomes in the included studies. RECENT FINDINGS: A total of 11 studies were included of which 10 between-group studies on DAS28 components were made. The remaining one study focused on within-group comparisons only. Median duration of the exercise intervention studies was 5 months, and the median number of participants was 55. Six out of the 10 between-group studies reported no significant differences between groups in DAS28 components between exercise + medication vs. medication only. Four studies showed significant reductions in disease activity outcomes for the exercise + medication group compared with the medication-only group. Most studies were not adequately designed methodologically in order to investigate for comparisons of DAS28 components and had a high risk of multi-domain bias. Whether the simultaneous application of exercise therapy and DMARD medication in patients with RA has a combined effect on disease outcome remains unknown, due to weak methodological quality of existing studies. Future studies should focus on the combined effects by having disease activity as the primary outcome.

Patient perspective on exercise intervention in rheumatoid arthritis with high risk of cardiovascular disease: a pilot qualitative study.

The objective of the study was to gain an insight into the perceptions and experiences of patients with rheumatoid arthritis and a high cardiovascular disease risk (CVD-RA) when undergoing an exercise intervention aimed at improving their cardiorespiratory fitness. This qualitative study was part of a pilot study, which investigated the effects of an exercise intervention on cardiorespiratory fitness in patients with CVD-RA. Six patients were invited to participate in face-to-face semi-structured interviews. We invited patients who completed the exercise intervention as well as patients who withdrew from the exercise intervention. The interviews were analyzed according to the method of thematic analysis. Six patients were interviewed, of whom four patients completed and two patients discontinued the exercise intervention. The mean (SD) age was 58 (9.7) years, the median disease duration was 10 years, and five patients were female. The analyses revealed seven themes that provided insight into perceptions and experiences: (1) ability to understand reasons for actions; (2) the need to be seen; (3) reaching their maximum effort; (4) experiencing their limits; (5) wanting personalized exercise therapy; (6) happy to be physically active; (7) benefits of exercise. Patients perceived that they were able to perform a cardiopulmonary exercise test with maximum effort and achieved the prescribed intensity of the exercise intervention. They also experienced an improvement in their physical activity by incorporating physical activity in their daily live. Overarching principles that re-occurred in the themes were: the need to be viewed as a person and the importance of feeling safe.

Time-lapse imaging of human embryos fertilized with testicular sperm reveals an impact on the first embryonic cell cycle.

Testicular sperm is increasingly used during in vitro fertilization treatment. Testicular sperm has the ability to fertilize the oocyte after intracytoplasmic sperm injection (ICSI), but they have not undergone maturation during epididymal transport. Testicular sperm differs from ejaculated sperm in terms of chromatin maturity, incidence of DNA damage, and RNA content. It is not fully understood what the biological impact is of using testicular sperm, on fertilization, preimplantation embryo development, and postimplantation development. Our goal was to investigate differences in human preimplantation embryo development after ICSI using testicular sperm (TESE-ICSI) and ejaculated sperm. We used time-lapse embryo culture to study these possible differences. Embryos (n = 639) originating from 208 couples undergoing TESE-ICSI treatment were studied and compared to embryos (n = 866) originating from 243 couples undergoing ICSI treatment with ejaculated sperm. Using statistical analysis with linear mixed models, we observed that pronuclei appeared 0.55 h earlier in TESE-ICSI embryos, after which the pronuclear stage lasted 0.55 h longer. Also, significantly more TESE-ICSI embryos showed direct unequal cleavage from the 1-cell stage to the 3-cell stage. TESE-ICSI embryos proceeded faster through the cleavage divisions to the 5- and the 6-cell stage, but this effect disappeared when we adjusted our model for maternal factors. In conclusion, sperm origin affects embryo development during the first embryonic cell cycle, but not developmental kinetics to the 8-cell stage. Our results provide insight into the biological differences between testicular and ejaculated sperm and their impact during human fertilization.

Cardiorespiratory fitness and physical activity in people who have rheumatoid arthritis at an increased risk of cardiovascular disease: a cross-sectional study.

Lower cardiorespiratory fitness (CRF) and physical activity (PA) associate with higher cardiovascular disease (CVD) risk, but the relationship between CRF and PA in people who have rheumatoid arthritis (RA) at an increased CVD risk (CVD-RA) is not known. The objectives of this study were to determine the levels of CRF and PA in people who have CVD-RA and to investigate the association of CRF with PA in people who have CVD-RA. A total of 24 consecutive patients (19 women) with CVD-RA (> 4% for 10-year risk of fatal CVD development as calculated using the Systematic Coronary Risk Evaluation)-were included in the study. CRF was assessed with a graded maximal exercise test determining maximal oxygen uptake (VO2max). PA was assessed with an accelerometer to determine the amount of step count, sedentary, light and moderate-to-vigorous physical activity (MVPA) minutes per day. Mean age of patients was 65.3 ± 8.3 years. CRF mean values were 16.3 ± 1.2 ml·kg-1 min-1, mean step count per day was 6033 ± 2256, and the mean MVPA time was 16.7 min per day. Significant positive associations were found for CRF with step count (B = 0.001, P = 0.01) and MVPA time (B = 0.15, P = 0.02); a negative association was found for CRF with sedentary time (B = - 0.02, P = 0.03). CRF is low and is associated with step count, sedentary time and MVPA time in people who have RA at an increased CVD risk.

Residues of organochlorine pesticides (OCPs) in aquatic environment and risk assessment along Shaying River, China.

Organochlorine pesticides (OCPs) are pesticides with global scale ubiquity, persistence and bioaccumulation, which leave long-term residuals in the water body. OCPs' high toxicity poses significant threats to human health and aquatic biodiversity, making assessment of OCPs' impact on aquatic ecology and human health urgently necessary. In this research, the presence of 16 OCPs in surface water and groundwater along Shaying River, China, as well as OCPs concentration correlations, was investigated at 24 selected sampling sites. At the same time, the ecological risk and human carcinogenic risk were also analyzed by risk quotient method and USEPA's Risk Assessment Guidance, respectively. Results showed that the total concentration of OCPs ranged from 21.0 to 61.4 ng L-1 in groundwater, and 12.3-77.5 ng L-1 in surface water. Hexachlorocyclohexane (HCHs) and heptachlor were the prominent contaminants in groundwater, which indicated their use in the recent past and confirmed their persistence. The α-HCH/γ-HCH ratios in groundwater confirmed that γ-HCH (lindane) was used as main substitute of technical HCH in the study area. The correlation analysis illustrated that δ-HCH and γ-HCH played a dominant role in HCHs residue. Heptachlor and α-HCH, as well as endosulfan and heptachlor epoxide, had a strongly significant positive correlation, suggesting an associated usage of the two pair OCPs. An extremely high ecological risk for aquatic organism was observed for γ-HCH, heptachlor and dieldrin, while the carcinogenic risks posed by the selected OCPs in surface water and groundwater were all acceptable.

Children's everyday exposure to food marketing: an objective analysis using wearable cameras.

BACKGROUND: Over the past three decades the global prevalence of childhood overweight and obesity has increased by 47%. Marketing of energy-dense nutrient-poor foods and beverages contributes to this worldwide increase. Previous research on food marketing to children largely uses self-report, reporting by parents, or third-party observation of children's environments, with the focus mostly on single settings and/or media. This paper reports on innovative research, Kids'Cam, in which children wore cameras to examine the frequency and nature of everyday exposure to food marketing across multiple media and settings. METHODS: Kids'Cam was a cross-sectional study of 168 children (mean age 12.6 years, SD = 0.5) in Wellington, New Zealand. Each child wore a wearable camera on four consecutive days, capturing images automatically every seven seconds. Images were manually coded as either recommended (core) or not recommended (non-core) to be marketed to children by setting, marketing medium, and product category. Images in convenience stores and supermarkets were excluded as marketing examples were considered too numerous to count. RESULTS: On average, children were exposed to non-core food marketing 27.3 times a day (95% CI 24.8, 30.1) across all settings. This was more than twice their average exposure to core food marketing (12.3 per day, 95% CI 8.7, 17.4). Most non-core exposures occurred at home (33%), in public spaces (30%) and at school (19%). Food packaging was the predominant marketing medium (74% and 64% for core and non-core foods) followed by signs (21% and 28% for core and non-core). Sugary drinks, fast food, confectionary and snack foods were the most commonly encountered non-core foods marketed. Rates were calculated using Poisson regression. CONCLUSIONS: Children in this study were frequently exposed, across multiple settings, to marketing of non-core foods not recommended to be marketed to children. The study provides further evidence of the need for urgent action to reduce children's exposure to marketing of unhealthy foods, and suggests the settings and media in which to act. Such action is necessary if the Commission on Ending Childhood Obesity's vision is to be achieved.

Mortality in patients with rheumatoid arthritis: a 15-year prospective cohort study.

The aim of this study was to investigate (a) the mortality in a clinical cohort of patients with established rheumatoid arthritis in comparison with the general Dutch population over 15 years, (b) the trend in the mortality ratio during the study period, and (c) causes of death and compare these with the general population. In 1997, a sample of 1222 patients was randomly selected from the register of a large rheumatology outpatient clinic. Their mortality and primary causes of death between 1997 and 2012 were obtained from Statistics Netherlands. The standardized mortality ratio (SMR) for all-cause mortality and the number of life-years lost in the study period, adjusted for age, sex, and calendar year, were calculated. A linear poisson regression analysis was performed to evaluate change in all-cause SMR over time. Finally, the SMRs for cause-specific mortality were calculated. The mean age of the population at baseline was 60.4 (SD 15.4) years, and 72.6% of the patients were women. The estimated SMR (95% CI) for all-cause mortality was 1.54 (1.41, 1.67) with about one life-year lost over the study period. There was a trend to decreasing SMR (2% annually, p = .07). Mortality was higher compared with the general population for circulatory system diseases, respiratory system diseases, musculoskeletal system diseases, and digestive system diseases (p < .05). The observed mortality among patients with RA was 54% higher than in the general population after adjustment for age, sex and calendar year. More than one life-year was lost over 15 years, and the mortality tended to decrease over time. The mortality was higher for cardiovascular, respiratory, musculoskeletal and digestive diseases.

Current practices used for the prevention of central venous catheter-associated infection in hematopoietic stem cell transplantation recipients: a survey from the Infectious Diseases Working Party and Nurses' Group of EBMT.

BACKGROUND: Central line-associated bloodstream infection (CLABSI) is one of the most common infectious complications after hematopoietic stem cell transplantation. To prevent this complication, international guidelines recommend the implementation of the CLABSI 'prevention bundle' consisting of hand hygiene, full barrier precautions, cleaning the insertion site with chlorhexidine, avoiding femoral sites for insertion, and removing unnecessary catheters. The aim of this survey was to analyze to what extent European Group for Blood and Marrow Transplantation (EBMT) centers have included the CLABSI prevention bundle in practice. METHODS: A questionnaire used for data collection was sent to the 545 EBMT centers worldwide, 103 of which responded. RESULTS: All 5 components of the CLABSI prevention bundle were recorded in 28% of the centers' standard operating procedures (SOP), and 21% of the centers answered that they used all of the bundle components in clinical practice. The most common recommendation absent from the SOP was specification of all the components of full barrier precautions (43% of the centers did not include at least 1 component). Skin disinfection with chlorhexidine before catheter insertion was reported by 66% centers. CLABSI rates were monitored in 21% of centers. CONCLUSIONS: Although most of the centers lacked 1 or more of the CLABSI prevention bundle components in their SOP, improvements could easily be made by updating the centers' SOP. The first important step is introduction of CLABSI rate monitoring in this high-risk patient population.

Validation of the Animated Activity Questionnaire (AAQ) for patients with hip and knee osteoarthritis: comparison to home-recorded videos.

A recently developed computerized Animated Activity Questionnaire (AAQ) uses video animations to measure limitations in basic daily activities in patients with hip or knee osteoarthritis (OA). The AAQ is less time and money consuming than performance-based tests and less burdensome for patients. Compared to patient-reported outcome measurements, the AAQ is less influenced by the perception of the patient. Previous validation studies of the AAQ showed promising results. Since the AAQ purports to measure activity limitations in real-life situations, this study aims to establish the construct validity of the AAQ by comparing the AAQ to home-recorded videos. Home-recorded videos of eleven basic activities performed by 22 OA patients were transformed into scores and subsequently correlated with the AAQ, the Hip disability and Knee injury Osteoarthritis Outcome Score (H/KOOS), and three performance-based tests (Stair Climbing Test, Timed Up and Go test, and the 30 s Chair Stand Test). The AAQ was expected to correlate highly with the home-recorded videos and the performance-based tests, and moderately with the H/KOOS. As hypothesized, the AAQ correlated highly with the home-recorded videos and performance-based tests (0.83 and, 0.73 respectively), but also unexpectedly highly with the H/KOOS (0.79). In conclusion, since the AAQ correlates highly with home-recorded videos, it seems to have potential as a measurement tool to assess limitations in activities close to the real-life situation, but this should be confirmed in a larger sample of patients.

Circular economy in drinking water treatment: reuse of ground pellets as seeding material in the pellet softening process.

Calcium carbonate pellets are produced as a by-product in the pellet softening process. In the Netherlands, these pellets are applied as a raw material in several industrial and agricultural processes. The sand grain inside the pellet hinders the application in some high-potential market segments such as paper and glass. Substitution of the sand grain with a calcite grain (100% calcium carbonate) is in principle possible, and could significantly improve the pellet quality. In this study, the grinding and sieving of pellets, and the subsequent reuse as seeding material in pellet softening were tested with two pilot reactors in parallel. In one reactor, garnet sand was used as seeding material, in the other ground calcite. Garnet sand and ground calcite performed equally well. An economic comparison and a life-cycle assessment were made as well. The results show that the reuse of ground calcite as seeding material in pellet softening is technologically possible, reduces the operational costs by €38,000 (1%) and reduces the environmental impact by 5%. Therefore, at the drinking water facility, Weesperkarspel of Waternet, the transition from garnet sand to ground calcite will be made at full scale, based on this pilot plant research.

DAMAGE RESEARCH WITH P. PENETRANS IN ASPARAGUS PLANTS.

During cultivation of asparagus plants growth can be inhibited and yield can be reduced by plant-parasitic nematodes. Plant raising companies assume that the root lesion nematode (Pratylenchus penetrans) can cause severe yield loss in asparagus plants. However quantitative information about yield reduction in relation to the degree of infestation of this nematode species in the field is lacking. Research was done in The Netherlands by Applied Plant Research (part of Wageningen University and Research Centre) to determine the maximum degree of yield loss of asparagus plants at high infestation levels of P. penetrans and to establish the height of the tolerance limit for this nematode species. Also was investigated whether a field application of a granular nematicide could prevent or reduce yield loss caused by P. penetrans. Research was done in the field at sandy soils at the PPO location near Vredepeel in The Netherlands over a period of two years. In the first year the most suitable field was selected and on this field different infestation levels of P. penetrans were created. In the second year asparagus was cultivated and plant yield (number and quality of deliverable plants and financial yield) was calculated. At high infestation levels of Pratylenchus penetrans maximum yield loss was 12% (which can mean a financial loss of 7.000 C per ha). Yield started to decrease at very low infestation levels of P. penetrans and no statistical reliable tolerance limit could be calculated. Field application of 40 kg per ha of Vydate 10 G just before sowing of asparagus, could almost completely prevent yield loss caused by P. penetrans. After harvest infestation levels of P. penetrans were much lower than could be expected if asparagus was a non-host for this nematode species. In this paper therefore it is suggested that asparagus plants are (actively) controlling P. penetrans.

Electrochemical arsenite oxidation for drinking water treatment: Mechanisms, by-product formation and energy consumption.

The mechanisms and by-product formation of electrochemical oxidation (EO) for As(III) oxidation in drinking water treatment using groundwater was investigated. Experiments were carried out using a flowthrough system, with an RuO2/IrO2 MMO Ti anode electrode, fed with synthetic and natural groundwater containing As(III) concentrations in a range of around 75 and 2 µg/L, respectively. Oxidation was dependent on charge dosage (CD) [C/L] and current density [A/m2], with the latter showing plateau behaviour for increasing intensity. As(III) concentrations of <0.3 µg/L were obtained, indicating oxidation of 99.9 % of influent As(III). Achieving this required a higher charge dosage for the natural groundwater (>40 C/L) compared to the oxidation in the synthetic water matrix (20 C/L), indicating reaction with natural organic matter or other compounds. As(III) oxidation in groundwater required an energy consumption of 0.09 and 0.21 kWh/m3, for current densities of 20 and 60 A/m2, respectively. At EO settings relevant for As(III) oxidation, in the 30-100 C/L CD range, the formation of anodic by-products, as trihalomethanes (THMs) (0.11-0.75 µg/L) and bromate (<0.2 µg/L) was investigated. Interestingly, concentrations of the formed by-products did not exceed strictest regulatory standards of 1 µg/L, applicable to Dutch tap water. This study showed the promising perspective of EO as electrochemical advanced oxidation process (eAOP) in drinking water treatment as alternative for the conventional use of strong oxidizing chemicals.

Availability and marketing of food and beverages to children through sports settings: a systematic review.

OBJECTIVE: The current systematic review aimed to identify and critically appraise research on food environments in sports settings, including research into the types of food and beverages available, the extent and impact of food and beverage sponsorship and marketing, and views about food environments among key stakeholders. DESIGN: A systematic review. Fourteen English-language studies (two were papers describing different facets of the same study), published between 1985 and 2011, were identified from searches of electronic databases and bibliographies of primary studies. SETTING: Most studies originated from Australia (n 10), with the remaining studies originating in the UK (n 1), New Zealand (n 1), the USA (n 1) and Canada (n 1). Data were collected from observations in stadia, websites and televised sports events, through in-depth interviews, focus groups and surveys with sports club members, parents and quick serve restaurant managers. RESULTS: Literature exploring food environments in sports settings was limited and had some important methodological limitations. No studies comprehensively described foods available at clubs or stadia, and only one explored the association between food and beverage sponsorship and club incomes. Club policies focused on the impact of health promotion funding rather than the impact of sponsorship or food availability in sports settings. CONCLUSIONS: Further research, including comprehensive studies of the food environment in sports settings, is required to document the availability, sponsorship and marketing of food and beverages at national, regional and club levels and to estimate how sports settings may influence children's diets.

Climate change mitigation by recovery of energy from the water cycle: a new challenge for water management.

Waternet is responsible for drinking water treatment and distribution, wastewater collection and treatment, and surface water management and control (quality and quantity) in and around Amsterdam. Waternet has the ambition to operate climate neutral in 2020. To realise this ambition, measures are required to compensate for the emission of 53,000 ton CO(2)-eq/year. Energy recovery from the water cycle looks very promising. First, calculations reveal that energy recovery from the water cycle in and around Amsterdam may contribute to a total reduction in greenhouse gas emissions up to 148,000 ton CO(2)-eq/year. The challenge for the coming years is to choose combinations of all the possibilities to fulfil the energy demand as much as possible. Only then the use of fossil fuel can be minimized and inevitable greenhouse gas emissions can be compensated, supporting the target to operate climate neutral in 2020.

Exercise intervention on cardiorespiratory fitness in rheumatoid arthritis patients with high cardiovascular disease risk: a single-arm pilot study.

OBJECTIVE: In patients with rheumatoid arthritis (RA) with cardiovascular disease risk, it is unknown whether exercises are safe, improve cardiorespiratory fitness and reduce disease-related symptoms and cardiovascular-disease (CVD) risk factors. We aimed to investigate in RA patients with CVD risk: (1) safety of medium to high-intensity aerobic exercises, (2) potential changes of cardiorespiratory fitness and (3) disease activity and CVD risk factors in response to the exercises. METHODS: Single-arm pilot-exercise intervention study including 26 consecutive patients (21 women) with > 4% 10-year risk of CVD mortality according to the Dutch Systematic Coronary Risk Evaluation. Aerobic exercises consisted of two supervised-sessions and five home-sessions per week for 12 weeks. Patients were required to exercise at intensities between 65 and 85% of their maximum heart rate. To assess safety, we recorded exercise related adverse events. Before and after the exercises, cardiorespiratory fitness was assessed with a graded maximal oxygen-uptake exercise test, while disease activity was evaluated via the Disease Activity Score-28 (DAS28) using the erythrocyte segmentation rate (ESR). Resting blood pressure, ESR and total cholesterol were assessed as CVD risk factors. RESULTS: Twenty out of 26 patients performed the 12-week exercises without any adverse events. According to patients, withdrawals were unrelated to the exercises. Exercises increased cardiorespiratory fitness (pre: 15.91 vs. post: 18.15 ml.kg-1 min-1, p = 0.003) and decreased DAS28 (pre: 2.86 vs. post: 2.47, p = 0.04). No changes were detected in CVD risk factors. CONCLUSION: A 12-week exercise intervention seems to be safe and improves cardiorespiratory fitness and disease activity in patients with RA with a high risk for cardiovascular diseases. Key Points 1. Rheumatoid arthritis patients with high cardiovascular disease risk were able to perform a maximum exercise test and a 12-week aerobic-based medium-to-high intensity exercise intervention. 2. The exercise intervention improved cardiorespiratory fitness and disease activity in rheumatoid arthritis patients with high cardiovascular disease risk. 3. Cardiorespiratory fitness levels were still low post-exercise intervention (i.e. 18.15 ml.kg-1min-1 compared to the 20.9 ml.kg-1min-1 baseline mean of the RA patients without CVD risk).

How do tobacco retail displays affect cessation attempts? Findings from a qualitative study.

BACKGROUND: Tobacco retail displays promote smoking experimentation among youth; however, little is known about their effect on smokers making a quit attempt. Calls to ban tobacco retail displays would be strengthened if this measure would deter initiation and support cessation. METHODS: Semistructured in-depth interviews were conducted with 20 individuals, from two New Zealand provincial cities, who had attempted to quit smoking in the last 6 months. RESULTS: Tobacco products had high visibility, and elicited emotional and physical reactions that created on-going temptation, complicated cessation attempts and stimulated impulse purchases. Participants strongly supported banning tobacco retail displays primarily because they thought this would reduce youth initiation, promote greater consistency with smoke-free promotions and assist those attempting to quit. CONCLUSIONS: The effects of tobacco retail displays on smokers making a cessation attempt are explored. The findings are consistent with experimental and survey research, and expand a growing evidence base that supports government-mandated bans on tobacco retail displays.

Population-based study on the seroprevalence of parvovirus B19 in Amsterdam.

A study was undertaken to estimate the seroprevalence of parvovirus B19 infection in the general adult population of Amsterdam, The Netherlands. To our knowledge this is the first study testing parvovirus B19 in a random sample of the Dutch adult population. The study was a cross-sectional survey, and the study sample was stratified by age and ethnicity, with deliberate oversampling of minority ethnic groups. Serum samples obtained from 1,323 residents in 2004 were tested for antibodies to parvovirus B19. Basic demographic data (gender, age, country of birth, and number of children) were also available. Sixty-two percent of the participants were seropositive; corrected for the oversampling the estimated prevalence in the Amsterdam adult population was 61%. No specific predictors or risk groups for seropositivity were identified. In our urban adult study population no positive correlation with increasing neither age, nor significant differences between age groups were found. These results imply that almost 40% of the adult Amsterdam population is susceptible to infection. J. Med. Virol. 81:1305-1309, 2009. (c) 2009 Wiley-Liss, Inc.

Why cytoplasmic signalling proteins should be recruited to cell membranes.

It has been suggested that localization of signal-transduction proteins close to the cell membrane causes an increase in their rate of encounter after activation. We maintain that such an increase in the first-encounter rate is too small to be responsible for truly enhanced signal transduction. Instead, the function of membrane localization is to increase the number (or average lifetime) of complexes between cognate signal transduction proteins and hence increase the extent of activation of downstream processes. This is achieved by concentrating the proteins in the small volume of the area just below the plasma membrane. The signal-transduction chain is viewed simply as operating at low default intensity because one of its components is present at a low concentration. The steady signalling level of the chain is enhanced 1000-fold by increasing the concentration of that component. This occurs upon 'piggyback' binding to a membrane protein, such as the activated receptor, initiating the signal-transduction chain. For the effect to occur, the protein translocated to the membrane cannot be free but has to remain organized by being piggyback bound to a receptor, membrane lipid(s) or scaffold. We discuss an important structural constraint imposed by this mechanism on signal transduction proteins that might also account for the presence of adaptor proteins.

2600-years of stratospheric volcanism through sulfate isotopes.

High quality records of stratospheric volcanic eruptions, required to model past climate variability, have been constructed by identifying synchronous (bipolar) volcanic sulfate horizons in Greenland and Antarctic ice cores. Here we present a new 2600-year chronology of stratospheric volcanic events using an independent approach that relies on isotopic signatures (Δ33S and in some cases Δ17O) of ice core sulfate from five closely-located ice cores from Dome C, Antarctica. The Dome C stratospheric reconstruction provides independent validation of prior reconstructions. The isotopic approach documents several high-latitude stratospheric events that are not bipolar, but climatically-relevant, and diverges deeper in the record revealing tropospheric signals for some previously assigned bipolar events. Our record also displays a collapse of the Δ17O anomaly of sulfate for the largest volcanic eruptions, showing a further change in atmospheric chemistry induced by large emissions. Thus, the refinement added by considering both isotopic and bipolar correlation methods provides additional levels of insight for climate-volcano connections and improves ice core volcanic reconstructions.