Adverse childhood experiences and substance misuse in young people in India: results from the multisite cVEDA cohort.

BACKGROUND: Adverse childhood experiences (ACEs) increases vulnerability to externalising disorders such as substance misuse. The study aims to determine the prevalence of ACEs and its association with substance misuse. METHODS: Data from the Consortium on Vulnerability to Externalising Disorders and Addictions (cVEDA) in India was used (n = 9010). ACEs were evaluated using the World Health Organisation (WHO) Adverse Childhood Experiences International Questionnaire whilst substance misuse was assessed using the WHO Alcohol, Smoking and Substance Involvement Screening Test. A random-effects, two-stage individual patient data meta-analysis explained the associations between ACEs and substance misuse with adjustments for confounders such as sex and family structure. RESULTS: 1 in 2 participants reported child maltreatment ACEs and family level ACEs. Except for sexual abuse, males report more of every individual childhood adversity and are more likely to report misusing substances compared with females (87.3% vs. 12.7%). In adolescents, family level ACEs (adj OR 4.2, 95% CI 1.5-11.7) and collective level ACEs (adj OR 6.6, 95% CI 1.4-31.1) show associations with substance misuse whilst in young adults, child level ACEs such as maltreatment show similar strong associations (adj OR 2.0, 95% CI 1.1-3.5). CONCLUSION: ACEs such as abuse and domestic violence are strongly associated with substance misuse, most commonly tobacco, in adolescent and young adult males in India. The results suggest enhancing current ACE resilience programmes and 'trauma-informed' approaches to tackling longer-term impact of ACEs in India. FUNDING: Newton Bhabha Grant jointly funded by the Medical Research Council, UK (MR/N000390/1) and the Indian Council of Medical Research (ICMR/MRC-UK/3/M/2015-NCD-I).

Percutaneous management of pulmonary metastases arising from colorectal cancer; a systematic review.

BACKGROUND: Radiofrequency ablation (RFA) is a well-established treatment modality for colorectal hepatic metastases, the success of which has prompted its use to treat other lesions such as colorectal pulmonary metastases (CRPM). Our aim was to perform a systematic review of the evidence and to assess the safety and effectiveness of ablative techniques in the management of CRPM. METHOD: A literature search was performed using PubMed, Embase, Cochrane Library, CINAHL and Google scholar databases to identify studies, which analysed ablative techniques and their effectiveness in the management of CRPM. The primary outcome measures were overall survival, local recurrence rates and disease free survival. Secondary outcome measures were complication (major/minor), chest drain insertion rates and follow up duration. RESULTS: Eight studies were included in the review with a total of 903 patients and all of which used RFA for ablation. Mortality from ablation was <1% with overall survival ranging from 31 to 67 months. 1, 3 and 5 year survival ranges of 84-95%, 35-72% and 20-54% respectively. Local progression following ablation ranged from 9 to 21%. Major complication rates were noted in 0.5%-8% of patients with minor complications ranging between 7% and 33%. 23% of patients required chest drain insertion post procedure. CONCLUSION: s: RFA is a safe and effective technique for the management of CRPM. However, in the absence of large randomised controlled trials it is unclear where RFA should sit in the treatment algorithm for patients with CRPM.

Predicting the minimum liquid surface tension activity of pseudomonads expressing biosurfactants.

UNLABELLED: Bacteria produce a variety of biosurfactants capable of significantly reducing liquid (aqueous) surface tension (γ) with a range of biological roles and biotechnological uses. To determine the lowest achievable surface tension (γMin ), we tested a diverse collection of Pseudomonas-like isolates from contaminated soil and activated sludge and identified those expressing biosurfactants by drop-collapse assay. Liquid surface tension-reducing ability was quantitatively determined by tensiometry, with 57 isolates found to significantly lower culture supernatant surface tensions to 24·5-49·1 mN m(-1) . Differences in biosurfactant behaviour determined by foaming, emulsion and oil-displacement assays were also observed amongst isolates producing surface tensions of 25-27 mN m(-1) , suggesting that a range of structurally diverse biosurfactants were being expressed. Individual distribution identification (IDI) analysis was used to identify the theoretical probability distribution that best fitted the surface tension data, which predicted a γMin of 24·24 mN m(-1) . This was in agreement with predictions based on earlier work of published mixed bacterial spp. data, suggesting a fundamental limit to the ability of bacterial biosurfactants to reduce surface tensions in aqueous systems. This implies a biological restriction on the synthesis and export of these agents or a physical-chemical restriction on their functioning once produced. SIGNIFICANCE AND IMPACT OF THE STUDY: Numerous surveys of biosurfactant-producing bacteria have been conducted, but only recently has an attempt been made to predict the minimum liquid surface tension these surface-active agents can achieve. Here, we determine a theoretical minimum of 24 mN m(-1) by statistical analysis of tensiometry data, suggesting a fundamental limit for biosurfactant activity in bacterial cultures incubated under standard growth conditions. This raises a challenge to our understanding of biosurfactant expression, secretion and function, as well as being of interest to biotechnology where they are used in an increasingly wide range of applications.

Quorum-quenching activity of the AHL-lactonase from Bacillus licheniformis DAHB1 inhibits Vibrio biofilm formation in vitro and reduces shrimp intestinal colonisation and mortality.

Vibrio parahaemolyticus is a significant cause of gastroenteritis resulting from the consumption of undercooked sea foods and often cause significant infections in shrimp aquaculture. Vibrio virulence is associated with biofilm formation and is regulated by N-acylated homoserine lactone (AHL)-mediated quorum sensing. In an attempt to reduce vibrio colonisation of shrimps and mortality, we screened native intestinal bacilli from Indian white shrimps (Fenneropenaeus indicus) for an isolate which showed biofilm-inhibitory activity (quorum quenching) against the pathogen V. parahaemolyticus DAHP1. The AHL-lactonase (AiiA) expressed by one of these, Bacillus licheniformis DAHB1, was characterised as having a broad-spectrum AHL substrate specificity and intrinsic resistance to the acid conditions of the shrimp intestine. Purified recombinant AiiA inhibited vibrio biofilm development in a cover slip assay and significantly attenuated infection and mortality in shrimps reared in a recirculation aquaculture system. Investigation of intestinal samples also showed that AiiA treatment also reduced vibrio viable counts and biofilm development as determined by confocal laser scanning microscopy (CLSM) imaging. These findings suggest that the B. licheniformis DAHB1 quorum-quenching AiiA might be developed for use as a prophylactic treatment to inhibit or reduce vibrio colonisation and mortality of shrimps in aquaculture.

Discontinuity of the incudo-stapedial joint within a fully aerated middle ear and mastoid on computed tomography: A clinico-radiological study of its aetiology and clinical consequence.

AIM: To investigate the aetiology and clinical consequences of incudo-stapedial (IS) discontinuity when it is demonstrated on computed tomography (CT) within a fully aerated middle ear and mastoid. METHODS AND MATERIALS: Patients with CT evidence of IS discontinuity within a fully aerated middle ear and mastoid were prospectively identified. Clinical history, otoscopic findings, audiometry, and CT data were evaluated. Predefined criteria were used to determine the likely aetiology of IS discontinuity, whether it was diagnosed prior to the CT study, and the clinical consequences in terms of degree of conductive hearing loss and requirement for surgical correction. The range of CT appearances was evaluated. RESULTS: The IS discontinuity in 34/36 ears was felt to be due to incus erosion secondary to chronic otitis, on the basis of clinical history and otoscopic findings. The IS discontinuity was rarely evident prior to CT with long-process deficiency being identified in only 5/36 cases. The mean air bone gap was only 22.5 dB. The ossicular defect was surgically addressed in only four cases. The incus deficiency was confined to the lower-third on CT in 19/36 cases. CONCLUSION: When IS discontinuity is demonstrated within a fully aerated middle ear and mastoid, the most likely aetiology is of acquired incus erosion due to chronic otitis media. The IS discontinuity on CT is usually not evident otoscopically. It usually results in only mild conductive hearing loss and the ossicular discontinuity was rarely surgically addressed in the present series.

The Enactive Torch: A New Tool for the Science of Perception.

The cognitive sciences are increasingly coming to terms with the embodied, embedded, extended, and experiential aspects of the mind. Exemplifying this shift, the enactive approach points to an essential role of goal-directed bodily activity in the generation of meaningful perceptual experience, i.e., sense-making. Here, building on recent insights into the transformative effects of practical tool-use, we make use of the enactive approach in order to provide a definition of an enactive interface in terms of augmented sense-making. We introduce such a custom-built interface, the Enactive Torch, and present a study of its experiential effects. The results demonstrate that the user experience is not adequately captured by any standardly assumed perceptual modality; rather, it is a new feeling that is mediated by the design of the device and shaped by the overall situation of the task. Taken together these findings show that there is much to be gained by synergies between engineering and the cognitive sciences in the creation of new experience-centered technology. We suggest that the guiding principle should be the design of interfaces that serve as a transparent medium for augmenting our natural skills of interaction with the world, instead of requiring conscious attention to the interface as an opaque object in the world.

Effects of high dose oestrogen therapy on circulating inflammatory markers.

INTRODUCTION: Whilst initial studies suggested HRT reduced the incidence of coronary heart disease, recent studies have suggested HRT increases cardiovascular risk. The route of HRT administration appears important with oral oestrogen significantly increasing levels of inflammatory markers and transdermal oestrogen causing no such changes. As the effects of the very high levels of oestrogen taken by male to female transsexuals are poorly understood this study has compared the changes occurring in circulating inflammatory markers following 6 months oral or transdermal oestrogen therapy. MATERIALS AND METHODS: 23 patients (mean age 36+/-10 years) about to commence oral oestrogen were enrolled into Group 1. Group 2 comprised 7 patients (mean age 47+/-6 years) about to commence transdermal oestrogen. Plasma lipids (total cholesterol, triglyceride and HDL cholesterol); cytokines (IL-1, IL-6, IL-8, TNFalpha); antioxidants (superoxide dismutase, total nitric oxide, glutathione) and clotting factors (Factor V11, Factor V111, Factor 1X, fibrinogen) were measured after 0, 2, 4 and 6 months treatment. RESULTS: No significant differences were found in plasma lipid levels. Group 1 patients showed significantly raised levels of IL-6, IL-1 and IL-8 during the first 2-4 months of treatment. Thereafter levels fell. Levels of SOD, FV11 and FV1X in Group 1 also increased over the study period. Patients receiving transdermal oestrogen showed elevated levels of GSH in the second month of treatment, but no significant changes in any of the other parameters measured. The rise in levels of IL-1 and Factor IX in the second month of treatment was significantly higher in the oral group than in the transdermal group. No other significant differences between the treatment groups were found. CONCLUSION: Transsexual patients receiving oral oestrogen showed significant changes in inflammatory markers involved in the pathogenesis of vascular disease. No such changes were associated with transdermal oestrogen. Changes in two inflammatory markers were significantly greater than among patients receiving transdermal oestrogen.

Multiple Didymella teleomorphs are linked to the Phoma clematidina morphotype.

The fungal pathogen Phoma clematidina is used as a biological agent to control the invasive plant species Clematis vitalba in New Zealand. Research conducted on P. clematidina as a potential biocontrol agent against C. vitalba, led to the discovery of two perithecial-forming strains. To assess the diversity of P. clematidina and to clarify the teleomorph-anamorph relationship, phylogenetic analyses of 18 P. clematidina strains, reference strains representing the Phoma sections in the Didymellaceae and strains of related species associated with Clematis were conducted. Partial sequences of the ITS1, ITS2 and 5.8S rRNA gene, the ss-tubulin gene and 28S rRNA gene were used to clarify intra- and inter-species relationships. These analyses revealed that P. clematidina resolves into three well-supported clades which appear to be linked to differences in host specificity. Based on these findings, Didymella clematidis is newly described and the descriptions of P. clematidina and D. vitalbina are amended.

Therapeutic potential of computer to cerebral cortex implantable devices.

In this article, an overview of some of the latest developments in the field of cerebral cortex to computer interfacing (CCCI) is given. This is posed in the more general context of Brain-Computer Interfaces in order to assess advantages and disadvantages. The emphasis is clearly placed on practical studies that have been undertaken and reported on, as opposed to those speculated, simulated or proposed as future projects. Related areas are discussed briefly only in the context of their contribution to the studies being undertaken. The area of focus is notably the use of invasive implant technology, where a connection is made directly with the cerebral cortex and/or nervous system. Tests and experimentation which do not involve human subjects are invariably carried out a priori to indicate the eventual possibilities before human subjects are themselves involved. Some of the more pertinent animal studies from this area are discussed. The paper goes on to describe human experimentation, in which neural implants have linked the human nervous system bidirectionally with technology and the internet. A view is taken as to the prospects for the future for CCCI, in terms of its broad therapeutic role.

The structure-function relationship of WspR, a Pseudomonas fluorescens response regulator with a GGDEF output domain.

The GGDEF response regulator WspR couples the chemosensory Wsp pathway to the overproduction of acetylated cellulose and cell attachment in the Pseudomonas fluorescens SBW25 wrinkly spreader (WS) genotype. Here, it is shown that WspR is a diguanylate cyclase (DGC), and that DGC activity is elevated in the WS genotype compared to that in the ancestral smooth (SM) genotype. A structure-function analysis of 120 wspR mutant alleles was employed to gain insight into the regulation and activity of WspR. Firstly, 44 random and defined pentapeptide insertions were produced in WspR, and the effects determined using assays based on colony morphology, attachment to surfaces and cellulose production. The effects of mutations within WspR were interpreted using a homology model, based on the crystal structure of Caulobacter crescentus PleD. Mutational analyses indicated that WspR activation occurs as a result of disruption of the interdomain interface, leading to the release of effector-domain repression by the N-terminal receiver domain. Quantification of attachment and cellulose production raised significant questions concerning the mechanisms of WspR function. The conserved RYGGEEF motif of WspR was also subjected to mutational analysis, and 76 single amino acid residue substitutions were tested for their effects on WspR function. The RYGGEEF motif of WspR is functionally conserved, with almost every mutation abolishing function.

Defining the Q-site of Escherichia coli fumarate reductase by site-directed mutagenesis, fluorescence quench titrations and EPR spectroscopy.

We have used fluorescence quench titrations, EPR spectroscopy and steady-state kinetics to study the effects of site-directed mutants of FrdB, FrdC and FrdD on the proximal menaquinol (MQH(2)) binding site (Q(P)) of Escherichia coli fumarate reductase (FrdABCD) in cytoplasmic membrane preparations. Fluorescence quench (FQ) titrations with the fluorophore and MQH(2) analog 2-n-heptyl-4-hydroxyquinoline-N-oxide (HOQNO) indicate that the Q(P) site is defined by residues from FrdB, FrdC and FrdD. In FQ titrations, wild-type FrdABCD binds HOQNO with an apparent K(d) of 2.5 nM, and the following mutations significantly increase this value: FrdB-T205H (K(d) = 39 nM); FrdB-V207C (K(d) = 20 nM); FrdC-E29L (K(d) = 25 nM); FrdC-W86R (no detectable binding); and FrdD-H80K (K(d) = 20 nM). In all titrations performed, data were fitted to a monophasic binding equation, indicating that no additional high-affinity HOQNO binding sites exist in FrdABCD. In all cases where HOQNO binding is detectable by FQ titration, it can also be observed by EPR spectroscopy. Steady-state kinetic studies of fumarate-dependent quinol oxidation indicate that there is a correlation between effects on HOQNO binding and effects on the observed K(m) and k(cat) values, except in the FrdC-E29L mutant, in which HOQNO binding is observed, but no enzyme turnover is detected. In this case, EPR studies indicate that the lack of activity arises because the enzyme can only remove one electron from reduced MQH(2), resulting in it being trapped in a form with a bound menasemiquinone radical anion. Overall, the data support a model for FrdABCD in which there is a single redox-active and dissociable Q-site.

Glucocorticoids and insulin sensitivity: dissociation of insulin's metabolic and vascular actions.

Insulin sensitivity in tissues such as a skeletal muscle and fat is closely correlated with insulin action in the vasculature, but the mechanism underlying this is unclear. We investigated the effect of dexamethasone on insulin-stimulated glucose disposal and vasodilation in healthy males to test the hypothesis that a reduction in glucose disposal would be accompanied by a reduction in insulin action in the vasculature. We performed a double-blind, placebo-controlled, cross-over trial comparing insulin sensitivity (measured by the euglycemic hyperinsulinemic clamp) and vascular insulin action (measured by small vessel wire myography) in young healthy males allocated to placebo or 1 mg dexamethasone twice daily for 6 d, each in random order. Six days of dexamethasone therapy was associated with a 30% (95% confidence interval, 19.1-40.0%) fall in insulin sensitivity. Despite this, there was no difference in insulin-mediated vasodilation between phases. Dexamethasone had no effect on circulating markers of endothelial function, such as D-dimer, von Willebrand factor, and tissue plasminogen activator. By short-term exposure to high dose dexamethasone we were able to differentially affect the metabolic and vascular actions of insulin. This implies that, using this model, there is physiological uncoupling of the effects of insulin in different tissues.

Identification of the vectors of lymphatic filariasis in the Lower Shire Valley, southern Malawi.

An investigation of lymphatic filariasis vectors in Malawi is reported. Anopheles funestus, A. arabiensis, and A. gambiae sensu stricto had high rates of filarial infection (2.2-3.1%) and carried infective larvae. Anopheles funestus was the predominant species collected (77.6%) and was the primary vector during the study period of April to May 2002.

The malaria vectors of the Lower Shire valley, Malawi.

The aim of this study was to characterise breeding sites and climatic factors that influence the abundance of malaria vectors in the Lower Shire valley, Malawi. We regularly sampled adult and larval mosquitoes over the transition periods between the wet and dry seasons during 2000 and 2001. Three potential malaria vectors, An. arabiensis, An. gambine sensu stricto and An. funestus, and a fourth non-vector species An. quadriannulatus, were identified. (This is the first record of An. quadriannulatus in Malawi). These four species bred predominately in larger water bodies, particularly rice paddies, and to a lesser extent in boreholes and puddles. Smaller temporary pools and puddles evaporated too quickly to permit the completion of larval development. Abundance of An. gambiae s.l. was closely associated with minimum temperatures. We discuss the relevance of the findings to malaria vector control in Malawi.

Qualified nurses' smoking prevalence: their reasons for smoking and desire to quit.

UNLABELLED: AIM AND RATIONALE: The preventable nature of smoking related diseases places a major responsibility for health promotion on all health professionals. This study used a questionnaire to survey qualified nurses in Northern Ireland as to smoking prevalence and their desire to quit the habit. It also explores their knowledge base relating to smoking related diseases and their motivation to act as health promoters with patients who smoke. METHODS: A random sample (n=1074) of qualified nurses employed by the Health and Social Services Trusts, private, and voluntary organizations in the province were surveyed. RESULTS: Results show that 25.8% were smokers, 19% were ex-smokers and 55.2% were nonsmokers. Three quarters expressed a wish to stop within 6-months. Almost all smokers and half of ex-smokers had taken up the habit prior to commencing nursing. 'Addiction' and 'enjoyment' were given as the principle reasons for continued smoking. Health reasons were paramount in smokers' desire to stop smoking. CONCLUSIONS: These findings suggest that smoking prevalence among qualified nurses in no greater than that reported by females in the general Northern Ireland population. Results also indicate that those nurses who smoke were less willing to take on the role of a health promoter with patients who smoke. Implications and recommendations for practice, education and research are explored.

Impaired endothelial function in isolated human uremic resistance arteries.

BACKGROUND: Patients with chronic renal failure (CRF) face a markedly increased risk of cardiovascular death. CRF is frequently complicated by hypertension and changes in both the heart (left ventricular hypertrophy) and the vasculature (endothelial dysfunction and accelerated atherosclerosis). The mechanisms underlying changes in vascular function and specifically endothelial dysfunction are unclear. This present study therefore examined subcutaneous resistance artery function in vitro, comparing adult uremic patients and controls using wire myography. METHODS: Subcutaneous fat biopsies were obtained from 12 patients with CRF (median serum creatinine 735 micromol/L) at the time of renal transplantation or peritoneal dialysis catheter insertion, and from eight controls without renal disease at the time of abdominal surgery. Resistance arteries were mounted on a wire myograph. Their contractile ability was tested with high potassium depolarization, and endothelial integrity was tested by relaxation to acetylcholine. Cumulative concentration-response curves were then constructed for norepinephrine, endothelin-1, acetylcholine, and sodium nitroprusside (SNP). RESULTS: Following preconstriction with norepinephrine, vessels from uremic patients vasodilated less well to acetylcholine compared with vessels from controls [maximum % relaxation 77% (range 41, 97) vs. 98% (78, 100), P < 0.001]. The vasodilation to SNP was similar [95% (63, 100) vs. 94% (71, 100), P = 0.751]. There was a trend toward increased maximum pressure (kPa) achieved with both norepinephrine and endothelin-1 in vessels from uremic patients, and the contractions to both of these agents were more prolonged in the uremic vessels. CONCLUSIONS: The pattern of normal vasodilation to SNP but reduced vasodilation to acetylcholine is consistent with endothelial dysfunction due to impaired nitric oxide (NO) production in uremic vessels. Similar results have been demonstrated in vivo in uremia, one suggested mechanism being accumulation of endogenous inhibitors of NO synthase such as asymmetric dimethylarginine (ADMA). This in vitro study suggests that a short-lived circulating factor is not entirely responsible and that there may be an inherent abnormality in endothelial function in uremia, although the exact pathophysiology remains unclear. Endothelial dysfunction may predispose the patient to accelerated atherosclerosis and may be involved in the pathogenesis of hypertension in end-stage renal failure.

C-terminal interactions between the XerC and XerD site-specific recombinases.

Studies of the site-specific recombinase Cre suggest a key role for interactions between the C-terminus of the protein and a region located about 30 residues from the C-terminus in linking in a cyclical manner the four recombinase monomers present in a recombination complex, and in controlling the catalytic activity of each monomer. By extrapolating the Cre DNA recombinase structure to the related site-specific recombinases XerC and XerD, it is predicted that the extreme C-termini of XerC and XerD interact with alpha-helix M in XerD and the equivalent region of XerC respectively. Consequently, XerC and XerD recombinases deleted for C-terminal residues, and mutated XerD proteins containing single amino acid substitutions in alphaM or in the C-terminal residues were analysed. Deletion of C-terminal residues of XerD has no measurable effect on co-operative interactions with XerC in DNA-binding assays to the recombination site dif, whereas deletion of 5 or 10 residues of XerC reduces co-operativity with XerD some 20-fold. Co-operative interactions between pairs of truncated proteins during dif DNA binding are reduced 20- to 30-fold. All of the XerD mutants, except one, were catalytically proficient in vitro; nevertheless, many failed to mediate a recombination reaction on supercoiled plasmid in vivo or in vitro, implying that the ability to form a productive recombination complex and/or mediate a controlled recombination reaction is impaired.