An in vitro toxicological assessment of two electronic cigarettes: E-liquid to aerosolisation.

Interest in the toxicological assessment of iterations of e-cigarette devices, e-liquid formulations and flavour use is increasing. Here, we describe a multiple test matrix and in vitro approach to assess the biological impact of differing e-cigarette activation mechanism (button vs. puff-activated) and heating technology (cotton vs. ceramic wick). The e-liquids selected for each device contained the same nicotine concentration and flavourings. We tested both e-liquid and aqueous extract of e-liquid aerosol using a high throughput cytotoxicity and genotoxicity screen. We also conducted whole aerosol assessment both in a reconstituted human airway lung tissue (MucilAir) with associated endpoint assessment (cytotoxicity, TEER, cilia beat frequency and active area) and an Ames whole aerosol assay with up to 900 consecutive undiluted puffs. Following this testing it is shown that the biological impact of these devices is similar, taking into consideration the limitations and capturing efficiencies of the different testing matrices. We have contextualised these responses against previous published reference cigarette data to establish the comparative reduction in response consistent with reduced risk potential of the e-cigarette products tested in this study as compared to conventional cigarettes.

Preferences for Delivering Brief Alcohol Intervention to Risky Drinking Parents in Children's Social Care: A Discrete Choice Experiment.

AIMS: Many parents in contact with children's social care services misuse alcohol however do not meet the threshold for specialist alcohol treatment, and typically do not receive appropriate support for their needs. Brief alcohol interventions have been found to be effective in healthcare settings, however, it is unknown whether the brief intervention structure delivered within health settings would transfer well into children's social care. This paper aims to examine the characteristics of brief intervention for alcohol misusing parents which social care practitioners consider to be important and acceptable to implement in this sector. METHODS: We assessed preferences for, and acceptability of, brief alcohol intervention with parents in contact with children's social care using a discrete choice experiment. We recruited 205 children's social care practitioners from London and the North East of England. Data were analysed using mixed logit which accounted for repeated responses. FINDINGS: Six attributes showed statistically significant coefficients, suggesting that a brief intervention with these attributes would encourage implementation. These were: level of alcohol-related risk targeted; intervention recipient; timing of intervention; duration of sessions; number of sessions and intervention structure. The attribute of most importance identified based on the attribute with the largest coefficient in the conditional logit model was risk level. CONCLUSIONS: Brief alcohol interventions delivered to parents in social care should focus on the impact upon children and the wider family, they should be a flexible part of on-going casework and should be more intensive and less structured.

Allergenic proteases cleave the chemokine CX3CL1 directly from the surface of airway epithelium and augment the effect of rhinovirus.

CX3CL1 has been implicated in allergen-induced airway CD4+ T-lymphocyte recruitment in asthma. As epidemiological evidence supports a viral infection-allergen synergy in asthma exacerbations, we postulated that rhinovirus (RV) infection in the presence of allergen augments epithelial CX3CL1 release. Fully differentiated primary bronchial epithelial cultures were pretreated apically with house dust mite (HDM) extract and infected with rhinovirus-16 (RV16). CX3CL1 was measured by enzyme-linked immunosorbent assay and western blotting, and shedding mechanisms assessed using inhibitors, protease-activated receptor-2 (PAR-2) agonist, and recombinant CX3CL1-expressing HEK293T cells. Basolateral CX3CL1 release was unaffected by HDM but stimulated by RV16; inhibition by fluticasone or GM6001 implicated nuclear factor-κB and ADAM (A Disintegrin and Metalloproteinase) sheddases. Conversely, apical CX3CL1 shedding was stimulated by HDM and augmented by RV16. Although fluticasone or GM6001 reduced RV16+HDM-induced apical CX3CL1 release, heat inactivation or cysteine protease inhibition completely blocked CX3CL1 shedding. The HDM effect was via enzymatic cleavage of CX3CL1, not PAR-2 activation, yielding a product mitogenic for smooth muscle cells. Extracts of Alternaria fungus caused similar CX3CL1 shedding. We have identified a novel mechanism whereby allergenic proteases cleave CX3CL1 from the apical epithelial surface to yield a biologically active product. RV16 infection augmented HDM-induced CX3CL1 shedding-this may contribute to synergy between allergen exposure and RV infection in triggering asthma exacerbations and airway remodeling.

Stomatal behaviour of irrigated Vitis vinifera cv. Syrah following partial root removal.

We examined stomatal behaviour of a grapevine cultivar (Vitis vinifera L. cv. Syrah) following partial root removal under field conditions during progressively developing water deficits. Partial root removal led to an increase in hydraulic resistances along the soil-to-leaf pathway and leaf wilting symptoms appeared in the root-pruned plants immediately following root removal. Leaves recovered from wilting shortly thereafter, but hydraulic resistances were sustained. In comparison with the non-root pruned vines, leaves of root-pruned vines showed an immediate decrease in both pre-dawn (ψPD) and midday (ψleaf) leaf water potential. The decline in ψPD was unexpected in as much as soil moisture was not altered and it has been shown that axial water transport readily occurs in woody perennials. Only ~30% of the functional root system was removed, thus leaving the system mainly intact for water redistribution. Stem water potential (ψStem) and leaf gas exchanges of CO2 (A) and H2O (E) also declined immediately following root pruning. The lowering of ψPD, ψleaf, ψStem, A and E was sustained during the entire growing season and was not dependent on irrigation during that time. This, and a close relationship between stomatal conductance (gs) and leaf-specific hydraulic conductance (Kplant), indicated that the stomatal response was linked to plant hydraulics. Stomatal closure was observed only in the root-restricted plants and at times of very high evaporative demand (VPD). In accordance with the Ball-Berry stomatal control model proposed by Ball et al. (1987), the stomatal sensitivity factor was also lower in the root-restricted plants than in intact plants as soil water availability decreased. Although ψPD, ψStem and ψLeaf changed modestly and gradually following root removal, gs changed dramatically and abruptly following removal. These results suggest the involvement of stomatal restricting signals being propagated following removal of roots.

Genotoxicity screening via the γH2AX by flow assay.

The measurement of serine139-phosphorylated histone H2AX (γH2AX) provides a biomarker of DNA double-strand breaks (DSBs) and may identify potential genotoxic activity. In order to evaluate a flow cytometry assay for γH2AX detection (hereafter termed the γH2AX by flow assay), 6 prototypical (3 pro- and 3 proximate) genotoxins, i.e. dimethylbenz[a]anthracene (DMBA), 2-acetylaminofluorene (2-AAF), benzo[a]pyrene (B[a]P), methyl methane sulphonate (MMS), methyl nitrosourea (MNU) and 4-nitroquinoline oxide (4NQO), were selected to define assay evaluation criteria. In addition, 3 non-genotoxic cytotoxins (phthalic anhydride, n-butyl chloride and hexachloroethane) were included to investigate the influence of cytotoxicity on assay performance. At similar cytotoxicity levels (relative cell counts; RCC 75-40%) all prototypical genotoxins induced marked concentration-dependent increases in γH2AX compared with the non-genotoxins. As a result, assay evaluation criteria for a positive effect were defined as >1.5-fold γH2AX @ RCC >25%. Twenty five additional chemicals with diverse structures and genotoxic activity were selected to evaluate the γH2AX by flow assay. Results were compared with Ames bacterial and in vitro mammalian genotoxicity tests (mouse lymphoma assay and/or chromosome aberration assay). γH2AX by flow assay results were highly predictive of Ames (sensitivity 100%; specificity 67%; concordance 82%) and in vitro mammalian genotoxicity tests (sensitivity 91%; specificity 89%; concordance 91%) and provide additional evidence that γH2AX is a biomarker of potential genotoxic activity, underpinned mechanistically by the cellular response to DSBs. Discordant findings were predominately attributed to differences in specificity for some mammalian cell genotoxins that are Ames non-mutagens or for "biologically-irrelevant" positives in the mammalian tests. Simple anilines were classified as genotoxic following rat liver S9-mediated bioactivation, however, effects on γH2AX were atypical and limited to a small sub-population of S-phase nuclei. Nevertheless, the γH2AX by flow assay represents a novel genotoxicity assay with the potential to flag both pro- and proximate genotoxins.

Transcutaneous oximetry in clinical practice: consensus statements from an expert panel based on evidence.

Transcutaneous oximetry (PtcO2) is finding increasing application as a diagnostic tool to assess the peri-wound oxygen tension of wounds, ulcers, and skin flaps. It must be remembered that PtcO2 measures the oxygen partial pressure in adjacent areas of a wound and does not represent the actual partial pressure of oxygen within the wound, which is extremely difficult to perform. To provide clinical practice guidelines, an expert panel was convened with participants drawn from the transcutaneous oximetry workshop held on June 13, 2007, in Maui, Hawaii. Important consensus statements were (a) tissue hypoxia is defined as a PtcO2 <40 mm Hg; (b) in patients without vascular disease, PtcO2 values on the extremity increase to a value >100 mm Hg when breathing 100% oxygen under normobaric pressures; (c) patients with critical limb ischemia (ankle systolic pressure of < or =50 mm Hg or toe systolic pressure of < or =30 mm Hg) breathing air will usually have a PtcO2 <30 mm Hg; (d) low PtcO2 values obtained while breathing normobaric air can be caused by a diffusion barrier; (e) a PtcO2 <40 mm Hg obtained while breathing normobaric air is associated with a reduced likelihood of amputation healing; (f) if the baseline PtcO2 increases <10 mm Hg while breathing 100% normobaric oxygen, this is at least 68% accurate in predicting failure of healing post-amputation; (g) an increase in PtcO2 to >40 mm Hg during normobaric air breathing after revascularization is usually associated with subsequent healing, although the increase in PtcO2 may be delayed; (h) PtcO2 obtained while breathing normobaric air can assist in identifying which patients will not heal spontaneously.

Use of evidence-based practices in pregnancy and childbirth: South East Asia Optimising Reproductive and Child Health in Developing Countries project.

BACKGROUND: The burden of mortality and morbidity related to pregnancy and childbirth remains concentrated in developing countries. SEA-ORCHID (South East Asia Optimising Reproductive and Child Health In Developing countries) is evaluating whether a multifaceted intervention to strengthen capacity for research synthesis, evidence-based care and knowledge implementation improves adoption of best clinical practice recommendations leading to better health for mothers and babies. In this study we assessed current practices in perinatal health care in four South East Asian countries and determined whether they were aligned with best practice recommendations. METHODOLOGY/PRINCIPAL FINDINGS: We completed an audit of 9550 medical records of women and their 9665 infants at nine hospitals; two in each of Indonesia, Malaysia and The Philippines, and three in Thailand between January-December 2005. We compared actual clinical practices with best practice recommendations selected from the Cochrane Library and the World Health Organization Reproductive Health Library. Evidence-based components of the active management of the third stage of labour and appropriately treating eclampsia with magnesium sulphate were universally practiced in all hospitals. Appropriate antibiotic prophylaxis for caesarean section, a beneficial form of care, was practiced in less than 5% of cases in most hospitals. Use of the unnecessary practices of enema in labour ranged from 1% to 61% and rates of episiotomy for vaginal birth ranged from 31% to 95%. Other appropriate practices were commonly performed to varying degrees between countries and also between hospitals within the same country. CONCLUSIONS/SIGNIFICANCE: Whilst some perinatal health care practices audited were consistent with best available evidence, several were not. We conclude that recording of clinical practices should be an essential step to improve quality of care. Based on these findings, the SEA-ORCHID project team has been developing and implementing interventions aimed at increasing compliance with evidence-based clinical practice recommendations to improve perinatal practice in South East Asia.

The relationship between changes in interstitial creatine kinase and game-related impacts in rugby union.

AIM: The primary purpose of this study was to investigate the relationship between the pre-game to post-game changes in creatine kinase concentration (Delta[CK]) and impact-related game statistics in elite rugby union players. METHODS: Twenty-three elite male rugby union players each provided interstitial fluid samples obtained via electrosonophoresis (ESoP) 210 min before and within a maximum time of 30 min after up to five rugby union games. Specific game statistics that were deemed to be important in determining the relationship between impact and [CK] were obtained from AnalyRugby software for each individual player. Regression equations to predict Delta[CK] from game statistics were created using a backwards random-effects maximum likelihood regression. RESULTS: The Delta[CK] (mean (SD)) from pre-game to post-game was 926.8 (204.2) IU. Game time and time defending were significantly correlated to Delta[CK] in both the forwards and backs. The predicted Delta[CK] (mean (95% confidence limit)) was 1439.8 (204.9) IU for the forwards and 545.3 (78.0) IU for the backs and was significantly correlated with the actual Delta[CK] (r = 0.69 and r = 0.74). CONCLUSIONS: CK increased from pre-game to post-game in a position-specific manner. A large proportion of the Delta[CK] can be explained by physical impact and thus can be predicted using a prescribed number of game statistics. As the Delta[CK] is an indicator of muscle damage, the prediction of Delta[CK] provides a theoretical basis for recovery strategies and adjustment of subsequent training sessions after rugby union games.

Importance of internal hydraulic redistribution for prolonging the lifespan of roots in dry soil.

Redistribution of water within plants could mitigate drought stress of roots in zones of low soil moisture. Plant internal redistribution of water from regions of high soil moisture to roots in dry soil occurs during periods of low evaporative demand. Using minirhizotrons, we observed similar lifespans of roots in wet and dry soil for the grapevine 'Merlot' (Vitis vinifera) on the rootstock 101-14 Millardet de Gramanet (Vitis riparia x Vitis rupestris) in a Napa County, California vineyard. We hypothesized that hydraulic redistribution would prevent an appreciable reduction in root water potential and would contribute to prolonged root survivorship in dry soil zones. In a greenhouse study that tested this hypothesis, grapevine root systems were divided using split pots and were grown for 6 months. With thermocouple psychrometers, we measured water potentials of roots of the same plant in both wet and dry soil under three treatments: control (C), 24 h light + supplemental water (LW) and 24 h light only (L). Similar to the field results, roots in the dry side of split pots had similar survivorship as roots in the wet side of the split pots (P = 0.136) in the C treatment. In contrast, reduced root survivorship was directly associated with plants in which hydraulic redistribution was experimentally reduced by 24 h light. Dry-side roots of plants in the LW treatment lived half as long as the roots in the wet soil despite being provided with supplemental water (P < 0.0004). Additionally, pre-dawn water potentials of roots in dry soil under 24 h of illumination (L and LW) exhibited values nearly twice as negative as those of C plants (P = 0.034). Estimates of root membrane integrity using electrolyte leakage were consistent with patterns of root survivorship. Plants in which nocturnal hydraulic redistribution was reduced exhibited more than twice the amount of electrolyte leakage in dry roots compared to those in wet soil of the same plant. Our study demonstrates that besides a number of ecological advantages to protecting tissues against desiccation, internal hydraulic redistribution of water is a mechanism consistent with extended root survivorship in dry soils.

Geographically based investigation of the influence of very-preterm births on routine mortality statistics from the UK and Australia.

BACKGROUND: Comparisons of national perinatal and neonatal mortality often neglect the underlying causes. OBJECTIVE: To assess effects of very-preterm births in the UK and Australia. SETTING: Two geographically defined populations: the former Trent Health Region of the UK and New South Wales (NSW)/the Australian Capital Territory (ACT), Australia. METHOD: All births 22(+0) to 31(+6) weeks in 2000, 2001 and 2002 were identified by established surveys of perinatal care. Rates of birth and death were compared. RESULTS: The population of NSW/ACT was 35% higher and there were 66% more births than in Trent (273 495 vs 164 824). The proportion of liveborn infants between 22 and 31 weeks gestation was about 25% higher in Trent (NSW/ACT 2945, rate per 1000 live births 10.82 (95% CI 10.43 to 11.22); Trent 2208, rate per 1000 live births 13.47 (95% CI 12.92 to 14.05)). The proportion of these infants admitted to a neonatal unit was also higher in Trent (91.2% vs 94.4%; OR 1.63 (95% CI 1.30 to 2.05)). Unadjusted mortality in infants admitted to a neonatal unit was similar: NSW/ACT 332/2686 (12.4%); Trent 284/2085 (13.6%); unadjusted OR 1.12 (95% CI 0.94 to 1.33; p = 0.21). CONCLUSIONS: The higher rates of very premature birth and more ready admission to neonatal intensive care for infants in the UK may help to explain why perinatal and neonatal mortality are higher there than in Australia. Efforts to understand why the rate of premature birth in the UK is so high should be a national priority.

Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants.

BACKGROUND: Respiratory failure due to lung immaturity is a major cause of mortality in preterm infants. Although the use of intermittent positive pressure ventilation (IPPV) in neonates with respiratory failure saves lives, its use is associated with lung injury and chronic lung disease (CLD). Conventional IPPV is provided at 30-80 breaths per minute, while a newer form of ventilation called high frequency oscillatory ventilation (HFOV) provides 'breaths' at 10 - 15 cycles per second. This has been shown to result in less lung injury in experimental studies. OBJECTIVES: The objective of this review is to determine the effect of the elective use of high frequency oscillatory ventilation (HFOV) as compared to conventional ventilation (CV) in preterm infants who are mechanically ventilated for respiratory distress syndrome (RDS), on the incidence of chronic lung disease, mortality and other complications associated with prematurity and assisted ventilation. SEARCH STRATEGY: Searches were made of the Oxford Database of Perinatal Trials, MEDLINE, EMBASE, previous reviews including cross references, abstracts, conferences and symposia proceedings, expert informants, journal hand searching by the Cochrane Collaboration, mainly in the English language. The search was updated in April 2007. SELECTION CRITERIA: Randomised controlled trials comparing HFOV and CV in preterm or low birth weight infants with pulmonary dysfunction, mainly due to RDS, who were given IPPV. Randomisation and commencement of treatment needed to be as soon as possible after the start of IPPV and usually in the first 12 hours of life. DATA COLLECTION AND ANALYSIS: The methodological quality of each trial was independently reviewed by the various authors. The standard effect measures are relative risk (RR) and risk difference (RD). From 1/RD the number needed to treat (NNT) to produce one outcome were calculated. For all measures of effect, 95% confidence intervals were used. In subgroup analyses the 99% CIs are also given for summary RRs in the text. Meta-analysis was performed using a fixed effects model. Where heterogeneity was over 50%, the random effects RR is also given. MAIN RESULTS: Fifteen eligible studies of 3,585 infants were included. Meta-analysis comparing HFOV with CV revealed no evidence of effect on mortality at 28 - 30 days of age or at approximately term equivalent age. These results were consistent across studies and in subgroup analyses. The effect of HFOV on CLD in survivors at term equivalent gestational age was inconsistent across studies and the reduction was of borderline significance overall. Subgroups of trials showed a significant reduction in CLD with HFOV when high volume strategy for HFOV was used, when piston oscillators were used for HFOV, when lung protective strategies for CV were not used, when randomisation occurred at two to six hours of age, and when inspiratory:expiratory ratio of 1:2 was used for HFOV. In the meta-analysis of all trials, pulmonary air leaks occurred more frequently in the HFOV group. In some studies, short-term neurological morbidity with HFOV was found, but this effect was not statistically significant overall. The subgroup of two trials not using a high volume strategy with HFOV found increased rates of Grade 3 or 4 intraventricular haemorrhage and of periventricular leukomalacia. An adverse effect of HFOV on long-term neurodevelopment was found in one large trial but not in the five other trials that reported this outcome. The rate of retinopathy of prematurity is reduced overall in the HFOV group. AUTHORS' CONCLUSIONS: There is no clear evidence that elective HFOV offers important advantages over CV when used as the initial ventilation strategy to treat preterm infants with acute pulmonary dysfunction. There may be a small reduction in the rate of CLD with HFOV use, but the evidence is weakened by the inconsistency of this effect across trials and the overall borderline significance. Future trials on elective HFOV should target those infants who are at most risk of CLD (extremely preterm infants), compare different strategies for generating HFOV and CV, and report important long-term neurodevelopmental outcomes.

WITHDRAWN: Antiplatelet agents for preventing and treating pre-eclampsia.

BACKGROUND: Pre-eclampsia is associated with deficient intravascular production of prostacyclin, a vasodilator, and excessive production of thromboxane, a platelet-derived vasoconstrictor and stimulant of platelet aggregation. These observations led to the hypotheses that antiplatelet agents, and low dose aspirin in particular, might prevent or delay the development of pre-eclampsia. OBJECTIVES: To assess the effectiveness and safety of antiplatelet agents when given to women at risk of developing pre-eclampsia, and to those with established pre-eclampsia. SEARCH STRATEGY: This review drew on the search strategy developed for the Pregnancy and Childbirth Group as a whole. The Cochrane Controlled Trials Register was also searched, The Cochrane Library 1999 Issue 1, Embase was searched from 1994-1999 and hand searches were performed of the congress proceedings of the International and European Societies for the Study of Hypertension in Pregnancy. SELECTION CRITERIA: All randomised trials comparing antiplatelet agents with either placebo or no antiplatelet agent during pregnancy. Quasi random study designs were excluded. Participants were pregnant women considered to be at risk of developing pre-eclampsia, and those with pre-eclampsia before delivery. Women treated postpartum were excluded. Interventions were any comparisons of an antiplatelet agent (such as low dose aspirin or dipyridamole) with either placebo or no antiplatelet agent. DATA COLLECTION AND ANALYSIS: Assessment of trials for inclusion in the review and extraction of data was performed independently and unblinded by two reviewers. Data were entered into the Review Manager software and double checked. MAIN RESULTS: Forty two trials involving over 32,000 women were included in this review, with 30,563 women in the prevention trials. There is a 15% reduction in the risk of pre-eclampsia associated with the use of antiplatelet agents [32 trials with 29,331 women; relative risk (RR) 0.85, 95% confidence interval (0.78, 0.92); Number needed to treat (NNT) 89, (59, 167)]. This reduction is regardless of risk status at trial entry or whether a placebo was used, and irrespective of the dose of aspirin or gestation at randomisation.Twenty three trials (28,268 women) reported preterm delivery. There is a small (8%) reduction in the risk of delivery before 37 completed weeks [RR 0.92, (0.88, 0.97); NNT 72 (44, 200)]. Baby deaths were reported in 30 trials (30,093 women). Overall there is a 14% reduction in baby deaths in the antiplatelet group [RR 0.86, (0.75, 0.98); NNT 250 (125, >10000)]. Small for gestational age babies were reported in 25 trials (20,349 women), with no overall difference between the groups, RR 0.92, (0.84, 1.01). There were no significant differences between treatment and control groups in any other measures of outcome. Five trials compared antiplatelet agents with placebo or no antiplatelet agent for the treatment of pre-eclampsia. There are insufficient data for any firm conclusions about the possible effects of these agents when used for treatment of pre-eclampsia. AUTHORS' CONCLUSIONS: Antiplatelet agents, in this review largely low dose aspirin, have small-moderate benefits when used for prevention of pre-eclampsia. Further information is required to assess which women are most likely to benefit, when treatment should be started, and at what dose.

Consequences of insect herbivory on grape fine root systems with different growth rates.

Herbivory tolerance has been linked to plant growth rate where plants with fast growth rates are hypothesized to be more tolerant of herbivory than slower-growing plants. Evidence supporting this theory has been taken primarily from observations of aboveground organs but rarely from roots. Grapevines differing in overall rates of new root production, were studied in Napa Valley, California over two growing seasons in an established vineyard infested with the sucking insect, grape phylloxera (Daktulosphaira vitifoliae Fitch). The experimental vineyard allowed for the comparison of two root systems that differed in rates of new root tip production (a 'fast grower', Vitis berlandieri x Vitis rupestris cv. 1103P, and a slower-growing stock, Vitis riparia x Vitis rupestris cv. 101-14 Mgt). Each root system was grafted with a genetically identical shoot system (Vitis vinifera cv. Merlot). Using minirhizotrons, we did not observe any evidence of spatial or temporal avoidance of insect populations by root growth. Insect infestations were abundant throughout the soil profile, and seasonal peaks in phylloxera populations generally closely followed peaks in new root production. Our data supported the hypothesis that insect infestation was proportional to the number of growing tips, as indicated by similar per cent infestation in spite of a threefold difference in root tip production. In addition, infested roots of the fast-growing rootstock exhibited somewhat shorter median lifespans (60 d) than the slower-growing rootstock (85 d). Lifespans of uninfested roots were similar for the two rootstocks (200 d). As a consequence of greater root mortality of younger roots, infested root populations in the fast-growing rootstock had an older age structure. While there does not seem to be a trade-off between potential growth rate and relative rate of root infestation in these cultivars, our study indicates that a fast-growing root system may more readily shed infested roots that are presumably less effective in water and nutrient uptake. Thus, differences in root tip production may be linked to differences in the way plants cope with roots that are infested by sucking insects.

No interaction between the serotonin transporter polymorphism (5-HTTLPR) and childhood adversity or recent stressful life events on symptoms of depression: results from two community surveys.

In this study we investigated interactions between the 5-HTTLPR genotype and environmental risk factors (G x E) on symptoms of depression in two large Australian community samples of adolescents and young adults. We postulated that a significant interaction between the 5-HTTLPR genotype and environmental risk factors of childhood adversity or stressful life events on symptoms of depression would be observed in subjects with at least one short allele (s/l or s/s) compared with subjects with no short alleles (l/l). We did not find significant G x E interactions between the 5-HTTLPR genotype and recent stressful life events or childhood adversity on symptoms of depression in our sample populations. However, we did find adolescents aged 17-18 years homozygous for the long allele (l/l) and exposed to persistently high levels of family adversity over a 6-year period were at a greater risk of depression than subjects with the same genotype exposed to no or persistently low levels of family adversity. This interaction should be interpreted cautiously due to the small number of depressed subjects in the sample with persistently high levels of family adversity.

Antiplatelet agents for preventing pre-eclampsia and its complications.

BACKGROUND: Pre-eclampsia is associated with deficient intravascular production of prostacyclin, a vasodilator, and excessive production of thromboxane, a vasoconstrictor and stimulant of platelet aggregation. These observations led to the hypotheses that antiplatelet agents, low-dose aspirin in particular, might prevent or delay development of pre-eclampsia. OBJECTIVES: To assess the effectiveness and safety of antiplatelet agents for women at risk of developing pre-eclampsia. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (July 2006), the Cochrane Central Register of Controlled Trials (The Cochrane Library 2005, Issue 1), EMBASE (1994 to November 2005) and handsearched congress proceedings of the International and European Societies for the Study of Hypertension in Pregnancy. SELECTION CRITERIA: All randomised trials comparing antiplatelet agents with either placebo or no antiplatelet agent were included. Quasi-random studies were excluded. Participants were pregnant women at risk of developing pre-eclampsia. Interventions were any comparisons of an antiplatelet agent (such as low-dose aspirin or dipyridamole) with either placebo or no antiplatelet. DATA COLLECTION AND ANALYSIS: Two authors assessed trials for inclusion and extracted data independently. MAIN RESULTS: Fifty-nine trials (37,560 women) are included. There is a 17% reduction in the risk of pre-eclampsia associated with the use of antiplatelet agents ((46 trials, 32,891 women, relative risk (RR) 0.83, 95% confidence interval (CI) 0.77 to 0.89), number needed to treat (NNT) 72 (52, 119)). Although there is no statistical difference in RR based on maternal risk, there is a significant increase in the absolute risk reduction of pre-eclampsia for high risk (risk difference (RD) -5.2% (-7.5, -2.9), NNT 19 (13, 34)) compared with moderate risk women (RD -0.84 (-1.37, -0.3), NNT 119 (73, 333)). Antiplatelets were associated with an 8% reduction in the relative risk of preterm birth (29 trials, 31,151 women, RR 0.92, 95% CI 0.88 to 0.97); NNT 72 (52, 119)), a 14% reduction in fetal or neonatal deaths (40 trials, 33,098 women, RR 0.86, 95% CI 0.76 to 0.98); NNT 243 (131, 1,666) and a 10% reduction in small-for-gestational age babies (36 trials, 23,638 women, RR 0.90, 95% CI0.83 to 0.98). There were no statistically significant differences between treatment and control groups for any other outcomes. AUTHORS' CONCLUSIONS: Antiplatelet agents, largely low-dose aspirin, have moderate benefits when used for prevention of pre-eclampsia and its consequences. Further information is required to assess which women are most likely to benefit, when treatment is best started, and at what dose.

Antihypertensive drug therapy for mild to moderate hypertension during pregnancy.

BACKGROUND: Mild to moderate hypertension during pregnancy is common. Antihypertensive drugs are often used in the belief that lowering blood pressure will prevent progression to more severe disease, and thereby improve outcome. OBJECTIVES: To assess the effects of antihypertensive drug treatments for women with mild to moderate hypertension during pregnancy. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (March 2006), the Cochrane Central Register of Controlled Trials (The Cochrane Library 2005, Issue 3), MEDLINE (1966 to November 2005), LILACS (1984 to November 2005) and EMBASE (1974 to November 2005). SELECTION CRITERIA: All randomised trials evaluating any antihypertensive drug treatment for mild to moderate hypertension during pregnancy defined, whenever possible, as systolic blood pressure 140 to 169 mmHg and diastolic blood pressure 90 to 109 mmHg. Comparisons were of one or more antihypertensive drug(s) with placebo, with no antihypertensive drug, or with another antihypertensive drug, and where treatment was planned to continue for at least seven days. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data. MAIN RESULTS: Forty-six trials (4282 women) were included. Twenty-eight trials compared an antihypertensive drug with placebo/no antihypertensive drug (3200 women). There is a halving in the risk of developing severe hypertension associated with the use of antihypertensive drug(s) (19 trials, 2409 women; relative risk (RR) 0.50; 95% confidence interval (CI) 0.41 to 0.61; risk difference (RD) -0.10 (-0.12 to -0.07); number needed to treat (NNT) 10 (8 to 13)) but little evidence of a difference in the risk of pre-eclampsia (22 trials, 2702 women; RR 0.97; 95% CI 0.83 to 1.13). Similarly, there is no clear effect on the risk of the baby dying (26 trials, 3081 women; RR 0.73; 95% CI 0.50 to 1.08), preterm birth (14 trials, 1992 women; RR 1.02; 95 % CI 0.89 to 1.16), or small-for-gestational-age babies (19 trials, 2437 women; RR 1.04; 95 % CI 0.84 to 1.27). There were no clear differences in any other outcomes. Nineteen trials (1282 women) compared one antihypertensive drug with another. Beta blockers seem better than methyldopa for reducing the risk of severe hypertension (10 trials, 539 women, RR 0.75 (95 % CI 0.59 to 0.94); RD -0.08 (-0.14 to 0.02); NNT 12 (6 to 275)). There is no clear difference between any of the alternative drugs in the risk of developing proteinuria/pre-eclampsia. Other outcomes were only reported by a small proportion of studies, and there were no clear differences. AUTHORS' CONCLUSIONS: It remains unclear whether antihypertensive drug therapy for mild to moderate hypertension during pregnancy is worthwhile.

Prenatal predictors of mortality in very preterm infants cared for in the Australian and New Zealand Neonatal Network.

AIM: To identify antenatal and perinatal risk factors for in-hospital mortality of babies born within the Australian and New Zealand Neonatal Network (ANZNN). METHODS: Data were collected prospectively as part of the ongoing audit of high-risk infants (birth weight <1500 g or gestation <32 weeks) admitted to all level III neonatal units in Australia and New Zealand. Antenatal and intrapartum factors to 1 min of age were examined in 11 498 infants with gestational age >24 weeks. Risk and protective factors for mortality were derived from logistic regression models fitted to 1998-9 data and validated on 2000-1 data. RESULTS: For the whole cohort of infants born between 1998 and 2001, prematurity was the dominant risk factor, infants born at 25 weeks having 32 times greater odds of death than infants born at 31 weeks. Low birth weight for gestational age also had a dose-response effect: the more growth restricted the infant the greater the risk of mortality; infants below the 3rd centile had eight times greater odds of death than those between the 25th and 75th centiles. Male sex was also a significant risk factor (odds ratio (OR) 1.55, 95% confidence interval (CI) 1.31 to 1.82). Maternal hypertension in pregnancy was protective (OR 0.46, 95% CI 0.36 to 0.50). The predictive model for mortality had an area under the receiver operating characteristic curve of 0.82. CONCLUSIONS: Risk of mortality can be predicted with good accuracy with factors up to the 1 min Apgar score. By using gestation rather than birth weight as the main indicator of maturity, these data confirm that weight for gestational age is an independent risk factor for mortality.

Activity of OGG1 variants in the repair of pro-oxidant-induced 8-oxo-2'-deoxyguanosine.

Cells are continuously exposed to damaging reactive oxygen species (ROS), which are produced from both endogenous and exogenous sources. 8-Oxodeoxyguanosine (8-oxodG) is an abundant base lesion formed during oxidative stress which, if not repaired, can give rise to G:C-->T:A transversions in DNA. The 8-oxoguanine DNA glycosylase-1 (OGG1)-initiated base excision repair (BER) pathway operates to remove 8-oxodG lesions. Ogg1 deletion and polymorphism may result in a hypermutator phenotype and susceptibility to oxidative pathologies including cancer. Limited and conflicting evidence exists regarding the repair capacity of a prevalent human OGG1 (hOGG1) polymorphism, the Cys326-hOGG1 variant. The formamidopyrimidine DNA glycosylase (FPG)-modified comet assay was used to investigate the ability of sodium dichromate, potassium bromate and Ro19-8022 (+light) to induce DNA damage in mogg1(-/-) null (KO) and wild-type (WT) mouse embryonic fibroblasts (MEFs) and to assess hOGG1 variant-initiated BER capacities under conditions of oxidative stress. Treatment of WT MEFs with these pro-oxidant agents induced direct DNA strand breaks in a concentration-dependent manner, whereas, identical treatment of KO MEFs produced no effect. In contrast, KO MEFs accumulated significantly more FPG-sensitive sites than WT MEFs. Expression of hOGG1 in KO MEFs restored the WT phenotype in response to all pro-oxidants tested. The results suggest OGG1-initiated BER generates direct DNA strand breaks detected by the conventional comet assay, thus it is important that researchers do not interpret these as direct damage per se but rather a reflection of the repair process. The data also indicate Cys326-hOGG1-initiated BER is transiently impaired with respect to Ser326-hOGG1 (wild-type)- and Gly326-hOGG1 (artificial)-initiated BER following pro-oxidant treatment, possibly via hOGG1 cysteine 326 oxidation. This finding suggests the homozygous cys326/cys326 genotype may be classified as a biomarker of disease susceptibility, which is in support of a growing body of epidemiological evidence.